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A global effort toward standards for data sharing in biomedical imaging : Developing Consensus and Infrastructure for Global Data Interoperability. 面向生物医学成像数据共享标准的全球努力:为全球数据互操作性发展共识和基础设施。
IF 6.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-01 Epub Date: 2025-12-03 DOI: 10.1038/s44319-025-00652-w
Sophie L Winter, Josh Moore, Adriana A S Tavares, Graham Galloway, Michel Dojat, Dario Livio Longo, Ryan Sullivan, Aastha Mathur, Linda Chaabane
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引用次数: 0
TMEM251 loss-induced autophagy dysfunction in the anterior cingulate cortex contributes to chronic postoperative pain. TMEM251缺失引起的前扣带皮层自噬功能障碍与慢性术后疼痛有关。
IF 6.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-01 Epub Date: 2025-12-03 DOI: 10.1038/s44319-025-00646-8
Yaowei Xu, Fei Xing, Xin Wei, Xiaoling Wang, Xiaoshan Shi, Zhongyu Wang, Na Xing, Jingjing Yuan, Zhisong Li, Wei Zhang

Macroautophagy/autophagy plays a crucial role in maintaining nervous system homeostasis but its role in chronic postoperative pain (CPOP) remains poorly understood. Here, we identify impaired autophagy and the accumulation of synaptic proteins in the anterior cingulate cortex (ACC) during the maintenance of CPOP after skin/muscle incision and retraction (SMIR). Lysosomal hydrolase levels are reduced upon SMIR, accompanied by a deficiency of the lysosomal trafficking protein transmembrane protein 251 (TMEM251, also named LYSET). TMEM251 overexpression alleviates impaired autophagy, accumulation of synaptic proteins within autophagy substrates, and maintenance of CPOP in SMIR mice. Conversely, TMEM251 knockdown induces autophagy impairment, accumulation of synaptic proteins, and chronic pain phenotypes in naive mice. Autophagy dysfunction is most pronounced in CaMKIIα-positive neurons in the ACC post-surgery, resulting in their activation, which is mitigated by TMEM251 overexpression. Chemogenetic activation of CaMKIIα neurons exacerbates autophagy impairment and CPOP, while their inhibition rescues SMIR-induced autophagy and pain phenotypes. Taken together, our study highlights the close relationship between impaired autophagy and neuronal activation in the promotion of chronic postoperative pain.

巨噬/自噬在维持神经系统稳态中起着至关重要的作用,但其在慢性术后疼痛(CPOP)中的作用仍然知之甚少。在这里,我们发现在皮肤/肌肉切开和收缩(SMIR)后CPOP维持期间,前扣带皮层(ACC)的自噬受损和突触蛋白积累。溶酶体水解酶水平在SMIR时降低,并伴有溶酶体运输蛋白跨膜蛋白251 (TMEM251,也称为LYSET)的缺乏。TMEM251过表达可减轻SMIR小鼠自噬受损、自噬底物内突触蛋白的积累和CPOP的维持。相反,TMEM251基因敲低可诱导小鼠自噬损伤、突触蛋白积累和慢性疼痛表型。自噬功能障碍在ACC术后camkii α阳性神经元中最为明显,导致其激活,TMEM251过表达可减轻其激活。CaMKIIα神经元的化学发生激活加剧了自噬损伤和CPOP,而它们的抑制可以挽救smir诱导的自噬和疼痛表型。综上所述,我们的研究强调了自噬受损和神经元激活在促进慢性术后疼痛中的密切关系。
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引用次数: 0
Author Correction: A1 is induced by pathogen ligands to limit myeloid cell death and NLRP3 inflammasome activation. 作者更正:A1是由病原体配体诱导的,以限制髓细胞死亡和NLRP3炎性体的激活。
IF 6.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-01 Epub Date: 2025-12-22 DOI: 10.1038/s44319-025-00609-z
Mary Speir, Hazel Tye, Timothy A Gottschalk, Daniel S Simpson, Tirta M Djajawi, Pankaj Deo, Rebecca L Ambrose, Stephanie A Conos, Jack Emery, Gilu Abraham, Ashlyn Pascoe, Sebastian A Hughes, Ashley Weir, Edwin D Hawkins, Isabella Kong, Marco J Herold, Jaclyn S Pearson, Najoua Lalaoui, Thomas Naderer, James E Vince, Kate E Lawlor
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引用次数: 0
Actin waves guide an outward movement of microclusters in the lymphocyte immunological synapse. 肌动蛋白波引导淋巴细胞免疫突触中的微团向外移动。
IF 6.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-22 DOI: 10.1038/s44319-025-00676-2
Aheria Dey, Samuel Z Khiangte, Srishti Mandal, Huw Colin-York, Marco Fritzsche, Sumantra Sarkar, Sudha Kumari

