{"text_format":"1","workbook":"xlsx","n_sheets":3,"sheets":["Main","Abstract","Notes"],"not_rendered":{"charts":0,"images":0,"macros":1,"external_links":0,"defined_names":2,"comments":0,"pivot_tables":0},"unopened":[],"bounds":{"document_bytes":16777216,"sheet_cells":100000,"rows_first":2000,"rows_last":500,"rows_between":2000,"halvings":0,"cell_chars":16384,"cell_head_chars":4096},"cells_cut":0,"cells_raw":0,"read":"whole","date_system":"1900"}

{"sheet":"Main","index":0,"n_rows":236,"n_cols":10,"rows_kept":236,"cut":false,"hidden":false,"merged":[[1,1,1,3]]}
["Retinoids and CNS development",null,null,null,null,null,"PubMed query used:  (retinoid OR retinoic OR Vitamin A) AND (((central nervous system[mh] OR brain OR CNS OR nervous system or nerve) AND (embryonic development OR embryology OR fetus OR embryo)) OR Nervous System Malformations[mh]) AND (review[pt] OR review[tiab])"]
[null,"Your search terms"]
["PMID","retin","cephal","disorder","Total","Pub Yr","Title","Fauthor","LinkPMID","tiab"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I4,I4)","v":10521699},{"$f":"(LEN($J4) - LEN(SUBSTITUTE(LOWER($J4),LOWER(B$3),\"\")))/LEN(B$3)","v":21},{"$f":"(LEN($J4) - LEN(SUBSTITUTE(LOWER($J4),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J4) - LEN(SUBSTITUTE(LOWER($J4),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B4:D4)","v":21},1999,"Interactions of retinoid binding proteins and enzymes in retinoid metabolism.","Napoli",10521699,"Interactions of retinoid binding proteins and enzymes in retinoid metabolism.    Abstract:   Naturally occurring retinoids (vitamin A or retinol and its active metabolites) are vital for vision, controlling the differentiation program of epithelial cells in the digestive tract and respiratory system, skin, bone, the nervous system, the immune system, and for hematopoiesis. Retinoids are essential for growth, reproduction (conception and embryonic development), and resistance to and recovery from infection. The functions of retinoids in the embryo begin soon after conception and continue throughout the lifespan of all vertebrates. Both naturally occurring and synthetic retinoids are used in the therapy of various skin diseases, especially acne, for augmenting the treatment of diabetes, and as cancer chemopreventive agents. Retinol metabolites serve as ligands that activate specific transcription factors in the superfamily of steroid/retinoid/thyroid/vitamin D/orphan receptors and thereby control gene expression. Additionally, retinoids may also function through non-genomic actions. Various retinoid binding proteins serve as partners in retinoid function. These binding proteins show high specificity and affinity for specific retinoids and seem to control retinoid metabolism in vivo qualitatively and quantitatively by reducing free retinoid concentrations, protecting retinoids from non-specific interactions, and chaperoning access of metabolic enzymes to retinoids. Implementation of the physiological effects of retinoids depends on the spatial-temporal expressions of binding proteins, receptors and metabolic enzymes. This review will discuss current understanding of the enzymes that catalyze retinol and retinoic acid metabolism and their unique and integral relationship to retinoid binding proteins."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I5,I5)","v":16688755},{"$f":"(LEN($J5) - LEN(SUBSTITUTE(LOWER($J5),LOWER(B$3),\"\")))/LEN(B$3)","v":18},{"$f":"(LEN($J5) - LEN(SUBSTITUTE(LOWER($J5),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J5) - LEN(SUBSTITUTE(LOWER($J5),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B5:D5)","v":18},2006,"Overview of retinoid metabolism and function.","Blomhoff",16688755,"Overview of retinoid metabolism and function.    Abstract:   Retinoids (vitamin A) are crucial for most forms of life. In chordates, they have important roles in the developing nervous system and notochord and many other embryonic structures, as well as in maintenance of epithelial surfaces, immune competence, and reproduction. The ability of all-trans retinoic acid to regulate expression of several hundred genes through binding to nuclear transcription factors is believed to mediate most of these functions. The role of all-trans retinoic may extend beyond the regulation of gene transcription because a large number of noncoding RNAs also are regulated by retinoic acid. Additionally, extra-nuclear mechanisms of action of retinoids are also being identified. In organisms ranging from prokaryotes to humans, retinal is covalently linked to G protein-coupled transmembrane receptors called opsins. These receptors function as light-driven ion pumps, mediators of phototaxis, or photosensory pigments. In vertebrates phototransduction is initiated by a photochemical reaction where opsin-bound 11-cis-retinal is isomerized to all-trans-retinal. The photosensitive receptor is restored via the retinoid visual cycle. Multiple genes encoding components of this cycle have been identified and linked to many human retinal diseases. Central aspects of vitamin A absorption, enzymatic oxidation of all-trans retinol to all-trans retinal and all-trans retinoic acid, and esterification of all-trans retinol have been clarified. Furthermore, specific binding proteins are involved in several of these enzymatic processes as well as in delivery of all-trans retinoic acid to nuclear receptors. Thus, substantial progress has been made in our understanding of retinoid metabolism and function. This insight has improved our view of retinoids as critical molecules in vision, normal embryonic development, and in control of cellular growth, differentiation, and death throughout life."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I6,I6)","v":15882777},{"$f":"(LEN($J6) - LEN(SUBSTITUTE(LOWER($J6),LOWER(B$3),\"\")))/LEN(B$3)","v":16},{"$f":"(LEN($J6) - LEN(SUBSTITUTE(LOWER($J6),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J6) - LEN(SUBSTITUTE(LOWER($J6),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B6:D6)","v":16},2005,"Role of retinoid signalling in the adult brain.","Lane",15882777,"Role of retinoid signalling in the adult brain.    Abstract:   Vitamin A (all-trans-retinol) is the parent compound of a family of natural and synthetic compounds, the retinoids. Retinoids regulate gene transcription in numerous cells and tissues by binding to nuclear retinoid receptor proteins, which act as transcription factors. Much of the research conducted on retinoid signalling in the nervous system has focussed on developmental effects in the embryonic or early postnatal brain. Here, we review the increasing body of evidence indicating that retinoid signalling plays an important role in the function of the mature brain. Components of the metabolic pathway for retinoids have been identified in adult brain tissues, suggesting that all-trans-retinoic acid (ATRA) can be synthesized in discrete regions of the brain. The distribution of retinoid receptor proteins in the adult nervous system is different from that seen during development; and suggests that retinoid signalling is likely to have a physiological role in adult cortex, amygdala, hypothalamus, hippocampus, striatum and associated brain regions. A number of neuronal specific genes contain recognition sequences for the retinoid receptor proteins and can be directly regulated by retinoids. Disruption of retinoid signalling pathways in rodent models indicates their involvement in regulating synaptic plasticity and associated learning and memory behaviours. Retinoid signalling pathways have also been implicated in the pathophysiology of Alzheimers disease, schizophrenia and depression. Overall, the data underscore the likely importance of adequate nutritional Vitamin A status for adult brain function and highlight retinoid signalling pathways as potential novel therapeutic targets for neurological diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I7,I7)","v":8649720},{"$f":"(LEN($J7) - LEN(SUBSTITUTE(LOWER($J7),LOWER(B$3),\"\")))/LEN(B$3)","v":13},{"$f":"(LEN($J7) - LEN(SUBSTITUTE(LOWER($J7),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J7) - LEN(SUBSTITUTE(LOWER($J7),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B7:D7)","v":13},1995,"[The participation of retinoic acid in embryonic and postembryonic development].","Maden",8649720,"[The participation of retinoic acid in embryonic and postembryonic development].    Abstract:   Retinoids are low molecular weight, lipophilic derivatives of vitamin A which have profound effects upon the development of various embryonic systems. Here I review the these effects on developing and regenerating limbs, regenerating amphibian tails and the developing central nervous system (CNS). In the regenerating amphibian limb, retinoids can proximalise, posteriorise and ventralise the axes. In the chick limb bud retinoids can only posteriorise the tissue. In the regenerating amphibian tail retinoids can homoetically transform tail tissue into hindlimb tissue. In the developing and regenerating limb retinoic acid has been detected endogenously, confirming that this molecule plays a role in the generation of pattern and limbs cannot develop in the absence of retinoic acid. In the developing CNS retinoic acid specifically affects the hindbrain where it causes a transformation of anterior rhombomeres into more posterior ones. Again, endogenous retinoic acid has been detected in the CNS and in the absence of retinoids the posterior hindbrain has been found to be affected. The effects of retinoids on the CNS are most likely to be mediated via the Hox genes acting in the mesoderm after gastrulation. It has also been proposed that the establishment of the head-to-tail axis in the mesoderm is established by retinoic acid. These data show that retinoids play an important role in both the development and regeneration of various systems in the embryo and post-embryonically."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I8,I8)","v":21855651},{"$f":"(LEN($J8) - LEN(SUBSTITUTE(LOWER($J8),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J8) - LEN(SUBSTITUTE(LOWER($J8),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J8) - LEN(SUBSTITUTE(LOWER($J8),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B8:D8)","v":11},2012,"Emerging roles for retinoids in regeneration and differentiation in normal and disease states.","Gudas",21855651,"Emerging roles for retinoids in regeneration and differentiation in normal and disease states.    Abstract:   The vitamin A (retinol) metabolite, all-trans retinoic acid (RA), is a signaling molecule that plays key roles in the development of the body plan and induces the differentiation of many types of cells. In this review the physiological and pathophysiological roles of retinoids (retinol and related metabolites) in mature animals are discussed. Both in the developing embryo and in the adult, RA signaling via combinatorial Hox gene expression is important for cell positional memory. The genes that require RA for the maturation/differentiation of T cells are only beginning to be cataloged, but it is clear that retinoids play a major role in expression of key genes in the immune system. An exciting, recent publication in regeneration research shows that ALDH1a2 (RALDH2), which is the rate-limiting enzyme in the production of RA from retinaldehyde, is highly induced shortly after amputation in the regenerating heart, adult fin, and larval fin in zebrafish. Thus, local generation of RA presumably plays a key role in fin formation during both embryogenesis and in fin regeneration. HIV transgenic mice and human patients with HIV-associated kidney disease exhibit a profound reduction in the level of RARβ protein in the glomeruli, and HIV transgenic mice show reduced retinol dehydrogenase levels, concomitant with a greater than 3-fold reduction in endogenous RA levels in the glomeruli. Levels of endogenous retinoids (those synthesized from retinol within cells) are altered in many different diseases in the lung, kidney, and central nervous system, contributing to pathophysiology. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I9,I9)","v":9478050},{"$f":"(LEN($J9) - LEN(SUBSTITUTE(LOWER($J9),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J9) - LEN(SUBSTITUTE(LOWER($J9),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J9) - LEN(SUBSTITUTE(LOWER($J9),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B9:D9)","v":11},1998,"Retinoids and their receptors in vertebrate embryogenesis.","Smith",9478050,"Retinoids and their receptors in vertebrate embryogenesis.    Abstract:   Vitamin A and its derivatives, the retinoids, participate in formation of diverse embryonic structures, including face, heart, eye, limb and nervous system. Studies of retinoid-deficient and -treated embryos, and of receptor null mutants, provide evidence that this participation involves interactions between retinoids and their receptors. Targeted retinoid application and retinoid deficiency, using in ovo avian embryos, has identified early cardiogenic contributions, including cardiocyte gene expression and differentiation, heart tube fusion and laterality, and segmental identity. Also useful is a mammalian model, which targets retinoid deficiency to distinct gestational windows, circumventing limitations of traditional deficiency studies and current null mutant technologies. Rat embryos made deficient in retinoids during gestational d 11.5-13.5 exhibit specific cardiac, limb, ocular and nervous system deficits. That many of the anomalies previously reported in retinoid receptor null mutants are observed in deficiency confirms that ligand-receptor interactions are essential for embryonic development. Other defects are novel, reemphasizing the functional redundancy of retinoid receptors and that retinoid receptors have multiple and overlapping contributions to morphogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I10,I10)","v":8801179},{"$f":"(LEN($J10) - LEN(SUBSTITUTE(LOWER($J10),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J10) - LEN(SUBSTITUTE(LOWER($J10),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J10) - LEN(SUBSTITUTE(LOWER($J10),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B10:D10)","v":11},1996,"Retinoids and Hox genes.","Marshall",8801179,"Retinoids and Hox genes.    Abstract:   The vertebrate embryonic body plan is constructed through the interaction of many developmentally regulated genes that supply cells with the essential positional and functional information they require to migrate to their appropriate destination and generate the proper structures. Some molecular cues involved in patterning the central nervous system, particularly in the hindbrain, are interpreted by the Hox homeobox genes. Retinoids can affect the expression of Hox genes in cells lines and embryonic tissues; the hindbrain and branchial region of the head are particularly sensitive to the teratogenic effects of retinoic acid. The presence of endogenous retinoic acid, together with the distribution of retinoid binding proteins and nuclear receptors in the developing embryo, strongly suggest that retinoic acid is a natural morphogen in vertebrate development. The molecular basis for the interaction between retinoic acid and the Hox genes has been aided in part by approaches using deletion analysis in transgenic mice carrying lacZ reporter constructs. Such studies have identified functional retinoic acid response elements within flanking sequences of some of the most 3 Hox genes, suggesting a direct interaction between the genes and retinoic acid. Furthermore, as demonstrated using transgenic mice carrying Hoxb-1/lacZ constructs, multiple retinoic acid response elements may cooperate with positive and negative regulatory enhancers to specify pattern formation in the vertebrate embryo. These types of studies strongly support the normal roles of retinoids in patterning vertebrate embryogenesis through the Hox genes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I11,I11)","v":10191129},{"$f":"(LEN($J11) - LEN(SUBSTITUTE(LOWER($J11),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J11) - LEN(SUBSTITUTE(LOWER($J11),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J11) - LEN(SUBSTITUTE(LOWER($J11),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B11:D11)","v":10},1999,"Retinal degeneration in retinitis pigmentosa and neuronal ceroid lipofuscinosis: An overview.","Birch",10191129,"Retinal degeneration in retinitis pigmentosa and neuronal ceroid lipofuscinosis: An overview.    Abstract:   Retinal degeneration is an early consequence of the group of lysosomal storage diseases collectively referred to as the neuronal ceroid lipofuscinoses (NCLs). This review details specialized techniques that have evolved for retinal assessment in patients with hereditary retinal degeneration. A standard ERG protocol is described for assessing rod- and cone-mediated function. Standardization will be crucial for planning and implementing multicenter trials as rational therapeutic intervention becomes available. In recent years, there has been a dramatic increase in knowledge of the molecular biological bases of retinitis pigmentosa and allied retinal degenerations. Rather than attempting a comprehensive summary, this review stresses the concepts of genetic, allelic, and clinical heterogeneity, which have obvious parallels in the NCLs. Many of the mutations that cause retinal degeneration are in genes that encode photoreceptor cascade proteins; others are in genes that encode photoreceptor structural proteins. Recent advances in linking the retinal degeneration slow (RDS) and ATP-binding cassette transporter retina (ABCR) genes to a variety of disease phenotypes will be summarized. Clinical heterogeneity even among family members with the same mutation raises the possibility that modifying factors, either genetic or environmental, could influence the severity of the disease. Here, we focus on vitamin A and docosahexaenoic acid, two potential nutritional modifiers that have received considerable attention in recent years."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I12,I12)","v":17061260},{"$f":"(LEN($J12) - LEN(SUBSTITUTE(LOWER($J12),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J12) - LEN(SUBSTITUTE(LOWER($J12),LOWER(C$3),\"\")))/LEN(C$3)","v":7},{"$f":"(LEN($J12) - LEN(SUBSTITUTE(LOWER($J12),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B12:D12)","v":9},2006,"Genetic patterning of the mammalian telencephalon by morphogenetic molecules and transcription factors.","Takahashi",17061260,"Genetic patterning of the mammalian telencephalon by morphogenetic molecules and transcription factors.    Abstract:   Patterning centers that produce gradients of morphogenetic molecules, including fibroblast growth factor (FGF), bone morphogenetic proteins (BMP), Wnt, Sonic hedgehog (Shh), and retinoic acid (RA), are located in telencephalic anlage during early stages of development. Genetic evidence based on loss-of-function and gain-of-function studies indicate that they are involved in regional specification of the dorsal, ventral, and lateral telencephalon. For patterning of the dorsal telencephalon, FGF8 controls the anteroposterior patterning, while BMP and Wnt molecules regulate the mediolateral patterning. Shh and retinoic acid regulate patterning of the ventral and the lateral telencephalon. The regionalization of telencephalon is accompanied by expression of region-specific codes of transcription factors, which in turn regulate different phases of neuronal development to generate different cell types in each brain region. Therefore, bioactive signals of morphogenetic molecules are translated into transcription factor codes for regional specification, which subsequently leads to neurogenesis of the diversity of cell types in different regions of the telencephalon."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I13,I13)","v":9478047},{"$f":"(LEN($J13) - LEN(SUBSTITUTE(LOWER($J13),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J13) - LEN(SUBSTITUTE(LOWER($J13),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J13) - LEN(SUBSTITUTE(LOWER($J13),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B13:D13)","v":9},1998,"Vitamin A and embryonic development: an overview.","Zile",9478047,"Vitamin A and embryonic development: an overview.    Abstract:   Vitamin A is an essential micronutrient throughout the life cycle. Its active form, retinoic acid via retinoid receptors, is involved in signal transduction pathways regulating development. Both the lack and excess of vitamin A during embryonic development result in congenital malformations. Approaches to examine the function of vitamin A in embryonic development have included treatment with excess retinoids and the use of retinoid receptor knock-out mice, which have provided important insights into the complexity of the retinoid signaling system. A recently explored model is the retinoid ligand knock-out, i.e., the vitamin A-deficient embryo. Early development can be successfully examined in the vitamin A-deficient avian embryo, in which bioactive retinoids can rescue the deficient genotype as well as phenotype. In this model it has been possible to unequivocally link the physiological function of vitamin A to development of heart, embryonal circulatory and central nervous systems and the regulation of heart asymmetry. Several developmental genes regulated by endogenous vitamin A during early embryogenesis have been identified. Retinoid receptors and their endogenous ligands, the vitamin A-active forms, are present in the early embryo. It is the developmentally regulated biogeneration of the vitamin A-active forms via distinct spatio-temporal metabolic pathways that is critically linked to the initiation of retinoid signal transduction during embryonic development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I14,I14)","v":7626495},{"$f":"(LEN($J14) - LEN(SUBSTITUTE(LOWER($J14),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J14) - LEN(SUBSTITUTE(LOWER($J14),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J14) - LEN(SUBSTITUTE(LOWER($J14),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B14:D14)","v":9},1995,"The cellular retinoic acid binding proteins.","Donovan",7626495,"The cellular retinoic acid binding proteins.    Abstract:   The two cellular retinoic acid binding proteins, CRABP I and CRABP II, belong to a family of small cytosolic lipid binding proteins and are highly conserved during evolution. Both proteins are expressed during embryogenesis, particularly in the developing nervous system, craniofacial region and limb bud. CRABP I is also expressed in several adult tissues, however, in contrast, CRABP II expression appears to be limited to the skin. It is likely that these proteins serve as regulators in the transport and metabolism of retinoic acid in the developing embryo and throughout adult life. It has been proposed that CRABP I sequesters retinoic acid in the cytoplasm and prevents nuclear uptake of retinoic acid. A role in catabolism of retinoic acid has also been proposed. Recent gene targeting experiments have shown that neither of the two CRABPs are essential for normal embryonic development or adult life. Examination of CRABP I expression at subcellular resolution reveals a differential cytoplasmic and/or nuclear localization of the protein. A regulated nuclear uptake of CRABP I implies a role for this protein in the intracellular transport of retinoic acid. A protein mediated mechanism which controls the nuclear uptake of retinoic acid may play an important role in the transactivation of the nuclear retinoic acid receptors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I15,I15)","v":1877746},{"$f":"(LEN($J15) - LEN(SUBSTITUTE(LOWER($J15),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J15) - LEN(SUBSTITUTE(LOWER($J15),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J15) - LEN(SUBSTITUTE(LOWER($J15),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B15:D15)","v":9},1991,"A hypothetical mechanism for fetal alcohol syndrome involving ethanol inhibition of retinoic acid synthesis at the alcohol dehydrogenase step.","Duester",1877746,"A hypothetical mechanism for fetal alcohol syndrome involving ethanol inhibition of retinoic acid synthesis at the alcohol dehydrogenase step.    Abstract:   Ethanol acts as a teratogen causing brain, craniofacial, and limb abnormalities in those suffering from fetal alcohol syndrome. Normal embryonic development of the vertebrate nervous system and limbs has recently been shown to be governed by retinoic acid, the active form of vitamin A. Retinol dehydrogenase is an enzyme needed to convert vitamin A (retinol) to retinoic acid, a molecule that specifies embryonic pattern formation by controlling gene expression. Ethanol acts as a competitive inhibitor of the retinol dehydrogenase activity attributed to mammalian alcohol dehydrogenase (ADH), an enzyme that uses both retinol and ethanol as substrates. An hypothesis is presented in which many of the abnormalities observed in fetal alcohol syndrome may be caused by high levels of ethanol acting as a competitive inhibitor of ADH-catalyzed retinol oxidation in the embryo or fetus. This would presumably result in a reduction of retinoic acid synthesis in embryonic tissues such as the nervous system and limbs that require critical levels of this molecule to specify spatial patterns."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I16,I16)","v":11746213},{"$f":"(LEN($J16) - LEN(SUBSTITUTE(LOWER($J16),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J16) - LEN(SUBSTITUTE(LOWER($J16),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J16) - LEN(SUBSTITUTE(LOWER($J16),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B16:D16)","v":8},2001,"Hindbrain patterning revisited: timing and effects of retinoic acid signalling.","Begemann",11746213,"Hindbrain patterning revisited: timing and effects of retinoic acid signalling.    Abstract:   Retinoids play a critical role in patterning, segmentation, and neurogenesis of the posterior hindbrain and it has been proposed that they act as a posteriorising signal during hindbrain development. Until now, direct evidence that endogenous retinoid signalling acts through a gradient to specify cell fates along the anteroposterior axis has been missing. Two recent studies tested the requirement for retinoid signalling in the developing hindbrain through systematic application of a pan-retinoic acid receptor antagonist. They demonstrate a stage-dependent requirement for increasing retinoid signalling activity along the hindbrain that proceeds from anterior to posterior. Together these findings challenge the concept of a stable gradient of retinoic acid across the hindbrain and warrant a re-interpretation of the phenotypes obtained by genetic and nutritional disruption of retinoid signalling in the amniote embryo."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I17,I17)","v":9607169},{"$f":"(LEN($J17) - LEN(SUBSTITUTE(LOWER($J17),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J17) - LEN(SUBSTITUTE(LOWER($J17),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J17) - LEN(SUBSTITUTE(LOWER($J17),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B17:D17)","v":8},1997,"Retinoid-regulated gene expression in neural development.","Clagett-Dame",9607169,"Retinoid-regulated gene expression in neural development.    Abstract:   The discovery and development of information surrounding the retinoic acid receptors (RAR and RXR) has ushered in a new era in understanding the molecular mechanism of action of vitamin A in embryonic development and cellular differentiation. The mechanisms involved in the regulation of gene expression by the retinoids is at least partially known and involves binding of the RAR and RXR to retinoic acid response elements. Additional factors, including coregulatory proteins, associated regulatory elements, and cell-specific factors, may also be involved in determining the specificity of retinoid-regulation of gene expression during development. During embryogenesis, retinoids are required for the development of the posterior hindbrain and its associated structures, as well as for the survival and differentiation of certain classes of neurons and neural crest cell derivatives. At least some of the effects of retinoid on hindbrain development are related to the regulation of Hox gene expression. Additional retinoid-regulated genes have been implicated in nervous system development, and the manner in which they lead to phenotypic changes during embryogenesis remains to be determined."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I18,I18)","v":7576306},{"$f":"(LEN($J18) - LEN(SUBSTITUTE(LOWER($J18),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J18) - LEN(SUBSTITUTE(LOWER($J18),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J18) - LEN(SUBSTITUTE(LOWER($J18),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B18:D18)","v":8},1995,"Retinoic acid and retinoic acid receptors in development.","Sucov",7576306,"Retinoic acid and retinoic acid receptors in development.    Abstract:   The vitamin A derivative retinoic acid (RA) and related compounds (retinoids) are utilized as signaling molecules in a diverse array of developmental and physiological regulatory processes, including many important in the developing and mature nervous system. Retinoids function by interaction with high affinity receptors of the nuclear receptor family, which also mediate the effects of steroid and thyroid hormones and which act in the nucleus as transcription factors. This review summarizes current knowledge of the molecular mechanisms of retinoid action, the complex role of retinoid receptors in a variety of hormonal signaling processes, and illustrates current efforts to more fully understand the biological functions of retinoid receptors through analysis of downstream gene regulatory networks and studies of mouse gene knockout systems."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I19,I19)","v":1667403},{"$f":"(LEN($J19) - LEN(SUBSTITUTE(LOWER($J19),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J19) - LEN(SUBSTITUTE(LOWER($J19),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J19) - LEN(SUBSTITUTE(LOWER($J19),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B19:D19)","v":8},1991,"Retinoid-binding proteins in craniofacial development.","Dencker",1667403,"Retinoid-binding proteins in craniofacial development.    Abstract:   Cephalic neural crest cells are known to form the frontonasal mesenchyme and contribute to the mesenchyme of the visceral arches. Retinoids affect neural crest cells and their derivatives during development, and thus cause craniofacial, thymus, and conotruncal heart malformations. In addition, retinoids induce malformations of the central nervous system (CNS). Retinoic acid (RA) and its congeners accumulate in a saturable manner in neural crest and neural crest-derived cells, in the hindbrain, and the spinal cord of mouse embryos. Cellular retinoic acid-binding protein (CRABP) was localized by immunohistochemistry in the same areas as were the labelled RA congeners. Thus, CRABP and RA congeners were found in the transitional zone between surface ectoderm and neuropeithelium, from where neural crest cells are known to emanate (day 8 1/2). Later, specific labelling was found in the frontonasal mesenchyme and in the visceral arches. Also in the trunk, neural crest cells were labelled. In CNS, strong staining was seen in the rhombomeres (especially numbers 4-6) of the hindbrain and in the spinal cord. Retinol and cellular retinol-binding protein (CRBP) were more evenly distributed, with exception of surface ectoderm, epithelium of gut, and myocardium, where CRBP was specifically expressed. These findings are discussed in relation to the differential expression of nuclear RA receptors and homeobox genes in the craniofacial region and in the hindbrain. It is possible that RA is important for the normal pattern formation in these regions and acts as a morphogen as previously proposed in limb development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I20,I20)","v":24060345},{"$f":"(LEN($J20) - LEN(SUBSTITUTE(LOWER($J20),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J20) - LEN(SUBSTITUTE(LOWER($J20),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J20) - LEN(SUBSTITUTE(LOWER($J20),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B20:D20)","v":7},2014,"The use of cultured human fetal retinal pigment epithelium in studies of the classical retinoid visual cycle and retinoid-based disease processes.","Hu",24060345,"The use of cultured human fetal retinal pigment epithelium in studies of the classical retinoid visual cycle and retinoid-based disease processes.    Abstract:   Human fetal retinal pigment epithelium (hfRPE), when harvested by mechanical dissection and cultured initially under low calcium conditions, will proliferate and tolerate cryopreservation for future use. Cryopreserved cells can be subsequently thawed and cultured in standard calcium and in the presence of appropriate nutrients to a high state of differentiation, allowing recapitulation of multiple in vivo functions. In this review we briefly discuss some of our previous studies of the classical retinoid visual cycle and introduce current studies in our laboratory that involve two new areas of investigation; the dynamic response of the receptor for retinol binding protein, STRA6 to the addition of holo-retinol binding protein to the culture medium and the protective complement-based response of hfRPE to the ingestion of toxic byproducts of the visual cycle. This response is studied in the context of genotyped hfRPE expressing either predisposing or protective variants of complement factor H."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I21,I21)","v":20711710},{"$f":"(LEN($J21) - LEN(SUBSTITUTE(LOWER($J21),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J21) - LEN(SUBSTITUTE(LOWER($J21),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J21) - LEN(SUBSTITUTE(LOWER($J21),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B21:D21)","v":7},2010,"The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease.","Tsybovsky",20711710,"The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease.    Abstract:   ATP-binding cassette transporters (ABC transporters) utilize the energy of ATP hydrolysis to translocate an unusually diverse set of substrates across cellular membranes. ABCA4, also known as ABCR, is a approximately 250 kDa single-chain ABC transporter localized to the disk margins of vertebrate photoreceptor outer segments. It is composed of two symmetrically organized halves, each comprising six membrane-spanning helices, a large glycosylated exocytoplasmic domain located inside the disk, and a cytoplasmic domain with an ATP-binding cassette. Hundreds of mutations in ABCA4 are known to cause impaired vision and blindness such as in Stargardt disease as well as related disorders. Biochemical and animal model studies in combination with patient analyses suggest that the natural substrate of ABCA4 is retinylidene-phosphatidylethanolamine (N-retinylidene-PE), a precursor of potentially toxic diretinal compounds. ABCA4 prevents accumulation of N-retinylidene-PE inside the disks by transporting it to the cytoplasmic side of the disk membrane where it can dissociate, allowing the released all-trans-retinal to enter the visual cycle. The pathogenesis of diseases caused by mutations in ABCA4 is complex, comprising a loss-of-function component as well as photoreceptor stress caused by protein mislocalization and misfolding."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I22,I22)","v":16688767},{"$f":"(LEN($J22) - LEN(SUBSTITUTE(LOWER($J22),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J22) - LEN(SUBSTITUTE(LOWER($J22),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J22) - LEN(SUBSTITUTE(LOWER($J22),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B22:D22)","v":7},2006,"Retinoic acid and hindbrain patterning.","Glover",16688767,"Retinoic acid and hindbrain patterning.    Abstract:   Retinoid signaling plays an important role in the developmental patterning of the hindbrain. Studies of the teratogenic effects of retinoids showed early on that the hindbrain suffered patterning defects in cases of retinoid excess or deficiency. Closer examination of these effects in animal models suggested that retinoids might play a physiological role in specifying the antero-posterior axis of the hindbrain. This idea was supported by the localization of retinoid synthetic and degradative enzymes, binding proteins, and receptors to the hindbrain and neighboring regions of the neuroepithelium and the mesoderm. In parallel, it became clear that the molecular patterning of the hindbrain, in terms of the regionalized expression of Hox genes and other developmental regulatory genes, is profoundly influenced by retinoid signaling."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I23,I23)","v":11238746},{"$f":"(LEN($J23) - LEN(SUBSTITUTE(LOWER($J23),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J23) - LEN(SUBSTITUTE(LOWER($J23),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J23) - LEN(SUBSTITUTE(LOWER($J23),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B23:D23)","v":7},2001,"Function of vitamin A in vertebrate embryonic development.","Zile",11238746,"Function of vitamin A in vertebrate embryonic development.    Abstract:   Advances in molecular biology and retinoic acid receptor research have significantly contributed to the understanding of the role of vitamin A during vertebrate development. Examination of the function of this vitamin during very early developmental stages using the completely vitamin A-depleted avian embryo has revealed that the vitamin A requirement begins at the time of formation of the primitive heart, circulation and specification of hindbrain. The lack of vitamin A at this critical time results in gross abnormalities and early embryonic death. In rodent models, vitamin A deficiency can be targeted to later gestational windows and documents the need for vitamin A for more advanced stages of development. Major target tissues of vitamin A deficiency include the heart, central nervous system and structures derived from it, the circulatory, urogenital and respiratory systems, and the development of skull, skeleton and limbs. These abnormalities are also evident in mice mutants from retinoid receptor knockouts; they have revealed both morphological and molecular aspects of vitamin A function during development. Retinoic acid receptors (RAR) in partnership with retinoid X receptor (RXR)alpha appear to be the important retinoid receptor transcription factors regulating vitamin A function at the gene level during development via the physiologic ligand all-trans-retinoic acid. Homeostasis of retinoic acid is maintained by developmentally regulated vitamin A metabolism enzyme systems. Inadequate vitamin A nutrition during early pregnancy may account for some pediatric congenital abnormalities."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I24,I24)","v":8801178},{"$f":"(LEN($J24) - LEN(SUBSTITUTE(LOWER($J24),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J24) - LEN(SUBSTITUTE(LOWER($J24),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J24) - LEN(SUBSTITUTE(LOWER($J24),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B24:D24)","v":7},1996,"Embryonic development and pattern formation.","Morriss-Kay",8801178,"Embryonic development and pattern formation.    Abstract:   During embryogenesis, information encoded in the genome is translated into cell proliferation, morphogenesis, and early stages of differentiation. Embryonic pattern arises from the spatial and temporal regulation and coordination of these events. The vitamin A (retinol) derivative retinoic acid (RA) is essential for normal development. Mammalian embryos are protected against vitamin A deficiency by maternal retinoid homeostasis until stored retinoids fall to very low levels. Retinol binding protein, which is synthesized in the yolk sac placenta of rodent embryos and in the syncytiotrophoblast of the human placenta, is essential for access of retinol to the embryo. Synthesis and metabolism of RA may involve cytoplasmic binding proteins, but the observation that mutants lacking these proteins are normal or near-normal suggests that they are not essential. Severe congenital vitamin A deficiency results in a spectrum of malformations including defects of the eye, lungs, cardiovascular system, and urogenital system. Extreme deficiency results as well in forelimb abnormalities and cleft face, but the embryos are not viable. Similar abnormalities are observed in embryos lacking two retinoid receptors, but loss of one receptor results in either normal development or mild abnormalities. Two single-receptor null mutants, RARgamma-/- and RXRalpha-/-, show regional pattern-specific resistance to teratogenic levels of RA. Mutations leading to abnormality of the structure or regulation of RA signaling pathway genes may be an important cause of human congenital abnormality."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I25,I25)","v":6233342},{"$f":"(LEN($J25) - LEN(SUBSTITUTE(LOWER($J25),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J25) - LEN(SUBSTITUTE(LOWER($J25),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J25) - LEN(SUBSTITUTE(LOWER($J25),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B25:D25)","v":7},1984,"Isotretinoin and pregnancy.","Stern",6233342,"Isotretinoin and pregnancy.    Abstract:   Approximately 120,000 women of childbearing age used isotretinoin in the first 16 months after its release for the treatment of cystic acne. In September, 1983, the American Academy of Dermatology requested its members to relate the outcome of pregnancies of women inadvertently exposed to isotretinoin ( Accutane ) during pregnancy to its Adverse Drug Reaction Reporting System ( ADRRS ). Of nine pregnancies reported, seven ended in spontaneous abortion or the birth of an infant with birth defects. Of thirty-five pregnancies with isotretinoin exposure reported to the ADRRS or the U.S. Food and Drug Administration, twenty-nine (83%) resulted in spontaneous abortion or infants with birth defects. The most frequently reported severe birth defects involved the central nervous system (microcephaly or hydrocephalus) and the cardiovascular system (anomalies of the great vessels). Microtia or absence of external ears were also noted in a majority of cases. These findings illustrate the usefulness of specialty-based reporting of adverse drug effects and emphasize the teratogenic risk of isotretinoin in humans. Physicians need to fully and carefully inform women of childbearing age of these risks."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I26,I26)","v":25134739},{"$f":"(LEN($J26) - LEN(SUBSTITUTE(LOWER($J26),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J26) - LEN(SUBSTITUTE(LOWER($J26),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J26) - LEN(SUBSTITUTE(LOWER($J26),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B26:D26)","v":6},2015,"Signaling through retinoic acid receptors in cardiac development: Doing the right things at the right times.","Xavier-Neto",25134739,"Signaling through retinoic acid receptors in cardiac development: Doing the right things at the right times.    Abstract:   Retinoic acid (RA) is a terpenoid that is synthesized from vitamin A/retinol (ROL) and binds to the nuclear receptors retinoic acid receptor (RAR)/retinoid X receptor (RXR) to control multiple developmental processes in vertebrates. The available clinical and experimental data provide uncontested evidence for the pleiotropic roles of RA signaling in development of multiple embryonic structures and organs such eyes, central nervous system, gonads, lungs and heart. The development of any of these above-mentioned embryonic organ systems can be effectively utilized to showcase the many strategies utilized by RA signaling. However, it is very likely that the strategies employed to transfer RA signals during cardiac development comprise the majority of the relevant and sophisticated ways through which retinoid signals can be conveyed in a complex biological system. Here, we provide the reader with arguments indicating that RA signaling is exquisitely regulated according to specific phases of cardiac development and that RA signaling itself is one of the major regulators of the timing of cardiac morphogenesis and differentiation. We will focus on the role of signaling by RA receptors (RARs) in early phases of heart development. This article is part of a Special Issue entitled: Nuclear receptors in animal development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I27,I27)","v":20850526},{"$f":"(LEN($J27) - LEN(SUBSTITUTE(LOWER($J27),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J27) - LEN(SUBSTITUTE(LOWER($J27),LOWER(C$3),\"\")))/LEN(C$3)","v":5},{"$f":"(LEN($J27) - LEN(SUBSTITUTE(LOWER($J27),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B27:D27)","v":6},2011,"Aberrant forebrain signaling during early development underlies the generation of holoprosencephaly and coloboma.","Gongal",20850526,"Aberrant forebrain signaling during early development underlies the generation of holoprosencephaly and coloboma.    Abstract:   In this review, we highlight recent literature concerning the signaling mechanisms underlying the development of two neural birth defects, holoprosencephaly and coloboma. Holoprosencephaly, the most common forebrain defect, occurs when the cerebral hemispheres fail to separate and is typically associated with mispatterning of embryonic midline tissue. Coloboma results when the choroid fissure in the eye fails to close. It is clear that Sonic hedgehog (Shh) signaling regulates both forebrain and eye development, with defects in Shh, or components of the Shh signaling cascade leading to the generation of both birth defects. In addition, other intercellular signaling pathways are known factors in the incidence of holoprosencephaly and coloboma. This review will outline recent advances in our understanding of forebrain and eye embryonic pattern formation, with a focus on zebrafish studies of Shh and retinoic acid pathways. Given the clear overlap in the mechanisms that generate both diseases, we propose that holoprosencephaly and coloboma can represent mild and severe aspects of single phenotypic spectrum resulting from aberrant forebrain development. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I28,I28)","v":11198137},{"$f":"(LEN($J28) - LEN(SUBSTITUTE(LOWER($J28),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J28) - LEN(SUBSTITUTE(LOWER($J28),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J28) - LEN(SUBSTITUTE(LOWER($J28),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B28:D28)","v":6},2001,"Treatable forms of retinitis pigmentosa associated with systemic neurological disorders.","Grant",11198137,"Treatable forms of retinitis pigmentosa associated with systemic neurological disorders.    Abstract:   In this chapter; we have described the role of nutritional supplements or selective dietary restriction (or both) on the maintenance and function of the retina and nervous system in some diseases. Oral vitamin A therapy has proven to be effective in the treatment of the common forms of retinitis pigmentosa. Bassen-Kornzweig disease can be treated with vitamin A and vitamin E and, in some cases, with vitamin K. Vitamin E therapy for Friedreich-like ataxia associated with retinitis pigmentosa has been shown to be effective in the short term. Classic Refsums disease responds to a low phytol-low phytanic acid diet. Undoubtedly, future research will bring more insight into the biochemical pathways responsible for other diseases and, it is hoped, aid in developing treatments for additional retinal degenerations associated with systemic neurological disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I29,I29)","v":1842359},{"$f":"(LEN($J29) - LEN(SUBSTITUTE(LOWER($J29),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J29) - LEN(SUBSTITUTE(LOWER($J29),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J29) - LEN(SUBSTITUTE(LOWER($J29),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B29:D29)","v":6},1991,"The involvement of retinoic acid in the development of the vertebrate central nervous system.","Maden",1842359,"The involvement of retinoic acid in the development of the vertebrate central nervous system.    Abstract:   We discuss here both previously published data and our current experiments which suggest that the vitamin A derivative, retinoic acid (RA), may play a role in the development of the vertebrate central nervous system (CNS). This evidence comes from the following: both an excess and a deficiency of vitamin A causes embryonic defects of the CNS; RA has been detected endogenously in the CNS; RA stimulates neurite outgrowth; the retinoic acid receptors have been detected with interesting distributions in the CNS; the binding protein for retinol, namely cellular retinol binding protein (CRBP) is found in the radial glia of the ventral floor plate; the binding protein for RA, namely, cellular retinoic acid binding protein (CRABP) is found in particular sets of axons in the developing spinal cord, in particular rhombomeres in the developing hindbrain and in the neural crest. Some hypotheses for the possible role of RA in various aspects of CNS development are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I30,I30)","v":25683350},{"$f":"(LEN($J30) - LEN(SUBSTITUTE(LOWER($J30),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J30) - LEN(SUBSTITUTE(LOWER($J30),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J30) - LEN(SUBSTITUTE(LOWER($J30),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B30:D30)","v":5},2015,"Retinoic acid as a therapeutic option in Alzheimers disease: a focus on cholinergic restoration.","Szutowicz",25683350,"Retinoic acid as a therapeutic option in Alzheimers disease: a focus on cholinergic restoration.    