PNAS Nexus最新文献_第7页

CHCHD2 P14L, found in amyotrophic lateral sclerosis, exhibits cytoplasmic mislocalization and alters Ca2+ homeostasis 在肌萎缩性脊髓侧索硬化症中发现的 CHCHD2 P14L 具有细胞质定位错误的特点，会改变 Ca2+ 稳态

PNAS Nexus Pub Date : 2024-07-30 DOI: 10.1093/pnasnexus/pgae319

Aya Ikeda, Hongrui Meng, Daisuke Taniguchi, Muneyo Mio, Manabu Funayama, Kenya Nishioka, Mari Yoshida, Yuanzhe Li, Hiroyo Yoshino, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, Yohei Okubo, Takashi Sakurai, Taku Amo, Ikuko Aiba, Yufuko Saito, Yuko Saito, Shigeo Murayama, Naoki Atsuta, Ryoichi Nakamura, Genki Tohnai, Yuishin Izumi, Mitsuya Morita, Asako Tamura, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Toru Yamashita, Jun Sone, Ryuji Kaji, Gen Sobue, Yuzuru Imai, Nobutaka Hattori

{"title":"CHCHD2 P14L, found in amyotrophic lateral sclerosis, exhibits cytoplasmic mislocalization and alters Ca2+ homeostasis","authors":"Aya Ikeda, Hongrui Meng, Daisuke Taniguchi, Muneyo Mio, Manabu Funayama, Kenya Nishioka, Mari Yoshida, Yuanzhe Li, Hiroyo Yoshino, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, Yohei Okubo, Takashi Sakurai, Taku Amo, Ikuko Aiba, Yufuko Saito, Yuko Saito, Shigeo Murayama, Naoki Atsuta, Ryoichi Nakamura, Genki Tohnai, Yuishin Izumi, Mitsuya Morita, Asako Tamura, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Toru Yamashita, Jun Sone, Ryuji Kaji, Gen Sobue, Yuzuru Imai, Nobutaka Hattori","doi":"10.1093/pnasnexus/pgae319","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae319","url":null,"abstract":"CHCHD2 and CHCHD10, linked to Parkinson's disease and amyotrophic lateral sclerosis-frontotemporal dementia (ALS), respectively, are mitochondrial intermembrane proteins that form a heterodimer. This study aimed to investigate the impact of the CHCHD2 P14L variant, implicated in ALS, on mitochondrial function and its subsequent effects on cellular homeostasis. The missense variant of CHCHD2, P14L, found in a cohort of patients with ALS, mislocalized CHCHD2 to the cytoplasm, leaving CHCHD10 in the mitochondria. Drosophila lacking the CHCHD2 ortholog exhibited mitochondrial degeneration. In contrast, human CHCHD2 P14L, but not wild-type human CHCHD2, failed to suppress this degeneration, suggesting that P14L is a pathogenic variant. The mitochondrial Ca2+ buffering capacity was reduced in Drosophila neurons expressing human CHCHD2 P14L. The altered Ca2+-buffering phenotype was also observed in cultured human neuroblastoma SH-SY5Y cells expressing CHCHD2 P14L. In these cells, transient elevation of cytoplasmic Ca2+ facilitated the activation of calpain and caspase-3, accompanied by the processing and insolubilization of TDP-43. These observations suggest that CHCHD2 P14L causes abnormal Ca2+ dynamics and TDP-43 aggregation, reflecting the pathophysiology of ALS.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Singular effect of linkage on long-term genetic gain in Fisher's infinitesimal model 费雪无穷小模型中连锁对长期遗传增益的奇异效应

PNAS Nexus Pub Date : 2024-07-26 DOI: 10.1093/pnasnexus/pgae314

Elise Tourrette, Olivier C Martin

{"title":"Singular effect of linkage on long-term genetic gain in Fisher's infinitesimal model","authors":"Elise Tourrette, Olivier C Martin","doi":"10.1093/pnasnexus/pgae314","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae314","url":null,"abstract":"During the founding of the field of quantitative genetics, Fisher formulated in 1918 his “infinitesimal model” that provided a novel mathematical framework to describe the Mendelian transmission of quantitative traits. If the infinitely many genes in that model are assumed to segregate independently during reproduction, corresponding to having no linkage, directional selection asymptotically leads to a constant genetic gain at each generation. In reality, genes are subject to strong linkage because they lie on chromosomes and thus segregate in a correlated way. Various approximations have been used in the past to study that more realistic case of the infinitesimal model with the expectation that the asymptotic gain per generation is modestly decreased. To treat this system even in the strong linkage limit, we take the genes to lie on continuous chromosomes. Surprisingly, the consequences of genetic linkage are in fact rather singular, changing the nature of the long-term gain per generation: the asymptotic gain vanishes rather than being simply decreased. Nevertheless, the per-generation gain tends to zero sufficiently slowly for the total gain, accumulated over generations, to be unbounded.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Predictability of human mobility during the COVID-19 pandemic in the United States 美国 COVID-19 大流行期间人员流动的可预测性

