印度坎普尔理工学院生物科学系，东京大学理学研究科

Abstract

β-arrestins (βarrs) are multifunctional proteins involved in signaling and regulation of seven transmembrane receptors (7TMRs), and their interaction is driven primarily by agonist-induced receptor activation and phosphorylation. Here, we present seven cryo–electron microscopy structures of βarrs either in the basal state, activated by the muscarinic receptor subtype 2 (M2R) through its third intracellular loop, or activated by the βarr-biased decoy D6 receptor (D6R). Combined with biochemical, cellular, and biophysical experiments, these structural snapshots allow the visualization of atypical engagement of βarrs with 7TMRs and also reveal a structural transition in the carboxyl terminus of βarr2 from a β strand to an α helix upon activation by D6R. Our study provides previously unanticipated molecular insights into the structural and functional diversity encoded in 7TMR-βarr complexes with direct implications for exploring novel therapeutic avenues.

摘要：

β-抑制蛋白（βarrs）是参与七次跨膜受体（7TMR）信号传导和调控的多功能蛋白。它们的相互作用主要由激动剂诱导的受体活化和磷酸化驱动。在本研究中，我们展示了βarrs七种冷冻电子显微镜结构，它们要么处于基础状态，由毒蕈碱受体亚型2（M2R）通过其第三个细胞内环激活，要么由βarr偏向诱饵D6受体（D6R）激活。结合生化、细胞和生物物理实验，这些结构快照可以将βarr与7TMR的非典型结合可视化，并揭示βarr2羧基末端在D6R激活后从β链到α螺旋的结构转变。我们的研究为7TMR-βarr复合物编码的结构和功能多样性提供了前所未有的分子水平分析，对探索新的治疗途径具有直接意义。

4.Convergence in carnivorous pitcher plants reveals a mechanism for composite trait evolution

英国杜伦大学生物科学系，英国伦敦自然历史博物馆，美国明尼苏达大学德卢斯校区化学和生物化学系，加拿大哥伦比亚大学化学系，加拿大哥伦比亚大学植物学系，美国牛津大学生物系

Abstract

Composite traits involve multiple components that, only when combined, gain a new synergistic function. Thus, how they evolve remains a puzzle. We combined field experiments, microscopy, chemical analyses, and laser Doppler vibrometry with comparative phylogenetic analyses to show that two carnivorous Nepenthes pitcher plant species independently evolved similar adaptations in three distinct traits to acquire a new, composite trapping mechanism. Comparative analyses suggest that this new trait arose convergently through "spontaneous coincidence" of the required trait combination, rather than directional selection in the component traits. Our results indicate a plausible mechanism for composite trait evolution and highlight the importance of stochastic phenotypic variation as a facilitator of evolutionary novelty.

摘要：

复合性状涉及多个组分，只有当它们结合在一起时，才能获得新的协同效应。因此，它们如何进化仍然是一个谜。我们结合田间实验、显微镜观察、化学分析、激光多普勒振测法与比较系统发育分析，揭示了两种肉食性猪笼草物种在三个不同性状上独立进化出类似的适应性以获得一个新的复合诱捕机制。比较分析表明，这一新性状是通过所需性状组合的“自发巧合”趋同产生的，而不是通过在组分性状中的定向选择出现的。我们的研究结果表明了复合性状进化的一种可能的机制，并强调了随机表型变异作为进化新颖性的促进因素的重要性。

5.The genetic basis of a recent transition to live-bearing in marine snails

海螺近期向胎生转变的遗传基础

英国谢菲尔德大学生物科学学院

Abstract

Key innovations are fundamental to biological diversification, but their genetic basis is poorly understood. A recent transition from egg-laying to live-bearing in marine snails (Littorina spp.) provides the opportunity to study the genetic architecture of an innovation that has evolved repeatedly across animals. Individuals do not cluster by reproductive mode in a genome-wide phylogeny, but local genealogical analysis revealed numerous small genomic regions where all live-bearers carry the same core haplotype. Candidate regions show evidence for live-bearer-specific positive selection and are enriched for genes that are differentially expressed between egg-laying and live-bearing reproductive systems. Ages of selective sweeps suggest that live-bearer-specific alleles accumulated over more than 200,000 generations. Our results suggest that new functions evolve through the recruitment of many alleles rather than in a single evolutionary step.

关键创新是生物多样性的基础，但其遗传基础尚不清楚。海螺（滨螺属）近期从卵生到胎生的转变有助于研究一种在动物之间反复进化的创新的遗传结构。在全基因组系统发育中，个体并不按繁殖模式聚类，但当地系谱分析揭示了许多小型基因组区域，在这些区域中，所有胎生海螺都携带相同的核心单倍型。候选区域显示出胎生动物特异性的正选择的证据，并且其中富集了在卵生和胎生繁殖系统之间差异表达的基因。选择性扫描的年龄表明，胎生动物特异性等位基因积累了超过20万代。我们的研究结果表明，新的功能是通过招募许多等位基因来进化，而非通过一个单一的步骤。

Volume 383| Issue 6679| 12 JANUARY 2024

• 8篇NEWS

• 10篇INSIGHTS

• 其中3篇LETTERS， 4篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK

• 13篇RESEARCH

• 其中12篇RESEARCH ARTICLES，1篇REVIEW

• 1篇EDITORIAL

1.Deterministic reprogramming of neutrophils within tumors

新加坡科学技术研究局（A*STAR），新加坡免疫学研究所（SIgN），上海交通大学医学院附属仁济医院上海免疫治疗研究所

Abstract

Neutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Here, we demonstrate that immature and mature neutrophils that enter tumors undergo irreversible epigenetic, transcriptional, and proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1+ state. Reprogrammed dcTRAIL-R1+ neutrophils predominantly localize to a glycolytic and hypoxic niche at the tumor core and exert pro-angiogenic function that favors tumor growth. We found similar trajectories in neutrophils across multiple tumor types and in humans, suggesting that targeting this program may provide a means of enhancing certain cancer immunotherapies.

摘要：

中性粒细胞越来越被认为是参与肿瘤免疫应答的关键角色，并与不良临床结局相关。尽管近年来对癌症中性粒细胞状态多样性的研究取得了进展，但控制个体发育的共同轨迹和机制以及这些中性粒细胞状态之间的关系仍然不清楚。本研究表明未成熟和成熟的中性粒细胞进入肿瘤后经历不可逆的表观遗传、转录和蛋白组修饰，转变成独特的终末分化dcTRAIL-R1+态。重编程的dcTRAIL-R1+中性粒细胞主要定位于肿瘤核心的糖酵解和缺氧环境，并发挥有利于肿瘤生长的促血管生成功能。我们在人类多个肿瘤类型的中性粒细胞中发现了类似的轨迹，这表明靶向该重编程过程或许能为优化某些癌症免疫治疗方法提供新思路。

2.Illusory generalizability of clinical prediction models

美国耶鲁大学医学院精神病学系,美国耶鲁大学生物统计学系

Abstract

It is widely hoped that statistical models can improve decision-making related to medical treatments. Because of the cost and scarcity of medical outcomes data, this hope is typically based on investigators observing a model's success in one or two datasets or clinical contexts. We scrutinized this optimism by examining how well a machine learning model performed across several independent clinical trials of antipsychotic medication for schizophrenia. Models predicted patient outcomes with high accuracy within the trial in which the model was developed but performed no better than chance when applied out-of-sample. Pooling data across trials to predict outcomes in the trial left out did not improve predictions. These results suggest that models predicting treatment outcomes in schizophrenia are highly context-dependent and may have limited generalizability.

人们普遍希望统计模型可以改善临床相关决策。由于医疗结果数据需要耗费成本，并具有稀缺性，研究人员往往希望通过一两个数据集或临床背景下观察到模型的成功。我们通过检验机器学习模型在几个独立的关于抗精神分裂症药物的临床试验中的表现来审视这种乐观性。在其所来源的队列中，模型对预测患者结局的准确性很高，但在这些样本外应用时，模型的表现与随机结果没有差别。将试验数据汇总来预测被遗漏的试验的结果并没有改善预测结果。这些结果表明，精神分裂症中预测治疗效果的模型高度依赖于试验背景，在推广应用时具有局限性。

3.Hyperglycosylation of prosaposin in tumor dendritic cells drives immune escape

肿瘤树突状细胞中鞘脂激活蛋白原的高糖基化驱动免疫逃逸

美国哈佛医学院波士顿儿童医院

Abstract

Tumors develop strategies to evade immunity by suppressing antigen presentation. In this work, we show that prosaposin (pSAP) drives CD8 T cell–mediated tumor immunity and that its hyperglycosylation in tumor dendritic cells (DCs) leads to cancer immune escape. We found that lysosomal pSAP and its single-saposin cognates mediated disintegration of tumor cell–derived apoptotic bodies to facilitate presentation of membrane-associated antigen and T cell activation. In the tumor microenvironment, transforming growth factor–β (TGF-β) induced hyperglycosylation of pSAP and its subsequent secretion, which ultimately caused depletion of lysosomal saposins. pSAP hyperglycosylation was also observed in tumor-associated DCs from melanoma patients, and reconstitution with pSAP rescued activation of tumor-infiltrating T cells. Targeting DCs with recombinant pSAP triggered tumor protection and enhanced immune checkpoint therapy. Our studies demonstrate a critical function of pSAP in tumor immunity and may support its role in immunotherapy.