The lymphocyte immune response begins with antigen recognition on antigen-presenting cells, leading to the formation of the immunological synapse-a specialized interface for biochemical and biophysical exchange. At the synapse, most antigen-engaged receptor microclusters move inward toward the central supramolecular activation cluster (cSMAC) via retrograde F-actin flow, eventually clearing from the cell surface. This retrograde movement and receptor downregulation maintain antigen receptor homeostasis, critical for adaptive immunity, though its regulation remains unclear. Using live T cells, we identify a significant pool of antigen-engaged microclusters moving anterogradely toward the cell periphery, rather than the cSMAC. This movement is driven by actin waves propagating outward and coupling to microclusters through the Wiskott-Aldrich Syndrome Protein. These findings reveal a previously unrecognized mode of actin dynamics-anterograde actin waves-that co-exist with retrograde flow and direct microclusters away from the downregulation zone. This dual actin behavior underscores the complex cytoskeletal mechanisms T cells employ to regulate receptor distribution and maintain signaling homeostasis during immune activation.

淋巴细胞的免疫反应始于抗原呈递细胞对抗原的识别,导致免疫突触的形成,这是生化和生物物理交换的专门界面。在突触中,大多数抗原受体微团通过f -肌动蛋白逆行流动向中央超分子激活团(cSMAC)内移动,最终从细胞表面清除。这种逆行运动和受体下调维持抗原受体稳态,对适应性免疫至关重要,尽管其调控尚不清楚。使用活的T细胞,我们发现了一个重要的抗原接合微团向细胞周围顺行移动,而不是向cmac移动。这种运动是由肌动蛋白波向外传播并通过Wiskott-Aldrich综合征蛋白耦合到微团驱动的。这些发现揭示了一种以前未被认识的肌动蛋白动力学模式-顺行肌动蛋白波-与逆行血流共存,并直接微团远离下调区。这种双肌动蛋白行为强调了T细胞在免疫激活过程中调节受体分布和维持信号稳态的复杂细胞骨架机制。
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引用次数: 0
Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants. 接近标记蛋白质组学揭示了重塑的相互作用组和致病性SHP2变异的定位改变。
IF 6.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-22 DOI: 10.1038/s44319-025-00674-4
Anne E van Vlimmeren, Lauren C Tang, Ziyuan Jiang, Abhishek Iyer, Rashmi Voleti, Konstantin Krismer, Jellert T Gaublomme, Marko Jovanovic, Neel H Shah

Missense mutations in PTPN11, which encodes the protein tyrosine phosphatase SHP2, are common in several developmental disorders and cancers. While many mutations disrupt auto-inhibition and hyperactivate SHP2, several do not enhance catalytic activity. Both activating and non-activating mutations could potentially drive pathogenic signaling by altering SHP2 interactions or localization. We employed proximity-labeling proteomics to map the interaction networks of wild-type SHP2, ten clinically relevant mutants, and SHP2 bound to an inhibitor that stabilizes its auto-inhibited state. Our analyses reveal mutation- and inhibitor-dependent alterations in the SHP2 interactome, with several mutations also changing localization. Some mutants show increased mitochondrial localization and impact mitochondrial function. This study provides a resource for exploring SHP2 signaling and offers new insights into the molecular basis of SHP2-driven diseases. Furthermore, this work highlights the capacity for proximity-labeling proteomics to detect missense-mutation-dependent changes in protein interactions and localization.

