Novartis Foundation Symposium最新文献

{"title":"Linking innate to adaptive immunity through dendritic cells.","authors":"R. Steinman","doi":"10.1002/9780470035399.CH9","DOIUrl":"https://doi.org/10.1002/9780470035399.CH9","url":null,"abstract":"The function of dendritic cells (DCs) in linking innate to adaptive immunity is often summarized with two terms. DCs are sentinels, able to capture, process and present antigens and to migrate to lymphoid tissues to select rare, antigen-reactive T cell clones. DCs are also sensors, responding to a spectrum of environmental cues by extensive differentiation or maturation. The type of DC and the type of maturation induced by different stimuli influences the immunological outcome, such as the differentiation of Thl vs. Th2 T cells. Here we summarize the contributions of DCs to innate defences, particularly the production of immune enhancing cytokines and the activation of innate lymphocytes. Then we outline three innate features of DCs that influence peripheral tolerance and lead to adaptive immunity: a specialized endocytic system for antigen capture and processing, location and movements in vivo, and maturation in response to an array of stimuli. A new approach to the analysis of DC biology is to target antigens selectively to maturing DCs in vivo. This leads to stronger, more prolonged and broader (many immunogenic peptides) immunity by both T cells and B cells.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"279 1","pages":"101-9; discussion 109-13, 216-9"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"51137787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytoskeletal defects in amyotrophic lateral sclerosis (motor neuron disease).","authors":"J. Julien, S. Millecamps, J. Kriz","doi":"10.1002/0470093765.CH12","DOIUrl":"https://doi.org/10.1002/0470093765.CH12","url":null,"abstract":"There is growing evidence for the involvement of cytoskeletal defects in the pathogenesis of motor neuron disease and especially in components of the microtubule-based transport system. Here we will review our recent work aiming to elucidate the role of peripherin in amyotrophic lateral sclerosis (ALS) and to address the mechanism of disease caused by deletions in the ALS2 gene that cause recessive forms of juvenile ALS and primary lateral sclerosis (PLS). Peripherin is an intermediate filament protein detected in spheroids, a hallmark of ALS, and increased levels of peripherin mRNA have been found in some ALS cases. Our transgenic mouse and cell culture studies support the view of a peripherin involvement in ALS. However, a gene knockout approach demonstrated that peripherin is not a key contributor of motor neuron disease caused by mutant superoxide dismutase linked to familial ALS. A recent breakthrough in the field of ALS came with the discovery of frameshift deletions in the ALS2 gene coding for Alsin. Our transfection experiments in cultured cells suggest that Alsin is a cytoskeletal protein with dual endosomal and centrosomal localizations. We have generated a mouse knockout for Alsin that develops progressive motor dysfunction during ageing. Thus, it is anticipated that this mouse model will be useful to investigate the pathogenic pathways linked to Alsin gene mutations.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"4 2","pages":"183-92; discussion 192-6, 227-30"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470093765.CH12","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50760628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural dynamics in cortical networks--precision of joint-spiking events.","authors":"A. Aertsen, M. Diesmann, M. Gewaltig, S. Grün, S. Rotter","doi":"10.1002/0470846674.CH15","DOIUrl":"https://doi.org/10.1002/0470846674.CH15","url":null,"abstract":"Electrophysiological studies of cortical function on the basis of multiple single-neuron recordings reveal neuronal interactions which depend on stimulus context and behavioural events. These interactions exhibit dynamics on different time scales, with time constants down to the millisecond range. Mechanisms underlying such dynamic organization of the cortical network were investigated by experimental and theoretical approaches. We review some recent results from these studies, concentrating on the occurrence of precise joint-spiking events in cortical activity, both in physiological and in model neural networks. These findings suggest that a combinatorial neural code, based on rapid associations of groups of neurons co-ordinating their activity at the single spike level, is biologically feasible.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"45 4","pages":"193-204; discussion 204-7, 234-40"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470846674.CH15","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50768334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Signalling mechanisms for TRPC3 channels.","authors":"J. Putney, M. Trebak, G. Vazquez, B. Wedel, G. Bird","doi":"10.1002/0470862580.CH9","DOIUrl":"https://doi.org/10.1002/0470862580.CH9","url":null,"abstract":"The putative ion channel subunits TRPC3, TRPC6 and TRPC7 comprise a structurally related subgroup of the family of mammalian TRPC channels. As is the case for the founding member of the TRPC family, Drosophila TRP, the ion channels formed by these proteins appear to be activated in some manner downstream of phospholipase C (PLC). Earlier studies indicating that TRPC3 could be activated by depletion of intracellular stores (i.e. that it is a store-operated channel, SOC) were subsequently shown to be attributable to constitutive activity of the channels. Studies on the mechanism of activation of TRPC6 and TRPC7 indicated that PLC-dependent activation involved diacylglycerol and was independent of G proteins or inositol 1,4,5-trisphosphate (IP3). Although TRPC3 can also be activated by diacylglycerols, there is evidence suggesting that these channels can be activated by IP3 and the IP3 receptor through a conformational coupling mechanism. We have re-examined the activation mechanism for TRPC3 in mammalian cells by using HEK293 cell lines stably expressing human TRPC3. Our data indicate that, like TRPC6 and TRPC7, TRPC3 is activated by PLC-generated diacylglycerol and is independent of G proteins or IP3. However, in an avian pre-B cell line, TRPC3 can function either as a diacylglycerol-activated channel, or as a SOC. The mechanism of regulation of TRPC3 in this cell line appears to be related to the level of expression of the protein.