原创 李朔 华西医院耳鼻喉科

【Science】2025年01月03日-2025年01月31日刊论文导读

期刊介绍：

《Science》（科学杂志）是一份由美国科学促进会（American Association for the Advancement of Science，简称AAAS）出版的著名科学杂志。该杂志创建于1880年，是全球最具影响力和知名度的跨学科科学期刊之一。该杂志以发表高质量、原创性的科学研究论文和评论而闻名，涵盖了各个科学领域，包括生命科学、物理学、化学、地球与环境科学、工程技术等。它是科学领域内同行评议制度的支持者，通过评审和编辑确保所发表的研究具有学术水平和可靠性。除了研究论文外，该杂志还经常刊发关于科学前沿、科学政策、科学教育和科学社会问题的评论文章。《Science》还定期发布一些专题特刊，深入探讨特定主题或领域的最新进展。因其在科学界的声望和影响力，《Science》成为科学家们追求学术卓越和科学创新的重要平台之一。最新影响因子为44.7。

VOLUME 387|ISSUE 6729|03 January 2025

在2025年01月03日，《Science》共发表文章31篇

①7篇NEWS

②9篇INSIGHTS,其中1篇EXPERT VOICES，4篇PERSPECTIVES，1篇POLICY FORUM，2本BOOK，1篇LETTERS,

③15篇RESEARCH,其中1篇REVIEWS，14篇RESEARCH ARTICLES,1篇EDITORIAL

1.Landscape profiling of PET depolymerases using a natural sequence cluster framework

使用自然序列聚类框架对PET解聚酶进行景观剖析

韩国大邱庆北国立大学KNU微生物研究所

Abstract

Enzymes capable of breaking down polymers have been identified from natural sources and developed for industrial use in plastic recycling. However, there are many potential starting points for enzyme optimization that remain unexplored. We generated a landscape of 170 lineages of 1894 polyethylene terephthalate depolymerase (PETase) candidates and performed profiling using sampling approaches with features associated with PET-degrading capabilities. We identified three promising yet unexplored PETase lineages and two potent PETases, Mipa-P and Kubu-P. An engineered variant of Kubu-P outperformed benchmarks in terms of PET depolymerization in harsh environments, such as those with high substrate load and ethylene glycol as the solvent.

摘要：

科学家发现了一些可分解塑料聚合物的酶，并将其应用于工业塑料回收，但仍存在许多优化与改造上的潜力。研究人员从1894种候选聚对苯二甲酸乙二醇酯解聚酶（PET 酶）中筛选出170个品系，并利用与PET降解能力相关的特征采样方法进行了分析。发现了三种前景广阔但尚未开发的PET酶谱系和两种强效PET酶Mipa-P和Kubu-P。Kubu-P的一个工程变体在严苛条件（如底物负荷高和乙二醇作为溶剂的环境）中的PET解聚能力优于基准。

2.Rare germline structural variants increase risk for pediatric solid tumors

罕见的种系结构变异会增加儿童实体瘤的风险

儿科肿瘤科，达纳-法伯癌症研究院，波士顿，马萨诸塞州，美国

Abstract

Pediatric solid tumors are a leading cause of childhood disease mortality. In this work, we examined germline structural variants (SVs) as risk factors for pediatric extracranial solid tumors using germline genome sequencing of 1765 affected children, their 943 unaffected parents, and 6665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and increased risk of solid tumors in male children. The overall impact of germline SVs was greatest in neuroblastoma, where we uncovered burdens of ultrarare SVs that cause loss of function of highly expressed, mutationally constrained genes, as well as noncoding SVs predicted to disrupt chromatin domain boundaries. Collectively, we estimate that rare germline SVs explain 1.1 to 5.6% of pediatric cancer liability, establishing them as an important component of disease predisposition.

摘要：

小儿实体瘤是造成儿童死亡的重要原因。本研究对1765名患病儿童、他们的943名未患病父母及6665名成人对照的种系基因组测序进行了分析，探讨了种系结构变异（SV）在小儿颅外实体瘤风险中的作用。结果发现：大于1兆碱基（>1 Mb）的超大染色体结构异常与男性儿童实体瘤风险升高显著相关。此外，研究发现种系结构变异对神经母细胞瘤影响最为突出，包括存在大量极其罕见的结构变异，这些变异会导致高表达且对突变十分敏感的基因丧失功能，还有一些非编码区的结构变异可能会破坏染色质结构域边界。综合而言，研究估计罕见种系SV可解释1.1%～5.6%的儿科癌症发病风险，表明这些变异在疾病易感性中具有重要地位。

3.Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein

保护性抗体靶向疟疾子孢子蛋白裂解所揭示的隐性表位

抗体生物学部门，免疫遗传学实验室，美国国立过敏和传染病研究所，美国国立卫生研究院，美国马里兰州罗克维尔

Abstract

The most advanced monoclonal antibodies (mAbs) and vaccines against malaria target the central repeat region or closely related sequences within the Plasmodium falciparum circumsporozoite protein (PfCSP). Here, using an antigen-agnostic strategy to investigate human antibody responses to whole sporozoites, we identified a class of mAbs that target a cryptic PfCSP epitope that is only exposed after cleavage and subsequent pyroglutamylation (pGlu) of the newly formed N terminus. This pGlu-CSP epitope is not targeted by current anti-PfCSP mAbs and is not included in the licensed malaria vaccines. MAD21-101, the most potent mAb in this class, confers sterile protection against Pf infection in a human liver-chimeric mouse model. These findings reveal a site of vulnerability on the sporozoite surface that can be targeted by next-generation antimalarial interventions.

摘要

最先进的单克隆抗体（mAbs）和疟疾疫苗针对恶性疟原虫环孢子子蛋白（PfCSP）的中心重复区或相似序列。本研究中，研究人员利用抗原识别策略研究了人类对整个疟原虫子孢子的抗体反应，发现了一类mAbs的靶向 PfCSP 的一个隐蔽表位，该表位只有在新形成的N端发生裂解和随后的焦谷氨酰化（pGlu）后才会暴露出来。目前的抗PfCSP mAbs并不针对这一pGlu-CSP表位，也不包括在已获许可的疟疾疫苗中。MAD21-101是该类药物中最有效的mAb，它能在人肝嵌合小鼠模型中对Pf感染产生无菌保护。这些发现揭示了孢子虫表面的一个薄弱环节，下一代抗疟干预措施可将其作为靶点。

4.Direct photoreception by pituitary endocrine cells regulates hormone release and pigmentation

垂体内分泌细胞的直接感光调节激素释放和色素沉着

海洋生物科学系，东京大学大气海洋研究所，日本柏市

Abstract

The recent discovery of nonvisual photoreceptors in various organs has raised expectations for uncovering their roles and underlying mechanisms. In this work, we identified a previously unrecognized hormone-releasing mechanism in the pituitary of the Japanese rice fish (medaka) induced by light. Ca2+imaging analysis revealed that melanotrophs, a type of pituitary endocrine cell that secretes melanocyte-stimulating hormone, robustly increase the concentration of intracellular Ca2+during short-wavelength light exposure. Moreover, we identified Opn5m as the key molecule that drives this response. Knocking out opn5m attenuated melanogenesis by reducing tyrosinase expression in the skin. Our findings suggest a mechanism in which direct reception of short-wavelength light by pituitary melanotrophs triggers a pathway that might contribute to protection from ultraviolet radiation in medaka.