PNAS Nexus Pub Date : 2024-07-26 DOI: 10.1093/pnasnexus/pgae308

Michal Hajlasz, Sen Pei

{"title":"Predictability of human mobility during the COVID-19 pandemic in the United States","authors":"Michal Hajlasz, Sen Pei","doi":"10.1093/pnasnexus/pgae308","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae308","url":null,"abstract":"Human mobility is fundamental to a range of applications including epidemic control, urban planning, and traffic engineering. While laws governing individual movement trajectories and population flows across locations have been extensively studied, the predictability of population-level mobility during the COVID-19 pandemic driven by specific activities such as work, shopping, and recreation remains elusive. Here we analyze mobility data for six place categories at the US county level from February 15th, 2020, to November 23rd, 2021 and measure how the predictability of these mobility metrics changed during the COVID-19 pandemic. We quantify the time-varying predictability in each place category using an information-theoretic metric, permutation entropy. We find disparate predictability patterns across place categories over the course of the pandemic, suggesting differential behavioral changes in human activities perturbed by disease outbreaks. Notably, predictability change in foot traffic to residential locations is mostly in the opposite direction to other mobility categories. Specifically, visits to residences had the highest predictability during stay-at-home orders in March 2020, while visits to other location types had low predictability during this period. This pattern flipped after the lifting of restrictions during summer 2020. We identify four key factors, including weather conditions, population size, COVID-19 case growth, and government policies, and estimate their nonlinear effects on mobility predictability. Our findings provide insights on how people change their behaviors during public health emergencies and may inform improved interventions in future epidemics.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"81 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A structure-redesigned intrinsically disordered peptide that selectively inhibits a plant transcription factor in jasmonate signaling 一种经结构重新设计的内在无序肽，可选择性地抑制茉莉酸信号转导过程中的植物转录因子

PNAS Nexus Pub Date : 2024-07-26 DOI: 10.1093/pnasnexus/pgae312

Yousuke Takaoka, Ruiqi Liu, Minoru Ueda

{"title":"A structure-redesigned intrinsically disordered peptide that selectively inhibits a plant transcription factor in jasmonate signaling","authors":"Yousuke Takaoka, Ruiqi Liu, Minoru Ueda","doi":"10.1093/pnasnexus/pgae312","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae312","url":null,"abstract":"Plant hormone-related transcription factors are key regulators of plant development, responses to environmental stress such as climate changes, pathogens and pests. These transcription factors often function as families that exhibit genetic redundancy in higher plants, and are affected by complex crosstalk mechanisms between different plant hormones. These properties make it difficult to analyze and control them in many cases. In this study, we introduced a chemical inhibitor to manipulate plant hormone-related transcription factors, focusing on the jasmonate and ethylene signaling pathways, with the key transcription factors MYC2/3/4 and EIN3/EIL1. This study revealed that JAZ10CMID, the binding domain of the repressor involved in the desensitization of both transcription factors, is an intrinsically disordered region in the absence of binding partners. Chemical inhibitors have been designed based on this interaction to selectively inhibit MYC transcription factors while leaving EIN3/EIL1 unaffected. This peptide inhibitor effectively disrupts MYC-mediated responses while activating EIN3-mediated responses and successfully uncouples the crosstalk between jasmonate and ethylene signaling in Arabidopsis thaliana. Furthermore, the designed peptide inhibitor was also shown to selectively inhibit the activity of MpMYC, an ortholog of AtMYC in Marchantia polymorpha, demonstrating its applicability across different plant species. This underscores the potential of using peptide inhibitors for specific transcription factors to elucidate hormone crosstalk mechanisms in non-model plants without genetic manipulation. Such a design concept for chemical fixation of the disordered structure is expected to limit the original multiple binding partners and provide useful chemical tools in chemical biology research.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure of the intact Tom20 receptor in the human translocase of the outer membrane complex 人类外膜复合体易位酶中完整 Tom20 受体的结构

