PNAS Nexus最新文献_第5页

Collagen VI deposition primes the glioblastoma microenvironment for invasion through mechanostimulation of β-catenin signaling 胶原蛋白VI沉积通过机械刺激β-catenin信号传导为胶质母细胞瘤微环境的侵袭提供动力

PNAS Nexus Pub Date : 2024-08-22 DOI: 10.1093/pnasnexus/pgae355

Junghwa Cha, Erika A Ding, Emily M Carvalho, Annabelle Fowler, Manish K Aghi, Sanjay Kumar

{"title":"Collagen VI deposition primes the glioblastoma microenvironment for invasion through mechanostimulation of β-catenin signaling","authors":"Junghwa Cha, Erika A Ding, Emily M Carvalho, Annabelle Fowler, Manish K Aghi, Sanjay Kumar","doi":"10.1093/pnasnexus/pgae355","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae355","url":null,"abstract":"While glioblastoma (GBM) progression is associated with extensive extracellular matrix (ECM) secretion, the causal contributions of ECM secretion to invasion remain unclear. Here we investigate these contributions by combining engineered materials, proteomics, analysis of patient data, and a model of bevacizumab-resistant GBM. We find that GBM cells cultured in engineered 3D hyaluronic acid hydrogels secrete ECM prior to invasion, particularly in the absence of exogenous ECM ligands. Proteomic measurements reveal extensive secretion of collagen VI, and collagen VI-associated transcripts are correspondingly enriched in microvascular proliferation regions of human GBMs. We further show that bevacizumab-resistant GBM cells deposit more collagen VI than their responsive counterparts, which is associated with marked cell-ECM stiffening. COL6A3 deletion in GBM cells reduces invasion, β-catenin signaling, and expression of mesenchymal markers, and these effects are amplified in hypoxia. Our studies strongly implicate GBM cell-derived collagen VI in microenvironmental remodeling to facilitate invasion.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"403 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196080","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

Ubiquitin-driven protein condensation stabilizes clathrin-mediated endocytosis 泛素驱动的蛋白质缩聚可稳定凝集素介导的内吞作用

PNAS Nexus Pub Date : 2024-08-22 DOI: 10.1093/pnasnexus/pgae342

Feng Yuan, Sadhana Gollapudi, Kasey J Day, Grant Ashby, Arjun Sangani, Brandon T Malady, Liping Wang, Eileen M Lafer, Jon M Huibregtse, Jeanne C Stachowiak

{"title":"Ubiquitin-driven protein condensation stabilizes clathrin-mediated endocytosis","authors":"Feng Yuan, Sadhana Gollapudi, Kasey J Day, Grant Ashby, Arjun Sangani, Brandon T Malady, Liping Wang, Eileen M Lafer, Jon M Huibregtse, Jeanne C Stachowiak","doi":"10.1093/pnasnexus/pgae342","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae342","url":null,"abstract":"Clathrin-mediated endocytosis is an essential cellular pathway that enables signaling and recycling of transmembrane proteins and lipids. During endocytosis, dozens of cytosolic proteins come together at the plasma membrane, assembling into a highly interconnected network that drives endocytic vesicle biogenesis. Recently, multiple groups have reported that early endocytic proteins form flexible condensates, which provide a platform for efficient assembly of endocytic vesicles. Given the importance of this network in the dynamics of endocytosis, how might cells regulate its stability? Many receptors and endocytic proteins are ubiquitylated, while early endocytic proteins such as Eps15 contain ubiquitin-interacting motifs. Therefore, we examined the influence of ubiquitin on the stability of the early endocytic protein network. In vitro, we found that recruitment of small amounts of polyubiquitin dramatically increased the stability of Eps15 condensates, suggesting that ubiquitylation could nucleate endocytic assemblies. In live cell imaging experiments, a version of Eps15 that lacked the ubiquitin-interacting motif failed to rescue defects in endocytic initiation created by Eps15 knockout. Furthermore, fusion of Eps15 to a deubiquitylase enzyme destabilized nascent endocytic sites within minutes. In both in vitro and live cell settings, dynamic exchange of Eps15 proteins, a measure of protein network stability, was decreased by Eps15-ubiquitin interactions and increased by loss of ubiquitin. These results collectively suggest that ubiquitylation drives assembly of the flexible protein network responsible for catalyzing endocytic events. More broadly, this work illustrates a biophysical mechanism by which ubiquitylated transmembrane proteins at the plasma membrane could regulate the efficiency of endocytic internalization.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196283","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

Maximized response by structural optimization of soft elastic composite systems 通过优化软弹性复合材料系统结构实现响应最大化

