Stargazin modulates AMPA receptor gating and trafficking by distinct domains

AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors mediate fast excitatory synaptic transmission in the brain. These ion channels rapidly deactivate and desensitize, which determine the time course of synaptic transmission. Here, we find that the AMPA receptor interacting protein, stargazin, not only mediates AMPA receptor trafficking but also shapes synaptic responses by slowing channel deactivation and desensitization. The cytoplasmic tail of stargazin determines receptor trafficking, whereas the ectodomain controls channel properties. Stargazin alters AMPA receptor kinetics by increasing the rate of channel opening. Disrupting the interaction of stargazin ectodomain with hippocampal AMPA receptors alters the amplitude and shape of synaptic responses, establishing a crucial function for stargazin in controlling the efficacy of synaptic transmission in the brain.     

Condensin association with histone H2A shapes mitotic chromosomes

Chromosome structure is dynamically regulated during cell division, and this regulation is dependent, in part, on condensin. The localization of condensin at chromosome arms is crucial for chromosome partitioning during anaphase. Condensin is also enriched at kinetochores but its precise role and loading machinery remain unclear. Here we show that fission yeast (Schizosaccharomyces pombe) kinetochore proteins Pcs1 and Mde4--homologues of budding yeast (Saccharomyces cerevisiae) monopolin subunits and known to prevent merotelic kinetochore orientation--act as a condensin 'recruiter' at kinetochores, and that condensin itself may act to clamp microtubule binding sites during metaphase. In addition to the regional recruitment factors, overall condensin association with chromatin is governed by the chromosomal passenger kinase Aurora B. Aurora-B-dependent phosphorylation of condensin promotes its association with histone H2A and H2A.Z, which we identify as conserved chromatin 'receptors' of condensin. Condensin phosphorylation and its deposition onto chromosome arms reach a peak during anaphase, when Aurora B kinase relocates from centromeres to the spindle midzone, where the separating chromosome arms are positioned. Our results elucidate the molecular basis for the spatiotemporal regulation of mitotic chromosome architecture, which is crucial for chromosome partitioning.     

Atom-resolved imaging of ordered defect superstructures at individual grain boundaries

The ability to resolve spatially and identify chemically atoms in defects would greatly advance our understanding of the correlation between structure and property in materials. This is particularly important in polycrystalline materials, in which the grain boundaries have profound implications for the properties and applications of the final material. However, such atomic resolution is still extremely difficult to achieve, partly because grain boundaries are effective sinks for atomic defects and impurities, which may drive structural transformation of grain boundaries and consequently modify material properties. Regardless of the origin of these sinks, the interplay between defects and grain boundaries complicates our efforts to pinpoint the exact sites and chemistries of the entities present in the defective regions, thereby limiting our understanding of how specific defects mediate property changes. Here we show that the combination of advanced electron microscopy, spectroscopy and first-principles calculations can provide three-dimensional images of complex, multicomponent grain boundaries with both atomic resolution and chemical sensitivity. The high resolution of these techniques allows us to demonstrate that even for magnesium oxide, which has a simple rock-salt structure, grain boundaries can accommodate complex ordered defect superstructures that induce significant electron trapping in the bandgap of the oxide. These results offer insights into interactions between defects and grain boundaries in ceramics and demonstrate that atomic-scale analysis of complex multicomponent structures in materials is now becoming possible.     