摘要：

肿瘤通过抑制抗原呈递来建立免疫逃逸的机制。在本研究中，我们发现，鞘脂激活蛋白原（prosaposin，pSAP）驱动CD8 T细胞介导的肿瘤免疫，其在肿瘤树突状细胞（DCs）中的高糖基化导致了癌症免疫逃逸。我们发现，溶酶体pSAP和它的单-鞘脂激活蛋白同源物介导了肿瘤细胞源性凋亡小体的解体，以促进膜相关抗原的呈递和T细胞活化。在肿瘤微环境中，转化生长因子-β（TGF-β）诱导pSAP的高糖基化及其随后的分泌，这最终导致溶酶体鞘脂激活蛋白的耗竭。在黑素瘤患者的肿瘤相关DCs中也观察到了pSAP的高糖基化，并且pSAP的重组挽救了肿瘤浸润性T细胞的活化。用重组pSAP靶向DCs可触发肿瘤保护并增强免疫检查点治疗的效果。我们的研究证明了pSAP在肿瘤免疫中的关键功能，并可能支持其在免疫治疗中的作用。

4.Antibody production relies on the tRNA inosine wobble modification to meet biased codon demand

抗体的产生依赖于tRNA肌苷摆动修饰以满足密码子的需求

美国麻省理工学院

Abstract

Antibodies are produced at high rates to provide immunoprotection, which puts pressure on the B cell translational machinery. Here, we identified a pattern of codon usage conserved across antibody genes. One feature thereof is the hyperutilization of codons that lack genome-encoded Watson-Crick transfer RNAs (tRNAs), instead relying on the posttranscriptional tRNA modification inosine (I34), which expands the decoding capacity of specific tRNAs through wobbling. Antibody-secreting cells had increased I34 levels and were more reliant on I34 for protein production than naïve B cells. Furthermore, antibody I34-dependent codon usage may influence B cell passage through regulatory checkpoints. Our work elucidates the interface between the tRNA pool and protein production in the immune system and has implications for the design and selection of antibodies for vaccines and therapeutics。

摘要：

为提供免疫保护力，抗体以高速率生成，这给B细胞的翻译机制带来了压力。在本研究中，我们发现了抗体基因中密码子的一种保守使用模式。其中一个特征是过度利用缺乏基因组编码的沃森-克里克tRNAs的密码子，而不是依赖于转录后的tRNA修饰肌苷（I34），后者能通过摇摆效应扩大特定tRNAs的解码能力。抗体分泌细胞的I34水平增加，并且比幼稚B细胞更依赖于I34来产生蛋白质。此外，抗体I34依赖性密码子的使用可能通过调节检查点影响B细胞传代。我们的研究阐明了免疫系统中tRNA库和蛋白质产生之间的接口，并对疫苗和治疗中所用抗体的设计和筛选具有重要意义。

Volume 383| Issue 6680| 19 JANUARY 2024

• 8篇NEWS

• 10篇INSIGHTS

• 其中3篇LETTERS， 4篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK

• 12篇RESEARCH ARTICLES

• 1篇EDITORIAL

1.Priming agents transiently reduce the clearance of cell-free DNA to improve liquid biopsies

启动剂可瞬时降低游离DNA的清除率，优化液体活检技术

美国麻省理工学院科赫综合癌症研究所，哈佛-麻省理工学院健康科学与技术部，麻省理工学院和哈佛大学博德研究所

Abstract

Liquid biopsies enable early detection and monitoring of diseases such as cancer, but their sensitivity remains limited by the scarcity of analytes such as cell-free DNA (cfDNA) in blood. Improvements to sensitivity have primarily relied on enhancing sequencing technology ex vivo. We sought to transiently augment the level of circulating tumor DNA (ctDNA) in a blood draw by attenuating its clearance in vivo. We report two intravenous priming agents given 1 to 2 hours before a blood draw to recover more ctDNA. Our priming agents consist of nanoparticles that act on the cells responsible for cfDNA clearance and DNA-binding antibodies that protect cfDNA. In tumor-bearing mice, they greatly increase the recovery of ctDNA and improve the sensitivity for detecting small tumors.

摘要：

液体活检技术能够早期检测和监测癌症等疾病，但其灵敏度仍然因血液中的游离DNA（cfDNA）等分析物的稀缺而受到限制。灵敏度的提高主要依赖于增强体外测序技术。我们试图降低抽血时循环肿瘤DNA（ctDNA）在体内的清除率来暂时地提高它在血液中的水平。我们发现在抽血前1至2小时静脉注射两种启动剂延迟了体内ctDNA的清除，从而得到了更多的ctDNA。我们的启动剂由作用于cfDNA清除细胞的纳米颗粒和保护cfDNA的DNA结合抗体组成。在荷瘤小鼠中，它们大大提高了ctDNA的回收率，并提高了小肿瘤检测的灵敏度。

2.Persistent complement dysregulation with signs of thromboinflammation in active Long Covid

瑞士苏黎世大学医院免疫学系，苏黎世联邦理工学院生物系统科学与工程系

Abstract

Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome coronavirus 2 infection. Analysis of >6500 proteins in 268 longitudinal samples revealed dysregulated activation of the complement system, an innate immune protection and homeostasis mechanism, in individuals experiencing Long Covid. Thus, active Long Covid was characterized by terminal complement system dysregulation and ongoing activation of the alternative and classical complement pathways, the latter associated with increased antibody titers against several herpesviruses possibly stimulating this pathway. Moreover, markers of hemolysis, tissue injury, platelet activation, and monocyte-platelet aggregates were increased in Long Covid. Machine learning confirmed complement and thromboinflammatory proteins as top biomarkers, warranting diagnostic and therapeutic interrogation of these systems.

摘要：

长期新冠肺炎是一种病因不明的虚弱病症。我们对确诊严重急性呼吸综合征冠状病毒2型感染后随访12个月的COVID-19患者的血清进行了多模式蛋白质组学分析。对268个纵向样本中>6500种蛋白质的分析显示，在长期新冠肺炎的患者个体中，补体系统（一种先天免疫保护和稳态机制）激活失调。因此，活动性长期新冠肺炎的特征是终末补体系统失调以及替代补体途径和经典补体途径的持续激活，后者与针对可能刺激该途径的几种疱疹病毒的抗体滴度增加有关。此外，溶血、组织损伤、血小板活化和单核细胞-血小板聚集的标志物在长期新冠肺炎中增加。机器学习证实了补体蛋白和血栓炎性蛋白是长期新冠肺炎中最重要的生物标志物，需要对这些物质系统进行诊断和治疗。

3.Impact of HLA class I functional divergence on HIV control

人类白细胞抗原Ⅰ类分子（HLA-1）功能分化对HIV控制的影响

美国国家癌症研究所，弗雷德里克国家癌症研究实验室

Abstract

Heterozygosity of Human leukocyte antigen (HLA) class I genes is linked to beneficial outcomes after HIV infection, presumably through greater breadth of HIV epitope presentation and cytotoxic T cell response. Distinct allotype pairs, however, differ in the extent to which they bind shared sets of peptides. We developed a functional divergence metric that measures pairwise complementarity of allotype-associated peptide binding profiles. Greater functional divergence for pairs of HLA-A and/or HLA-B allotypes was associated with slower AIDS progression and independently with enhanced viral load control. The metric predicts immune breadth at the peptide level rather than gene level and redefines HLA heterozygosity as a continuum differentially affecting disease outcome. Functional divergence may affect response to additional infections, vaccination, immunotherapy, and other diseases where HLA heterozygote advantage occurs.

人类白细胞抗原（HLA）I类基因的杂合性与HIV感染后的获益结果有关，可能是通过更广泛的HIV表位呈递和细胞毒性T细胞应答来实现的。然而，不同的同种异型对在它们结合共享肽组的程度上有所不同。我们开发了一种“功能相似度度量标准”来测量同种异型相关肽结合谱的成对互补性。HLA-A和/或HLA-B同种异型对的功能分歧越大，艾滋病进程越慢，且这种效果独立于病毒载量控制的加强。该指标在肽水平而不是基因水平上预测免疫广度，并将HLA杂合性重新定义为影响疾病结局的连续体。功能分化可能影响人体对额外感染、疫苗接种、免疫治疗和其他有HLA杂合子优势发生的疾病的反应。

Volume 383| Issue 6681| 26 JANUARY 2024

• 8篇NEWS

• 10篇INSIGHTS

• 其中3篇LETTERS， 4篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK

• 13篇RESEARCH ARTICLES

• 1篇EDITORIAL

1.Changing fitness effects of mutations through long-term bacterial evolution

法国巴黎城市大学和巴黎北索邦大学，英国伦敦帝国学院生命科学系，西班牙马德里理工大学，美国哈佛医学院生物医学信息学系和系统药理学实验室

Abstract

The distribution of fitness effects of new mutations shapes evolution, but it is challenging to observe how it changes as organisms adapt. Using Escherichia coli lineages spanning 50,000 generations of evolution, we quantify the fitness effects of insertion mutations in every gene. Macroscopically, the fraction of deleterious mutations changed little over time whereas the beneficial tail declined sharply, approaching an exponential distribution. Microscopically, changes in individual gene essentiality and deleterious effects often occurred in parallel; altered essentiality is only partly explained by structural variation. The identity and effect sizes of beneficial mutations changed rapidly over time, but many targets of selection remained predictable because of the importance of loss-of-function mutations. Taken together, these results reveal the dynamic-but statistically predictable-nature of mutational fitness effects。

新突变适应性效应的分布塑造了进化，但在生物适应过程中观测这些分布的变化仍具挑战性。本研究使用跨越5万代演化的大肠杆菌谱系，量化了每一种基因插入突变的适应性效应。从宏观上看，有害突变的比例随着时间的推移变化不大，而有益突变比例急剧下降，接近指数分布。从微观上看，个体基因必要性和有害影响的变化往往是平行发生的；变化的必要性只能部分用结构变异来解释。随着时间的推移，有益突变的特性和效应大小迅速变化，但由于功能丧失突变的重要性，许多选择目标仍然是可预测的。总之，这些结果揭示了突变适应性效应可预测的统计学动态属性。

2.The transcription factor ZEB2 drives the formation of age-associated B cells

转录因子ZEB2驱动年龄相关B细胞的形成

上海交通大学医学院附属上海仁济医院，上海市上海市人民医院个体化免疫中心

Abstract

Age-associated B cells (ABCs) accumulate during infection, aging, and autoimmunity, contributing to lupus pathogenesis. In this study, we screened for transcription factors driving ABC formation and found that zinc finger E-box binding homeobox 2 (ZEB2) is required for human and mouse ABC differentiation in vitro. ABCs are reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with toll-like receptor 7 (TLR7)-driven lupus, ZEB2 is essential for ABC formation and autoimmune pathology. ZEB2 binds to +20-kb myocyte enhancer factor 2b (Mef2b)'s intronic enhancer, repressing MEF2B-mediated germinal center B cell differentiation and promoting ABC formation. ZEB2 also targets genes important for ABC specification and function, including Itgax. ZEB2-driven ABC differentiation requires JAK-STAT (Janus kinase-signal transducer and activator of transcription), and treatment with JAK1/3 inhibitor reduces ABC accumulation in autoimmune mice and patients. Thus, ZEB2 emerges as a driver of B cell autoimmunity.