PNAS Nexus Pub Date : 2024-08-21 DOI: 10.1093/pnasnexus/pgae353

Lukas Fischer, Andreas M Menzel

引用次数: 0

Mantis: high-throughput 4D imaging and analysis of the molecular and physical architecture of cells Mantis：对细胞的分子和物理结构进行高通量 4D 成像和分析

PNAS Nexus Pub Date : 2024-08-09 DOI: 10.1093/pnasnexus/pgae323

Ivan E Ivanov, Eduardo Hirata-Miyasaki, Talon Chandler, Rasmi Cheloor-Kovilakam, Ziwen Liu, Soorya Pradeep, Chad Liu, Madhura Bhave, Sudip Khadka, Carolina Arias, Manuel D Leonetti, Bo Huang, Shalin B Mehta

{"title":"Mantis: high-throughput 4D imaging and analysis of the molecular and physical architecture of cells","authors":"Ivan E Ivanov, Eduardo Hirata-Miyasaki, Talon Chandler, Rasmi Cheloor-Kovilakam, Ziwen Liu, Soorya Pradeep, Chad Liu, Madhura Bhave, Sudip Khadka, Carolina Arias, Manuel D Leonetti, Bo Huang, Shalin B Mehta","doi":"10.1093/pnasnexus/pgae323","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae323","url":null,"abstract":"High-throughput dynamic imaging of cells and organelles is essential for understanding complex cellular responses. We report Mantis, a high-throughput 4D microscope that integrates two complementary, gentle, live-cell imaging technologies: remote-refocus label-free microscopy and oblique light-sheet fluorescence microscopy. Additionally, we report shrimPy, an open-source software for high-throughput imaging, deconvolution, and single-cell phenotyping of 4D data. Using Mantis and shrimPy, we achieved high-content correlative imaging of molecular dynamics and the physical architecture of 20 cell lines every 15 minutes over 7.5 hours. This platform also facilitated detailed measurements of the impacts of viral infection on the architecture of host cells and host proteins. The Mantis platform can enable high-throughput profiling of intracellular dynamics, long-term imaging and analysis of cellular responses to perturbations, and live-cell optical screens to dissect gene regulatory networks.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141938314","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

Indication of long-range correlations governing city size 城市规模的长期相关性指标

PNAS Nexus Pub Date : 2024-08-09 DOI: 10.1093/pnasnexus/pgae329

Yunfei Li, Deniz Ural, Jan W Kantelhardt, D. Rybski

引用次数: 0

Associations between 1930s HOLC grades and estimated population burden of cardiovascular disease risk factors in 2020 1930 年代 HOLC 等级与 2020 年心血管疾病风险因素人口负担估计值之间的关系

PNAS Nexus Pub Date : 2024-08-09 DOI: 10.1093/pnasnexus/pgae301

Hanxue Wei, B. Spoer, Andrea R Titus, T. Lampe, Marc N. Gourevitch, Jacob W Faber, Steven J Korzeniewski, Samantha J Bauer, Lorna E. Thorpe

{"title":"Associations between 1930s HOLC grades and estimated population burden of cardiovascular disease risk factors in 2020","authors":"Hanxue Wei, B. Spoer, Andrea R Titus, T. Lampe, Marc N. Gourevitch, Jacob W Faber, Steven J Korzeniewski, Samantha J Bauer, Lorna E. Thorpe","doi":"10.1093/pnasnexus/pgae301","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae301","url":null,"abstract":"\u0000 Studies have recently begun to explore the potential long term health impacts of homeownership policies implemented in the New Deal era. We investigated the association between assigned grades of lending risk by the Home Owners’ Load Corporation (HOLC) maps from the 1930s and present-day prevalence of three cardiovascular risk factors (diabetes and obesity in 2020, and hypertension in 2019), estimated at the census tract level in the United States. To minimize potential confounding, we adjusted for sociodemographic data from the time period when HOLC maps were made. We calculated propensity scores (predicted probability of receiving a HOLC grade) and created a pseudo-population using inverse probability weighting (IPW). We then employed marginal structural models (MSM) to estimate prevalence differences comparing A vs B, B vs C, and C vs D HOLC grades. Adjusting only for regions, a less desirable HOLC grade was associated with higher estimated prevalence rates of present-day cardiovascular risk factors; however, most differences were no longer significant after applying propensity-score methods. The one exception was that prevalence of diabetes, hypertension, and obesity were all higher in C vs B graded census tracts, while no differences were observed for C-D and A-B comparisons. These results contribute to a small body of evidence that suggests historical “yellowlining” (as C grade was in color yellow) may have had persistent impacts on neighborhood-level cardiovascular risk factors 80 years later.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"31 33","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141924608","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