Abstract:   Retinoic acid is a potent cell differentiating factor, which through its nuclear receptors affects a vast range of promoter sites in brain neuronal and glial cells in every step of embryonic and postnatal life. Its capacities, facilitating maturation of neurotransmitter phenotype in different groups of neurons, pave the way for its application as a potential therapeutic agent in neurodegenerative diseases including Alzheimers disease. Retinoic acid was found to exert particularly strong enhancing effects on acetylcholine transmitter functions in brain cholinergic neurons, loss of which is tightly linked to the development of cognitive and memory deficits in course of different cholinergic encephalopathies. Here, we review cholinotrophic properties of retinoic acid and its derivatives, which may justify their application in the management of Alzheimers disease and the related neurodegenerative conditions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I31,I31)","v":20865785},{"$f":"(LEN($J31) - LEN(SUBSTITUTE(LOWER($J31),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J31) - LEN(SUBSTITUTE(LOWER($J31),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J31) - LEN(SUBSTITUTE(LOWER($J31),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B31:D31)","v":5},2010,"The neurobehavioral teratology of retinoids: a 50-year history.","Adams",20865785,"The neurobehavioral teratology of retinoids: a 50-year history.    Abstract:   This review of the central nervous system (CNS) and behavioral teratology of the retinoids over the last 50 years is a commemorative retrospective organized by decade to show the prominent research focus within each period and the most salient findings. In the 1960s, research focused on the gross CNS malformations associated with exposure and the delineation of dose-response and stage-specific responses in rodent models. Relevant scientific events before and during the 1960s are also discussed to provide the zeitgeist in which the field of neurobehavioral teratology emerged in the 1970s. During this period, studies demonstrated that adverse effects on postnatal behavior could be produced in animals exposed to doses of vitamin A lower than those that were teratogenic or impacted growth. Work during the 1980s showed an overrepresentation of behavioral studies focused on the reliability of screening methods, while the marked effects of human exposure were illustrated in children born to women treated with isotretinoin during pregnancy. The human catastrophe invigorated research during the 1990s, a period when technological advances allowed more elegant examinations of the developing CNS, of biochemical, cellular, and molecular developmental events and regulatory actions, and of the effects of direct genetic manipulations. Likewise, research in the 1990s reflected a reinvigoration of research in neurobehavioral teratology evinced in studies that used animal models to try to better understand human vulnerability. These foci continued in the 2000-2010 period while examinations of the role of retinoids in brain development and lifelong functioning became increasingly sophisticated and broader in scope. This review of the work on retinoids also provides a lens on the more general ontogeny of the field of neurobehavioral teratology. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I32,I32)","v":20638138},{"$f":"(LEN($J32) - LEN(SUBSTITUTE(LOWER($J32),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J32) - LEN(SUBSTITUTE(LOWER($J32),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J32) - LEN(SUBSTITUTE(LOWER($J32),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B32:D32)","v":5},2010,"Development of canal cholesteatoma in a patient with prenatal isotretinoin exposure.","Van Abel",20638138,"Development of canal cholesteatoma in a patient with prenatal isotretinoin exposure.    Abstract:    PURPOSE : To describe the clinical and radiologic findings in a case of isotretinoin embryopathy-like syndrome and discuss management of hearing loss, congenital external auditory canal (EAC) stenosis, and EAC cholesteatoma.  METHODS : Review of medical, audiological, and radiological records.  RESULTS : An 8 year old female presented with bilateral moderate conductive hearing loss, bilateral microtia, left EAC stenosis, and right EAC atresia, secondary to prenatal isotretinoin exposure. Comorbidities included developmental delay, ventricular septal defect, hypotonia, and retinal maldevelopment. The left EAC was sharply upsloping with a 2mm-diameter meatus. Computed tomography (CT) scan of the temporal bone demonstrated normal middle and inner ears bilaterally; serial CT scans over 6 years demonstrated progressive development of left canal cholesteatoma. Implantation of a right BAHA system was performed, followed by left canalplasty and excision of cholesteatoma with facial nerve monitoring. An endaural incision was utilized to avoid compromising future microtia repair. Postoperative left-sided hearing improved to mild low-frequency conductive hearing loss rising to normal at 2000 Hz and above.  CONCLUSIONS : Despite extensive precautions for its use, isotretinoin remains a cause of major birth defects, including sensorineural, conductive or mixed hearing loss. Congenital EAC stenosis is much less common than congenital atresia or acquired stenosis; optimal surgical approaches vary depending on hearing status and facial nerve anatomy. Close monitoring for development of canal cholesteatoma is necessary."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I33,I33)","v":17259011},{"$f":"(LEN($J33) - LEN(SUBSTITUTE(LOWER($J33),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J33) - LEN(SUBSTITUTE(LOWER($J33),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J33) - LEN(SUBSTITUTE(LOWER($J33),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B33:D33)","v":5},2007,"A review of the functional role and of the expression profile of retinoid signaling and of nuclear receptors in human spinal cord.","Malaspina",17259011,"A review of the functional role and of the expression profile of retinoid signaling and of nuclear receptors in human spinal cord.    Abstract:   Spinal cord degenerative pathologies in humans cause extensive disability and require a broad range of specialist and palliative medical interventions. In amyotrophic lateral sclerosis (ALS), motor cell loss leads to extensive paralysis and to death from respiratory failure in 3-5 years form disease onset. A wide range of molecular changes forms the basis of spinal cord involvement in ALS, including the reactivation of molecular pathways with potentially neurorestorative properties. Central to this tissue repair mechanism is the differential regulation of components of the retinoid signaling (ReS), a molecular pathway encompassing a variety of proteins functioning as transporters, signaling factors and metabolizing enzymes for retinoic acid. In this paper, we review the strong body of experimental evidence supporting retinoid signalings primary role in spinal cord embryonic differentiation and its likely survival-promoting function in ALS. We discuss the potential involvement in ALS pathogenesis of a subgroup of nuclear receptors (NRs) that act as functional partners of retinoid receptors in human spinal cord. We also provide a review of the expression profile of 25 ReS and NRs genes in human adult spinal cord and in motor neurons of healthy and ALS individuals, using data retrieved from independent datasets obtained through serial analysis of gene expression and array investigations. Based on published expression data, we outline a tentative expression profile of ReS and functionally synergic NR genes in human spinal cord that could guide further experiments to clarify the role of these molecules in mature nervous tissue and suggest potential treatment strategies that could have therapeutic potentials in ALS."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I34,I34)","v":16688769},{"$f":"(LEN($J34) - LEN(SUBSTITUTE(LOWER($J34),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J34) - LEN(SUBSTITUTE(LOWER($J34),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J34) - LEN(SUBSTITUTE(LOWER($J34),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B34:D34)","v":5},2006,"Role of all-trans retinoic acid in neurite outgrowth and axonal elongation.","Clagett-Dame",16688769,"Role of all-trans retinoic acid in neurite outgrowth and axonal elongation.    Abstract:   The vitamin A metabolite, all-trans retinoic acid (atRA) plays essential roles in nervous system development, including neuronal patterning, survival, and neurite outgrowth. Our understanding of how the vitamin A acid functions in neurite outgrowth comes largely from cultured embryonic neurons and model neuronal cell systems including human neuroblastoma cells. Specifically, atRA has been shown to increase neurite outgrowth from embryonic DRG, sympathetic, spinal cord, and olfactory receptor neurons, as well as dissociated cerebra and retina explants. A role for atRA in axonal elongation is also supported by a limited number of studies in vivo, in which a deficiency in retinoid signaling produced either by dietary or genetic means has been shown to alter neurite outgrowth from the spinal cord and hindbrain regions. Human neuroblastoma cells also show enhanced numbers of neurites and longer processes in response to atRA. The mechanism whereby retinoids regulate neurite outgrowth includes, but is not limited to, the regulation of the transcription of neurotrophin receptors. More recent evidence supports a role for atRA in regulating components of other signaling pathways or candidate neurite-regulating factors. Some of these effects, such as that on neuron navigator 2 (NAV2), may be direct, whereas others may be secondary to other atRA-induced changes in the cell. This review focuses on what is currently known about neurite initiation and growth, with emphasis on the manner in which atRA may influence these events."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I35,I35)","v":16688760},{"$f":"(LEN($J35) - LEN(SUBSTITUTE(LOWER($J35),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J35) - LEN(SUBSTITUTE(LOWER($J35),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J35) - LEN(SUBSTITUTE(LOWER($J35),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B35:D35)","v":5},2006,"Once and again: retinoic acid signaling in the developing and regenerating olfactory pathway.","Rawson",16688760,"Once and again: retinoic acid signaling in the developing and regenerating olfactory pathway.    Abstract:   Retinoic acid (RA), a member of the steroid/thyroid superfamily of signaling molecules, is an essential regulator of morphogenesis, differentiation, and regeneration in the mammalian olfactory pathway. RA-mediated teratogenesis dramatically alters olfactory pathway development, presumably by disrupting retinoid-mediated inductive signaling that influences initial olfactory epithelium (OE) and bulb (OB) morphogenesis. Subsequently, RA modulates the genesis, growth, or stability of subsets of OE cells and OB interneurons. RA receptors, cofactors, and synthetic enzymes are expressed in the OE, OB, and anterior subventricular zone (SVZ), the site of neural precursors that generate new OB interneurons throughout adulthood. Their expression apparently accommodates RA signaling in OE cells, OB interneurons, and slowly dividing SVZ neural precursors. Deficiency of vitamin A, the dietary metabolic RA precursor, leads to cytological changes in the OE, as well as olfactory sensory deficits. Vitamin A therapy in animals with olfactory system damage can accelerate functional recovery. RA-related pathology as well as its potential therapeutic activity may reflect endogenous retinoid regulation of neuronal differentiation, stability, or regeneration in the olfactory pathway from embryogenesis through adulthood. These influences may be in register with retinoid effects on immune responses, metabolism, and modulation of food intake."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I36,I36)","v":15072263},{"$f":"(LEN($J36) - LEN(SUBSTITUTE(LOWER($J36),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J36) - LEN(SUBSTITUTE(LOWER($J36),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J36) - LEN(SUBSTITUTE(LOWER($J36),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B36:D36)","v":5},2004,"Retinoids and binding proteins in the cerebellum during lifetime.","Parenti",15072263,"Retinoids and binding proteins in the cerebellum during lifetime.    Abstract:   The vertebrate nervous system is one of the main sites where retinoids and related binding proteins play their critical roles. The cerebellum is subjected to the effects of retinoids over its lifetime. The retinoid binding proteins are differently expressed during life: CRBP I, expressed in the adult cerebellum, is possibly involved in plasticity during memory processes. CRABP I, expressed in the embryonic cerebellum, is involved in the development of the organ and in cellular differentiation. In particular, since the expression of CRABP I coincides with earliest cerebellar differentiation, it is probably involved in this critical step, participating in a complex network of regulatory genes expressed in the mes/methencephalon such as Fgf8, Wnt1, En1/2, Pax2/5, Otx2 and Gbx2. Finally, the way for metabolic synchronization of isthmic cell populations and the putative existence of alternative pathways for CRABP I to regulate RA are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I37,I37)","v":12584240},{"$f":"(LEN($J37) - LEN(SUBSTITUTE(LOWER($J37),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J37) - LEN(SUBSTITUTE(LOWER($J37),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J37) - LEN(SUBSTITUTE(LOWER($J37),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B37:D37)","v":5},2003,"Megalin and the neurodevelopmental biology of sonic hedgehog and retinol.","McCarthy",12584240,"Megalin and the neurodevelopmental biology of sonic hedgehog and retinol.    Abstract:   Megalin is a receptor expressed by embryonic epithelia that mediates endocytosis of numerous ligands, including sonic hedgehog (Shh) and retinol, the precursor to retinoic acid (RA). The importance of Shh and RA signaling in neurodevelopment, combined with the fact that megalin-deficient mice show profound neurodevelopmental abnormalities, has raised questions as to the possible role of megalin in Shh and RA signaling. Several mechanisms could explain how megalin influences Shh and RA signaling in the context of neurodevelopment. These include the involvement of megalin in the transport of Shh and retinol within neuroepithelia, as well as direct signal transduction as a response to binding of Shh and retinol to megalin."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I38,I38)","v":11045401},{"$f":"(LEN($J38) - LEN(SUBSTITUTE(LOWER($J38),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J38) - LEN(SUBSTITUTE(LOWER($J38),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J38) - LEN(SUBSTITUTE(LOWER($J38),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B38:D38)","v":5},2000,"Retinoids and nephron mass control.","Gilbert",11045401,"Retinoids and nephron mass control.    Abstract:   Advances in the molecular biology of retinoids have provided evidence that vitamin A profoundly influences the differentiation of the whole embryo. In addition to its well-characterized role in primary body axis and central nervous system formation, vitamin A is also required for the ad hoc development of numerous tissues and organs, including the kidney. This review will focus on the emerging evidence that the development of the urogenital tract depends on retinoids. In order to understand the role of vitamin A during kidney development, the mechanisms and sites of retinoic acid production are presented. In addition, an overview of the molecular targets that may be regulated by retinoic acid is included. Together, these elements support the concept that control of vitamin A homeostasis during renal organogenesis might control nephrogenesis via specific gene expression. The clinical impact of variations in vitamin A status during pregnancy is discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I39,I39)","v":10766019},{"$f":"(LEN($J39) - LEN(SUBSTITUTE(LOWER($J39),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J39) - LEN(SUBSTITUTE(LOWER($J39),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J39) - LEN(SUBSTITUTE(LOWER($J39),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B39:D39)","v":5},2000,"Soluble factors and the development of rod photoreceptors.","Levine",10766019,"Soluble factors and the development of rod photoreceptors.    Abstract:   Photoreceptors are the most abundant cell type in the vertebrate neural retina. Like the other retinal neurons and the Müller glia, they arise from a population of precursor cells that are multipotent and intrinsic to the retina. Approximately 10 years ago, several studies demonstrated that retinal precursor cells (RPCs) are competent to respond to environmental factors that promote cell type determination and differentiation. Since those studies, significant effort has been directed at identifying the molecular nature of these environmental signals and understanding the precise mechanisms they employ to drive RPCs towards the different retinal fates. In this review, we describe the recent progress toward understanding how environmental factors influence the development of vertebrate rod photoreceptors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I40,I40)","v":10673856},{"$f":"(LEN($J40) - LEN(SUBSTITUTE(LOWER($J40),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J40) - LEN(SUBSTITUTE(LOWER($J40),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J40) - LEN(SUBSTITUTE(LOWER($J40),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B40:D40)","v":5},2000,"[Refsum disease].","Bernscherer",10673856,"[Refsum disease].    Abstract:   For the first time in literature the authors interpret the pathography of Refsums disease, in the case of their patient, as pseudo-hypervitaminosis A. The biochemical basis of the clinical picture is a defect in the activity of phytanic-acid-alpha-hydrolase belonging to the peroxisomal system. As a consequence, phytanic acid accumulates in the serum and in the parenchymal tissues. Retinol, an alcohol with high molecular weight, is a natural ligand of nuclear RXR (retinoid-X-receptor), which plays an important role in the regulation of peroxisoma synthesis. In Refsums disease the phytanic acid accumulated because of the enzyme defect competes with the biotransformation derivates (all-trans-retinoic acid, 9-cis-retinoic acid) of the all-trans-retinol (vitamin A) for the nuclear RX receptor binding sites, and as a very potent receptoractivator it causes the intestinal symptoms of hypervitaminosis A. The authors review the procedure of fatty-acid chromatography necessary for the establishment of the diagnosis and discuss--in addition to dietary restrictions--recent therapeutic possibilities, like plasmapheresis, cascade filtration, lipapheresis and oral batylalcohol treatment."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I41,I41)","v":10523053},{"$f":"(LEN($J41) - LEN(SUBSTITUTE(LOWER($J41),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J41) - LEN(SUBSTITUTE(LOWER($J41),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J41) - LEN(SUBSTITUTE(LOWER($J41),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B41:D41)","v":5},1999,"Vitamins and brain development.","Ramakrishna",10523053,"Vitamins and brain development.    Abstract:   Effects of deficiency of vitamins on early development of brain have been reviewed. Unusual developmental problems in neurogenesis specific for the brain and impairment of its functional capacities due to vitamin deficiency have been discussed. The species-specific quot;critical periodsquot; in development of various systems have been mentioned. Indices such as reflex activity, locomotion, special senses, cognition and adaptive behavior were used for assessing brain maturation in experimental models and humans. Significant examples include brain anomalies in humans and other mammals caused by retinoid excess or deficit; increase in calbindin D28K, a vitamin D dependent calcium-binding protein during postnatal period in rat; hydrocephalus and exencephaly in prenatal rats and subarachnoidal or intracerebral hemorrhage in infants caused by vitamin E deficiency. Peripheral neuropathic lesions leading to infantile beriberi is caused by thiamine deficiency. Impaired growth in retinal layers leading to delay in maturation of electroretinogram and depth-perception in postnatal rats occur due to pyridoxine deficiency. Infants of severely vitamin B12 deficient mothers show abnormalities in behavior involving basal ganglia and pyramidal tract. Folic acid deficiency results in delayed maturation of the basic electroencepalographic patterns. In addition, vitamin-interactions leading to developmental errors have been pointed out. Vitamin B6 deficiency impairs vitamin B12 absorption and biotin deficiency may be aggravated by pantothenic acid deficiency. Vitamin C deficiency resulting in impaired metabolism may produce symptoms of deficiency of folic acid. Another characteristic examples is that iron absorption from dietary sources is dependent on ascorbic acid."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I42,I42)","v":9025880},{"$f":"(LEN($J42) - LEN(SUBSTITUTE(LOWER($J42),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J42) - LEN(SUBSTITUTE(LOWER($J42),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J42) - LEN(SUBSTITUTE(LOWER($J42),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B42:D42)","v":5},1996,"Retinoic acid embryopathy: case report and review of literature.","Coberly",9025880,"Retinoic acid embryopathy: case report and review of literature.    Abstract:   Isotretinoin use as a treatment for acne has increased tremendously and, with it, the problems of associated birth defects. We feel that pathologists should be familiar with isotretinoin embryopathy and its pathogenesis in order to assist in differentiating this syndrome from other genetic syndromes that involve branchial arch defects, such as DiGeorge syndrome or velocardiofacial syndrome. Although selected autopsy findings have been presented in epidemiologic reports, to our knowledge a detailed autopsy report has not been published. We therefore wish to present a complete case study of isotretinoin embryopathy that illustrates the pathologic diagnostic criteria and correlates these with the clinical findings. Although the syndromes major features are explained by the drugs effect on neural crest cells, it has been postulated that isotretinoin also affects other cells in the central nervous system. Our current case supports this theory and shows that these changes in the nervous system may present significant functional impairment, while not presenting visible anatomic changes on either imaging studies or routine histologic examinations."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I43,I43)","v":8841771},{"$f":"(LEN($J43) - LEN(SUBSTITUTE(LOWER($J43),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J43) - LEN(SUBSTITUTE(LOWER($J43),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J43) - LEN(SUBSTITUTE(LOWER($J43),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B43:D43)","v":5},1996,"Retinoid signalling during embryogenesis.","Pijnappel",8841771,"Retinoid signalling during embryogenesis.    Abstract:    CONCLUSION : Retinoids are suspected to have multiple functions during embryogenesis, which are carried out via various different signal transduction pathways involving active retinoids and nuclear retinoid receptors. Research focuses on the identification of the retinoid signal transduction components involved, and on their specific functions during development. Recent findings in this field are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I44,I44)","v":8005030},{"$f":"(LEN($J44) - LEN(SUBSTITUTE(LOWER($J44),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J44) - LEN(SUBSTITUTE(LOWER($J44),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J44) - LEN(SUBSTITUTE(LOWER($J44),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B44:D44)","v":5},1994,"Normal neurulation in mammals.","Morriss-Kay",8005030,"Normal neurulation in mammals.    Abstract:   During mammalian neurulation regional differences are evident between the cranial region, in which neurulation is most complex, the trunk as far as the caudal neuropore and the secondary neurulation region of the caudal trunk plus tail. Differences among these three regions are characterized by specific patterns of morphogenesis and by specific patterns of gene expression. During cranial neurulation distinct regions develop in the brain and the presomitic hindbrain forms seven rhombomeric divisions. The first clear morphological boundary is the preotic sulcus (later transformed into the gyrus between rhombomeres 2 and 3), which may limit cell movement as neuroepithelial cells rostral to it flow towards and into the rapidly expanding forebrain region. The formation of rhombomeres as morphological entities and the development of a normal rhombomere-specific pattern of homeobox and other gene expression domains depend on relatively low levels of retinoic acid. Retinoic acid receptors, which are retinoic acid-activated transcription factors, and retinoid binding proteins, which control the availability of retinoic acid to the receptors, show regional patterns of expression in the cranial, trunk and caudal regions of the neuroepithelium during neurulation. These patterns suggest a possible mechanism for region-specific gene expression during neurulation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I45,I45)","v":8463566},{"$f":"(LEN($J45) - LEN(SUBSTITUTE(LOWER($J45),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J45) - LEN(SUBSTITUTE(LOWER($J45),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J45) - LEN(SUBSTITUTE(LOWER($J45),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B45:D45)","v":5},1993,"[Teratogenicity of retinoids. A case and review of the literature].","Heckel",8463566,"[Teratogenicity of retinoids. A case and review of the literature].    Abstract:   Retinoids are vitamin A derivatives used in dermatology. One of them, isotretinoin, is frequently prescribed for refractory juvenile acne. The teratogenetic power of this drug is substantial, being estimated at 15 to 45% of exposures in utero. The risk is maximum in the first trimester of pregnancy and persists up to one month after treatment has been discontinued. The most frequently described multiple malformation syndrome involves the face, the central nervous system and the heart. There is also a 20 to 30% rate of spontaneous abortion. The authors report a case where exposure during the first trimester did not result in foetal malformation. From a full review of the literature the various malformations observed, the presumed mechanisms of teratogenesis and the strict rules of prescription and surveillance in women child-bearing age are presented. The problem of the measures to be taken in case of retinoid treatment during pregnancy is discussed. The teratogenic risk from other retinoids is dealt with."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I46,I46)","v":3547011},{"$f":"(LEN($J46) - LEN(SUBSTITUTE(LOWER($J46),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J46) - LEN(SUBSTITUTE(LOWER($J46),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J46) - LEN(SUBSTITUTE(LOWER($J46),LOWER(D$3),\"\")))/LEN(D$3)","v":3},{"$f":"SUM(B46:D46)","v":5},1987,"Nevoid basal-cell carcinoma syndrome.","Gorlin",3547011,"Nevoid basal-cell carcinoma syndrome.    Abstract:   The nevoid basal-cell carcinoma syndrome is characterized by major manifestations, such as multiple basal-cell carcinomata, cysts of the jaws, and skeletal--specifically, rib--abnormalities. Findings in 53 patients and a review of the literature document both major and lesser-known manifestations of the disorder. The odontogenic keratocyst, which usually appears during adolescence, has a marked tendency to recur. In addition to the skin tumors, milia, epidermoid cysts, chalazia, comedones, and palmar and plantar pits are frequent. The skin tumors, originally thought to be independent of sun exposure, are more common in sun-exposed areas and are far less frequent and occur at a much later age in blacks than in whites. There is some evidence that radiation of the skin promotes the appearance of skin cancers in this disorder. Unilateral linear nevoid basal-cell carcinomas with comedones may represent postzygotic somatic mutation. A proclivity to other forms of neoplasia exists. Patients with this syndrome have had medulloblastoma, meningioma, ovarian fibroma, ovarian fibrosarcoma, fibrosarcoma of the jaws, cardiac fibroma, fetal rhabdomyoma, and lymphatic or chylous cysts of the mesentery. In addition to the usual modalities of treatment, topical immunotherapy and topical 5-fluorouracil have been used with success. Oral synthetic retinoids, such as 13-cis-retinoic acid, have been used to prevent new lesions from appearing and to arrest the growth of older lesions by inducing differentiation. The independent observations of increased prostaglandin levels associated both with odontogenic keratocyst expansion and aggression of basal cell cancers merit further investigation both as a fundamental cellular mechanism and as a possible basis for treatment (e.g., with antiprostaglandins). The key to pre- and early postnatal diagnosis of the disorder--as well as to an understanding of the basic abnormality--lies in molecular genetics. Prime attention should be given to finding the site of the gene through the use of DNA and other markers."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I47,I47)","v":22959670},{"$f":"(LEN($J47) - LEN(SUBSTITUTE(LOWER($J47),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J47) - LEN(SUBSTITUTE(LOWER($J47),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J47) - LEN(SUBSTITUTE(LOWER($J47),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B47:D47)","v":4},2012,"A vitamin for the brain.","Shearer",22959670,"A vitamin for the brain.    Abstract:   In the central nervous system (CNS) the function of retinoic acid, the active metabolite of vitamin A, is best understood from its action in guiding embryonic development; as development comes to completion, retinoic acid signaling declines. However, it is increasingly recognized that this signaling mechanism does not disappear in the adult brain but becomes more regionally focused and takes on new roles. These functions are often tied to processes of neural plasticity whether in the hippocampus, through homeostatic neural plasticity, the olfactory bulb or the hypothalamus. The role of retinoic acid in the control of plastic processes has led to suggestions of its involvement in neural disorders, both degenerative and psychiatric. This review presents a snapshot of developments in these areas over recent years."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I48,I48)","v":22318625},{"$f":"(LEN($J48) - LEN(SUBSTITUTE(LOWER($J48),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J48) - LEN(SUBSTITUTE(LOWER($J48),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J48) - LEN(SUBSTITUTE(LOWER($J48),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B48:D48)","v":4},2012,"Retinoic acid signalling during development.","Rhinn",22318625,"Retinoic acid signalling during development.    Abstract:   Retinoic acid (RA) is a vitamin A-derived, non-peptidic, small lipophilic molecule that acts as ligand for nuclear RA receptors (RARs), converting them from transcriptional repressors to activators. The distribution and levels of RA in embryonic tissues are tightly controlled by regulated synthesis through the action of specific retinol and retinaldehyde dehydrogenases and by degradation via specific cytochrome P450s (CYP26s). Recent studies indicate that RA action involves an interplay between diffusion (morphogen-like) gradients and the establishment of signalling boundaries due to RA metabolism, thereby allowing RA to finely control the differentiation and patterning of various stem/progenitor cell populations. Here, we provide an overview of the RA biosynthesis, degradation and signalling pathways and review the main functions of this molecule during embryogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I49,I49)","v":19427305},{"$f":"(LEN($J49) - LEN(SUBSTITUTE(LOWER($J49),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J49) - LEN(SUBSTITUTE(LOWER($J49),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J49) - LEN(SUBSTITUTE(LOWER($J49),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B49:D49)","v":4},2009,"Retinoic acid signaling in mammalian eye development.","Cvekl",19427305,"Retinoic acid signaling in mammalian eye development.    Abstract:   Retinoic acid (RA) is a biologically active metabolite of vitamin A (retinol) that serves as a signaling molecule during a number of developmental and physiological processes. RA signaling plays multiple roles during embryonic eye development. RA signaling is initially required for reciprocal interactions between the optic vesicle and invaginating lens placode. RA signaling promotes normal development of the ventral retina and optic nerve through its activities in the neural crest cell-derived periocular mesenchyme. RA coordinates these processes by regulating biological activities of a family of non-steroid hormone receptors, RARalpha/beta/gamma, and RXRalpha/beta/gamma. These DNA-binding transcription factors recognize DNA as RAR/RXR heterodimers and recruit multiprotein transcriptional co-repressor complexes. RA-binding to RAR receptors induces a conformational change in the receptor, followed by the replacement of co-repressor with co-activator complexes. Inactivation of RARalpha/beta/gamma receptors in the periocular mesenchyme abrogates anterior eye segment formation. This review summarizes recent genetic studies of RA signaling and progress in understanding the molecular mechanism of transcriptional co-activators that function with RAR/RXR."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I50,I50)","v":18418469},{"$f":"(LEN($J50) - LEN(SUBSTITUTE(LOWER($J50),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J50) - LEN(SUBSTITUTE(LOWER($J50),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J50) - LEN(SUBSTITUTE(LOWER($J50),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B50:D50)","v":4},2006,"Retinoid-related Orphan Receptors (RORs): Roles in Cellular Differentiation and Development.","Jetten",18418469,"Retinoid-related Orphan Receptors (RORs): Roles in Cellular Differentiation and Development.    Abstract:   Retinoid-related orphan receptors RORalpha, -beta, and -gamma are transcription factors belonging to the steroid hormone receptor superfamily. During embryonic development RORs are expressed in a spatial and temporal manner and are critical in the regulation of cellular differentiation and the development of several tissues. RORalpha plays a key role in the development of the cerebellum particularly in the regulation of the maturation and survival of Purkinje cells. In RORalpha-deficient mice, the reduced production of sonic hedgehog by these cells appears to be the major cause of the decreased proliferation of granule cell precursors and the observed cerebellar atrophy. RORalpha has been implicated in the regulation of a number of other physiological processes, including bone formation. RORbeta expression is largely restricted to several regions of the brain, the retina, and pineal gland. Mice deficient in RORbeta develop retinal degeneration that results in blindness. RORgamma is essential for lymph node organogenesis. In the intestine RORgamma is required for the formation of several other lymphoid tissues: Peyers patches, cryptopatches, and isolated lymphoid follicles. RORgamma plays a key role in the generation of lymphoid tissue inducer (LTi) cells that are essential for the development of these lymphoid tissues. In addition, RORgamma is a critical regulator of thymopoiesis. It controls the differentiation of immature single-positive thymocytes into double-positive thymocytes and promotes the survival of double-positive thymocytes by inducing the expression of the anti-apoptotic gene Bcl-X(L). Interestingly, all three ROR receptors appear to play a role in the control of circadian rhythms. RORalpha positively regulates the expression of Bmal1, a transcription factor that is critical in the control of the circadian clock. This review intends to provide an overview of the current status of the functions RORs have in these biological processes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I51,I51)","v":17662965},{"$f":"(LEN($J51) - LEN(SUBSTITUTE(LOWER($J51),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J51) - LEN(SUBSTITUTE(LOWER($J51),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J51) - LEN(SUBSTITUTE(LOWER($J51),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B51:D51)","v":4},2008,"Regulation of photoreceptor gene expression by Crx-associated transcription factor network.","Hennig",17662965,"Regulation of photoreceptor gene expression by Crx-associated transcription factor network.    Abstract:   Rod and cone photoreceptors in the mammalian retina are special types of neurons that are responsible for phototransduction, the first step of vision. Development and maintenance of photoreceptors require precisely regulated gene expression. This regulation is mediated by a network of photoreceptor transcription factors centered on Crx, an Otx-like homeodomain transcription factor. The cell type (subtype) specificity of this network is governed by factors that are preferentially expressed by rods or cones or both, including the rod-determining factors neural retina leucine zipper protein (Nrl) and the orphan nuclear receptor Nr2e3; and cone-determining factors, mostly nuclear receptor family members. The best-documented of these include thyroid hormone receptor beta2 (Tr beta2), retinoid related orphan receptor Ror beta, and retinoid X receptor Rxr gamma. The appropriate function of this network also depends on general transcription factors and cofactors that are ubiquitously expressed, such as the Sp zinc finger transcription factors and STAGA co-activator complexes. These cell type-specific and general transcription regulators form complex interactomes; mutations that interfere with any of the interactions can cause photoreceptor development defects or degeneration. In this manuscript, we review recent progress on the roles of various photoreceptor transcription factors and interactions in photoreceptor subtype development. We also provide evidence of auto-, para-, and feedback regulation among these factors at the transcriptional level. These protein-protein and protein-promoter interactions provide precision and specificity in controlling photoreceptor subtype-specific gene expression, development, and survival. Understanding these interactions may provide insights to more effective therapeutic interventions for photoreceptor diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I52,I52)","v":16733532},{"$f":"(LEN($J52) - LEN(SUBSTITUTE(LOWER($J52),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J52) - LEN(SUBSTITUTE(LOWER($J52),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J52) - LEN(SUBSTITUTE(LOWER($J52),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B52:D52)","v":4},2006,"Retinoic acid signaling and the evolution of chordates.","Marlétaz",16733532,"Retinoic acid signaling and the evolution of chordates.    Abstract:   In chordates, which comprise urochordates, cephalochordates and vertebrates, the vitamin A-derived morphogen retinoic acid (RA) has a pivotal role during development. Altering levels of endogenous RA signaling during early embryology leads to severe malformations, mainly due to incorrect positional codes specifying the embryonic anteroposterior body axis. In this review, we present our current understanding of the RA signaling pathway and its roles during chordate development. In particular, we focus on the conserved roles of RA and its downstream mediators, the Hox genes, in conveying positional patterning information to different embryonic tissues, such as the endoderm and the central nervous system. We find that some of the control mechanisms governing RA-mediated patterning are well conserved between vertebrates and invertebrate chordates, such as the cephalochordate amphioxus. In contrast, outside the chordates, evidence for roles of RA signaling is scarce and the evolutionary origin of the RA pathway itself thus remains elusive. In sum, to fully understand the evolutionary history of the RA pathway, future research should focus on identification and study of components of the RA signaling cascade in non-chordate deuterostomes (such as hemichordates and echinoderms) and other invertebrates, such as insects, mollusks and cnidarians."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I53,I53)","v":15359008},{"$f":"(LEN($J53) - LEN(SUBSTITUTE(LOWER($J53),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J53) - LEN(SUBSTITUTE(LOWER($J53),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J53) - LEN(SUBSTITUTE(LOWER($J53),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B53:D53)","v":4},2004,"Retinoic acid signaling in the nervous system of adult vertebrates.","Mey",15359008,"Retinoic acid signaling in the nervous system of adult vertebrates.    Abstract:   The majority of the functions of vitamin A are carried out by its metabolite, retinoic acid (RA), a potent transcriptional activator acting through members of the nuclear receptor family of transcription factors. In the CNS, RA was first recognized to be essential for the control of patterning and differentiation in the developing embryo. It has recently come to light, however, that many of the same functions that RA directs in the embryo are involved in the regulation of plasticity and regeneration in the adult brain. The same intricate metabolic control system of synthetic and catabolic enzymes, combined with cytoplasmic binding proteins, is used in both embryo and adult to create regions of high and low RA to modulate gene transcription. This review summarizes some of the discoveries in the new field of retinoid neurobiology including its functions in neural plasticity and LTP in the hippocampus; its possible role in motor disorders such as Parkinsons disease, motoneuron disease, and Huntingtons disease; its role in regeneration after sciatic nerve and spinal cord injury; and its possible involvement in psychiatric diseases such as depression."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I54,I54)","v":12911743},{"$f":"(LEN($J54) - LEN(SUBSTITUTE(LOWER($J54),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J54) - LEN(SUBSTITUTE(LOWER($J54),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J54) - LEN(SUBSTITUTE(LOWER($J54),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B54:D54)","v":4},2003,"Too much of a good thing: retinoic acid as an endogenous regulator of neural differentiation and exogenous teratogen.","McCaffery",12911743,"Too much of a good thing: retinoic acid as an endogenous regulator of neural differentiation and exogenous teratogen.    Abstract:   Retinoic acid (RA) is essential for both embryonic and adult growth, activating gene transcription via specific nuclear receptors. It is generated, via a retinaldehyde intermediate, from retinol (vitamin A). RA levels require precise regulation by controlled synthesis and catabolism, and when RA concentrations deviate from normal, in either direction, abnormal growth and development occurs. This review describes: (i) how the pattern of RA metabolic enzymes controls the actions of RA; and (ii) the type of abnormalities that result when this pattern breaks down. Examples are given of RA control of the anterior/posterior axis of the hindbrain, the dorsal/ventral axis of the spinal cord, as well as certain sex-specific segments of the spinal cord, using varied animal models including mouse, quail and mosquitofish. These functions are highly sensitive to abnormal changes in RA concentration. In rodents, the control of neural patterning and differentiation are disrupted when RA concentrations are lowered, whereas inappropriately high concentrations of RA result in abnormal development of cerebellum and hindbrain nuclei. The latter parallels the malformations seen in the human embryo exposed to RA due to treatment of the mother with the acne drug Accutane (13-cis RA) and, in cases where the child survives beyond birth, a particular set of behavioural anomalies can be described. Even the adult brain may be susceptible to an imbalance of RA, particularly the hippocampus. This report shows how the properties of RA as a neural induction agent and organizer of segmentation can explain the consequences of RA depletion and overexpression."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I55,I55)","v":11932986},{"$f":"(LEN($J55) - LEN(SUBSTITUTE(LOWER($J55),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J55) - LEN(SUBSTITUTE(LOWER($J55),LOWER(C$3),\"\")))/LEN(C$3)","v":3},{"$f":"(LEN($J55) - LEN(SUBSTITUTE(LOWER($J55),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B55:D55)","v":4},2002,"Teratogenesis of holoprosencephaly.","Cohen",11932986,"Teratogenesis of holoprosencephaly.    Abstract:   Teratogenic causes of holoprosencephaly are critically assessed. A brief general review of holoprosencephaly is followed by four tables summarizing etiologic factors. Subjects evaluated here include: 1) maternal diabetes; 2) ethyl alcohol; 3) retinoic acid; 4) mutated genes and teratogens involving the sonic hedgehog signaling network and cholesterol biosynthesis; and 5) cholesterol trafficking, sterol adducts, target tissue response, and sterol sensing domain."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I56,I56)","v":11775054},{"$f":"(LEN($J56) - LEN(SUBSTITUTE(LOWER($J56),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J56) - LEN(SUBSTITUTE(LOWER($J56),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J56) - LEN(SUBSTITUTE(LOWER($J56),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B56:D56)","v":4},2001,"Development of pigment cells in the brain of ascidian tadpole larvae: insights into the origins of vertebrate pigment cells.","Sato",11775054,"Development of pigment cells in the brain of ascidian tadpole larvae: insights into the origins of vertebrate pigment cells.    Abstract:   In vertebrates, melanins produced in specialized pigment cells are required for visual acuity, camouflage, sexual display and protection from ultra violet (UV) radiation. There are three pigment cell types that are classified based on their distinct embryonic origins. Retinal pigment epithelium (RPE) cells originate from the outer layer of the optic cup. Pigment cells of the pineal organ are formed from the developing diencephalon. Melanocytes are derived from the neural crest unique to vertebrate embryos. Some of these pigment cells also play roles that are independent of the activity of tyrosinase, the key melanogenesis enzyme, or melanin: production of substrate(s) for catecholamine synthesis, maintenance of endolymph composition in the cochlea, maintenance of photoreceptor cells in the retina and retinoid metabolism essential for the visual cycle. To deduce the evolutionary origins of vertebrate pigment cells and a possible archetypal genetic circuitry, which may have been modified and utilized to generate multiple pigment cell types, comparison of developmental mechanisms of pigment cells between vertebrates and closely related invertebrate ascidians are proposed to provide useful information. The tadpole-type larva of ascidians possesses two melanin-containing pigment cells, termed the otolith and ocellus pigment cells, in the brain that are believed to be required for photo- and geotactic responses during swimming. In this review, current knowledge on the development of the two ascidian pigment cells is summarized, i.e. complete cell lineage, structure and expression of genes encoding two melanogenesis enzymes, and molecular developmental mechanisms involving BMP-CHORDIN antagonism, and possible evolutionary relationships between ascidian and vertebrate pigment cells are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I57,I57)","v":11580199},{"$f":"(LEN($J57) - LEN(SUBSTITUTE(LOWER($J57),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J57) - LEN(SUBSTITUTE(LOWER($J57),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J57) - LEN(SUBSTITUTE(LOWER($J57),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B57:D57)","v":4},2001,"Role and distribution of retinoic acid during CNS development.","Maden",11580199,"Role and distribution of retinoic acid during CNS development.    Abstract:   Retinoic acid (RA), the biologically active derivative of vitamin A, induces a variety of embryonal carcinoma and neuroblastoma cell lines to differentiate into neurons. The molecular events underlying this process are reviewed with a view to determining whether these data can lead to a better understanding of the normal process of neuronal differentiation during development. Several transcription factors, intracellular signaling molecules, cytoplasmic proteins, and extracellular molecules are shown to be necessary and sufficient for RA-induced differentiation. The evidence that RA is an endogenous component of the developing central nervous system (CNS) is then reviewed, data which include high-pressure liquid chromotography (HPLC) measurements, reporter systems and the distribution of the enzymes that synthesize RA. The latter is particularly relevant to whether RA signals in a paracrine fashion on adjacent tissues or whether it acts in an autocrine manner on cells that synthesize it. It seems that a paracrine system may operate to begin early patterning events within the developing CNS from adjacent somites and later within the CNS itself to induce subsets of neurons. The distribution of retinoid-binding proteins, retinoid receptors, and RA-synthesizing enzymes is described as well as the effects of knockouts of these genes. Finally, the effects of a deficiency and an excess of RA on the developing CNS are described from the point of view of patterning the CNS, where it seems that the hindbrain is the most susceptible part of the CNS to altered levels of RA or RA receptors and also from the point of view of neuronal differentiation where, as in the case of embryonal carcinoma (EC) cells, RA promotes neuronal differentiation. The crucial roles played by certain genes, particularly the Hox genes in RA-induced patterning processes, are also emphasized."