摘要

近期在多种器官中发现的非视觉感光受体激发了对其功能和作用机制的探索。本研究中，研究人员在日本青鳉的垂体中发现了一种新颖的光诱导激素释放机制。钙离子成像分析显示，分泌促黑素细胞激素的垂体内分泌细胞在短波长光照下，其细胞内Ca2+浓度显著升高。此外，研究发现Opn5m是驱动这种反应的关键分子，它的缺失会降低皮肤酪氨酸酶表达，从而抑制黑色素生成。研究结果表明，垂体黑色素营养体直接接收短波长光，可能会触发一条有助于保护青鳉免受紫外线辐射的途径。

5.Engineering synthetic phosphorylation signaling networks in human cells

在人类细胞中设计合成磷酸化信号网络

生物工程系，莱斯大学，美国德克萨斯州休斯顿市

Abstract

Protein phosphorylation signaling networks have a central role in how cells sense and respond to their environment. We engineered artificial phosphorylation networks in which reversible enzymatic phosphorylation cycles were assembled from modular protein domain parts and wired together to create synthetic phosphorylation circuits in human cells. Our design scheme enabled model-guided tuning of circuit function and the ability to make diverse network connections; synthetic phosphorylation circuits can be coupled to upstream cell surface receptors to enable fast-timescale sensing of extracellular ligands, and downstream connections can regulate gene expression. We engineered cell-based cytokine controllers that dynamically sense and suppress activated T cells. Our work introduces a generalizable approach that allows the design of signaling circuits that enable user-defined sense-and-respond function for diverse biosensing and therapeutic applications.

摘要

蛋白质磷酸化信号网络在细胞感知并响应外界环境中扮演了核心角色。研究人员将可逆的磷酸化酶循环从模块化的蛋白质结构域中组装起来并互相连接，从而在人体细胞中构建出合成磷酸化回路。该设计方案可在模型指导下调整电路功能，并能建立多种网络连接；合成磷酸化电路可与上游细胞表面受体耦合，实现对细胞外配体的快速时间尺度感应，下游连接可调控基因表达。设计了基于细胞的细胞因子控制器，可动态感知和抑制活化的 T 细胞。该研究介绍了一种可通用的方法，它允许设计信号通路，从而实现用户定义的感知和响应功能，可应用于各种生物传感和治疗应用。

6.Competitive social feedback amplifies the role of early life contingency in male mice

竞争性社会反馈放大了雄性小鼠早期生命偶然性的作用

神经生物学与行为系，康奈尔大学，美国纽约州伊萨卡

Abstract

Contingency (or "luck") in early life plays an important role in shaping individuals' development. By comparing the developmental trajectories of functionally genetically identical free-living mice who either experienced high levels of resource competition (males) or did not (females), we show that competition magnifies early contingency. Male resource competition results in a feedback loop that magnifies the importance of early contingency and pushes individuals onto divergent, self-reinforcing life trajectories, while the same process appears absent in females. Our results indicate that the strength of sexual selection may be self-limiting, and they highlight the potential for contingency to lead to differences in life outcomes, even in the absence of any underlying differences in ability ("merit").

摘要

早期生活中的偶然性（或称“运气”）在塑造个体发展中起着重要作用。通过比较功能基因相同的自由生活小鼠的发展轨迹其中雄性小鼠经历了高水平的资源竞争，而雌性小鼠没有，研究发现竞争会放大早期偶然性的重要性。雄性资源竞争形成了一种反馈循环，放大了早期偶然性的重要性，并将个体推向不同、自我强化的生活轨迹，而这一过程在雌性中似乎并不存在。本研究结果表明，性选择的强度可能是自我限制的，同时强调了偶然性在导致生活结果差异方面的潜在作用，即使在缺乏任何潜在能力（“优点”）差异的情况下也是如此。

7.Sensation is dispensable for the maturation of the vestibulo-ocular reflex

感觉对于前庭-眼反射的成熟是非必需的

纽约大学格罗斯曼医学院耳鼻喉科、神经科学与生理学系及神经科学研究所，美国纽约

Abstract

Vertebrates stabilize gaze using a neural circuit that transforms sensed instability into compensatory counterrotation of the eyes. Sensory feedback tunes this vestibulo-ocular reflex throughout life. We studied the functional development of vestibulo-ocular reflex circuit components in the larval zebrafish, with and without sensation. Blind fish stabilize gaze normally, and neural responses to body tilts mature before behavior. In contrast, synapses between motor neurons and the eye muscles mature with a time course similar to behavioral maturation. Larvae without vestibular sensory experience, but with mature neuromuscular junctions, had a strong vestibulo-ocular reflex. Development of the neuromuscular junction, and not sensory experience, therefore determines the rate of maturation of an ancient behavior.

摘要

脊椎动物通过神经回路来稳定视线，这一回路将感知到的不稳定性转化为眼睛的补偿性运动。感官反馈会终生调节这中前庭-眼反射。该文章研究了无感知与有感知的斑马鱼幼体在前庭-眼反射回路组件功能发展方面的差异。失明的斑马鱼能正常地稳定注视，且其对身体倾斜的神经反应在行为出现之前就已经成熟。相比之下，运动神经元与眼肌之间的突触成熟与行为成熟的进程相似。那些没有前庭感官经验但拥有成熟神经肌肉接头的幼鱼，其前庭-眼动反射依然很强。因此，神经肌肉接头的发展，而非感官经验，决定了这一古老行为的成熟速度。

VOLUME 387|ISSUE 6730|10 January 2025

在2025年01月10日，《Science》共发表文章32篇

①7篇NEWS

②10篇INSIGHTS,其中1篇EXPERT VOICES，4篇PERSPECTIVES，1篇POLICY FORUM，2本BOOKS，2篇LETTERS

③15篇RESEARCH,其中15篇RESEARCH ARTICLES

Decoding the molecular interplay of CD20 and therapeutic antibodies with fast volumetric nanoscopy

用快速体积纳米显微镜解码CD20和治疗性抗体的分子相互作用

德国维尔茨堡大学生物中心生物技术与生物物理系

Abstract

Elucidating the interaction between membrane proteins and antibodies requires whole-cell imaging at high spatiotemporal resolution. Lattice light-sheet (LLS) microscopy offers fast volumetric imaging but suffers from limited spatial resolution. DNA-based point accumulation for imaging in nanoscale topography (DNA-PAINT) achieves molecular resolution but is restricted to two-dimensional imaging owing to long acquisition times. We have developed two-dye imager (TDI) probes that enable ~15-fold faster imaging. Combining TDI-DNA-PAINT and LLS microscopy on immunological B cells revealed the oligomeric states and interaction of endogenous CD20 with the therapeutic monoclonal antibodies (mAbs) rituximab, ofatumumab, and obinutuzumab. Our results demonstrate that CD20 is abundantly expressed on microvilli that bind mAbs, which leads to an antibody concentration-dependent B cell polarization and stabilization of microvilli protrusions. These findings could aid rational design of improved immunotherapies targeting tumor-associated antigens.

