Novartis Foundation Symposium最新文献

{"title":"A model for step-wise assembly of heterochromatin in yeast.","authors":"D. Moazed, Adam D Rudner, Julie Huang, G. J. Hoppe, J. Tanny","doi":"10.1002/0470862637.CH4","DOIUrl":"https://doi.org/10.1002/0470862637.CH4","url":null,"abstract":"Gene silencing involves the assembly of DNA into specialized chromatin domains that are inaccessible to trans-acting factors and are epigenetically inherited. In the budding yeast Saccharomyces cerevisiae, silent heterochromatic DNA domains occur at telomeres, the silent mating type loci, and the rDNA repeats. At telomeres and the mating type loci, silencing requires the Sir2, Sir3 and Sir4 proteins, the conserved N-termini of histones H3 and H4, and a number of chromatin assembly factors. The Sir proteins form a multimeric complex that binds preferentially to deacetylated nucleosomes through the Sir3 and Sir4 subunits. The Sir2 subunit possesses an unusual NAD-dependent deacetylase activity that is required for silencing at each of the above loci. Recent studies have shown that silent chromatin domains are assembled in a step-wise manner involving sequential cycles of deacetylation and SIR complex binding. Sir2-dependent deacetylation is specifically required for the spreading of the complex to regions beyond nucleation sites but not for its initial binding to DNA at the mating type loci and telomeres. A distinct Sir2 complex called RENT is required for silencing at rDNA. In contrast to telomeres and the mating type loci, Sir2 activity is not required for association of RENT with rDNA.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"11 2","pages":"48-56; discussion 56-62, 163-9"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470862637.CH4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50776964","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":"Genetic blockade of the insulin-like growth factor 1 receptor for human malignancy.","authors":"Y. Adachi, Choon‐Taek Lee, D. Carbone","doi":"10.1002/0470869976.CH11","DOIUrl":"https://doi.org/10.1002/0470869976.CH11","url":null,"abstract":"Growth factor receptor signals, including insulin-like growth factor (IGF)-1 receptor (IGF-1R), are required for carcinogenesis and tumour progression in many human malignancies. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, including trastuzumab and gefitinib. In this paper, we review strategies of the genetic blockade of IGF-1/IGF-1R that validate this receptor as a promising anticancer target. Adenoviruses efficiently transduce malignant epithelial cells in culture and are useful for such target validation and potentially also as clinical therapeutics. To block IGF-1R signalling, we constructed adenoviruses expressing antisense IGF-1R and two truncated IGF-1R (482 and 950 amino acids long, IGF-1R/482st and IGF-1R/950st, respectively) that function as dominant negative inhibitors (IGF-1R/dn). The truncated receptors were also cloned into tetracycline regulated expression vectors to study the effects of modulating this pathway without the use of viral vectors. Blocking for IGF-1R suppressed tumorigenicity both in vitro and invivo and effectively blocked both IGF-1 and IGF-2-induced activation of Akt-1. IGF-1R/dn expression increased radiation- and chemotherapy-induced apoptosis and these combination therapies with chemotherapy were very effective against tumours in mice. In an intraperitoneal dissemination mouse model, blockade of IGF-IR reduced dissemination and prolonged survival times. IGF-1R/482st was more effective than IGF-IR/950st due to its bystander effect. These studies confirm the validity of IGF-1R as a therapeutic target and genetic blockade as a potential strategy for several malignancies, including lung, colon and pancreatic carcinoma.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"9 4","pages":"177-89; discussion 190-2, 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.CH11","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50784718","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":"Ectonucleotidases in the nervous system.","authors":"H. Zimmermann","doi":"10.1002/9780470032244.CH10","DOIUrl":"https://doi.org/10.1002/9780470032244.CH10","url":null,"abstract":"Extracellular nucleotides are hydrolysed by enzymes of the plasma membrane with an extracellularly oriented catalytic site (ectonucleotidases). Members of several families of ectonucleotidases can contribute to extracellular nucleotide hydrolysis. They have been characterized in molecular and functional terms. A major role of these enzymes is in the modulation of ligand availability at nucleotide and nucleoside receptors. The enzymes reveal a wide and partially overlapping tissue distribution. The diversity of the individual family members is considerable and it is still difficult to assign identified enzymes to the modulation of purinergic signalling pathways. In the brain, members of all ectonucleotidase-families are expressed. Proposed physiological functions include modulation of synaptic transmission, of the ATP-mediated propagation of glial Ca2+ waves, of microglial function, adult neurogenesis or the control of vascular tone, haemostasis and thromboregulation.