PNAS Nexus Pub Date : 2024-07-26 DOI: 10.1093/pnasnexus/pgae269

Jiayue Su, Xuyang Tian, Ziyi Wang, Jiawen Yang, Shan Sun, Sen-Fang Sui

引用次数: 0

Neuropeptide Y receptor activation preserves inner retinal integrity through PI3K/Akt signaling in a glaucoma mouse model 在青光眼小鼠模型中，激活神经肽 Y 受体可通过 PI3K/Akt 信号传导保护视网膜内层的完整性

PNAS Nexus Pub Date : 2024-07-26 DOI: 10.1093/pnasnexus/pgae299

Viswanthram Palanivel, Vivek Gupta, Nitin Chitranshi, Ole Tietz, Roshana Vander Wall, Reuben Blades, Kanishka Pushpitha Maha Thananthirige, Akanksha Salkar, Chao Shen, Mehdi Mirzaei, Veer Gupta, Stuart L Graham, Devaraj Basavarajappa

{"title":"Neuropeptide Y receptor activation preserves inner retinal integrity through PI3K/Akt signaling in a glaucoma mouse model","authors":"Viswanthram Palanivel, Vivek Gupta, Nitin Chitranshi, Ole Tietz, Roshana Vander Wall, Reuben Blades, Kanishka Pushpitha Maha Thananthirige, Akanksha Salkar, Chao Shen, Mehdi Mirzaei, Veer Gupta, Stuart L Graham, Devaraj Basavarajappa","doi":"10.1093/pnasnexus/pgae299","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae299","url":null,"abstract":"Neuropeptide Y (NPY), an endogenous peptide composed of 36 amino acids, has been investigated as a potential therapeutic agent for neurodegenerative diseases due to its neuroprotective attributes. This study investigated the neuroprotective effects of NPY in a mouse model of glaucoma characterized by elevated intraocular pressure (IOP) and progressive retinal ganglion cell (RGC) degeneration. Elevated IOP in mice was induced through intracameral microbead injections, accompanied by intravitreal administration of NPY peptide. The results demonstrated that NPY treatment preserved both the structural and functional integrity of the inner retina and mitigated axonal damage and degenerative changes in the optic nerve under high IOP conditions. Further, NPY treatment effectively reduced inflammatory glial cell activation, as evidenced by decreased expression of GFAP and Iba-1. Notably, endogenous NPY expression and its receptors (NPY-Y1R and NPY-Y4R) levels were negatively affected in the retina under elevated IOP conditions. NPY treatment restored these changes to a significant extent. Molecular analysis revealed that NPY mediates its protective effects through the MAPK and PI3K/Akt signaling pathways. These findings highlight the therapeutic potential of NPY in glaucoma treatment, underscoring its capacity to preserve retinal health, modulate receptor expression under stress, reduce neuroinflammation, and impart protection against axonal impairment.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The intron binding protein EMB-4 is an opposite regulator of cold and high temperature tolerance in Caenorhabditis elegans 内含子结合蛋白 EMB-4 是草履虫耐寒和耐高温的相反调节因子

PNAS Nexus Pub Date : 2024-07-26 DOI: 10.1093/pnasnexus/pgae293

Akane Ohta, Yuki Sato, Kazuho Isono, Takuma Kajino, Keisuke Tanaka, Teruaki Taji, Atsushi Kuhara

引用次数: 0

Delineating the shape of COPII coated membrane bud 描绘 COPII 涂层膜芽的形状

PNAS Nexus Pub Date : 2024-07-26 DOI: 10.1093/pnasnexus/pgae305

Sanjoy Paul, Anjon Audhya, Qiang Cui

{"title":"Delineating the shape of COPII coated membrane bud","authors":"Sanjoy Paul, Anjon Audhya, Qiang Cui","doi":"10.1093/pnasnexus/pgae305","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae305","url":null,"abstract":"Curvature-generating proteins that direct membrane trafficking assemble on the surface of lipid bilayers to bud transport intermediates, which move protein and lipid cargoes from one cellular compartment to another. However, it remains unclear what controls the overall shape of the membrane bud once curvature induction has begun. In vitro experiments showed that excessive concentrations of the COPII protein Sar1 promoted the formation of membrane tubules from synthetic vesicles, while COPII-coated transport intermediates in cells are generally more spherical or lobed in shape. To understand the origin of these morphological differences, we employ atomistic, coarse-grained (CG), and continuum mesoscopic simulations of membranes in the presence of multiple curvature-generating proteins. We first characterize the membrane bending ability of amphipathic peptides derived from the amino terminus of Sar1, as a function of inter-peptide angle and concentration using an atomistic bicelle simulation protocol. Then, we employ CG simulations to reveal that Sec23 and Sec24 control the relative spacing between Sar1 protomers and form the inner-coat unit through an attachment with Sar1. Finally, using Dynamical Triangulated Surface (DTS) simulations based on the Helfrich Hamiltonian, we demonstrate that the uniform distribution of spacer molecules among curvature-generating proteins is crucial to the spherical budding of the membrane. Overall, our analyses suggest a new role for Sec23, Sec24 and cargo proteins in COPII mediated membrane budding process in which they act as spacers to preserve a dispersed arrangement of Sar1 protomers and help determine the overall shape of the membrane bud.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"79 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Main manuscript for “Partisans neither expect nor receive reputational rewards for sharing falsehoods over truth online” "游击队员在网上分享谬误而非真相，既不指望也得不到声誉奖励 "主要手稿