ddy小鼠替代大鼠的经济简便的抗焦虑药筛选改进模型--间氯苯哌嗪诱导的小鼠明暗箱焦虑模型

目的建立一个部分模拟临床病理的简便易得、经济有效的用于筛选和研制抗焦虑药的模型.方法用间氯苯哌嗪(mCPP)诱导产生焦虑,观察ddy小鼠和ICR小鼠在明暗箱的行为表现.结果 mCPP在SC 1-4mg/kg的剂量下即可显著降低ddy小鼠在明箱的活动次数,而对暗箱的活动次数影响不显著;1mg/kg与4mg/kg组比较,在明箱的活动次数无显著差异;mCPP在SC 2-10mg/kg的剂量下对ICR小鼠在明箱的的活动次数影响不太显著,只在10mg/kg剂量下才显著;而对暗箱的活动次数却影响较大,在2mg/kg的剂量下即可显著降低活动次数.用安定对该模型进行验证,发现只用较小的样本量即可得出显著结果.结论用ddy小鼠可以取代Wistar大鼠建立mCPP诱导焦虑的明暗箱模型,在样本量较小的情况下即可得到有效结果.所以是一个能够克服大鼠实验缺点的、简便易得且经济有效的用于筛选和研制抗焦虑药的良好模型.但用mCPP诱导的焦虑模型对小鼠的种属有选择性,ICR小鼠不适于上述模型.     

Cblb is a major susceptibility gene for rat type 1 diabetes mellitus

The autoimmune disease type 1 diabetes mellitus (insulin-dependent diabetes mellitus, IDDM) has a multifactorial etiology. So far, the major histocompatibility complex (MHC) is the only major susceptibility locus that has been identified for this disease and its animal models. The Komeda diabetes-prone (KDP) rat is a spontaneous animal model of human type 1 diabetes in which the major susceptibility locus Iddm/kdp1 accounts, in combination with MHC, for most of the genetic predisposition to diabetes. Here we report the positional cloning of Iddm/kdp1 and identify a nonsense mutation in Cblb, a member of the Cbl/Sli family of ubiquitin-protein ligases. Lymphocytes of the KDP rat infiltrate into pancreatic islets and several tissues including thyroid gland and kidney, indicating autoimmunity. Similar findings in Cblb-deficient mice are caused by enhanced T-cell activation. Transgenic complementation with wildtype Cblb significantly suppresses development of the KDP phenotype. Thus, Cblb functions as a negative regulator of autoimmunity and Cblb is a major susceptibility gene for type 1 diabetes in the rat. Impairment of the Cblb signaling pathway may contribute to human autoimmune diseases, including type 1 diabetes.     

Structure in the early afterglow light curve of the gamma-ray burst of 29 March 2003

Gamma-ray bursts (GRBs) are energetic explosions that for 0.01-100 s are the brightest gamma-ray sources in the sky. Observations of the early evolution of afterglows are expected to provide clues about the nature of the bursts, but their rapid fading has hampered such studies; some recent rapid localizations of bursts have improved the situation. Here we report an early detection of the very bright afterglow of the burst of 29 March 2003 (GRB030329). Our data show that, even early in the afterglow phase, the light curve shows unexpectedly complicated structures superimposed on the fading background.     

气流阻力负荷对阻塞性睡眠呼吸暂停患者流速容量曲线的影响

探讨加用气流阻力负荷（ＦＲＬ） 状态下流速容量（ＦＶ） 曲线检查对初检ＯＳＡ 患者的意义对象为２４ 名健康成年男性及２１ 例男性阻塞性睡眠呼吸暂停（ＯＳＡ） 患者经整夜多导睡眠仪检查诊断或排除ＯＳＡ模拟实验结果发现只有同时加上可陷闭管及ＦＲＬ 时,才出现显著吸气气流受限无ＦＲＬ时,ＦＶ 曲线（ 以ＦＥＦ５０／ＦＩＦ５０ 比值大于１ 为指标） 检查发现ＯＳＡ的敏感性和特异性分别为３３ ．３ ％ 和９１ ．６ ％ ,阳性预测率为６３ ．６ ％ 加用ＦＲＬ 时敏感性为７６ ．２ ％ ,特异性为７５ ％ ,阳性预测率为７２ ．２ ％ 吸、呼气相峰值流速比值及中期峰值流速比值与ＯＳＡ 严重呈显著相关联合应用加ＦＲＬ及常规ＦＬ曲线检查可能对ＯＳＡ 患者初筛有较高价值     

A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction

Cerebral infarction is the most common type of stroke and often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C (PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples (P = 5.1 x 10(-7), crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14-year follow-up cohort study in Hisayama (Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction (P = 0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKCeta was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.     

Optogenetic stimulation of a hippocampal engram activates fear memory recall

A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.