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"276 1","pages":"113-28; discussion 128-30, 233-7, 275-81"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/9780470032244.CH10","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"51134407","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":"New insights into the role of pendrin (SLC26A4) in inner ear fluid homeostasis.","authors":"L. Everett","doi":"10.1002/0470029579.CH14","DOIUrl":"https://doi.org/10.1002/0470029579.CH14","url":null,"abstract":"For over 100 years after the first description of the disorder, the molecular pathology underlying the deafness and thyroid pathology in Pendred syndrome (PS) remained unknown. In 1997, early progress towards understanding the molecular basis of the disorder was made when we identified the PS gene and found it to belong to the SLC26 family of anion transporters. The realization that an anion transporter was responsible for these clinical features soon highlighted a potential role for pendrin in thyroid hormone biosynthesis. The role of pendrin in deafness, however, remained unclear. Our determination of its expression pattern in the inner ear along with the development of a mouse with a targeted disruption of the Slc26a4 gene has revealed that Slc26a4 is expressed in areas of the endolymphatic compartment known to play a role in endolymph reabsorption and that absence of this protein leads to a profound prenatal endolymphatic hydrops and destruction of many of the epithelial cells surrounding the scala media. The precise mechanisms underlying endolymph reabsorption in the inner ear are not yet known; these studies, however, provide some of the groundwork for allowing the future delineation of these processes.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"60 50","pages":"213-25; discussion 225-30, 261-4"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470029579.CH14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50753649","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":"Gastroenteritis viruses: an overview.","authors":"R. Glass, J. Bresee, B. Jiang, J. Gentsch, T. Ando, R. Fankhauser, J. Noel, U. Parashar, B. Rosen, S. Monroe","doi":"10.1002/0470846534.CH2","DOIUrl":"https://doi.org/10.1002/0470846534.CH2","url":null,"abstract":"Acute gastroenteritis is among the most common illnesses of humankind, and its associated morbidity and mortality are greatest among those at the extremes of age, children and the elderly. In developing countries, gastroenteritis is a common cause of death in children < 5 years that can be linked to a wide variety of pathogens. In developed countries, while deaths from diarrhoea are less common, much illness leads to hospitalization or doctor visits. Much of the gastroenteritis in children is caused by viruses belonging to four distinct families--rotaviruses, caliciviruses, astroviruses and adenoviruses. Other viruses, such as the toroviruses, picobirnaviruses, picornavirus (the Aichi virus), and enterovirus 22, may play a role as well. Viral gastroenteritis occurs with two epidemiologic patterns, diarrhoea that is endemic in children and outbreaks that affect people of all ages. Viral diarrhoea in children is caused by group A rotaviruses, enteric adenoviruses, astroviruses and the caliciviruses; the illness affects all children worldwide in the first few years of life regardless of their level of hygiene, quality of water, food or sanitation, or type of behaviour. For all but perhaps the caliciviruses, these infections provide immunity from severe disease upon reinfection. Epidemic viral diarrhoea is caused primarily by the Norwalk-like virus genus of the caliciviruses. These viruses affect people of all ages, are often transmitted by faecally contaminated food or water, and are therefore subject to control by public health measures. The tremendous antigenic diversity of caliciviruses and short-lived immunity to infection permit repeated episodes throughout life. In the past decade, the molecular characterization of many of these gastroenteritis viruses has led to advances both in our understanding of the pathogens themselves and in development of a new generation of diagnostics. Application of these more sensitive methods to detect and characterize individual agents is just beginning, but has already opened up new avenues to reassess their disease burden, examine their molecular epidemiology, and consider new directions for their prevention and control through vaccination, improvements in food and water quality and sanitary practices.