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"64 12","pages":"123-33; discussion 133-9, 155-9, 263-6"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470862580.CH9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50775976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probabilistic mechanisms in sensorimotor control.","authors":"Konrad Paul Kording, D. Wolpert","doi":"10.1002/9780470034989.CH15","DOIUrl":"https://doi.org/10.1002/9780470034989.CH15","url":null,"abstract":"Uncertainty constitutes a fundamental constraint on human sensorimotor control. Our sensors are noisy and do not provide perfect information about all the properties of the world. Moreover, our muscles generate noisy outputs and many tasks we perform vary in an unpredictable way. Here we review the computations that the CNS uses in the face of such sensory, motor and task uncertainty. We show that the CNS reduces the uncertainty in estimates about the state of the world by using a Bayesian combination of prior knowledge and sensory feedback. It is shown that these mechanisms generalize to state estimation of ones own body during movement. We review how the CNS optimizes decisions based on these estimates, examining the error criterion that people optimize when performing targeted movements. Finally, we describe how signal-dependent noise on the motor output places constraints on performance. Goal-directed movement arises from a model in which the statistics of our actions are optimized. Together these studies provide a probabilistic framework for sensorimotor control.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"270 1","pages":"191-8; discussion 198-202, 232-7"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"51136096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin and IGF-1 receptor trafficking and signalling.","authors":"Michelangelo Foti, M. Moukil, Pierrick Dudognon, J. Carpentier","doi":"10.1002/0470869976.CH8","DOIUrl":"https://doi.org/10.1002/0470869976.CH8","url":null,"abstract":"Receptor-mediated endocytosis governs the entry of receptors inside the cells. In the case of signalling receptors, e.g. tyrosine kinase receptors, the process is ligand-dependent and includes a series of surface events which determines the specificity of the internalization process and the activation of distinct signal transduction pathways. Tyrosine kinase receptors, e.g. the insulin/IGF-1 receptors, are initially located outside the internalization gates (the clathrin-coated pits) and concentrated on thin digitations of the cell surface: the microvilli. In the case of the insulin receptor, specific motifs of the beta subunit are responsible for anchoring the receptor to microvilli. However, the molecular mechanisms by which this motif mediates this anchoring are poorly understood and necessitate further studies. In particular, the association of insulin receptors with cytoskeletal elements or specific lipidic domains concentrated on microvilli (e.g. lipid rafts) are under investigation as these interactions may provide the appropriate environment for the transduction of the insulin metabolic effects. Upon ligand binding, activated insulin receptors complexed to insulin are released from microvilli, segregate in clathrin-coated pits and enter the cells. In endosomes, insulin is uncoupled from its receptor and recycles back to the cell surface, whereas the hormone is degraded in lysosomes thus terminating the wave of signalling. These steps participate in the biological activity of the hormone via: (1) a regulation of cell sensitivity to the hormone through a fine tuning of the number of surface receptors; (2) termination of the signalling by intracellular degradation of the ligands; and (3) giving the receptors access to plasma membrane domains and intracellular compartments from which distinct signalling pathways originate. Current studies are designed to compare the behaviour of IGF-1 receptors to that of insulin receptors to establish whether different localization on the plasma membrane, trafficking pathways and/or kinetics of signalling might explain the different biological activities of these two receptors.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"25 1","pages":"125-41; discussion 141-7, 265-8"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470869976.CH8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50785254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sexual selection for indicators of intelligence.","authors":"Geoffrey P. Miller","doi":"10.1002/0470870850.CH16","DOIUrl":"https://doi.org/10.1002/0470870850.CH16","url":null,"abstract":"Many traits in many species have evolved through sexual selection specifically to function as 'fitness indicators' that reveal good genes and good health. Sexually selected fitness indicators typically show (1) higher coefficients of phenotypic and genetic variation than survival traits, (2) at least moderate genetic heritabilities and (3) positive correlations with many aspects of an animal's general condition, including body size, body symmetry, parasite resistance, longevity and freedom from deleterious mutations. These diagnostic criteria also appear to describe human intelligence (the g factor). This paper argues that during human evolution, mate choice by both sexes focused increasingly on intelligence as a major heritable component of biological fitness. Many human-specific behaviours (such as conversation, music production, artistic ability and humour) may have evolved principally to advertise intelligence during courtship. Though these mental adaptations may be modular at the level of psychological functioning, their efficiencies may be tightly intercorrelated because they still tap into common genetic and neurophysiological variables associated with fitness itself. Although the g factor (like the superordinate factor of fitness itself) probably exists in all animal species, humans evolved an unusually high degree of interest in assessing each other's intelligence during courtship and other social interactions--and, consequently, a unique suite of highly g-loaded mental adaptations for advertising their intelligence to one another through linguistic and cultural interaction. This paper includes nine novel, testable predictions about human intelligence derived from sexual selection theory.