Proceedings of the National Academy of Sciences of the United States of America最新文献_第3页

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 : 2026-05-12 Epub Date: 2026-05-04 DOI: 10.1073/pnas.2610120123

Bevil R Conway, Spencer R Loggia

引用次数: 0

Structural promiscuity in the human circulatory IgA1 clonal repertoire. 人循环IgA1克隆库的结构混杂性。

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 : 2026-05-12 Epub Date: 2026-05-06 DOI: 10.1073/pnas.2533440123

Amber D Rolland, Sofia Kalaidopoulou Nteak, Gestur Vidarsson, Albert Bondt, Albert J R Heck

{"title":"Structural promiscuity in the human circulatory IgA1 clonal repertoire.","authors":"Amber D Rolland, Sofia Kalaidopoulou Nteak, Gestur Vidarsson, Albert Bondt, Albert J R Heck","doi":"10.1073/pnas.2533440123","DOIUrl":"https://doi.org/10.1073/pnas.2533440123","url":null,"abstract":"Immunoglobulin A (IgA) is the most abundant antibody in humans, with high concentrations in both mucosae/secretions and circulation. While mucosal IgA has been studied extensively, characterization of human IgA in serum and its distinctive functions lags behind. Circulatory IgA is regularly assumed to be monomeric, despite some reports describing a minor population of J-chain-coupled dimers. Here, we first charted the compositional landscape of human serum IgA in individual healthy donors. In addition to the expected predominating monomers, we consistently observed J-coupled dimers, even representing ~30% of one donor's total serum IgA. To determine whether these structurally distinct populations were also clonally distinct, we employed mass spectrometry-based IgA1 clonal profiling in sera of two donors. Our data revealed the majority of IgA1 clones are present solely as monomers, with a smaller number exclusively dimeric. Strikingly, a third population of IgA1 clones is present in circulation as both monomers and J-coupled dimers. In fact, these shared, structurally promiscuous IgA1 clones dominated both individuals' serum IgA1 clonal repertoires. Our findings suggest every unique IgA1 clone could potentially be produced as a variable mixture of monomers and J-coupled dimers, but what exactly determines this ratio requires further investigation. This finding is important, as monomers and J-coupled dimers have distinct characteristics in antigen binding, receptor activation, and clearance from circulation, with several reports highlighting, for instance, the enhanced neutralization capacity of dimeric IgA. As we show here, the human immune system is not merely capable of producing both forms but apparently prefers doing so in parallel.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 19","pages":"e2533440123"},"PeriodicalIF":9.1,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842025","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

Traveling-wave transcranial alternating current stimulation (twtACS) causally links neural timing to cognitive function. 行波经颅交流电刺激（twtACS）将神经时序与认知功能联系起来。

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 : 2026-05-12 Epub Date: 2026-05-05 DOI: 10.1073/pnas.2527296123

Sangjun Lee, Jimin Park, Ivan Alekseichuk, Taylor A Berger, Ana M G Manea, Harry Tran, Gabriela Delgado Salazar, Seth D König, Alexander B Herman, David P Darrow, Jan Zimmermann, Alexander Opitz

{"title":"Traveling-wave transcranial alternating current stimulation (twtACS) causally links neural timing to cognitive function.","authors":"Sangjun Lee, Jimin Park, Ivan Alekseichuk, Taylor A Berger, Ana M G Manea, Harry Tran, Gabriela Delgado Salazar, Seth D König, Alexander B Herman, David P Darrow, Jan Zimmermann, Alexander Opitz","doi":"10.1073/pnas.2527296123","DOIUrl":"https://doi.org/10.1073/pnas.2527296123","url":null,"abstract":"Cortical traveling waves (TWs) are brain oscillation patterns that support the transfer of neural information across distinct brain regions, with their direction shaping cognitive function. However, direct evidence for their causal influence on brain dynamics and behavior remains lacking. Here, we establish such a causal link by externally applying TW-like electric field patterns. To achieve this, we develop a noninvasive brain stimulation protocol, traveling-wave transcranial alternating current stimulation (twtACS). twtACS can generate a precise directional electric field that propagates across the cortical surface, which we validate using human intracranial recordings. In monkey recordings, we show that neural spiking was directionally modulated, shifting systematically across space in line with the direction of twtACS. In humans, twtACS led to direction-dependent improvements in cognitive performance. Together, these findings demonstrate that externally imposed TWs can causally shape neural activity and cognition, highlighting the potential of twtACS as a neuromodulation technique for cognitive enhancement.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 19","pages":"e2527296123"},"PeriodicalIF":9.1,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842039","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