年龄相关B细胞（ABCs）在感染、衰老和自身免疫过程中积累，导致狼疮病变。在这项研究中，我们筛选了驱动ABC形成的转录因子，并发现E盒结合锌指蛋白2（ZEB2）是人类和小鼠ABC体外分化所必需的。在ZEB2单倍体不足的个体和B细胞缺乏Zeb2的小鼠中，ABC减少。在Toll样受体7（TLR7）驱动的狼疮小鼠中，ZEB2是ABC形成和自身免疫病理所必需的。ZEB2与+20-kb肌细胞增强因子2b（Mef2b）的内含子增强子结合，抑制MEF2B介导的生发中心B细胞分化并促进ABC形成。ZEB2还靶向对ABC规范和功能有重要作用的基因，包括Itgax。ZEB2驱动的ABC分化需要JAK-STAT（Janus激酶信号转导和转录激活因子），JAK1/3抑制剂治疗可减少自身免疫小鼠和患者中ABC的积累。因此，ZEB2是B细胞自身免疫的驱动因素。

3.Establishing a synthetic orthogonal replication system enables accelerated evolution in E. coli

英国剑桥医学研究理事会分子生物学实验室

Abstract

The evolution of new function in living organisms is slow and fundamentally limited by their critical mutation rate. Here, we established a stable orthogonal replication system in Escherichia coli. The orthogonal replicon can carry diverse cargos of at least 16.5 kilobases and is not copied by host polymerases but is selectively copied by an orthogonal DNA polymerase (O-DNAP), which does not copy the genome. We designed mutant O-DNAPs that selectively increase the mutation rate of the orthogonal replicon by two to four orders of magnitude. We demonstrate the utility of our system for accelerated continuous evolution by evolving a 150-fold increase in resistance to tigecycline in 12 days. And, starting from a GFP variant, we evolved a 1000-fold increase in cellular fluorescence in 5 days.

生物体中新功能的进化是缓慢的，并且从根本上受到其临界突变率的限制。在本研究中，我们在大肠杆菌中建立了一个稳定的正交复制系统。正交复制子可以携带至少16.5KB的不同货物（这里指代目标基因），并且不被宿主聚合酶复制，而是被不复制基因组的正交DNA聚合酶（O-DNAP）选择性地复制。我们设计的突变型O-DNAPs，能选择性地将正交复制子的突变率增加2-4个数量级。我们通过在12天内对替加环素的耐药性增加150倍，证明了我们的系统在加速持续进化方面的效用。而且，从绿色荧光蛋白（green fluorescent protein，GFP）突变体开始，我们在5天内使细胞荧光增加了1000倍。

4.Receptor-associated kinases control the lipid provisioning program in plant–fungal symbiosis

美国博伊斯汤普森研究所

Abstract

The mutualistic association between plants and arbuscular mycorrhizal (AM) fungi requires intracellular accommodation of the fungal symbiont and maintenance by means of lipid provisioning. Symbiosis signaling through lysin motif (LysM) receptor-like kinases and a leucine-rich repeat receptor-like kinase DOES NOT MAKE INFECTIONS 2 (DMI2) activates transcriptional programs that underlie fungal passage through the epidermis and accommodation in cortical cells. We show that two Medicago truncatula cortical cell-specific, membrane-bound proteins of a CYCLIN-DEPENDENT KINASE-LIKE (CKL) family associate with, and are phosphorylation substrates of, DMI2 and a subset of the LysM receptor kinases. CKL1 and CKL2 are required for AM symbiosis and control expression of transcription factors that regulate part of the lipid provisioning program. Onset of lipid provisioning is coupled with arbuscule branching and with the REDUCED ARBUSCULAR MYCORRHIZA 1 (RAM1) regulon for complete endosymbiont accommodation.

• 7篇NEWS

• 10篇INSIGHTS

• 其中3篇LETTERS， 4篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK

• 13篇RESEARCH ARTICLES

• 1篇EDITORIAL

  
  

1.Hydrolytic endonucleolytic ribozyme (HYER) is programmable for sequence-specific DNA cleavage

清华大学生命科学学院北京生命科学中心

Abstract

Ribozymes are catalytic RNAs with diverse functions including self-splicing and polymerization. This work aims to discover natural ribozymes that behave as hydrolytic and sequence-specific DNA endonucleases, which could be repurposed as DNA manipulation tools. Focused on bacterial group II-C introns, we found that many systems without intron-encoded protein propagate multiple copies in their resident genomes. These introns, named HYdrolytic Endonucleolytic Ribozymes (HYERs), cleaved RNA, single-stranded DNA, bubbled double-stranded DNA (dsDNA), and plasmids in vitro. HYER1 generated dsDNA breaks in the mammalian genome. Cryo-electron microscopy analysis revealed a homodimer structure for HYER1, where each monomer contains a Mg2+-dependent hydrolysis pocket and captures DNA complementary to the target recognition site (TRS). Rational designs including TRS extension, recruiting sequence insertion, and heterodimerization yielded engineered HYERs showing improved specificity and flexibility for DNA manipulation.

核酶是一类具有催化作用的RNA，具有自身剪接和聚合等多种功能。这项研究的目的是发现作为水解性和序列特异性DNA内切酶的天然核酶，它可以作为DNA操作工具被重新利用。我们发现，在细菌II-C组内含子中，许多没有内含子编码蛋白的系统在其驻留基因组中会繁殖多个拷贝。这些内含子被称为水解型内切核酶（HYERs），其在体外切割RNA、单链DNA、气泡双链DNA（dsDNA）和质粒。HYER1在哺乳动物基因组中产生dsDNA断端。冷冻电子显微镜分析揭示了HYER1的同源二聚体结构，其中每个单体含有一个依赖Mg2+的水解口袋，并捕获与目标识别位点（TRS）互补的DNA。包括TRS延伸、募集序列插入和异源二聚化在内的合理设计产生了工程化的HYERs，DNA操作的特异性和灵活性得到了改善。

2.Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127

美国迈阿密米勒医学院，美国纪念斯隆-凯特琳癌症中心

Abstract

Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

布鲁顿酪氨酸激酶（BTK）的共价和非共价抑制剂的使用越来越多，在B细胞恶性肿瘤患者中发现了一系列获得性耐药BTK突变。在本研究中，我们确定了具有不同酶活性的BTK中的抑制剂抗性突变，包括一些损害BTK酶活性同时赋予维持B细胞受体（BCR）信号传导的新型蛋白质-蛋白质相互作用的突变。此外，我们描述了一种临床阶段的BTK和IKZF1/3降解剂NX-2127，它可以结合和蛋白酶解每种突变的BTK蛋白形式，从而有效阻断BCR信号传导。在使用NX-2127治疗的慢性淋巴细胞白血病患者中BTK降解率达到80%以上，证明了概念验证的治疗效果。这些数据揭示了突变的BTK的致癌功能，该功能对临床批准的BTK抑制剂产生耐药性，但可通过患者体内BTK的降解来克服。

3.Whole-brain spatial organization of hippocampal single-neuron projectomes

上海中国科学院神经科学研究所，神经科学国家重点实验室，北京中国科学院大学，上海临港实验室，上海科技大学生命科学与技术学院

Abstract

Mapping single-neuron projections is essential for understanding brain-wide connectivity and diverse functions of the hippocampus (HIP). Here, we reconstructed 10,100 single-neuron projectomes of mouse HIP and classified 43 projectome subtypes with distinct projection patterns. The number of projection targets and axon-tip distribution depended on the soma location along HIP longitudinal and transverse axes. Many projectome subtypes were enriched in specific HIP subdomains defined by spatial transcriptomic profiles. Furthermore, we delineated comprehensive wiring diagrams for HIP neurons projecting exclusively within the HIP formation (HPF) and for those projecting to both intra- and extra-HPF targets. Bihemispheric projecting neurons generally projected to one pair of homologous targets with ipsilateral preference. These organization principles of single-neuron projectomes provide a structural basis for understanding the function of HIP neurons.

