RESUMO
Despite the recognition that cortical thickness is heritable and correlates with intellectual ability in children and adolescents, the genes contributing to individual differences in these traits remain unknown. We conducted a large-scale association study in 1583 adolescents to identify genes affecting cortical thickness. Single-nucleotide polymorphisms (SNPs; n=54,837) within genes whose expression changed between stages of growth and differentiation of a human neural stem cell line were selected for association analyses with average cortical thickness. We identified a variant, rs7171755, associating with thinner cortex in the left hemisphere (P=1.12 × 10(-)(7)), particularly in the frontal and temporal lobes. Localized effects of this SNP on cortical thickness differently affected verbal and nonverbal intellectual abilities. The rs7171755 polymorphism acted in cis to affect expression in the human brain of the synaptic cell adhesion glycoprotein-encoding gene NPTN. We also found that cortical thickness and NPTN expression were on average higher in the right hemisphere, suggesting that asymmetric NPTN expression may render the left hemisphere more sensitive to the effects of NPTN mutations, accounting for the lateralized effect of rs7171755 found in our study. Altogether, our findings support a potential role for regional synaptic dysfunctions in forms of intellectual deficits.
Assuntos
Encéfalo/anatomia & histologia , Cognição/fisiologia , Inteligência/fisiologia , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Animais , Células Cultivadas , Feminino , Estudos de Associação Genética , Humanos , Processamento de Imagem Assistida por Computador , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Metanálise como Assunto , Camundongos , Camundongos Transgênicos , Análise em Microsséries , Células-Tronco Neurais/fisiologia , Testes NeuropsicológicosRESUMO
Glycogen synthase kinase 3 (GSK3) is a widely expressed, constitutively active, serine/threonine kinase that is negatively regulated by both Wnt and insulin via two independent signalling pathways. GSK3 is an important mediator in many physiological processes including glycogen metabolism, apoptosis and gene transcription. In addition, GSK3 is implicated in diseases such as Alzheimer's, schizophrenia and cancer, where it exhibits deregulated activity. In this study, we sought to determine the neuronal genes regulated by both Wnt and insulin in an in vitro cell culture model to further elucidate the signalling roles GSK3 plays in the CNS. Affymetrix Rat Genome 230 2.0 whole genome microarrays were used to explore the expression profiles of rat primary cortical neurones treated with recombinant Wnt3a (10 nM) or insulin (50 nM) for 2 h. Following a conservative correction (Bonferroni) for multiple testing, seven genes were identified to be differentially expressed from controls; four of these genes were regulated by insulin and three genes were regulated by both insulin and Wnt3a. The data were also analysed using a false discovery rate cut off, which is a less stringent correction for multiple testing. This approach yielded 105 genes that were differentially regulated from controls; 72 of the gene changes were attributable to insulin treatment, 11 were because of Wnt3a treatment and 22 genes were altered by both insulin and Wnt3a. These data demonstrate that the Wnt and insulin pathways exhibit both divergent and overlapping signalling activities in neuronal cells. The overlapping transcriptional response was not attributable to Wnt3a activating Akt. These findings have ramifications for neurodevelopment and neurological diseases, in which the Wnt and insulin signalling pathways are implicated.
Assuntos
Córtex Cerebral/metabolismo , Perfilação da Expressão Gênica , Insulina/genética , Neurônios/metabolismo , Proteínas Wnt/genética , Animais , Western Blotting , Núcleo Celular/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Regulação para Baixo/genética , Regulação para Baixo/fisiologia , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Insulina/fisiologia , Luciferases/análise , Análise em Microsséries , Fosforilação , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima/genética , Regulação para Cima/fisiologia , Proteínas Wnt/fisiologia , Proteína Wnt3 , beta Catenina/metabolismoRESUMO
Antiserums to wild-type alkaline phosphatase from Escherichia coli were prepared and tested for reactivity with phosphatases altered by point mutations. Eight out of the nine mutant enzymes were distinguished from the wild type with quantitative microcomplement fixation. The structural changes are among the smallest yet observed immunologically.
