封面故事:「能人」的新形象
封面圖片：P. Gunz, S. Neubauer & F. Spoor
本期封面所示為基於來自坦尚尼亞Olduvai Gorge、距今180萬年的模式標本Olduvai Hominid 7 (OH 7) 的骨頭重建的一個 「能人」(Homo habilis)頭骨。透明部分是基於來自肯亞的編號為KNM-ER 1813的頭蓋，將其進行了變形處理，以適合OH 7。
「能人」首次在1964年4月4日的Nature雜誌上首次介紹，當時將其作為 「人屬」的已知最早成員。此後這些年存在的挑戰一直是，弄清其他哪些化石也屬於 「能人」，這一任務因OH 7下頜骨的失真而變得複雜化(這種失真掩蓋了其最初形狀)。現在，研究人員利用計算機斷層掃描(CT)和3D成像技術對OH 7的下頜骨和穹窿骨進行了最先進的虛擬重建，以重新排列破碎了的部分。
該「能人」標本有了新的形象：它有一個原始下頜的形狀(與 「阿法南方古猿」即 「露西」的下頜形狀相似)，同時又有一個與早期 「直立人」一樣大的大腦。這一新證據表明，「人屬」的多個演化分支的存在時間遠遠超過距今200萬年前。
論文原文
Reconstructed Homo habilis type OH 7 suggests deep-rooted species diversity in early Homo
Abstract
Besides Homo erectus (sensu lato), the eastern African fossil record of early Homo has been interpreted as representing either a single variable species, Homo habilis1, or two species2, 3, 4, 5, 6. In the latter case, however, there is no consensus over the respective groupings, and which of the two includes OH 7, the 1.8-million-year-old H. habilis holotype7. This partial skull and hand from Olduvai Gorge remains pivotal to evaluating the early evolution of the Homo lineage, and by priority names one or other of the two taxa. However, the distorted preservation of the diagnostically important OH 7 mandible has hindered attempts to compare this specimen with other fossils8, 9. Here we present a virtual reconstruction of the OH 7 mandible, and compare it to other early Homo fossils. The reconstructed mandible is remarkably primitive, with a long and narrow dental arcade more similar to Australopithecus afarensis than to the derived parabolic arcades of Homo sapiens or H. erectus.
photo by sunny panchal
大麻素對進食的複雜效應
以前的研究工作確定了下丘腦 「阿黑皮素原」(POMC)神經元在因飽感而減少進食方面所起作用，說明促進進食的信號可能會降低POMC神經活性。
Tamas Horvath及同事對這一觀點進行了驗證，發現令人意外的是，大麻素進食信號會增強POMC神經活性。
這種矛盾的POMC神經激發作用對於在飽感狀態由 「大麻素受體-1」的激活所觸發的對進食的應有促進來說是必不可少的。
作者得出結論認為，大麻素對進食的總體效應可能是由突觸前和突觸後兩種效應驅動的(這兩種效應彼此還可能是獨立的)，而造成總體行為變化的是它們在時間上的同步。
論文原文
Hypothalamic POMC neurons promote cannabinoid-induced feeding
Abstract
Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide β-endorphin. CB1R activation selectively increases β-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.
photo by dan cretu
運動前的腦活動
在很多物種中，運動開始之前都發現：運動皮層和運動前皮層中的神經活動增加。這種活動對於將要發生的運動的方向來說往往不是特定的，它與運動信號有什麼關係仍不清楚。
在這項研究中，Karel Svoboda 及同事分析了小鼠前側向運動皮層內的神經元對運動規劃的貢獻。他們發現了具有相應於其各自功能反應的不同連接的不同神經元類群：投射到下遊區域的神經元類群比投射到其他皮層目標的神經元類群對於將要發生的運動的方向更有選擇性。
這些結果突顯了在行為過程中測出的複雜神經反應需要怎樣按照它們所參與的神經迴路的組織方式來加以解讀。
論文原文
A motor cortex circuit for motor planning and movement
Abstract
Activity in motor cortex predicts specific movements seconds before they occur, but how this preparatory activity relates to upcoming movements is obscure. We dissected the conversion of preparatory activity to movement within a structured motor cortex circuit. An anterior lateral region of the mouse cortex (a possible homologue of premotor cortex in primates) contains equal proportions of intermingled neurons predicting ipsi- or contralateral movements, yet unilateral inactivation of this cortical region during movement planning disrupts contralateral movements. Using cell-type-specific electrophysiology, cellular imaging and optogenetic perturbation, we show that layer 5 neurons projecting within the cortex have unbiased laterality. Activity with a contralateral population bias arises specifically in layer 5 neurons projecting to the brainstem, and only late during movement planning. These results reveal the transformation of distributed preparatory activity into movement commands within hierarchically organized cortical circuits.
