《自然》一周论文导读
生物学Biology
Stochastic synaptic plasticity underlying compulsion in a model of addiction
成瘾模型中随机突触可塑性
▲ 作者：Vincent Pascoli、Agnès Hiver、Ruud Van Zessen、Michaël Loureiro、Ridouane Achargui、Masaya Harada、Jérôme Flakowski、Christian Lüscher
▲ 链接：
https://www.nature.com/articles/s41586-018-0789-4
▲ 摘要：
中脑缘多巴胺系统的激活增强了目标导向行为。通过重复的刺激——例如长期滥用药物——这种强化可能会变得具有强迫性，仍继续摄入甚至会面临重大负面后果。
在这里，研究人员让老鼠有机会自我刺激多巴胺能神经元，并观察到只有一小部分老鼠在遭受电击时能够坚持下来。强迫性压迫与眼窝额叶皮层（OFC）活动有关。
虽然对OFC神经元的短暂抑制能暂时缓解强迫性强化，但研究者发现，在坚持不懈的小鼠中，从OFC到纹状体的传输是永久性增强的。
研究人员表示，从OFC到背侧纹状体的突触强化传递会驱动强迫性强化，这是成瘾的一种明确症状。
▲ Abstract
Activation of the mesolimbic dopamine system reinforces goal-directed behaviours. With repetitive stimulation—for example, by chronic drug abuse—the reinforcement may become compulsive and intake continues even in the face of major negative consequences. Here we gave mice the opportunity to optogenetically self-stimulate dopaminergic neurons and observed that only a fraction of miceper severed if they had to endure an electric shock. Compulsive lever pressing was associated with an activity peak in the projection terminals from the orbito frontal cortex (OFC) to the dorsal striatum. Although brief inhibition of OFC neurons temporarily relieved compulsive reinforcement, we found that transmission from the OFC to the striatum was permanently potentiated inpersevering mice. To establish causality, we potentiated these synapses in vivoin mice that stopped optogenetic self-stimulation of dopamine neurons because of punishment； this led to compulsive lever pressing, whereas depotentiation inpersevering mice had the converse effect. In summary, synaptic potentiation of transmission from the OFC to the dorsal striatum drives compulsive reinforcement, a defining symptom of addiction.
Structure of native lens connexin 46/50 intercellular channels by cryo-EM
低温电镜下联接蛋白46/50细胞间通道的结构
▲ 作者：Janette B.Myers、Bassam G.Haddad、Susan E.O’Neill、Dror S.Chorev、Craig C.Yoshioka、Steve L.Reichow，et al
▲ 链接：
https://www.nature.com/articles/s41586-018-0786-7
▲ 摘要：
缝隙连接通过组装12个联接蛋白亚基建立了细胞间通讯的直接通路。不同联接蛋白亚型的协同组装会产生具有独特属性的通道，并支持跨细胞类型的通信。
本文采用单粒子冷冻电镜研究了由联接蛋白 46和联接蛋白50组成的间隙连接通道（Cx46/50），并首次对联接蛋白26进行了比较分析，并结合计算研究阐明了控制间隙连接选择通透性的关键能量特征。
▲ Abstract
Gap junctions establish direct pathways for cell-to-cell communication through the assembly of twelve connexin subunits that form intercellular channels connecting neighbouring cells. Co-assembly of different connexin isoforms
produces channels with unique properties and enables communication across celltypes. Here we used single-particle cryo-electron microscopy to investigate the structural basis of connexin co-assembly in native lens gap junction channels composed of connexin 46 and connexin 50 (Cx46/50). We provide the first comparative analysis to connexin 26 (Cx26), which—together with computational studies—elucidates key energetic features governing gap junction permselectivity. Cx46/50 adopts an open-state conformation that is distinctfrom the Cx26 crystal structure, yet it appears to be stabilized by a conserved set of hydrophobic anchoring residues. ‘Hot spots’ of genetic mutations linked to hereditary cataract formation map to the core structural–functional elements identified in Cx46/50, suggesting explanations for many of the disease-causing effects.