Decoding the structure of GPR151 via NELiS. 通过NELiS解码GPR151的结构。

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 : 2026-05-12 Epub Date: 2026-05-05 DOI: 10.1073/pnas.2534234123

Yumeng Wang, Luyu Fan, Qianqian Song, Yaning Li, Jiayu Jin, Qiaoyu Zhao, Weijie Gu, Xiangyi Shi, Dianfan Li, Yao Cong, Sheng Wang

{"title":"Decoding the structure of GPR151 via NELiS.","authors":"Yumeng Wang, Luyu Fan, Qianqian Song, Yaning Li, Jiayu Jin, Qiaoyu Zhao, Weijie Gu, Xiangyi Shi, Dianfan Li, Yao Cong, Sheng Wang","doi":"10.1073/pnas.2534234123","DOIUrl":"https://doi.org/10.1073/pnas.2534234123","url":null,"abstract":"Structure determination of orphan G protein-coupled receptors (GPCRs) is hindered by lack of known ligands and their inherent instability during purification. Conventional thermostability screening requires ligands or purified protein, limiting its utility for orphan GPCRs. Here, we present the Nb6-Enabled Ligand-Free Stabilization Platform (NELiS)-a ligand- and purification-independent method for identifying stabilizing mutations. Applied to GPR151, an orphan GPCR enriched in habenula and implicated in neuropsychiatric disorders, NELiS identified four mutations that significantly improved thermostability and expression, allowing receptor purification. Using the stabilized and purified receptor, we further found a high-affinity, GPR151-specific nanobody that facilitated structural determination. Structural analysis revealed unconventional activation-resistant features across canonical motifs and an autoinhibitory N-terminal region occupying the orthosteric pocket. Functional studies confirmed a unique activation mechanism and the critical role of the N terminus in receptor maturation and trafficking. These results establish NELiS as a generalizable tool for structural and functional investigation of orphan GPCRs.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 19","pages":"e2534234123"},"PeriodicalIF":9.1,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842068","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

Improving the job market in economics (and beyond…). 改善经济领域的就业市场（以及其他领域）。

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 : 2026-05-12 Epub Date: 2026-05-04 DOI: 10.1073/pnas.2609971123

Peter L Rousseau

引用次数: 0

Chiral inversion mutagenesis identifies geometrically constrained residues within self-associating low-complexity domains. 手性反转诱变识别几何约束残基在自关联低复杂性域。

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 : 2026-05-12 Epub Date: 2026-05-06 DOI: 10.1073/pnas.2535888123

Ryan L Beckner, Lily Kim, Christien Carter, Abby Walterscheid, Glen Liszczak

{"title":"Chiral inversion mutagenesis identifies geometrically constrained residues within self-associating low-complexity domains.","authors":"Ryan L Beckner, Lily Kim, Christien Carter, Abby Walterscheid, Glen Liszczak","doi":"10.1073/pnas.2535888123","DOIUrl":"10.1073/pnas.2535888123","url":null,"abstract":"Many protein low-complexity domains (LCDs) self-associate to enable cellular function, yet fundamental questions remain regarding how polypeptide chemical and structural features beyond side chain identity contribute to LCD-LCD interactions. For instance, the folds adopted by globular proteins emerge from constraints enforced by homochirality of genetically encoded polypeptides. However, it remains unclear to what extent similar geometric constraints apply to LCD self-association. Herein, we use protein total and semi-synthesis to probe the contribution of Cα stereochemistry to LCD self-association with synthetic Chiral Inversion Mutagenesis (ChIM). By introducing targeted L-to-D amino acid inversions, ChIM identifies Cα stereocenters under geometric constraint without modification of side-chain functionalities. We apply ChIM to the LCDs of inner nuclear lamina protein Emerin and neurofilament light chain and find that chiral inversion produces strongly position-dependent effects upon LCD self-association. Our study describes essential structural features that enable LCD self-association and chemical strategies to interrogate LCD biochemistry.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 19","pages":"e2535888123"},"PeriodicalIF":9.1,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841989","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