photo by kelly-stewart
炎症的有益作用
除了激發先天和後天免疫外，炎症還能通過我們基本上還不知道的機制觸發組織修復和再生。這項研究在一個小鼠實驗性結腸炎模型中顯示了一個獨立於STAT3的治癒通道通過涉及gp130(白介素-6家族細胞因子的一個共受體)和下遊效應子Src、Yes、YAP及Notch的一個過程是如何被激發的。
論文原文
A gp130–Src–YAP module links inflammation to epithelial regeneration
Abstract
Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
photo by peter nielsen
一個仿生液體門控系統
生物小孔在選擇性地協調不同環境之間的多相運輸不致發生堵塞方面給人印象深刻的表現，啟發人們去構建模仿這種行為的合成小孔。
但構建單獨一個能夠選擇性處理和控制複雜多相運輸的系統仍是一個遙遠的願望，汙染幾乎不可避免。
Xu Hou等人發現，通過毛細管穩定的流體能夠可逆地將小孔密封在閉合狀態，並可在壓力下迅速重新配置，以生成內壁上有流體的開啟小孔。
因為每種運輸物質都有一個不同的、可以合理調節的門控閾限壓力，所以一個系統能夠為氣-液分選以及為對一個 「微流體流」中的一種氣-水-油三相混合物進行分離而動態地被調製。
這種液體門控方式能夠對微觀以及宏觀流體系統進行高效的、防汙染的長期操作，這在一系列不同應用中將會被證明是有用的。
論文原文
Liquid-based gating mechanism with tunable multiphase selectivity and antifouling behaviour
Abstract
Living organisms make extensive use of micro- and nanometre-sized pores as gatekeepers for controlling the movement of fluids, vapours and solids between complex environments. The ability of such pores to coordinate multiphase transport, in a highly selective and subtly triggered fashion and without clogging, has inspired interest in synthetic gated pores for applications ranging from fluid processing to 3D printing and lab-on-chip systems1, 2, 3, 4, 5, 6, 7, 8, 9, 10. But although specific gating and transport behaviours have been realized by precisely tailoring pore surface chemistries and pore geometries6, 11, 12, 13, 14, 15, 16, 17, a single system capable of controlling complex, selective multiphase transport has remained a distant prospect, and fouling is nearly inevitable11, 12. Here we introduce a gating mechanism that uses a capillary-stabilized liquid as a reversible, reconfigurable gate that fills and seals pores in the closed state, and creates a non-fouling, liquid-lined pore in the open state. Theoretical modelling and experiments demonstrate that for each transport substance, the gating threshold—the pressure needed to open the pores—can be rationally tuned over a wide pressure range. This enables us to realize in one system differential response profiles for a variety of liquids and gases, even letting liquids flow through the pore while preventing gas from escaping. These capabilities allow us to dynamically modulate gas–liquid sorting in a microfluidic flow and to separate a three-phase air–water–oil mixture, with the liquid lining ensuring sustained antifouling behaviour. Because the liquid gating strategy enables efficient long-term operation and can be applied to a variety of pore structures and membrane materials, and to micro- as well as macroscale fluid systems, we expect it to prove useful in a wide range of applications.
Abstract: "The dawn of old stars" Classic xanthene dyes like eosin Y (gr. εος=goddess of dawn) and green-light irradiation can replace precious metal complexes for the organocatalytic asymmetric-alkylation of aldehydes rendering the process purely organic.
烯丙基碳-氫鍵的直接芳基化
James Cuthbertson 和David MacMillan 介紹了用於烯丙基sp3 碳-氫鍵的直接芳基化反應的一個新的通用方法，這為不需要通過引入外來官能團、而只是通過簡單的、但卻惰性的構造單元的偶聯來合成複雜有機分子提供了一個潛在方法。通過與光氧化還原和基於硫醇的有機催化相結合，這個反應只需要溫和的條件，並且能夠適用於一系列不同的烯烴和缺電子芳烴偶聯配體。
論文原文
The direct arylation of allylic sp3 C–H bonds via organic and photoredox catalysis
Abstract
The direct functionalization of unactivated sp3 C–H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts1, the establishment of general and mild strategies for the engagement of sp3 C–H bonds in C–C bond forming reactions has proved difficult.
具有與疫苗作用相似的HIV-1侵入抑制劑
這項研究介紹了新的一類強效HIV-1侵入抑制劑，它們能夠通過一個基因療法載體來輸送，可以成為傳統HIV-1疫苗的有效替代藥物。
為了進入細胞，HIV-1首先要與其細胞受體CD4結合，然後再與共受體CCR5 或CXCR4結合。 這一新的侵入抑制劑由融合到一個模仿硫代肽的CCR5上的免疫粘附素CD4-Ig組成。
這種融合體(被稱為eCD4-Ig)會 「貪婪地」結合HIV-1的Env蛋白，不可逆轉地使其失活。Michael Farzan及同事發現，這種抑制劑的藥效和作用範圍都極大，能100%地中和一組對中和有抵抗力的多樣化HIV-1。當利用一種 「腺相關病毒」將這種抑制劑送入獼猴體內時，它能面對用病毒進行的多種挑戰對獼猴提供保護。
論文原文
AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges
Abstract
Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs)1, 2. However, even the best bNAbs neutralize 10–50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC80) > 5 μg ml−1), suggesting that high concentrations of these antibodies would be necessary to achieve general protection3, 4, 5, 6. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean half-maximum inhibitory concentration (IC50) < 0.05 μg ml−1). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2 and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46 and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17–77 μg ml−1 of fully functional rhesus eCD4-Ig for more than 40 weeks, and these macaques were protected from several infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well-characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.