摘要

阐明膜蛋白与抗体之间的相互作用需要在高时空分辨率下进行全细胞成像。晶格光片显微镜（LLS）提供快速的体积成像，但其空间分辨率有限。基于DNA的纳米尺度拓扑成像点聚集（DNA-PAINT）能够实现分子分辨率，但由于采集时间较长，通常仅限于二维成像。本研究开发了双染料成像探针（TDI），使成像速度提高约15倍。将TDI-DNA-PAINT与LLS显微镜结合用于免疫B细胞的研究，揭示了内源性CD20的聚合状态及其与治疗性单克隆抗体（mAbs）利妥昔单抗、奥法木单抗和奥比替尼的相互作用。本研究结果表明，CD20在结合mAbs的微绒毛上丰富表达，导致抗体浓度依赖的B细胞极化和微绒毛突出结构的稳定。这些发现可能有助于合理设计针对肿瘤相关抗原的改进免疫疗法。

2.Sexually dimorphic dopaminergic circuits determine sex preference

性别二态性的多巴胺能回路决定了性别偏好

中国西安交通大学生命科学与技术学院，神经科学研究中心，教育部生物医学信息工程重点实验室，第一附属医院神经内科

Abstract

Sociosexual preference is critical for reproduction and survival. However, neural mechanisms encoding social decisions on sex preference remain unclear. In this study, we show that both male and female mice exhibit female preference but shift to male preference when facing survival threats; their preference is mediated by the dimorphic changes in the excitability of ventral tegmental area dopaminergic (VTADA) neurons. In males, VTADAprojections to the nucleus accumbens (NAc) mediate female preference, and those to the medial preoptic area mediate male preference. In females, firing-pattern (phasic-like versus tonic-like) alteration of the VTADA-NAc projection determines sociosexual preferences. These findings define VTADAneurons as a key node for social decision-making and reveal the sexually dimorphic DA circuit mechanisms underlying sociosexual preference.

摘要

社会性偏好对繁殖和生存至关重要。然而，编码性别偏好的社会决策的神经机制仍不清楚。本研究发现雄性和雌性小鼠都表现出对雌性的偏好，但在面临生存威胁时，偏好会转向雄性；这种偏好是通过腹侧被盖区多巴胺（VTADA）神经元兴奋性的性别二态性变化介导的。在雄性中，VTADA神经元向伏隔核（NAc）的投射介导了对雌性的偏好，而向内侧视前区的投射介导了对雄性的偏好。在雌性中，VTADA-NAc投射的放电模式（相位型或张力型）变化决定了社会性偏好。这些发现将VTADA神经元定义为社会决策的重要节点，并揭示了性别二态性多巴胺回路机制在社会性偏好中的作用。

3.Superstable lipid vacuoles endow cartilage with its shape and biomechanics

超稳定的脂质空泡赋予软骨其形状和生物力学特性

1加州大学欧文分校发展与细胞生物学系，美国加州 欧文

2加州大学欧文分校苏和比尔·格罗斯干细胞研究中心，美国加州欧文

Abstract

Conventionally, the size, shape, and biomechanics of cartilages are determined by their voluminous extracellular matrix. By contrast, we found that multiple murine cartilages consist of lipid-filled cells calledl ipochondrocytes. Despite resembling adipocytes, lipochondrocytes were molecularly distinct and produced lipids exclusively through de novo lipogenesis. Consequently, lipochondrocytes grew uniform lipid droplets that resisted systemic lipid surges and did not enlarge upon obesity. Lipochondrocytes also lacked lipid mobilization factors, which enabled exceptional vacuole stability and protected cartilage from shrinking upon starvation. Lipid droplets modulated lipocartilage biomechanics by decreasing the tissue's stiffness, strength, and resilience. Lipochondrocytes were found in multiple mammals, including humans, but not in nonmammalian tetrapods. Thus, analogous to bubble wrap, superstable lipid vacuoles confer skeletal tissue with cartilage-like properties without "packing foam-like" extracellular matrix.

摘要

传统上，软骨的特性主要由其细胞外基质决定。然而，本研究发现小鼠的软骨主要由一种叫做脂质软骨细胞（lipochondrocytes）的细胞组成，这些细胞充满了脂质。尽管与脂肪细胞相似，但脂质软骨细胞在分子上有所不同，并且它们只能通过新生脂肪生成来产生脂质。脂质软骨细胞内的脂质小滴均匀生长，能够抵御全身脂质水平的剧增，且在肥胖状态下也不会增大。此外，这些细胞缺乏脂质动员相关因子，使其保持卓越的空泡稳定性，从而保护软骨在饥饿状态下不发生收缩。脂质小滴通过降低组织的硬度、强度和弹性，调节脂质软骨的生物力学特性。脂质软骨细胞在多种哺乳动物中都已被发现，包括人类，但在非哺乳类四足动物中未见存在。因此，这些超稳定的脂质空泡赋予骨骼类似软骨的特性，而无需依赖“泡沫包装”般的细胞外基质。

4.Parallel gene expansions drive rapid dietary adaptation in herbivorous woodrats

平行基因扩增驱动食草性木鼠的快速饮食适应

犹他大学生物科学学院 美国犹他州盐湖城

Abstract

How mammalian herbivores evolve to feed on chemically defended plants remains poorly understood. In this study, we investigated the adaptation of two species of woodrats (Neotoma lepida and N. bryanti) to creosote bush (Larrea tridentata), a toxic shrub that expanded across the southwestern United States after the Last Glacial Maximum. We found that creosote-adapted woodrats have elevated gene dosage across multiple biotransformation enzyme families. These duplication events occurred independently across species and substantially increase expression of biotransformation genes, especially within the glucuronidation pathway. We propose that increased gene dosage resulting from duplication is an important mechanism by which animals initially adapt to novel environmental pressures.

摘要

哺乳动物食草动物如何进化以适应具有化学防御机制的植物仍然知之甚少。在这项研究中，研究人员调查了两种木鼠（Neotoma lepida 和 N. bryanti）对三齿拉雷亚灌木（Larrea tridentata）的适应情况，这是一种在末次冰盛期后扩展到美国西南部的有毒灌木。研究发现，适应三齿拉雷亚灌木的木鼠在多个生物转化酶家族中表现出基因剂量增加。这些基因重复事件在不同物种间独立发生，并显著增加了生物转化基因的表达，尤其是在糖苷酸化途径中。因此，该研究提出，基因重复导致的基因剂量增加是动物最初适应新环境压力的重要机制。

5.Bile acid synthesis impedes tumor-specific T cell responses during liver cancer

胆汁酸合成阻碍了肝癌中肿瘤特异性T细胞反应

美国加利福尼亚州拉荷亚，索尔克生物研究所免疫生物学与微生物致病学中心

Abstract

The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. Furthermore, different BAs regulated CD8+T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.

摘要

癌症的代谢环境对抗肿瘤免疫具有重要影响，但器官特异性代谢物如何在肿瘤微环境中影响免疫监视仍不明确。研究发现，初级和次级结合胆汁酸的积累是人类肝细胞癌和实验性肝癌模型中的代谢特征。通过去除胆汁酸结合酶BAAT来抑制肝细胞中的结合胆汁酸合成，可增强肿瘤特异性T细胞反应，减少肿瘤生长，同时提高肿瘤对抗PD-1免疫治疗的敏感性。此外，不同类型的胆汁酸对CD8+ T细胞的调节作用有所不同；初级胆汁酸会诱导氧化应激，而次级胆汁酸石胆酸则通过内质网应激抑制T细胞功能，但这一抑制效果可以被熊去氧胆酸缓解。因此，调节胆汁酸合成或增加饮食中熊去氧胆酸的摄入有助于改善肝癌模型中的肿瘤免疫治疗效果。

VOLUME 387|ISSUE 6731|17 January 2025

在2025年01月17日，《Science》共发表文章32篇

①7篇NEWS

②10篇INSIGHTS,其中1篇EXPERT VOICES，4篇PERSPECTIVES，2本BOOKS，3篇LETTERS

③15篇RESEARCH,其中15篇RESEARCH ARTICLES

1.Distinct myeloid-derived suppressor cell populations in human glioblastoma

人类胶质母细胞瘤中的不同髓源抑制细胞群体

宾夕法尼亚大学佩雷尔曼医学院神经外科，宾夕法尼亚州费城，美国

Abstract

The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood. We performed single-cell RNA sequencing of immune and tumor cells from 33 gliomas, identifying two distinct myeloid-derived suppressor cell (MDSC) populations in isocitrate dehydrogenase-wild-type (IDT-WT) glioblastoma: an early progenitor MDSC (E-MDSC) population with up-regulation of metabolic and hypoxia pathways and a monocytic MDSC (M-MDSC) population. Spatial transcriptomics demonstrated that E-MDSCs geographically colocalize with metabolic stem-like tumor cells in the pseudopalisading region. Ligand-receptor analysis revealed cross-talk between these cells, where glioma stem-like cells produce chemokines attracting E-MDSCs, which in turn produce growth factors for the tumor cells. This interaction is absent in IDH-mutant gliomas, associated with hypermethylation and repressed gene expression of MDSC-attracting chemokines. Our study elucidates specific MDSCs that may facilitate glioblastoma progression and mediate tumor immunosuppression.