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"22 2","pages":"5-19; discussion 19-25"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470846534.CH2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50763953","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":"Rotavirus RNA replication and gene expression.","authors":"J. Patton","doi":"10.1002/0470846534.CH5","DOIUrl":"https://doi.org/10.1002/0470846534.CH5","url":null,"abstract":"Rotavirus mRNAs are capped but non-polyadenylated and serve as templates for both the synthesis of viral proteins and the segmented dsRNA genome. Viral proteins involved in RNA replication include the RNA polymerase (VP1), the core scaffold protein (VP2) and the non-structural RNA-binding proteins (NSP2 and NSP5). VP2 enhances dsRNA synthesis in vitro, possibly by forming platform structures on which VP1 functions. NSP2 octamers have NTPase and helix-destabilizing activity, and in conjunction with the phosphoprotein NSP5, are proposed to facilitate RNA packaging. The structure of the mRNA template contributes importantly to RNA replication. In particular, base-pairing between the 5' and 3'-ends of viral mRNA generates panhandle structures which promote minus-strand synthesis. For the group A rotaviruses, the 3'-consensus sequence, 5'-UGUGACC-3', which extends as a 3'-tail from the panhandles, also contributes to efficient minus-strand synthesis. Besides containing cis-acting replication signals, the 3'-end of viral mRNAs contains information that stimulates gene expression in infected cells. Specifically, the last four nucleotides of the 3'-consensus sequence, 5'-GACC-3', operate as a virus-specific translation enhancer (3'TE) via a process thought to involve recognition of the element by NSP3. The NSP3-3'TE complex may mimic the function of complexes formed by eukaryotic poly(A)-tails and poly(A)-binding protein, thereby promoting more efficient translation of viral mRNAs.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"59 1","pages":"64-77; discussion 77-81"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470846534.CH5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50764312","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":"The sarcoplasmic reticulum in disease and smooth muscle dysfunction: therapeutic potential.","authors":"A. Brading","doi":"10.1002/0470853050.CH18","DOIUrl":"https://doi.org/10.1002/0470853050.CH18","url":null,"abstract":"The functions of the sarcoplasmic reticulum (SR) in diseased smooth muscle can be investigated by measuring Ca2+ transients in response to agonist application, and through cell homogenization, isolation of microsomes and measurements of Ca-ATPase activity (SERCA). Such measurements have indicated that contractile dysfunction may be associated with degradation of SERCA in some systems, such as hypertrophied bladder smooth muscle. However, the postulated roles of the SR in smooth muscle function vary from one tissue to another and SR may mediate relaxation as well as contraction. Function seems to depend on the precise location of the SR with respect to the plasma membrane and its Ca2+-activated ion channels, the Ca2+ transporters, the cavaeoli, the mitochondria, and the contractile machinery. In diseases characterized by smooth muscle dysfunction, the size of the smooth muscle cells is frequently altered, as occurs in the hypertrophy seen in gut and bladder obstruction and hypertension. This will inevitably lead to alterations in the morphology and the function of the SR. Any therapeutic potential awaits considerable advances in our understanding of the systems in individual smooth muscles and the development of selective drugs.