《自然》一周論文導讀

生物學Biology

　　Stochastic synaptic plasticity underlying compulsion in a model of addiction

　　成癮模型中隨機突觸可塑性

　　▲ 作者：Vincent Pascoli、Agnès Hiver、Ruud Van Zessen、Micha?l Loureiro、Ridouane Achargui、Masaya Harada、Jér?me Flakowski、Christian Lüscher

　　▲ 鏈接：

　　https://www.nature.com/articles/s41586-018-0789-4

　　▲ 摘要：

　　中腦緣多巴胺系統的激活增強了目標導向行為。通過重復的刺激——例如長期濫用藥物——這種強化可能會變得具有強迫性，仍繼續攝入甚至會面臨重大負面后果。

　　在這里，研究人員讓老鼠有機會自我刺激多巴胺能神經元，并觀察到只有一小部分老鼠在遭受電擊時能夠堅持下來。強迫性壓迫與眼窩額葉皮層（OFC）活動有關。

　　雖然對OFC神經元的短暫抑制能暫時緩解強迫性強化，但研究者發現，在堅持不懈的小鼠中，從OFC到紋狀體的傳輸是永久性增強的。

　　研究人員表示，從OFC到背側紋狀體的突觸強化傳遞會驅動強迫性強化，這是成癮的一種明確癥狀。

　　▲ 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

　　低溫電鏡下聯接蛋白46/50細胞間通道的結構

　　▲ 作者：Janette B.Myers、Bassam G.Haddad、Susan E.O’Neill、Dror S.Chorev、Craig C.Yoshioka、Steve L.Reichow，et al

　　▲ 鏈接：

　　https://www.nature.com/articles/s41586-018-0786-7

　　▲ 摘要：

　　縫隙連接通過組裝12個聯接蛋白亞基建立了細胞間通訊的直接通路。不同聯接蛋白亞型的協同組裝會產生具有獨特屬性的通道，并支持跨細胞類型的通信。

　　本文采用單粒子冷凍電鏡研究了由聯接蛋白 46和聯接蛋白50組成的間隙連接通道（Cx46/50），并首次對聯接蛋白26進行了比較分析，并結合計算研究闡明了控制間隙連接選擇通透性的關鍵能量特征。

　　▲ 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

　　尸源性人類生長激素樣本中β淀粉樣蛋白傳播證據

　　▲ 作者：Silvia A.Purro、Mark A.Farrow、JacquelineLinehan、Tamsin Nazari、David Mengel、Takaomi Saido、John Collinge，et al

　　▲ 鏈接：

　　https://www.nature.com/articles/s41586-018-0790-y

　　▲ 摘要：

　　2015年發表的一篇論文報告稱，曾有8名病人接受了被朊病毒污染的尸源性人類生長激素（c-hGH）治療，且之后死于克雅病（CJD），其中4名病人的腦內出現了β淀粉樣蛋白病理。

　　β淀粉樣蛋白病理是大腦淀粉樣血管病（CAA）和阿爾茨海默氏癥的一種標志。

　　此次，研究人員獲取了病人曾被暴露的部分c-hGH樣本。他們采用生物化學方式分析是否存在β淀粉樣蛋白和tau蛋白，結果發現若干樣本的檢測結果為陽性。

　　之后，研究人員為基因改造小鼠——這些小鼠會表達突變型人化淀粉樣前體蛋白（APP）基因，注射了c-hGH樣本。

　　注射240天后，接受原始c-hGH樣本注射的小鼠產生了β淀粉樣蛋白沉積和CAA，但是各種對照組小鼠幾乎完全沒有出現這種情況。

　　這提供了實驗證據支持一種假設：β淀粉樣蛋白病理可以通過醫源性方式進行人際傳播。

　　▲ 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.

古生物學Paleontology

　　Soft-tissue evidence for homeothermy and crypsis in a Jurassic ichthyosaur

　　侏羅紀魚龍恒溫和保護色的軟組織證據

　　▲ 作者：JohanLindgren、Peter Sj?vall、Volker Thiel、Wenxia Zheng、Shosuke Ito、KazumasaWakamatsu，et al

　　▲ 鏈接：

　　https://www.nature.com/articles/s41586-018-0775-x

　　▲ 摘要：

　　魚龍是一種已經滅絕的海洋爬行動物，與現代齒鯨有著明顯的外部相似性。

　　研究人員分析了狹翼魚龍屬的一個保存完好的魚龍樣本的皮膚組織成分，該樣本具有1.8億年左右的歷史。

　　他們發現了魚龍原始光滑的皮膚殘留。其皮膚仍具有彈性，由真皮、表皮和皮下脂肪組成。

　　皮下脂肪是現代海洋哺乳動物的一個特征，它可以抵御寒冷，幫助漂浮，這是首次鑒定出魚龍脂肪化石，證實魚龍為溫血動物。

　　研究人員還發現，魚龍皮膚的著色模式表明魚龍具有“反影”，即下腹部顏色較淺，而上表面顏色較深。

　　這種著色模式可見于許多現代海洋哺乳動物，用于偽裝、抵御紫外線及調節熱量。

　　▲ 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.