摘要

胶质瘤相关的髓系细胞在肿瘤生长和免疫逃逸中的作用仍然不够了解。本研究对33个胶质瘤样本的免疫细胞和肿瘤细胞进行了单细胞RNA测序，在异柠檬酸脱氢酶野生型（IDH-WT）胶质母细胞瘤识别出两种不同的髓系来源抑制细胞（MDSC）亚群：一种早期前体MDSC（E-MDSC）亚群，其代谢和缺氧通路上调，以及另一种单核细胞MDSC（M-MDSC）亚群。空间转录组学分析显示，E-MDSC在假边缘区与代谢干样肿瘤细胞共定位。配体-受体分析揭示了这些细胞之间的相互作用，胶质瘤干细胞样细胞产生趋化因子吸引E-MDSC，而E-MDSC又产生促进肿瘤细胞生长的生长因子。在IDH突变的胶质瘤中，这种相互作用是缺失的，并与MDSC吸引趋化因子的高甲基化和基因表达抑制相关。本研究阐明了可能促进胶质母细胞瘤的进展并介导肿瘤免疫抑制的特定MDSC亚群。

2.Neuronal-ILC2 interactions regulate pancreatic glucagon and glucose homeostasis

神经元-ILC2相互作用调节胰腺胰高血糖素和葡萄糖稳态

香帕利马基金会，香帕利马德未知中心，香帕利马德研究，葡萄牙里斯本

Abstract

The immune system shapes body metabolism, while interactions between peripheral neurons and immune cells control tissue homeostasis and immunity. However, whether peripheral neuroimmune interactions orchestrate endocrine system functions remains unexplored. After fasting, mice lacking type 2 innate lymphoid cells (ILC2s) displayed disrupted glucose homeostasis, impaired pancreatic glucagon secretion, and inefficient hepatic gluconeogenesis. Additionally, intestinal ILC2s were found in the pancreas, which was dependent on their expression of the adrenergic beta 2 receptor. Targeted activation of catecholaminergic intestinal neurons promoted the accumulation of ILC2s in the pancreas. Our work provides evidence that immune cells can be regulated by neuronal signals in response to fasting, activating an inter-organ communication route that promotes pancreatic endocrine function and regulation of blood glucose levels.

摘要

免疫系统影响身体代谢，外周神经元与免疫细胞的相互作用则维持组织内稳态和免疫力。然而，外周神经免疫相互作用对内分泌系统功能的协调作用尚未探讨。

在禁食状态下，缺乏2型先天淋巴细胞（ILC2s）的老鼠表现出葡萄糖稳态紊乱、胰腺胰高血糖素分泌受损和肝脏糖异生效率低下。此外，在胰腺中发现了肠道ILC2s，这取决于它们对肾上腺素能β2 受体的表达。靶向激活儿茶酚胺能肠神经元可促进 ILC2 在胰腺中的聚集。该研究证明免疫细胞可通过神经元信号调节对禁食的反应，激活器官间通信途径，促进胰腺内分泌功能和血糖水平的调节。

3.A panoramic view of cell population dynamics in mammalian aging

哺乳动物衰老中细胞群体动态的全景视图

单细胞基因组学与群体动态实验室，洛克菲勒大学，美国纽约

Abstract

To elucidate aging-associated cellular population dynamics, we present PanSci, a single-cell transcriptome atlas profiling >20 million cells from 623 mouse tissues across different life stages, sexes, and genotypes. This comprehensive dataset reveals >3000 different cellular states and >200 aging-associated cell populations. Our panoramic analysis uncovered organ-, lineage-, and sex-specific shifts in cellular dynamics during life-span progression. Moreover, we identify both systematic and organ-specific alterations in immune cell populations associated with aging. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte dependent. Our "cell-omics" strategy enhances comprehension of cellular aging and lays the groundwork for exploring the complex cellular regulatory networks in aging and aging-associated diseases.

摘要

为了阐明与衰老相关的细胞群体动态，本研究推出了PanSci，一个涵盖623个小鼠组织中超过2000万个细胞的单细胞转录组图谱，涵盖不同生命阶段、性别和基因型。该数据集揭示了超过3000种细胞状态和200种衰老相关细胞群体。分析发现，细胞动态在生命历程中表现出器官、谱系和性别特异性的变化。此外，识别了与衰老相关的免疫细胞群体的系统性和器官特异性改变，并探讨了免疫系统在衰老中的调节作用，确定了特定的依赖淋巴细胞的年龄相关细胞的群体扩展。本研究采用的“细胞组学”策略加深了对细胞衰老的理解，并为探索衰老及相关疾病中复杂的细胞调控网络奠定了基础。

4.Tactile edges and motion via patterned microstimulation of the human somatosensory cortex

通过模式化微刺激人类体感皮层来感知触觉边缘和运动信息

芝加哥大学生物与解剖学系，美国伊利诺伊州芝加哥

Abstract

Intracortical microstimulation (ICMS) of somatosensory cortex evokes tactile sensations whose properties can be systematically manipulated by varying stimulation parameters. However, ICMS currently provides an imperfect sense of touch, limiting manual dexterity and tactile experience. Leveraging our understanding of how tactile features are encoded in the primary somatosensory cortex (S1), we sought to inform individuals with paralysis about local geometry and apparent motion of objects on their skin. We simultaneously delivered ICMS through electrodes with spatially patterned projected fields (PFs), evoking sensations of edges. We then created complex PFs that encode arbitrary tactile shapes and skin indentation patterns. By delivering spatiotemporally patterned ICMS, we evoked sensation of motion across the skin, the speed and direction of which could be controlled. Thus, we improved individuals' tactile experience and use of brain-controlled bionic hands.

摘要

体感皮层的皮层内微刺激（ICMS）能够引发触觉感受，其特性可通过调整刺激参数进行系统性地控制。然而，现有的ICMS提供的触觉体验不够完善，限制了手部灵活性。基于对初级体感皮层（S1）中触觉特征编码的理解，本研究旨在向瘫痪个体传递关于其皮肤上物体的几何形状和运动感知信息。通过带有空间模式化投影场（PFs）的电极施加ICMS，可以激发边缘感知，并创造复杂的PFs以编码任意触觉形状和皮肤凹陷模式。通过时空模式化的ICMS，可以在皮肤上引发可控的运动感知，从而改善了个体的触觉体验和脑控仿生手的使用。

5.Reconstitution of synaptic junctions orchestrated by teneurin-latrophilin complexes

由teneurin-latrophilin复合体调控的突触重建

霍华德·休斯医学研究所分子与细胞生理学系，美国加利福尼亚州斯坦福大学

Abstract

Synapses are organized by trans-synaptic adhesion molecules that coordinate assembly of pre- and postsynaptic specializations, which, in turn, are composed of scaffolding proteins forming liquid-liquid phase-separated condensates. Presynaptic teneurins mediate excitatory synapse organization by binding to postsynaptic latrophilins; however, the mechanism of action of teneurins, driven by extracellular domains evolutionarily derived from bacterial toxins, remains unclear. In this work, we show that only the intracellular sequence, a dimerization sequence, and extracellular bacterial toxin-derived latrophilin-binding domains of Teneurin-3 are required for synapse organization, suggesting that teneurin-induced latrophilin clustering mediates synaptogenesis. Intracellular Teneurin-3 sequences capture liquid-liquid phase-separated presynaptic active zone scaffolds, enabling us to reconstitute an entire synaptic junction from purified proteins in which trans-synaptic teneurin-latrophilin complexes recruit phase-separated pre- and postsynaptic specializations.