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I58,I58)","v":10497330},{"$f":"(LEN($J58) - LEN(SUBSTITUTE(LOWER($J58),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J58) - LEN(SUBSTITUTE(LOWER($J58),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J58) - LEN(SUBSTITUTE(LOWER($J58),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B58:D58)","v":4},1999,"Heads or tails? Retinoic acid will decide.","Maden",10497330,"Heads or tails? Retinoic acid will decide.    Abstract:   A recent study (Niederreither et al. Nat Genet 1999;21:444-448 [Ref. 1]) describes the phenotype of a gene knockout for an enzyme, retinaldehyde dehydrogenase 2 (RALDH-2), that synthesizes retinoic acid (RA) in the early embryo. The effects generated by this single enzyme mutation are remarkably similar to those previously described in vitamin A-deprivation studies and compound retinoic acid receptor knockouts, which involve multiple systems of the embryo. With other data on the distribution of RA, its role in axial specification of the early embryo is considerably clarified. Surprisingly, it seems that head development is unaffected in these RALDH-2 knockout embryos; thus, the anterior of the embryo does not require RA, despite the observations that the hindbrain seems exquisitely sensitive to RA perturbation. Head development may be realised by a cytochrome P450 enzyme (CYP26), which has been described recently. Between these two opposing forces, the hindbrain develops."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I59,I59)","v":8664424},{"$f":"(LEN($J59) - LEN(SUBSTITUTE(LOWER($J59),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J59) - LEN(SUBSTITUTE(LOWER($J59),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J59) - LEN(SUBSTITUTE(LOWER($J59),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B59:D59)","v":4},1995,"Prenatal craniofacial development: new insights on normal and abnormal mechanisms.","Johnston",8664424,"Prenatal craniofacial development: new insights on normal and abnormal mechanisms.    Abstract:   Technical advances are radically altering our concepts of normal prenatal craniofacial development. These include concepts of germ layer formation, the establishment of the initial head plan in the neural plate, and the manner in which head segmentation is controlled by regulatory (homeobox) gene activity in neuromeres and their derived neural crest cells. There is also a much better appreciation of ways in which new cell associations are established. For example, the associations are achieved by neural crest cells primarily through cell migration and subsequent cell interactions that regulate induction, growth, programmed cell death, etc. These interactions are mediated primarily by two groups of regulatory molecules: quot;growth factorsquot; (e.g., FGF and TGF alpha) and the so-called steroid/thyroid/retinoic acid superfamily. Considerable advances have been made with respect to our understanding of the mechanisms involved in primary and secondary palate formation, such as growth, morphogenetic movements, and the fusion/merging phenomenon. Much progress has been made on the mechanisms involved in the final differentiation of skeletal tissues. Molecular genetics and animal models for human malformations are providing many insights into abnormal development. A mouse model for the fetal alcohol syndrome (FAS), a mild form of holoprosencephaly, demonstrates a mid-line anterior neural plate deficiency which leads to olfactory placodes being positioned too close to the mid-line, and other secondary changes. Work on animal models for the retinoic acid syndrome (RAS) shows that there is major involvement of neural crest cells. There is also major crest cell involvement in similar syndromes, apparently including hemifacial microsomia. Later administration of retinoic acid prematurely and excessively kills ganglionic placodal cells and leads to a malformation complex virtually identical to the Treacher Collins syndrome. Most clefts of the lip and/or palate appear to have a multifactorial etiology. Genetic variations in TGF alpha s, RAR alpha s, NADH dehydrogenase, an enzyme involved in oxidative metabolism, and cytochrome P-450, a detoxifying enzyme, have been implicated as contributing genetic factors. Cigarette smoking, with the attendant hypoxia, is a probable contributing environmental factor. It seems likely that few clefts involve single major genes. In most cases, the pathogenesis appears to involve inadequate contact and/or fusion of the facial prominences or palatal shelves. Specific mutations in genes for different FGF receptor molecules have been identified for achondroplasia and Crouzons syndrome, and in a regulatory gene (Msx2) for one type of craniosynostosis. Poorly co-ordinated control of form and size of structures, or groups of structures (e.g., teeth and jaws), by regulatory genes should do much to explain the very frequent quot;mismatchesquot; found in malocclusions and other dentofacial quot;deformitiesquot;. Future directions for research, including possibilities for prevention, are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I60,I60)","v":7632866},{"$f":"(LEN($J60) - LEN(SUBSTITUTE(LOWER($J60),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J60) - LEN(SUBSTITUTE(LOWER($J60),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J60) - LEN(SUBSTITUTE(LOWER($J60),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B60:D60)","v":4},1995,"Prenatal craniofacial development: new insights on normal and abnormal mechanisms.","Johnston",7632866,"Prenatal craniofacial development: new insights on normal and abnormal mechanisms.    Abstract:   Technical advances are radically altering our concepts of normal prenatal craniofacial development. These include concepts of germ layer formation, the establishment of the initial head plan in the neural plate, and the manner in which head segmentation is controlled by regulatory (homeobox) gene activity in neuromeres and their derived neural crest cells. There is also a much better appreciation of ways in which new cell associations are established. For example, the associations are achieved by neural crest cells primarily through cell migration and subsequent cell interactions that regulate induction, growth, programmed cell death, etc. These interactions are mediated primarily by two groups of regulatory molecules: quot;growth factorsquot; (e.g., FGF and TGFalpha) and the so-called steroid/thyroid/retinoic acid superfamily. Considerable advances have been made with respect to our understanding of mechanisms involved in primary and secondary palate formation, such as growth, morphogenetic movements, and the fusion/merging phenomenon. Much progress has been made on the mechanisms involved in the final differentiation of skeletal tissues. Molecular genetics and animal models for human malformations are providing many insights into abnormal development. A mouse model for the fetal alcohol syndrome(FAS), a mild form of holoprosencephaly, demonstrates a mid-line anterior neural plate deficiency which leads to olfactory placodes being positioned too close to the mid-line, and other secondary changes. Work on animal models for the retinoic acid syndrome (RAS) shows that there is major involvement of neural crest cells. There is also major crest cell involvement in similar syndromes, apparently including hemifacial microsomia. Later administration of retinoic acid prematurely and excessively kills ganglionic placodal cells and leads to a malformation complex virtually identical to the Treacher Collins syndrome. Most clefts of the lip and/or palate appear to have a multifactorial etiology. Genetic variations in TGF alpha s, RAR alpha s, NADH dehydrogenase, an enzyme involved in oxidative metabolism, and cytochrome P-450, a detoxifying enzyme, have been implicated as contributing genetic factors. Cigarette smoking, with the attendant hypoxia, is a probable contributing environmental factor. It seems likely that few clefts involve single major genes. In most cases, the pathogenesis appears to involve inadequate contact and/or fusion of the facial prominences or palatal shelves. Specific mutations in genes for different FGF receptor molecules have been identified for achondroplasia and Crouzons syndrome, and in a regulatory gene (Msx2) for one type of craniosynostosis.(ABSTRACT TRUNCATED AT 400 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I61,I61)","v":7499738},{"$f":"(LEN($J61) - LEN(SUBSTITUTE(LOWER($J61),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J61) - LEN(SUBSTITUTE(LOWER($J61),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J61) - LEN(SUBSTITUTE(LOWER($J61),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B61:D61)","v":4},1995,"[Isotretinoin (RoAccutane) embryopathy. A case report].","Pilorget",7499738,"[Isotretinoin (RoAccutane) embryopathy. A case report].    Abstract:   Retinoids are synthetic vitamin A derivatives, particularly used in dermatology. Their prescription in women of childbearing age can cause, if pregnancy occurs, a serious malformative embryopathy, mainly involving external ear, brain and heart. A neonatal case caused by isotretinoin (RoAccutane) emphasizes the clinical and epidemiological data concerning this embryopathy. The aetiopathological hypothesis of an interaction between isotretinoin and Hox genes is advanced. Prophylactic measures are difficult since neonatal reported cases are uncommon, but antenatal exposition to this strong teratogenic agent results in multiple spontaneous abortions or pregnancy interruptions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I62,I62)","v":7720551},{"$f":"(LEN($J62) - LEN(SUBSTITUTE(LOWER($J62),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J62) - LEN(SUBSTITUTE(LOWER($J62),LOWER(C$3),\"\")))/LEN(C$3)","v":3},{"$f":"(LEN($J62) - LEN(SUBSTITUTE(LOWER($J62),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B62:D62)","v":4},1994,"Caudalization by the amphibian organizer: brachyury, convergent extension and retinoic acid.","Yamada",7720551,"Caudalization by the amphibian organizer: brachyury, convergent extension and retinoic acid.    Abstract:   Caudalization, which is proposed to be one of two functions of the amphibian organizer, initiates posterior pathways of neural development in the dorsalized ectoderm. In the absence of caudalization, dorsalized ectoderm only expresses the most anterior (archencephalic) differentiation. In the presence of caudalization, dorsalized ectorderm develops various levels of posterior neural tissues, depending on the extent of caudalization. A series of induction experiments have shown that caudalization is mediated by convergent extension: cell motility that is based on directed cell intercalation, and is essential for the morphogenesis of posterior axial tissues. During amphibian development, convergent extension is first expressed all-over the mesoderm and, after mesoderm involution, it becomes localized to the posterior mid-dorsal mesoderm, which produces notochord. This expression pattern of specific down regulation of convergent extension is also followed by the expression of the brachyury homolog. Furthermore, mouse brachyury has been implicated in the regulation of tissue elongation on the one hand, and in the control of posterior differentiation on the other. These observations suggest that protein encoded by the brachyury homolog controls the expression of convergent extension in the mesoderm. The idea is fully corroborated by a genetic study of mouse brachyury, which demonstrates that the gene product produces elongation of the posterior embryonic axis. However, there exists evidence for the induction of posterior dorsal mesodermal tissues, if brachyury homolog protein is expressed in the ectoderm. In both cases the brachyury homolog contributes to caudalization. A number of other genes appear to be involved in caudalization. The most important of these is pintavallis, which contains a fork-head DNA binding domain. It is first expressed in the marginal zone. After mesoderm involution, it is present not only in the presumptive notochord, but also in the floor plate. This is in contrast to the brachyury homolog, whose expression is restricted to mesoderm. The morphogenetic effects of exogenous RA on anteroposterior specification during amphibian embryogenesis are reviewed. The agent inhibits archencephalic differentiation and enhances differentiation of deuterencephalic and trunk levels. Thus the effect of exogenous RA on morphogenesis of CNS is very similar to that of caudalization, which is proposed to occur through the normal action of the organizer. According to a detailed analysis of the effect of lithium on morphogenesis induced by the Cynops organizer, lithium has a caudalizing effect closely comparable with that of RA. Furthermore, lithium induces convergent extension in the prechordal plate, which normally does not show cell motility.(ABSTRACT TRUNCATED AT 400 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I63,I63)","v":7950323},{"$f":"(LEN($J63) - LEN(SUBSTITUTE(LOWER($J63),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J63) - LEN(SUBSTITUTE(LOWER($J63),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J63) - LEN(SUBSTITUTE(LOWER($J63),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B63:D63)","v":4},1994,"Retinoic acid and homeobox gene regulation.","Langston",7950323,"Retinoic acid and homeobox gene regulation.    Abstract:   Hox genes have been shown to be important regulators of pattern formation in vertebrates. Retinoic acid has been shown to affect the expression of Hox genes in vitro and in vivo, and some of its effects on development correspond to changes in Hox gene expression. The idea that retinoic acid is not simply a powerful pharmocological agent, but rather that it plays an important role in creating the normal expression patterns of Hox genes, is provided by the recent identification of retinoic acid responsive enhancers near Hox genes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I64,I64)","v":8297038},{"$f":"(LEN($J64) - LEN(SUBSTITUTE(LOWER($J64),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J64) - LEN(SUBSTITUTE(LOWER($J64),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J64) - LEN(SUBSTITUTE(LOWER($J64),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B64:D64)","v":4},1993,"Mammalian neural crest and neural crest derivatives.","Morriss-Kay",8297038,"Mammalian neural crest and neural crest derivatives.    Abstract:   In the mammalian embryonic trunk, neural crest cells emigrate from the closed neural tube in a cranio-caudal sequences and appear to have similar migration pathways and derivatives to those of avian embryos. In the cranial region, however, there are mammalian-specific features, which are related to the mammalian-specific pattern of cranial neurulation. Midbrain and rostral hindbrain neural crest cells emigrate from widely open neural folds; caudal hindbrain crest emigrates in a caudo-rostral sequence, following the sequence of neural tube closure in this region. The forebrain is also a source of neural crest cells at early stages of neurulation; both forebrain and midbrain crest cells contribute to the frontonasal mesenchyme, although their relative contributions have not been analysed. Few studies have provided direct information about mammalian neural crest cell derivatives. Studies on the effects of retinoid excess on craniofacial development provide indirect evidence that mammalian cranial neural crest, like that of avian embryos, includes two populations whose differentiated phenotype and morphological tissue structure are determined prior to emigration. Retinoid-induced shortening of the preotic hindbrain leads to abnormal migration pathways of the neural crest cells that normally migrate into the mandibular arch to form Meckels cartilage, so that an ectopic Meckels cartilage-like structure forms in the maxillary region of the face. Slow descent of the heart in retinoid-exposed embryos enables the quot;wrongquot; crest cell population to populate the wall of the truncus arteriosus. These observations correlate well with observations of retinoid-induced craniofacial and heart abnormalities in human infants."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I65,I65)","v":1812131},{"$f":"(LEN($J65) - LEN(SUBSTITUTE(LOWER($J65),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J65) - LEN(SUBSTITUTE(LOWER($J65),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J65) - LEN(SUBSTITUTE(LOWER($J65),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B65:D65)","v":4},1991,"Teratogenic effects of alcohol and isotretinoin on craniofacial development: an analysis of animal models.","Webster",1812131,"Teratogenic effects of alcohol and isotretinoin on craniofacial development: an analysis of animal models.    Abstract:   The teratogens alcohol and isotretinoin cause different patterns of facial dysmorphogenesis in the human. For isotretinoin the pattern is consistent with interference with the normal development of the cranial neural crest, particularly that destined for the second visceral arch. In vitro studies in the rat indicate that, at threshold levels of exposure to isotretinoin, the development of the second arch crest represents the most sensitive process of organogenic development. For alcohol, the facial abnormalities result from exposure very early in development, during the gastrulation process. There is no evidence that this is a peculiarly sensitive stage of development with respect to alcohol; animal studies indicate that other processes in the organogenic period are equally or more vulnerable. The emphasis given to the abnormal facial features in the fetal alcohol syndrome is considered a phenomenon associated with the exclusivity of syndromes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I66,I66)","v":1812129},{"$f":"(LEN($J66) - LEN(SUBSTITUTE(LOWER($J66),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J66) - LEN(SUBSTITUTE(LOWER($J66),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J66) - LEN(SUBSTITUTE(LOWER($J66),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B66:D66)","v":4},1991,"Animal models for human craniofacial malformations.","Johnston",1812129,"Animal models for human craniofacial malformations.    Abstract:   Holoprosencephaly malformations, of which the fetal alcohol syndrome appears to be a mild form, can result from medial anterior neural plate deficiencies as demonstrated in an ethanol treated animal model. These malformations are associated with more medial positioning of the nasal placodes and resulting underdevelopment or absence of the medial nasal prominences (MNPs) and their derivatives. Malformations seen in the human retinoic acid syndrome (RAS) can be produced by administration of the drug 13-cis-retinoic acid in animals. Primary effects on neural crest cells account for most of these RAS malformations. Many of the malformations seen in the RAS are similar to those of hemifacial microsomia, suggesting similar neural crest involvement. Excessive cell death, apparently limited to trigeminal ganglion neuroblasts of placodal origin, follows 13-cis retinoic acid administration at the time of ganglion formation and leads to malformations virtually identical to those of the Treacher Collins syndrome (TCS). Secondary effects on neural crest cells in the area of the ganglion appear to be responsible for the TCS malformations. Malformations of the DiGeorge Syndrome are similar to those of the RAS and can be produced in mice by ethanol administration or by quot;knocking outquot; a homeobox gene (box 1.5). Human and animal studies indicate that cleft lips of multifactorial etiology may be generically susceptible because of small MNP)s or other MNP developmental alterations, such as those found in A/J mice, that make prominence contact more difficult. Experimental maternal hypoxia in mice indicates that cigarette smoking may increase the incidence of cleft lip by interfering with morphogenetic movements. Other human cleft lips may result from the action of a single major gene coding for TGF-alpha variants. A study with mouse palatal shelves in culture and other information suggest that a fusion problem may be involved."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I67,I67)","v":2472150},{"$f":"(LEN($J67) - LEN(SUBSTITUTE(LOWER($J67),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J67) - LEN(SUBSTITUTE(LOWER($J67),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J67) - LEN(SUBSTITUTE(LOWER($J67),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B67:D67)","v":4},1989,"c-src and other proto-oncogenes implicated in neuronal differentiation.","Ingraham",2472150,"c-src and other proto-oncogenes implicated in neuronal differentiation.    Abstract:   The proto-oncogene c-src has been implicated in the development and mature function of the nervous system. pp60c-src, the protein product of the c-src gene, is a tyrosine protein kinase that is highly enriched in fetal neural tissue. pp60c-src appears in two phases of neuronal development. Neuroectodermal cells of gastrulating embryos first express pp60c-src around the time of commitment to neuronal or glial pathways. Later, committed neuroepithelial cells express pp60c-src near the onset of terminal neuronal differentiation. Immunocytochemical analyses of pp60c-src in developing chick retina, telencephalon, and cerebellum show immunoreactivity concentrated in regions rich in growth cones and neurites. Moreover, pp60c-src is concentrated approximately 10-fold in a biochemical fraction from fetal rat brain that is enriched in nerve growth cone membranes. These results point toward a function for pp60c-src in neurite outgrowth. A functional role for other proto-oncogenes in the development of the nervous system was indicated from a study of the expression of a battery of proto-oncogenes during the retinoic acid-induced differentiation of the mouse embryonal carcinoma cell line P19 to a neuronal phenotype. Nuclear runoff transcription of the proto-oncogenes c-src, c-fms, c-sis, N-ras, c-myc, and c-fos was observed in proliferating and retinoic acid-treated cells."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I68,I68)","v":24989467},{"$f":"(LEN($J68) - LEN(SUBSTITUTE(LOWER($J68),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J68) - LEN(SUBSTITUTE(LOWER($J68),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J68) - LEN(SUBSTITUTE(LOWER($J68),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B68:D68)","v":3},2014,"[Neural differentiation of pluripotent stem cells and application for metal-induced neural toxicity study].","Taniguchi",24989467,"[Neural differentiation of pluripotent stem cells and application for metal-induced neural toxicity study].    Abstract:   Metals are effectively used in biological systems under the strict regulation for exploiting their specific and broad reactivities. For example, manganese (Mn) can induce catecholamines-mediated oxidative biological damage in cooperation with iron (Fe) and/or copper (Cu). In children, the damage could induce developmental disorders such as attention deficit hyperactivity disorder (ADHD). We hypothesize that infant neurons are more labile to metals than adult ones due to the prematured protection systems and sensitive differentiating cells. An experimental system reconstituting neural differentiation is expected to assess the influences of endogenous/exogenous factors including metals. In this study, we investigated an impact of Mn together with Fe and dopamine (DA) on neural differentiation of mouse embryonic stem cells (mESCs). The differentiation of mESCs was initiated by embryoid bodies (EBs) formation in the presence of all-trans retinoic acid, and then EBs were treated with Mn, Fe and/or DA. Then, the mRNA levels of neural differentiation marker genes (Nestin, Emx2, Mtap2, Th, Olig2 and Gfap) were examined using realtime RT-PCR analysis. Mn or DA alone reduced Mtap2, Th and Olig2 expression levels and increased Nestin. Moreover, combined treatment of Mn and DA also increased Nestin expression level. On the other hand, Fe alone reduced Mtap2, Th and Olig2 expression levels, and increased Emx2. Combined treatments of Fe with Mn or DA also tended to increase Emx2 expression level. These effects emerged at about 100 times less concentration than that inducing cytotoxicity in human neuroblastoma. The present study showed that Mn inhibits neural development, and that our mESCs system can be a useful tool to elucidate the toxicity mechanism as well as to evaluate the effects of metals and chemicals on differentiating cells."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I69,I69)","v":24928143},{"$f":"(LEN($J69) - LEN(SUBSTITUTE(LOWER($J69),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J69) - LEN(SUBSTITUTE(LOWER($J69),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J69) - LEN(SUBSTITUTE(LOWER($J69),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B69:D69)","v":3},2015,"ZebRA: An overview of retinoic acid signaling during zebrafish development.","Samarut",24928143,"ZebRA: An overview of retinoic acid signaling during zebrafish development.    Abstract:   Retinoic acid (RA), the main active vitamin A derivative, is crucial for embryo development, regulating cellular processes, embryo patterning and organogenesis. Many studies performed in mammalian or avian models have successfully undertaken the investigation of the role played by RA during embryogenesis. Since the early 1980s, the zebraﬁsh (Danio rerio) has emerged as a powerful developmental model to study the in vivo role of RA during embryogenesis. Unlike mammalian models, zebraﬁsh embryogenesis is external, not only allowing the observation of the translucent embryo from the earliest steps but also providing an easily accessible system for pharmacological treatment or genetic approaches. Therefore, zebraﬁsh research largely participates in deciphering the role of RA during development. This review aims at illustrating different concepts of RA signaling based on the research performed on zebraﬁsh. Indeed, RA action relies on a multitude of cross-talk with other signaling pathways and requires a coordinated, dynamic and ﬁne-regulation of its level and activity in both temporal and spatial dimensions. This review also highlights major advances that have been discovered using zebraﬁsh such as the observation of the RA gradient in vivo for the ﬁrst time, the effects of RA signaling in brain patterning, its role in establishing left-right asymmetry and its effects on the development of a variety of organs and tissues including the heart, blood, bone and fat. This review demonstrates that the zebraﬁsh is a convenient and powerful model to study retinoic acid signaling during vertebrate embryogenesis. This article is part of a Special Issue entitled: Nuclear receptors in animal development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I70,I70)","v":21482409},{"$f":"(LEN($J70) - LEN(SUBSTITUTE(LOWER($J70),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J70) - LEN(SUBSTITUTE(LOWER($J70),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J70) - LEN(SUBSTITUTE(LOWER($J70),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B70:D70)","v":3},2011,"The membrane receptor for plasma retinol-binding protein, a new type of cell-surface receptor.","Sun",21482409,"The membrane receptor for plasma retinol-binding protein, a new type of cell-surface receptor.    Abstract:   Vitamin A is essential for diverse aspects of life ranging from embryogenesis to the proper functioning of most adult organs. Its derivatives (retinoids) have potent biological activities such as regulating cell growth and differentiation. Plasma retinol-binding protein (RBP) is the specific vitamin A carrier protein in the blood that binds to vitamin A with high affinity and delivers it to target organs. A large amount of evidence has accumulated over the past decades supporting the existence of a cell-surface receptor for RBP that mediates cellular vitamin A uptake. Using an unbiased strategy, this specific cell-surface RBP receptor has been identified as STRA6, a multitransmembrane domain protein with previously unknown function. STRA6 is not homologous to any protein of known function and represents a new type of cell-surface receptor. Consistent with the diverse functions of vitamin A, STRA6 is widely expressed in embryonic development and in adult organ systems. Mutations in human STRA6 are associated with severe pathological phenotypes in many organs such as the eye, brain, heart, and lung. STRA6 binds to RBP with high affinity and mediates vitamin A uptake into cells. This review summarizes the history of the RBP receptor research, its expression in the context of known functions of vitamin A in distinct human organs, structure/function analysis of this new type of membrane receptor, pertinent questions regarding its very existence, and its potential implication in treating human diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I71,I71)","v":20842651},{"$f":"(LEN($J71) - LEN(SUBSTITUTE(LOWER($J71),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J71) - LEN(SUBSTITUTE(LOWER($J71),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J71) - LEN(SUBSTITUTE(LOWER($J71),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B71:D71)","v":3},2010,"The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis.","Pennimpede",20842651,"The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis.    Abstract:   Retinoic acid (RA) is a pleiotropic derivative of vitamin A, or retinol, which is responsible for all of the bioactivity associated with this vitamin. The teratogenic influences of vitamin A deficiency and excess RA in rodents were first observed more than 50 years ago. Efforts over the last 15-20 years have refined these observations by defining the molecular mechanisms that control RA availability and signaling during murine embryonic development. This review will discuss our current understanding of the role of RA in teratogenesis, with specific emphasis on the essential function of the RA catabolic CYP26 enzymes in preventing teratogenic consequences caused by uncontrolled distribution of RA. Particular focus will be paid to the RA-sensitive tissues of the caudal and cranial regions, the limb, and the testis, and how genetic mutation of factors controlling RA distribution have revealed important roles for RA during embryogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I72,I72)","v":19918803},{"$f":"(LEN($J72) - LEN(SUBSTITUTE(LOWER($J72),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J72) - LEN(SUBSTITUTE(LOWER($J72),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J72) - LEN(SUBSTITUTE(LOWER($J72),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B72:D72)","v":3},2010,"Genetics and development of neural tube defects.","Copp",19918803,"Genetics and development of neural tube defects.    Abstract:   Congenital defects of neural tube closure (neural tube defects; NTDs) are among the commonest and most severe disorders of the fetus and newborn. Disturbance of any of the sequential events of embryonic neurulation produce NTDs, with the phenotype (eg anencephaly, spina bifida) varying depending on the region of neural tube that remains open. While mutation of gt; 200 genes is known to cause NTDs in mice, the pattern of occurrence in humans suggests a multifactorial polygenic or oligogenic aetiology. This emphasizes the importance of gene-gene and gene-environment interactions in the origins of these defects. A number of cell biological functions are essential for neural tube closure, with defects of the cytoskeleton, cell cycle and molecular regulation of cell viability prominent among the mouse NTD mutants. Many transcriptional regulators and proteins that affect chromatin structure are also required for neural tube closure, although the downstream molecular pathways regulated by these proteins is unknown. Some key signalling pathways for NTDs have been identified: over-activation of sonic hedgehog signalling and loss of function in the planar cell polarity (non-canonical Wnt) pathway are potent causes of NTD, with requirements also for retinoid and inositol signalling. Folic acid supplementation is an effective method for primary prevention of a proportion of NTDs in both humans and mice, although the embryonic mechanism of folate action remains unclear. Folic acid-resistant cases can be prevented by inositol supplementation in mice, raising the possibility that this could lead to an additional preventive strategy for human NTDs in future."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I73,I73)","v":19651648},{"$f":"(LEN($J73) - LEN(SUBSTITUTE(LOWER($J73),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J73) - LEN(SUBSTITUTE(LOWER($J73),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J73) - LEN(SUBSTITUTE(LOWER($J73),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B73:D73)","v":3},2009,"Developmental basis of the rostro-caudal organization of the brainstem respiratory rhythm generator.","Champagnat",19651648,"Developmental basis of the rostro-caudal organization of the brainstem respiratory rhythm generator.    Abstract:   The Hox genetic network plays a key role in the anteroposterior patterning of the rhombencephalon at pre- and early-segmental stages of development of the neural tube. In the mouse, it controls development of the entire brainstem respiratory neuronal network, including the pons, the parafacial respiratory group (pFRG) and the pre-Bötzinger complex (preBötC). Inactivation of Krox20/Egr2 eliminates the pFRG activity, thereby causing life-threatening neonatal apnoeas alternating with respiration at low frequency. Another respiratory abnormality, the complete absence of breathing, is induced when neuronal synchronization fails to develop in the preBötC. The present paper summarizes data on a third type of respiratory deficits induced by altering Hox function at pontine levels. Inactivation of Hoxa2, the most rostrally expressed Hox gene in the hindbrain, disturbs embryonic development of the pons and alters neonatal inspiratory shaping without affecting respiratory frequency and apnoeas. The same result is obtained by the Phox2a(+/-) mutation modifying the number of petrosal chemoafferent neurons, by eliminating acetylcholinesterase and by altering Hox-dependent development of the pons with retinoic acid administration at embryonic day 7.5. In addition, embryos treated with retinoic acid provide a mouse model for hyperpnoeic episodic breathing, widely reported in pre-term neonates, young girls with Retts syndrome, patients with Joubert syndrome and adults with Cheyne-Stokes respiration. We conclude that specific respiratory deficits in vivo are assignable to anteroposterior segments of the brainstem, suggesting that the adult respiratory neuronal network is functionally organized according to the rhombomeric, Hox-dependent segmentation of the brainstem in embryos."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I74,I74)","v":17979744},{"$f":"(LEN($J74) - LEN(SUBSTITUTE(LOWER($J74),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J74) - LEN(SUBSTITUTE(LOWER($J74),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J74) - LEN(SUBSTITUTE(LOWER($J74),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B74:D74)","v":3},2007,"Prospective teratology of retinoic acid metabolic blocking agents (RAMBAs) and loss of CYP26 activity.","McCaffery",17979744,"Prospective teratology of retinoic acid metabolic blocking agents (RAMBAs) and loss of CYP26 activity.    Abstract:   All-trans retinoic acid (atRA) is the transcriptionally active product of vitamin A and induces gene expression via specific receptors at nM concentrations. Essential enzymes that regulate the local levels of atRA are the CYP26 members of the cytochrome P450 family, which catabolize atRA. Compounds that have been designed to inhibit these enzymes are known as Retinoic Acid Metabolic Blocking Agents (RAMBAs). Treatment with these compounds will raise endogenous atRA levels and may be therapeutic for the treatment of diseases that respond to high atRA concentrations, including several types of cancer as well as skin conditions such as psoriasis and acne. This review describes the mechanism of action of the RAMBAs and discusses the potential side effects of these compounds. atRA is highly teratogenic and the potential teratogenicity of the RAMBAs is described by comparison with the abnormalities resulting from null mutation of individual CYP26 genes. The possible effects of RAMBAs on the adult brain are also described that have the potential for harm but, in the right circumstances, may also be beneficial."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I75,I75)","v":17510980},{"$f":"(LEN($J75) - LEN(SUBSTITUTE(LOWER($J75),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J75) - LEN(SUBSTITUTE(LOWER($J75),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J75) - LEN(SUBSTITUTE(LOWER($J75),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B75:D75)","v":3},2007,"Regulatory factor X4 variant 3: a transcription factor involved in brain development and disease.","Zhang",17510980,"Regulatory factor X4 variant 3: a transcription factor involved in brain development and disease.    Abstract:   Regulatory factor X4 variant 3 (RFX4_v3) is a recently identified transcription factor specifically expressed in the brain. Gene disruption in mice demonstrated that interruption of a single allele (heterozygous, +/-) prevented formation of the subcommissural organ (SCO), resulting in congenital hydrocephalus, whereas interruption of two alleles (homozygous, -/-) caused fatal failure of dorsal midline brain structure formation. These mutagenesis studies implicated RFX4_v3 in early brain development as well as the genesis of the SCO. Rfx4_v3 deficiency presumably causes abnormalities in brain by altering the expression levels of many genes that are crucial for brain morphogenesis, such as the signaling components in the Wnt, bone morphogenetic protein, and retinoic acid pathways. RFX4_v3 might affect these critical signaling pathways in brain development. Cx3cl1, a chemokine gene highly expressed in brain, was identified as a direct target for RFX4_v3, indicating that RFX4_v3 possesses trans-acting activity to stimulate gene expression. Rfx4_v3 is highly expressed in the suprachiasmatic nucleus and might be involved in regulating the circadian clock. One haplotype in RFX4_v3 gene is linked to a higher risk of bipolar disorder, suggesting that this protein might contribute to the pathogenesis of the disease. This Mini-Review describes our current knowledge about RFX4_v3, an important protein that appears to be involved in many aspects of brain development and disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I76,I76)","v":12557202},{"$f":"(LEN($J76) - LEN(SUBSTITUTE(LOWER($J76),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J76) - LEN(SUBSTITUTE(LOWER($J76),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J76) - LEN(SUBSTITUTE(LOWER($J76),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B76:D76)","v":3},2003,"Retinoic acid, a regeneration-inducing molecule.","Maden",12557202,"Retinoic acid, a regeneration-inducing molecule.    Abstract:   Retinoic acid (RA) is the biologically active metabolite of vitamin A. It is a low molecular weight, lipophilic molecule that acts on the nucleus to induce gene transcription. In amphibians and mammals, it induces the regeneration of several tissues and organs and these examples are reviewed here. RA induces the quot;super-regenerationquot; of organs that can already regenerate such as the urodele amphibian limb by respecifying positional information in the limb. In organs that cannot normally regenerate such as the adult mammalian lung, RA induces the complete regeneration of alveoli that have been destroyed by various noxious treatments. In the mammalian central nervous system (CNS), which is another tissue that cannot regenerate, RA does not induce neurite outgrowth as it does in the embryonic CNS, because one of the retinoic acid receptors, RAR beta 2, is not up-regulated. When RAR beta 2 is transfected into the adult spinal cord in vitro, then neurite outgrowth is stimulated. In all these cases, RA is required for the development of the organ, in the first place suggesting that the same gene pathways are likely to be used for both development and regeneration. This suggestion, therefore, might serve as a strategy for identifying potential tissue or organ targets that have the capacity to be stimulated to regenerate."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I77,I77)","v":11604126},{"$f":"(LEN($J77) - LEN(SUBSTITUTE(LOWER($J77),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J77) - LEN(SUBSTITUTE(LOWER($J77),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J77) - LEN(SUBSTITUTE(LOWER($J77),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B77:D77)","v":3},2001,"Origins of anteroposterior patterning and Hox gene regulation during chordate evolution.","Schilling",11604126,"Origins of anteroposterior patterning and Hox gene regulation during chordate evolution.    Abstract:   All chordates share a basic body plan and many common features of early development. Anteroposterior (AP) regions of the vertebrate neural tube are specified by a combinatorial pattern of Hox gene expression that is conserved in urochordates and cephalochordates. Another primitive feature of Hox gene regulation in all chordates is a sensitivity to retinoic acid during embryogenesis, and recent developmental genetic studies have demonstrated the essential role for retinoid signalling in vertebrates. Two AP regions develop within the chordate neural tube during gastrulation: an anterior forebrain-midbrain region specified by Otx genes and a posterior hindbrain-spinal cord region specified by Hox genes. A third, intermediate region corresponding to the midbrain or midbrain-hindbrain boundary develops at around the same time in vertebrates, and comparative data suggest that this was also present in the chordate ancestor. Within the anterior part of the Hox-expressing domain, however, vertebrates appear to have evolved unique roles for segmentation genes, such as Krox-20, in patterning the hindbrain. Genetic approaches in mammals and zebrafish, coupled with molecular phylogenetic studies in ascidians, amphioxus and lampreys, promise to reveal how the complex mechanisms that specify the vertebrate body plan may have arisen from a relatively simple set of ancestral developmental components."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I78,I78)","v":11058754},{"$f":"(LEN($J78) - LEN(SUBSTITUTE(LOWER($J78),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J78) - LEN(SUBSTITUTE(LOWER($J78),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J78) - LEN(SUBSTITUTE(LOWER($J78),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B78:D78)","v":3},2000,"Amphibian choroid plexus lipocalin, Cpl1.","Lepperdinger",11058754,"Amphibian choroid plexus lipocalin, Cpl1.    Abstract:   Choroid plexus lipocalin 1 (Cpl1) has been isolated from the African clawed toad (Xenopus laevis) and the cane toad (Bufo marinus). Xcpl1 has been used as a marker for studying early neural development. Due to its retinoid binding properties and the fact that it causes dysmorphogenesis when overexpressed in the early embryo, the protein product is considered to be part of the retinoic acid signalling pathway. Later in development and during adulthood, the epithelial cell sheet of the choroid plexus which forms the blood-cerebrospinal fluid barrier expresses cpl1 as the predominant secretory protein. These data, the similarity of Cpl1 to prostaglandin D(2) synthase and its functional homology to transthyretin will be discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I79,I79)","v":10889064},{"$f":"(LEN($J79) - LEN(SUBSTITUTE(LOWER($J79),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J79) - LEN(SUBSTITUTE(LOWER($J79),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J79) - LEN(SUBSTITUTE(LOWER($J79),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B79:D79)","v":3},2000,"Retinoid signalling and hindbrain patterning.","Gavalas",10889064,"Retinoid signalling and hindbrain patterning.    Abstract:   Retinoid signalling has been implicated in regulating a wide variety of processes in vertebrate development. Recent advances from analyses on the synthesis, degradation and distribution of retinoids in combination with functional analysis of signalling components have provided important insights into the regulation of patterning the nervous system and the hindbrain in particular."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I80,I80)","v":9134036},{"$f":"(LEN($J80) - LEN(SUBSTITUTE(LOWER($J80),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J80) - LEN(SUBSTITUTE(LOWER($J80),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J80) - LEN(SUBSTITUTE(LOWER($J80),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B80:D80)","v":3},1997,"Retinoic acid, neoplasia, differentiation and development.","Berry",9134036,"Retinoic acid, neoplasia, differentiation and development.    Abstract:   Retinoic acid has pronounced effects on cultures of neoplastic cells. These have attracted the attention of pathologists, but it is important to note that much of the critical data about retinoic acid has been obtained from the current extension of our knowledge in the field of development. Some of these changes are reviewed here."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I81,I81)","v":8981600},{"$f":"(LEN($J81) - LEN(SUBSTITUTE(LOWER($J81),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J81) - LEN(SUBSTITUTE(LOWER($J81),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J81) - LEN(SUBSTITUTE(LOWER($J81),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B81:D81)","v":3},1996,"Similarities in genetic mental retardation and neuroteratogenic syndromes.","Adams",8981600,"Similarities in genetic mental retardation and neuroteratogenic syndromes.    Abstract:   Principles and mechanisms of neurobehavioral teratogenesis are used to show commonalities between manifestations of abnormal development consequent to genetic abnormality or teratogenic exposure. A comparison and contrast of both the neuropathological and neuropsychological characteristics of children with early embryonic exposure to isotretinoin (Accutane) or with selected mental retardation syndromes is presented. Putative mechanisms of retinoid teratogenesis through the disruption of normal retinoid-triggered embryogenesis and the alteration of homeobox gene expression are discussed. Interference with homeobox gene expression as an avenue to the perturbation of early developmental processes and the production of hindbrain and craniofacial abnormalities is then proposed as a common basis for the translation and expression of several genetic mental retardation syndromes. Finally, dose-response effects and other modulators of vulnerability to abnormal development are used to provide a conceptual framework for the understanding of variability in the expression of genetically caused abnormalities."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I82,I82)","v":8767511},{"$f":"(LEN($J82) - LEN(SUBSTITUTE(LOWER($J82),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J82) - LEN(SUBSTITUTE(LOWER($J82),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J82) - LEN(SUBSTITUTE(LOWER($J82),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B82:D82)","v":3},1996,"Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action.","Köhrle",8767511,"Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action.    Abstract:   Development and tissue-specific deiodination of thyroid hormone leads to both activation of the prohormone thyroxine to the thyromimetically active T3 as well as to inactivation of T3 and its conjugates or inactivation of T4 to yield potential regulatory active rT3. At least three deiodinase isoenzymes have so far been characterized and cloned, and the deiodinase isozymes represent a new family of eukaryotic selenoproteins for which an enzyme function could be assigned. Selenium status apparently regulates the expression of these deiodinase isozymes to different extent indicating that a hierarchy of selenium incorporation exists for those enzymes. Currently, it appears that selenium deficiency does not affect expression of type II 5-deiodinase or 5-deiodinase to a marked extent in vivo whereas type I 5-deiodinase at least in liver and kidney is reduced in severe selenium deficiency. However, daily selenium intake in normal mideuropeans already saturates the requirement for the expression of the deiodinase isoenzymes. So far, only reduced expression of 5-D I and decreased T 3 production has been observed in specific diets such as for PKU or in cystic fibrosis, where transport of ions (iodide, selenite?) might be affected. Further alterations of T3 production by 5-D I activity are observed under the conditions of the low T3 syndrome, which comprise a broad spectrum of clinical disorders from carbohydrate withdrawal to intensive care patients. It is not yet clear if selenium supplementation or T3 treatment is beneficial to these patients. The marked tissue-specificity of expression of the deiodinases requires more detailed examinations on the relation between these enzymes and the expression of thyroid hormone action, which is mediated by the nuclear T3 receptor family or receptors and signal transduction molecules in the mitochondria, plasma membrane, or cytoskeleton. The location of the deiodinase enzymes either at the inner side of the plasma membrane or the cytosolic side of the endoplasmic reticulum positions these enzymes to a strategically important location enabling them to act as gate-keepers to the nuclear receptors. Similar to other enzymes involved in the activation or inactivation of compounds with hormone or signalling function, the deiodinases are key elements in the intracrine regulation of hormone activation in target tissues or inactivation in non-target tissues. Therefore, a detailed molecular, cell biological and physiological analysis of the function, regulation and gene structure of these enzymes is required before a development of tissue- or enzyme-specific pharmacological intervention is possible. Nevertheless, first data indicate that reduced 5-deiodinase type I expression in tumor tissues can be re-induced by treatment with retinoids at least in follicular thyroid carcinoma. Further studies are needed to prove that retinoids might be a useful therapeutic tool for re-differentiation therapy of thyroid carcinoma which are inaccessible to surgical intervention or lack radio-iodide uptake and storage. The important function and regio- and cell-specific expression of deiodinase isozymes in the central nervous system is far from being understood. Current first evidence suggests a close interaction between thyroid hormone deiodination, thyroid hormone concentration, and expression of thyroid hormone responsive genes in the adult brain as well as tight regulation and interaction between thyroid hormone metabolism and neurotransmitter synthesis release and action."