PNAS Nexus Pub Date : 2024-07-25 DOI: 10.1093/pnasnexus/pgae287

Isaias Ghezae, Jillian J Jordan, Izzy B Gainsburg, Mohsen Mosleh, Gordon Pennycook, Robb Willer, David G Rand

{"title":"Main manuscript for “Partisans neither expect nor receive reputational rewards for sharing falsehoods over truth online”","authors":"Isaias Ghezae, Jillian J Jordan, Izzy B Gainsburg, Mohsen Mosleh, Gordon Pennycook, Robb Willer, David G Rand","doi":"10.1093/pnasnexus/pgae287","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae287","url":null,"abstract":"A frequently invoked explanation for the sharing of false over true political information is that partisans are motivated by their reputations. In particular, it is often argued that by indiscriminately sharing news that is favorable to one’s political party, regardless of whether it is true–or perhaps especially when it is not true–partisans can signal loyalty to their group, and improve their reputations in the eyes of their online networks. Across three survey studies (total N = 3,038), and an analysis of over 26,000 tweets, we explored these hypotheses by measuring the reputational benefits that people anticipate and receive from sharing different content online. In the survey studies, we showed participants actual news headlines that varied in (a) veracity, and (b) favorability to their preferred political party. Across all three studies, participants anticipated that sharing true news would bring more reputational benefits than sharing false news. Critically, while participants also expected greater reputational benefits for sharing news favorable to their party, the perceived reputation value of veracity was no smaller for more favorable headlines. We found a similar pattern when analyzing engagement on Twitter: among headlines that were politically favorable to a user’s preferred party, true headlines elicited more approval than false headlines.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatial regulation of substrate adhesion directs fibroblast morphotype and phenotype 基质粘附的空间调控引导成纤维细胞的形态和表型

PNAS Nexus Pub Date : 2024-07-25 DOI: 10.1093/pnasnexus/pgae289

Mirko D’Urso, Ignasi Jorba, Atze van der Pol, Carlijn V C Bouten, Nicholas A Kurniawan

{"title":"Spatial regulation of substrate adhesion directs fibroblast morphotype and phenotype","authors":"Mirko D’Urso, Ignasi Jorba, Atze van der Pol, Carlijn V C Bouten, Nicholas A Kurniawan","doi":"10.1093/pnasnexus/pgae289","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae289","url":null,"abstract":"Switching of fibroblast phenotype to myofibroblast is a hallmark of a wide variety of tissue pathologies. This phenotypical switch is known to be influenced by humoral factors such as TGF-β, but also by mechanical and physical cues in the cellular environment, and is accompanied by distinctive changes in cell morphology. However, the causative link between these cues, the concomitant morphological changes, and the resulting phenotypic switch remain elusive. Here we use protein micropatterning to spatially control dermal fibroblast adhesion without invoking exogenous mechanical changes and demonstrate that varying the spatial configuration of focal adhesions is sufficient to direct fibroblast phenotype. We further developed an automated morphometry analysis pipeline, which revealed focal adhesion eccentricity as the primary determinant of cell state positioning along the spectrum of fibroblast phenotype. Moreover, linear fibronectin patterns that constrain the focal adhesions were found to promote a further phenotype transition, characterized by dispersed expression of alpha-smooth muscle actin, pointing to an interesting possibility of controlling fibroblast phenotype beyond the canonical fibroblast–myofibroblast axis. Together, our study reveals that the spatial configuration of adhesion to the cellular microenvironment is a key factor governing fibroblast morphotype and phenotype, shedding new light on fibroblast phenotype regulation.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141774956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0