摘要

突触的形成由跨突触粘附分子调控，这些分子协调前后突触特化结构的组装，这些特化结构则由形成液-液相分离冷凝物的支架蛋白构成。突触前teneurins通过与突触后latrophilins结合介导兴奋性突触的组织，但由细菌毒素来源的细胞外结构域驱动作用机制尚不明确。研究表明，仅需Teneurin-3的细胞内序列、二聚化序列和源自细菌毒素的latrophilin结合结构域即可完成突触组织，表明teneurin诱导的latrophilin聚集促进突触生成。Teneurin-3的细胞内序列捕获液-液相分离的前突触活跃区支架，从而使研究人员能够从纯化蛋白质中重建整个突触连接，其中跨突触的teneurin-latrophilin复合体招募相分离的前后突触特化。

6.Muscle-derived myostatin is a major endocrine driver of follicle-stimulating hormone synthesis

肌肉源性肌抑制素是促卵泡激素合成的主要内分泌驱动因素

加拿大魁北克省蒙特利尔麦吉尔大学药理学与治疗学系

Abstract

Myostatin is a paracrine myokine that regulates muscle mass in a variety of species, including humans. In this work, we report a functional role for myostatin as an endocrine hormone that directly promotes pituitary follicle-stimulating hormone (FSH) synthesis and thereby ovarian function in mice. Previously, this FSH-stimulating role was attributed to other members of the transforming growth factor-β family, the activins. Our results both challenge activin's eponymous role in FSH synthesis and establish an unexpected endocrine axis between skeletal muscle and the pituitary gland. Our data also suggest that efforts to antagonize myostatin to increase muscle mass may have unintended consequences on fertility.

摘要

肌抑制素是一种旁分泌肌肉因子，调节人类及其他物种的肌肉质量。本研究发现肌抑制素作为一种内分泌激素，可以直接促进小鼠垂体促卵泡激素（FSH）的合成，进而影响卵巢功能。之前，促卵泡激素的刺激作用被认为由转化生长因子β家族的活化素所介导的。本研究结果不仅质疑了激活素在FSH合成中的同名作用，还揭示了骨骼肌与垂体之间存在意想不到的内分泌轴。此外，数据还表明，拮抗肌抑制素以增加肌肉质量可能对生育产生意想不到的影响。

VOLUME 387|ISSUE 6732|24 January 2025

在2025年01月24日，《Science》共发表文章29篇

①5篇NEWS

②10篇INSIGHTS,其中4篇PERSPECTIVES，1个POLICY FORUM,2本BOOKS，3篇LETTERS

③14篇RESEARCH,其中14篇RESEARCH ARTICLES

1.Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension

肺动脉高压中的溶酶体功能障碍和炎性甾醇代谢

美国宾夕法尼亚州匹兹堡匹兹堡大学医学科学家培训计划

Abstract

Vascular inflammation regulates endothelial pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulated lysosomal activity and cholesterol metabolism activate pathogenic inflammation, but their relevance to PAH is unclear. Nuclear receptor coactivator 7 (NCOA7) deficiency in endothelium produced an oxysterol and bile acid signature through lysosomal dysregulation, promoting endothelial pathophenotypes. This oxysterol signature overlapped with a plasma metabolite signature associated with human PAH mortality. Mice deficient for endothelial Ncoa7 or exposed to an inflammatory bile acid developed worsened PAH. Genetic predisposition to NCOA7 deficiency was driven by single-nucleotide polymorphism rs11154337, which alters endothelial immunoactivation and is associated with human PAH mortality. An NCOA7-activating agent reversed endothelial immunoactivation and rodent PAH. Thus, we established a genetic and metabolic paradigm that links lysosomal biology and oxysterol processes to endothelial inflammation and PAH.

摘要

血管炎症调节内皮病理表型，尤其在肺动脉高压（PAH）中。溶酶体活性和胆固醇代谢失调会激活病理性炎症，但与PAH的关系尚不明确。内皮细胞中核受体共激活因子7（NCOA7）的缺失会导致溶酶体功能紊乱，产生氧固醇和胆汁酸特征，促进内皮病理表型。这种氧固醇特征与人类PAH死亡率相关的血浆代谢物特征重叠。缺失Ncoa7或暴露于炎性胆汁酸的小鼠表现出更严重的PAH。NCOA7缺失的遗传易感性由单核苷酸多态性rs11154337驱动，影响内皮细胞免疫激活，并与人类PAH患者死亡率相关。一种NCOA7激活剂可逆转内皮免疫激活和啮齿动物PAH。因此，本研究建立了一个将溶酶体生物学和氧固醇过程与内皮炎症及PAH相联系的遗传和代谢模型。

2.Highly multiplexed spatial transcriptomics in bacteria

细菌中的高通量空间转录组学

美国麻省波士顿儿童医院细胞与分子医学项目

Abstract

Single-cell decisions made in complex environments underlie many bacterial phenomena. Image-based transcriptomics approaches offer an avenue to study such behaviors, yet these approaches have been hindered by the massive density of bacterial messenger RNA. To overcome this challenge, we combined 1000-fold volumetric expansion with multiplexed error-robust fluorescence in situ hybridization (MERFISH) to create bacterial-MERFISH. This method enables high-throughput, spatially resolved profiling of thousands of operons within individual bacteria. Using bacterial-MERFISH, we dissected the response of Escherichia coli to carbon starvation, systematically mapped subcellular RNA organization, and charted the adaptation of a gut commensal Bacteroides thetaiotaomicron to micrometer-scale niches in the mammalian colon. We envision that bacterial-MERFISH will be broadly applicable to the study of bacterial single-cell heterogeneity in diverse, spatially structured, and native environments.

摘要

复杂环境中的单细胞决策是许多细菌行为的基础。基于图像的转录组学方法为研究这种行为提供了新的途径，但细菌信使RNA的高密度限制了这些方法的应用。为此，本研究结合1000倍体积扩展与多重耐误差荧光原位杂交（MERFISH），开发了细菌-MERFISH方法。这种方法可以对单个细菌内的成千上万个操纵子进行高通量和空间分辨的分析。利用细菌-MERFISH技术，本研究解析了大肠杆菌对碳饥饿的反应，系统地绘制了亚细胞RNA的组织结构，并揭示了肠道共生菌拟杆菌在哺乳动物结肠微米级生态位的适应。本研究认为细菌-MERFISH将在多样化、空间结构化和自然环境中的细菌单细胞异质性研究中得到广泛应用。

3.Identification of the subventricular tegmental nucleus as brainstem reward center

室下被盖核被确定为脑干奖励中心

匈牙利布达佩斯 HUN-任 实验医学研究所大脑皮层研究实验室

Abstract

Rewards are essential for motivation, decision-making, memory, and mental health. We identified the subventricular tegmental nucleus (SVTg) as a brainstem reward center. In mice, reward and its prediction activate the SVTg, and SVTg stimulation leads to place preference, reduced anxiety, and accumbal dopamine release. Mice self-stimulate the SVTg, which can also be activated directly by the neocortex, resulting in effective inhibition of the lateral habenula, a region associated with depression. This mechanism may also explain why SVTg suppression induces aversion and increases fear. The translational relevance of these findings is supported by evidence in the rat, monkey, and human brainstem, establishing SVTg as a key hub for reward processing, emotional valence, and motivation.