Transmission of amyloid-β protein pathology from cadaveric pituitary growth hormone
尸源性人类生长激素样本中β淀粉样蛋白传播证据
▲ 作者：Silvia A.Purro、Mark A.Farrow、JacquelineLinehan、Tamsin Nazari、David Mengel、Takaomi Saido、John Collinge，et al
▲ 链接：
https://www.nature.com/articles/s41586-018-0790-y
▲ 摘要：
2015年发表的一篇论文报告称，曾有8名病人接受了被朊病毒污染的尸源性人类生长激素（c-hGH）治疗，且之后死于克雅病（CJD），其中4名病人的脑内出现了β淀粉样蛋白病理。
β淀粉样蛋白病理是大脑淀粉样血管病（CAA）和阿尔茨海默氏症的一种标志。
此次，研究人员获取了病人曾被暴露的部分c-hGH样本。他们采用生物化学方式分析是否存在β淀粉样蛋白和tau蛋白，结果发现若干样本的检测结果为阳性。
之后，研究人员为基因改造小鼠——这些小鼠会表达突变型人化淀粉样前体蛋白（APP）基因，注射了c-hGH样本。
注射240天后，接受原始c-hGH样本注射的小鼠产生了β淀粉样蛋白沉积和CAA，但是各种对照组小鼠几乎完全没有出现这种情况。
这提供了实验证据支持一种假设：β淀粉样蛋白病理可以通过医源性方式进行人际传播。
▲ Abstract
We previously reported the presence of amyloid-β protein (Aβ) deposits in individuals with Creutzfeldt–Jakob disease (CJD) who had been treated during childhood with human cadaveric pituitary-derived growth hormone (c-hGH) contaminated with prions. The marked deposition of parenchymal and vascular Aβ in these relatively young individuals with treatment-induced (iatrogenic) CJD (iCJD), in contrast to other prion-disease patients and population controls, allied with the ability of Alzheimer’s disease brain homogenates to seed Aβ deposition in laboratory animals, led us to argue that the implicated c-hGH batches might have been contaminated with Aβ seeds as well as with prions. However, this was necessarily an association, and not an experimental, study inhumans and causality could not be concluded. Given the public health importanceof our hypothesis, we proceeded to identify and biochemically analyse archivedvials of c-hGH. Here we show that certain c-hGH batches to which patients with iCJD and Aβ pathology were exposed have substantial levels of Aβ40, Aβ42 and tau proteins, and that this material can seed the formation of Aβ plaques and cerebral Aβ−amyloid angiopathy in intracerebrally inoculated mice expressing a mutant, humanized amyloid precursor protein. These results confirm the presence of Aβ seeds in archived c-hGH vials and are consistent with the hypothesized iatrogenic human transmission of Aβ pathology. This experimental confirmation has implications for both the prevention and the treatment of Alzheimer’s disease, and should prompt a review of the risk of iatrogenic transmission of Aβ seeds by medical and surgical procedures long recognized to pose a risk of accidental prion transmission.
古生物学Paleontology
Soft-tissue evidence for homeothermy and crypsis in a Jurassic ichthyosaur
侏罗纪鱼龙恒温和保护色的软组织证据
▲ 作者：JohanLindgren、Peter Sjövall、Volker Thiel、Wenxia Zheng、Shosuke Ito、KazumasaWakamatsu，et al
▲ 链接：
https://www.nature.com/articles/s41586-018-0775-x
▲ 摘要：
鱼龙是一种已经灭绝的海洋爬行动物，与现代齿鲸有着明显的外部相似性。
研究人员分析了狭翼鱼龙属的一个保存完好的鱼龙样本的皮肤组织成分，该样本具有1.8亿年左右的历史。
他们发现了鱼龙原始光滑的皮肤残留。其皮肤仍具有弹性，由真皮、表皮和皮下脂肪组成。
皮下脂肪是现代海洋哺乳动物的一个特征，它可以抵御寒冷，帮助漂浮，这是首次鉴定出鱼龙脂肪化石，证实鱼龙为温血动物。
研究人员还发现，鱼龙皮肤的着色模式表明鱼龙具有“反影”，即下腹部颜色较浅，而上表面颜色较深。
这种着色模式可见于许多现代海洋哺乳动物，用于伪装、抵御紫外线及调节热量。
▲ Abstract
Ichthyosaurs are extinct marine reptiles that display a notable external similarity to modern toothed whales. Here we show that this resemblance is more than skin deep. We apply a multi disciplinary experimental approach to characterize the cellular and molecular composition of integumental tissues in an exceptionally preserved specimen of the Early Jurassic ichthyosaur Stenopterygius. Our analyses recovered still-flexible remnants of the original scaleless skin, which comprises morphologically distinct epidermal and dermal layers. These are underlain by insulating blubber that would have augmented streamlining, buoyancy and homeothermy. Additionally, we identify endogenous proteinaceous and lipid constituents, together with keratinocytes and branched melanophores that contain eumelanin pigment. Distributional variation of melanophores across the body suggests countershading, possibly enhanced by physiological adjustments of colour to enable photoprotection, concealment and/or thermoregulation. Convergence of ichthyosaurs with extant marine amniotes thus extends to the ultra structural and molecular levels, reflecting the omnipresent constraints of their shared adaptation to pelagic life.
-
焦点事件
-
焦点事件
-
项目成果
-
焦点事件
-
焦点事件
-
焦点事件
-
焦点事件
-
焦点事件
-
项目成果