绘制单神经元投射对于理解海马体（HIP）的全脑连接和各种功能至关重要。在本研究中，我们重建了10100个小鼠HIP的单神经元投射体，区分出43类投射模型各异的投射体亚型。投射目标的数量和轴突尖端的分布取决于沿着HIP纵轴和横轴的神经元胞体位置。许多投射体亚型在空间转录组图谱定义的特定HIP亚域中富集。此外，我们描绘了仅在HIP形成（HPF）内投射的HIP神经元以及同时投射到HPF内部和外部目标的HIP神经元的综合线路图谱。双半球投射神经元一般投射到同侧偏好的一对同源靶区。单神经元投射体的组织原理为理解HIP神经元的功能提供了结构基础。

4.Blood pressure pulsations modulate central neuronal activity via mechanosensitive ion channels

德国里根斯堡大学动物学研究所神经生理学组，德国汉堡-埃彭多夫大学医学中心分子神经生物学中心

Abstract

The transmission of the heartbeat through the cerebral vascular system causes intracranial pressure pulsations. We discovered that arterial pressure pulsations can directly modulate central neuronal activity. In a semi-intact rat brain preparation, vascular pressure pulsations elicited correlated local field oscillations in the olfactory bulb mitral cell layer. These oscillations did not require synaptic transmission but reflected baroreceptive transduction in mitral cells. This transduction was mediated by a fast excitatory mechanosensitive ion channel and modulated neuronal spiking activity. In awake animals, the heartbeat entrained the activity of a subset of olfactory bulb neurons within ~20 milliseconds. Thus, we propose that this fast, intrinsic interoceptive mechanism can modulate perception-for example, during arousal-within the olfactory bulb and possibly across various other brain areas.

摘要：

心跳通过脑血管系统的传输引起颅内压脉动。我们发现，动脉压脉动可以直接调节中枢神经元的活动。在一个半完整的大鼠大脑中，血管压力脉动引起嗅球僧帽细胞层相关的局部场振荡。这些振荡不需要突触传递，但反映了僧帽细胞的压力感受性转导。这种转导是由快速兴奋性机械敏感离子通道介导的，并调节神经元的尖峰活动。在清醒的动物中，心跳在约20毫秒内引起嗅球神经元子集的活动。因此，我们提出，这种快速的内在内感受机制可以在嗅球内（也可能在其他多个脑区内）调节知觉（例如在睡眠觉醒期间的知觉）。

5.Grounded language acquisition through the eyes and ears of a single child

美国纽约大学数据科学中心，美国纽约大学心理学系

Abstract

Starting around 6 to 9 months of age, children begin acquiring their first words, linking spoken words to their visual counterparts. How much of this knowledge is learnable from sensory input with relatively generic learning mechanisms, and how much requires stronger inductive biases? Using longitudinal head-mounted camera recordings from one child aged 6 to 25 months, we trained a relatively generic neural network on 61 hours of correlated visual-linguistic data streams, learning feature-based representations and cross-modal associations. Our model acquires many word-referent mappings present in the child's everyday experience, enables zero-shot generalization to new visual referents, and aligns its visual and linguistic conceptual systems. These results show how critical aspects of grounded word meaning are learnable through joint representation and associative learning from one child's input.

大约从6到9个月大开始，孩子开始习得他们的第一个单词，并将口语单词与视觉单词联系起来。这些知识中有多少是可以通过相对通用的学习机制从感官输入中学习到的，又有多少需要更强的归纳偏倚？我们使用头戴式摄像机记录了一名的幼儿从6个月大到25个月大的第一视角，根据61小时的相关视觉语言数据流、基于学习特征的表征和跨模态关联训练了一个相对通用的神经网络模型。我们的模型获得了儿童日常生活中存在的许多单词指涉映射，实现了对新的视觉指涉的零样本泛化，并调整其视觉和语言的概念系统保持一致。这些结果表明，通过来源于一个儿童的联合表征和联想学习，可以学习到基础词义的关键部分。

6.Type III-B CRISPR-Cas cascade of proteolytic cleavages

荷兰瓦赫宁根大学微生物学实验室美国德克萨斯大学奥斯汀分校分子生物科学系

Abstract

The generation of cyclic oligoadenylates and subsequent allosteric activation of proteins that carry sensory domains is a distinctive feature of type III CRISPR-Cas systems. In this work, we characterize a set of associated genes of a type III-B system from Haliangium ochraceum that contains two caspase-like proteases, SAVED-CHAT and PCaspase (prokaryotic caspase), co-opted from a cyclic oligonucleotide-based antiphage signaling system (CBASS). Cyclic tri-adenosine monophosphate (AMP)-induced oligomerization of SAVED-CHAT activates proteolytic activity of the CHAT domains, which specifically cleave and activate PCaspase. Subsequently, activated PCaspase cleaves a multitude of proteins, which results in a strong interference phenotype in vivo in Escherichia coli. Taken together, our findings reveal how a CRISPR-Cas-based detection of a target RNA triggers a cascade of caspase-associated proteolytic activities.

摘要：

产生环状寡腺苷酸，随后变构活化的携带感知结构域的蛋白质是III型CRISPR-Cas系统的显著特征。在本研究中，我们从Haliangium ochraceum（一种菌属）表征了III-B型系统的一组相关基因，其包含两个半胱天冬酶样蛋白酶，即SAVED-CHAT和PCaspase，它们来自基于环寡核苷酸的噬菌体信号系统(CBASS)。单磷酸腺苷（AMP）诱导的SAVED-CHAT寡聚化激活了CHAT结构域的蛋白水解活性，其能特异性切割并激活PCaspase。随后，活化的PCaspase裂解大量蛋白质，这导致大肠杆菌体内出现强干扰表型。总之，我们的研究结果揭示了基于CRISPR-Cas的靶向RNA检测如何触发caspase相关蛋白水解活性的级联反应。

7.Local activation of CA1 pyramidal cells induces theta-phase precession

特拉维夫大学萨戈尔神经科学学院

Abstract

Hippocampal theta-phase precession is involved in spatiotemporal coding and in generating multineural spike sequences, but how precession originates remains unresolved. To determine whether precession can be generated directly in hippocampal area CA1 and disambiguate multiple competing mechanisms, we used closed-loop optogenetics to impose artificial place fields in pyramidal cells of mice running on a linear track. More than one-third of the CA1 artificial fields exhibited synthetic precession that persisted for a full theta cycle. By contrast, artificial fields in the parietal cortex did not exhibit synthetic precession. These findings are incompatible with precession models based on inheritance, dual-input, spreading activation, inhibition-excitation summation, or somato-dendritic competition. Thus, a precession generator resides locally within CA1

海马θ相位旋进参与时空编码和产生多神经脉冲序列，但旋进如何产生仍然没有明确。为了确定是否可以直接在海马CA1区产生旋进并区分多种竞争机制，我们使用闭环光遗传学在线性轨道上运行的小鼠的锥体细胞中施加人工位置场。超过三分之一的CA1人工场表现出持续一个整个θ周期的合成旋进。相比之下，顶叶皮层的人工场并没有表现出合成旋进。这些发现与基于遗传、双输入、扩散激活、抑制-兴奋总和或体细胞-树突竞争的旋进模型不相容。因此，一个旋进发生器只局限于CA1区域内。

Volume 383| Issue 6683| 9 FEBRUARY 2024

• 7篇NEWS

• 10篇INSIGHTS

• 其中3篇LETTERS， 4篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK

• 15篇RESEARCH ARTICLES

• 1篇EDITORIAL

1.Corpora cavernosa fibroblasts mediate penile erection

瑞典卡罗林斯卡学院细胞和分子生物学系

Abstract

Penile erection is mediated by the corpora cavernosa, a trabecular-like vascular bed that enlarges upon vasodilation, but its regulation is not completely understood. Here, we show that perivascular fibroblasts in the corpora cavernosa support vasodilation by reducing norepinephrine availability. The effect on penile blood flow depends on the number of fibroblasts, which is regulated by erectile activity. Erection dynamically alters the positional arrangement of fibroblasts, temporarily down-regulating Notch signaling. Inhibition of Notch increases fibroblast numbers and consequently raises penile blood flow. Continuous Notch activation lowers fibroblast numbers and reduces penile blood perfusion. Recurrent erections stimulate fibroblast proliferation and limit vasoconstriction, whereas aging reduces the number of fibroblasts and lowers penile blood flow. Our findings reveal adaptive, erectile activity-dependent modulation of penile blood flow by fibroblasts.

阴茎勃起是由海绵体介导的，海绵体是一种在血管舒张时扩张的小梁样血管床，但其调节机制尚不完全清楚。在本研究中，我们发现海绵体血管周围成纤维细胞通过减少去甲肾上腺素的供应来支持血管舒张。对阴茎血流量的影响取决于成纤维细胞的数量，而成纤维细胞的数量受勃起活动的调节。勃起动态改变成纤维细胞的位置排列，暂时下调Notch信号。抑制Notch会增加成纤维细胞数量，从而提高阴茎血流量。持续的Notch激活降低了成纤维细胞数量并减少了阴茎血液灌注。反复勃起刺激成纤维细胞增殖并限制血管收缩，而衰老减少成纤维细胞的数量并降低阴茎血流量。我们的研究结果揭示了成纤维细胞对阴茎血流量的适应性、勃起活动依赖性调节。

2.Lineage-specific intolerance to oncogenic drivers restricts histological transformation

美国纽约威尔康奈尔医学院Meyer癌症中心

Abstract

Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC after treatment with targeted therapies. In this study, we designed models to follow the conversion of LUAD to SCLC and found that the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells that transcriptionally resemble the pulmonary basal lineage. These findings suggest that histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs.

