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881.
Yizhar O Fenno LE Prigge M Schneider F Davidson TJ O'Shea DJ Sohal VS Goshen I Finkelstein J Paz JT Stehfest K Fudim R Ramakrishnan C Huguenard JR Hegemann P Deisseroth K 《Nature》2011,477(7363):171-178
Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80?Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms. 相似文献
882.
Morin RD Mendez-Lago M Mungall AJ Goya R Mungall KL Corbett RD Johnson NA Severson TM Chiu R Field M Jackman S Krzywinski M Scott DW Trinh DL Tamura-Wells J Li S Firme MR Rogic S Griffith M Chan S Yakovenko O Meyer IM Zhao EY Smailus D Moksa M Chittaranjan S Rimsza L Brooks-Wilson A Spinelli JJ Ben-Neriah S Meissner B Woolcock B Boyle M McDonald H Tam A Zhao Y Delaney A Zeng T Tse K Butterfield Y Birol I Holt R Schein J Horsman DE Moore R Jones SJ Connors JM Hirst M Gascoyne RD Marra MA 《Nature》2011,476(7360):298-303
Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis. 相似文献
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887.
Gebhardt T Whitney PG Zaid A Mackay LK Brooks AG Heath WR Carbone FR Mueller SN 《Nature》2011,477(7363):216-219
Infections localized to peripheral tissues such as the skin result in the priming of T-cell responses that act to control pathogens. Activated T cells undergo migrational imprinting within the draining lymph nodes, resulting in memory T cells that provide local and systemic protection. Combinations of migrating and resident memory T cells have been implicated in long-term peripheral immunity, especially at the surfaces that form pathogen entry points into the body. However, T-cell immunity consists of separate CD4(+) helper T cells and CD8(+) killer T cells, with distinct effector and memory programming requirements. Whether these subsets also differ in their ability to form a migrating pool involved in peripheral immunosurveillance or a separate resident population responsible for local infection control has not been explored. Here, using mice, we show key differences in the migration and tissue localization of memory CD4(+) and CD8(+) T cells following infection of the skin by herpes simplex virus. On resolution of infection, the skin contained two distinct virus-specific memory subsets; a slow-moving population of sequestered CD8(+) T cells that were resident in the epidermis and confined largely to the original site of infection, and a dynamic population of CD4(+) T cells that trafficked rapidly through the dermis as part of a wider recirculation pattern. Unique homing-molecule expression by recirculating CD4(+) T effector-memory cells mirrored their preferential skin-migratory capacity. Overall, these results identify a complexity in memory T-cell migration, illuminating previously unappreciated differences between the CD4(+) and CD8(+) subsets. 相似文献
888.
Gibson L Lee TM Koh LP Brook BW Gardner TA Barlow J Peres CA Bradshaw CJ Laurance WF Lovejoy TE Sodhi NS 《Nature》2011,478(7369):378-381
Human-driven land-use changes increasingly threaten biodiversity, particularly in tropical forests where both species diversity and human pressures on natural environments are high. The rapid conversion of tropical forests for agriculture, timber production and other uses has generated vast, human-dominated landscapes with potentially dire consequences for tropical biodiversity. Today, few truly undisturbed tropical forests exist, whereas those degraded by repeated logging and fires, as well as secondary and plantation forests, are rapidly expanding. Here we provide a global assessment of the impact of disturbance and land conversion on biodiversity in tropical forests using a meta-analysis of 138 studies. We analysed 2,220 pairwise comparisons of biodiversity values in primary forests (with little or no human disturbance) and disturbed forests. We found that biodiversity values were substantially lower in degraded forests, but that this varied considerably by geographic region, taxonomic group, ecological metric and disturbance type. Even after partly accounting for confounding colonization and succession effects due to the composition of surrounding habitats, isolation and time since disturbance, we find that most forms of forest degradation have an overwhelmingly detrimental effect on tropical biodiversity. Our results clearly indicate that when it comes to maintaining tropical biodiversity, there is no substitute for primary forests. 相似文献
889.
Yalcin B Wong K Agam A Goodson M Keane TM Gan X Nellåker C Goodstadt L Nicod J Bhomra A Hernandez-Pliego P Whitley H Cleak J Dutton R Janowitz D Mott R Adams DJ Flint J 《Nature》2011,477(7364):326-329
Structural variation is widespread in mammalian genomes and is an important cause of disease, but just how abundant and important structural variants (SVs) are in shaping phenotypic variation remains unclear. Without knowing how many SVs there are, and how they arise, it is difficult to discover what they do. Combining experimental with automated analyses, we identified 711,920 SVs at 281,243 sites in the genomes of thirteen classical and four wild-derived inbred mouse strains. The majority of SVs are less than 1?kilobase in size and 98% are deletions or insertions. The breakpoints of 160,000 SVs were mapped to base pair resolution, allowing us to infer that insertion of retrotransposons causes more than half of SVs. Yet, despite their prevalence, SVs are less likely than other sequence variants to cause gene expression or quantitative phenotypic variation. We identified 24 SVs that disrupt coding exons, acting as rare variants of large effect on gene function. One-third of the genes so affected have immunological functions. 相似文献
890.
Grbić M Van Leeuwen T Clark RM Rombauts S Rouzé P Grbić V Osborne EJ Dermauw W Ngoc PC Ortego F Hernández-Crespo P Diaz I Martinez M Navajas M Sucena É Magalhães S Nagy L Pace RM Djuranović S Smagghe G Iga M Christiaens O Veenstra JA Ewer J Villalobos RM Hutter JL Hudson SD Velez M Yi SV Zeng J Pires-daSilva A Roch F Cazaux M Navarro M Zhurov V Acevedo G Bjelica A Fawcett JA Bonnet E Martens C Baele G Wissler L Sanchez-Rodriguez A Tirry L Blais C Demeestere K Henz SR Gregory TR Mathieu J 《Nature》2011,479(7374):487-492