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I83,I83)","v":8603050},{"$f":"(LEN($J83) - LEN(SUBSTITUTE(LOWER($J83),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J83) - LEN(SUBSTITUTE(LOWER($J83),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J83) - LEN(SUBSTITUTE(LOWER($J83),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B83:D83)","v":3},1996,"Chicken ovalbumin upstream promoter-transcription factors and their regulation.","Qiu",8603050,"Chicken ovalbumin upstream promoter-transcription factors and their regulation.    Abstract:   COUP-TFs are orphan members of the steroid/thyroid hormone receptor superfamily. COUP-TF homologues have been cloned in several species, from Drosophila to man. The vertebrate COUP-TFs can be classified into four subgroups according to sequence homology in their ligand-binding domain. COUP-TFs bind to AGGTCA direct repeats or palindromes with various spacings. These include the response elements of several other members of the superfamily, the vitamin D receptor, the thyroid hormone receptor, the retinoic acid receptor, the retinoid X receptor, the peroxisome proliferation activated regulator, and the hepatocyte nuclear factor-4. COUP-TF response elements have been identified in the promoters of many genes and COUP-TFs have been shown to act as negative regulators both in vitro and in vivo. They can compete with the above mentioned receptors for binding to the common response elements. The ratio of COUP-TF and the other positive regulator determines the transcriptional state of the particular gene in any given moment. COUP-TFs are expressed in the developing central nervous system of mouse and zebra-fish. In addition, they are also expressed in many organs during mouse organogenesis. The expression pattern and profile of COUP-TFs favor the hypothesis that they are involved in development and differentiation. The expression of COUP-TFs are also highly regulated. P19 embryonal carcinoma cells have been used as a model system to study COUP-TF regulation. COUP-TFs are up-regulated in retinoic acid (RA) treated P19 cells. Transient transfection assay showed that mouse COUP-TFII promoter directly responded to RA treatment, suggesting that COUP-TF expression is directly regulated by RA signaling pathway."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I84,I84)","v":25558812},{"$f":"(LEN($J84) - LEN(SUBSTITUTE(LOWER($J84),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J84) - LEN(SUBSTITUTE(LOWER($J84),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J84) - LEN(SUBSTITUTE(LOWER($J84),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B84:D84)","v":2},2015,"Retinoic acid signaling and neuronal differentiation.","Janesick",25558812,"Retinoic acid signaling and neuronal differentiation.    Abstract:   The identification of neurological symptoms caused by vitamin A deficiency pointed to a critical, early developmental role of vitamin A and its metabolite, retinoic acid (RA). The ability of RA to induce post-mitotic, neural phenotypes in various stem cells, in vitro, served as early evidence that RA is involved in the switch between proliferation and differentiation. In vivo studies have expanded this quot;opposing signalquot; model, and the number of primary neurons an embryo develops is now known to depend critically on the levels and spatial distribution of RA. The proneural and neurogenic transcription factors that control the exit of neural progenitors from the cell cycle and allow primary neurons to develop are partly elucidated, but the downstream effectors of RA receptor (RAR) signaling (many of which are putative cell cycle regulators) remain largely unidentified. The molecular mechanisms underlying RA-induced primary neurogenesis in anamniote embryos are starting to be revealed; however, these data have been not been extended to amniote embryos. There is growing evidence that bona fide RARs are found in some mollusks and other invertebrates, but little is known about their necessity or functions in neurogenesis. One normal function of RA is to regulate the cell cycle to halt proliferation, and loss of RA signaling is associated with dedifferentiation and the development of cancer. Identifying the genes and pathways that mediate cell cycle exit downstream of RA will be critical for our understanding of how to target tumor differentiation. Overall, elucidating the molecular details of RAR-regulated neurogenesis will be decisive for developing and understanding neural proliferation-differentiation switches throughout development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I85,I85)","v":25398731},{"$f":"(LEN($J85) - LEN(SUBSTITUTE(LOWER($J85),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J85) - LEN(SUBSTITUTE(LOWER($J85),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J85) - LEN(SUBSTITUTE(LOWER($J85),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B85:D85)","v":2},2014,"Nutrition implications for fetal alcohol spectrum disorder.","Young",25398731,"Nutrition implications for fetal alcohol spectrum disorder.    Abstract:   Prenatal alcohol exposure produces a multitude of detrimental alcohol-induced defects in children collectively known as fetal alcohol spectrum disorder (FASD). Children with FASD often exhibit delayed or abnormal mental, neural, and physical growth. Socioeconomic status, race, genetics, parity, gravidity, age, smoking, and alcohol consumption patterns are all factors that may influence FASD. Optimal maternal nutritional status is of utmost importance for proper fetal development, yet is often altered with alcohol consumption. It is critical to determine a means to resolve and reduce the physical and neurological malformations that develop in the fetus as a result of prenatal alcohol exposure. Because there is a lack of information on the role of nutrients and prenatal nutrition interventions for FASD, the focus of this review is to provide an overview of nutrients (vitamin A, docosahexaenoic acid, folic acid, zinc, choline, vitamin E, and selenium) that may prevent or alleviate the development of FASD. Results from various nutrient supplementation studies in animal models and FASD-related research conducted in humans provide insight into the plausibility of prenatal nutrition interventions for FASD. Further research is necessary to confirm positive results, to determine optimal amounts of nutrients needed in supplementation, and to investigate the collective effects of multiple-nutrient supplementation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I86,I86)","v":23579094},{"$f":"(LEN($J86) - LEN(SUBSTITUTE(LOWER($J86),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J86) - LEN(SUBSTITUTE(LOWER($J86),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J86) - LEN(SUBSTITUTE(LOWER($J86),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B86:D86)","v":2},2013,"Retinoic acid signaling in spinal cord development.","Lara-Ramírez",23579094,"Retinoic acid signaling in spinal cord development.    Abstract:   Retinoic acid (RA) is an important signaling molecule mediating intercellular communication through vertebrate development. Here, we present and discuss recent information on the roles of the RA signaling pathway in spinal cord development. RA is an important player in the patterning and definition of the spinal cord territory from very early stages of development, even before the appearance of the neural plate and further serves a role in the patterning of the spinal cord both along the dorsoventral and anteroposterior axes, particularly in the promotion of neuronal differentiation. It is thus required to establish a variety of neuronal cell types at specific positions of the spinal cord. The main goal of this review is to gather information from vertebrate models, including fish, frogs, chicken and mice, and to put this information in a comparative context in an effort to visualize how the RA pathway was incorporated into the evolving vertebrate spinal cord and to identify mechanisms that are both common and different in the various vertebrate models. In doing so, we try to reconstruct how spinal cord development has been regulated by the RA signaling cascade through vertebrate diversification, highlighting areas which require further studies to obtain a better understanding of the evolutionary events that shaped this structure in the vertebrate lineage."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I87,I87)","v":23266215},{"$f":"(LEN($J87) - LEN(SUBSTITUTE(LOWER($J87),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J87) - LEN(SUBSTITUTE(LOWER($J87),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J87) - LEN(SUBSTITUTE(LOWER($J87),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B87:D87)","v":2},2012,"Dynamics and precision in retinoic acid morphogen gradients.","Schilling",23266215,"Dynamics and precision in retinoic acid morphogen gradients.    Abstract:   Retinoic acid (RA) regulates many cellular behaviors during embryonic development and adult homeostasis. Like other morphogens, RA forms gradients through the use of localized sources and sinks, feedback, and interactions with other signals; this has been particularly well studied in the context of hindbrain segmentation in vertebrate embryos. Yet, as a small lipophilic molecule derived from a dietary source-vitamin A-RA differs markedly from better-studied polypeptide morphogens in its mechanisms of transport, signaling, and removal. Computational models suggest that the distinctive features of RA gradients make them particularly robust to large perturbations. Such features include combined positive and negative feedback effects via intracellular fatty acid binding proteins and RA-degrading enzymes. Here, we discuss how these features, together with feedback interactions among RA target genes, help enable RA to specify multiple, accurate pattern elements in the developing hindbrain, despite operating in an environment of high cellular and biochemical uncertainty and noise."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I88,I88)","v":22945385},{"$f":"(LEN($J88) - LEN(SUBSTITUTE(LOWER($J88),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J88) - LEN(SUBSTITUTE(LOWER($J88),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J88) - LEN(SUBSTITUTE(LOWER($J88),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B88:D88)","v":2},2012,"Does the cranial mesenchyme contribute to neural fold elevation during neurulation?","Zohn",22945385,"Does the cranial mesenchyme contribute to neural fold elevation during neurulation?    Abstract:   The central nervous system is derived from the neural plate, which undergoes a series of complex morphogenetic events resulting in formation of the neural tube in a process known as neurulation. The cellular behaviors driving neurulation in the cranial region involve forces generated by the neural tissue itself as well as the surrounding epithelium and mesenchyme. Of interest, the cranial mesenchyme underlying the neural plate undergoes stereotypical rearrangements hypothesized to drive elevation of the neural folds. As the neural folds rise, the hyaluronate-rich extracellular matrix greatly expands resulting in increased space between individual cranial mesenchyme cells. Based on inhibitor studies, expansion of the extracellular matrix has been implicated in driving neural fold elevation; however, because the surrounding neural and epidermal ectoderm were also affected by inhibitor exposure, these studies are inconclusive. Similarly, treatment of neurulating embryos with teratogenic doses of retinoic acid results in altered organization of the cranial mesenchyme, but alterations in surrounding tissues are also observed. The strongest evidence for a critical role for the cranial mesenchyme in neural fold elevation comes from studies of genes expressed exclusively in the cranial mesenchyme that when mutated result in exencephaly associated with abnormal organization of the cranial mesenchyme. Twist is the best studied of these and is expressed in both the paraxial mesoderm and neural crest derived cranial mesenchyme. In this article, we review the evidence implicating the cranial mesenchyme in providing a driving force for neural fold elevation to evaluate whether there are sufficient data to support this hypothesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I89,I89)","v":22293229},{"$f":"(LEN($J89) - LEN(SUBSTITUTE(LOWER($J89),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J89) - LEN(SUBSTITUTE(LOWER($J89),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J89) - LEN(SUBSTITUTE(LOWER($J89),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B89:D89)","v":2},2012,"Therapeutic potential of motor neurons differentiated from embryonic stem cells and induced pluripotent stem cells.","López-González",22293229,"Therapeutic potential of motor neurons differentiated from embryonic stem cells and induced pluripotent stem cells.    Abstract:   Degeneration of motor neurons (MN) caused by disease or injury leads to paralysis and is fatal in some conditions. To date, there are no effective treatments for MN disorders; therefore, cell therapy is a promising strategy to replace lost MN. Embryonic stem (ES) cells isolated from the inner cell mass of mammalian blastocysts self-renew and are pluripotent because they differentiate into cell types of the three germinal layers. Reprogramming of adult cells to a state similar to ES cells, termed induced pluripotent stem (iPS) cells, has been recently reported. It is well established that pluripotent cell types can give rise to specialized phenotypes, including neurons. Mouse, monkey and human MN can be differentiated from ES and iPS cells using procedures generally involving embryoid bodies formation and stimulation with retinoic acid and Sonic hedgehog. Differentiated MN express characteristic molecular markers such as Islet1, HB9 and Choline acetyltransferase, exhibit electrophysiological maturity and are able to form synaptic contacts similar to neuromuscular junctions in vitro. Furthermore, transplanted MN promote functional recovery in animal models of neurodegenerative diseases and MN injury. The potential clinical applications of stem cell-derived MN was enhanced after iPS cell derivation, which makes possible the generation of patient-specific pluripotent cells for autologous cell replacement therapies and may be used for drug development and disease modeling. This review summarizes MN differentiation protocols from ES and iPS cells in regard to neuronal differentiation efficiency, expression of MN markers and functional properties in vitro, as well as their therapeutic effects after grafting."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I90,I90)","v":21664474},{"$f":"(LEN($J90) - LEN(SUBSTITUTE(LOWER($J90),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J90) - LEN(SUBSTITUTE(LOWER($J90),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J90) - LEN(SUBSTITUTE(LOWER($J90),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B90:D90)","v":2},2011,"Pyridoxine supply in human development.","Bowling",21664474,"Pyridoxine supply in human development.    Abstract:   Vitamin B(6) has an important role in the function of the human nervous system. Experimental data are not generally available on the role in human development, but significant conclusions may be made from studies of the effect of disorders of B(6) vitamer metabolism. Vitamin B(6) comprises seven compounds - pyridoxal, pyridoxine, pyridoxamine and their respective 5 phosphates. The common active form in human tissue is the 5-phosphate form of pyridoxal (PLP) most of which is found in muscle bound to phosphorylase. Like many vitamins, B(6) can function both as a co-enzyme and as a chaperone. Pyridoxal-5-phosphate is the metabolically active form and is involved in 100 enzymatic reactions including carbohydrate, amino acid, and fatty acid metabolism. There is evidence that in some situations B(6) vitamers can function as antioxidants. The fetus is dependent on the placenta for supply of vitamin B(6) and the demand correlates with amino acid metabolism. Few reports are available on the role of B(6) in embryogenesis. Studies of human disorders where B(6) metabolism is blocked show a major role in neurotransmitter function with secondary cerebral and cerebellar hypoplasia. Pyridoxine potentiates vitamin A teratogenicity and an excess leads to peripheral nerve cell degeneration. The key role of vitamin B(6) in the developing human is in metabolism, especially of the neurotransmitters."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I91,I91)","v":21495966},{"$f":"(LEN($J91) - LEN(SUBSTITUTE(LOWER($J91),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J91) - LEN(SUBSTITUTE(LOWER($J91),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J91) - LEN(SUBSTITUTE(LOWER($J91),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B91:D91)","v":2},2011,"Neural induction and patterning in Mammalian pluripotent stem cells.","Osakada",21495966,"Neural induction and patterning in Mammalian pluripotent stem cells.    Abstract:   Embryonic stem (ES) cells are derived from the inner cell mass (ICM) of blastocyst stage embryos, while induced pluripotent stem (iPS) cells are generated from somatic cells through transient overexpression of defined transcription factors. When transplanted into a preimplantation embryo, ES cells and iPS cells can differentiate into any cell type, including germ cells. Moreover, they can grow in culture indefinitely while maintaining pluripotency. In vitro differentiation of ES cells and iPS cells recapitulates many aspects of in vivo embryogenesis. The acquisition of neural fates (neural induction) in ES cells can be controlled by bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and Wnt signaling, while the production of specific neural cell types (neural patterning) can be controlled by exogenous patterning signals such as Wnt, BMP, Shh, FGF, and retinoic acid. In response to these signals, ES cells can differentiate into a wide range of neural cell types that correlate with their positions along the anterior-posterior and dorsal-ventral axes. ES cell and iPS cell culture systems will provide materials for cell replacement therapy, and can be used as in vitro models for disease and drug testing as well as development. Here we review spatiotemporal control of neural differentiation of mammalian pluripotent stem cells, with a special emphasis on the relationship between in vivo embryogenesis and in vitro ES cell differentiation. Retinal differentiation from ES cells and iPS cells is also outlined."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I92,I92)","v":20419766},{"$f":"(LEN($J92) - LEN(SUBSTITUTE(LOWER($J92),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J92) - LEN(SUBSTITUTE(LOWER($J92),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J92) - LEN(SUBSTITUTE(LOWER($J92),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B92:D92)","v":2},2010,"Epidemiologic and genetic aspects of spina bifida and other neural tube defects.","Au",20419766,"Epidemiologic and genetic aspects of spina bifida and other neural tube defects.    Abstract:   The worldwide incidence of neural tube defects (NTDs) ranges from 1.0 to 10.0 per 1,000 births with almost equal frequencies between two major categories: anencephaly and spina bifida (SB). Epidemiological studies have provided valuable insight for (a) researchers to identify nongenetic and genetic factors contributing to etiology, (b) public health officials to design and implement policies to prevent NTD pregnancies, and (c) individuals to take precautions to reduce the chance of having an NTD-affected pregnancy. Despite extensive research, our knowledge of the genetic etiology of human NTDs is limited. Although more than 200 small animal models with NTDs exist, most of these models do not replicate the human disease phenotype. Over a hundred candidate genes have been examined for risk association to human SB. The candidate genes studied include those important in folic acid metabolism, glucose metabolism, retinoid metabolism, and apoptosis. Many genes that regulate transcription in early embryogenesis and maintain planar cell polarity have also been tested as candidates. Additionally, genes identified through mouse models of NTDs have been explored as candidates. We do not know how many genes in the human genome may confer risk for NTDs in human. Less than 20% of the studied candidate genes have been determined to confer even a minor effect on risk association. Many studies have provided conflicting conclusions due to limitations in study design that potentially affect the power of statistical analysis. Future directions such as genomewide association studies (GWAS) and whole exome or even whole genome sequencing are discussed as possible avenues to identify genes that affect risk for human NTDs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I93,I93)","v":20233652},{"$f":"(LEN($J93) - LEN(SUBSTITUTE(LOWER($J93),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J93) - LEN(SUBSTITUTE(LOWER($J93),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J93) - LEN(SUBSTITUTE(LOWER($J93),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B93:D93)","v":2},2010,"Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance.","Su",20233652,"Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance.    Abstract:   Docosahexaenoic acid (DHA, 22:6n-3) is specifically enriched in the brain and mainly anchored in the neuronal membrane, where it is involved in the maintenance of normal neurological function. Most DHA accumulation in the brain takes place during brain development in the perinatal period. However, hippocampal DHA levels decrease with age and in the brain disorder Alzheimers disease (AD), and this decrease is associated with reduced hippocampal-dependent spatial learning memory ability. A potential mechanism is proposed by which the n-3 fatty acids DHA and eicosapentaenoic acid (20:5n-3) aid the development and maintenance of spatial learning memory performance. The developing brain or hippocampal neurons can synthesize and take up DHA and incorporate it into membrane phospholipids, especially phosphatidylethanolamine, resulting in enhanced neurite outgrowth, synaptogenesis and neurogenesis. Exposure to n-3 fatty acids enhances synaptic plasticity by increasing long-term potentiation and synaptic protein expression to increase the dendritic spine density, number of c-Fos-positive neurons and neurogenesis in the hippocampus for learning memory processing. In aged rats, n-3 fatty acid supplementation reverses age-related changes and maintains learning memory performance. n-3 fatty acids have anti-oxidative stress, anti-inflammation, and anti-apoptosis effects, leading to neuron protection in the aged, damaged, and AD brain. Retinoid signaling may be involved in the effects of DHA on learning memory performance. Estrogen has similar effects to n-3 fatty acids on hippocampal function. It would be interesting to know if there is any interaction between DHA and estrogen so as to provide a better strategy for the development and maintenance of learning memory."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I94,I94)","v":19032739},{"$f":"(LEN($J94) - LEN(SUBSTITUTE(LOWER($J94),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J94) - LEN(SUBSTITUTE(LOWER($J94),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J94) - LEN(SUBSTITUTE(LOWER($J94),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B94:D94)","v":2},2008,"Nevoid basal cell carcinoma syndrome (Gorlin syndrome).","Lo Muzio",19032739,"Nevoid basal cell carcinoma syndrome (Gorlin syndrome).    Abstract:   Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a hereditary condition characterized by a wide range of developmental abnormalities and a predisposition to neoplasms. The estimated prevalence varies from 1/57,000 to 1/256,000, with a male-to-female ratio of 1:1. Main clinical manifestations include multiple basal cell carcinomas (BCCs), odontogenic keratocysts of the jaws, hyperkeratosis of palms and soles, skeletal abnormalities, intracranial ectopic calcifications, and facial dysmorphism (macrocephaly, cleft lip/palate and severe eye anomalies). Intellectual deficit is present in up to 5% of cases. BCCs (varying clinically from flesh-colored papules to ulcerating plaques and in diameter from 1 to 10 mm) are most commonly located on the face, back and chest. The number of BBCs varies from a few to several thousand. Recurrent jaw cysts occur in 90% of patients. Skeletal abnormalities (affecting the shape of the ribs, vertebral column bones, and the skull) are frequent. Ocular, genitourinary and cardiovascular disorders may occur. About 5-10% of NBCCS patients develop the brain malignancy medulloblastoma, which may be a potential cause of early death. NBCCS is caused by mutations in the PTCH1 gene and is transmitted as an autosomal dominant trait with complete penetrance and variable expressivity. Clinical diagnosis relies on specific criteria. Gene mutation analysis confirms the diagnosis. Genetic counseling is mandatory. Antenatal diagnosis is feasible by means of ultrasound scans and analysis of DNA extracted from fetal cells (obtained by amniocentesis or chorionic villus sampling). Main differential diagnoses include Bazex syndrome, trichoepithelioma papulosum multiplex and Torres syndrome (Muir-Torres syndrome). Management requires a multidisciplinary approach. Keratocysts are treated by surgical removal. Surgery for BBCs is indicated when the number of lesions is limited; other treatments include laser ablation, photodynamic therapy and topical chemotherapy. Radiotherapy should be avoided. Vitamin A analogs may play a preventive role against development of new BCCs. Life expectancy in NBCCS is not significantly altered but morbidity from complications can be substantial. Regular follow-up by a multi-specialist team (dermatologist, neurologist and odontologist) should be offered. Patients with NBCCS should strictly avoid an excessive sun exposure."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I95,I95)","v":18816852},{"$f":"(LEN($J95) - LEN(SUBSTITUTE(LOWER($J95),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J95) - LEN(SUBSTITUTE(LOWER($J95),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J95) - LEN(SUBSTITUTE(LOWER($J95),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B95:D95)","v":2},2008,"How degrading: Cyp26s in hindbrain development.","White",18816852,"How degrading: Cyp26s in hindbrain development.    Abstract:   The vitamin A derivative retinoic acid performs many functions in vertebrate development and is thought to act as a diffusible morphogen that patterns the anterior-posterior axis of the hindbrain. Recent work in several systems has led to insights into how the spatial distribution of retinoic acid is regulated. These have shown local control of synthesis and degradation, and computational models suggest that degradation by the Cyp26 enzymes plays a critical role in the formation of a morphogen gradient as well as its ability to compensate for fluctuations in RA levels."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I96,I96)","v":18071033},{"$f":"(LEN($J96) - LEN(SUBSTITUTE(LOWER($J96),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J96) - LEN(SUBSTITUTE(LOWER($J96),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J96) - LEN(SUBSTITUTE(LOWER($J96),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B96:D96)","v":2},2007,"Functional implication of the vitamin A signaling pathway in the brain.","Tafti",18071033,"Functional implication of the vitamin A signaling pathway in the brain.    Abstract:   Vitamin A is necessary for normal embryonic development, but its role in the adult brain is poorly understood. Vitamin A derivatives, retinoids, are involved in a complex signaling pathway that regulates gene expression and, in the central nervous system, controls neuronal differentiation and neural tube patterning. Although a major functional implication of retinoic signaling has been repeatedly suggested in synaptic plasticity, learning and memory, sleep, schizophrenia, depression, Parkinson disease, and Alzheimer disease, the targets and the underlying mechanisms in the adult brain remain elusive."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I97,I97)","v":17560195},{"$f":"(LEN($J97) - LEN(SUBSTITUTE(LOWER($J97),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J97) - LEN(SUBSTITUTE(LOWER($J97),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J97) - LEN(SUBSTITUTE(LOWER($J97),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B97:D97)","v":2},2007,"Stephen L. Gans Distinguished Overseas Lecture. The neural crest in pediatric surgery.","Tovar",17560195,"Stephen L. Gans Distinguished Overseas Lecture. The neural crest in pediatric surgery.    Abstract:    AIM : This review highlights the relevance of the neural crest (NC) as a developmental control mechanism involved in several pediatric surgical conditions and the investigative interest of following some of its known signaling pathways.  METHODS : The participation of the NC in facial clefts, ear defects, branchial fistulae and cysts, heart outflow tract and aortic arch anomalies, pigmentary disorders, abnormal enteric innervation, neural tumors, hemangiomas, and vascular anomalies is briefly reviewed. Then, the literature on clinical and experimental esophageal atresia-tracheoesophageal fistula (EA-TEF) and congenital diaphragmatic hernia (CDH) is reviewed for the presence of associated NC defects. Finally, some of the molecular signaling pathways involved in both conditions (sonic hedgehog, Hox genes, and retinoids) are summarized.  RESULTS : The association of facial, cardiovascular, thymic, parathyroid, and C-cell defects together with anomalies of extrinsic and intrinsic esophageal innervation in babies and/or animals with both EA-TEF and CDH strongly supports the hypothesis that NC is involved in the pathogenesis of these malformative clusters. On the other hand, both EA-TEF and CDH are observed in mice mutant for genes involved in the previously mentioned signaling pathways.  CONCLUSIONS : The investigation of NC-related molecular pathogenic pathways involved in malformative associations like EA-TEF and CDH that are induced by chromosomal anomalies, chemical teratogens, and engineered mutations is a promising way of clarifying why and how some pediatric surgical conditions occur. Pediatric surgeons should be actively involved in these investigations."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I98,I98)","v":16860961},{"$f":"(LEN($J98) - LEN(SUBSTITUTE(LOWER($J98),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J98) - LEN(SUBSTITUTE(LOWER($J98),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J98) - LEN(SUBSTITUTE(LOWER($J98),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B98:D98)","v":2},2007,"A speculative essay on retinoic acid regulation of neural stem cells in the developing and aging olfactory system.","Rawson",16860961,"A speculative essay on retinoic acid regulation of neural stem cells in the developing and aging olfactory system.    Abstract:   Circulating signals like the acidic derivative of vitamin A: retinoic acid (RA) may regulate resident stem cells in the adult nervous system, particularly in the olfactory pathway. RA is an essential factor for inducing neural stem or precursor cells that give rise to olfactory receptor neurons (ORNs) and olfactory bulb (OB) interneurons (OBINs) during embryonic development. Similar precursors in the adult brain constantly generate new ORNs and OBINs, and embryonic signaling pathways, like that via RA, may be retained or reactivated for this purpose. We have shown that RA regulates neural precursors in the embryonic and adult olfactory pathway. Moreover, RA administration after olfactory system damage stimulates an immune response and yields a more rapid recovery of olfactory-guided behavior. We suggest that olfactory integrity may be maintained by RA-mediated regulation of neurogenesis as well as local immune responses, and that aging compromises these mechanisms. The chemical senses, particularly olfaction, decline in aged individuals, and RA (via vitamin A) levels may also decline, perhaps due to changes in appetite and food intake. This synergy may result in a high prevalence of olfactory pathology in aged individuals."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I99,I99)","v":16688759},{"$f":"(LEN($J99) - LEN(SUBSTITUTE(LOWER($J99),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J99) - LEN(SUBSTITUTE(LOWER($J99),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J99) - LEN(SUBSTITUTE(LOWER($J99),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B99:D99)","v":2},2006,"Retinoids and nonvertebrate chordate development.","Fujiwara",16688759,"Retinoids and nonvertebrate chordate development.    Abstract:   Retinoic acid (RA) is required for the differentiation and morphogenesis of chordate-specific features, such as the antero-posterior regionalization of the dorsal hollow nerve cord and neural crest cells. RA receptors (RARs) have been reported exclusively in chordates, suggesting that the acquisition of the RAR gene was important for chordate evolution. A scenario is presented here for the establishment of an RAR-mediated developmental regulatory system during the course of chordate evolution. In the common chordate ancestor, RAR came to control the spatial expression pattern of Hox genes in the ectoderm and endoderm along the antero-posterior axis. In these germ layers, RA was required for the differentiation of epidermal sensory neurons and the morphogenesis of pharyngeal gill slits, respectively. As the diffuse epidermal nerve net in the chordate ancestor became centralized to form the dorsal nerve cord, the epidermal Hox expression pattern was carried into the central nervous system. Because the Hox code here came to specify neuronal identity along the antero-posterior axis, RA became inextricably linked to the antero-posterior patterning of the chordate central nervous system."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I100,I100)","v":16429120},{"$f":"(LEN($J100) - LEN(SUBSTITUTE(LOWER($J100),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J100) - LEN(SUBSTITUTE(LOWER($J100),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J100) - LEN(SUBSTITUTE(LOWER($J100),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B100:D100)","v":2},2006,"Mechanisms of ventral patterning in the vertebrate nervous system.","Lupo",16429120,"Mechanisms of ventral patterning in the vertebrate nervous system.    Abstract:   Dorsoventral patterning of the neural tube has a crucial role in shaping the functional organization of the CNS. It is well established that hedgehog signalling plays a key role in specifying ventral cell types throughout the neuroectoderm, and major progress has been made in elucidating how hedgehog signalling works in this ventral specification. In addition, other molecular pathways, including nodal, retinoic acid and fibroblast growth factor signalling, have been identified as important molecular cues for ventral patterning of the spinal cord, telencephalon and eye. Here, we discuss recent advances in this field, highlighting the emerging interplay of these signalling pathways in the molecular specification of ventral patterning at different rostrocaudal levels of the CNS."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I101,I101)","v":15955577},{"$f":"(LEN($J101) - LEN(SUBSTITUTE(LOWER($J101),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J101) - LEN(SUBSTITUTE(LOWER($J101),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J101) - LEN(SUBSTITUTE(LOWER($J101),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B101:D101)","v":2},2005,"Retinoic acid induction of ES-cell-derived neurons: the radial glia connection.","Glaser",15955577,"Retinoic acid induction of ES-cell-derived neurons: the radial glia connection.    Abstract:   Neuronal induction by retinoic acid (RA) is commonly used in embryonic stem (ES) cell differentiation. Two recent papers show that this paradigm induces a population of neurogenic precursors with properties of radial glia. Upon differentiation, RA-treated cells give rise to a defined and developmentally restricted neuronal lineage. This role of RA in cell fate specification provides new perspectives for studying the radial glia-neuron transition and for generating homogenous populations of neurons from ES cells."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I102,I102)","v":15838445},{"$f":"(LEN($J102) - LEN(SUBSTITUTE(LOWER($J102),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J102) - LEN(SUBSTITUTE(LOWER($J102),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J102) - LEN(SUBSTITUTE(LOWER($J102),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B102:D102)","v":2},2005,"Congenital oculomotor nerve synkinesis associated with fetal retinoid syndrome.","Morrison",15838445,"Congenital oculomotor nerve synkinesis associated with fetal retinoid syndrome.    Abstract:    INTRODUCTION : Isotretinoin (RA), used for the treatment of cystic acne, is a powerful teratogen, causing craniofacial dysmorphisms and neural tube defects. We present two patients with RA embryopathy and oculomotor nerve synkinesis.  METHODS : Retrospective review of patient records.  RESULTS : Two patients presented with third nerve synkinesis and fetal RA exposure. Both had marked elevation of the upper eyelids on adduction such that the lid fissures alternately opened and closed on gaze from side to side. Both patients showed typical dysmorphisms of RA embryopathy. The first patient had complete agenesis of the cerebellar vermix and died at 2 years. The second patient had restricted extraocular muscles in one eye and was exotropic and hypotropic.  DISCUSSION : Both patients demonstrated simultaneous innervation of the medial rectus and levator palpebrae muscles causing coincident lid elevation in adduction. This evidence of oculomotor nerve synkinesis is consistent with animal studies showing abnormalities in the formation of cranial nerve ganglia following fetal RA exposure.  CONCLUSION : RA is a powerful teratogen. These patients provide additional clinical evidence of its influence on neural migration during early development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I103,I103)","v":15543094},{"$f":"(LEN($J103) - LEN(SUBSTITUTE(LOWER($J103),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J103) - LEN(SUBSTITUTE(LOWER($J103),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J103) - LEN(SUBSTITUTE(LOWER($J103),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B103:D103)","v":2},2004,"Possible pathomechanisms of sudden infant death syndrome: key role of chronic hypoxia, infection/inflammation states, cytokine irregularities, and metabolic trauma in genetically predisposed infants.","Prandota",15543094,"Possible pathomechanisms of sudden infant death syndrome: key role of chronic hypoxia, infection/inflammation states, cytokine irregularities, and metabolic trauma in genetically predisposed infants.    Abstract:   Chronic hypoxia, viral infections/bacterial toxins, inflammation states, biochemical disorders, and genetic abnormalities are the most likely trigger of sudden infant death syndrome (SIDS). Autopsy studies have shown increased pulmonary density of macrophages and markedly more eosinophils in the lungs accompanied by increased T and B lymphocytes. The elevated levels of immunoglobulins, about 20% more muscle in the pulmonary arteries, increased airway smooth muscle cells, and increased fetal hemoglobin and erythropoietin are evidence of chronic hypoxia before death. Other abnormal findings included mucosal immune stimulation of the tracheal wall, duodenal mucosa, and palatine tonsils, and circulating interferon. Low normal or higher blood levels of cortisol often with petechiae on intrathoracic organs, depleted maternal IgG antibodies to endotoxin core (EndoCAb) and early IgM EndoCAb triggered, partial deletions of the C4 gene, and frequent IL-10-592*A polymorphism in SIDS victims as well as possible hypoxia-induced decreased production of antiinflammatory, antiimmune, and antifibrotic cytokine IL-10, may be responsible for the excessive reactions to otherwise harmless infections. In SIDS infants, during chronic hypoxia and times of infection/inflammation, several proinflammatory cytokines are released in large quantities, sometimes also representing a potential source of tissue damage if their production is not sufficiently well controlled, eg, by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). These proinflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting metabolism of several endogenous lipophilic substances, such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances. In SIDS victims, chronic hypoxia, TNF-alpha and other inflammatory cytokines, and arachidonic acid (AA) as well as n-3 polyunsaturated fatty acids (FA), stimulated and/or augmented superoxide generation by polymorphonuclear leukocytes, which contributed to tissue damage. Chronic hypoxia, increased amounts of nonheme iron in the liver and adrenals of these infants, enhanced activity of CYP2C9 regarded as the functional source of reactive oxygen species (ROS) in some endothelial cells, and nicotine accumulation in tissues also intensified production of ROS. These increased quantities of proinflammatory cytokines, ROS, AA, and nitric oxide (NO) also resulted in suppression of many CYP450 and other enzymes, eg, phosphoenolpyruvate carboxykinase (PEPCK), an enzyme important in the metabolism of FA during gluconeogenesis and glyceroneogenesis. PEPCK deficit found in SIDS infants (caused also by vitamin A deficiency) and eventually enhanced by PACAP lipolysis of adipocyte triglycerides resulted in an increased FA level in blood because of their impaired reesterification to triacylglycerol in adipocytes. In turn, the overproduction and release of FA into the blood of SIDS victims could lead to the metabolic syndrome and an early phase of type 2 diabetes. This is probably the reason for the secondary overexpression of the hepatic CYP2C8/9 content and activity reported in SIDS infants, which intensified AA metabolism. Pulmonary edema and petechial hemorrhages often present in SIDS victims may be the result of the vascular leak syndrome caused by IL-2 and IFN-alpha. Chronic hypoxia with the release of proinflammatory mediators IL-1alpha, IL-1beta and IL-6, and overloading of the cardiovascular and respiratory systems due to the narrowing airways and small pulmonary arteries of these children could also contribute to the development of these abnormalities. Moreover, chronic hypoxia of SIDS infants induced also production of hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulated synthesis and release of different growth factors by vascular endothelial cells and intensified subclinical inflammatory reactions in the central nervous system, perhaps potentiated also by PACAP and VIP gene mutations. These processes could lead to the development of brainstem gliosis and disorders in the release of neuromediators important for physiologic sleep regulation. All these changes as well as eventual PACAP abnormalities could result in disturbed homeostatic control of the cardiovascular and respiratory responses of SIDS victims, which, combined with the nicotine effects and metabolic trauma, finally lead to death in these often genetically predisposed children."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I104,I104)","v":15273988},{"$f":"(LEN($J104) - LEN(SUBSTITUTE(LOWER($J104),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J104) - LEN(SUBSTITUTE(LOWER($J104),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J104) - LEN(SUBSTITUTE(LOWER($J104),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B104:D104)","v":2},2004,"Opposing FGF and retinoid pathways: a signalling switch that controls differentiation and patterning onset in the extending vertebrate body axis.","Diez del Corral",15273988,"Opposing FGF and retinoid pathways: a signalling switch that controls differentiation and patterning onset in the extending vertebrate body axis.    Abstract:   Construction of the trunk/caudal region of the vertebrate embryo involves a set of distinct molecules and processes whose relationships are just coming into focus. In addition to the subdivision of the embryo into head and trunk domains, this quot;caudalisationquot; process requires the establishment and maintenance of a stem zone. This sequentially generates caudal tissues over a long period which then undergo differentiation and patterning in the extending body axis. Here we review recent studies that show that changes in the signalling properties of the paraxial mesoderm act as a switch that controls onset of differentiation and pattern in the spinal cord. These findings identify distinct roles for different caudalising factors; in particular, Fibroblast Growth Factor (FGF) inhibits differentiation in the caudal stem zone, while Retinoic acid (RA) provided rostrally by somitic mesoderm is required for neuronal differentiation and establishment of ventral neural pattern. Furthermore, the mutual opposition of FGF and RA pathways controls not only neural differentiation but also mesoderm segmentation and might also underlie the progressive assignment of rostrocaudal identity by regulating Hox gene availability and activation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I105,I105)","v":12867709},{"$f":"(LEN($J105) - LEN(SUBSTITUTE(LOWER($J105),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J105) - LEN(SUBSTITUTE(LOWER($J105),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J105) - LEN(SUBSTITUTE(LOWER($J105),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B105:D105)","v":2},2003,"Acquisition of retinoic acid signaling pathway and innovation of the chordate body plan.","Fujiwara",12867709,"Acquisition of retinoic acid signaling pathway and innovation of the chordate body plan.    Abstract:   Retinoic acid (RA) regulates many of the chordate-specific and vertebrate-specific characters. These include the anteroposterior pattern of the dorsally located central nervous system, pharynx with gill slits, neural crest cells, limb morphogenesis and anteroposteriorly organized vertebrae. The necessity of endogenous RA and the RA receptor (RAR) has been demonstrated by mutant analyses, vitamin A-deficient animals and various other methods. Since RAR has been identified only in chordates, the acquisition of the RAR-mediated RA signaling pathway is thought to be an important event for the innovation of the chordate body plan. RA-synthesizing aldehyde dehydrogenases and RA-degrading enzymes also seem to be chordate-specific. The expression pattern of these genes in ascidian embryos is similar to that in vertebrate embryos. These results suggest that the RA signaling cascade, with various regulators and modifiers, had been already well established in the common chordate ancestor. RA also regulates morphogenesis during the asexual reproduction of ascidians, suggesting that RA may also have played a part in producing diversity within the chordate groups."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I106,I106)","v":12848275},{"$f":"(LEN($J106) - LEN(SUBSTITUTE(LOWER($J106),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J106) - LEN(SUBSTITUTE(LOWER($J106),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J106) - LEN(SUBSTITUTE(LOWER($J106),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B106:D106)","v":2},2003,"The potential role for arachidonic and docosahexaenoic acids in protection against some central nervous system injuries in preterm infants.","Crawford",12848275,"The potential role for arachidonic and docosahexaenoic acids in protection against some central nervous system injuries in preterm infants.    Abstract:   The risk of central nervous, visual, and auditory damage increases from 2/1000 live births in the normal birthweight to gt; 200/1000 as birthweight falls below 1500 g. Such babies are most likely to be born preterm. Advances in infant care have led to increasing numbers of very-low-birthweight, preterm infants surviving to school age with moderate to severe brain damage. Steroids are one of the current treatments, but they cause significant, long-term problems. The evidence reported here suggests an additional approach to protecting the very preterm infant by supporting neurovascular membrane integrity. The complications of preterm, very-low-birthweight babies include bronchopulmonary dysplasia, retinopathy of prematurity, intraventricular hemorrhage, periventricular leukomalacia, and necrotizing enterocolitis, all of which have a vascular component. Arachidonic acid (AA) and DHA are essential, structural, and functional constituents of cell membranes. They are especially required for the growth and function of the brain and vascular systems, which are the primary biofocus of human fetal growth. Molecular dynamics and experimental evidence suggest that DHA could be the ligand for the retinoid X receptor (RXR) in neural tissue. RXR activation is an obligatory step in signaling to the nucleus and in the regulation of gene expression. Very preterm babies are born with minimal fat stores and suboptimal circulating levels of these nutrients. Postnatally, they lose the biomagnification of the proportions of AA and DHA by the placenta for the fetus. No current nutritional management repairs these deficits. The placental biomagnification profile highlights AA rather than DHA. The resultant fetal FA profile closely resembles that of the vascular endothelium and not the brain. Without this nourishment, cell membrane abnormalities would be predicted. We present a scientific rationale for a common pathogenic process in the complications of prematurity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I107,I107)","v":11814548},{"$f":"(LEN($J107) - LEN(SUBSTITUTE(LOWER($J107),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J107) - LEN(SUBSTITUTE(LOWER($J107),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J107) - LEN(SUBSTITUTE(LOWER($J107),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B107:D107)","v":2},2002,"ArRAnging the hindbrain.","Gavalas",11814548,"ArRAnging the hindbrain.    