肺腺癌（LUAD）和小细胞肺癌（SCLC）被认为起源于肺不同的上皮细胞类型。有趣的是，LUAD在靶向治疗后组织学上可转化为SCLC。在这项研究中，我们设计了模型来跟踪LUAD向SCLC的转化过程，并发现组织学转化的障碍集中在对Myc的耐受性上，Myc是肺神经内分泌细胞的谱系特异性驱动因子。组织学转化经常伴随Akt通路的激活。通过操纵这条通路，使得对Myc作为一个致癌驱动因子的耐受性增强，产生罕见的干细胞样细胞，这些细胞在转录层面上与肺基底细胞系类似。这些发现表明，组织学转化可能需要基底干细胞固有的可塑性，从而耐受以前不相容的致癌驱动程序。

Volume 383| Issue 6684| 16 FEBRURY 2024

• 7篇NEWS

• 10篇INSIGHTS

• 其中3篇LETTERS， 4篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK

• 14篇RESEARCH ARTICLES

• 1篇EDITORIAL

1.The lipid globotriaosylceramide promotes germinal center B cell responses and antiviral immunity

美国哈佛医学院波士顿儿童医院儿科细胞和分子医学项目

Abstract

Influenza viruses escape immunity owing to rapid antigenic evolution, which requires vaccination strategies that allow for broadly protective antibody responses. We found that the lipid globotriaosylceramide (Gb3) expressed on germinal center (GC) B cells is essential for the production of high-affinity antibodies. Mechanistically, Gb3 bound and disengaged CD19 from its chaperone CD81, permitting CD19 to translocate to the B cell receptor complex to trigger signaling. Moreover, Gb3 regulated major histocompatibility complex class II expression to increase diversity of T follicular helper and GC B cells reactive with subdominant epitopes. In influenza infection, elevating Gb3, either endogenously or exogenously, promoted broadly reactive antibody responses and cross-protection. These data demonstrate that Gb3 determines the affinity and breadth of B cell immunity and has potential as a vaccine adjuvant.

摘要：

流感病毒由于快速的抗原进化而能逃避免疫，这就需要能产生广泛保护性抗体反应的疫苗接种策略。我们发现在生发中心（GC）B细胞表达的脂球三糖基神经酰胺（Gb3）在产生高亲和力抗体的过程中是必不可少的。从机制上讲，Gb3结合并使CD19与其分子伴侣CD81脱离，从而能使CD19易位到B细胞受体复合物以触发信号传导。此外，Gb3调节主要组织相容性复合物II的表达，以增加与次优势表位反应的T滤泡辅助细胞和生发中心B细胞的多样性。在流感感染中，内源性或外源性Gb3的升高可促进广泛的反应性抗体应答和交叉保护。这些数据表明，Gb3决定了B细胞免疫的亲和力和广度，并具有作为疫苗佐剂的潜力。

2.Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG

中国医学科学院北京协和医学院基础医学研究所免疫学教研室

Abstract

The identification of mechanisms to store glucose carbon in the form of glycogen rather than fat in hepatocytes has important implications for the prevention of nonalcoholic fatty liver disease (NAFLD) and other chronic metabolic diseases. In this work, we show that glycogenesis uses its intermediate metabolite uridine diphosphate glucose (UDPG) to antagonize lipogenesis, thus steering both mouse and human hepatocytes toward storing glucose carbon as glycogen. The underlying mechanism involves transport of UDPG to the Golgi apparatus, where it binds to site-1 protease (S1P) and inhibits S1P-mediated cleavage of sterol regulatory element-binding proteins (SREBPs), thereby inhibiting lipogenesis in hepatocytes. Consistent with this mechanism, UDPG administration is effective at treating NAFLD in a mouse model and human organoids. These findings indicate a potential opportunity to ameliorate disordered fat metabolism in the liver.

在肝细胞中以糖原而不是脂肪的形式储存葡萄糖碳的机制的确定对于预防非酒精性脂肪肝（NAFLD）和其他慢性代谢疾病具有重要意义。在本研究中，我们发现，糖原利用其中间代谢产物尿苷二磷酸葡萄糖（UDPG）拮抗脂肪生成，从而使小鼠和人类肝细胞以糖原形式贮存葡萄糖碳。其潜在机制包括将UDPG转运至高尔基体，在高尔基体中与位点1蛋白酶（S1P）结合，并抑制S1P介导的固醇调节元件结合蛋白（SREBPs）裂解，从而抑制肝细胞中的脂肪生成。与这种机制一致，在小鼠模型和人类类器官中使用UDPG可有效治疗NAFLD。这些发现为改善肝脏脂肪代谢紊乱提供了潜在的可能性。

3.An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance

美国哈佛大学化学与化学生物学系，美国伊利诺伊大学芝加哥分校生物科学系

Abstract

We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.

我们提出了桥联大双环抗生素克雷霉素（CRM）的设计概念、化学合成方法、和微生物学评价标准。它具有足以克服使现代抗生素失效的进化多样的抗生素耐药性的能力。CRM在体外及体内对革兰氏阳性菌和革兰氏阴性菌均表现出显著的功效，包括对耐多药的金黄色葡萄球菌、大肠杆菌和铜绿假单胞菌的抗性。我们通过确定其密度泛函理论计算、溶液状态、固态和（野生型）核糖体结合的结构，发现CRM具有为核糖体结合而高度预组装的特性，这些结构在宏环亚单位内完全一致。最后，我们报道了CRM与细菌核糖体结合的额外两个x射线晶体结构，这两种结构分别由两种核糖体RNA甲基化酶（氯霉素-氟苯尼考耐药（Cfr）和红霉素耐药核糖体RNA甲基化酶（Erm）修饰。这揭示了靶标和抗生素的让步调整，允许CRM在其他抗生素失败的情况下保持结合。

4.ATR blocks telomerase from converting DNA breaks into telomeres

美国洛克菲勒大学细胞生物学和遗传学实验室

Abstract

Telomerase, the enzyme that maintains telomeres at natural chromosome ends, should be repressed at double-strand breaks (DSBs), where neotelomere formation can cause terminal truncations. We developed an assay to detect neotelomere formation at Cas9- or I-SceI-induced DSBs in human cells. Telomerase added telomeric repeats to DSBs, leading to interstitial telomeric repeat insertions or the formation of functional neotelomeres accompanied by terminal deletions. The threat that telomerase poses to genome integrity was minimized by ataxia telangiectasia and Rad3-related (ATR) kinase signaling, which inhibited telomerase at resected DSBs. In addition to acting at resected DSBs, telomerase used the extruded strand in the Cas9 enzyme-product complex as a primer for neotelomere formation. We propose that although neotelomere formation is detrimental in normal human cells, it may allow cancer cells to escape from breakage-fusion-bridge cycles.

Volume 383| Issue 6685| 23 FEBRURY 2024

• 8篇NEWS

• 12篇INSIGHTS

• 其中3篇LETTERS， 4篇PERSPECTIVES，3篇POLICY FORUM，2本BOOK

• 17篇RESEARCH

• 其中1篇REVIEW,16篇RESEARCH ARTICLES

• 2篇EDITORIAL

1.SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

美国雪松-西奈医学中心理事会再生医学研究所，美国雪松-西奈医学中心生物医学科学部

Abstract

The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach for a head-to-head comparison of injury-induced SOX9 lineages, we identified a dynamic SOX9 switch in repairing epithelia. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9on-off). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9on-on Cadherin6pos cell state. These reprogrammed cells generated substantial single-cell WNT activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses. Thus, we have uncovered a sensor of epithelial repair status, the activity of which determines regeneration with or without fibrosis.

摘要：

在相同的微环境中，愈合步骤中有或没有纤维化尚不清楚。急性肾损伤（AKI）后，受损的近端肾小管上皮细胞激活SOX9进行自我修复。使用多模式方法对损伤诱导的SOX9谱系进行头对头比较，我们鉴定了修复上皮中的动态SOX9开关。再生上皮的细胞系沉默了SOX9并在没有纤维化的情况下愈合（SOX9 on-off）。相比之下，具有未恢复的顶基极性的谱系在持续的努力再生过程中保持SOX9的活性，这被定义为SOX9on-on Cadherin6pos细胞状态。这些重编程的细胞产生大量的单细胞WNT活性，在邻近的成纤维细胞中引起纤维增殖反应，将AKI驱动为慢性肾脏疾病。移植的人肾显示出类似的SOX9/CDH6/WNT2B应答。因此，我们发现了上皮修复状态的传感器，其活性决定了有无纤维化的再生。

2.An immunogenetic basis for lung cancer risk

美国麻省理工学院和哈佛大学博德研究所，芬兰赫尔辛基大学芬兰分子医学研究所，美国西奈山伊坎医学院

Abstract

Cancer risk is influenced by inherited mutations, DNA replication errors, and environmental factors. However, the influence of genetic variation in immunosurveillance on cancer risk is not well understood. Leveraging population-level data from the UK Biobank and FinnGen, we show that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the HLA-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and HLA-II+ epithelial cells. In lung cancer, widespread loss of HLA-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thus, our findings nominate genetic variation in immunosurveillance as a critical risk factor for lung cancer.