Spontaneous symmetry breaking of cooperation between species 自发打破物种间合作的对称性

PNAS Nexus Pub Date : 2024-08-09 DOI: 10.1093/pnasnexus/pgae326

Christoph Hauert, György Szabó

{"title":"Spontaneous symmetry breaking of cooperation between species","authors":"Christoph Hauert, György Szabó","doi":"10.1093/pnasnexus/pgae326","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae326","url":null,"abstract":"In mutualistic associations two species cooperate by exchanging goods or services with members of another species for their mutual benefit. At the same time competition for reproduction primarily continues with members of their own species. In intra-species interactions the prisoner's dilemma is the leading mathematical metaphor to study the evolution of cooperation. Here we consider inter-species interactions in the spatial prisoner's dilemma, where members of each species reside on one lattice layer. Cooperators provide benefits to neighbouring members of the other species at a cost to themselves. Hence, interactions occur across layers but competition remains within layers. We show that rich and complex dynamics unfold when varying the cost-to-benefit ratio of cooperation, r. Four distinct dynamical domains emerge that are separated by critical phase transitions, each characterized by diverging fluctuations in the frequency of cooperation: (i) for large r cooperation is too costly and defection dominates; (ii) for lower r cooperators survive at equal frequencies in both species; (iii) lowering r further results in an intriguing, spontaneous symmetry breaking of cooperation between species with increasing asymmetry for decreasing r; (iv) finally, for small r, bursts of mutual defection appear that increase in size with decreasing r and eventually drive the populations into absorbing states. Typically one species is cooperating and the other defecting and hence establish perfect asymmetry. Intriguingly and despite the symmetrical model setup, natural selection can nevertheless favour the spontaneous emergence of asymmetric evolutionary outcomes where, on average, one species exploits the other in a dynamical equilibrium.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141968954","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

Low-affinity LFA1-dependent outside-in signaling mediates avidity modulation via the Rabin8-Rab8 axis 依赖于低亲和力 LFA1 的外入信号通过 Rabin8-Rab8 轴介导热度调节

PNAS Nexus Pub Date : 2024-08-08 DOI: 10.1093/pnasnexus/pgae332

N. Kondo, Yoshihiro Ueda, T. Kinashi

{"title":"Low-affinity LFA1-dependent outside-in signaling mediates avidity modulation via the Rabin8-Rab8 axis","authors":"N. Kondo, Yoshihiro Ueda, T. Kinashi","doi":"10.1093/pnasnexus/pgae332","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae332","url":null,"abstract":"\u0000 Lymphocyte interactions mediated by leukocyte integrin LFA1 and intercellular adhesion molecules (ICAMs) are important for lymphocyte trafficking and antigen recognition. Integrins are regulated by the modulation of ligand-binding affinity and avidity (valency). Although the mechanism underlying high-affinity LFA1 binding has been investigated extensively, the molecular mechanisms by which low-affinity multivalent binding initiates adhesion remain unclear. We previously showed that ICAM1 and monoclonal antibodies that recognize specific LFA1 conformations induce the accumulation of LFA1 at the contact surface. Here, we found that the small GTPase Rab8 is critical for intracellular transport and accumulation of LFA1 at cell contact areas mediated by low-affinity LFA1-dependent outside-in signaling. Super-resolution microscopy revealed that Rab8 co-localized with LFA1 in small vesicles near the contact membrane. Inactivation of Rab8 decreased ICAM1-dependent adhesion and substantially reduced LFA1 density on the contact membrane. The GTP-bound active form of Rab8 increased cell adhesiveness and promoted LFA1 accumulation at the contact area through co-trafficking with LFA1. Rab8 activation was induced by low-affinity conformation-dependent outside-in signaling via the guanine exchange factor Rabin8, which induced Rab8 activation at the cell contact area independent of Rap1. Single-molecule imaging of ICAM1 on a supported planner lipid bilayer demonstrated that Rab8 increased the frequency of LFA1-ICAM1 interactions without affecting their binding lifetime, indicating that Rab8 is mainly involved in the modulation of LFA1 avidity rather than LFA1 affinity. The present findings underscore the importance of low-affinity conformation-dependent outside-in signaling via the Rabin8-Rab8 axis leading to initiation of LFA1 transport to the contact area.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"20 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141928474","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

Clustering of negative topological charges precedes plastic failure in 3D glasses 负拓扑电荷的聚集先于 3D 眼镜的塑性失效