Assuntos
Fosfatase Alcalina/análise , Sequência de Aminoácidos , Testes de Fixação de Complemento , Escherichia coli/enzimologia , Glutamatos , Glutamina , Soros Imunes , Lisina , Métodos , Microquímica , Biologia Molecular , Mutação , TirosinaRESUMO
In contrast to an earlier report, we find that the primitive vertebrate Eptatretus possesses a muscle lactate dehydrogenase whose molecular size is like that of lactate dehydrogenases from higher vertebrates. The molecular size of lactate dehydrogenase appears to have remained constant during evolution.
Assuntos
L-Lactato Desidrogenase , Peso Molecular , Animais , Cromatografia , Enguias , Músculos/análise , Espectrofotometria , LínguaRESUMO
The history of psychoanalysis in Germany during the Second World War must be seen in the context of institutional and professional developments along the lines of the intersection of medicine and psychology during the first half of the twentieth century. The moral ambiguities of the integration of psychoanalysis and psychotherapy into the structures of modern industrial society were magnified and brutally supplemented in the course of the partial professionalization of these disciplines in Germany under the Nazi dictatorship. A study of the continuities in the history of psychoanalysis and psychotherapy in Germany since 1939 can provide insight into the moral and practical vicissitudes of professionalism in modern society as well as into the social history of Germany under Hitler.
Assuntos
Sistemas Políticos/história , Psiquiatria/história , Alemanha , História do Século XX , HumanosRESUMO
An instrument designed to measure quantitatively the contour of the human cornea is described. This apparatus can be used to btain enlarged cross sections of the cornea without harming the eye in any way. An image of a brightly illuminated slit is projected onto the cornea. The intersection of the slit image with the surface of cornea constitutes a section plane through the cornea. The undistorted, enlarged images of selected sections are recorded photographically as corneagrams.
RESUMO
An immunological approach has been used for the study of alkaline phosphatase evolution in bacteria of the family Enterobacteriaceae. Antisera were prepared against alkaline phosphatase from Escherichia coli and Klebsiella aerogenes and tested against the unpurified alkaline phosphatases of 32 strains of enterobacteria by double diffusion and quantitative micro-complement fixation. The immunological relationships detected among the alkaline phosphatases of enterobacteria agree approximately with those reported for five other enzymes, as well as with the tryptic peptide pattern similarities found for two other enzymes, and with the relationships detected by interspecific deoxyribonucleic acid hybridization tests.
Assuntos
Fosfatase Alcalina , Evolução Biológica , Enterobacteriaceae/enzimologia , Fosfatase Alcalina/análise , Sequência de Aminoácidos , Animais , Cromatografia DEAE-Celulose , Cromatografia em Gel , Testes de Fixação de Complemento , Reações Cruzadas , DNA Bacteriano/análise , Eletroforese Descontínua , Enterobacteriaceae/classificação , Enterobacteriaceae/imunologia , Epitopos , Erwinia/enzimologia , Escherichia coli/enzimologia , Soros Imunes , Imunodifusão , Klebsiella/enzimologia , Masculino , Proteus/enzimologia , Coelhos/imunologia , Salmonella/enzimologia , Serratia/enzimologia , Shigella/enzimologiaRESUMO
A mutant strain of Escherichia coli capable of growth on l-1,2-propanediol was isolated previously. The mutant is characterized by constitutive production of a propanediol:nicotinamide adenenine dinucleotide (NAD) oxidoreductase which is essential for the new growth property. In the present study, it is shown that phage P1 cotransduces the genetic locus conferring this property and the genes for the utilization of l-fucose. A further indication of a relationship between these two growth properties is provided by the observation that wild-type E. coli excretes propanediol during fermentation of l-fucose. Under these conditions, a propanediol dehydrogenase (lactaldehyde reductase) is induced. This enzyme migrates on diethylaminoethyl-cellulose with the propanediol dehydrogenase produced constitutively by the mutant strain. A key event in the establishment of the ability to grow on propanediol is evidently a shift in the expression and function of propanediol dehydrogenase; an enzyme catalyzing formation of a reduced fermentation product anaerobically in wild-type cells functions aerobically to oxidize this same product in the mutant. l-Lactaldehyde, which is thus derived from propanediol, is converted to l-lactate by another dehydrogenase (l-lactaldehyde:NAD oxidoreductase) which is constitutively produced by both wild-type and mutant cells. The normal function of this enzyme is not yet established. l-Lactate is converted to pyruvate by an inducible NAD-independent l-lactate dehydrogenase. Thus, the carbons of propanediol are brought into the central metabolic network of the cell.