Abstract:   The retinoic acid (RA)-dependent mechanisms that orchestrate the development of the hindbrain have been the focus of intense studies over the last decade. A wide range of model systems and experimental approaches have been used to provide important insights into hindbrain patterning. A recent paper could help to unify seemingly disparate observations across species and experimental approaches. Specification of the entire caudal hindbrain is fully dependent on retinoic acid, and specification of individual rhombomeres (r) follows a strict rostrocaudal sequence at precise developmental time windows. Progressively higher RA signalling is necessary for assigning more posterior territories. Complete RA deficiency results in the caudal hindbrain assuming an r4-like identity, which is postulated to be the hindbrain ground state."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I108,I108)","v":11545254},{"$f":"(LEN($J108) - LEN(SUBSTITUTE(LOWER($J108),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J108) - LEN(SUBSTITUTE(LOWER($J108),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J108) - LEN(SUBSTITUTE(LOWER($J108),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B108:D108)","v":2},2001,"Embryonic stem cell-derived neurogenesis. Retinoic acid induction and lineage selection of neuronal cells.","Guan",11545254,"Embryonic stem cell-derived neurogenesis. Retinoic acid induction and lineage selection of neuronal cells.    Abstract:   Embryonic stem (ES) cells are able to differentiate in vitro into endodermal, mesodermal, and ectodermal cell types. However. the spontaneous development of neuronal cells from ES cells is rather limited. Therefore, specific protocols to increase the differentiation of neuronal cells have been established, such as retinoic acid (RA) induction and lineage selection of neuronal cells. High concentrations of RA resulted in efficient neuronal differentiation paralleled by the expression of tissue-specific genes, proteins, ion channels, and receptors in a developmentally controlled manner. Because the developmental pattern and survival capacity of RA-induced neuronal cells were limited, specific differentiation protocols by lineage selection of neuronal cells have been established using growth and extracellular matrix factors. After formation of cells of the three primary germ layers, mesodermal differentiation was inhibited by serum depletion, and neural precursor cells were generated by addition of basic fibroblast growth factor, followed by differentiation induction by neuronal differentiation factors. Further application of survival-promoting factors such as neurotrophic factors and cytokines at terminal stages resulted in a significant increase, survival, and maintenance of dopaminergic neurons. In the future, these cellular systems will be applicable: (1) for studying commitment and neuronal specification in vitro, (2) as pharmacological assays for drug screening, and (3) for the selective isolation of differentiated neuronal cells which may be used as a source for cell and tissue grafts."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I109,I109)","v":11420972},{"$f":"(LEN($J109) - LEN(SUBSTITUTE(LOWER($J109),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J109) - LEN(SUBSTITUTE(LOWER($J109),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J109) - LEN(SUBSTITUTE(LOWER($J109),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B109:D109)","v":2},2001,"Retinoic acid synthesis and breakdown in the developing mouse retina.","Dräger",11420972,"Retinoic acid synthesis and breakdown in the developing mouse retina.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I110,I110)","v":11376439},{"$f":"(LEN($J110) - LEN(SUBSTITUTE(LOWER($J110),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J110) - LEN(SUBSTITUTE(LOWER($J110),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J110) - LEN(SUBSTITUTE(LOWER($J110),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B110:D110)","v":2},2000,"Molecular determinants of neural crest migration.","Maschhoff",11376439,"Molecular determinants of neural crest migration.    Abstract:   Normal septation of the cardiac outflow tract requires migration of neural crest cells from the posterior rhombencephalon to the branchial arches and developing conotruncal endocardial cushions. Proper migration of these cells is mediated by a variety of molecular cues. Adhesion molecules, such as integrins, are involved in the interaction of neural crest cells with the extracellular matrix, while cadherins allow neural crest cells to interact with each other during their migration. Pax3 appears to be important for proliferation of neural crest precursors, and connexin-43-mediated gap junction communication influences the rate of migration. Endothelin and its receptors are required for normal postmigratory differentiation. Platelet-derived growth factor and retinoic acid have roles in neural crest migration and differentiation as well. Finally, the similarity between the cardiovascular malformations seen in the DiGeorge and 22q11 deletion syndromes and animal models of neural crest deficiency has led to the examination of the role of genes located near or within the DiGeorge critical region in neural crest migration."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I111,I111)","v":11131523},{"$f":"(LEN($J111) - LEN(SUBSTITUTE(LOWER($J111),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J111) - LEN(SUBSTITUTE(LOWER($J111),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J111) - LEN(SUBSTITUTE(LOWER($J111),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B111:D111)","v":2},2001,"Neural patterning in the vertebrate embryo.","Altmann",11131523,"Neural patterning in the vertebrate embryo.    Abstract:   The embryonic central nervous system (CNS) is patterned along its antero-posterior, dorsal-ventral, and left-right axes. Along the dorsal-ventral axis, cell fate determination occurs during and following neural tube closure and involves the action of two opposing signaling pathways: SHH ventrally from the notochord and BMP/GDF dorsally from the boundary of neural and nonneural ectoderm and later from the roof plate. In addition, Wnt and retinoic acid signaling have been shown to act in dorsal-ventral patterning; however, their roles are understood in less detail. Along the antero-posterior axis, signals divide the neural tube into four major divisions: forebrain, midbrain, hindbrain, and spinal cord, and these differences can be detected soon after the formation of the neural plate. The FGF, Wnt, and retinoic acid signaling pathways have been implicated in the caudalization of neural tissue. Boundaries of Hox gene expression are observed along the anteroposterior axis and have been suggested to be involved in establishing different identities in the hindbrain and spinal cord. Complex gene expression patterns in the brain suggest the development of neuromeres dividing the brain into different regions that are elaborated further during development. Patterning along the left-right axis occurs concurrently with antero-posterior and dorsal-ventral patterning during gastrulation. A leading candidate for initiating asymmetry is activin, which acts through Nodal and Lefty before any morphological differences are observed. The big challenge will be understanding how these diverse signaling pathways interact both temporally and spatially to generate the complex adult nervous system."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I112,I112)","v":10817966},{"$f":"(LEN($J112) - LEN(SUBSTITUTE(LOWER($J112),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J112) - LEN(SUBSTITUTE(LOWER($J112),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J112) - LEN(SUBSTITUTE(LOWER($J112),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B112:D112)","v":2},2000,"Regulation of retinoic acid signaling in the embryonic nervous system: a master differentiation factor.","McCaffery",10817966,"Regulation of retinoic acid signaling in the embryonic nervous system: a master differentiation factor.    Abstract:   This review describes some of the properties of retinoic acid (RA) in its functions as a locally synthesized differentiation factor for the developing nervous system. The emphasis is on the characterization of the metabolic enzymes that synthesize and inactivate RA, and which determine local RA concentrations. These enzymes create regions of autocrine and paracrine RA signaling in the embryo. One mechanism by which RA can act as a differentiation agent is through the induction of growth factors and their receptors. Induction of growth factor receptors in neural progenitor cells can lead to growth factor dependency, and the consequent developmental fate of the cell will depend on the local availability of growth factors. Because RA activates the early events of cell differentiation, which then induce context-specific differentiation programs, RA may be called a master differentiation factor."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I113,I113)","v":10394471},{"$f":"(LEN($J113) - LEN(SUBSTITUTE(LOWER($J113),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J113) - LEN(SUBSTITUTE(LOWER($J113),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J113) - LEN(SUBSTITUTE(LOWER($J113),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B113:D113)","v":2},1999,"Forebrain induction, retinoic acid, and vulnerability to schizophrenia: insights from molecular and genetic analysis in developing mice.","LaMantia",10394471,"Forebrain induction, retinoic acid, and vulnerability to schizophrenia: insights from molecular and genetic analysis in developing mice.    Abstract:   Schizophrenia is thought to be a disease of early development that ultimately affects forebrain neurons and circuits. There may be a relationship between disrupted forebrain development; malformations of the limb, face, and heart; and signaling via the steroid-like hormone retinoic acid (RA) in some schizophrenic patients. The limbs, face, heart, and forebrain all develop from sites where neural crest-derived, RA-producing mesenchyme contributes to induction and differentiation of adjacent epithelia. Induction between neural crest-derived, RA-producing mesenchyme, the anterior neural tube, and the anterior surface epithelium of the embryo guides regional differentiation and pathway formation during forebrain development. Furthermore, there are at least two mouse mutations--in the Pax-6 and Gli-3 genes--that cause peripheral malformations and specifically disrupt neural crest mediated, RA-dependent induction and differentiation in the forebrain. These observations suggest that induction might provide a common target for genes that alter morphogenesis of peripheral structures, disrupt RA-signaling, and compromise forebrain development. In the forebrain, some of these disruptions might influence the numbers or cellular properties of neurons and circuits. Such changes might be reflected in the aberrant forebrain function that characterizes schizophrenia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I114,I114)","v":9184328},{"$f":"(LEN($J114) - LEN(SUBSTITUTE(LOWER($J114),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J114) - LEN(SUBSTITUTE(LOWER($J114),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J114) - LEN(SUBSTITUTE(LOWER($J114),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B114:D114)","v":2},1997,"Prorhombomeric subdivision of the mammalian embryonic hindbrain: is it functionally meaningful?","Ruberte",9184328,"Prorhombomeric subdivision of the mammalian embryonic hindbrain: is it functionally meaningful?    Abstract:   The technique of whole embryo culture has made significant contributions to understanding the mechanisms of morphogenesis in mammalian embryos, especially with respect to cranial neurulation and neural crest cell migration. This study traces the fate of two specifically mammalian structures, the preotic and otic sulci. Their formation at the 1/2- and 3-somite stages respectively, divides the hindbrain neuroepithelium into prorhombomeres A, B and C. The preotic sulcus is a deeply recessed structure that forms the rostral boundary of expression of both Hoxb-2 and the first domain of Krox-20. The otic sulcus is a shallow concavity in which the second Krox-20 domain is expressed. DiI labeling followed by whole embryo culture confirmed that the later fate of the preotic sulcus is the rhombomere 2/3 boundary, and the fate of the otic sulcus is the cranial part of rhombomere 5. Structurally, the preotic and otic sulci show no specialization with respect to actin, tubulin or proteoglycans, but their maintenance depends on contact with the subjacent mesenchyme. Their formation is inhibited by exposure of embryos to retinoic acid prior to the onset of somitic segmentation, indicating that the molecular events governing prorhombomeric subdivision of the hindbrain are retinoic acid-sensitive. The preotic sulcus may be essential for neuroepithelial cell movement towards and into the rapidly enlarging forebrain; the otic sulcus may simply delineate the caudal boundary of prorhombomere B, an area with a discrete neural crest cell population discontinuous with those rostral and caudal to it. Understanding the positional relationships of the preotic and otic sulci to later rhombomeric segments makes them useful landmarks for experimental purposes, but there is no evidence that prorhombomeres are functionally significant as the precursors of rhombomeric segments."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I115,I115)","v":9276994},{"$f":"(LEN($J115) - LEN(SUBSTITUTE(LOWER($J115),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J115) - LEN(SUBSTITUTE(LOWER($J115),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J115) - LEN(SUBSTITUTE(LOWER($J115),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B115:D115)","v":2},1997,"Nutritional metabolic diseases of poultry and disorders of the biological antioxidant defence system.","Mézes",9276994,"Nutritional metabolic diseases of poultry and disorders of the biological antioxidant defence system.    Abstract:   Deficiencies or disturbances of nutrition cause a variety of diseases and can arise in different ways. The amount of a particular nutrient in the diet may be insufficient to meet the requirements, the diet may contain substances that inactivate the nutrient or inhibit its absorption/utilisation, or metabolism may be upset by the interaction of dietary and environmental factors. Peroxidation of lipids or oxygen free radical generation in general is a physiological process important for cell metabolism, division and differentiation and also for the biosynthesis of hormones and prostaglandins. Free radicals generated through these processes are effectively scavenged by the antioxidant defence system. Uncontrolled lipid oxidation caused by disturbances of that system may play a crucial role in some important poultry diseases and toxicoses. The first route of lipid peroxide loading of the organism is via the feed, such as through oxidised lipids. Oxidised fatty acids are absorbed from the intestine mainly in the form of unsaturated keto compounds and initiate lipid peroxidation in the tissues. The second problem is the insufficient amount of antioxidants in the feed, e.g. vitamin E deficiency. Nutritional encephalomalacia is a problem in poultry production which depends both on the actual vitamin E supply and the dietary amount of polyunsaturated fatty acids. In young birds the primary target of vitamin E deficiency is the brain because it contains low amounts of vitamin E, and the vitamin E content of the liver acting as store decreases rapidly during the first week of life. Besides vitamin E, other components of the antioxidant system, e.g. the antioxidant enzymes (catalase and glutathione peroxidase) also have low activity in the brain as compared to other major tissues. The brain is highly susceptible to oxidative stress because of the accumulation of polyunsaturated fatty acids. The third source of free radical generation is the toxic level of different feed ingredients, e.g. toxicoses caused by vitamin A, selenium, and ionophore antibiotics. Other important aspects of antioxidants (e.g. vitamin E and selenium) in poultry are stimulation of the immune response (e.g. in the case of vaccination) and reduction of the risks of free radical formation as a result of macrophage function."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I116,I116)","v":2663306},{"$f":"(LEN($J116) - LEN(SUBSTITUTE(LOWER($J116),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J116) - LEN(SUBSTITUTE(LOWER($J116),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J116) - LEN(SUBSTITUTE(LOWER($J116),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B116:D116)","v":2},1989,"Deleterious effects of drugs on the developing nervous system.","Dodson",2663306,"Deleterious effects of drugs on the developing nervous system.    Abstract:   In the past two decades, several categories of drugs have emerged as serious neuroteratogens. These include vitamin A congeners, isotretinoin and etretinate, certain antiepileptic drugs, especially trimethadione, and valproic acid. Other antiepileptic drugs have low teratogenic potential and variably affect the developing CNS. When multiple antiepileptics are administered during pregnancy, however, the risk to the fetus increases considerably."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I117,I117)","v":3074910},{"$f":"(LEN($J117) - LEN(SUBSTITUTE(LOWER($J117),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J117) - LEN(SUBSTITUTE(LOWER($J117),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J117) - LEN(SUBSTITUTE(LOWER($J117),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B117:D117)","v":2},1988,"Teratogens and craniofacial malformations: relationships to cell death.","Sulik",3074910,"Teratogens and craniofacial malformations: relationships to cell death.    Abstract:   Environmental agents including ethanol, 13-cis retinoic acid (RA, Accutane), the antimetabolite methotrexate, periods of hypoxia, ionizing radiation or hyperthermic stress, when administered acutely to pregnant experimental animals, induce stage-dependent craniofacial malformations comparable to those in corresponding human teratogen syndromes. Acute treatment regimens have allowed analysis of cell populations initially affected and subsequent dysmorphogenetic sequences as well as speculation relative to mechanisms of teratogenesis. In rodent models, ethanol and RA appear to affect similar cell populations and comparable malformations can be induced by both agents. When administered during gastrulation they cause a major insult to the anterior neural plate which results in characteristic ocular, brain and facial malformations comparable to those seen in the fetal alcohol syndrome. Exposure to these drugs at a time just prior to and during neural crest cell migration into the craniofacial and cervical regions results in malformations comparable to those seen in the Di-George sequence and/or retinoic acid embryopathy. Slightly later, at the time that the epibranchial placodes are active, insult results in mandibulofacial dysostosis-like syndromes. We propose that the pattern of these malformations is related to the particular vulnerability of cells in the vicinity of normal programmed cell death. Cell death is also associated with ionizing radiation and hyperthermia-induced malformations. Both of these teratogens are particularly damaging to the early development of the eye and central nervous system. Teratogenic temperature elevations result in arrest of mitotic activity and death of cells in mitosis. Hypoxia is also associated with cell death in specific regions and subsequent malformation. For example, death of cells in the invaginating olfactory placode has recently been associated with cleft lip formation. The relationship of hypoxia-induced cell death to energy requirements is being explored. Acute treatment with methotrexate results in frontonasal dysplasia (median facial clefts). Combined effects of fluid imbalance, lack of proliferation or death of frontonasal mesenchyme appear to be involved. Although the mechanisms of craniofacial malformation are complex, a common feature for many is excessive cell death for which the embryo may be unable to compensate. Excessive cell death in regions of programmed cell death represents an important, yet little appreciated, mechanism of teratogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I118,I118)","v":400679},{"$f":"(LEN($J118) - LEN(SUBSTITUTE(LOWER($J118),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J118) - LEN(SUBSTITUTE(LOWER($J118),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J118) - LEN(SUBSTITUTE(LOWER($J118),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B118:D118)","v":2},1979,"Binding proteins for retinol in retina and pigment epithelium.","Maraini",400679,"Binding proteins for retinol in retina and pigment epithelium.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I119,I119)","v":26043871},{"$f":"(LEN($J119) - LEN(SUBSTITUTE(LOWER($J119),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J119) - LEN(SUBSTITUTE(LOWER($J119),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J119) - LEN(SUBSTITUTE(LOWER($J119),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B119:D119)","v":1},2015,"Neural crest derivatives in ocular development: discerning the eye of the storm.","Williams",26043871,"Neural crest derivatives in ocular development: discerning the eye of the storm.    Abstract:   Neural crest cells (NCCs) are vertebrate-specific transient, multipotent, migratory stem cells that play a crucial role in many aspects of embryonic development. These cells emerge from the dorsal neural tube and subsequently migrate to different regions of the body, contributing to the formation of diverse cell lineages and structures, including much of the peripheral nervous system, craniofacial skeleton, smooth muscle, skin pigmentation, and multiple ocular and periocular structures. Indeed, abnormalities in neural crest development cause craniofacial defects and ocular anomalies, such as Axenfeld-Rieger syndrome and primary congenital glaucoma. Thus, understanding the molecular regulation of neural crest development is important to enhance our knowledge of the basis for congenital eye diseases, reflecting the contributions of these progenitors to multiple cell lineages. Particularly, understanding the underpinnings of neural crest formation will help to discern the complexities of eye development, as these NCCs are involved in every aspect of this process. In this review, we summarize the role of ocular NCCs in eye development, particularly focusing on congenital eye diseases associated with anterior segment defects and the interplay between three prominent molecules, PITX2, CYP1B1, and retinoic acid, which act in concert to specify a population of neural crest-derived mesenchymal progenitors for migration and differentiation, to give rise to distinct anterior segment tissues. We also describe recent findings implicating this stem cell population in ocular coloboma formation, and introduce recent evidence suggesting the involvement of NCCs in optic fissure closure and vascular development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I120,I120)","v":25332098},{"$f":"(LEN($J120) - LEN(SUBSTITUTE(LOWER($J120),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J120) - LEN(SUBSTITUTE(LOWER($J120),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J120) - LEN(SUBSTITUTE(LOWER($J120),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B120:D120)","v":1},2015,"The gene regulatory networks underlying formation of the auditory hindbrain.","Willaredt",25332098,"The gene regulatory networks underlying formation of the auditory hindbrain.    Abstract:   Development and evolution of auditory hindbrain nuclei are two major unsolved issues in hearing research. Recent characterization of transgenic mice identified the rhombomeric origins of mammalian auditory nuclei and unraveled genes involved in their formation. Here, we provide an overview on these data by assembling them into rhombomere-specific gene regulatory networks (GRNs), as they underlie developmental and evolutionary processes. To explore evolutionary mechanisms, we compare the GRNs operating in the mammalian auditory hindbrain with data available from the inner ear and other vertebrate groups. Finally, we propose that the availability of genomic sequences from all major vertebrate taxa and novel genetic techniques for non-model organisms provide an unprecedented opportunity to investigate development and evolution of the auditory hindbrain by comparative molecular approaches. The dissection of the molecular mechanisms leading to auditory structures will also provide an important framework for auditory processing disorders, a clinical problem difficult to tackle so far. These data will, therefore, foster basic and clinical hearing research alike."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I121,I121)","v":24902666},{"$f":"(LEN($J121) - LEN(SUBSTITUTE(LOWER($J121),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J121) - LEN(SUBSTITUTE(LOWER($J121),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J121) - LEN(SUBSTITUTE(LOWER($J121),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B121:D121)","v":1},2015,"Segregating neural and mechanosensory fates in the developing ear: patterning, signaling, and transcriptional control.","Raft",24902666,"Segregating neural and mechanosensory fates in the developing ear: patterning, signaling, and transcriptional control.    Abstract:   The vertebrate inner ear is composed of multiple sensory receptor epithelia, each of which is specialized for detection of sound, gravity, or angular acceleration. Each receptor epithelium contains mechanosensitive hair cells, which are connected to the brainstem by bipolar sensory neurons. Hair cells and their associated neurons are derived from the embryonic rudiment of the inner ear epithelium, but the precise spatial and temporal patterns of their generation, as well as the signals that coordinate these events, have only recently begun to be understood. Gene expression, lineage tracing, and mutant analyses suggest that both neurons and hair cells are generated from a common domain of neural and sensory competence in the embryonic inner ear rudiment. Members of the Shh, Wnt, and FGF families, together with retinoic acid signals, regulate transcription factor genes within the inner ear rudiment to establish the axial identity of the ear and regionalize neurogenic activity. Close-range signaling, such as that of the Notch pathway, specifies the fate of sensory regions and individual cell types. We also describe positive and negative interactions between basic helix-loop-helix and SoxB family transcription factors that specify either neuronal or sensory fates in a context-dependent manner. Finally, we review recent work on inner ear development in zebrafish, which demonstrates that the relative timing of neurogenesis and sensory epithelial formation is not phylogenetically constrained."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I122,I122)","v":24315941},{"$f":"(LEN($J122) - LEN(SUBSTITUTE(LOWER($J122),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J122) - LEN(SUBSTITUTE(LOWER($J122),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J122) - LEN(SUBSTITUTE(LOWER($J122),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B122:D122)","v":1},2014,"Active signals, gradient formation and regional specificity in neural induction.","Pera",24315941,"Active signals, gradient formation and regional specificity in neural induction.    Abstract:   The question of how the vertebrate embryo gives rise to a nervous system is of paramount interest in developmental biology. Neural induction constitutes the earliest step in this process and is tightly connected with development of the embryonic body axes. In the Xenopus embryo, perpendicular gradients of BMP and Wnt signals pattern the dorsoventral and anteroposterior body axes. Both pathways need to be inhibited to allow anterior neural induction to occur. FGF8 and IGF are active neural inducers that together with BMP and Wnt signals are integrated at the level of Smad 1/5/8 phosphorylation. Hedgehog (Hh) also contributes to anterior neural induction. Suppressor-of-fused plays an important role in intertwining the Hh and Wnt pathways. Distinct mechanisms are discussed that establish morphogen gradients and integrate retinoic acid and FGF signals during posterior development. These findings not only improve our understanding of regional specification in neural induction, but have profound implications for mammalian stem cell research and regenerative medicine."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I123,I123)","v":24125182},{"$f":"(LEN($J123) - LEN(SUBSTITUTE(LOWER($J123),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J123) - LEN(SUBSTITUTE(LOWER($J123),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J123) - LEN(SUBSTITUTE(LOWER($J123),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B123:D123)","v":1},2014,"The midkine family of growth factors: diverse roles in nervous system formation and maintenance.","Winkler",24125182,"The midkine family of growth factors: diverse roles in nervous system formation and maintenance.    Abstract:    UNLABELLEDMidkines are heparin-binding growth factors involved in a wide range of biological processes. Originally identified as retinoic acid inducible genes, midkines are widely expressed during embryogenesis with particularly high levels in the developing nervous system. During postnatal stages, midkine expression generally ceases but is often up-regulated under disease conditions, most notably those affecting the nervous system. Midkines are known as neurotrophic factors, as they promote neurite outgrowth and neuron survival in cell culture. Surprisingly, however, mouse embryos deficient for midkine (knockout mice) are phenotypically normal, which suggests functional redundancy by related growth factors. During adult stages, on the other hand, midkine knockout mice develop striking deficits in neuroprotection and regeneration after drug-induced neurotoxicity and injury. The detailed mechanisms by which midkine controls neuron formation, differentiation and maintenance remain unclear. Recent studies in zebrafish and chick have provided important insight into the role of midkine and its putative receptor, anaplastic lymphoma kinase, in cell cycle control in the central and peripheral nervous systems. A recent structural analysis of zebrafish midkine furthermore revealed essential protein domains required for biological activity that serve as promising novel targets for future drug designs. This review will summarize latest findings in the field that help to better understand the diverse roles of midkine in nervous system formation and maintenance.  LINKED ARTICLES : This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I124,I124)","v":24029702},{"$f":"(LEN($J124) - LEN(SUBSTITUTE(LOWER($J124),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J124) - LEN(SUBSTITUTE(LOWER($J124),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J124) - LEN(SUBSTITUTE(LOWER($J124),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B124:D124)","v":1},2013,"Revisiting the role of GCNF in embryonic development.","Wang",24029702,"Revisiting the role of GCNF in embryonic development.    Abstract:   GCNF (NR6A1) is essential for embryonic development. GCNF belongs to the nuclear receptor (NR) gene family, it is distantly related to other NRs and is the only member of subfamily 6. As the ligand for GCNF has not been identified, GCNF is designated an orphan nuclear receptor. GCNF has been found to be a transcriptional repressor, through specific binding to DR0 response elements, which is found in the Oct4 proximal promoter for example. GCNF is expressed widely in early mouse embryos, and later in the developing nervous system. GCNF knockout mouse embryos die around E10.5. GCNF is required for the restriction of Oct4 expression to primordial germ cells after gastrulation. GCNF is expressed in ES/EC cells and during their differentiation, and has been reported to be required for pluripotency gene repression during retinoic acid (RA)-induced mES cell differentiation. GCNF can interact with DNA methylation proteins, and is suggested to recruit DNA methylation complexes to repress and silence Oct4 expression. Nuclear receptor regulation in embryonic development is a complex process, as different nuclear receptors have overlapping and distinct functions. In-depth exploration of GCNF function and mechanism of action will help to comprehensively understand the nuclear receptor regulation in embryonic development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I125,I125)","v":23390117},{"$f":"(LEN($J125) - LEN(SUBSTITUTE(LOWER($J125),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J125) - LEN(SUBSTITUTE(LOWER($J125),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J125) - LEN(SUBSTITUTE(LOWER($J125),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B125:D125)","v":1},2014,"Mid-hindbrain malformations due to drugs taken during pregnancy.","Merlini",23390117,"Mid-hindbrain malformations due to drugs taken during pregnancy.    Abstract:   Although genetic defects are the leading cause of central nervous system malformations including in the posterior fossa, specific malformative patterns should alert the clinician to consider rather a teratogenic etiology. We discuss the imaging features of 2 mid-hindbrain malformations consecutive to the intake of isotretinoin (Roaccuatane®; case 1) and misoprostol (Cytotec®; case 2) during pregnancy and review the pertinent literature. We correlate the morphological appearance of the mid-hindbrain malformation, as seen on high-resolution magnetic resonance imaging to possible drug-induced pathogenetical mechanisms. The recognition of characteristic imaging patterns enables diagnosis of and/or confirmation of suspected drug-induced hindbrain malformations. This has important medicolegal implications and also clinical significance to avoid unsuccessful and misleading genetic testing."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I126,I126)","v":22771225},{"$f":"(LEN($J126) - LEN(SUBSTITUTE(LOWER($J126),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J126) - LEN(SUBSTITUTE(LOWER($J126),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J126) - LEN(SUBSTITUTE(LOWER($J126),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B126:D126)","v":1},2012,"Influence of mineral and vitamin supplements on pregnancy outcome.","Hovdenak",22771225,"Influence of mineral and vitamin supplements on pregnancy outcome.    Abstract:   The literature was searched for publications on minerals and vitamins during pregnancy and the possible influence of supplements on pregnancy outcome. Maternal iron (Fe) deficiency has a direct impact on neonatal Fe stores and birth weight, and may cause cognitive and behavioural problems in childhood. Fe supplementation is recommended to low-income pregnant women, to pregnant women in developing countries, and in documented deficiency, but overtreatment should be avoided. Calcium (Ca) deficiency is associated with pre-eclampsia and intra-uterine growth restriction. Supplementation may reduce both the risk of low birth weight and the severity of pre-eclampsia. Gestational magnesium (Mg) deficiency may cause hematological and teratogenic damage. A Cochrane review showed a significant low birth weight risk reduction in Mg supplemented individuals. Intake of cereal-based diets rich in phytate, high intakes of supplemental Fe, or any gastrointestinal disease, may interfere with zinc (Zn) absorption. Zn deficiency in pregnant animals may limit fetal growth. Supplemental Zn may be prudent for women with poor gastrointestinal function, and in Zn deficient women, increasing birth weight and head circumference, but no evidence was found for beneficial effects of general Zn supplementation during pregnancy. Selenium (Se) is an antioxidant supporting humoral and cell-mediated immunity. Low Se status is associated with recurrent abortion, pre-eclampsia and IUGR, and although beneficial effects are suggested there is no evidence-based recommendation for supplementation. An average of 20-30% of pregnant women suffer from any vitamin deficiency, and without prophylaxis, about 75% of these would show a deficit of at least one vitamin. Vitamin B6 deficiency is associated with pre-eclampsia, gestational carbohydrate intolerance, hyperemesis gravidarum, and neurologic disease of infants. About 25% of pregnant women in India are folate deficient. Folate deficiency may lead to congenital malformations (neural tube damage, orofacial clefts, cardiac anomalies), anaemia and spontaneous abortions, and pre-eclampsia, IUGR and abruption placentae. Pregestational supplementation of folate prevents neural tube defects. A daily supplemental dose of 400 μg/day of folate is recommended when planning pregnancy. In developing countries diets are generally low in animal products and consequently in vitamin B12 content. An insufficient supply may cause reduced fetal growth. In vegetarian women, supplementation of vitamin B12 may be needed. Vitamin A deficiency is prevalent in the developing world, impairing Fe status and resistance to infections. The recommended upper limit for retinol supplements is 3000 IU/day. Vitamin A supplementation enhances birth weight and growth in infants born to HIV-infected women. Overdosing should be avoided. Low concentrations of vitamin C seem to increase the development of pre-eclampsia, and supplementation may be beneficial. Supplementation with vitamin D in the third trimester in vitamin D deficient women seems to be beneficial. The use of vitamins E, although generally considered quot;healthyquot;, may be harmful to the pregnancy outcome by disrupting a physiologic oxidative gestational state and is consequently not recommended to prevent pre-eclampsia. Further studies on specific substances are needed as the basis for stratified, placebo-controlled analyses."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I127,I127)","v":22595346},{"$f":"(LEN($J127) - LEN(SUBSTITUTE(LOWER($J127),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J127) - LEN(SUBSTITUTE(LOWER($J127),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J127) - LEN(SUBSTITUTE(LOWER($J127),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B127:D127)","v":1},2012,"The neural crest in cardiac congenital anomalies.","Keyte",22595346,"The neural crest in cardiac congenital anomalies.    Abstract:   This review discusses the function of neural crest as they relate to cardiovascular defects. The cardiac neural crest cells are a subpopulation of cranial neural crest discovered nearly 30 years ago by ablation of premigratory neural crest. The cardiac neural crest cells are necessary for normal cardiovascular development. We begin with a description of the crest cells in normal development, including their function in remodeling the pharyngeal arch arteries, outflow tract septation, valvulogenesis, and development of the cardiac conduction system. The cells are also responsible for modulating signaling in the caudal pharynx, including the second heart field. Many of the molecular pathways that are known to influence specification, migration, patterning and final targeting of the cardiac neural crest cells are reviewed. The cardiac neural crest cells play a critical role in the pathogenesis of various human cardiocraniofacial syndromes such as DiGeorge, Velocardiofacial, CHARGE, Fetal Alcohol, Alagille, LEOPARD, and Noonan syndromes, as well as Retinoic Acid Embryopathy. The loss of neural crest cells or their dysfunction may not always directly cause abnormal cardiovascular development, but are involved secondarily because crest cells represent a major component in the complex tissue interactions in the head, pharynx and outflow tract. Thus many of the human syndromes linking defects in the heart, face and brain can be better understood when considered within the context of a single cardiocraniofacial developmental module with the neural crest being a key cell type that interconnects the regions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I128,I128)","v":23362027},{"$f":"(LEN($J128) - LEN(SUBSTITUTE(LOWER($J128),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J128) - LEN(SUBSTITUTE(LOWER($J128),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J128) - LEN(SUBSTITUTE(LOWER($J128),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B128:D128)","v":1},2011,"Prenatal exposures associated with neurodevelopmental delay and disabilities.","Diav-Citrin",23362027,"Prenatal exposures associated with neurodevelopmental delay and disabilities.    Abstract:   Neurobehavioral teratology refers to the study of the abnormal development of the structure and the behavioral functions of the central nervous system, which result from exposure to exogenous agents during prenatal development. The focus of this review is the effects of various prenatal exposures on human neurodevelopment. Studies that deal with the adverse effects of infectious agents (rubella, cytomegalovirus, and toxoplasma), teratogenic drugs (e.g., antiepileptic drugs such as phenytoin, valproate, and carbamazepine, coumarin derivatives, and retinoids), alcohol, and other substances of abuse will be reviewed. Additionally, prenatal exposure to industrial or environmental chemicals (e.g., lead, methylmercury, and polycarbonated biphenyls) as well as exposure of the embryo or fetus to high amounts of ionizing radiation will be addressed. Possible mechanisms of selected neurobehavioral teratogens will also be discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I129,I129)","v":21872806},{"$f":"(LEN($J129) - LEN(SUBSTITUTE(LOWER($J129),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J129) - LEN(SUBSTITUTE(LOWER($J129),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J129) - LEN(SUBSTITUTE(LOWER($J129),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B129:D129)","v":1},2011,"Vitamin D and the brain.","Harms",21872806,"Vitamin D and the brain.    Abstract:   Vitamin D is a member of the superfamily of nuclear steroid transcription regulators and as such, exerts transcriptional control over a large number of genes. Several other steroids, such as thyroid hormones, vitamin A, androgens and the glucocorticoids, are known as neurosteroids and their role in brain development and function is well defined. It has only been in the last decade or so that vitamin D has been thought to function as a neurosteroid. In this review we have collated a diverse array of data describing the presence of vitamin D metabolites and the receptor in the brain, the evidence that vitamin D may be an important modulator of brain development, and the potential role of vitamin D in neurological and neuropsychiatric disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I130,I130)","v":21189687},{"$f":"(LEN($J130) - LEN(SUBSTITUTE(LOWER($J130),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J130) - LEN(SUBSTITUTE(LOWER($J130),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J130) - LEN(SUBSTITUTE(LOWER($J130),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B130:D130)","v":1},2010,"The role of quaking in mammalian embryonic development.","Justice",21189687,"The role of quaking in mammalian embryonic development.    Abstract:   Functional studies of the mouse quaking gene (Qk) have focused on its role in the postnatal central nervous system during myelination. However, the death of the majority of homozygous mouse quaking alleles revealed that quaking has a critical role in embryonic development prior to the start of myelination. Surprisingly, the lethal alleles revealed that quaking has a function in embryonic blood vessel formation and remodeling. Further studies ofthe extraembryonic yolk sac showed that Qk regulates visceral endoderm differentiated function at the cellular level, including the local synthesis of retinoic acid (RA), which then exerts paracrine control of endothelial cells within adjacent mesoderm. Endoderm-derived RA regulates proliferation of endothelial cells and extracellular matrix (ECM) production, which in a reciprocal manner, modulates visceral endoderm survival and function. Although exogenous RA can rescue endothelial cell growth control and ECM production in mutants carrying a lethal mutation, which lack functional Qk, neither visceral endoderm function nor vascular remodeling is restored. Thus, Qk also regulates cell autonomous functions of visceral endoderm that are critical for vascular remodeling. Interestingly, quaking is highly expressed during normal cardiac development, particularly in the outflow tract, suggesting potentially unique functions in the developing heart. Together, the work on Qk in mammalian embryos reveals an essential, yet under appreciated, role in cardiovascular development. This suggests that certain functions may remain conserved in the early embryo throughout the evolution of nonvertebrate and vertebrate organisms and that additional roles for quaking remain to be discovered."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I131,I131)","v":21044078},{"$f":"(LEN($J131) - LEN(SUBSTITUTE(LOWER($J131),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J131) - LEN(SUBSTITUTE(LOWER($J131),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J131) - LEN(SUBSTITUTE(LOWER($J131),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B131:D131)","v":1},2011,"α-secretase in Alzheimers disease: molecular identity, regulation and therapeutic potential.","Lichtenthaler",21044078,"α-secretase in Alzheimers disease: molecular identity, regulation and therapeutic potential.    Abstract:   Ectodomain shedding of the amyloid precursor protein (APP) by the metalloprotease activity α-secretase is a key regulatory event preventing the generation of the Alzheimers disease (AD) amyloid β peptide. Proteases similar to α-secretase are essential for diverse physiological processes, such as embryonic development, cell adhesion and neuronal guidance. Previously, several proteases were suggested as candidate α-secretases for APP, in particular members of the ADAM family (a disintegrin and metalloprotease). Two recent studies analyzed primary neurons, which are the cell type affected in AD, and finally demonstrated that the constitutively cleaving α-secretase activity is selectively mediated by ADAM10. An increase in α-secretase cleavage is considered a therapeutic approach for AD. However, the molecular mechanisms regulating α-secretase cleavage remain only partly understood. Signaling pathways activating protein kinase C and MAP kinase play a central role in stimulating α-secretase cleavage of APP. Additionally, several recent publications demonstrate that ADAM10 expression and α-secretase cleavage of APP are tightly controlled at the level of transcription, e.g. by retinoic acid receptors and sirtuins, and at the level of translation and protein trafficking. This review focuses on the recent progress made in unraveling the molecular identity, regulation and therapeutic potential of α-secretase in Alzheimers disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I132,I132)","v":20576803},{"$f":"(LEN($J132) - LEN(SUBSTITUTE(LOWER($J132),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J132) - LEN(SUBSTITUTE(LOWER($J132),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J132) - LEN(SUBSTITUTE(LOWER($J132),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B132:D132)","v":1},2010,"Orphan nuclear receptors in breast cancer pathogenesis and therapeutic response.","Riggins",20576803,"Orphan nuclear receptors in breast cancer pathogenesis and therapeutic response.    Abstract:   Nuclear receptors comprise a large family of highly conserved transcription factors that regulate many key processes in normal and neoplastic tissues. Most nuclear receptors share a common, highly conserved domain structure that includes a carboxy-terminal ligand-binding domain. However, a subgroup of this gene family is known as the orphan nuclear receptors because to date there are no known natural ligands that regulate their activity. Many of the 25 nuclear receptors classified as orphan play critical roles in embryonic development, metabolism, and the regulation of circadian rhythm. Here, we review the emerging role(s) of orphan nuclear receptors in breast cancer, with a particular focus on two of the estrogen-related receptors (ERRalpha and ERRgamma) and several others implicated in clinical outcome and response or resistance to cytotoxic or endocrine therapies, including the chicken ovalbumin upstream promoter transcription factors, nerve growth factor-induced B, DAX-1, liver receptor homolog-1, and retinoic acid-related orphan receptor alpha. We also propose that a clearer understanding of the function of orphan nuclear receptors in mammary gland development and normal mammary tissues could significantly improve our ability to diagnose, treat, and prevent breast cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I133,I133)","v":20398728},{"$f":"(LEN($J133) - LEN(SUBSTITUTE(LOWER($J133),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J133) - LEN(SUBSTITUTE(LOWER($J133),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J133) - LEN(SUBSTITUTE(LOWER($J133),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B133:D133)","v":1},2010,"Pituitary tumors: cell type-specific roles for BMP-4.","Labeur",20398728,"Pituitary tumors: cell type-specific roles for BMP-4.    