Pub Date : 2024-08-22DOI: 10.1093/pnasnexus/pgae355
Junghwa Cha, Erika A Ding, Emily M Carvalho, Annabelle Fowler, Manish K Aghi, Sanjay Kumar
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.
虽然胶质母细胞瘤（GBM）的进展与广泛的细胞外基质（ECM）分泌有关，但 ECM 分泌对侵袭的因果关系仍不清楚。在这里，我们结合了工程材料、蛋白质组学、患者数据分析以及贝伐珠单抗耐药 GBM 模型，对这些贡献进行了研究。我们发现，在工程化三维透明质酸水凝胶中培养的 GBM 细胞会在入侵前分泌 ECM，尤其是在没有外源 ECM 配体的情况下。蛋白质组测量显示胶原 VI 大量分泌，胶原 VI 相关转录本也相应地富集在人类 GBM 的微血管增殖区域。我们进一步发现，贝伐珠单抗耐药的 GBM 细胞比有反应的细胞沉积更多的胶原 VI，这与细胞-ECM 的明显硬化有关。GBM 细胞中 COL6A3 的缺失会减少侵袭、β-catenin 信号转导和间充质标记物的表达，这些效应在缺氧时会放大。我们的研究有力地证明了 GBM 细胞来源的胶原蛋白 VI 在微环境重塑中促进了侵袭。
{"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}
Pub Date : 2024-08-22DOI: 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
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.
{"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}
Pub Date : 2024-08-21DOI: 10.1093/pnasnexus/pgae353
Lukas Fischer, Andreas M Menzel
Soft actuators triggered in a wire- and contactless way advance soft robotics, for instance, concerning microsurgical perspectives. For optimal performance in this and other contexts, maximized stimuli-responsiveness is frequently desirable. We demonstrate on the example of soft magnetoelastic systems how analytical theoretical measures in combination with computer simulations provide tools to develop optimized components. To enhance the overall macroscopic response, we adjust microstructural properties. Our strategy guides us towards ideally structured soft materials that can be fabricated using modern technologies.
{"title":"Maximized response by structural optimization of soft elastic composite systems","authors":"Lukas Fischer, Andreas M Menzel","doi":"10.1093/pnasnexus/pgae353","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae353","url":null,"abstract":"Soft actuators triggered in a wire- and contactless way advance soft robotics, for instance, concerning microsurgical perspectives. For optimal performance in this and other contexts, maximized stimuli-responsiveness is frequently desirable. We demonstrate on the example of soft magnetoelastic systems how analytical theoretical measures in combination with computer simulations provide tools to develop optimized components. To enhance the overall macroscopic response, we adjust microstructural properties. Our strategy guides us towards ideally structured soft materials that can be fabricated using modern technologies.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142196081","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}
Pub Date : 2024-08-09DOI: 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
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.
{"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}
Pub Date : 2024-08-09DOI: 10.1093/pnasnexus/pgae329
Yunfei Li, Deniz Ural, Jan W Kantelhardt, D. Rybski
City systems are characterized by the functional organization of cities on a regional or country scale. While there is a relatively good empirical and theoretical understanding of city size distributions, insights about their spatial organization remain on a conceptual level. Here we analyze empirically the correlations between the sizes of cities (in terms of area) across long distances. Therefore, we (i) define city clusters, (ii) obtain the neighborhood network from Voronoi cells, and (iii) apply a fluctuation analysis along all shortest paths. We find that most European countries exhibit long-range correlations but in several cases these are anti-correlations. In an analogous way we study a model inspired by Central Places Theory and find that it leads to positive long-range correlations, unless there is strong additional spatial disorder – contrary to intuition. We conclude that the interactions between cities extend over large distances reaching the country scale. Our findings have policy relevance as urban development or decline can affect cities at a considerable distance.