编码蛋白酪氨酸磷酸酶SHP2的PTPN11的错义突变在几种发育障碍和癌症中很常见。虽然许多突变破坏了自身抑制并过度激活了SHP2,但一些突变并不增强催化活性。激活和非激活突变都可能通过改变SHP2相互作用或定位来潜在地驱动致病性信号传导。我们使用接近标记蛋白质组学来绘制野生型SHP2、10个临床相关突变体以及SHP2与一种稳定其自身抑制状态的抑制剂结合的相互作用网络。我们的分析揭示了SHP2相互作用组的突变和抑制剂依赖性改变,其中一些突变也改变了定位。一些突变体表现出线粒体定位增加并影响线粒体功能。该研究为探索SHP2信号通路提供了资源,并为SHP2驱动疾病的分子基础提供了新的见解。此外,这项工作强调了接近标记蛋白质组学检测蛋白质相互作用和定位中的错义突变依赖变化的能力。
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引用次数: 0
Does solo publication still make sense? : Single-authored publications have been essential to scientific progress but are now facing extinction. 单独出版还有意义吗?单一作者的出版物对科学进步至关重要,但现在正面临灭绝。
IF 6.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-16 DOI: 10.1038/s44319-025-00677-1
Valentí Rull
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引用次数: 0
Apelin signaling acts as a molecular switch between endothelial and hematopoietic stem cell fates. Apelin信号作为内皮细胞和造血干细胞命运之间的分子开关。
IF 6.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-16 DOI: 10.1038/s44319-025-00656-6
Jean Eberlein, Nadja Groos, Navina Shrestha Duwal, Wade W Sugden, Trista E North, Christian S M Helker

Hematopoietic stem and progenitor cells (HSPCs) emerge from arterial endothelial cells (ECs) through a process termed endothelial-to-hematopoietic-transition (EHT), a process induced by paracrine signals and driven by a transcriptional cascade. Despite inductive signals being broadly received by ECs in the dorsal aorta (DA), only a subset of ECs undergoes EHT, while others maintain their vascular identity. The molecular mechanisms that determine this selective fate decision remain poorly understood. Here, we discover Apelin signaling as a critical regulator of cell fates in the DA, acting as a molecular switch to balance vascular and hematopoietic identities. We show that Apelin receptor (Aplnr)-expressing ECs retain their arterial identity, while Aplnr non-expressing ECs are primed to become hemogenic endothelial cells (HECs) and transition into HSPCs. Loss of Apelin signaling leads to excessive EC-to-HEC conversion and increased HSPC numbers. Conversely, forced Aplnr expression abolishes HSPC formation by maintaining EC identity. These findings reveal that Apelin signaling regulates HSPC formation by preserving endothelial identity. In summary, our findings establish Apelin signaling as a critical regulator for balancing endothelial and hematopoietic fates.

造血干细胞和祖细胞(HSPCs)由动脉内皮细胞(ECs)通过一个称为内皮到造血转化(EHT)的过程产生,这一过程由旁分泌信号诱导并由转录级联驱动。尽管背主动脉(DA)的ECs广泛接收感应信号,但只有一部分ECs经历EHT,而其他ECs保持其血管身份。决定这种选择性命运决定的分子机制仍然知之甚少。在这里,我们发现Apelin信号是DA中细胞命运的关键调节因子,作为平衡血管和造血身份的分子开关。我们发现,表达Apelin受体(Aplnr)的内皮细胞保留了其动脉特性,而不表达applnr的内皮细胞则被诱导成为造血内皮细胞(hec)并转变为HSPCs。Apelin信号的丢失导致ec到hec的过度转化和HSPC数量的增加。相反,强制表达Aplnr通过保持EC的同一性来消除HSPC的形成。这些发现表明,Apelin信号通过保持内皮细胞身份来调节HSPC的形成。总之,我们的研究结果确立了Apelin信号作为平衡内皮和造血命运的关键调节因子。
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引用次数: 0
Conserved lipid metabolic reprogramming confers hypoxic and aging resilience. 保守的脂质代谢重编程赋予缺氧和衰老恢复能力。
IF 6.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-11 DOI: 10.1038/s44319-025-00664-6
Wei I Jiang, Goncalo Dias do Vale, Quentinn Pearce, Kaitlyn Kong, Wenbin Zhou, Jeffrey G McDonald, James E Cox, Neel S Singhal, Dengke K Ma