Abstract:   BMP-4 plays a crucial role not only in the formation of the anterior pituitary during embryo development but also in the pathogenesis of pituitary tumors in adults. In tumor cells, BMP-4 promotes prolactin secretion and lactotroph cell proliferation through a Smad-estrogen receptor crosstalk but it inhibits ACTH production and cell proliferation of corticotrophs. In addition, BMP-4 increases GH secretion in rat pituitary tumor somatolactotroph GH3 cells and FSHbeta subunit gene transcription in the murine gonadotroph cell line, LbetaT2. Therefore, BMP-4 has a differential role on different types of pituitary tumors: it promotes pituitary prolactinoma while it inhibits corticotroph pathogenesis in Cushings disease. The modulation of BMP-4 also plays an important role in the therapeutic mechanism of action of bromocriptine, somatostatin analogs and retinoic acid."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I134,I134)","v":19229271},{"$f":"(LEN($J134) - LEN(SUBSTITUTE(LOWER($J134),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J134) - LEN(SUBSTITUTE(LOWER($J134),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J134) - LEN(SUBSTITUTE(LOWER($J134),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B134:D134)","v":1},2009,"Ocular teratogens: old acquaintances and new dangers.","Tandon",19229271,"Ocular teratogens: old acquaintances and new dangers.    Abstract:   Recent research into animal studies has contributed significantly to understanding the pathophysiology of some well-known teratogens, such as alcohol. Techniques, such as positron emission tomography (PET) and retinal synaptogenesis studies, have helped determine the specific areas in the developing brain and ocular structures, which are targeted by various teratogens. In this article, we also highlight a few newer agents, such as benzodiazepines, with potential for ocular malformation and morbidity in the developing foetus."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I135,I135)","v":19166910},{"$f":"(LEN($J135) - LEN(SUBSTITUTE(LOWER($J135),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J135) - LEN(SUBSTITUTE(LOWER($J135),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J135) - LEN(SUBSTITUTE(LOWER($J135),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B135:D135)","v":1},2009,"Intrinsic versus extrinsic determinants during the development of Purkinje cell dendrites.","Sotelo",19166910,"Intrinsic versus extrinsic determinants during the development of Purkinje cell dendrites.    Abstract:   The peculiar shape and disposition of Purkinje cell (PC) dendrites, planar and highly branched, offers an optimal model to analyze cellular and molecular regulators for the acquisition of neuronal dendritic trees. During the first 2 weeks after the end of the proliferation period, PCs undergo a 2-phase remodeling process of their dendrites. The first phase consists in the complete retraction of the primitive but extensive dendritic tree, together with the formation of multiple filopodia-like processes arising from the cell body. In the second phase, there is a progressive disappearance of the somatic processes along with rapid growth and branching of the mature dendrite. Mature Purkinje cell dendrites bear two types of spiny protrusions, named spine and thorn. The spines are numerous, elongated, located at the distal dendritic compartment and form synapses with parallel fibers, whereas the thorns are shorter, rounded, emerge from the proximal compartment and synapse with climbing fibers. Different culture models and mutant mice analyses suggest the identification of intrinsic versus extrinsic determinants of the Purkinje cell dendritic development. The early phase of dendritic remodeling might be cell autonomous and regulated by specific transcription factors such as retinoid-related orphan receptor alpha (RORalpha). Afferent fibers, trophic factors and hormones regulate the orientation and growth of the mature dendritic tree contributing, with still unknown intrinsic factors, to sculpt its general architecture. The formation of spines appears as an intrinsic phenomenon independent of their presynaptic partner, the parallel fibers, and confined to the distal compartment by inhibitory influences of the climbing fibers along the proximal compartment."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I136,I136)","v":19030789},{"$f":"(LEN($J136) - LEN(SUBSTITUTE(LOWER($J136),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J136) - LEN(SUBSTITUTE(LOWER($J136),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J136) - LEN(SUBSTITUTE(LOWER($J136),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B136:D136)","v":1},2008,"Treatment of mice with retinoids in vivo and in vitro.","Morriss-Kay",19030789,"Treatment of mice with retinoids in vivo and in vitro.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I137,I137)","v":17148746},{"$f":"(LEN($J137) - LEN(SUBSTITUTE(LOWER($J137),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J137) - LEN(SUBSTITUTE(LOWER($J137),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J137) - LEN(SUBSTITUTE(LOWER($J137),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B137:D137)","v":1},2006,"Targeting components of the stress system as potential therapies for the metabolic syndrome: the peroxisome-proliferator-activated receptors.","Yumuk",17148746,"Targeting components of the stress system as potential therapies for the metabolic syndrome: the peroxisome-proliferator-activated receptors.    Abstract:   The three peroxisome-proliferator-activated receptor (PPAR) subtypes PPAR-alpha, PPAR-gamma, and PPAR-delta are ligand-activated transcription factors of the nuclear receptor family. PPARs form obligate heterodimers with the retinoid X receptor, which bind to peroxisome-proliferator-response elements (PPREs). PPAR-alpha is expressed mainly in liver, brown fat, kidney, heart, and skeletal muscle; PPAR-gamma in intestine and adipose tissue; PPAR-alpha and PPAR-gamma are both expressed in vascular endothelium, smooth muscle cells, macrophages, and foam cells; PPAR-delta in skeletal muscle, human embryonic kidney, intestine, heart, adipose tissue, developing brain, and keratinocytes. Intense interest in the development of drugs with new mechanisms of action for the metabolic syndrome has focused attention on nuclear receptors, such as PPARs that function as regulators of energy homeostasis. Agonists of PPAR-alpha and PPAR-gamma are currently used to treat diabetic dyslipidemia and type 2 diabetes. Dual PPAR-alpha/gamma agonists and PPAR-alpha/gamma/delta pan-agonists are under investigation for treatment of cardiovascular disease and the metabolic syndrome. Selective PPAR modulators (SPPARMs) are PPAR ligands that possess desirable efficacy and improved tolerance. Efforts are being made to identify novel partial agonists or antagonists for PPAR-gamma in order to combine their antidiabetic and antiobesity effects. Glucocorticoids are major mediators of the stress response and could be the link between stress and PPAR activator signaling and thus may affect the downstream metabolic pathways involved in fuel homeostasis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I138,I138)","v":17030124},{"$f":"(LEN($J138) - LEN(SUBSTITUTE(LOWER($J138),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J138) - LEN(SUBSTITUTE(LOWER($J138),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J138) - LEN(SUBSTITUTE(LOWER($J138),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B138:D138)","v":1},2006,"Sonic hedgehog signaling in forebrain development and its interactions with pathways that modify its effects.","Bertrand",17030124,"Sonic hedgehog signaling in forebrain development and its interactions with pathways that modify its effects.    Abstract:   During the development of the nervous system and other organs in the embryo, a limited set of master signaling pathways are used repeatedly for induction, patterning and growth. Among these, the Sonic hedgehog (Shh) pathway is crucial for the development of many structures in the brain. How the context-specific interplay between these various signaling pathways produces distinct temporal and spatial outcomes is not clear. Resolving this problem is a major goal in the study of cell and organ development. Here, we focus on signaling events during dorso-ventral patterning of the embryonic forebrain in vertebrates. In particular, we discuss the role of the Shh pathway in this process and on its interactions with the FGF, retinoic acid and Nodal pathways and other information cascades that modify its effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I139,I139)","v":16989911},{"$f":"(LEN($J139) - LEN(SUBSTITUTE(LOWER($J139),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J139) - LEN(SUBSTITUTE(LOWER($J139),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J139) - LEN(SUBSTITUTE(LOWER($J139),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B139:D139)","v":1},2006,"The VIP-receptor system in neuroblastoma cells.","Muller",16989911,"The VIP-receptor system in neuroblastoma cells.    Abstract:   Neuroblastoma (NB), the most common extracranial tumor during childhood arises from the embryonic sympathetic nervous system. Remarkably, NB can spontaneously regress, even after metastasis, leading to complete remission. Subpopulations of neuroblastic (N-type) and nonneuronal cells coexist in NB. Expression of the high-affinity nerve growth factor (NGF) TrkA receptor in NB is correlated with good prognosis, while MYCN amplification is associated with advanced stages of disease. N-type cells undergo differentiation when treated with different compounds, such as retinoids, phorbol esters, growth and neurotrophic NGF and neuropeptides, especially vasoactive intestinal peptide (VIP). These substances stabilize proliferation, leading to a more mature neuronal phenotype, neurite outgrowth and induction of expression of sympathetic neuronal markers. Therefore, receptors for these substances and their associated signalling pathways, appear like promising targets for the development of novel NB therapeutics. The aim of the present review is to summarize the quite considerable array of data, concerning production of VIP and related peptides, expression of their receptors in NB and the key regulation exerted by the VIP-receptor system in the control of NB cell behaviour."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I140,I140)","v":16872363},{"$f":"(LEN($J140) - LEN(SUBSTITUTE(LOWER($J140),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J140) - LEN(SUBSTITUTE(LOWER($J140),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J140) - LEN(SUBSTITUTE(LOWER($J140),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B140:D140)","v":1},2006,"Neurotransmitter receptor expression and activity during neuronal differentiation of embryonal carcinoma and stem cells: from basic research towards clinical applications.","Ulrich",16872363,"Neurotransmitter receptor expression and activity during neuronal differentiation of embryonal carcinoma and stem cells: from basic research towards clinical applications.    Abstract:   Embryonal carcinoma and embryonic stem cells have served as models to understand basic aspects of neuronal differentiation and are promising candidates for regenerative medicine. Besides being well characterized regarding the capability of embryonal carcinoma and embryonic stem cells to be precursors of different tissues, the molecular mechanisms controlling neuronal differentiation are hardly understood. Neuropeptide and neurotransmitter receptors are expressed at early stages of differentiation prior to synaptogenesis, triggering transient changes in calcium concentration and inducing neurone-specific gene expression. In vitro neuronal differentiation of embryonal carcinoma and embryonic stem cells closely resembles early neuronal development in vivo. Murine P19 EC cells are a well-characterized model for in vitro differentiation, which upon treatment with retinoic acid differentiate into neurones. Expression and activity of various receptor proteins is regulated during their differentiation. Stimulation of kinin-B2, endothelin-B, muscarinic acetylcholine, and N-methyl-D-aspartate receptors results in transient increases of intracellular free calcium concentration [Ca(2+)](i) in P19 cells undergoing neuronal differentiation, whereas embryonal cells do not respond or show a smaller change in [Ca(2+)](i) than differentiating cells. Receptor inhibition, as studied with the example of the kinin-B2 receptor, aborts neuronal maturation of P19 cells, demonstrating the crucial importance of B2 receptors during the differentiation process. Future success in obtaining desired neuronal phenotypes from pluripotent cells in vitro may offer new therapeutic perspectives for curing genetic and acquired dysfunctions of the developing and adult nervous system."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I141,I141)","v":16818384},{"$f":"(LEN($J141) - LEN(SUBSTITUTE(LOWER($J141),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J141) - LEN(SUBSTITUTE(LOWER($J141),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J141) - LEN(SUBSTITUTE(LOWER($J141),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B141:D141)","v":1},2006,"RORalpha, a pivotal nuclear receptor for Purkinje neuron survival and differentiation: from development to ageing.","Boukhtouche",16818384,"RORalpha, a pivotal nuclear receptor for Purkinje neuron survival and differentiation: from development to ageing.    Abstract:   RORalpha (Retinoid-related Orphan Receptor) is a transcription factor belonging to the superfamily of nuclear receptors. The spontaneous staggerer (sg) mutation, which consists of a deletion in the Rora gene, has been shown to cause the loss of function of the RORalpha protein. The total loss of RORalpha expression leads to cerebellar developmental defects, particularly to a dramatic decreased survival of Purkinje cells and an early block in the differentiation process. This review focuses on recent studies which position RORalpha as a pivotal factor controlling Purkinje cell survival and differentiation, from development to ageing."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I142,I142)","v":16688770},{"$f":"(LEN($J142) - LEN(SUBSTITUTE(LOWER($J142),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J142) - LEN(SUBSTITUTE(LOWER($J142),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J142) - LEN(SUBSTITUTE(LOWER($J142),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B142:D142)","v":1},2006,"Retinoids and spinal cord development.","Maden",16688770,"Retinoids and spinal cord development.    Abstract:   The role that RA plays in the development and patterning of the spinal cord is discussed. The morphogenetic process of neurulation is described in which RA plays a role because in the absence of RA signaling spina bifida results. Following neural induction, RA is involved in several patterning events in the spinal cord. It is one of the posteriorizing factors along with FGFs and Wnts and as such patterns the cervical spinal cord acting via the Hoxc transcription factors. It is involved in the induction of neural differentiation via genes such as NeuroM. It plays a part in patterning the dorsoventral axis of the anterior spinal cord where it interacts with FGF, Shh, and BMPs and induces an interneuronal population of neurons called V0 and V1 and a subset of motor neurons known as LMCs. To perform these actions RA is synthesized in the adjacent paraxial mesoderm by the enzyme RALDH2 and acts in a paracrine fashion on the developing neural tube. In the final action of RA, it begins to be synthesized within the neural tube at brachial and lumbar levels in the LMCs. Later-born neurons migrate through this RALDH2-expressing region and induce differentiation in these migrating neurons, which become a subset of LMC neurons known as LMCls. Thus RA acts several times over in the development of the spinal cord and not on the cells in which it is synthesized, but in adjacent cells in a paracrine manner."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I143,I143)","v":15965107},{"$f":"(LEN($J143) - LEN(SUBSTITUTE(LOWER($J143),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J143) - LEN(SUBSTITUTE(LOWER($J143),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J143) - LEN(SUBSTITUTE(LOWER($J143),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B143:D143)","v":1},2005,"Engineering a dopaminergic phenotype in stem/precursor cells: role of Nurr1, glia-derived signals, and Wnts.","Arenas",15965107,"Engineering a dopaminergic phenotype in stem/precursor cells: role of Nurr1, glia-derived signals, and Wnts.    Abstract:   Recent results from clinical trials using fetal tissue grafts in patients with Parkinsons disease (PD) have indicated that current surgical strategies for dopamine cell replacement therapy need to be improved in order to achieve better functional integration of the grafts and to avoid dyskinesias. Previous studies using rich dopaminergic (DA) cell suspensions have provided proof-of-concept that PD patients can benefit from cell replacement therapy. Stem cells have been proposed as better candidates for cell replacement therapy in PD since they can be standardized, expanded, and engineered in vitro. Recent developments indicate that cell preparations enriched in DA neurons can be generated in vitro, but their functional integration in animal models of disease is still far from optimal. This is not entirely surprising considering our limited knowledge of the development of DA neurons and the reduced number of factors that have been implemented in stem cell differentiation protocols. This review will focus on three aspects of DA neuron development: (1) the function of Nurr1 and retinoid X receptors (RXR) in the differentiation of DA precursors and in the survival of DA neurons; (2) the role of glia in DA neurogenesis and the differentiation of DA precursors; and (3) the function of the Wnt family of lipoproteins in the proliferation and differentiation of DA precursors. A greater understanding of the cellular and molecular mechanisms that control DA neuron development, as well as their functional integration in vivo, are likely to ultimately contribute to the development of novel stem cell replacement therapies for PD."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I144,I144)","v":15956766},{"$f":"(LEN($J144) - LEN(SUBSTITUTE(LOWER($J144),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J144) - LEN(SUBSTITUTE(LOWER($J144),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J144) - LEN(SUBSTITUTE(LOWER($J144),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B144:D144)","v":1},2005,"Genesis of alcohol-induced craniofacial dysmorphism.","Sulik",15956766,"Genesis of alcohol-induced craniofacial dysmorphism.    Abstract:   The initial diagnosis of fetal alcohol syndrome (FAS) in the United States was made because of the facial features common to the first cohort of patients. This article reviews the development of an FAS mouse model whose craniofacial features are remarkably similar to those of affected humans. The model is based on short-term maternal treatment with a high dosage of ethanol at stages of pregnancy that are equivalent to Weeks 3 and 4 of human gestation. At these early stages of development, alcohols insult to the developing face is concurrent with that to the brain, eyes, and inner ear. That facial and central nervous system defects consistent with FAS can be induced by more quot;realisticquot; alcohol dosages as illustrated with data from an oral alcohol intake mouse model in which maternal blood alcohol levels do not exceed 200 mg/dl. The ethanol-induced pathogenesis involves apoptosis that occurs within 12 hrs of alcohol exposure in selected cell populations of Day 7, 8, and 9 mouse embryos. Experimental evidence from other species also shows that apoptosis underlies ethanol-induced malformations. With knowledge of sensitive and resistant cell populations at specific developmental stages, studies designed to identify the basis for these differing cellular responses and, therefore, to determine the primary mechanisms of ethanols teratogenesis are possible. For example, microarray comparisons of sensitive and resistant embryonic cell populations have been made, as have in situ studies of gene expression patterns in the populations of interest. Studies that illustrate agents that are effective in diminishing or exacerbating ethanols teratogenesis have also been helpful in determining mechanisms. Among these agents are antioxidants, sonic hedgehog protein, retinoids, and the peptides SAL and NAP."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I145,I145)","v":15936325},{"$f":"(LEN($J145) - LEN(SUBSTITUTE(LOWER($J145),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J145) - LEN(SUBSTITUTE(LOWER($J145),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J145) - LEN(SUBSTITUTE(LOWER($J145),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B145:D145)","v":1},2005,"The mechanisms of dorsoventral patterning in the vertebrate neural tube.","Wilson",15936325,"The mechanisms of dorsoventral patterning in the vertebrate neural tube.    Abstract:   We describe the essential features of and the molecules involved in dorsoventral (DV) patterning in the neural tube. The neural tube is, from its very outset, patterned in this axis as there is a roof plate, floor plate, and differing numbers and types of neuroblasts. These neuroblasts develop into different types of neurons which express a different range of marker genes. Early embryological experiments identified the notochord and the somites as being responsible for the DV patterning of the neural tube and we now know that 4 signaling molecules are involved and are generated by these surrounding structures. Fibroblast growth factors (FGFs) are produced by the caudal mesoderm and must be down-regulated before neural differentiation can occur. Retinoic acid (RA) is produced by the paraxial mesoderm and is an inducer of neural differentiation and patterning and is responsible for down-regulating FGF. Sonic hedgehog (Shh) is produced by the notochord and floor plate and is responsible for inducing ventral neural cell types in a concentration-dependent manner. Bone morphogenetic proteins (BMPs) are produced by the roof plate and are responsible for inducing dorsal neural cell types in a concentration-dependent manner. Subsequently, RA is used twice more. Once from the somites for motor neuron differentiation and secondly RA is used to define the motor neuron subtypes, but in the latter case it is generated within the neural tube from differentiating motor neurons rather than from outside. These 4 signaling molecules also interact with each other, generally in a repressive fashion, and DV patterning shows how complex these interactions can be."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I146,I146)","v":15834938},{"$f":"(LEN($J146) - LEN(SUBSTITUTE(LOWER($J146),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J146) - LEN(SUBSTITUTE(LOWER($J146),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J146) - LEN(SUBSTITUTE(LOWER($J146),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B146:D146)","v":1},2005,"Non-neural ectoderm is really neural: evolution of developmental patterning mechanisms in the non-neural ectoderm of chordates and the problem of sensory cell homologies.","Holland",15834938,"Non-neural ectoderm is really neural: evolution of developmental patterning mechanisms in the non-neural ectoderm of chordates and the problem of sensory cell homologies.    Abstract:   In chordates, the ectoderm is divided into the neuroectoderm and the so-called non-neural ectoderm. In spite of its name, however, the non-neural ectoderm contains numerous sensory cells. Therefore, the term quot;non-neuralquot; ectoderm should be replaced by quot;general ectoderm.quot; At least in amphioxus and tunicates and possibly in vertebrates as well, both the neuroectoderm and the general ectoderm are patterned anterior/posteriorly by mechanisms involving retinoic acid and Hox genes. In amphioxus and tunicates the ectodermal sensory cells, which have a wide range of ciliary and microvillar configurations, are mostly primary neurons sending axons to the CNS, although a minority lack axons. In contrast, vertebrate mechanosensory cells, called hair cells, are all secondary neurons that lack axons and have a characteristic eccentric cilium adjacent to a group of microvilli of graded lengths. It has been highly controversial whether the ectodermal sensory cells in the oral siphons of adult tunicates are homologous to vertebrate hair cells. In some species of tunicates, these cells appear to be secondary neurons, and microvillar and ciliary configurations of some of these cells approach those of vertebrate hair cells. However, none of the tunicate cells has all the characteristics of a hair cell, and there is a high degree of variation among ectodermal sensory cells within and between different species. Thus, similarities between the ectodermal sensory cells of any one species of tunicate and craniate hair cells may well represent convergent evolution rather than homology."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I147,I147)","v":15340833},{"$f":"(LEN($J147) - LEN(SUBSTITUTE(LOWER($J147),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J147) - LEN(SUBSTITUTE(LOWER($J147),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J147) - LEN(SUBSTITUTE(LOWER($J147),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B147:D147)","v":1},2004,"Nurr1, an orphan nuclear receptor with essential functions in developing dopamine cells.","Perlmann",15340833,"Nurr1, an orphan nuclear receptor with essential functions in developing dopamine cells.    Abstract:   Nurr1 is a transcription factor that is expressed in the embryonic ventral midbrain and is critical for the development of dopamine (DA) neurons. It belongs to the conserved family of nuclear receptors but lacks an identified ligand and is therefore referred to as an orphan receptor. Recent structural studies have indicated that Nurr1 belongs to a class of ligand-independent nuclear receptors that are unable to bind cognate ligands. However, Nurr1 can promote signaling via its heterodimerization partner, the retinoid X receptor (RXR). RXR ligands can promote the survival of DA neurons via a process that depends on Nurr1-RXR heterodimers. In developing DA cells, Nurr1 is required for the expression of several genes important for DA synthesis and function. However, Nurr1 is probably also important for the maintenance of adult DA neurons and plays additional less-well-elucidated roles in other regions of the central nervous system and in peripheral tissues."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I148,I148)","v":15265774},{"$f":"(LEN($J148) - LEN(SUBSTITUTE(LOWER($J148),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J148) - LEN(SUBSTITUTE(LOWER($J148),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J148) - LEN(SUBSTITUTE(LOWER($J148),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B148:D148)","v":1},2004,"Interaction of the glucocorticoid receptor and the chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII): implications for the actions of glucocorticoids on glucose, lipoprotein, and xenobiotic metabolism.","De Martino",15265774,"Interaction of the glucocorticoid receptor and the chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII): implications for the actions of glucocorticoids on glucose, lipoprotein, and xenobiotic metabolism.    Abstract:   Glucocorticoids exert their extremely diverse effects on numerous biologic activities of humans via only one protein module, the glucocorticoid receptor (GR). The GR binds to the glucocorticoid response elements located in the promoter region of target genes and regulates their transcriptional activity. In addition, GR associates with other transcription factors through direct protein-protein interactions and mutually represses or stimulates each others transcriptional activities. The latter activity of GR may be more important than the former one, granted that mice harboring a mutant GR, which is active in terms of protein-protein interactions but inactive in terms of transactivation via DNA, survive and procreate, in contrast to mice with a deletion of the entire GR gene that die immediately after birth. We recently found that GR physically interacts with the chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), which plays a critical role in the metabolism of glucose, cholesterol, and xenobiotics, as well as in the development of the central nervous system in fetus. GR stimulates COUP-TFII-induced transactivation by attracting cofactors via its activation function-1, while COUP-TFII represses the GR-governed transcriptional activity by tethering corepressors, such as the silencing mediator for retinoid and thyroid hormone receptors (SMRT) and the nuclear receptor corepressors (NCoRs) via its C-terminal domain. Their mutual interaction may play an important role in gluconeogenesis, lipoprotein metabolism, and enzymatic clearance of clinically important compounds and bioactive chemicals, by regulating their rate-limiting enzymes and molecules, including the phosphoenolpyruvate carboxykinase (PEPCK), the cytochrome P450 CYP3A and CYP7A, and several apolipoproteins. It appears that glucocorticoids exert their intermediary effects partly via physical interaction with COUP-TFII."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I149,I149)","v":14674484},{"$f":"(LEN($J149) - LEN(SUBSTITUTE(LOWER($J149),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J149) - LEN(SUBSTITUTE(LOWER($J149),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J149) - LEN(SUBSTITUTE(LOWER($J149),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B149:D149)","v":1},2003,"The roles of retinoic acid during inner ear development.","Romand",14674484,"The roles of retinoic acid during inner ear development.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I150,I150)","v":12766945},{"$f":"(LEN($J150) - LEN(SUBSTITUTE(LOWER($J150),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J150) - LEN(SUBSTITUTE(LOWER($J150),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J150) - LEN(SUBSTITUTE(LOWER($J150),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B150:D150)","v":1},2003,"About face: signals and genes controlling jaw patterning and identity in vertebrates.","Richman",12766945,"About face: signals and genes controlling jaw patterning and identity in vertebrates.    Abstract:   The embryonic vertebrate face is composed of similarly sized buds of neural crest-derived mesenchyme encased in epithelium. These buds or facial prominences grow and fuse together to give the postnatal morphology characteristic of each species. Here we review the role of neural crest cells and foregut endoderm in differentiating facial features. We relate the developing facial prominences to the skeletal structure of the face and review the signals and genes that have been shown to play an important role in facial morphogenesis. We also examine two experiments one at the genetic level and one at the signal level in which transformation of facial prominences and subsequent change of jaw identity was induced. We propose that signals such as retinoids and BMPs and downstream transcription factors such as Distal-less related genes specify jaw identity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I151,I151)","v":12415292},{"$f":"(LEN($J151) - LEN(SUBSTITUTE(LOWER($J151),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J151) - LEN(SUBSTITUTE(LOWER($J151),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J151) - LEN(SUBSTITUTE(LOWER($J151),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B151:D151)","v":1},2002,"Retinoid signalling in the development of the central nervous system.","Maden",12415292,"Retinoid signalling in the development of the central nervous system.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I152,I152)","v":12324383},{"$f":"(LEN($J152) - LEN(SUBSTITUTE(LOWER($J152),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J152) - LEN(SUBSTITUTE(LOWER($J152),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J152) - LEN(SUBSTITUTE(LOWER($J152),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B152:D152)","v":1},2002,"Sensory organ development in the inner ear: molecular and cellular mechanisms.","Bryant",12324383,"Sensory organ development in the inner ear: molecular and cellular mechanisms.    Abstract:   The molecular mechanisms underlying the specification of sensory organs in the inner ear and the development of hair and supporting cells within these organs are described. The different organs are all derived from a common pro-sensory region, and may be specified by their proximity to the boundaries between compartments - broad domains within the otocyst defined by the asymmetric expression patterns of transcription factors. Activation of Notch may specify the pro-sensory region, and lateral inhibition mediated by Notch signalling influences whether cells of common lineage in a sensory patch differentiate as either hair cells or supporting cells. The transcription factors Math1 and Brn3.1 are required for hair cell differentiation, and supporting cells express negative regulators of neurogenesis, Hes1 and Hes5. Retinoic acid and thyroid hormone influence early aspects and timing of hair cell differentiation, respectively. Development of the hair cells mechanosensory hair bundle involves interactions between the cytoskeleton, cell-surface adhesion molecules, receptors and associated extracellular matrix."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I153,I153)","v":12060827},{"$f":"(LEN($J153) - LEN(SUBSTITUTE(LOWER($J153),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J153) - LEN(SUBSTITUTE(LOWER($J153),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J153) - LEN(SUBSTITUTE(LOWER($J153),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B153:D153)","v":1},2002,"A model of the development of the brain as a construct of the thyroid system.","Howdeshell",12060827,"A model of the development of the brain as a construct of the thyroid system.    Abstract:   Thyroid hormone is essential for normal brain development. However, little is known about the molecular and cellular mechanisms that mediate thyroid hormone action on the developing brain or the developmental events selectively affected. Consequently, although a large number of environmental chemicals interfere with the thyroid system, there are few neurodevelopmental end points to recruit for toxicological studies. Therefore, my goal here is to review what is known about the relative timing of normal brain construction and thyroid system development, with special focus on the period of in utero development in humans and the comparable developmental period in laboratory rats. These data are presented as a timeline to aid in the identification of thyroid-sensitive end points in brain development and to highlight important data gaps. I discuss the known influence of certain synthetic chemicals on the thyroid system and include a brief review of the effects of developmental exposure to chemicals on thyroid system function. The relationship between the thyroid hormone and retinoic acid systems, as well as the thyroid hormone sensitivity of the developing cochlea, is also discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I154,I154)","v":11891692},{"$f":"(LEN($J154) - LEN(SUBSTITUTE(LOWER($J154),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J154) - LEN(SUBSTITUTE(LOWER($J154),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J154) - LEN(SUBSTITUTE(LOWER($J154),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B154:D154)","v":1},2002,"PAGOD syndrome: eighth case and comparison to animal models of congenital vitamin A deficiency.","Macayran",11891692,"PAGOD syndrome: eighth case and comparison to animal models of congenital vitamin A deficiency.    Abstract:   We observed a 46, XY infant with atrophy of the optic nerve, complex congenital heart disease including a double outlet right ventricle, hypoplasia of the right pulmonary artery and lung, eventration of the diaphragm, and ambiguous genitalia. The baby died of cardiac arrhythmias at 204 days. The pattern of malformations was compatible with pulmonary tract and pulmonary artery, agonadism, omphalocele, diaphragmatic defect, and dextrocardia (PAGOD) syndrome. The condition may resemble the malformation complex associated with developmental deficiency of vitamin A or retinoic acid, as described in animal models."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I155,I155)","v":11251992},{"$f":"(LEN($J155) - LEN(SUBSTITUTE(LOWER($J155),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J155) - LEN(SUBSTITUTE(LOWER($J155),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J155) - LEN(SUBSTITUTE(LOWER($J155),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B155:D155)","v":1},2001,"OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): a review of 14 cases.","Keppler-Noreuil",11251992,"OEIS complex (omphalocele-exstrophy-imperforate anus-spinal defects): a review of 14 cases.    Abstract:   OEIS complex refers to a combination of defects consisting of omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects. Possible embryologic mechanisms proposed for these findings have included: a single defect of early blastogenesis or a defect of mesodermal migration during the primitive streak period. Fourteen cases with OEIS complex and related malformations were reviewed for demographic features, prenatal and family histories, and clinical, radiological and pathological findings including the frequency and types of associated anomalies. The pathogenetic mechanisms causing OEIS complex and related malformations, such as anorectal and spinal defects, are discussed. The findings in these cases illustrate the spectrum of defects that can occur in the embryologic development of the cloaca and the urorectal septum. Differences in the timing and extent of mesenchymal ingrowth as well as cloacal membrane rupture may account for these variable findings. A developmental field defect involving the intraembryonic mesoderm suggests a possible etiologic role for homeobox genes, such as HLXB9 with mutations, resulting in anorectal and spine abnormalities, or retinoic acid receptors. OEIS complex with its mostly sporadic occurrence suggests etiologic heterogeneity with a possible role for environmental and genetic causes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I156,I156)","v":10592388},{"$f":"(LEN($J156) - LEN(SUBSTITUTE(LOWER($J156),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J156) - LEN(SUBSTITUTE(LOWER($J156),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J156) - LEN(SUBSTITUTE(LOWER($J156),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B156:D156)","v":1},1999,"An in vitro pathway from embryonic stem cells to neurons and glia.","Gottlieb",10592388,"An in vitro pathway from embryonic stem cells to neurons and glia.    Abstract:   Mouse embryonic stem (ES) cells can be induced to differentiate into neurons and glia in vitro. Induction protocols are straightforward and involve culture in the presence of retinoic acid. They result in an efficient conversion of undifferentiated ES cells to neural cells. Mature neurons produced have the key physiological, morphological and molecular properties of primary cultured neurons derived from the central nervous system. Most significantly, they form functional chemical synapses that utilize either glutamate, GABA or glycine as neurotransmitters. ES cell-derived glial cells also correspond well with their normal counterparts. During induction, ES cells undergo a series of developmental steps that resemble key stages in the early mouse embryo. This supports the hypothesis that the in vitro pathway is a valid model of the normal developmental pathway leading to neurons and glia. The in vitro system combines three experimental strengths. It is suitable for genetic manipulation, affords large numbers of cells and allows precise manipulation of the culture environment. It is thus suitable for a wide variety of mechanistic studies in the areas of neural development and cell biology."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I157,I157)","v":9932511},{"$f":"(LEN($J157) - LEN(SUBSTITUTE(LOWER($J157),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J157) - LEN(SUBSTITUTE(LOWER($J157),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J157) - LEN(SUBSTITUTE(LOWER($J157),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B157:D157)","v":1},1998,"The role of retinoids in developmental mechanisms in embryos.","Maden",9932511,"The role of retinoids in developmental mechanisms in embryos.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I158,I158)","v":9822569},{"$f":"(LEN($J158) - LEN(SUBSTITUTE(LOWER($J158),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J158) - LEN(SUBSTITUTE(LOWER($J158),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J158) - LEN(SUBSTITUTE(LOWER($J158),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B158:D158)","v":1},1998,"Vertebrate development: a nervous vitamin.","Maden",9822569,"Vertebrate development: a nervous vitamin.    Abstract:   The vitamin A-related retinoids have recently been shown to be involved in the development of the central nervous system, both in specifying position along the head-to-tail axis and in the development of a specific subset of motor neurons."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I159,I159)","v":9722169},{"$f":"(LEN($J159) - LEN(SUBSTITUTE(LOWER($J159),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J159) - LEN(SUBSTITUTE(LOWER($J159),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J159) - LEN(SUBSTITUTE(LOWER($J159),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B159:D159)","v":1},1998,"The roles of steroidogenic factor 1 in endocrine development and function.","Parker",9722169,"The roles of steroidogenic factor 1 in endocrine development and function.    Abstract:   The nuclear hormone receptor family--structurally-related transcriptional regulators that mediate the actions of steroid hormones, thyroid hormone, vitamin D, and retinoids--also includes orphan members that lack known activating ligands. One of these orphan receptors, steroidogenic factor 1 (SF-1), has recently been shown to play key roles in steroidogenic cell function within the adrenal cortex and gonads. SF-1 also contributes to reproductive function at all three levels of the hypothalamic-pituitary-gonadal axis. Key insights into these roles came from analyses of SF-1 knockout mice, which revealed adrenal and gonadal agenesis with consequent male-to-female sex reversal of their internal and external genitalia, impaired gonadotrope function, and agenesis of the ventromedial hypothalamic nucleus. This report reviews the data that have established SF-1 as a critical mediator of endocrine differentiation and function."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I160,I160)","v":9673850},{"$f":"(LEN($J160) - LEN(SUBSTITUTE(LOWER($J160),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J160) - LEN(SUBSTITUTE(LOWER($J160),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J160) - LEN(SUBSTITUTE(LOWER($J160),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B160:D160)","v":1},1998,"Retinoids and related signals in early development of the vertebrate central nervous system.","Durston",9673850,"Retinoids and related signals in early development of the vertebrate central nervous system.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I161,I161)","v":9507049},{"$f":"(LEN($J161) - LEN(SUBSTITUTE(LOWER($J161),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J161) - LEN(SUBSTITUTE(LOWER($J161),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J161) - LEN(SUBSTITUTE(LOWER($J161),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B161:D161)","v":1},1998,"The development of the vertebrate inner ear.","Torres",9507049,"The development of the vertebrate inner ear.    Abstract:   The inner ear is a complex sensory organ responsible for balance and sound detection in vertebrates. It originates from a transient embryonic structure, the otic vesicle, that contains all of the information to develop autonomously into the mature inner ear. We review here the development of the otic vesicle, bringing together classical embryological experiments and recent genetic and molecular data. The specification of the prospective ectoderm and its commitment to the otic fate are very early events and can be related to the expression of genes with restricted expression domains. A combinatorial gene expression model for placode specification and diversification, based on classical embryological evidence and gene expression patterns, is discussed. The formation of the otic vesicle is dependent on inducing signals from endoderm, mesoderm and neuroectoderm. Ear induction consists of a sequence of discrete instructions from those tissues that confer its final identity on the otic field, rather than a single all-or-none process. The important role of the neural tube in otic development is highlighted by the abnormalities observed in mouse mutants for the Hoxa1, kreisler and fgf3 genes and those reported in retinoic acid-deficient quails. Still, the nature of the relation between the neural tube and otic development remains unclear. Gene targeting experiments in the mouse have provided evidence for genes potentially involved in regional and cell-fate specification in the inner ear. The disruption of the mouse Brn3.1 gene identifies the first mutation affecting sensory hair-cell specification, and mutants for Pax2 and Nkx5.1 genes show their requirement for the development of specific regions of the otic vesicle. Several growth-factors contribute to the patterned cell proliferation of the otic vesicle. Among these, IGF-I and FGF-2 are expressed in the otic vesicle and may act in an autocrine manner. Finally, little is known about early mechanisms involved in guiding ear innervation. However, targeted disruption of genes coding for neurotrophins and Trk receptors have shown that once synaptic contacts are established, they depend on specific trophic interactions that involve these two gene families. The accessibility of new cellular and molecular approaches are opening new perspectives in vertebrate development and are also starting to be applied to ear development. This will allow this classical and attractive model system to see a rapid progress in the near future."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I162,I162)","v":9535511},{"$f":"(LEN($J162) - LEN(SUBSTITUTE(LOWER($J162),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J162) - LEN(SUBSTITUTE(LOWER($J162),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J162) - LEN(SUBSTITUTE(LOWER($J162),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B162:D162)","v":1},1998,"Structural and gene expression abnormalities induced by retinoic acid in the forebrain.","Clotman",9535511,"Structural and gene expression abnormalities induced by retinoic acid in the forebrain.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I163,I163)","v":9504042},{"$f":"(LEN($J163) - LEN(SUBSTITUTE(LOWER($J163),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J163) - LEN(SUBSTITUTE(LOWER($J163),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J163) - LEN(SUBSTITUTE(LOWER($J163),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B163:D163)","v":1},1998,"What are the molecular mechanisms of neural tube defects?","Corcoran",9504042,"What are the molecular mechanisms of neural tube defects?    Abstract:   Neural tube defects (NTDs) are some of the most common human malformations. The vast majority of NTDs can be prevented by the administration of folic acid; however, to date there has been no effective treatment of folic acid-resistant NTDs. A recent paper has confirmed an earlier report that the administration of inositol to the curly tail mutant mouse, which is a model of folate-resistant NTDs, can cure such defects. The molecular pathway by which this is achieved is thought to occur by the up-regulation of the retinoic acid receptor beta in the underlying hindgut endoderm, correcting a proliferation defect. However, alternative explanations also may account for NTDs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I164,I164)","v":9434862},{"$f":"(LEN($J164) - LEN(SUBSTITUTE(LOWER($J164),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J164) - LEN(SUBSTITUTE(LOWER($J164),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J164) - LEN(SUBSTITUTE(LOWER($J164),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B164:D164)","v":1},1997,"Craniofacial abnormalities induced by the ectopic expression of homeobox genes.","Whiting",9434862,"Craniofacial abnormalities induced by the ectopic expression of homeobox genes.    Abstract:   In this paper I have tried to bring together work that highlights the role of homeobox genes in generating craniofacial form. I review both normal and disrupted embryogenesis and ask whether mis-expression of the homeobox genes outside their normal domains could be contributing to congenital facial abnormalities arising from either genetic or teratogenic actions. Experimentally generated transgenic mice carrying loss- or gain-of-function mutations in homeobox genes, in combination with their normal expression patterns, have allowed us to compile and test models of embryonic specification based around a Hox/homeobox code. These models form the basis on which the functional questions are considered. There are four major sections covering different experimental approaches designed to ectopically induce homeobox genes in the head. Transgenic mice, where heterologous promoters drive a given Hox gene in the head, have shown that the more posteriorly expressed Hox genes tend to have a significant effect only on the skull bones of mesodermal origin whereas those normally expressed more anteriorly, in the hindbrain and branchial arches, can affect more anterior branchial arch and neural crest-derived structures. Manipulation experiments which can induce homeobox genes in small, localised regions of the facial precursors show clear and dramatic effects of this expression on facial development. Null mutations in predicted repressors of Hox gene expression, however, do not appear to give rise to substantial craniofacial abnormalities. Retinoic acid, on the other hand, is well known for its teratogenic actions and its ability to induce Hox gene expression. Evidence is now accumulating that at least some of its teratogenic actions may be mediated by its regulation of the Hox and other homeobox genes in the head."