地球科學Geoscience

　　Origin of spatial variation in US East Coast sea-level trends during 1900–2017

　　1900~2017年美國東海岸海平面變化趨勢的空間變化起源

　　▲ 作者：ChristopherG. Piecuch、Peter Huybers、Carling C.Hay、Andrew C.Kemp、Martin P.Tingley，et al

　　▲ 鏈接：

　　https://www.nature.com/articles/s41586-018-0787-6

　　▲ 摘要：

　　確定相對海平面（海平面相對于地殼的高度）的歷史趨勢成因是預測未來變化的先決條件。

　　在過去的一個世紀里，美國東海岸的變化速度在空間上是多變的，相對海平面在中大西洋海灣的上升速度要快于在南大西洋灣和緬因州灣。

　　這里，研究人員使用概率方法分析了儀器數據和重構模型，表明1900~2017年間地殼垂直運動對美國東海岸相對海平面變化趨勢的區域空間差異起主導作用。

　　研究還發現，在這一時期，相對海平面的變化趨勢出現了一個與冰川消融無關的沿海梯度。

　　總之，結果表明，美國東海岸相對海平面長期上升速度的空間變化，主要是由地質過程造成的，這些地質過程將以類似的速度持續數百年。

　　▲ Abstract

　　Identifying the causes of historical trends in relative sea level—the height of the sea surface relative to Earth’s crust—is a prerequisite for predicting future changes. Rates of change along the eastern coast of the USA (the US East Coast) during the past century were spatially variable, and relative sea level rose faster along the Mid-Atlantic Bight than along the South Atlantic Bight and the Gulf of Maine. Past studies suggest that Earth’s ongoing response to the last deglaciation, surface redistribution of ice and water and changes in ocean circulation contributed considerably to this large-scale spatial pattern. Here we analyse instrumental data and proxy reconstructions using probabilistic methods to show that vertical motions of Earth’s crust exerted the dominant control on regional spatial differences in relative sea-level trends along the US East Coast during 1900–2017, explaining most of the large-scale spatial variance. Rates of coastal subsidence caused by ongoing relaxation of the peripheral forebulge associated with the last deglaciationare strongest near North Carolina, Maryland and Virginia. Such structure indicates that Earth’s elastic lithosphere is thicker than has been assumed in other models. We also find a substantial coastal gradient in relative sea-level trends over this period that is unrelated to deglaciation and suggests contributions from twentieth-century redistribution of ice and water. Our results indicate that the majority of large-scale spatial variation in long-term rates of relative sea-level rise on the US East Coast is due to geological processes that will persist at similar rates for centuries.

　　Chemical differentiation, cold storage and remobilization of magma in the Earth’s crust

　　地殼中巖漿的化學分化、冷凝和再活動

　　▲ 作者：M. D. Jackson、J. Blundy、R. S. J. Sparks

　　▲ 鏈接：

　　https://www.nature.com/articles/s41586-018-0746-2

　　▲ 摘要：

　　地殼中巖漿的形成、儲存和化學分化在火成巖地質學和火山學中具有重要意義。

　　最近的數據正在挑戰一個多世紀以來支撐地殼巖漿活動模型的高熔分“巖漿房”范式，并指出巖漿通常儲存在低熔分的“泥漿儲層”中。

　　泥漿儲層的多孔和滲透性框架由緊密堆積的晶體構成，但地殼巖漿作用的許多共同特征尚未使用“巖漿房”或“泥漿儲層”的概念進行解釋。

　　本研究發現，反應熔體流動是一個關鍵的，但迄今為止一直被忽視。泥漿儲層中的反應熔體流動產生低結晶度、化學分化的（硅質）巖漿，這些巖漿上升形成較淺的侵入體或噴發到地表。

　　研究人員認為，巖漿的儲存和分化的實現主要依賴于長期泥漿儲層中的反應性熔體流動，而非巖漿房內的分級結晶過程。

　　▲ Abstract

　　The formation, storage and chemical differentiation of magma in the Earth’s crustis of fundamental importance in igneous geology and volcanology. Recent data are challenging the high-melt-fraction ‘magma chamber’ paradigm that has underpinned models of crustal magmatism for over a century, suggesting instead that magma is normally stored in low-melt-fraction ‘mush reservoirs’. A mush reservoir comprises a porous and permeable framework of closely packed crystals with melt present in the pore space. However, many common features of crustal magmatism have not yet been explained by either the ‘chamber’ or ‘mush reservoir’ concepts. Here we show that reactive melt flow is a critical, but hitherto neglected, process in crustal mush reservoirs, caused by buoyant melt percolating upwards through, and reacting with, the crystals. Reactive melt flow in mush reservoirs produces the low-crystallinity, chemicallydifferentiated (silicic) magmas that ascend to form shallower intrusions orerupt to the surface. These magmas can host much older crystals, stored at low and even sub-solidus temperatures, consistent with crystal chemistry data. Changes in local bulk composition caused by reactive melt flow, rather than large increases in temperature, produce the rapid increase in melt fraction that remobilizes these cool -or cold-stored crystals. Reactive flow can also produce bimodality in magma compositions sourced from mid -to lower-crustal reservoirs. Trace-element profiles generated by reactive flow are similar to those observed in a well studied reservoir now exposed at the surface. We propose that magma storage and differentiation primarily occurs by reactivemelt flow in long-lived mush reservoirs, rather than by the commonly invoked process of fractional crystallization in magma chambers.