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"51 3","pages":"244-54; discussion 254-7, 272-6"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470853050.CH18","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50770044","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":"Cardiac conduction and arrhythmia: insights from Nkx2.5 mutations in mouse and humans.","authors":"P. Jay, C. Berul, Makoto Tanaka, M. Ishii, Y. Kurachi, S. Izumo","doi":"10.1002/0470868066.CH14","DOIUrl":"https://doi.org/10.1002/0470868066.CH14","url":null,"abstract":"The phenotypes of cardiac conduction and rhythm disorders are very well characterized because of the large numbers of affected patients who seek medical treatment. The few disorders where the genetic basis is known has led to a commonly held notion that the abnormal function of ion pumps, channels and connexins (ICC) causes conduction defects and arrhythmias. Although probably true in general, the ICC-centric model underemphasizes alternative mechanisms involving the organization of cells or mechanisms of gene expression. NKX2.5 was one of the first cardiac transcription factors identified that when mutated causes congenital heart disease and conduction defects in human. We present two hypotheses for the pathogenesis of conduction defects and arrhythmias as caused by transcription factor haploinsufficiency that are alternatives to a strictly ICC-centric model. First, conduction defects may arise from anatomic underdevelopment of the conduction system in utero. Second, the cardiac arrhythmias associated with Nkx2.5 mutation may result from the non-uniform alteration in a population of cardiac myocytes of the levels of channel proteins, leading to increased electrical heterogeneity. We propose that consideration of the two alternative hypotheses, in addition to the traditional ICC-centric model, should lead to a richer understanding of cardiac conduction defects and arrhythmogenesis.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"187 5","pages":"227-38; discussion 238-41, 276-9"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470868066.CH14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50778926","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":"Implications of the broader phenotype for concepts of autism.","authors":"A. Bailey, J. Parr","doi":"10.1002/0470869380.CH3","DOIUrl":"https://doi.org/10.1002/0470869380.CH3","url":null,"abstract":"Autism, like many new diseases, was initially characterized by its most severe phenotypic manifestation and the ability to explain these distinctive features has been the benchmark against which explanatory models have subsequently been judged. Our understanding of the significance of milder phenotypes in other relatives has shifted from presumed environmental aetiological factors to variable manifestations of a complex disease process. In this paper we outline how the challenge of explaining the full range of phenotypic expression inevitably leads to more complex models of disease process than previously supposed. The implications of milder phenotypes for genetic, neurobiological and cognitive models of autism will be considered in relationship to several key features of complex diseases: complexity, hierarchy, emergence and coherence.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"16 9","pages":"26-35; discussion 36-47, 109-11, 281-97"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470869380.CH3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50784208","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":"Functional analysis of fronto-striatal reconstruction by striatal grafts.","authors":"S. Dunnett","doi":"10.1002/0470870834.CH3","DOIUrl":"https://doi.org/10.1002/0470870834.CH3","url":null,"abstract":"Excitotoxic lesions of the neostriarum induce cognitive and motor deficits in experimental animals, and model both the neuropathology and symptoms of Huntington's disease. Striatal grafts implanted into the denervated striatum survive, differentiate into both striatal- and non-striatal like neurons, restore input and output connections of the damaged striatum, and alleviate both motor and cognitive impairments in experimental rats and monkeys. Several lines of evidence suggest that the functional recovery is mediated by the grafts providing a reconstruction of the cortico-striato-pallidal circuitries of the host forebrain, including functional mapping of circuitry by immediate early gene induction, push-pull perfusion, microdialysis, electrophysiology, the lack of efficacy of pharmacological treatments and the behavioural studies themselves. Detailed analysis of motor recovery in an operant lateralized choice reaction time test indicares that for optimal functional recovery the animals require specific retraining in the stimulus-response associations lost by the lesions, which may have important implications for optimizing the functional efficacy of striatal grafts both in experimental models and clinical trials.","PeriodicalId":19323,"journal":{"name":"Novartis Foundation Symposium","volume":"46 8","pages":"21-41; discussion 41-52"},"PeriodicalIF":0.0,"publicationDate":"2008-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0470870834.CH3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50786198","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}