摘要：

癌症风险受遗传突变、DNA复制错误和环境因素的影响。然而，免疫监视下的基因变异对癌症风险的影响尚不清楚。利用来自英国Biobank和FinnGen数据库的人群数据，我们发现人类白细胞抗原（HLA）-II位点的杂合性与吸烟者肺癌风险降低有关。精细定位发现HLA-II肽结合凹槽中的氨基酸杂合性可降低肺癌风险。单细胞分析表明吸烟可驱动促进肺部促炎巨噬细胞和HLA-II+上皮细胞的富集。在肺癌中，HLA-II杂合性（LOH）的广泛缺失促进了具有更大新肽库的等位基因的缺失。因此，我们的研究结果将免疫监视中的遗传变异列为了肺癌的关键风险因素。

3.Structural basis for sugar perception by Drosophila gustatory receptors

浙江大学医学院附属第四医院生物物理系、神经内科，浙江 杭州南湖脑机接口研究所，浙江大学医学院附属第二医院神经内科、心内科

Abstract

Insects rely on a family of seven transmembrane proteins called gustatory receptors (GRs) to encode different taste modalities, such as sweet and bitter. We report structures of Drosophila sweet taste receptors GR43a and GR64a in the apo and sugar-bound states. Both GRs form tetrameric sugar-gated cation channels composed of one central pore domain (PD) and four peripheral ligand-binding domains (LBDs). Whereas GR43a is specifically activated by the monosaccharide fructose that binds to a narrow pocket in LBDs, disaccharides sucrose and maltose selectively activate GR64a by binding to a larger and flatter pocket in LBDs. Sugar binding to LBDs induces local conformational changes, which are subsequently transferred to the PD to cause channel opening. Our studies reveal a structural basis for sugar recognition and activation of GRs.

摘要：

昆虫依靠称为味觉受体（GRs）的七次跨膜蛋白家族来编码不同的味觉模式，例如甜味和苦味。我们报道了果蝇甜味受体GR43a和GR64a在apo（这里指未结合糖）和结合糖状态下的结构。两种GRs都形成了由一个中心孔结构域（PD）和四个外周配体结合结构域（LBD）组成的四聚体糖门控阳离子通道。GR43a被LBDs中与窄口袋结合的单糖果糖特异性激活，而二糖蔗糖和麦芽糖通过与LBDs中更大、更平坦的口袋结合来选择性地激活GR64a。糖与LBDs结合诱导了局部构象变化，随后转移到PD以导致通道开放。我们的研究揭示了糖识别和激活GRs的结构基础。

4.Patterns of recombination in snakes reveal a tug-of-war between PRDM9 and promoter-like features

美国纽约哥伦比亚大学生物科学系，美国国立卫生研究院儿童健康与人类发展研究所

Abstract

In some mammals, notably humans, recombination occurs almost exclusively where the protein PRDM9 binds, whereas in vertebrates lacking an intact PRDM9, such as birds and canids, recombination rates are elevated near promoter-like features. To determine whether PRDM9 directs recombination in nonmammalian vertebrates, we focused on an exemplar species with a single, intact PRDM9 ortholog, the corn snake (Pantherophis guttatus). Analyzing historical recombination rates along the genome and crossovers in pedigrees, we found evidence that PRDM9 specifies the location of recombination events, but we also detected a separable effect of promoter-like features. These findings reveal that the uses of PRDM9 and promoter-like features need not be mutually exclusive and instead reflect a tug-of-war that is more even in some species than others.

在一些哺乳动物（尤其是人类）中，重组几乎只发生在蛋白质PRDM9结合的点位，而在缺乏完整PRDM9的脊椎动物中，如鸟类和犬科动物，启动子样特征附近的重组率升高。为了确定PRDM9是否引导了非哺乳动物脊椎动物的重组，我们重点研究了具有单个完整PRDM9直系同源物的典型物种，即玉米蛇（Pantherophis guttatus）。通过分析基因组中的历史重组率和谱系中的交叉，我们发现了PRDM9指定重组位置的证据，但我们也检测到了启动子样特征的可分离效应。这些发现表明，PRDM9和启动子样特征的用处不一定是互斥的，而是反映了在某些物种中比其他物种更激烈的拉锯战。

5.Transition of human γ-tubulin ring complex into a closed conformation during microtubule nucleation

西班牙巴塞罗那科学技术学院基因组调控中心，西班牙国家癌症研究中心（CNIO）结构生物学项目

Abstract

Microtubules are essential for intracellular organization and chromosome segregation. They are nucleated by the γ-tubulin ring complex (γTuRC). However, isolated vertebrate γTuRC adopts an open conformation that deviates from the microtubule structure, raising the question of the nucleation mechanism. In this study, we determined cryo-electron microscopy structures of human γTuRC bound to a nascent microtubule. Structural changes of the complex into a closed conformation ensure that γTuRC templates the 13-protofilament microtubules that exist in human cells. Closure is mediated by a latch that interacts with incorporating tubulin, making it part of the closing mechanism. Further rearrangements involve all γTuRC subunits and the removal of the actin-containing luminal bridge. Our proposed mechanism of microtubule nucleation by human γTuRC relies on large-scale structural changes that are likely the target of regulation in cells.

微管对于细胞内构架和染色体分离至关重要。它们是由γ-微管蛋白环复合物（γTuRC）成核的。然而，孤立的脊椎动物γTuRC的与微管结构不同的开放构象，表明成核机制仍是一个未解之谜。在这项研究中，我们确定了与新生微管结合的人γTuRC的冷冻电子显微镜结构。复合物的结构变化形成一个闭合构象，确保γTuRC为存在于人类细胞中的13条原纤丝微管提供模板。闭合是由与微管蛋白相互作用的闩锁介导的，是闭合机制的一部分。进一步的重排涉及所有γTuRC亚基和含肌动蛋白的管腔桥的去除。我们提出的人类γTuRC微管成核机制依赖于大规模的结构变化，这些变化可能是细胞中调控的目标。

Volume 383| Issue 6686| 1 MARCH 2024

• 8篇NEWS

• 10篇INSIGHTS

• 其中3篇LETTERS， 4篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK

• 16篇RESEARCH

• 其中1篇REVIEW,15篇RESEARCH ARTICLES

• 1篇EDITORIAL

1.Native architecture of a human GBP1 defense complex for cell-autonomous immunity to infection

美国耶鲁大学医学院霍华德休斯医学研究所，美国耶鲁系统生物学研究所

美国耶鲁大学医学院微生物发病机制，耶鲁大学医学院免疫生物学系

Abstract

All living organisms deploy cell-autonomous defenses to combat infection. In plants and animals, large supramolecular complexes often activate immune proteins for protection. In this work, we resolved the native structure of a massive host-defense complex that polymerizes 30,000 guanylate-binding proteins (GBPs) over the surface of gram-negative bacteria inside human cells. Construction of this giant nanomachine took several minutes and remained stable for hours, required guanosine triphosphate hydrolysis, and recruited four GBPs plus caspase-4 and Gasdermin D as a cytokine and cell death immune signaling platform. Cryo-electron tomography suggests that GBP1 can adopt an extended conformation for bacterial membrane insertion to establish this platform, triggering lipopolysaccharide release that activated coassembled caspase-4. Our "open conformer" model provides a dynamic view into how the human GBP1 defense complex mobilizes innate immunity to infection.

摘要：

所有生物体都部署细胞自主防御来对抗感染。在植物和动物中，大型超分子复合物通常会激活免疫蛋白以提供保护。在本研究中，我们解析了一种巨大的宿主防御复合物的天然结构，该复合物在人类细胞内的革兰氏阴性细菌表面聚合了30,000个鸟苷酸结合蛋白（GBPs）。这种巨型纳米结构的构建耗时几分钟并稳定数小时，且需要水解三磷酸鸟苷，作为细胞因子和细胞死亡免疫信号平台招募四种GBPs和caspase-4以及Gasdermin D。冷冻电镜断层成像表明，GBP1可以采取扩展构象插入细菌膜从而构建该平台，并触发脂多糖释放从而激活共组装的caspase-4。我们的“开放构象”模型为人类GBP1防御复合体调动先天免疫力以应对感染的过程提供了一个动态视角。

2.The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants

人类前TCRα缺乏的免疫病理学特征：从罕见变异到常见变异

法国巴黎内克尔儿童疾病医院内克尔分部传染病人类遗传学实验室，法国巴黎西岱大学，美国国立卫生研究院国家过敏和传染病研究所临床免疫学和微生物学实验室，美国费城儿童医院儿科过敏免疫学科，法国巴黎大学科钦研究所，法国巴黎皮提耶-萨尔佩特里尔医院生物血液学系，法国索邦大学，巴黎癌症研究所CURAMUS，加拿大麦吉尔大学Dahdaleh基因组医学研究所人类遗传学系等

Abstract

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αβ T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αβ T cells, autoimmune conditions were more frequent in these patients compared with the general population.

摘要：

我们描述了具有罕见的双等位基因功能缺失的PTCRA变体的人类中，这些变异损害了前T细胞受体α（pre-TCRα）的表达。出生时循环中的幼稚αβT细胞计数低，并且这一状态会随着时间的推移而持续存在，但其记忆αβT细胞计数正常，γδT细胞计数高。它们的TCRα库具有偏向性特征，表明非经典胸腺分化途径可以挽救αβT细胞的发育。这些人中只有少数人出现感染、淋巴细胞增生和/或自身免疫的症状表现。我们还发现，在中东和南亚地区，每4000人中就有1人是常见亚形态PTCRA变体的纯合子。他们的循环幼稚αβT细胞计数正常，但γδT细胞计数高。尽管残留的pre-TCRα表达驱动了更多αβT细胞的分化，与普通人群相比，这些患者的自身免疫疾病发生率明显更高。

3.SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity

独立于其催化活性的SynGAP可调节突触可塑性和认知

美国约翰霍普金斯大学医学院Kavli神经科学发现研究所

Abstract

SynGAP is an abundant synaptic GTPase-activating protein (GAP) critical for synaptic plasticity, learning, memory, and cognition. Mutations in SYNGAP1 in humans result in intellectual disability, autistic-like behaviors, and epilepsy. Heterozygous Syngap1-knockout mice display deficits in synaptic plasticity, learning, and memory and exhibit seizures. It is unclear whether SynGAP imparts structural properties at synapses independently of its GAP activity. Here, we report that inactivating mutations within the GAP domain do not inhibit synaptic plasticity or cause behavioral deficits. Instead, SynGAP modulates synaptic strength by physically competing with the AMPA-receptor-TARP excitatory receptor complex in the formation of molecular condensates with synaptic scaffolding proteins. These results have major implications for developing therapeutic treatments for SYNGAP1-related neurodevelopmental disorders.

