Proceedings of the National Academy of Sciences of the United States of America最新文献_第7页

Integrative mapping reveals molecular features underlying the mechanism of nucleocytoplasmic transport. 综合定位揭示了核胞质转运机制的分子特征。

IF 9.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-21 Epub Date: 2025-10-16 DOI: 10.1073/pnas.2507559122

Barak Raveh, Roi Eliasian, Shaked Rashkovits, Daniel Russel, Ryo Hayama, Samuel Sparks, Digvijay Singh, Roderick Y H Lim, Elizabeth Villa, Michael P Rout, David Cowburn, Andrej Sali

{"title":"Integrative mapping reveals molecular features underlying the mechanism of nucleocytoplasmic transport.","authors":"Barak Raveh, Roi Eliasian, Shaked Rashkovits, Daniel Russel, Ryo Hayama, Samuel Sparks, Digvijay Singh, Roderick Y H Lim, Elizabeth Villa, Michael P Rout, David Cowburn, Andrej Sali","doi":"10.1073/pnas.2507559122","DOIUrl":"10.1073/pnas.2507559122","url":null,"abstract":"<p><p>Nuclear pore complexes (NPCs) enable rapid, selective, and robust nucleocytoplasmic transport. To explain how transport emerges from the system components and their interactions, we used experimental data and theoretical information to construct an integrative Brownian dynamics model of transport through an NPC, coupled to a kinetic model of transport in the cell. The model recapitulates key aspects of transport for a wide range of molecular cargoes, including preribosomes and viral capsids. Our model quantifies how flexible phenylalanine-glycine (FG) repeat proteins create an entropic barrier to passive diffusion and how this barrier is selectively lowered in facilitated diffusion by the many transient interactions of nuclear transport receptors with the FG repeats. Selective transport is enhanced by \"fuzzy\" multivalent interactions, redundant FG repeat mass, coupling to the energy-dependent RanGTP concentration gradient, and exponential dependence of transport kinetics on the transport barrier. Our model will facilitate rational modulation of the NPC and its artificial mimics.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"122 42","pages":"e2507559122"},"PeriodicalIF":9.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neuronal plasticity at puberty in mouse hypothalamic Kiss1 neurons that control fertility. 小鼠下丘脑Kiss1神经元在青春期控制生育的神经元可塑性。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-21 DOI: 10.1073/pnas.2512855122

Yuanxin Zhang,Leonie M Pakulat,Szabolcs Takács,Lauren Campbell,Elisa Galliano,Erik Hrabovszky,William H Colledge,Susan Jones

{"title":"Neuronal plasticity at puberty in mouse hypothalamic Kiss1 neurons that control fertility.","authors":"Yuanxin Zhang,Leonie M Pakulat,Szabolcs Takács,Lauren Campbell,Elisa Galliano,Erik Hrabovszky,William H Colledge,Susan Jones","doi":"10.1073/pnas.2512855122","DOIUrl":"https://doi.org/10.1073/pnas.2512855122","url":null,"abstract":"Puberty is a critical transition period to achieve reproductive capacity in all mammalian species. At puberty, hypothalamic Kiss1 neurons release kisspeptin, stimulating gonadotropin-releasing hormone (GnRH) release and activating the hypothalamic-pituitary-gonadal (HPG) axis. Here, we show that Kiss1 neurons in the arcuate nucleus of the hypothalamus (Kiss1ARC) of female mice undergo profound intrinsic plasticity at puberty. Kiss1ARC neurons in brain slices from 3-wk-old mice, when depolarized, typically fire a short high-frequency burst of action potentials before falling silent. This would make them unsuitable for the sustained activity that is required to activate pulsatile GnRH secretion and the HPG axis. At 4 wk of age and after puberty, Kiss1ARC neurons can fire a sustained train of action potentials. There is a concomitant hyperpolarization in action potential threshold and postspike minimum voltage and larger medium after-hyperpolarizations (mAHP) and hyperpolarization-induced voltage sags. Transcriptomic profiling showed significant changes in ion channel expression after puberty. Using quantitative PCR, we confirmed changes in genes encoding voltage-gated sodium, calcium, potassium, and cation channels. Blocking hyperpolarization-induced cation channels caused Kiss1ARC neurons from postpuberty mice to fire less sustained trains of action potentials. Recordings from Kiss1ARC neurons in mice after ovariectomy and 17β-estradiol replacement revealed a critical window of estrogen-dependent plasticity between 3 and 6 wk, which is essential for the maturation of Kiss1ARC neurons and the development of their adult electrophysiological activity. This represents an example of sex steroid-dependent plasticity in the mammalian brain at puberty.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"1 1","pages":"e2512855122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Therapeutic IgG- and IgM-specific proteases disarm the acetylcholine receptor autoantibodies that drive myasthenia gravis pathology. 治疗性IgG和igm特异性蛋白酶解除驱动重症肌无力病理的乙酰胆碱受体自身抗体。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-21 DOI: 10.1073/pnas.2505984122