摘要

奖励对动机、决策、记忆和心理健康至关重要。本研究确认室下被盖核（SVTg）是脑干的奖励中心。在小鼠中，奖励及其预测能激活SVTg，刺激SVTg可导致位置偏好、焦虑减少以及伏隔核多巴胺释放。小鼠能够进行SVTg自我刺激，而SVTg还可通过新皮层直接激活，进而有效抑制与抑郁相关的侧脑室。因此，这一机制可能解释了SVTg抑制为何引起厌恶和增加恐惧情绪。这些发现的转化意义得到了大鼠、猴子和人类脑干证据的支持，确立SVTg为奖励处理、情绪价值和动机的关键枢纽。

Rapid in silico directed evolution by a protein language model with EVOLVEpro

利用 EVOLVEpro 的蛋白质语言模型实现快速硅定向进化

哈佛医学院布莱根和妇女医院，医学系医学工程分部，美国马萨诸塞州波士顿

Abstract

Directed protein evolution is central to biomedical applications but faces challenges such as experimental complexity, inefficient multiproperty optimization, and local maxima traps. Although in silico methods that use protein language models (PLMs) can provide modeled fitness landscape guidance, they struggle to generalize across diverse protein families and map to protein activity. We present EVOLVEpro, a few-shot active learning framework that combines PLMs and regression models to rapidly improve protein activity. EVOLVEpro surpasses current methods, yielding up to 100-fold improvements in desired properties. We demonstrate its effectiveness across six proteins in RNA production, genome editing, and antibody binding applications. These results highlight the advantages of few-shot active learning with minimal experimental data over zero-shot predictions. EVOLVEpro opens new possibilities for artificial intelligence-guided protein engineering in biology and medicine.

摘要

定向蛋白质进化对生物医学应用至关重要，但面临实验复杂性、多属性优化效率低和局部极值陷阱等挑战。尽管蛋白质语言模型（PLMs）能够提供适应度景观的模型指导，但它们在不同蛋白质家族之间的泛化和活性映射方面存在困难。本研究提出了EVOLVEpro，这是一个结合PLMs和回归模型的少样本主动学习框架，能够快速提升蛋白质活性。EVOLVEpro超越现有方法，针对所需属性的改进最高可达100倍。本研究验证了其在RNA生产、基因组编辑和抗体结合应用中对六种蛋白质的有效性。这些结果表明，在少量实验数据下，少样本主动学习优于零样本预测。EVOLVEpro为人工智能指导的生物学和医学蛋白质工程开辟了新可能。

5.Systematic identification of Y-chromosome gene functions in mouse spermatogenesis

小鼠精子发生中Y染色体基因功能的系统性识别

性染色体生物学实验室，弗朗西斯·克里克研究所，英国伦敦

Abstract

The mammalian Y chromosome is essential for male fertility, but which Y genes regulate spermatogenesis is unresolved. We addressed this by generating 13 Y-deletant mouse models. In Eif2s3y, Uty, and Zfy2 deletants, spermatogenesis was impaired. We found that Uty regulates spermatogonial proliferation, revealed a role for Zfy2 in promoting meiotic sex chromosome pairing, and uncovered unexpected effects of Y genes on the somatic testis transcriptome. In the remaining single Y-gene deletants, spermatogenesis appeared unperturbed, but testis transcription was still altered. Multigene deletions, including a human-infertility AZFa model, exhibited phenotypes absent in single Y deletants. Thus, Y genes may regulate spermatogenesis even if they show no phenotypes when deleted individually. This study advances our knowledge of Y evolution and infertility and provides a resource to dissect Y-gene functions in other tissues.

摘要

哺乳动物Y染色体对雄性生育能力至关重要，但哪些Y基因调控精子发生仍不明确。本研究通过构建13种Y缺失小鼠模型来解决此问题。在Eif2s3y、Uty和Zfy2缺失模型中，精子发生受损。研究发现，Uty调控精原细胞增殖，Zfy2在促进减数分裂性染色体配对中发挥作用，并揭示了Y基因对体性睾丸转录组的意外影响。其他单Y染色体基因缺失模型中精子发生未受干扰，但睾丸转录仍发生改变。多基因缺失模型（如人类不育的AZFa模型）表现出在单Y缺失模型中没有观察到的表型。 因此，Y染色体基因可能调控精子发生，即使个体缺失不表现出表型。本研究加深了对Y染色体进化和不育的理解，并提供了研究Y基因在其他组织功能的资源。

6.A single gene orchestrates androgen variation underlying male mating morphs in ruffs

单个基因调控流苏鹬雄性交配形态中的雄激素变异

马克斯·普朗克生物智能研究所，德国锡维森

Abstract

Androgens are pleiotropic and play pivotal roles in the formation and variation of sexual phenotypes. We show that differences in circulating androgens between the three male mating morphs in ruff sandpipers are linked to 17-beta hydroxysteroid dehydrogenase 2 (HSD17B2), encoded by a gene within the supergene that determines the morphs. Low-testosterone males had higher HSD17B2 expression in blood than high-testosterone males, as well as in brain areas related to social behaviors and testosterone production. Derived HSD17B2 isozymes, which are absent in high-testosterone males but preferentially expressed in low-testosterone males, converted testosterone to androstenedione faster than the ancestral isozyme. Thus, a combination of evolutionary changes in regulation, sequence, and structure of a single gene introduces endocrine variation underlying reproductive phenotypes.

摘要

雄激素具有多重效应，在性状的形成和变化中发挥关键作用。本研究发现，三种雄性交配形态的流苏鹬之间循环雄激素的差异与决定这些形态的超基因中的17-β羟基类固醇脱氢酶2（HSD17B2）有关。低睾酮雄性血液中HSD17B2的表达高于高睾酮水平雄性，并且在与社会行为和睾酮生产相关的大脑区域也表现出更高的表达。衍生的HSD17B2同工酶在高睾酮雄性中缺失，而在低睾酮雄性中优先表达，其将睾酮转化为雄烯二酮的速度快于祖先同工酶。因此，这个单个基因在调控、序列和结构上的演化变化，导致了生殖表型下的内分泌变异。

7.Affinity maturation of antibody responses is mediated by differential plasma cell proliferation

抗体反应的亲和力成熟是通过不同的浆细胞增殖介导的

分子免疫学实验室，洛克菲勒大学，美国纽约州纽约市

Abstract

Increased antibody affinity over time after vaccination, known as affinity maturation, is a prototypical feature of immune responses. Recent studies have shown that a diverse collection of B cells, producing antibodies with a wide spectrum of different affinities, is selected into the plasma cell (PC) pathway. How affinity-permissive selection enables PC affinity maturation remains unknown. We found that PC precursors (prePCs) expressing high-affinity antibodies received higher levels of T follicular helper cell (TFHcell)-derived help and divided at higher rates compared with their lower-affinity counterparts once they left the germinal center. Our findings indicate that differential cell division by selected prePCs accounts for how diverse precursors develop into a PC compartment that mediates serological affinity maturation.