SynGAP是一种丰富的突触GTPase酶激活蛋白（GAP），对突触可塑性、学习、记忆和认知至关重要。人类SYNGAP1突变会导致智力障碍、自闭症样行为和癫痫。杂合子Syngap1敲除小鼠在突触可塑性、学习和记忆方面表现出缺陷，并有癫痫发作表现。目前尚不清楚SynGAP是否独立于其GAP活性赋予了突触结构特性。在本研究中，我们报告了GAP结构域内的失活突变不会抑制突触可塑性或导致行为缺陷。相反，SynGAP在突触支架蛋白的分子凝聚物形成过程中，通过与AMPA-受体-TARP兴奋性受体复合物进行物理竞争来调节突触强度。这些结果对开发SYNGAP1相关神经发育障碍的治疗方法具有重大意义。

4.Retrograde endocannabinoid signaling at inhibitory synapses in vivo

美国贝勒医学院神经病学和神经科学系美国斯坦福大学神经外科系，美国斯坦福大学生物工程系

Abstract

Endocannabinoid (eCB)-mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the difficulty in tracking eCB dynamics and synaptic plasticity during behavior. In mice navigating a linear track, we observed location-specific eCB signaling in hippocampal CA1 place cells, and this was detected both in the postsynaptic membrane and the presynaptic inhibitory axons. All-optical in vivo investigation of synaptic responses revealed that postsynaptic depolarization was followed by a suppression of inhibitory synaptic potentials. Furthermore, interneuron-specific cannabinoid receptor deletion altered place cell tuning. Therefore, rapid, postsynaptic, activity-dependent eCB signaling modulates inhibitory synapses on a timescale of seconds during behavior.

摘要：

尽管已有内源性大麻素（eCB）介导的抑制性突触的抑制作用假说，但这尚未在活体内被证明，因为在行为过程中难以跟踪eCB的动态和突触可塑性。在导航线性轨道的小鼠中，我们在海马CA1位置细胞中观察到位置特异性eCB信号传导，这在突触后膜和突触前抑制轴突中均被检测到。突触反应的全光学体内研究表明，突触后膜去极化之后抑制性突触电位受到抑制。此外，中间神经元特异性大麻素受体缺失改变了位置细胞的调谐特征。因此，快速的、突触后、活动依赖性的eCB信号在行为过程中以秒为单位调节抑制性突触。

5.A morphological basis for path-dependent evolution of visual systems

美国加利福尼亚大学圣芭芭拉分校，美国南卡罗来纳大学

Abstract

Path dependence influences macroevolutionary predictability by constraining potential outcomes after critical evolutionary junctions. Although it has been demonstrated in laboratory experiments, path dependence is difficult to demonstrate in natural systems because of a lack of independent replicates. Here, we show that two types of distributed visual systems recently evolved twice within chitons, demonstrating rapid and path-dependent evolution of a complex trait. The type of visual system that a chiton lineage can evolve is constrained by the number of openings for sensory nerves in its shell plates. Lineages with more openings evolve visual systems with thousands of eyespots, whereas those with fewer openings evolve visual systems with hundreds of shell eyes. These macroevolutionary outcomes shaped by path dependence are both deterministic and stochastic because possibilities are restricted yet not entirely predictable.

摘要：

路径依赖通过限制关键进化交汇点后的潜在结果来影响宏观进化的可预测性。尽管已经在实验中得到了证明，但由于缺乏独立的重复实验，路径依赖性很难在自然系统中得到证明。在本研究中，我们展示了在石鳖中近期出现的两次分布式视觉系统独立进化的实例，展示了复杂性状快速且受路径依赖影响的进化过程。石鳖谱系可以进化的视觉系统类型受到其壳板中感觉神经开口数量的限制。开口较多的谱系进化出具有数千个眼点的视觉系统，而开口较少的谱系进化出具有数百个壳眼的视觉系统。这些由路径依赖形成的宏观进化结果既是确定的，也是随机的，因为可能性是有限的，但又不能完全预测。

6.Touch sensation requires the mechanically gated ion channel ELKIN1

德国亥姆霍兹联合会马克斯·德尔布吕克分子医学中心

Abstract

Touch perception is enabled by mechanically activated ion channels, the opening of which excites cutaneous sensory endings to initiate sensation. In this study, we identify ELKIN1 as an ion channel likely gated by mechanical force, necessary for normal touch sensitivity in mice. Touch insensitivity in Elkin1-/- mice was caused by a loss of mechanically activated currents (MA currents) in around half of all sensory neurons activated by light touch (low-threshold mechanoreceptors). Reintroduction of Elkin1 into sensory neurons from Elkin1-/- mice restored MA currents. Additionally, small interfering RNA-mediated knockdown of ELKIN1 from induced human sensory neurons substantially reduced indentation-induced MA currents, supporting a conserved role for ELKIN1 in human touch. Our data identify ELKIN1 as a core component of touch transduction in mice and potentially in humans.

触觉是通过机械激活的离子通道实现的，离子通道的打开会兴奋皮肤感觉末梢以启动感觉。在这项研究中，我们鉴定出ELKIN1可能是机械门控的离子通道，在小鼠正常的触觉敏感性中是必需的。在Elkin1基因敲除（Elkin1-/-）的小鼠中，由于大约一半被轻触激活（低阈值机械感受器）的神经元失去了机械激活电流（MA电流），导致其出现触觉不敏感的现象。将Elkin1重新引入Elkin1-/-小鼠的感觉神经元中，恢复了MA电流。此外，在人类感觉神经元中小干扰RNA介导的ELKIN1敲除，显著减少了凹陷刺激引起的MA电流，支持了ELKIN1在人类触觉感知中的保守作用。我们的数据确定了ELKIN1是小鼠触觉传导的核心成分，也可能是人类触觉传导的核心成分。

Volume 383| Issue 6687| 8 MARCH 2024

• 9篇NEWS

• 9篇INSIGHTS

• 其中3篇LETTERS， 4篇PERSPECTIVES，1篇POLICY FORUM，1本BOOK

• 16篇RESEARCH

• 其中1篇REVIEW,15篇RESEARCH ARTICLES

• 1篇EDITORIAL

1.Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices

洛克菲勒大学Robin Chemers Neustein哺乳动物细胞生物学与发育实验室

Abstract

Lineage plasticity-a state of dual fate expression-is required to release stem cells from their niche constraints and redirect them to tissue compartments where they are most needed. In this work, we found that without resolving lineage plasticity, skin stem cells cannot effectively generate each lineage in vitro nor regrow hair and repair wounded epidermis in vivo. A small-molecule screen unearthed retinoic acid as a critical regulator. Combining high-throughput approaches, cell culture, and in vivo mouse genetics, we dissected its roles in tissue regeneration. We found that retinoic acid is made locally in hair follicle stem cell niches, where its levels determine identity and usage. Our findings have therapeutic implications for hair growth as well as chronic wounds and cancers, where lineage plasticity is unresolved.

摘要：

细胞谱系可塑性——一种双重命运表达的状态——是将干细胞从其生态位限制中释放出来，并将它们重定位到最需要的组织区域所必需的。在本研究中，我们发现，如果不解决谱系可塑性，皮肤干细胞就无法在体外有效地生成每个谱系，也无法在体内再生头发和修复损伤的表皮。通过筛选小分子化合物发现维生素A酸是一种关键的调节剂。结合高通量方法、细胞培养和体内小鼠遗传学，我们剖析了它在组织再生中的作用。小分子筛选出视黄酸作为关键调节剂。结合高通量方法、细胞培养和体内小鼠遗传学，我们剖析了它在组织再生中的作用。我们发现视黄酸是在毛囊干细胞生态位中局部产生的，其含量决定了毛囊干细胞特征和用途。我们的发现在谱系可塑性尚未解决的毛发生长、慢性伤口和癌症中具有治疗意义。

2.Brainstem control of vocalization and its coordination with respiration

脑干对发声的控制及其与呼吸的协调

美国麻省理工学院麦戈文脑研究所脑与认知科学系，美国杜克大学生物医学工程系，杜克大学医学中心神经生物学系

Abstract

Phonation critically depends on precise controls of laryngeal muscles in coordination with ongoing respiration. However, the neural mechanisms governing these processes remain unclear. We identified excitatory vocalization-specific laryngeal premotor neurons located in the retroambiguus nucleus (RAmVOC) in adult mice as being both necessary and sufficient for driving vocal cord closure and eliciting mouse ultrasonic vocalizations (USVs). The duration of RAmVOC activation can determine the lengths of both USV syllables and concurrent expiration periods, with the impact of RAmVOC activation depending on respiration phases. RAmVOC neurons receive inhibition from the preBötzinger complex, and inspiration needs override RAmVOC-mediated vocal cord closure. Ablating inhibitory synapses in RAmVOC neurons compromised this inspiration gating of laryngeal adduction, resulting in discoordination of vocalization with respiration. Our study reveals the circuits for vocal production and vocal-respiratory coordination.