The Arctic ground squirrel (AGS, Urocitellus parryii), an extreme hibernator, exhibits remarkable resilience to stressors like hypoxia and hypothermia, making it an ideal model for studying cellular metabolic adaptation. The underlying mechanisms of AGS resilience are largely unknown. Here, we use lipidomic and metabolomic profiling to discover specific downregulation of triglyceride lipids and upregulation of the lipid biosynthetic precursor malonic acid in AGS neural stem cells (NSC) versus murine NSCs. Inhibiting lipid biosynthesis recapitulates hypoxic resilience of squirrel NSCs. Extending this model, we find that acute exposure to hypoxia downregulates key lipid biosynthetic enzymes in C. elegans, while inhibiting lipid biosynthesis reduces mitochondrial fission and facilitates hypoxic survival. Moreover, inhibiting lipid biosynthesis protects against APOE4-induced pathologies and aging trajectories in C. elegans. These findings suggest triglyceride downregulation as a conserved metabolic resilience mechanism, offering insights into protective strategies for neural tissues under hypoxic or ischemic conditions, APOE4-induced pathologies and aging.

北极地松鼠(AGS, Urocitellus parryii)是一种极端冬眠动物,对缺氧和低温等压力源表现出非凡的恢复能力,使其成为研究细胞代谢适应的理想模型。AGS弹性的潜在机制在很大程度上是未知的。在这里,我们使用脂质组学和代谢组学分析来发现AGS神经干细胞(NSC)与小鼠NSCs中甘油三酯脂质的特异性下调和脂质生物合成前体丙二酸的特异性上调。抑制脂质生物合成再现了松鼠NSCs的缺氧恢复能力。扩展这一模型,我们发现急性缺氧会下调秀丽隐杆线虫关键的脂质生物合成酶,而抑制脂质生物合成会减少线粒体裂变,促进缺氧生存。此外,抑制脂质生物合成可以防止apoe4诱导的秀丽隐杆线虫的病理和衰老轨迹。这些发现表明甘油三酯下调是一种保守的代谢恢复机制,为缺氧或缺血条件下神经组织、apoe4诱导的病理和衰老的保护策略提供了见解。
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引用次数: 0
Structure-guided screening identifies Tucatinib as dual inhibitor for MCT1/2. 结构引导筛选确定图卡替尼为MCT1/2的双重抑制剂。
IF 6.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-11 DOI: 10.1038/s44319-025-00661-9
Binghong Xu, Xiaoyu Zhou, Yuanyue Shan, Sai Shi, Jiachen Li, Qinqin Liang, Ziyu Wang, Mingfeng Zhang, Yaxin Wang, Duanqing Pei, Sheng Ye

Cell surface glycoproteins Basigin or embigin form heterodimers with monocarboxylate transporters (MCTs), enhancing their membrane trafficking and modulating their transport functions. Cancer cells often reprogram their metabolism and depend on proton-coupled lactate transport mediated by MCTs to sustain their glycolytic state and to maintain intracellular pH. A deeper understanding of MCTs regulation may open avenues for the development of novel inhibitors, potentially applicable in clinical settings. Here, we determine the cryo-EM structures of the human MCT2-embigin complex in both apo and AR-C155858-bound states and observe that embigin engages in extensive interactions with MCT2, facilitating its localization to the plasma membrane and substrate transport. Given the high structural conservation among MCTs, we conduct virtual screening based on MCT1/2 structures and identify Tucatinib as an effective inhibitor of pyruvate transport mediated by both MCT1 and MCT2. We show that Tucatinib potently inhibits the proliferation and migration of cervical tumor cells in vitro and tumor growth in a mouse xenograft model, while exhibiting excellent biological safety. These findings offer molecular insights into the structural and functional mechanism of MCT2 and identify Tucatinib as novel dual inhibitor of both transporters.