{"title":"Indication of long-range correlations governing city size","authors":"Yunfei Li, Deniz Ural, Jan W Kantelhardt, D. Rybski","doi":"10.1093/pnasnexus/pgae329","DOIUrl":"https://doi.org/10.1093/pnasnexus/pgae329","url":null,"abstract":"\u0000 City systems are characterized by the functional organization of cities on a regional or country scale. While there is a relatively good empirical and theoretical understanding of city size distributions, insights about their spatial organization remain on a conceptual level. Here we analyze empirically the correlations between the sizes of cities (in terms of area) across long distances. Therefore, we (i) define city clusters, (ii) obtain the neighborhood network from Voronoi cells, and (iii) apply a fluctuation analysis along all shortest paths. We find that most European countries exhibit long-range correlations but in several cases these are anti-correlations. In an analogous way we study a model inspired by Central Places Theory and find that it leads to positive long-range correlations, unless there is strong additional spatial disorder – contrary to intuition. We conclude that the interactions between cities extend over large distances reaching the country scale. Our findings have policy relevance as urban development or decline can affect cities at a considerable distance.","PeriodicalId":516525,"journal":{"name":"PNAS Nexus","volume":"55 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922926","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}
Pub Date : 2024-08-09DOI: 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
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.
最近有研究开始探讨新政时期实施的房屋所有权政策对健康的潜在长期影响。我们调查了美国 20 世纪 30 年代房屋所有者贷款公司（HOLC）地图所指定的贷款风险等级与现今三种心血管风险因素（2020 年为糖尿病和肥胖症，2019 年为高血压）患病率之间的关联，这些患病率是在人口普查区一级估算的。为了尽量减少潜在的混杂因素，我们对 HOLC 地图绘制时期的社会人口数据进行了调整。我们计算了倾向分数（获得 HOLC 分级的预测概率），并使用反概率加权法（IPW）创建了一个伪人群。然后，我们采用边际结构模型（MSM）来估计 A 级与 B 级、B 级与 C 级、C 级与 D 级 HOLC 的流行率差异。仅对地区进行调整后，HOLC等级越低，现今心血管风险因素的估计患病率越高；但是，在应用倾向分数方法后，大多数差异不再显著。唯一的例外是，C 级人口普查区与 B 级人口普查区相比，糖尿病、高血压和肥胖症的患病率都更高，而 C-D 级和 A-B 级比较则没有发现差异。这些结果为一小部分证据做出了贡献，这些证据表明，历史上的 "黄线"（C 级为黄色）可能在 80 年后对邻里一级的心血管风险因素产生了持续影响。
{"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}
Pub Date : 2024-08-09DOI: 10.1093/pnasnexus/pgae326
Christoph Hauert, György Szabó
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.
在互惠联合体中，两个物种通过与另一个物种的成员交换物品或服务来进行合作，从而互惠互利。与此同时，它们主要与自己的物种成员进行繁殖竞争。在物种内部互动中，囚徒困境是研究合作进化的主要数学隐喻。在这里，我们考虑的是空间囚徒困境中的物种间互动，每个物种的成员都居住在一个晶格层上。合作者为邻近的另一物种成员提供利益，但自己要付出代价。因此，各层之间会发生相互作用，但各层内部仍存在竞争。我们的研究表明，当改变合作的成本收益比 r 时，会出现丰富而复杂的动态变化。出现了四个不同的动态领域，它们被临界相变分隔开来，每个领域的特点都是合作频率的波动不同：(i)当 r 较大时，合作成本过高，叛逃占主导地位；(ii)当 r 较小时，合作者在两个物种中的存活频率相等；(iii)当 r 进一步降低时，物种间的合作会出现有趣的、自发的对称性破坏，当 r 减小时，不对称程度增加；(iv)最后，当 r 较小时，会出现相互叛逃的爆发，其规模随着 r 的减小而增加，最终使种群进入吸收状态。通常情况下，一个物种是合作的，另一个物种是叛变的，因此建立了完美的不对称。耐人寻味的是，尽管模型设置是对称的，但自然选择还是有利于自发出现不对称的进化结果，即平均而言，一个物种在动态平衡中利用另一个物种。
{"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}
Pub Date : 2024-08-08DOI: 10.1093/pnasnexus/pgae332
N. Kondo, Yoshihiro Ueda, T. Kinashi
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.
{"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}
Pub Date : 2024-08-07DOI: 10.1093/pnasnexus/pgae315
Arabinda Bera, Matteo Baggioli, Timothy C Petersen, Timothy W Sirk, Amelia C Y Liu, Alessio Zaccone
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.
{"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}
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.
{"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}
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