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"33 1","pages":"260-70; discussion 270-80"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470870850.CH16","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50786527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene-environment interactions in breast cancer.","authors":"K. Chia","doi":"10.1002/9780470696781.CH11","DOIUrl":"https://doi.org/10.1002/9780470696781.CH11","url":null,"abstract":"Breast cancer is one of the most frequently diagnosed cancers in women. It accounts for 23% of all cancers, with an estimated 1.15 million new cases in 2002. The role of the environment, such as reproductive factors, has been well studied in many epidemiological studies. Breast cancers also tend to cluster in families and are more common in monozygotic twins. Some of this clustering occurs as part of specific familial breast cancer syndromes where disease results from single alleles conferring a high risk. However, such alleles are rare in the population, and highly penetrant variants of BRCA1 and BRCA2 account for less than 20% of the genetic risk of breast cancer. The more common sporadic form of breast cancer are probably due to a polygenic inheritance of breast cancer susceptibility upon which environmental factors act upon resulting in breast cancer occurrence. Recent high-throughput genome-wide association studies are identifying several such genes, each with small absolute risk but with significant population level implications. The study of gene-environment interactions has thus far been confined to candidate gene approaches. The lack of large prospective cohorts with thousands of incident breast cancer cases makes the study of gene-environment interactions using a nested case-control design extremely difficult.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"27 1","pages":"143-50; discussion 150-5, 181-3"},"PeriodicalIF":0.0,"publicationDate":"2008-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50674335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene-environment interaction and behavioral disorders: a developmental perspective based on endophenotypes.","authors":"M. Battaglia, C. Marino, M. Maziade, M. Molteni, F. D'Amato","doi":"10.1002/9780470696781.CH3","DOIUrl":"https://doi.org/10.1002/9780470696781.CH3","url":null,"abstract":"It has been observed that 'No aspect of human behavioral genetics has caused more confusion and generated more obscurantism than the analysis and interpretation of various types of non-additivity and non-independence of gene and environmental action and interaction' (Eaves LJ et al 1977 Br J Math Stat Psychol 30:1-42). On the other hand, a bulk of newly published studies appear to speak in favour of common and frequent interplay--and possibly interaction--between identified genetic polymorphisms and specified environmental variables in shaping behavior and behavioral disorders. Considerable interest has arisen from the introduction of putative functional 'endophenotypes' which would represent a more proximate biological link to genes, as well as an obligatory intermediate of behavior. While explicit criteria to identify valid endophenotypes have been offered, a number of new 'alternative phenotypes' are now being proposed as possible 'endophenotypes' for behavioral and psychiatric genetics research, sometimes with less than optimal stringency. Nonetheless, we suggest that some endophenotypes can be helpful in investigating several instances of gene-environment interactions and be employed as additional tools to reduce the risk for spurious results in this controversial area.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"23 6","pages":"31-41; discussion 41-7, 68-70"},"PeriodicalIF":0.0,"publicationDate":"2008-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50674191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene-environment interaction and the metabolic syndrome.","authors":"K. Adamo, F. Tesson","doi":"10.1002/9780470696781.CH8","DOIUrl":"https://doi.org/10.1002/9780470696781.CH8","url":null,"abstract":"The metabolic syndrome, which has been shown to affect as many as 20% of the general adult US population, is generally described as a cluster of cardiovascular risks factors, most notably obesity, type 2 diabetes or resistance to insulin-stimulated glucose uptake (insulin resistance), dyslipidaemia and hypertension. All these risk factors are under both genetic and environmental control; they are considered individually as complex genetic diseases. Prior to pharmacological interventions for hypertension, diabetes and dyslipidaemia, lifestyle changes, in particular weight loss (or weight maintenance) and physical activity, were prioritized and constituted an effective first-line intervention strategy. Here we want to focus on three clinical components of the metabolic syndrome and the environmental factors that are considered to be the most significant targets for primary interventions: type 2 diabetes and exercise, obesity and diet, and hypertension and salt. Our experimental approach is to go from candidate gene strategy to genome-wide association. The identification of the genetic component of these risk factors is a major challenge, and it is hoped that this would help unravel mechanistic pathways that can ultimately serve as new targets for therapeutic intervention.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"25 9","pages":"103-19; discussion 119-27"},"PeriodicalIF":0.0,"publicationDate":"2008-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50674479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}