photo by cheryl chan
食品乳化劑的有害影響
非遺傳因素是腸炎和代謝症候群等炎症發病的重要貢獻因素。本文作者發現，吃含乳化劑食物的小鼠會患輕度炎症和肥胖/代謝症候群。這些症狀與腸道微生物群-上皮組織之間的距離因黏膜層的降解而減小、以及微生物群組成和促炎潛力的改變有關。
乳化劑是人類飲食中常見食物添加劑，這些發現表明，需要就它們對腸道微生物群和人體健康的潛在影響做進一步研究。
論文原文
Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome
Abstract
The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota–host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine1. Thus, agents that disrupt mucus–bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro2, might be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century3. Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host–microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.
阿西替尼的抗白血病潛力
很多慢性骨髓性白血病(CMLs)和急性淋巴細胞白血病(ALLs)都是由BCR-ABL融合基因造成的。
用選擇性激酶抑制劑以BCR-ABL為目標進行治療使CML白血病的治療發生了革命性變化，但患者經常會對治療產生抵抗力，原因經常是由於BCR-ABL發生了二次突變。
在來自 CML 和ALL患者的初生細胞中對已經被批准上市和仍處在研究階段的抗癌藥物所做的這項大規模篩選中，Krister Wennerberg及同事發現 「阿西替尼」(一種被批准用於治療腎癌的多激酶抑制劑)在來自初發患者的CML和ALL細胞中(包括在具有二次抵抗力突變的細胞中)具有活性。在一位CML患者身上(對這位患者其他所有治療方案都已用盡)，通過「阿西替尼」的誘導，循環的BCR-ABL轉錄體水平降低了。這些初步的臨床發現顯示了將現有藥物改變用途用於治療其他類型癌症所具有的潛力。
論文原文
Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation
Abstract
The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30–50% of cases of adult acute lymphoblastic leukaemia1. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival2, but acquired drug resistance remains a challenge3, 4, 5. Point mutations in the ABL1 kinase domain weaken inhibitor binding6 and represent the most common clinical resistance mechanism. The BCR–ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib7, 8, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR–ABL1-driven leukaemia. Axitinib potently inhibited BCR–ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.
一個IRES掌管一切
翻譯對所有活生物的基因表達來說都至關重要，但用來招募核糖體和啟動蛋白合成的信號在不同生命領域卻截然不同。
雖然真核生物和原核生物都通過一個高度保守的核心核糖體結構來翻譯mRNA，但mRNA內被核糖體識別的兩種信號是卻相互排斥的。
Jeffrey Kieft及同事想知道是否會有一種被真核生物和原核生物都能識別的普遍信號，他們現在介紹了具有這種性質的一個真核病毒IRES (內部核糖體進入點)元素。該IRES與細菌和真核生物核糖體都能夠相似地、以依賴於結構的方式結合，但在細菌中該元素的結合會誘導核糖體位置發生一個變化，這種變化在真核生物核糖體中沒有被看到。
論文原文
Initiation of translation in bacteria by a structured eukaryotic IRES RNA
Abstract
The central dogma of gene expression (DNA to RNA to protein) is universal, but in different domains of life there are fundamental mechanistic differences within this pathway. For example, the canonical molecular signals used to initiate protein synthesis in bacteria and eukaryotes are mutually exclusive1. However, the core structures and conformational dynamics of ribosomes that are responsible for the translation steps that take place after initiation are ancient and conserved across the domains of life2. We wanted to explore whether an undiscovered RNA-based signal might be able to use these conserved features, bypassing mechanisms specific to each domain of life, and initiate protein synthesis in both bacteria and eukaryotes. Although structured internal ribosome entry site (IRES) RNAs can manipulate ribosomes to initiate translation in eukaryotic cells, an analogous RNA structure-based mechanism has not been observed in bacteria. Here we report our discovery that a eukaryotic viral IRES can initiate translation in live bacteria. We solved the crystal structure of this IRES bound to a bacterial ribosome to 3.8 Å resolution, revealing that despite differences between bacterial and eukaryotic ribosomes this IRES binds directly to both and occupies the space normally used by transfer RNAs. Initiation in both bacteria and eukaryotes depends on the structure of the IRES RNA, but in bacteria this RNA uses a different mechanism that includes a form of ribosome repositioning after initial recruitment. This IRES RNA bridges billions of years of evolutionary divergence and provides an example of an RNA structure-based translation initiation signal capable of operating in two domains of life.
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