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I165,I165)","v":9434861},{"$f":"(LEN($J165) - LEN(SUBSTITUTE(LOWER($J165),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J165) - LEN(SUBSTITUTE(LOWER($J165),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J165) - LEN(SUBSTITUTE(LOWER($J165),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B165:D165)","v":1},1997,"Induction of altered gene expression in early embryos.","Rogers",9434861,"Induction of altered gene expression in early embryos.    Abstract:   This review focuses on known genes whose expression may be perturbed by teratogens during early embryogenesis (preorganogenesis). Teratogens may disrupt embryogenesis by modifying positional information. Genes controlling positional information include those specifying the primary body axes: anterior-posterior, dorsal-ventral, or left-right. These genes often encode transcription factors, whose regulation or activation can stimulate aberrant tissue differentiation and morphogenesis. Alternatively, teratogens may directly affect cell differentiation, proliferation, or apoptosis. Hydrophilic signalling molecules such as growth factors and hydrophobic molecules such as retinoids regulate these processes. The signalling pathways activated often induce the coordinate regulation of tissue specific gene expression. In addition to modifying individual signalling pathways, teratogens can synergize with or antagonize the effects of other teratogens through inappropriate interactions between signal transduction pathways. Since teratogens may often directly or indirectly perturb the expression of known or as yet undescribed developmentally critical genes, this review also provides a short description of techniques to identify genes whose expression is altered by teratogens."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I166,I166)","v":9224274},{"$f":"(LEN($J166) - LEN(SUBSTITUTE(LOWER($J166),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J166) - LEN(SUBSTITUTE(LOWER($J166),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J166) - LEN(SUBSTITUTE(LOWER($J166),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B166:D166)","v":1},1997,"Retinoic acid. A key molecule for eye and photoreceptor development.","Hyatt",9224274,"Retinoic acid. A key molecule for eye and photoreceptor development.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I167,I167)","v":9073437},{"$f":"(LEN($J167) - LEN(SUBSTITUTE(LOWER($J167),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J167) - LEN(SUBSTITUTE(LOWER($J167),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J167) - LEN(SUBSTITUTE(LOWER($J167),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B167:D167)","v":1},1997,"Ectodermal patterning in vertebrate embryos.","Sasai",9073437,"Ectodermal patterning in vertebrate embryos.    Abstract:   Recent molecular insights on how the ectodermal layer is patterned in vertebrates are reviewed. Studies on the induction of the central nervous system (CNS) by Spemanns Organizer led to the isolation of noggin and chordin. These secretory proteins function by binding to, and inhibiting, ventral BMPs, in particular BMP-4. Neural induction can be considered as the dorsalization of ectoderm, in which low levels of BMP-signaling result in CNS formation. At high levels of BMP signaling the ectoderm adopts a ventral fate and skin is formed. In Xenopus the forming neural plate already has extensive dorsal-ventral (D-V) patterning, and neural induction and D-V patterning may share common molecular mechanisms. At later stages sonic hedgehog (shh) plays a principal role in D-V patterning, particularly in the neural tube of the amniote embryo. A great many transcription factor markers are available and mouse knockouts provide evidence of their involvement in the regional specification of the neural tube. Recent evidence indicating that differentiation of posterior CNS is promoted by FGF, Wnt-3a, and retinoic acid is reviewed from the point of view of the classical experiments of Nieuwkoop that defined an activation and a transformation step during neural induction."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I168,I168)","v":9598385},{"$f":"(LEN($J168) - LEN(SUBSTITUTE(LOWER($J168),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J168) - LEN(SUBSTITUTE(LOWER($J168),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J168) - LEN(SUBSTITUTE(LOWER($J168),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B168:D168)","v":1},1997,"Retinoids and posterior neural induction: a reevaluation of Nieuwkoops two-step hypothesis.","Kolm",9598385,"Retinoids and posterior neural induction: a reevaluation of Nieuwkoops two-step hypothesis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I169,I169)","v":9125371},{"$f":"(LEN($J169) - LEN(SUBSTITUTE(LOWER($J169),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J169) - LEN(SUBSTITUTE(LOWER($J169),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J169) - LEN(SUBSTITUTE(LOWER($J169),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B169:D169)","v":1},1997,"Hoxb-8 gain-of-function transgenic mice exhibit alterations in the peripheral nervous system.","Fanarraga",9125371,"Hoxb-8 gain-of-function transgenic mice exhibit alterations in the peripheral nervous system.    Abstract:   To understand the developmental role of Hoxb-8, this relatively 5 Hoxb gene was ectopically expressed in embryonic regions where only more 3 Hox genes are normally expressed. Hoxb-8 coding sequences driven by a retinoic acid receptor beta2 promoter fragment were introduced in the mouse germ line by pronuclear injection. The promoter was chosen with the aim to extend rostrally the expression domain of the gene in neurectoderm and mesoderm at the time of development when Hox gene expression domains are being established. Embryos developing from DNA-injected zygotes, and from transgenic mouse lines were analyzed. Pattern alterations were observed in transgenic embryos, some of which involved the peripheral nervous system. Spinal ganglia in the mouse are first detectable around embryonic day 9.5. By day 11.5, the first of these ganglia (C1, Frorieps ganglion) has degenerated in the mouse and other amniotes. In contrast, this first ganglion did persist in the Hoxb-8 gain-of-function transgenic mice. We have started to take advantage of the phenotype of transgenic versus wild-type embryos to understand the mechanisms underlying the ontogeny and degeneration of Frorieps ganglion in wild-type mice, and the role of Hoxb-8 in C1 maintenance in transgenic embryos. The present work describes a morphological, histological and immunocytological analysis of both the degenerating and the permanent C1, and a preliminary characterization of the axonal extensions from the transgenic C1. We discuss the methodology of generating gain-of-function transgenic mice to study the genetics of pattern formation along the antero-posterior axis, and the usefulness of analyzing these particular Hoxb-8 transgenic embryos to understand some aspects of the ontogenesis and development of the upper cervical dorsal root ganglia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I170,I170)","v":9034163},{"$f":"(LEN($J170) - LEN(SUBSTITUTE(LOWER($J170),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J170) - LEN(SUBSTITUTE(LOWER($J170),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J170) - LEN(SUBSTITUTE(LOWER($J170),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B170:D170)","v":1},1997,"Cytochromes P450 11: expression of the CYP19 (aromatase) gene: an unusual case of alternative promoter usage.","Simpson",9034163,"Cytochromes P450 11: expression of the CYP19 (aromatase) gene: an unusual case of alternative promoter usage.    Abstract:   Family 19 of the P450 super family is responsible for the conversion of C19 androgenic steroids to the corresponding estrogens, a reaction known as aromatization because it involves conversion of the delta4-3-one A-ring of the androgens to the corresponding phenolic A-ring characteristic of estrogens. The gene encoding human aromatase has been cloned and characterized and shown to be unusual compared to genes encoding other P450 enzymes, because there are numerous untranslated first exons that occur in aromatase transcripts in a tissue-specific fashion due to differential splicing as a consequence of the use of tissue-specific promoters. Thus, expression in the ovary uses a proximal promoter that is regulated primarily by cAMP. On the other hand, expression in the placenta uses a distal promoter located at least 40 kb upstream of the start of transcription that is regulated by retinoids. Other promoters are used in brain and adipose tissue. In the latter case, class I cytokines such as IL-6 and IL-11, as well as TNF-alpha, are important regulatory factors. A common 3-splice junction located upstream of the start of translation is used in all of the splicing events involved in the use of these various promoters. Thus, the coding region of the transcripts, and hence the protein, are identical regardless of the tissue site of expression; what differs in a tissue-specific fashion is the 5-end of the transcripts. This pattern of expression has great significance both from a phylogenetic and ontogenetic standpoint, as well as for the physiology and pathophysiology of estrogen formation, as will be discussed in this review."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I171,I171)","v":9157362},{"$f":"(LEN($J171) - LEN(SUBSTITUTE(LOWER($J171),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J171) - LEN(SUBSTITUTE(LOWER($J171),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J171) - LEN(SUBSTITUTE(LOWER($J171),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B171:D171)","v":1},1996,"[Development of the cutaneous nervous system].","Saxod",9157362,"[Development of the cutaneous nervous system].    Abstract:   Skin of vertebrates is richly innervated, mainly by sensory nerve fibres which form a well organized pattern, particularly around phaners. This innervation develops segmentally (dermatomes) from cutaneous branches provided by spinal nerves. The innervation begins at 13 days (E 13) in the mouse embryo and, although hair buds form at E 16, follicles are only innervated from 5 days postnatally being complete at about 20 days. In the chick skin, innervation forms a regular and characteristic pattern around feathers, and can be visualized on whole mounts. Its development can be traced from 6 days of development in relation to feather morphogenesis. Experiments producing non formation of spinal ganglia (X-ray irradiation or neural tube ablation) or production of neoapteria (hydrocortisone treatment) or ectopic feathers on scales (retinoic acid treatment) show there is a close link between feather development and nerve pattern formation. In vitro co-cultures of dorsal root ganglia and epidermis combined with the use of synthesis inhibitors and antibodies, showed that epidermis has a repulsive effect on nerve fibres mediated, at least in part, by chondroitin sulphate proteoglycans. These compounds have been localized, using antibodies mainly at the base of the feather buds and seem to play a key role in the construction of the fine nerve pattern around feather follicles. In conclusion, the specific nerve patterns are the final result of selective responses of growing nerve endings to unique combinations of local cues and conflicting interactions which are developmentally regulated in parallel with the morphogenesis of phaners."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I172,I172)","v":7584721},{"$f":"(LEN($J172) - LEN(SUBSTITUTE(LOWER($J172),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J172) - LEN(SUBSTITUTE(LOWER($J172),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J172) - LEN(SUBSTITUTE(LOWER($J172),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B172:D172)","v":1},1995,"[Midkine in relation to development and pathological status of the nervous system].","Muramatsu",7584721,"[Midkine in relation to development and pathological status of the nervous system].    Abstract:   Midkine (MK) is a novel heparin-binding growth factor whose expression is regulated by retinoic acid. Midkine is structurally unrelated to other growth factors, and together with pleiotrophin (PTN) subsequently cloned forms a new family of growth factors. Midkine enhances neurite outgrowth and survival of several embryonic neurons. Midkine mRNA is strongly expressed in the nervous system during the midgestation period, while the normal adult brain scarcely expresses it. Immunohistochemical studies revealed midkine localization beside radial glial processes along which neurons migrate. Upon experimental brain infarction in the rat, midkine expression in the ischemic region begins as early as 1 day after the operation. Senile plaques of patients with Alzheimers disease invariability express midkine. These findings indicate that midkine plays significant roles both in the formation and repair of the central nervous system and processes leading to its diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I173,I173)","v":7484378},{"$f":"(LEN($J173) - LEN(SUBSTITUTE(LOWER($J173),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J173) - LEN(SUBSTITUTE(LOWER($J173),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J173) - LEN(SUBSTITUTE(LOWER($J173),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B173:D173)","v":1},1995,"Retinoic acid synthesis in the developing spinal cord.","Dräger",7484378,"Retinoic acid synthesis in the developing spinal cord.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I174,I174)","v":7821640},{"$f":"(LEN($J174) - LEN(SUBSTITUTE(LOWER($J174),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J174) - LEN(SUBSTITUTE(LOWER($J174),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J174) - LEN(SUBSTITUTE(LOWER($J174),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B174:D174)","v":1},1994,"The expression of retinoic acid receptors in Xenopus development.","Sharpe",7821640,"The expression of retinoic acid receptors in Xenopus development.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I175,I175)","v":8005023},{"$f":"(LEN($J175) - LEN(SUBSTITUTE(LOWER($J175),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J175) - LEN(SUBSTITUTE(LOWER($J175),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J175) - LEN(SUBSTITUTE(LOWER($J175),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B175:D175)","v":1},1994,"Vitamins, folic acid and the cause and prevention of neural tube defects.","Seller",8005023,"Vitamins, folic acid and the cause and prevention of neural tube defects.    Abstract:   Primary prevention of neural tube defects has been demonstrated in humans by maternal therapy with multivitamins and folic acid or folic acid alone. It has also been shown in several animal models of neural tube defects. One of these, the curly tail mouse, has been used extensively to study which agents will prevent neural tube defects in embryos when administered to the mother in early pregnancy. Prevention is achieved with retinoic acid, inositol and the DNA inhibitors hydroxyurea, mitomycin C, 5-fluorouracil and cytosine arabinoside. In no case were neural tube defects prevented in every embryo. A possible preventive effect was seen with riboflavin, vitamin C and vitamin D2. Despite the use of a variety of dose levels, no prevention was achieved with folic acid, folinic acid, Pregnavite Forte F tablets, pyridoxine or vitamin B12, or triamcinolone and cycloheximide (inhibitors of mRNA and protein synthesis, respectively), zinc, homocysteine, methionine and thymidine. Various studies have investigated whether there is a biochemical lesion in folate metabolism in women who have had children with neural tube defects. While there is no difference in their dietary intake of folate compared with control patients, the correlation between their dietary folate and the level of folate in both serum and red blood cells is distorted. Also they are less efficient at raising their folate levels after a folate load. The effects are minor but may hint at a lesion which, if identified, could act as a marker for at risk women."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I176,I176)","v":7833854},{"$f":"(LEN($J176) - LEN(SUBSTITUTE(LOWER($J176),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J176) - LEN(SUBSTITUTE(LOWER($J176),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J176) - LEN(SUBSTITUTE(LOWER($J176),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B176:D176)","v":1},1994,"Hox genes and the identity of motor neurons in the hindbrain.","Kessel",7833854,"Hox genes and the identity of motor neurons in the hindbrain.    Abstract:   The Hox genes comprise a gene family of thirty-eight members in vertebrates. The genes are organized in four gene clusters and activated during gastrulation. Analysis of embryonic expression patterns has indicated that morphological segments along the body axis are characterized by different combinations of expressed Hox genes, the Hox codes. Hox codes can be influenced by exposing embryos to retinoic acid, concomitantly with perturbation of segmental identities. In the murine hindbrain this can be clearly demonstrated for the preotic region containing the trigeminal and facial motor nuclei. The correlation between normal or perturbed segment morphology and the Hox codes is reviewed and discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I177,I177)","v":7907865},{"$f":"(LEN($J177) - LEN(SUBSTITUTE(LOWER($J177),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J177) - LEN(SUBSTITUTE(LOWER($J177),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J177) - LEN(SUBSTITUTE(LOWER($J177),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B177:D177)","v":1},1993,"Molecular mechanisms of segmental patterning in the vertebrate hindbrain and neural crest.","Wilkinson",7907865,"Molecular mechanisms of segmental patterning in the vertebrate hindbrain and neural crest.    Abstract:   Recent work has shown that segmentation underlies the patterning of the vertebrate hindbrain and its neural crest derivatives. Several genes have been identified with segment-restricted expression, and evidence is now emerging regarding their function and regulatory relationships. The expression patterns of Hox genes and the phenotype of null mutants indicate roles in specifying segment identity. A zinc finger gene Krox-20 is a segment-specific regulator of Hox expression, and it seems probable that retinoic acid receptors also regulate Hox genes in the hindbrain. The receptor tyrosine kinase gene Sek may mediate cell-cell interactions that lead to segmentation. These studies provide a starting point for understanding the molecular basis of segmental patterning in the hindbrain."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I178,I178)","v":8494265},{"$f":"(LEN($J178) - LEN(SUBSTITUTE(LOWER($J178),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J178) - LEN(SUBSTITUTE(LOWER($J178),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J178) - LEN(SUBSTITUTE(LOWER($J178),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B178:D178)","v":1},1993,"Retinoids in embryonic development.","Eichele",8494265,"Retinoids in embryonic development.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I179,I179)","v":8179844},{"$f":"(LEN($J179) - LEN(SUBSTITUTE(LOWER($J179),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J179) - LEN(SUBSTITUTE(LOWER($J179),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J179) - LEN(SUBSTITUTE(LOWER($J179),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B179:D179)","v":1},1993,"Development of trophic interactions in the vertebrate peripheral nervous system.","Vogel",8179844,"Development of trophic interactions in the vertebrate peripheral nervous system.    Abstract:   During embryogenesis, the neurons of vertebrate sympathetic and sensory ganglia become dependent on neurotrophic factors, derived from their targets, for survival and maintenance of differentiated functions. Many of these interactions are mediated by the neurotrophins NGF, BDNF, and NT3 and the receptor tyrosine kinases encoded by genes of the trk family. Both sympathetic and sensory neurons undergo developmental changes in their responsiveness to NGF, the first neurotrophin to be identified and characterized. Subpopulations of sensory neurons do not require NGF for survival, but respond instead to BDNF or NT3 with enhanced survival. In addition to their classic effects on neuron survival, neurotrophins influence the differentiation and proliferation of neural crest-derived neuronal precursors. In both sympathetic and sensory systems, production of neurotrophins by target cells and expression of neurotrophin receptors by neurons are correlated temporally and spatially with innervation patterns. In vitro, embryonic sympathetic neurons require exposure to environmental cues, such as basic FGF and retinoic acid to acquire neurotrophin-responsiveness; in contrast, embryonic sensory neurons acquire neurotrophin-responsiveness on schedule in the absence of these molecules."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I180,I180)","v":8099265},{"$f":"(LEN($J180) - LEN(SUBSTITUTE(LOWER($J180),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J180) - LEN(SUBSTITUTE(LOWER($J180),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J180) - LEN(SUBSTITUTE(LOWER($J180),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B180:D180)","v":1},1993,"Homeobox genes in the developing central nervous system.","Boncinelli",8099265,"Homeobox genes in the developing central nervous system.    Abstract:   A number of genes containing sequences coding for DNA-binding domains homologues to homeobox sequences in Drosophila have been isolated in vertebrate and their mechanism of action have been studied. In Particular Hox family genes share with Drosophila homeotic genes a genomic organization in gene clusters and an expression pattern that is similar in a number of important respects. In situ hybridization experiment have shown that there is a strict correspondence, or colinearity, between the order of the Hox genes (3 to 5) within the chromosomal cluster and that of their expression domains (anterior to posterior) in the embryo. Recent data obtained in embryonal carcinoma (EC) cells induced to differentiate by retinoic acid (RA) cast some light on the molecular mechanisms underlying the colinear expression of the Hox genes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I181,I181)","v":7916256},{"$f":"(LEN($J181) - LEN(SUBSTITUTE(LOWER($J181),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J181) - LEN(SUBSTITUTE(LOWER($J181),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J181) - LEN(SUBSTITUTE(LOWER($J181),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B181:D181)","v":1},1993,"Molecular mechanisms of segmental patterning in the vertebrate hindbrain.","Wilkinson",7916256,"Molecular mechanisms of segmental patterning in the vertebrate hindbrain.    Abstract:   The finding that pattern formation in the vertebrate hindbrain occurs through a process of segmentation raises the question of the underlying molecular mechanisms. A number of genes have been implicated in this pattern through their segment-restricted expression, and the function and possible regulatory relationships of these are discussed. There is now strong evidence that certain Hox genes are involved in specifying hindbrain segments and neural crest derivatives that contribute to cranial ganglia and the branchial arches. It is likely that retinoic acid receptors either directly or indirectly regulate Hox gene expression in the hindbrain. The zinc finger gene Krox-20 controls the segment-restricted up-regulation of at least one Hox gene, Hox-B2. Studies of the Krox-20 gene reveal a progressive sharpening of its expression domains that reflect cellular interactions leading to segment formation. A receptor tyrosine kinase gene, Sek, has been implicated in such cellular interactions by its rhombomeric expression pattern. In addition, this receptor kinase may be involved in mesoderm segmentation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I182,I182)","v":1359884},{"$f":"(LEN($J182) - LEN(SUBSTITUTE(LOWER($J182),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J182) - LEN(SUBSTITUTE(LOWER($J182),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J182) - LEN(SUBSTITUTE(LOWER($J182),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B182:D182)","v":1},1992,"Retinoic acid and development of the central nervous system.","Maden",1359884,"Retinoic acid and development of the central nervous system.    Abstract:   We consider the evidence that RA, the vitamin A metabolite, is involved in three fundamental aspects of the development of the CNS: 1) the stimulation of axon outgrowth in particular neuronal sub-types; 2) the migration of the neural crest; and 3) the specification of rostrocaudal position in the developing CNS (forebrain, midbrain, hindbrain, spinal cord). The evidence we discuss involves RA-induction of neurites in cell cultures and explants of neural tissue; the teratological effects of RA on the embryos nervous system; the observation that RA can be detected endogenously in the spinal cord; and the fact that the receptors and binding proteins for RA are expressed in precise domains and neuronal cell types within the nervous system."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I183,I183)","v":1350531},{"$f":"(LEN($J183) - LEN(SUBSTITUTE(LOWER($J183),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J183) - LEN(SUBSTITUTE(LOWER($J183),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J183) - LEN(SUBSTITUTE(LOWER($J183),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B183:D183)","v":1},1992,"Mechanism of anteroposterior axis specification in vertebrates. Lessons from the amphibians.","Slack",1350531,"Mechanism of anteroposterior axis specification in vertebrates. Lessons from the amphibians.    Abstract:   Interest in the problem of anteroposterior specification has quickened because of our near understanding of the mechanism in Drosophila and because of the homology of Antennapedia-like homeobox gene expression patterns in Drosophila and vertebrates. But vertebrates differ from Drosophila because of morphogenetic movements and interactions between tissue layers, both intimately associated with anteroposterior specification. The purpose of this article is to review classical findings and to enquire how far these have been confirmed, refuted or extended by modern work. The quot;pre-molecularquot; work suggests that there are several steps to the process: (i) Formation of anteroposterior pattern in mesoderm during gastrulation with posterior dominance. (ii) Regional specific induction of ectoderm to form neural plate. (iii) Reciprocal interactions from neural plate to mesoderm. (iv) Interactions within neural plate with posterior dominance. Unfortunately, almost all the observable markers are in the CNS rather than in the mesoderm where the initial specification is thought to occur. This has meant that the specification of the mesoderm has been assayed indirectly by transplantation methods such as the Einsteckung. New molecular markers now supplement morphological ones but they are still mainly in the CNS and not the mesoderm. A particular interest attaches to the genes of the Antp-like HOX clusters since these may not only be markers but actual coding factors for anteroposterior levels. We have a new understanding of mesoderm induction based on the discovery of activins and fibroblast growth factors (FGFs) as candidate inducing factors. These factors have later consequences for anteroposterior pattern with activin tending to induce anterior, and FGF posterior structures. Recent work on neural induction has implicated cAMP and protein kinase C (PKC) as elements of the signal transduction pathway and has provided new evidence for the importance of tangential neural induction. The regional specificity of neural induction has been reinvestigated using molecular markers and provides conclusions rather similar to the classical work. Defects in the axial pattern may be produced by retinoic acid but it remains unclear whether its effects are truly coordinate ones or are concentrated in certain regions of high sensitivity. In general the molecular studies have supported and reinforced the quot;pre-molecular onesquot;. Important questions still remain: (i) How much pattern is there in the mesoderm (how many states?) (ii) How is this pattern generated by the invaginating organizer? (iii) Is there one-to-one transmission of codings to the neural plate? (iv) What is the nature of the interactions within the neural plate? (v) Are the HOX cluster genes really the anteroposterior codings?"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I184,I184)","v":1685594},{"$f":"(LEN($J184) - LEN(SUBSTITUTE(LOWER($J184),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J184) - LEN(SUBSTITUTE(LOWER($J184),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J184) - LEN(SUBSTITUTE(LOWER($J184),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B184:D184)","v":1},1991,"[The role of retinoic acid in the differentiation and embryogenesis].","Momoi",1685594,"[The role of retinoic acid in the differentiation and embryogenesis].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I185,I185)","v":1979485},{"$f":"(LEN($J185) - LEN(SUBSTITUTE(LOWER($J185),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J185) - LEN(SUBSTITUTE(LOWER($J185),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J185) - LEN(SUBSTITUTE(LOWER($J185),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B185:D185)","v":1},1990,"Retinoic acid: the morphogen of the main body axis?","Green",1979485,"Retinoic acid: the morphogen of the main body axis?    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I186,I186)","v":2576371},{"$f":"(LEN($J186) - LEN(SUBSTITUTE(LOWER($J186),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J186) - LEN(SUBSTITUTE(LOWER($J186),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J186) - LEN(SUBSTITUTE(LOWER($J186),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B186:D186)","v":1},1989,"Retinoids, homeobox genes, and limb morphogenesis.","Brockes",2576371,"Retinoids, homeobox genes, and limb morphogenesis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I187,I187)","v":2955181},{"$f":"(LEN($J187) - LEN(SUBSTITUTE(LOWER($J187),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J187) - LEN(SUBSTITUTE(LOWER($J187),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J187) - LEN(SUBSTITUTE(LOWER($J187),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B187:D187)","v":1},1987,"Major auricular malformations due to Accutane (isotretinoin).","Jahn",2955181,"Major auricular malformations due to Accutane (isotretinoin).    Abstract:   Vitamin A and vitamin A derivatives have been described as etiologic factors for a number of congenital malformations. Two infants are presented with major auricular malformations including anotia and severe microtia. The infants were products of a pregnancy complicated by Accutane ingestion during the first trimester. Both infants had associated central nervous system malformations. With the increasing use of Accutane for the treatment of cystic acne in young women of child-bearing age, the dangers of teratogenesis in the head and neck area are greatly increased. This presentation will review two such cases as well as give an overview of the embryogenesis and teratogenesis of the auricle."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I188,I188)","v":4063181},{"$f":"(LEN($J188) - LEN(SUBSTITUTE(LOWER($J188),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J188) - LEN(SUBSTITUTE(LOWER($J188),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J188) - LEN(SUBSTITUTE(LOWER($J188),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B188:D188)","v":1},1985,"Unruly hair.","Mortimer",4063181,"Unruly hair.    Abstract:   One of the difficulties dermatologists encounter when attempting to diagnose rare scalp hair abnormalities is knowing where to start. Faced with a patient presenting with frizzy hair it is helpful to have a systematic approach rather than simply thumb through the books. Price (1979) classifies anomalies of the hair shaft in to those associated with increased fragility which consequently give rise to alopecia, and those which are not thus associated. There is a significant group of disorders which present with unruly hair, and these have been described under all manner of titles, including crinkly, woolly, kinky, crimped, frizzly, steely, spunglass, in an attempt to define their clinical appearance. This only serves to confuse the issue as no one word adequately describes many of these abnormalities. I would like to suggest an approach for categorizing and diagnosing unruly hair forms, based on a review of the literature as well as on experience with such cases. This is a modified and extended version of the only previous classification of unruly hair proposed by Lantis and Pepper (1978). I accept that there are some individual cases which are difficult to classify and remain unique."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I189,I189)","v":3991734},{"$f":"(LEN($J189) - LEN(SUBSTITUTE(LOWER($J189),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J189) - LEN(SUBSTITUTE(LOWER($J189),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J189) - LEN(SUBSTITUTE(LOWER($J189),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B189:D189)","v":1},1985,"Induction-dependent and lineage-dependent models for cell diversification are mutually exclusive.","Holtzer",3991734,"Induction-dependent and lineage-dependent models for cell diversification are mutually exclusive.    Abstract:   The purpose of this brief review is to put into perspective just how little is known about the mechanisms that control the assembly of the differentiation program of any cell type. Any number of quot;trivialquot; changes in the microenvironment of a Friend erythroleukemic or of a neuroblastoma cell induces both covertly differentiated cells to reveal their lineage affiliations. Demethylating molecules, BudR, retinoic acid, cAMP, butyrate or other quot;inducing moleculesquot; do not, however, transform the descendents of the neuroblastoma cell into a Hb- synthesizing cell or vice versa. For thousands of generations both of these immortialized lines transmit to their daughters their unique, lineage-dependent differentiation programs with great fidelity. The stability of the inherited transcription complex that is ultimately responsible for this covert differentiation program of these cell lines--or of normal precursor cells--is awesome. Clearly, with these immortalized cells as with normal chick blastodisc cells, the cells microenvironment plays a major role in permitting or blocking the expression of the cells inherited differentiation program. But the program itself must be generated by intracellular mechanisms and must be inherited; its assembly is not dependent upon inductive events initiated by exogenous molecules."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I190,I190)","v":26178026},{"$f":"(LEN($J190) - LEN(SUBSTITUTE(LOWER($J190),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J190) - LEN(SUBSTITUTE(LOWER($J190),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J190) - LEN(SUBSTITUTE(LOWER($J190),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B190:D190)","v":0},2015,"Maternal micronutrient deficiencies and related adverse neonatal outcomes after bariatric surgery: a systematic review.","Jans",26178026,"Maternal micronutrient deficiencies and related adverse neonatal outcomes after bariatric surgery: a systematic review.    Abstract:   Pregnant and postpartum women with a history of bariatric surgery are at risk of micronutrient deficiencies as a result of the combination of physiologic changes related to pregnancy and iatrogenic postoperative alterations in the absorption and metabolism of crucial nutrients. This systematic review investigates micronutrient deficiencies and related adverse clinical outcomes in pregnant and postpartum women after bariatric surgery. A systematic approach involving critical appraisal was conducted independently by 2 researchers to examine deficiencies of phylloquinone, folate, iron, calcium, zinc, magnesium, iodide, copper, and vitamins A, D, and B-12 in pregnant and postpartum women after bariatric surgery, together with subsequent outcomes in the neonates. The search identified 29 relevant cases and 8 cohort studies. The quality of reporting among the case reports was weak according to the criteria based on the CARE (CAse REporting) guidelines as was that for the cohort studies based on the criteria from the Cohort Study Quality Assessment list of the Dutch Cochrane Center. The most common adverse neonatal outcomes related to maternal micronutrient deficiencies include visual complications (vitamin A), intracranial hemorrhage (phylloquinone), neurological and developmental impairment (vitamin B-12), and neural tube defects (folate). On the basis of the systematically collected information, we conclude that the evidence on micronutrient deficiencies in pregnant and postpartum women after bariatric surgery and subsequent adverse neonatal outcomes remains weak and inconclusive."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I191,I191)","v":25664848},{"$f":"(LEN($J191) - LEN(SUBSTITUTE(LOWER($J191),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J191) - LEN(SUBSTITUTE(LOWER($J191),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J191) - LEN(SUBSTITUTE(LOWER($J191),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B191:D191)","v":0},2015,"Building a second brain in the bowel.","Avetisyan",25664848,"Building a second brain in the bowel.    Abstract:   The enteric nervous system (ENS) is sometimes called the quot;second brainquot; because of the diversity of neuronal cell types and complex, integrated circuits that permit the ENS to autonomously regulate many processes in the bowel. Mechanisms supporting ENS development are intricate, with numerous proteins, small molecules, and nutrients that affect ENS morphogenesis and mature function. Damage to the ENS or developmental defects cause vomiting, abdominal pain, constipation, growth failure, and early death. Here, we review molecular mechanisms and cellular processes that govern ENS development, identify areas in which more investigation is needed, and discuss the clinical implications of new basic research."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I192,I192)","v":23466416},{"$f":"(LEN($J192) - LEN(SUBSTITUTE(LOWER($J192),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J192) - LEN(SUBSTITUTE(LOWER($J192),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J192) - LEN(SUBSTITUTE(LOWER($J192),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B192:D192)","v":0},2013,"Epigenetic regulation of neural stem cell fate during corticogenesis.","MuhChyi",23466416,"Epigenetic regulation of neural stem cell fate during corticogenesis.    Abstract:   The cerebral cortex comprises over three quarters of the brain, and serves as structural basis for the sophisticated perceptual and cognitive functions. It develops from common multipotent neural stem cells (NSCs) that line the neural tube. Development of the NSCs encompasses sequential phases of progenitor expansion, neurogenesis, and gliogenesis along with the progression of developmental stages. Interestingly, NSCs steadfastly march through all of these phases and give rise to specific neural cell types in a temporally defined and highly predictable manner. Herein, we delineate the intrinsic and extrinsic factors that dictate the progression and tempo of NSC differentiation during cerebral cortex development, and how epigenetic modifications contribute to the dynamic properties of NSCs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I193,I193)","v":22855724},{"$f":"(LEN($J193) - LEN(SUBSTITUTE(LOWER($J193),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J193) - LEN(SUBSTITUTE(LOWER($J193),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J193) - LEN(SUBSTITUTE(LOWER($J193),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B193:D193)","v":0},2012,"Molecular mechanisms of inner ear development.","Wu",22855724,"Molecular mechanisms of inner ear development.    Abstract:   The inner ear is a structurally complex vertebrate organ built to encode sound, motion, and orientation in space. Given its complexity, it is not surprising that inner ear dysfunction is a relatively common consequence of human genetic mutation. Studies in model organisms suggest that many genes currently known to be associated with human hearing impairment are active during embryogenesis. Hence, the study of inner ear development provides a rich context for understanding the functions of genes implicated in hearing loss. This chapter focuses on molecular mechanisms of inner ear development derived from studies of model organisms."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I194,I194)","v":22573366},{"$f":"(LEN($J194) - LEN(SUBSTITUTE(LOWER($J194),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J194) - LEN(SUBSTITUTE(LOWER($J194),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J194) - LEN(SUBSTITUTE(LOWER($J194),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B194:D194)","v":0},2012,"Stem cells, cancer stem-like cells, and natural products.","Efferth",22573366,"Stem cells, cancer stem-like cells, and natural products.    Abstract:   Somatic stem cells can be found in many rapidly regenerating tissues, e.g., the skin, gastrointestinal mucosa, and hematopoietic system, but are also present at low numbers in non-regenerative organs such as the heart and brain. In these organs, somatic stem cells aid in normal tissue homeostasis and repair after injury as well as self-renewal and the generation of specific progenitor cells during differentiation. Cancer stem-like cells are a small subpopulation of self-renewing cells that are able to proliferate upon appropriate stimulation and differentiate into heterogeneous lineages in tumors. Modulation of the behavior of normal tissue stem cells and cancer stem-like cells is an emerging and thriving new field of research. The present review gives an overview of the state-of-the-art findings and highlights perspectives for future scientific developments and clinical application."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I195,I195)","v":21801012},{"$f":"(LEN($J195) - LEN(SUBSTITUTE(LOWER($J195),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J195) - LEN(SUBSTITUTE(LOWER($J195),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J195) - LEN(SUBSTITUTE(LOWER($J195),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B195:D195)","v":0},2011,"Neurogenesis at the brain-cerebrospinal fluid interface.","Lehtinen",21801012,"Neurogenesis at the brain-cerebrospinal fluid interface.    Abstract:   Cerebral cortical progenitor cells can be classified into several different types, and each progenitor type integrates cell-intrinsic and cell-extrinsic cues to regulate neurogenesis. On one hand, cell-intrinsic mechanisms that depend upon appropriate apical-basal polarity are established by adherens junctions and apical complex proteins and are particularly important in progenitors with apical processes contacting the lateral ventricle. The apical protein complexes themselves are concentrated at the ventricular surface, and apical complex proteins regulate mitotic spindle orientation and cell fate. On the other hand, remarkably little is known about how cell-extrinsic cues signal to progenitors and couple with cell-intrinsic mechanisms to instruct neurogenesis. Recent research shows that the cerebrospinal fluid, which contacts apical progenitors at the ventricular surface and bathes the apical complex of these cells, provides growth- and survival-promoting cues for neural progenitor cells in developing and adult brain. This review addresses how the apical-basal polarity of progenitor cells regulates cell fate and allows progenitors to sample diffusible signals distributed by the cerebrospinal fluid. We also review several classes of signaling factors that the cerebrospinal fluid distributes to the developing brain to instruct neurogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I196,I196)","v":21524412},{"$f":"(LEN($J196) - LEN(SUBSTITUTE(LOWER($J196),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J196) - LEN(SUBSTITUTE(LOWER($J196),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J196) - LEN(SUBSTITUTE(LOWER($J196),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B196:D196)","v":0},2011,"[Human pluripotent stem cells: opening key for pathological modeling].","Maury",21524412,"[Human pluripotent stem cells: opening key for pathological modeling].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I197,I197)","v":20077417},{"$f":"(LEN($J197) - LEN(SUBSTITUTE(LOWER($J197),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J197) - LEN(SUBSTITUTE(LOWER($J197),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J197) - LEN(SUBSTITUTE(LOWER($J197),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B197:D197)","v":0},2010,"The influence of dietary status on the cognitive performance of children.","Benton",20077417,"The influence of dietary status on the cognitive performance of children.    Abstract:   The rapid rate of growth of the brain during the last third of gestation and the early postnatal stage makes it vulnerable to an inadequate diet, although brain development continues into adulthood and micronutrient status can influence functioning beyond infancy. Certain dietary deficiencies during the first 2 years of life, for example iodine and iron, create problems that are not reversed by a later adequate diet. It is important that the intake of micronutrients varies greatly between individuals as they are essential for metabolism in general and in particular cell division and hence growth. In developing countries, there is consistent evidence that the adequacy of diet has lasting implications for cognitive development. In particular, attention has been directed to protein-calorie malnutrition and more specifically the intake of iron, iodine and vitamin A, a deficiency of which damages eyesight. In industrialized countries variations in diet are less influential, although a few well-designed studies have reported that multivitamin and mineral supplementations influence anti-social behaviour and intelligence. In the short term, there is increasing evidence that the missing of breakfast has negative consequences late in the morning. A working hypothesis is that meals of a low rather than high glycaemic load are beneficial."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I198,I198)","v":18759328},{"$f":"(LEN($J198) - LEN(SUBSTITUTE(LOWER($J198),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J198) - LEN(SUBSTITUTE(LOWER($J198),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J198) - LEN(SUBSTITUTE(LOWER($J198),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B198:D198)","v":0},2008,"Neural differentiation of human embryonic stem cells.","Dhara",18759328,"Neural differentiation of human embryonic stem cells.    Abstract:   Availability of human embryonic stem cells (hESC) has enhanced human neural differentiation research. The derivation of neural progenitor (NP) cells from hESC facilitates the interrogation of human embryonic development through the generation of neuronal subtypes and supporting glial cells. These cells will likely lead to novel drug screening and cell therapy uses. This review will discuss the current status of derivation, maintenance and further differentiation of NP cells with special emphasis on the cellular signaling involved in these processes. The derivation process affects the yield and homogeneity of the NP cells. Then when exposed to the correct environmental signaling cues, NP cells can follow a unique and robust temporal cell differentiation process forming numerous phenotypes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I199,I199)","v":17250892},{"$f":"(LEN($J199) - LEN(SUBSTITUTE(LOWER($J199),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J199) - LEN(SUBSTITUTE(LOWER($J199),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J199) - LEN(SUBSTITUTE(LOWER($J199),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B199:D199)","v":0},2007,"Maternal effects and the evolution of brain size in birds: overlooked developmental constraints.","Garamszegi",17250892,"Maternal effects and the evolution of brain size in birds: overlooked developmental constraints.    