PNAS Nexus Pub Date : 2024-08-07 DOI: 10.1093/pnasnexus/pgae315

Arabinda Bera, Matteo Baggioli, Timothy C Petersen, Timothy W Sirk, Amelia C Y Liu, Alessio Zaccone

{"title":"Clustering of negative topological charges precedes plastic failure in 3D glasses","authors":"Arabinda Bera, Matteo Baggioli, Timothy C Petersen, Timothy W Sirk, Amelia C Y Liu, Alessio Zaccone","doi":"10.1093/pnasnexus/pgae315","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae315","url":null,"abstract":"The deformation mechanism in amorphous solids subjected to external shear remains poorly understood because of the absence of well-defined topological defects mediating the plastic deformation. The notion of soft spots has emerged as a useful tool to characterize the onset of irreversible rearrangements and plastic flow, but these entities are not clearly defined in terms of geometry and topology. In this study, we unveil the phenomenology of recently discovered, precisely defined topological defects governing the microscopic mechanical and yielding behavior of a model 3D glass under shear deformation. We identify the existence of vortex-like and anti-vortex-like topological defects within the 3D non-affine displacement field. The number density of these defects exhibits a significant anti-correlation with the plastic events, with defect proliferation-annihilation cycles matching the alternation of elastic-like segments and catastrophic plastic drops, respectively. Furthermore, we observe collective annihilation of these point-like defects via plastic events, with large local topological charge fluctuations in the vicinity of regions that feature strong non-affine displacements. We reveal that plastic yielding is driven by several large sized clusters of net negative topological charge, the massive annihilation of which triggers the onset of plastic flow. These findings suggest a geometric and topological characterization of soft spots and pave the way for the mechanistic understanding of topological defects as mediators of plastic deformation in glassy materials.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141938417","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

Development of a novel bacterial production system for recombinant bioactive proteins completely free from endotoxin contamination 开发完全不受内毒素污染的重组生物活性蛋白新型细菌生产系统

PNAS Nexus Pub Date : 2024-08-07 DOI: 10.1093/pnasnexus/pgae328

Go Kamoshida, Daiki Yamaguchi, Yuki Kaya, Toshiki Yamakado, Kenta Yamashita, Moe Aoyagi, Saaya Nagai, Noriteru Yamada, Yu Kawagishi, Mizuki Sugano, Yoshiaki Sakairi, Mikako Ueno, Norihiko Takemoto, Yuji Morita, Yukihito Ishizaka, Kinnosuke Yahiro

{"title":"Development of a novel bacterial production system for recombinant bioactive proteins completely free from endotoxin contamination","authors":"Go Kamoshida, Daiki Yamaguchi, Yuki Kaya, Toshiki Yamakado, Kenta Yamashita, Moe Aoyagi, Saaya Nagai, Noriteru Yamada, Yu Kawagishi, Mizuki Sugano, Yoshiaki Sakairi, Mikako Ueno, Norihiko Takemoto, Yuji Morita, Yukihito Ishizaka, Kinnosuke Yahiro","doi":"10.1093/pnasnexus/pgae328","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae328","url":null,"abstract":"Endotoxins, or lipopolysaccharides (LPS), are potent immunostimulatory molecules of critical concern in bacterial recombinant protein expression systems. The gram-negative bacterium Acinetobacter baumannii exhibits an interesting and unique phenotype characterized by the complete loss of LPS. In this study, we developed a novel system for producing recombinant proteins completely devoid of endotoxin contamination using LPS-deficient A. baumannii. We purified endotoxin-free functional green fluorescent protein, which reduced endotoxin contamination by approximately three orders of magnitude, and also purified the functional cytokine tumor necrosis factor (TNF)-α. Additionally, utilization of the Omp38 signal peptide of A. baumannii enabled the extracellular production of variable domain of heavy chain of heavy chain (VHH) antibodies. With these advantages, mNb6-tri-20aa, a multivalent VHH that specifically binds to the spike protein of severe acute respiratory syndrome coronavirus 2, was purified from the culture supernatant, and endotoxin contamination was reduced by a factor of approximately 2×105 compared to that in conventional expression systems. A virus neutralization assay demonstrated the functionality of the purified antibody in suppressing viral infections. Moreover, we applied our system to produce ozoralizumab, a multispecific VHH that binds to human TNF-α and albumin and is marketed as a rheumatoid arthritis drug. We successfully purified a functional antibody from endotoxin contamination. This system establishes a new, completely endotoxin-free platform for the expression of recombinant proteins, which distinguishes it from other bacterial expression systems, and holds promise for future applications.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141968990","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