Evaluating the statistical realism of LLM-generated social science data. 评估法学硕士生成的社会科学数据的统计现实性。

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 : 2026-05-12 Epub Date: 2026-05-08 DOI: 10.1073/pnas.2538145123

Yueqi Xie, Lemeng Liang, Shuzhen Li, Yifu Lu, Zhiwen Xiao, Mengdi Shi, Junming Huang, Mengdi Wang, Yu Xie

{"title":"Evaluating the statistical realism of LLM-generated social science data.","authors":"Yueqi Xie, Lemeng Liang, Shuzhen Li, Yifu Lu, Zhiwen Xiao, Mengdi Shi, Junming Huang, Mengdi Wang, Yu Xie","doi":"10.1073/pnas.2538145123","DOIUrl":"https://doi.org/10.1073/pnas.2538145123","url":null,"abstract":"Large language models (LLMs) hold great promise for generating social science data, potentially expanding the methodological toolkit of quantitative social research. Prior studies have primarily focused on individual-level predictability or behavioral plausibility of LLM-generated data. We propose a framework for assessing the validity of LLM-generated data by returning to the foundational principles of survey research in the social sciences. Just as surveys based on representative samples yield statistics that approximate the corresponding statistical moments of the target population, assessment should center on the ability of LLM-generated data to reproduce real-world, population-level statistical patterns. We introduce SSDataBench, a systematic benchmark designed to evaluate population-level statistical realism in LLM-generated social science data. The benchmark assesses five types of statistical patterns central to social research: univariate distributions, bivariate associations, multivariate outcome predictions, life event sequence distributions, and associations between life event sequences and covariates. We illustrate SSDataBench using four longitudinal datasets and three cross-sectional datasets spanning six major social domains: demographics, socioeconomic status, marriage, health, abilities, and attitudes. Our study reveals representational limitations in current LLMs under sparse conditioning settings, manifested in a pronounced tendency to compress real-world heterogeneity into simplified typological structures. Finally, we outline a roadmap toward improved statistical realism and report preliminary results indicating that domain-specific training can enhance population-level realism.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 19","pages":"e2538145123"},"PeriodicalIF":9.1,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857013","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

Evolution of species' range and niche in changing environments. 在变化的环境中物种范围和生态位的进化。

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 : 2026-05-12 Epub Date: 2026-05-08 DOI: 10.1073/pnas.2604510123

Jitka Polechová

{"title":"Evolution of species' range and niche in changing environments.","authors":"Jitka Polechová","doi":"10.1073/pnas.2604510123","DOIUrl":"https://doi.org/10.1073/pnas.2604510123","url":null,"abstract":"What causes species' niche and range margins to shift is not only a fundamental theoretical question, but also directly affects how we assess the resilience of natural populations in current and future environments. Yet despite the urgent need for theory that can predict evolutionary and ecological responses in times of accelerated climate change, the assumptions of current eco-evolutionary theory remain restrictive, with predictions neglecting important interactions between ecological and evolutionary forces. In this study, I provide quantitative, testable predictions on limits to adaptation in changing environments, which arise from the feedback between selection, genetic drift, and population dynamics. This eco-evolutionary feedback creates a tipping point beyond which adaptation fails as genetic drift overwhelms selection, and species' ranges contract from the margins or fragment abruptly-even under gradual environmental change. This \"expansion threshold\" is determined by three parameters: two quantifying the effects of spatial and temporal variability on the fitness of the population and one capturing the impact of genetic drift: the reduction of local genetic diversity across generations in finite populations. Genetic drift is strong in populations with small \"neighborhood size.\" Increasing dispersal, such as via assisted migration, enlarges neighborhood size, counteracting the loss of genetic variation due to genetic drift. This increases adaptive potential and can facilitate evolutionary rescue in changing environments. Conversely, beyond the expansion threshold, local genetic variance becomes depleted, increasing extinction probability. The theory provides general predictions for species' range and niche dynamics beyond standard ecological niche models, highlighting the fundamental impact of eco-evolutionary interactions.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 19","pages":"e2604510123"},"PeriodicalIF":9.1,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857029","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