摘要：

发声在很大程度上取决于喉部肌肉的精确控制与持续的呼吸协调。然而，控制这些过程的神经机制仍不清楚。我们发现位于成年小鼠疑核后核（RAmVOC）中的兴奋性发声特异性喉前运动神经元是驱动声带闭合和引发小鼠超声发声（USVs）的必要和充分条件。RAmVOC激活的持续时间可以决定USV音节和同时呼气期的长度，而RAmVOC激活的影响取决于呼吸时相。RAmVOC神经元接受来自前包钦格复合体的抑制，并且吸气需求优先于RAmVOC介导的声带闭合。消除RAmVOC神经元中的抑制性突触阻碍了喉内收的吸气门控，导致发声与呼吸不协调。我们的研究揭示了发声和发声-呼吸协调的通路。

3.Axonal self-sorting without target guidance in Drosophila visual map formation

果蝇视觉图谱形成中无目标导向的轴突自动分类

德国柏林自由大学神经生物学系德国柏林自由大学数学系

Abstract

The idea of guidance toward a target is central to axon pathfinding and brain wiring in general. In this work, we show how several thousand axonal growth cones self-pattern without target-dependent guidance during neural superposition wiring in Drosophila. Ablation of all target lamina neurons or loss of target adhesion prevents the stabilization but not the development of the pattern. Intravital imaging at the spatiotemporal resolution of growth cone dynamics in intact pupae and data-driven dynamics simulations reveal a mechanism by which >30,000 filopodia do not explore potential targets, but instead simultaneously generate and navigate a dynamic filopodial meshwork that steers growth directions. Hence, a guidance mechanism can emerge from the interactions of the axons being guided, suggesting self-organization as a more general feature of brain wiring.

摘要：

目标导向是轴突寻路和大脑神经网络的核心。在本研究中，我们展示了在果蝇的神经叠加布线过程中，数千个轴突生长锥如何在没有目标依赖导向的情况下自我模式化。消除所有靶层神经元或靶粘附的缺失阻碍了这种模式的稳定性，但不能阻止模式的发展。对完整蛹生长锥动态的时空分辨率活体成像和数据驱动动力学模拟揭示了一个机制，即超过30000个的丝状足不探索潜在目标，而是同时生成和引导一个动态丝状足网络，来引导生长方向。因此，一种引导机制可以从被引导的轴突的相互作用中产生，这表明自我组织是大脑布线的一个更普遍的特征。

4.Bioresorbable shape-adaptive structures for ultrasonic monitoring of deep-tissue homeostasis

美国西北大学奎里·辛普森生物电子研究所，美国华盛顿大学材料科学与工程研究所，美国华盛顿大学医学院神经外科，美国西北大学土木与环境工程系

Abstract

Monitoring homeostasis is an essential aspect of obtaining pathophysiological insights for treating patients. Accurate, timely assessments of homeostatic dysregulation in deep tissues typically require expensive imaging techniques or invasive biopsies. We introduce a bioresorbable shape-adaptive materials structure that enables real-time monitoring of deep-tissue homeostasis using conventional ultrasound instruments. Collections of small bioresorbable metal disks distributed within thin, pH-responsive hydrogels, deployed by surgical implantation or syringe injection, allow ultrasound-based measurements of spatiotemporal changes in pH for early assessments of anastomotic leaks after gastrointestinal surgeries, and their bioresorption after a recovery period eliminates the need for surgical extraction. Demonstrations in small and large animal models illustrate capabilities in monitoring leakage from the small intestine, the stomach, and the pancreas.

监测体内稳态是明确病理生理状态以治疗患者的一个重要方面。准确、及时地评估深部组织稳态失调通常需要昂贵的成像技术或侵入性活检。我们引入了一种可生物吸收的形状自适应材料结构，可以通过使用传统的超声仪器实时监测深层组织稳态。通过手术植入或注射器注射，将可生物吸收的小金属盘聚集在随pH变化而改变的薄层水凝胶中，让超声能够测量pH值的时空变化，可用于胃肠道手术后吻合口泄漏的早期评估，并且因为其具有生物可吸收性，在恢复后期不需要手术取出。在小型和大型动物模型中的实验证明了其监测小肠、胃和胰腺渗漏的能力。

5.Induction of durable remission by dual immunotherapy in SHIV-infected ART-suppressed macaques

美国哈佛医学院贝丝以色列女执事医疗中心病毒学和疫苗研究中心，美国威斯康星大学麦迪逊分校威斯康星州国家灵长类动物研究中心，美国约翰霍普金斯大学医学院医学系

Abstract

The eradication of the viral reservoir represents the major obstacle to the development of a clinical cure for established HIV-1 infection. Here, we demonstrate that the administration of N-803 (brand name Anktiva) and broadly neutralizing antibodies (bNAbs) results in sustained viral control after discontinuation of antiretroviral therapy (ART) in simian-human AD8 (SHIV-AD8)-infected, ART-suppressed rhesus macaques. N-803+bNAbs treatment induced immune activation and transient viremia but only limited reductions in the SHIV reservoir. Upon ART discontinuation, viral rebound occurred in all animals, which was followed by durable control in approximately 70% of all N-803+bNAb-treated macaques. Viral control was correlated with the reprogramming of CD8+ T cells by N-803+bNAb synergy. Thus, complete eradication of the replication-competent viral reservoir is likely not a prerequisite for the induction of sustained remission after discontinuation of ART.

根除病毒库是临床治愈HIV-1感染的主要难点。在本研究中，我们证明，SHIV-AD8感染的恒河猴停止抗逆转录病毒治疗(ART)后，使用N-803（品牌名Anktiva）和广谱中和抗体（bNAbs）可以持续控制病毒。N-803+bNAbs治疗可诱导免疫激活和短暂的病毒血症，但只能有限地减少SHIV库。停止ART后，所有动物的病毒含量出现了反弹，随后在大约70%的N-803+bNAb处理的恒河猴中病毒得到了持久控制。病毒控制与N-803+bNAb协同作用对CD8+ T细胞的重编程相关。因此，完全根除具有复制能力的病毒库可能不是在停用ART后诱导持久缓解的先决条件。

6.Prophage proteins alter long noncoding RNA and DNA of developing sperm to induce a paternal-effect lethality

美国宾夕法尼亚州立大学

Abstract

The extent to which prophage proteins interact with eukaryotic macromolecules is largely unknown. In this work, we show that cytoplasmic incompatibility factor A (CifA) and B (CifB) proteins, encoded by prophage WO of the endosymbiont Wolbachia, alter long noncoding RNA (lncRNA) and DNA during Drosophila sperm development to establish a paternal-effect embryonic lethality known as cytoplasmic incompatibility (CI). CifA is a ribonuclease (RNase) that depletes a spermatocyte lncRNA important for the histone-to-protamine transition of spermiogenesis. Both CifA and CifB are deoxyribonucleases (DNases) that elevate DNA damage in late spermiogenesis. lncRNA knockdown enhances CI, and mutagenesis links lncRNA depletion and subsequent sperm chromatin integrity changes to embryonic DNA damage and CI. Hence, prophage proteins interact with eukaryotic macromolecules during gametogenesis to create a symbiosis that is fundamental to insect evolution and vector control.

摘要：

噬菌体蛋白与真核生物大分子相互作用的程度大体是未知的。在本研究中，我们发现由内共生体沃尔巴克氏体的噬菌体WO编码的胞质不相容因子A（CifA）和B（CifB）蛋白，在果蝇精子发育过程中可改变长非编码RNA（lncRNA）和DNA，从而建立一种称为胞质不相容性（CI）的父系效应胚胎致死现象。CifA是一种核糖核酸酶（RNase），可酶解对精子生成过程中组蛋白到鱼精蛋白转化很重要的一种lncRNA。CifA和CifB都是脱氧核糖核酸酶（DNase），可在精子发生晚期加重DNA损伤。lncRNA敲除可增强CI，突变将lncRNA耗竭和随后的精子染色质完整性变化与胚胎DNA损伤和CI联系起来。因此，原噬菌体蛋白在配子发生过程中与真核大分子相互作用，形成共生关系，这对昆虫进化和媒介控制至关重要。

7.Sister chromatid cohesion is mediated by individual cohesin complexes

英国牛津大学生物化学系，英国牛津大学威廉·邓恩爵士病理学院，奥地利维也纳生物中心（VBC）奥地利科学院分子生物技术研究所（IMBA）

Abstract

Eukaryotic genomes are organized by loop extrusion and sister chromatid cohesion, both mediated by the multimeric cohesin protein complex. Understanding how cohesin holds sister DNAs together, and how loss of cohesion causes age-related infertility in females, requires knowledge as to cohesin's stoichiometry in vivo. Using quantitative super-resolution imaging, we identified two discrete populations of chromatin-bound cohesin in postreplicative human cells. Whereas most complexes appear dimeric, cohesin that localized to sites of sister chromatid cohesion and associated with sororin was exclusively monomeric. The monomeric stoichiometry of sororin:cohesin complexes demonstrates that sister chromatid cohesion is conferred by individual cohesin rings, a key prediction of the proposal that cohesion arises from the co-entrapment of sister DNAs.

真核生物基因组由环挤压和姐妹染色单体内聚来组装，两者都由多聚体黏连蛋白复合物介导。了解黏连蛋白如何将姐妹DNA结合在一起，以及内聚力的丧失如何导致女性与年龄相关的不孕症，需要了解黏连蛋白在体内的化学计量。通过定量超分辨率成像，我们在复制后的人类细胞中鉴定了两个离散的染色质结合的黏连蛋白群体。虽然大多数复合物呈二聚体，但定位于姐妹染色单体内黏连位点并与吸附素相关的黏连蛋白完全是单聚体的。吸附素-黏连蛋白复合物的单体化学计量表明，姐妹染色单体的内聚力是由单个黏连蛋白环赋予的，这是推断内聚力源于姐妹DNA的共嵌合这一观点的关键。

汇报人：李朔

导师：任建君

编辑：陈秋蓉

审核：任建君、胥飞宇