Abstract:   A central dogma for the evolution of brain size posits that the maintenance of large brains incurs developmental costs, because they need prolonged periods to grow during the early ontogeny. Such constraints are supported by the interspecific relationship between ontological differences and relative brain size in birds and mammals. Given that mothers can strongly influence the development of the offspring via maternal effects that potentially involve substances essential for growing brains, we argue that such effects may represent an important but overlooked component of developmental constraints on brain size. To demonstrate the importance of maternal effect on the evolution of brains, we investigated the interspecific relationship between relative brain size and maternal effects, as reflected by yolk testosterone, carotenoids, and vitamins A and E in a phylogenetic study of birds. Females of species with relatively large brains invested more in eggs in terms of testosterone and vitamin E than females of species with small brains. The effects of carotenoid and vitamin A levels on the evolution of relative brain size were weaker and non-significant. The association between relative brain size and yolk testosterone was curvilinear, suggesting that very high testosterone levels can be suppressive. However, at least in moderate physiological ranges, the positive relationship between components of maternal effects and relative brain size may imply one aspect of developmental costs of large brains. The relationship between vitamin E and relative brain size was weakened when we controlled for developmental mode, and thus the effect of this antioxidant may be indirect. Testosterone-enhanced neurogenesis and vitamin E-mediated defence against oxidative stress may have key functions when the brain of the embryo develops, with evolutionary consequences for relative brain size."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I200,I200)","v":16776268},{"$f":"(LEN($J200) - LEN(SUBSTITUTE(LOWER($J200),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J200) - LEN(SUBSTITUTE(LOWER($J200),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J200) - LEN(SUBSTITUTE(LOWER($J200),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B200:D200)","v":0},2006,"[Abnormalities in the development of adrenal gland].","Tanaka",16776268,"[Abnormalities in the development of adrenal gland].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I201,I201)","v":16258411},{"$f":"(LEN($J201) - LEN(SUBSTITUTE(LOWER($J201),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J201) - LEN(SUBSTITUTE(LOWER($J201),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J201) - LEN(SUBSTITUTE(LOWER($J201),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B201:D201)","v":0},2005,"[The action of oxidative stress induced by ethanol on the central nervous system (CNS)].","Augustyniak",16258411,"[The action of oxidative stress induced by ethanol on the central nervous system (CNS)].    Abstract:   The brain is an organ which metabolically consumes about 20% of the total oxygen received by the organism. This causes the generation of free radicals, especially in the presence of some xenobiotics, such as ethanol. In order to prevent free radical-induced cellular damage, the organism developed a defense mechanism, the antioxidative system. The content of both exogenous and endogenous antioxidants in the central nervous system (CNS) is very small in comparison with that of other tissues, which in relation to the high level of polyunsaturated fatty acids (PUFAs) makes the CNS exceptionally susceptible to free-radical damage. The antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GSSG-R) are present in the CNS i.e. in the cortex, cerebellum, hypothalamus, striatum, and spinal cord, where they are responsible for the brains basic functions, both physical and cognitive. Moreover, the highest activity of these enzymes is observed in neurons and/or glial cells. The activity of antioxidant enzymes is significantly changed in the CNS of animals chronically intoxicated with ethanol. The decrease in these activity may indicate at oxidative modification of the enzymatic proteins caused by free radicals which are generated during ethanol and acetaldehyde metabolism. It may also be caused by the decrease in the synthesis rate of these enzymes. However, the increase in the activity of antioxidant enzymes may often be explained as an adaptive reaction to an excess production of free radicals. The catalase is an exception in this respect because the decrease in its activity is related to the enhancement of protein synthesis. Ethanol intoxication also caused a decrease in GSH concentration, especially in the cerebellum, striatum, and cortex. This may be explained by the increase in the concentration of acetaldehyde, which is removed from cells with the use of this antioxidant. The antioxidative abilities of the CNS also depend on exogenous antioxidants which are provided to the organism during food intake. The most important exogenous antioxidant in the CNS is vitamin E. The content of vitamin E as well as that of vitamin C in the CNS is decreased, whereas the content of vitamin A is increased after ethanol administration. The high vitamin A level may cause damage of the central nervous system, especially in young rats exposed to ethanol in the prenatal period."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I202,I202)","v":16041760},{"$f":"(LEN($J202) - LEN(SUBSTITUTE(LOWER($J202),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J202) - LEN(SUBSTITUTE(LOWER($J202),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J202) - LEN(SUBSTITUTE(LOWER($J202),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B202:D202)","v":0},2005,"Role of morphogens in neural crest cell determination.","Jones",16041760,"Role of morphogens in neural crest cell determination.    Abstract:   The neural crest is a transient, migratory cell population found in all vertebrate embryos that generate a diverse range of cell and tissue derivatives including, but not limited, to the neurons and glia of the peripheral nervous system, smooth muscle, connective tissue, melanocytes, craniofacial cartilage, and bone. Over the past few years, many studies have provided tremendous insights into understanding the mechanisms regulating the induction and migration of neural crest cell development. This review highlights the surprising and perhaps unexpected roles for morphogens in these distinct processes. A comparison of studies performed in several different vertebrates emphasizes the requirement for coordination between multiple signaling pathways in the induction and migration of neural crest cells in the developing embryo."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I203,I203)","v":15611656},{"$f":"(LEN($J203) - LEN(SUBSTITUTE(LOWER($J203),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J203) - LEN(SUBSTITUTE(LOWER($J203),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J203) - LEN(SUBSTITUTE(LOWER($J203),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B203:D203)","v":0},2005,"Tuberous sclerosis and insulin resistance. Unlikely bedfellows reveal a TORrid affair.","Shah",15611656,"Tuberous sclerosis and insulin resistance. Unlikely bedfellows reveal a TORrid affair.    Abstract:   The TSC1-TSC2 tumor suppressor complex serves as an interface between insulin and nutrient signaling pathways and the cell growth machinery. Recent work has indicated that the TSC1-TSC2 complex plays a role in the pathobiology of a number of tumor predisposition syndromes, including tuberous sclerosis (TSC1/2), Peutz-Jeghers syndrome (LKB1), and Cowdens syndrome (PTEN), in which the TSC/Rheb/mTOR axis is inappropriately active secondary to loss of tumor suppressor function. Recent work has demonstrated that TSC deficiency imposes a negative autoregulatory loop that suppresses insulin signaling at the post-receptor level, effectively resulting in cell autonomous insulin resistance. Exploitation of this insulin signaling deficiency may hold promise among tailored clinical therapies designed to manage tuberous sclerosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I204,I204)","v":15296973},{"$f":"(LEN($J204) - LEN(SUBSTITUTE(LOWER($J204),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J204) - LEN(SUBSTITUTE(LOWER($J204),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J204) - LEN(SUBSTITUTE(LOWER($J204),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B204:D204)","v":0},2004,"Segmentation and compartition in the early avian hindbrain.","Lumsden",15296973,"Segmentation and compartition in the early avian hindbrain.    Abstract:   For the comparative embryologists of the early 20th century, the segment-like bulges that appear transiently during the early stages of vertebrate hindbrain development were both the object of fascination and the subject of vigorous dispute. Conflicting views were held as to the significance of these rhombomeres to brain development and their more general relevance to head evolution. Whether rhombomeres are inconsequential bumps in the embryonic brain or true segments-iterative or metameric units-has only recently been resolved. A number of studies using more modern techniques (such as immunohistochemistry, in situ hybridisation, axonal tracing, single cell labelling, heterotopic and orthotopic grafting, and the manipulation of gene expression by electroporation) have shown that the hindbrain has a truly metameric cellular organisation. The avian embryo has played a particularly prominent role in such studies by virtue of its large size and accessibility, its amenability to microsurgery, and its well-described anatomy. Furthermore, electrophysiological studies, also on avian embryos, have shown that segmentation of the parent neuroepithelium into rhombomeres plays a crucial part in establishing the functional organization of the hindbrain. Segmentation suggests the early allocation of defined sets of precursor cells and is therefore presumed to allow a specific identity for each successive segment to emerge from a common ground plan. This short review will focus on the contribution the avian embryo has made to our understanding of this fly-like region of the vertebrate brain, in respect of its morphology and neuronal architecture, the cellular and molecular mechanisms involved in establishing and maintaining the segments, and the molecular controls of segmental identity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I205,I205)","v":15212235},{"$f":"(LEN($J205) - LEN(SUBSTITUTE(LOWER($J205),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J205) - LEN(SUBSTITUTE(LOWER($J205),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J205) - LEN(SUBSTITUTE(LOWER($J205),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B205:D205)","v":0},2004,"[Recent advances in neuroblastoma research].","Imaizumi",15212235,"[Recent advances in neuroblastoma research].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I206,I206)","v":14608448},{"$f":"(LEN($J206) - LEN(SUBSTITUTE(LOWER($J206),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J206) - LEN(SUBSTITUTE(LOWER($J206),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J206) - LEN(SUBSTITUTE(LOWER($J206),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B206:D206)","v":0},2003,"The use of folic acid for the prevention of neural tube defects and other congenital anomalies.","Wilson",14608448,"The use of folic acid for the prevention of neural tube defects and other congenital anomalies.    Abstract:    OBJECTIVE : To provide information regarding the use of folic acid for the prevention of neural tube defects (NTDs) and other congenital anomalies, in order that physicians, midwives, nurses, and other health-care workers can assist in the education of women in the preconception phase of their health care. OPTION: Folic acid supplementation is problematic, since 50% of pregnancies are unplanned and the health status of women may not be optimal.  OUTCOMES : Folic acid supplementation has been proven to decrease or minimize specific birth defects.  EVIDENCE : A systematic review of the literature, including review and peer-reviewed articles, government publications, the previous Society of Obstetricians and Gynaecologists of Canada (SOGC) Policy Statement of March 1993, and statements from the American College of Obstetrics and Gynecology, was used to develop a new clinical practice guideline for the SOGC.  VALUES : Peer-review process within the committee structure.  BENEFITS, HARMS, AND COSTS : The benefit is reduced lethal and severe morbidity birth defects and the harm is minimal. The personal cost is of vitamin supplementation on a daily basis and eating a healthy diet.  RECOMMENDATIONS : 1. Women in the reproductive age group should be advised about the benefits of folic acid supplementation during wellness visits (birth control renewal, Pap testing, yearly examination), especially if pregnancy is contemplated. (III-A) 2. Women should be advised to maintain a healthy nutritional diet, as recommended in Canadas Food Guide to Healthy Eating (good or excellent sources of folic acid: broccoli, spinach, peas, Brussels sprouts, corn, beans, lentils, oranges). (III-A) 3. Women who could become pregnant should be advised to take a multivitamin containing 0.4 mg to 1.0 mg of folic acid daily. (II-1A) 4. Women taking a multivitamin with folic acid supplement should be advised not to take more than 1 daily dose of vitamin supplement, as indicated on the product label. (II-2A) 5. Women in intermediate- to high-risk categories for NTDs (NTD-affected previous pregnancy, family history, insulin-dependent diabetes, epilepsy treatment with valproic acid or carbamazepine) should be advised that high-dose folic acid (4.0 mg-5.0 mg daily) supplementation is recommended. This should be taken as folic acid alone, not in a multivitamin format, due to risk of excessive intake of other vitamins such as vitamin A. (I-A) 6. The choice of a 5 mg folic acid daily dose for women considering a pregnancy should be made under medical supervision after minimizing the risk of undiagnosed vitamin B12 deficiency (hypersegmentation of polymorphonuclear cells, macrocystic indices, large ovalocytes, leukopenia, thrombocytopenia, markedly elevated lactate dehydrogenase level, confirmed red blood cell folate level). (II-2A) 7. Signs or symptoms of vitamin B12 deficiency should be considered before initiating folic acid supplementation of doses greater than 1.0 mg. (III-A) 8. A three-generation pedigree on the families of both the pregnant woman and the biological father should be obtained to identify increased risk for congenital birth defects (i.e., NTD, cardiac, chromosomal, genetic). (III-A) 9. Women who become pregnant should be advised of the availability of noninvasive screening tests and invasive diagnostic tests for congenital birth defects (including NTDs): maternal serum quot;triple marker screenquot; at 15 to 20 weeks, ultrasound at 16 to 20 weeks, and amniocentesis after 15 weeks of pregnancy if a positive screening test is present. (I-A) VALIDATION: This is a revision of a previous guideline and information from other consensus reviews from medical and government publications has been used."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I207,I207)","v":12842416},{"$f":"(LEN($J207) - LEN(SUBSTITUTE(LOWER($J207),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J207) - LEN(SUBSTITUTE(LOWER($J207),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J207) - LEN(SUBSTITUTE(LOWER($J207),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B207:D207)","v":0},2003,"Programming the cardiovascular system, kidney and the brain--a review.","Wintour",12842416,"Programming the cardiovascular system, kidney and the brain--a review.    Abstract:   The concept that life before birth or the first environment is important in determining subsequent risk for the development of cardiovascular/metabolic disease is now gaining acceptance. There are substantial data from animal experiments that complement and enhance the epidemiological data from human studies. We argue that any factor which disrupts nephrogenesis, and lowers nephron number, during the period of active nephrogenesis, will induce malapadaptive changes in the future functioning of that kidney and predispose to the onset of adult hypertension. Such factors include exposure of the mother, to a particular low-protein diet, excess synthetic or natural glucocorticoid at certain critical periods, mild vitamin A deficiency, elevated blood glucose, unilateral nephrectomy during the period of nephrogenesis, as well as the deletion of one allele of a gene (GDNF) involved in normal metanephric development. All of these stresses are associated with a reduction (20-40 per cent) in total nephron number in the adult, and the development of hypertension. In some hypertensive models, (rats) there is evidence of alterations in the components of the hippocampal/hypothalamic/pituitary/adrenal axis, whereas in others (sheep) there are alterations in the expression of angiotensinogen (hypothalamus) and angiotensin II receptor type I (AT(1)) in the medulla oblongata. The surprising finding is that the period when the kidney and brain are most vulnerable is very early in development, when both organs are in an extremely primitive state of development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I208,I208)","v":12805994},{"$f":"(LEN($J208) - LEN(SUBSTITUTE(LOWER($J208),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J208) - LEN(SUBSTITUTE(LOWER($J208),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J208) - LEN(SUBSTITUTE(LOWER($J208),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B208:D208)","v":0},2002,"Formation of neural precursor cell populations by differentiation of embryonic stem cells in vitro.","Rathjen",12805994,"Formation of neural precursor cell populations by differentiation of embryonic stem cells in vitro.    Abstract:   Recent interest in the generation of neural lineages by differentiation of embryonic stem cells arises from the opportunities represented by a developmentally normal, unlimited source of material that can be manipulated genetically with precision. Several experimental approaches, which differ conceptually, in the route of differentiation and the characteristics of the resulting cell population have been reported. In this review we undertake a comparative analysis of these approaches and their suitability for experimental investigation or implantation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I209,I209)","v":12069675},{"$f":"(LEN($J209) - LEN(SUBSTITUTE(LOWER($J209),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J209) - LEN(SUBSTITUTE(LOWER($J209),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J209) - LEN(SUBSTITUTE(LOWER($J209),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B209:D209)","v":0},2002,"Vitamins for chronic disease prevention in adults: scientific review.","Fairfield",12069675,"Vitamins for chronic disease prevention in adults: scientific review.    Abstract:    CONTEXT : Although vitamin deficiency is encountered infrequently in developed countries, inadequate intake of several vitamins is associated with chronic disease.  OBJECTIVE : To review the clinically important vitamins with regard to their biological effects, food sources, deficiency syndromes, potential for toxicity, and relationship to chronic disease.  DATA SOURCES AND STUDY SELECTION : We searched MEDLINE for English-language articles about vitamins in relation to chronic diseases and their references published from 1966 through January 11, 2002.  DATA EXTRACTION : We reviewed articles jointly for the most clinically important information, emphasizing randomized trials where available.  DATA SYNTHESIS : Our review of 9 vitamins showed that elderly people, vegans, alcohol-dependent individuals, and patients with malabsorption are at higher risk of inadequate intake or absorption of several vitamins. Excessive doses of vitamin A during early pregnancy and fat-soluble vitamins taken anytime may result in adverse outcomes. Inadequate folate status is associated with neural tube defect and some cancers. Folate and vitamins B(6) and B(12) are required for homocysteine metabolism and are associated with coronary heart disease risk. Vitamin E and lycopene may decrease the risk of prostate cancer. Vitamin D is associated with decreased occurrence of fractures when taken with calcium.  CONCLUSIONS : Some groups of patients are at higher risk for vitamin deficiency and suboptimal vitamin status. Many physicians may be unaware of common food sources of vitamins or unsure which vitamins they should recommend for their patients. Vitamin excess is possible with supplementation, particularly for fat-soluble vitamins. Inadequate intake of several vitamins has been linked to chronic diseases, including coronary heart disease, cancer, and osteoporosis"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I210,I210)","v":11984869},{"$f":"(LEN($J210) - LEN(SUBSTITUTE(LOWER($J210),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J210) - LEN(SUBSTITUTE(LOWER($J210),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J210) - LEN(SUBSTITUTE(LOWER($J210),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B210:D210)","v":0},2002,"Constructing the hindbrain: insights from the zebrafish.","Moens",11984869,"Constructing the hindbrain: insights from the zebrafish.    Abstract:   The hindbrain is responsible for controlling essential functions such as respiration and heart beat that we literally do not think about most of the time. In addition, cranial nerves projecting from the hindbrain control muscles in the jaw, eye, and face, and receive sensory input from these same areas. In all vertebrates that have been studied, the hindbrain passes through a segmented phase shortly after the neural tube has formed, with a series of seven bulges--the rhombomeres--forming along the anterior-posterior extent of the neural tube. Our current understanding of vertebrate hindbrain development comes from integrating data from several model systems. Work on the chick has helped us to understand the cell biology of the rhombomeres, whereas the power of mouse molecular genetics has allowed investigation of the molecular mechanisms underlying their development. This review focuses on the special insights that the zebrafish system has provided to our understanding of hindbrain development. As we will discuss, work in the zebrafish has elucidated inductive events that specify the presumptive hindbrain domain and has identified genes required for hindbrain segmentation and the specification of segment identities."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I211,I211)","v":11596847},{"$f":"(LEN($J211) - LEN(SUBSTITUTE(LOWER($J211),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J211) - LEN(SUBSTITUTE(LOWER($J211),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J211) - LEN(SUBSTITUTE(LOWER($J211),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B211:D211)","v":0},2001,"Neural development, cell-cell signaling, and the quot;two-hitquot; hypothesis of schizophrenia.","Maynard",11596847,"Neural development, cell-cell signaling, and the quot;two-hitquot; hypothesis of schizophrenia.    Abstract:   To account for the complex genetics, the developmental biology, and the late adolescent/early adulthood onset of schizophrenia, the quot;two-hitquot; hypothesis has gained increasing attention. In this model, genetic or environmental factors disrupt early central nervous system (CNS) development. These early disruptions produce long-term vulnerability to a quot;second hitquot; that then leads to the onset of schizophrenia symptoms. The cell-cell signaling pathways involved in nonaxial induction, morphogenesis, and differentiation in the brain, as well as in the limbs and face, could be targets for a quot;first hitquot; during early development. These same pathways, redeployed for neuronal maintenance rather than morphogenesis, may be targets for a quot;second hitquot; in the adolescent or adult brain. Furthermore, dysregulation of cell-cell signaling by a quot;first hitquot; may prime the CNS for a pathologic response to a quot;second hitquot; via the same signaling pathway. Thus, parallel disruption of cell-cell signaling in both the developing and the mature CNS provides a plausible way of integrating genetic, developmental, and environmental factors that contribute to vulnerability and pathogenesis in schizophrenia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I212,I212)","v":11130478},{"$f":"(LEN($J212) - LEN(SUBSTITUTE(LOWER($J212),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J212) - LEN(SUBSTITUTE(LOWER($J212),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J212) - LEN(SUBSTITUTE(LOWER($J212),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B212:D212)","v":0},2000,"Symptom control in the pregnant cancer patient.","MacDougall",11130478,"Symptom control in the pregnant cancer patient.    Abstract:   While much attention has been devoted to cytotoxic drugs and radiation therapy in the pregnant cancer patient, the drugs used for management of symptoms and complications related to cancer during pregnancy have been overlooked. There is substantial overlap between the symptoms of cancer and cancer management and the symptoms related to pregnancy. The mainstay of symptom management is drug therapy and the potential for a drug to be embryotoxic or teratogenic depends on when it is given. In general, drugs not proven safe in pregnancy should be withheld, especially during the first trimester. The few drugs that have been proven to be teratogenic are alcohol, thalidomide, the folic acid antagonists (which includes methotrexate), diethylstilbestrol, and the vitamin A isomers, but there is a good deal of uncertainty about many other therapeutic agents. Placental transport of drugs from mother to fetus must be taken into consideration from the fifth week of gestation to parturition. Although the first trimester is the time of most organ development in the fetus, the brain continues to develop throughout pregnancy and may be damaged later in pregnancy, resulting in diminished intelligence or behavioral problems. This review will focus on the treatment of the most common symptoms of cancer in a pregnant patient and the potential for fetal damage."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I213,I213)","v":11061437},{"$f":"(LEN($J213) - LEN(SUBSTITUTE(LOWER($J213),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J213) - LEN(SUBSTITUTE(LOWER($J213),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J213) - LEN(SUBSTITUTE(LOWER($J213),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B213:D213)","v":0},2000,"Integrin function and regulation in development.","Tarone",11061437,"Integrin function and regulation in development.    Abstract:   Integrins are a large family of membrane receptors, consisting of alpha and beta subunits, that play a pivotal role in the interaction of cells with the extracellular matrix. Such interaction regulates the organization of cells in organs and tissues during development as well as cell differentiation and proliferation. We have shown that unfertilized oocytes express integrins that might be important during fertilization. We also analyzed nervous system and muscle tissue development showing that integrin expression is precisely regulated during organization of these tissues. The results indicate that two distinct integrin alpha subunits mediate the outgrowth of processes in nerve and glial cells. Alpha1 integrin, a laminin receptor, is up-regulated by nerve growth factor and other differentiation stimuli and is involved in neurite extension by nerve cells. In contrast, process extension by glial cells is likely to involve the alphaV integrin. Moreover, the latter integrin subunit is also transiently expressed in muscle of the embryo body where it localizes predominantly at developing myotendinous junctions. After birth this integrin disappears and is substituted by the alpha7 subunit. At the same time, important changes also occur in the expression of the associated beta subunit. In fact, the beta1A isoform which is expressed in fetal muscles, is substituted by beta1D. These isoforms are generated by alternative splicing and differ in only a few amino acid residues at the COOH terminus of the protein. This region of the molecule is exposed at the cytoplasmic face of the plasma membrane and is connected to the actin filaments. Our results show that beta1D, which is expressed only in striated muscle tissues, binds to both cytoskeletal and extracellular matrix proteins with an affinity higher than beta1A. Thus, beta1D provides a stronger link between the cytoskeleton and extracellular matrix necessary to support mechanical tension during muscle contraction. These results indicate that cells can regulate their interactions with the extracellular matrix by changing their expression of alpha integrin subunits and thus ligand specificity, or by more subtle changes involving alternative usage of different cytoplasmic domains. The important role of both alpha and beta integrin subunit cytoplasmic domains during development is further illustrated by the analysis of targeted mutations which we have generated by homologous recombination in mice."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I214,I214)","v":11031905},{"$f":"(LEN($J214) - LEN(SUBSTITUTE(LOWER($J214),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J214) - LEN(SUBSTITUTE(LOWER($J214),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J214) - LEN(SUBSTITUTE(LOWER($J214),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B214:D214)","v":0},2000,"[Vitamin A deficiency and neurological findings].","Tamai",11031905,"[Vitamin A deficiency and neurological findings].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I215,I215)","v":9835019},{"$f":"(LEN($J215) - LEN(SUBSTITUTE(LOWER($J215),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J215) - LEN(SUBSTITUTE(LOWER($J215),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J215) - LEN(SUBSTITUTE(LOWER($J215),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B215:D215)","v":0},1998,"How to build a vertebrate hindbrain. Lessons from genetics.","Schneider-Maunoury",9835019,"How to build a vertebrate hindbrain. Lessons from genetics.    Abstract:   During vertebrate embryogenesis, the hindbrain is the site of a segmentation process which leads to the formation, along the anterior-posterior axis, of 7-8 metameres called rhombomeres. This phenomenon plays an essential role in early hindbrain regionalisation and in the specification of the pattern of developing structures in this region of the brain. Data accumulated during the last 10 years have also shown that rhombomeres are units of gene expression and of cell lineage. Hence, a number of regulatory genes are expressed according to segment-specific patterns in the hindbrain and have been implicated in the pattern formation process. In this review, we focus on the analysis of the function and regulation of these genes along the different steps of hindbrain segmentation, from segment delimitation to acquisition of positional identity. On this basis, we propose a model for the control of early hindbrain development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I216,I216)","v":9787099},{"$f":"(LEN($J216) - LEN(SUBSTITUTE(LOWER($J216),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J216) - LEN(SUBSTITUTE(LOWER($J216),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J216) - LEN(SUBSTITUTE(LOWER($J216),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B216:D216)","v":0},1998,"Mammalian sex determination: from gonads to brain.","Vilain",9787099,"Mammalian sex determination: from gonads to brain.    Abstract:   In mammals, sex is determined by the Y chromosome, which encodes a testis-determining factor (TDF). This factor causes the undifferentiated embryonic gonads to develop as testes rather than ovaries. The testes subsequently produce the male sex hormones that are responsible for all male sexual characteristics. In 1990, the sex-determining gene, TDF, was identified and termed SRY in humans (Sry in mice). It encodes a protein containing a high mobility group (HMG) motif, which confers the ability to bind and to bend DNA. Genetic evidence supporting SRY as TDF came from the observation of a male phenotype in XX mice transgenic for a small genomic fragment containing Sry, and from the study of XY sex-reversed individuals who harbor de novo mutations in the SRY coding sequence. Other non-Y-linked genes involved in sex determination were subsequently found by genetic analysis of XY sex-reversed patients not explained by mutations in SRY. These genes are WT1, SF1, DAX1, and SOX9. A regulatory cascade hypothesis for mammalian sex determination, proposing that SRY represses a negative regulator of male development, was recently supported by observation of mice that expressed a DAX1 transgene and developed as XY sex-reversed females. The role of some sex-determining genes, such as DAX1 and SF1, in the development of the entire reproductive axis, a functionally integrated endocrine axis, leads to a new concept. Normal sexual development may result from the functional and developmental integration of a number of different genes that play roles in sex determination, sexual differentiation, and sexual behavior."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I217,I217)","v":8895453},{"$f":"(LEN($J217) - LEN(SUBSTITUTE(LOWER($J217),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J217) - LEN(SUBSTITUTE(LOWER($J217),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J217) - LEN(SUBSTITUTE(LOWER($J217),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B217:D217)","v":0},1996,"Patterning the vertebrate neuraxis.","Lumsden",8895453,"Patterning the vertebrate neuraxis.    Abstract:   Neuraxial patterning is a continuous process that extends over a protracted period of development. During gastrulation a crude anteroposterior pattern, detectable by molecular markers, is conferred on the neuroectoderm by signals from the endomesoderm that are largely inseparable from those of neural induction itself. This coarse-grained pattern is subsequently reinforced and refined by diverse, locally acting mechanisms. Segmentation and long-range signaling from organizing centers are prominent among the emerging principles governing regional pattern."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I218,I218)","v":8678822},{"$f":"(LEN($J218) - LEN(SUBSTITUTE(LOWER($J218),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J218) - LEN(SUBSTITUTE(LOWER($J218),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J218) - LEN(SUBSTITUTE(LOWER($J218),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B218:D218)","v":0},1996,"Teratogenic effects of alcohol: current status of animal research and in vitro models.","Guerri",8678822,"Teratogenic effects of alcohol: current status of animal research and in vitro models.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I219,I219)","v":8202280},{"$f":"(LEN($J219) - LEN(SUBSTITUTE(LOWER($J219),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J219) - LEN(SUBSTITUTE(LOWER($J219),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J219) - LEN(SUBSTITUTE(LOWER($J219),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B219:D219)","v":0},1994,"Vitamin A in embryonic development.","Maden",8202280,"Vitamin A in embryonic development.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I220,I220)","v":8293455},{"$f":"(LEN($J220) - LEN(SUBSTITUTE(LOWER($J220),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J220) - LEN(SUBSTITUTE(LOWER($J220),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J220) - LEN(SUBSTITUTE(LOWER($J220),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B220:D220)","v":0},1994,"Hedgehog, the floor plate, and the zone of polarizing activity.","Smith",8293455,"Hedgehog, the floor plate, and the zone of polarizing activity.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I221,I221)","v":8974361},{"$f":"(LEN($J221) - LEN(SUBSTITUTE(LOWER($J221),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J221) - LEN(SUBSTITUTE(LOWER($J221),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J221) - LEN(SUBSTITUTE(LOWER($J221),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B221:D221)","v":0},1994,"Recent findings on the mechanisms by which alcohol damages the developing nervous system.","West",8974361,"Recent findings on the mechanisms by which alcohol damages the developing nervous system.    Abstract:   General etiologic categories related to possible mechanisms of fetal alcohol-induced brain damage are explored. Possible general mechanisms include alterations in protein synthesis, prostaglandins, gangliosides, hypoxia and free radical damage. A multiple systems cascade is presented to illustrate how multiple mechanisms could act together to produce a variety of effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I222,I222)","v":8224477},{"$f":"(LEN($J222) - LEN(SUBSTITUTE(LOWER($J222),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J222) - LEN(SUBSTITUTE(LOWER($J222),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J222) - LEN(SUBSTITUTE(LOWER($J222),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B222:D222)","v":0},1993,"Lipocalin structure and function.","Sivaprasadarao",8224477,"Lipocalin structure and function.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I223,I223)","v":8518194},{"$f":"(LEN($J223) - LEN(SUBSTITUTE(LOWER($J223),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J223) - LEN(SUBSTITUTE(LOWER($J223),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J223) - LEN(SUBSTITUTE(LOWER($J223),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B223:D223)","v":0},1993,"Spemanns organizer: models and molecules.","Gilbert",8518194,"Spemanns organizer: models and molecules.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I224,I224)","v":1991316},{"$f":"(LEN($J224) - LEN(SUBSTITUTE(LOWER($J224),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J224) - LEN(SUBSTITUTE(LOWER($J224),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J224) - LEN(SUBSTITUTE(LOWER($J224),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B224:D224)","v":0},1991,"Motorizing the spinal cord.","Lumsden",1991316,"Motorizing the spinal cord.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I225,I225)","v":2099815},{"$f":"(LEN($J225) - LEN(SUBSTITUTE(LOWER($J225),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J225) - LEN(SUBSTITUTE(LOWER($J225),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J225) - LEN(SUBSTITUTE(LOWER($J225),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B225:D225)","v":0},1990,"Transcriptional control and the integration of cell-autonomous and environmental cues during development.","Karin",2099815,"Transcriptional control and the integration of cell-autonomous and environmental cues during development.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I226,I226)","v":2200466},{"$f":"(LEN($J226) - LEN(SUBSTITUTE(LOWER($J226),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J226) - LEN(SUBSTITUTE(LOWER($J226),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J226) - LEN(SUBSTITUTE(LOWER($J226),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B226:D226)","v":0},1990,"The role of nutrition in neural tube defects.","Scott",2200466,"The role of nutrition in neural tube defects.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I227,I227)","v":3287506},{"$f":"(LEN($J227) - LEN(SUBSTITUTE(LOWER($J227),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J227) - LEN(SUBSTITUTE(LOWER($J227),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J227) - LEN(SUBSTITUTE(LOWER($J227),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B227:D227)","v":0},1988,"Postnatal effects of prenatal insult.","Johnson",3287506,"Postnatal effects of prenatal insult.    Abstract:   Exogenous agents may perturb development during the embryonic period and adversely affect the formation of organs. However, adverse effects on development are not limited to the embryonic period nor are the manifestations restricted solely to outright gross structural malformation, but may instead be expressed as a decrement or abberration of postnatal function. Susceptibility to altered development may extend well into the postnatal period. Studies of functional parameters in several organ systems have demonstrated the broad-based susceptibility, subtlety of expression and potential of long-lasting effects of altered development assessed by physiologic assays. Adverse effects on functional development, whether in the CNS, reproductive, gastrointestinal, genitourinary, respiratory, or immune systems, etc., merit continuing investigation. From the viewpoint of risk estimation and hazard detection, evaluations of postnatal functional parameters may be relevant for several reasons. First, such parameters may serve as low-dose triggers. Second, they may be useful as a focal point for epidemiological studies. Finally, a more thorough understanding of the degree and magnitude of such postnatal functional deficits is needed since an adverse maternal effect may be transient, considered acceptable, or unperceived, but the effect on the conceptus may be permanent and severe. The immune and respiratory systems are discussed as two examples of how subtle and protean adverse effects on functional development may be."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I228,I228)","v":3524949},{"$f":"(LEN($J228) - LEN(SUBSTITUTE(LOWER($J228),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J228) - LEN(SUBSTITUTE(LOWER($J228),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J228) - LEN(SUBSTITUTE(LOWER($J228),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B228:D228)","v":0},1986,"Prescribing in pregnancy. Mineral and vitamin supplements.","Drife",3524949,"Prescribing in pregnancy. Mineral and vitamin supplements.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I229,I229)","v":3911268},{"$f":"(LEN($J229) - LEN(SUBSTITUTE(LOWER($J229),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J229) - LEN(SUBSTITUTE(LOWER($J229),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J229) - LEN(SUBSTITUTE(LOWER($J229),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B229:D229)","v":0},1985,"Functional consequences of zinc deficiency.","McClain",3911268,"Functional consequences of zinc deficiency.    Abstract:   Zinc is an essential trace element necessary for over 200 zinc metalloenzymes and required for normal nucleic acid, protein, and membrane metabolism. During the past two decades there has been a rapid expansion of knowledge concerning zinc metabolism in both normal and disease situations, including mechanisms for zinc absorption, excretion and internal redistribution of zinc after stress or trauma. Acrodermatitis enteropathica has been recognized to be a disease of impaired zinc absorption in man. A host of disease processes now are recognized to be complicated by zinc deficiency including alcoholic liver disease, sickle cell anemia, protein calorie malnutrition, and a variety of intestinal diseases including Crohns disease, sprue, short bowel syndrome and after jejunal ileal bypass. Zinc has proved to be an extremely interesting mineral to nutritionists and physicians because of its importance in normal physiology and biochemistry and because of the diverse presenting features of zinc deficiency. This paper reviews ten functional consequences of zinc deficiency and emphasizes certain consequences in which there have been new discoveries concerning their mechanism (e.g., anorexia) or their clinical importance (e.g., immune dysfunction)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I230,I230)","v":7031395},{"$f":"(LEN($J230) - LEN(SUBSTITUTE(LOWER($J230),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J230) - LEN(SUBSTITUTE(LOWER($J230),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J230) - LEN(SUBSTITUTE(LOWER($J230),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B230:D230)","v":0},1981,"The curly-tail mouse: an experimental model for human neural tube defects.","Seller",7031395,"The curly-tail mouse: an experimental model for human neural tube defects.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I231,I231)","v":389569},{"$f":"(LEN($J231) - LEN(SUBSTITUTE(LOWER($J231),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J231) - LEN(SUBSTITUTE(LOWER($J231),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J231) - LEN(SUBSTITUTE(LOWER($J231),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B231:D231)","v":0},1979,"Hypervitaminosis A induced teratogenesis.","Geelen",389569,"Hypervitaminosis A induced teratogenesis.    Abstract:   In the past decade, the toxicology of reproduction has become increasingly important. This branch of toxicology focuses on mutagenic and embryotoxic effects. The study of embryotoxicity requires an extensive knowledge of the interaction of drugs and embryonic tissues, normal and abnormal developmental processes, and the susceptible stages during prenatal development. Hypervitaminosis A is one of the most extensively studied teratogens. It produces defects in almost all organ systems. Therefore, this article will first of all review the vitamin A-induced malformations in several organ systems. Moreover, it will discuss their morphogenesis and the susceptible developmental stages. Thus, the first ten chapters will cover the following subjects: malformations of the nervous system, ocular malformations, malformations of the ear, craniofacial malformations, cleft palate, defects of the circulatory system, defects of the respiratory systems, defects of the digestive tract, urogenital defects, skeletal malformations, and abnormal postnatal development. Since in general little is known about the mechanisms involved in the induction of congenital defects, we think it is of great value to review the knowledge and experience that have been gathered by the experimental work with hypervitaminosis A. Therefore, the next chapters will discuss the following subjects: teratogenic effects in different species, minimum effective dose, interaction with other agents, influence of chemical form, solvent, and route of administration, pathophysiology of vitamin A embryotoxicity, and hypervitaminosis A and human pregnancy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I232,I232)","v":115164},{"$f":"(LEN($J232) - LEN(SUBSTITUTE(LOWER($J232),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J232) - LEN(SUBSTITUTE(LOWER($J232),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J232) - LEN(SUBSTITUTE(LOWER($J232),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B232:D232)","v":0},1979,"[Complexes of vitamin A with proteins and their role in the bodies of animals].","Chernukhina",115164,"[Complexes of vitamin A with proteins and their role in the bodies of animals].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I233,I233)","v":380681},{"$f":"(LEN($J233) - LEN(SUBSTITUTE(LOWER($J233),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J233) - LEN(SUBSTITUTE(LOWER($J233),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J233) - LEN(SUBSTITUTE(LOWER($J233),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B233:D233)","v":0},1979,"Scanning electron microscope studies of central nervous system development.","Waterman",380681,"Scanning electron microscope studies of central nervous system development.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I234,I234)","v":768831},{"$f":"(LEN($J234) - LEN(SUBSTITUTE(LOWER($J234),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J234) - LEN(SUBSTITUTE(LOWER($J234),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J234) - LEN(SUBSTITUTE(LOWER($J234),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B234:D234)","v":0},1976,"Zinc deficiency in pregnant, fetal and young rats.","Waterman",768831,"Zinc deficiency in pregnant, fetal and young rats.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I235,I235)","v":4882496},{"$f":"(LEN($J235) - LEN(SUBSTITUTE(LOWER($J235),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J235) - LEN(SUBSTITUTE(LOWER($J235),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J235) - LEN(SUBSTITUTE(LOWER($J235),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B235:D235)","v":0},1968,"[Some new aspects of calcium metabolism: applications to the physiology and pathology of ruminants].","Larvor",4882496,"[Some new aspects of calcium metabolism: applications to the physiology and pathology of ruminants].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I236,I236)","v":4331872},{"$f":"(LEN($J236) - LEN(SUBSTITUTE(LOWER($J236),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J236) - LEN(SUBSTITUTE(LOWER($J236),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J236) - LEN(SUBSTITUTE(LOWER($J236),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B236:D236)","v":0},1967,"Differentiation of connective tissues.","Thorp",4331872,"Differentiation of connective tissues.    Abstract:  "]

{"sheet":"Abstract","index":1,"n_rows":5,"n_cols":4,"rows_kept":5,"cut":false,"hidden":false,"merged":[[0,0,0,1]]}
["Abstract with highlights"]
["Article:",{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & C2,C2)","v":17061260},17061260,"Pub Yr: 2006"]
[]
["Title:","Genetic patterning of the mammalian telencephalon by morphogenetic molecules and transcription factors.",null,"Fauthor: Takahashi"]
["Title and Abstract:","Genetic patterning of the mammalian telencephalon by morphogenetic molecules and transcription factors.    Abstract:   Patterning centers that produce gradients of morphogenetic molecules, including fibroblast growth factor (FGF), bone morphogenetic proteins (BMP), Wnt, Sonic hedgehog (Shh), and retinoic acid (RA), are located in telencephalic anlage during early stages of development. Genetic evidence based on loss-of-function and gain-of-function studies indicate that they are involved in regional specification of the dorsal, ventral, and lateral telencephalon. For patterning of the dorsal telencephalon, FGF8 controls the anteroposterior patterning, while BMP and Wnt molecules regulate the mediolateral patterning. Shh and retinoic acid regulate patterning of the ventral and the lateral telencephalon. The regionalization of telencephalon is accompanied by expression of region-specific codes of transcription factors, which in turn regulate different phases of neuronal development to generate different cell types in each brain region. Therefore, bioactive signals of morphogenetic molecules are translated into transcription factor codes for regional specification, which subsequently leads to neurogenesis of the diversity of cell types in different regions of the telencephalon."]

{"sheet":"Notes","index":2,"n_rows":3,"n_cols":8,"rows_kept":3,"cut":false,"hidden":false,"merged":[]}
[null,"My Notes"]
["Chemical","PMID ","DOI","Note ","Title","LinkDOI","LinkID","Link"]
[null,{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & G3,G3)","v":15203181},null,"GABA and cp; picrotoxin and 3-mercaptopropionic acid","Cleft palate by picrotoxin or 3-MP and palatal shelf elevation in GABA-deficient mice.",null,15203181]