Alexandra C Bayer,Liliana M Sanmarco,Alex Pellerin,Gianvito Masi,Agustin Plasencia,Jordan M Anderson,Richard J Nowak,Valentina Damato,Luca Massacesi,Minh C Pham,Fatemeh Khani-Habibabadi,Heather Vital,Nathan Higginson-Scott,Kevin L Otipoby,Yi Xing,Ivan D Mascanfroni,Kevin C O'Connor

{"title":"Therapeutic IgG- and IgM-specific proteases disarm the acetylcholine receptor autoantibodies that drive myasthenia gravis pathology.","authors":"Alexandra C Bayer,Liliana M Sanmarco,Alex Pellerin,Gianvito Masi,Agustin Plasencia,Jordan M Anderson,Richard J Nowak,Valentina Damato,Luca Massacesi,Minh C Pham,Fatemeh Khani-Habibabadi,Heather Vital,Nathan Higginson-Scott,Kevin L Otipoby,Yi Xing,Ivan D Mascanfroni,Kevin C O'Connor","doi":"10.1073/pnas.2505984122","DOIUrl":"https://doi.org/10.1073/pnas.2505984122","url":null,"abstract":"Myasthenia gravis (MG) is an autoimmune disorder caused mainly by autoantibodies against the acetylcholine receptor (AChR), leading to muscle weakness. While treatments targeting AChR autoantibodies benefit many, some patients remain refractory, highlighting the need for personalized therapies. This study evaluates the therapeutic potential of S-1117, a pan-IgG-specific protease, in AChR autoantibody-mediated pathology. Using live cell-based assays, we examined AChR-specific monoclonal IgG autoantibodies (mAbs) and patient-derived serum samples for their effects on receptor binding, blockade, internalization, and complement activation, before and after treatment with S-1117. S-1117 effectively removed the crystallizable fragment (Fc)γ from both mAbs and serum IgG, impairing Fcγ-mediated complement activation in both soluble and antigen-bound forms. In cases with partial complement reduction, AChR-specific IgM contributed to complement deposition. AChR-IgM acted in concert with IgG in some patients to enhance complement deposition, while acting as main complement driver in others. An IgM-specific protease completely suppressed the pathogenic effects of AChR-IgM in two independent patient cohorts. These findings highlight the therapeutic potential of S-1117 in neutralizing AChR-IgG Fcγ-mediated effector functions and reveal an MG subset driven by IgM pathology. Our study shows that targeting both IgG- and IgM-mediated mechanisms with therapeutic proteases provides an approach to MG treatment and establishes a framework for patient stratification based on disease mechanisms, advancing precision medicine in MG.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"2 1","pages":"e2505984122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Robustness is better assessed with a few thoughtful models than with billions of regressions. 用几个深思熟虑的模型来评估稳健性，要比用数十亿次回归来评估稳健性更好。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-20 DOI: 10.1073/pnas.2521917122