细胞表面糖蛋白Basigin或embigin与单羧酸转运体(mct)形成异源二聚体,增强其膜运输并调节其运输功能。癌细胞经常重编程其代谢,并依赖于mct介导的质子偶联乳酸转运来维持其糖酵解状态和维持细胞内ph。对mct调控的更深入了解可能为开发新型抑制剂开辟道路,可能适用于临床环境。在这里,我们确定了人MCT2-embigin复合物在载脂蛋白和ar - c155858结合状态下的低温电镜结构,并观察到embigin与MCT2广泛相互作用,促进其定位到质膜和底物运输。鉴于mct之间的高度结构保守性,我们基于MCT1/2结构进行了虚拟筛选,并确定图卡替尼是MCT1和MCT2介导的丙酮酸转运的有效抑制剂。我们发现图卡替尼在体外有效抑制宫颈肿瘤细胞的增殖和迁移以及小鼠异种移植模型中的肿瘤生长,同时具有良好的生物安全性。这些发现为MCT2的结构和功能机制提供了分子见解,并确定图卡替尼是两种转运蛋白的新型双重抑制剂。
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引用次数: 0
JHY enables the transition from switchable to fixed ciliary waveforms in metazoan evolution. 在后生动物的进化中,JHY使纤毛波形从可切换到固定的转变成为可能。
IF 6.2 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-12-10 DOI: 10.1038/s44319-025-00671-7
Qingxia Chen, Shuxiang Ma, Hao Liu, Juyuan Liu, Qingchao Li, Qian Lyu, Hanxiao Yin, Junkui Zhao, Shanshan Nai, Ting Song, Hongbin Liu, Jun Zhou, Xiumin Yan, Xueliang Zhu, Huijie Zhao

Motile cilia are evolutionarily conserved protrusions critical for motility and homeostasis. Their rhythmic movements require the central pair microtubules (CP-MTs). While the initial CP-MT assembly in mammals is mediated by WDR47 and microtubule minus-end-binding CAMSAPs, the mechanism by which CP-MTs are stabilized remains unclear. Here, we demonstrate that WDR47 coordinates JHY and SPEF1 to maintain the stability of mammalian CP-MTs. By generating a proximity interactome of WDR47, we identify a group of CP-MT-associated proteins, including SPEF1 and JHY. WDR47 enriches JHY and SPEF1 to the central lumen and tip of nascent cilia, whereas SPEF1 recruits WDR47 and JHY to CP-MTs through direct interactions. Jhy deficiency in mice preferentially disrupts distal CP-MTs, resulting in rotatory ciliary beats. Phylogenetic analyses suggest conserved functions of WDR47 and SPEF1 in protozoa and metazoans, as well as a role for JHY in animals with radial or bilateral body symmetry. We propose that JHY emerges to further reinforce CP-MTs, enabling the transition from switchable to fixed ciliary waveforms in metazoan evolution.

运动纤毛是进化上保守的突起,对运动和体内平衡至关重要。它们有节奏的运动需要中央对微管(cp - mt)。虽然哺乳动物体内最初的CP-MT组装是由WDR47和微管负端结合CAMSAPs介导的,但CP-MT稳定的机制尚不清楚。在这里,我们证明WDR47协调JHY和SPEF1来维持哺乳动物cp - mt的稳定性。通过生成WDR47的近距离相互作用组,我们鉴定了一组cp - mt相关蛋白,包括SPEF1和JHY。WDR47将JHY和SPEF1富集到新生纤毛的中央管腔和尖端,而SPEF1则通过直接相互作用将WDR47和JHY招募到cp - mt。Jhy缺乏小鼠优先破坏远端cp - mt,导致旋转纤毛搏动。系统发育分析表明,WDR47和SPEF1在原生动物和后生动物中具有保守功能,而JHY在具有径向或双侧身体对称的动物中也有作用。我们认为JHY的出现进一步强化了cp - mt,使后生动物进化中从可切换的纤毛波形转变为固定的纤毛波形。
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引用次数: 0
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