Assuntos
Oxirredutases do Álcool/metabolismo , Escherichia coli/metabolismo , Fucose/metabolismo , Lactatos/metabolismo , Propilenoglicóis/metabolismo , Aerobiose , Aldeídos/biossíntese , Anaerobiose , Sistema Livre de Células , Cromatografia DEAE-Celulose , Indução Enzimática , Escherichia coli/enzimologia , Escherichia coli/crescimento & desenvolvimento , Fermentação , Glucose/metabolismo , L-Lactato Desidrogenase/metabolismo , Lactatos/biossíntese , Mutação , Propilenoglicóis/biossíntese , Piruvatos/biossíntese , Espectrofotometria , Estereoisomerismo , Transdução GenéticaRESUMO
1. Wires with a range of tensile properties are available for construction of a Stage 1 arch wire in the Begg orthodontic appliance. 2. Over a period of 3 days, a detectable amount of stress relaxation occurs in some orthodontic wires loaded initially to 20 kg.
Assuntos
Aparelhos Ortodônticos , Análise do Estresse Dentário , Resistência à Tração , Técnicas de Movimentação Dentária/instrumentaçãoRESUMO
The alkaline phosphatases of 29 strains of bacteria assigned by various authors to the genera Aerobacter, Klebsiella and Enterobacter were compared by the micro-complement fixation technique. On the basis of phosphatase resemblance, we recommend that all strains hitherto assigned to Aerobacter aerogenes and Enterobacter aerogenes be assigned to the genus Klebsiella.
Assuntos
Testes de Fixação de Complemento , Klebsiella/classificação , Fosfatase Alcalina/isolamento & purificação , Animais , Técnicas Bacteriológicas , Cromatografia em Gel , Reações Cruzadas , Eletroforese Descontínua , Enterobacter/classificação , Enterobacter/enzimologia , Enterobacter/imunologia , Escherichia coli/classificação , Escherichia coli/enzimologia , Escherichia coli/imunologia , Soros Imunes , Imunodifusão , Imunoeletroforese , Klebsiella/enzimologia , Klebsiella/imunologia , Masculino , Coelhos/imunologiaRESUMO
A computer model is described which is capable of predicting changes in cell composition, cell size, cell shape, and the timing of chromosome synthesis in response to changes in external glucose limitation. The model is constructed primarily from information on unrestricted growth in glucose minimal medium. The ability of the model to make reasonable quantitative predictions under glucose-limitation is a test of the plausibility of the basic biochemical mechanisms included in the model. Such a model should be of use in differentiating among competing hypotheses for biological mechanisms and in suggesting as yet unobserved phenomena. The last two points are illustrated with the testing of a mechanism for the control of the initiation of DNA synthesis and predictions on cell-width variations during the division cycle.
Assuntos
Simulação por Computador/história , Escherichia coli/crescimento & desenvolvimento , Glucose/história , Replicação do DNA , Escherichia coli/genética , Escherichia coli/metabolismo , Glucose/metabolismo , História do Século XX , Biossíntese de Proteínas , Transcrição GênicaRESUMO
A computer model is described which is capable of predicting changes in cell composition, cell size, cell shape, and the timing of chromosome synthesis in response to changes in external glucose limitation. The model is constructed primarily from information on unrestricted growth in glucose minimal medium. The ability of the model to make reasonable quantitative predictions under glucose-limitation is a test of the plausibility of the basic biochemical mechanisms included in the model. Such a model should be of use in differentiating among competing hypotheses for biological mechanisms and in suggesting as yet unobserved phenomena. The last two points are illustrated with the testing of a mechanism for the control of the initiation of DNA synthesis and predictions on cellwidth variations during the division cycle.