Katrin Auspurg

引用次数: 0

Reply to Bosten and Franklin: Children's color qualia structure is similar to adults'. 回复Bosten and Franklin：儿童的色质结构与成人相似。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-20 DOI: 10.1073/pnas.2525916122

Yusuke Moriguchi,Ryoichi Watanabe,Chifumi Sakata,Ariel Zeleznikow-Johnston,Jue Wang,Noburo Saji,Naotsugu Tsuchiya

引用次数: 0

Important design rules discovered for supramolecular multivalent ligands interacting with dynamic receptors. 发现了与动态受体相互作用的超分子多价配体的重要设计规则。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-20 DOI: 10.1073/pnas.2522205122

Heather D Maynard

引用次数: 0

The moving mantle beneath Hawaii: A new look at an old bend. 夏威夷地下移动的地幔：一个旧弯的新面貌。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-20 DOI: 10.1073/pnas.2524801122

R Dietmar Müller

引用次数: 0

Reply to Auspurg: On the limits of "justified" model spaces. 回复Auspurg：关于“合理的”模型空间的限制。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-20 DOI: 10.1073/pnas.2523374122

Michael Ganslmeier,Tim Vlandas

引用次数: 0

A yellow warbler is for the climate as a canary is for the coal mine. 黄莺之于气候，正如金丝雀之于煤矿。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-20 DOI: 10.1073/pnas.2524799122

Peter R Grant

引用次数: 0

Museum genomics suggests long-term population decline in a putatively extinct bumble bee. 博物馆基因组学表明，一种假定已灭绝的大黄蜂的种群数量长期下降。

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-20 DOI: 10.1073/pnas.2509749122

Rena M Schweizer,Jared A Grummer,Kerrigan B Tobin,Renee Corpuz,Scott M Geib,Diana Cox-Foster,Lynn S Kimsey,Jonathan B Uhuad Koch,Michael G Branstetter

{"title":"Museum genomics suggests long-term population decline in a putatively extinct bumble bee.","authors":"Rena M Schweizer,Jared A Grummer,Kerrigan B Tobin,Renee Corpuz,Scott M Geib,Diana Cox-Foster,Lynn S Kimsey,Jonathan B Uhuad Koch,Michael G Branstetter","doi":"10.1073/pnas.2509749122","DOIUrl":"https://doi.org/10.1073/pnas.2509749122","url":null,"abstract":"Pollinator declines globally threaten ecosystem stability and agricultural productivity. Reconstructing pollinator historic demographies provides an evolutionary perspective to understand contemporary population declines. The Franklin bumble bee (Bombus franklini), once endemic to Oregon and California and last observed alive in 2006, is emblematic of this phenomenon. We collected whole-genome sequence data from museum specimens spanning four decades to elucidate the genetic and demographic history of this potentially extinct species. Heterozygosity estimates of 25 individuals were remarkably low, and runs of homozygosity (ROH) patterns identified short segments suggestive of historical inbreeding, with some individuals having almost entire chromosomes in ROH. Demographic reconstructions revealed a marked decline in effective population size beginning in the late Pleistocene, with further declines in the last 400 y, which may have been influenced by fire and drought stressors. We found little to no genomic evidence implicating pathogens in the species' decline and used coalescent simulations to show that we would be able to detect recently reduced heterozygosity only when colony-level survival rates are 15 to 30%. We conclude that a combination of historically low effective population size and genetic diversity along with environmental stochasticity heightened this species' extinction vulnerability prior to recent anthropogenic stressors. This study demonstrates the utility of museum collections for clarifying genetic and demographic dynamics of rare species and suggests that B. franklini may have already been on a trajectory of decline prior to human impacts.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"68 1","pages":"e2509749122"},"PeriodicalIF":11.1,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0