摘要

    疫苗接种后抗体亲和力随时间增强，即亲和力成熟，是免疫反应的典型特征。研究表明，产生不同亲和力抗体的多样化B细胞被选入浆细胞（PC）通路。然而，亲和力选择如何促进PC亲和力成熟尚不明确。 研究发现，表达高亲和力抗体的PC前体细胞（prePCs）离开生发中心后，获得更多T滤泡辅助细胞（TFH细胞）的帮助，且分裂率高于低亲和力前体。这表明，prePCs的差异分裂解释了多样化前体如何发展为介导血清亲和力成熟的PC群体。

VOLUME 387|ISSUE 6733|31 January 2025

在2025年01月31日，《Science》共发表文章31篇

①5篇NEWS

②12篇INSIGHTS,其中1篇EXPERT VOICE，4篇PERSPECTIVES，1个POLICY FORUM,2本BOOKS，4篇LETTERS

③14篇RESEARCH,其中14篇RESEARCH ARTICLES

Hippocampal coding of identity, sex, hierarchy, and affiliation in a social group of wild fruit bats

野生果蝠社群中的身份、性别、等级和隶属关系的海马体编码

以色列雷霍沃特魏茨曼科学研究院脑科学系

美国伊利诺伊州芝加哥大学神经生物学系

Abstract

Social animals live in groups and interact volitionally in complex ways. However, little is known about neural responses under such natural conditions. Here, we investigated hippocampal CA1 neurons in a mixed-sex group of five to 10 freely behaving wild Egyptian fruit bats that lived continuously in a laboratory-based cave and formed a stable social network. In-flight, most hippocampal place cells were socially modulated and represented the identity and sex of conspecifics. Upon social interactions, neurons represented specific interaction types. During active observation, neurons encoded the bat's own position and head direction, together with the position, direction, and identity of multiple conspecifics. Identity-coding neurons encoded the same bat across contexts. The strength of identity coding was modulated by sex, hierarchy, and social affiliation. Thus, hippocampal neurons form a multidimensional sociospatial representation of the natural world.

摘要

群居动物在群体中以复杂的方式自愿互动，但在自然条件下的神经反应仍知之甚少。本研究探讨了在实验室洞穴中生活的五到十只混合性别的野生埃及果蝠的海马CA1神经元。这些蝙蝠形成了稳定的社会网络。在飞行中，大多数海马位置细胞受到社交因素的调节，代表同类的身份和性别。神经元在社会互动中表示特定的互动类型。主动观察时，神经元编码蝙蝠的自身位置和头部方向，以及多个同类的位置、方向和身份。身份编码神经元在不同环境中识别同一只蝙蝠，其编码强度受性别、等级和社交亲和力的影响。因此，海马体神经元构建了对自然世界的多维社会空间表征。

2.Scratching promotes allergic inflammation and host defense via neurogenic mast cell activation

抓痕通过神经源性肥大细胞激活促进过敏性炎症和宿主防御

美国宾夕法尼亚州匹兹堡大学皮肤科

Abstract

Itch is a dominant symptom in dermatitis, and scratching promotes cutaneous inflammation, thereby worsening disease. However, the mechanisms through which scratching exacerbates inflammation and whether scratching provides benefit to the host are largely unknown. We found that scratching was required for skin inflammation in mouse models dependent on FcεRI-mediated mast cell activation. Scratching-induced inflammation required pain-sensing nociceptors, the neuropeptide substance P, and the mast cell receptor MrgprB2. Scratching also increased cutaneous inflammation and augmented host defense to superficial Staphylococcus aureus infection. Thus, through the activation of nociceptor-driven neuroinflammation, scratching both exacerbated allergic skin disease and provided protection from S. aureus, reconciling the seemingly paradoxical role of scratching as a pathological process and evolutionary adaptation.

摘要

瘙痒是皮炎的主要症状，抓挠会加重皮肤炎症和疾病。然而，抓挠如何加剧炎症及其对宿主的益处机制仍不清楚。研究发现，在依赖FcεRI介导的肥大细胞激活的小鼠模型中，抓挠是皮肤炎症的必要因素。抓挠引发的炎症需要疼痛感知神经受体、神经肽物质P及肥大细胞受体MrgprB2。抓挠还增加了皮肤炎症，并增强了宿主对金黄色葡萄球菌感染的防御。因此，抓挠通过激活由神经受体驱动的神经炎症，既加重了过敏性皮肤病，又提供了对金黄色葡萄球菌的保护，调和了其作为病理过程与进化适应之间的看似矛盾作用。

3.Randomizing the human genome by engineering recombination between repeat elements

通过在重复元素间进行工程重组来随机化人类基因组

英国维康桑格研究所、美国哈佛医学院遗传学系

Abstract

We lack tools to edit DNA sequences at scales necessary to study 99% of the human genome that is noncoding. To address this gap, we applied CRISPR prime editing to insert recombination handles into repetitive sequences, up to 1697 per cell line, which enables generating large-scale deletions, inversions, translocations, and circular DNA. Recombinase induction produced more than 100 stochastic megabase-sized rearrangements in each cell. We tracked these rearrangements over time to measure selection pressures, finding a preference for shorter variants that avoided essential genes. We characterized 29 clones with multiple rearrangements, finding an impact of deletions on expression of genes in the variant but not on nearby genes. This genome-scrambling strategy enables large deletions, sequence relocations, and the insertion of regulatory elements to explore genome dispensability and organization.

摘要

目前缺乏足够的工具来编辑DNA序列，以研究99%非编码的人类基因组。为此，本研究利用CRISPR原位编辑向重复序列插入重组手柄，单个细胞系可插入多达1697个，从而实现大规模缺失、倒位、易位和环状DNA的生成。重组酶诱导后，每个细胞产生了超过100个随机兆碱基大小的重排。本研究实时跟踪这些重排以评估选择压力，发现对避免必需基因较短变体的受到偏好。分析了29个具有多重重排的克隆，发现缺失会影响变体中基因的表达，但对邻近基因没有影响。这种基因组打乱策略实现大规模缺失、序列重定位和调控元件的插入，以探索基因组的可有性和组织结构。

4.Multiplex generation and single-cell analysis of structural variants in mammalian genomes

哺乳动物基因组中结构变异的多重生成和单细胞分析

华盛顿大学基因组科学系，美国华盛顿州西雅图

Abstract

Studying the functional consequences of structural variants (SVs) in mammalian genomes is challenging because (i) SVs arise much less commonly than single-nucleotide variants or small indels and (ii) methods to generate, map, and characterize SVs in model systems are underdeveloped. To address these challenges, we developed Genome-Shuffle-seq, a method that enables the multiplex generation and mapping of thousands of SVs (deletions, inversions, translocations, and extrachromosomal circles) throughout mammalian genomes. We also demonstrate the co-capture of SV identity with single-cell transcriptomes, facilitating the measurement of SV impact on gene expression. We anticipate that Genome-Shuffle-seq will be broadly useful for the systematic exploration of the functional consequences of SVs on gene expression, the chromatin landscape, and three-dimensional nuclear architecture, while also initiating a path toward a minimal mammalian genome.