MCM8-9 helicase activity protects primordial germ cell development to prevent premature ovarian insufficiency. MCM8-9解旋酶活性保护原始生殖细胞发育，防止卵巢功能不全。

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 : 2026-05-12 Epub Date: 2026-05-05 DOI: 10.1073/pnas.2535910123

Xiaofei Jiao, Zhifang Li, Zhenghui Tang, Jun Xu, Lin-Yu Lu, Yidan Liu

{"title":"MCM8-9 helicase activity protects primordial germ cell development to prevent premature ovarian insufficiency.","authors":"Xiaofei Jiao, Zhifang Li, Zhenghui Tang, Jun Xu, Lin-Yu Lu, Yidan Liu","doi":"10.1073/pnas.2535910123","DOIUrl":"https://doi.org/10.1073/pnas.2535910123","url":null,"abstract":"MCM8 and MCM9 form a hexameric helicase critical for homologous recombination (HR). While their variants are strongly associated with premature ovarian insufficiency (POI), with many clustering within their AAA+ ATPase domains, the requirement for their helicase activity remains unknown. Here, we show that MCM8-9's helicase activity is essential for ovarian reserve preservation and POI prevention. Using a series of helicase-deficient mouse models, we demonstrate that this activity is dispensable for meiotic recombination but critically required for mitotic HR and primordial germ cell (PGC) development. The two distinct ATPase active sites of MCM8-9 exhibit marked functional asymmetry, a property regulated by residues within their Walker B motifs. Despite this asymmetry, both ATPase active sites are equally essential for MCM8-9's function in HR, PGC development, ovarian reserve preservation, and POI prevention. Our findings establish a direct mechanistic link between compromised MCM8-9 helicase activity and POI pathogenesis through its essential role in PGC development.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 19","pages":"e2535910123"},"PeriodicalIF":9.1,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841917","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

Pde4 mediates MHCII expression in oligodendroglia. Pde4介导MHCII在少突胶质细胞中的表达。

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 : 2026-05-12 Epub Date: 2026-05-05 DOI: 10.1073/pnas.2511231123

Miguel M Madeira, Zachary Hage, Dimitris Koliatsis, Alexandros G Kokkosis, Kimberly Nnah, Alexander J Rhee, Gilbert J Rahme, Katherine Kamvisios, Antonis E Koromilas, Barbara Rosati, David McKinnon, Stella E Tsirka

{"title":"Pde4 mediates MHCII expression in oligodendroglia.","authors":"Miguel M Madeira, Zachary Hage, Dimitris Koliatsis, Alexandros G Kokkosis, Kimberly Nnah, Alexander J Rhee, Gilbert J Rahme, Katherine Kamvisios, Antonis E Koromilas, Barbara Rosati, David McKinnon, Stella E Tsirka","doi":"10.1073/pnas.2511231123","DOIUrl":"https://doi.org/10.1073/pnas.2511231123","url":null,"abstract":"Chronic psychosocial stress is a major precipitant of Major Depressive Disorder (MDD), yet the glial mechanisms that translate sustained stress into maladaptive myelin and immune changes remain unclear. Using chronic social defeat stress and single-nucleus RNA sequencing of anterior medial PFC (mPFC) oligodendroglia, we identified a mature-oligodendrocyte cluster almost exclusively from stress-susceptible animals, marked by immune genes (MHCII) and upregulated Pde4b. Integration with a human MDD single-nucleus RNA sequencing dataset confirmed a conserved immune-like oligodendrocyte (ImOL) subset coexpressing Plp1 and Cd74 and enriched for Pde4b. Mechanistically, PDE4 inhibition with crisaborole elevated cAMP-PKA-CREB signaling, blocked IFNγ-induced MHCII expression, and engaged the eIF2α-ATF4/CHOP arm of the integrated stress response (ISR). In vivo modulation of the ISR with ISRIB or guanabenz bidirectionally controlled ImOL prevalence and stress-related behaviors. These findings position Pde4b-cAMP-ISR signaling as a regulator of oligodendroglial immune phenotypes and a promising target to modulate myelination and neuroinflammation in stress-related disorders.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"123 19","pages":"e2511231123"},"PeriodicalIF":9.1,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147841920","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