摘要

研究哺乳动物基因组中结构变异（SV）的功能后果具有挑战性，这主要因为（i）SV的出现频率远低于单核苷酸变异或小插入缺失，以及（ii）在模型系统中生成、映射和表征SV的方法尚不成熟。为了解决这些挑战，本研究开发了Genome-Shuffle-seq，这是一种能够实现哺乳动物基因组中成千上万的SV（缺失、倒位、易位和外染色体环）的多重生成和映射的方法。本研究还展示了与单细胞转录组共同捕获SV，从而便于测量SV对基因表达的影响。本研究预期Genome-Shuffle-seq将广泛应用于系统探索SV对基因表达、染色质结构和三维细胞核架构的功能影响，同时也为构建最简哺乳动物基因组开辟了一条道路。

5.TIR signaling activates caspase-like immunity in bacteria

TIR信号通路激活细菌中的半胱天冬酶样免疫反应

以色列雷霍沃特魏茨曼科学研究所分子遗传学系

Abstract

Caspase family proteases and Toll/interleukin-1 receptor (TIR)-domain proteins have central roles in innate immunity and regulated cell death in humans. We describe a bacterial immune system comprising both a caspase-like protease and a TIR-domain protein. We found that the TIR protein, once it recognizes phage invasion, produces the previously unknown immune signaling molecule adenosine 5'-diphosphate-cyclo[N7:1'']-ribose (N7-cADPR). This molecule specifically activates the bacterial caspase-like protease, which then indiscriminately degrades cellular proteins to halt phage replication. The TIR-caspase defense system, which we denote as type IV Thoeris, is abundant in bacteria and efficiently protects against phage propagation. Our study highlights the diversity of TIR-produced immune signaling molecules and demonstrates that cell death regulated by proteases of the caspase family is an ancient mechanism of innate immunity.

摘要

半胱天冬酶家族蛋白酶和Toll/白介素-1受体（TIR）结构域蛋白对人体的先天免疫和细胞死亡调控至关重要。本研究描述了一种细菌免疫系统，包含半胱天冬酶样蛋白酶和TIR结构域蛋白。当TIR蛋白识别噬菌体入侵时，会产生未知的免疫信号分子腺苷5'-二磷酸-环状[N7:1'']-核糖（N7-cADPR），该分子特异性激活细菌半胱天冬酶样蛋白酶，后者选择性降解细胞蛋白以阻止噬菌体复制。本研究称这种TIR-半胱天冬酶防御系统为IV型Thoeris，广泛存在于细菌中，有效阻止噬菌体传播。本研究强调了TIR产生的免疫信号分子的多样性，证明了半胱天冬酶家族的蛋白酶在调控细胞死亡方面是先天免疫的一种古老机制。

6.Structural basis of H3K36 trimethylation by SETD2 during chromatin transcription

在染色质转录过程中SETD2对H3K36的三甲基化的结构基础

美国哈佛医学院布拉瓦特尼克研究所

Abstract

During transcription, RNA polymerase II traverses through chromatin, and posttranslational modifications including histone methylations mark regions of active transcription. Histone protein H3 lysine 36 trimethylation (H3K36me3), which is established by the histone methyltransferase SET domain containing 2 (SETD2), suppresses cryptic transcription, regulates splicing, and serves as a binding site for transcription elongation factors. The mechanism by which the transcription machinery coordinates the deposition of H3K36me3 is not well understood. Here we provide cryo-electron microscopy structures of mammalian RNA polymerase II-DSIF-SPT6-PAF1c-TFIIS-IWS1-SETD2-nucleosome elongation complexes, revealing that the transcription machinery regulates H3K36me3 deposition by SETD2 on downstream and upstream nucleosomes. SPT6 binds the exposed H2A-H2B dimer during transcription, and the SPT6 death-like domain mediates an interaction with SETD2 bound to a nucleosome upstream of RNA polymerase II.

摘要

在转录过程中，RNA聚合酶II穿越染色质，翻译后修饰（如组蛋白甲基化）标记活跃转录区域。组蛋白H3赖氨酸36的三甲基化（H3K36me3）由含SET结构域的组蛋白甲基转移酶SETD2建立，抑制隐匿转录，调控剪接，并作为转录延伸因子的结合位点。然而，转录机制如何协调H3K36me3沉积的机制仍不清楚。本文提供了哺乳动物RNA聚合酶II-DSIF-SPT6-PAF1c-TFIIS-IWS1-SETD2-核小体延伸复合物的冷冻电子显微镜结构，揭示了转录机制如何通过SETD2调控上下游核小体上的H3K36me3沉积。SPT6在转录时结合暴露的H2A-H2B二聚体，而其死亡样结构域则介导与RNA聚合酶II上游的SETD2的相互作用。

7.Pre-exposure antibody prophylaxis protects macaques from severe influenza

预暴露抗体预防能有效保护猕猴免受严重流感

美国马里兰州贝塞斯达国家卫生研究院过敏和传染病研究所疫苗研究中心

Abstract

Influenza virus pandemics and seasonal epidemics have claimed countless lives. Recurrent zoonotic spillovers of influenza viruses with pandemic potential underscore the need for effective countermeasures. In this study, we show that pre-exposure prophylaxis with broadly neutralizing antibody (bnAb) MEDI8852 is highly effective in protecting cynomolgus macaques from severe disease caused by aerosolized highly pathogenic avian influenza H5N1 virus infection. Protection was antibody dose-dependent yet independent of Fc-mediated effector functions at the dose tested. Macaques receiving MEDI8852 at 10 milligrams per kilogram or higher had negligible impairment of respiratory function after infection, whereas control animals were not protected from severe disease and fatality. Given the breadth of MEDI8852 and other bnAbs, we anticipate that protection from unforeseen pandemic influenza A viruses is achievable.

摘要

流感病毒的大流行和季节性流行病造成了无数生命损失。反复出现的具有大流行潜力的流感病毒的动物宿主溢出，突显了有效对策的必要性。本研究表明，广泛中和抗体（bnAb）MEDI8852的暴露前预防能有效保护猕猴免受气溶胶传播的高致病性禽流感H5N1病毒引起的严重疾病。保护效果与抗体剂量相关，但与Fc介导的效应功能无关。接受10毫克/千克或更高剂量MEDI8852的猕猴在感染后几乎没有呼吸功能受损，而对照组动物未能抵御严重疾病和死亡。鉴于MEDI8852及其他bnAb的广泛性，本研究预计能够实现对不可预见的大流行流感A病毒的预防。

The time course and organization of hippocampal replay

海马体重放的时间进程和组织过程

加州大学伯克利分校神经科学系，美国加利福尼亚州伯克利

Abstract

The mechanisms by which the brain replays neural activity sequences remain unknown. Recording from large ensembles of hippocampal place cells in freely behaving rats, we observed that replay content is strictly organized over multiple timescales and governed by self-avoidance. After movement cessation, replays avoided the animal's previous path for 3 seconds. Chains of replays avoided self-repetition over a shorter timescale. We used a continuous attractor model of neural activity to demonstrate that neuronal fatigue both generates replay sequences and produces self-avoidance over the observed timescales. In addition, replay of past experience became predominant later into the stopping period, in a manner requiring cortical input. These results indicate a mechanism for replay generation that unexpectedly constrains which sequences can be produced across time.

摘要

  大脑重放神经活动序列的机制尚不明确。在自由活动的老鼠中记录大量海马位置细胞后，本研究发现重放内容在多个时间尺度上严格组织，并受到自我回避的控制。在运动停止后，重放避开了动物之前的路径，持续了3秒，而重放链在更短时间尺度上避免自我重复。本研究使用连续吸引子模型证明，神经疲劳既生成重放序列，又在观察到的时间尺度上导致自我回避。此外，过去经历的重放在停止期后期占主导地位，这一过程需要皮层输入。这些结果揭示了一种重放生成机制，意外限制了可产生的时间序列。

汇报人：李朔

导师：任建君

审核：庞文都、张宇阳、任建君