Pub Date : 2024-07-16DOI: 10.1101/2024.07.10.602956
Mark A. Buckner, Steven T. Hoge, B. Danforth
The Mojave and Sonoran Deserts, recognized as a global hotspot for bee biodiversity, are experiencing habitat degradation from urbanization, utility-scale solar energy (USSE) development, and climate change. In this study, we evaluated the current and future distribution of bee diversity in the region, assessed how protected areas safeguard bee species richness, and predicted how global change may affect bees across the region. Using Joint Species Distribution Models (JSDMs) of 148 bee species, we project changes in species distributions, occurrence area, and richness across the region under four global change scenarios between 1971 and 2050. We evaluated the threat posed by USSE development and predicted how climate change will affect the suitability of protected areas for conservation. Our findings indicate that changes in temperature and precipitation do not uniformly affect bee richness across the region. Protected areas in the Sonoran and Mojave Deserts are projected to experience mean losses of up to 5.8 species, whereas protected areas at higher elevations and transition zones may gain up to 7.8 species. Outside protected areas, bee diversity is threatened by urbanization and USSE development. Areas prioritized for future USSE development have an average species richness of 4.2 species higher than the study area average, and lower priority areas have 8.2 more species. USSE zones are expected to experience declines of 2.7 to 8.0 species by 2050 due to climate change alone. Despite the importance of solitary bees for pollination, their diversity is often overlooked in land management decisions. Our results show the utility of JSDMs for extending the usability of existing data-limited bee species records, easing the inclusion of these species in conservation and land management decision-making. The multiple threats from global change drivers underscore the importance of including ecologically vital, though often data-limited, species in land-use decisions.
{"title":"Forecasting the Effects of Global Change on a Bee Biodiversity Hotspot","authors":"Mark A. Buckner, Steven T. Hoge, B. Danforth","doi":"10.1101/2024.07.10.602956","DOIUrl":"https://doi.org/10.1101/2024.07.10.602956","url":null,"abstract":"The Mojave and Sonoran Deserts, recognized as a global hotspot for bee biodiversity, are experiencing habitat degradation from urbanization, utility-scale solar energy (USSE) development, and climate change. In this study, we evaluated the current and future distribution of bee diversity in the region, assessed how protected areas safeguard bee species richness, and predicted how global change may affect bees across the region. Using Joint Species Distribution Models (JSDMs) of 148 bee species, we project changes in species distributions, occurrence area, and richness across the region under four global change scenarios between 1971 and 2050. We evaluated the threat posed by USSE development and predicted how climate change will affect the suitability of protected areas for conservation. Our findings indicate that changes in temperature and precipitation do not uniformly affect bee richness across the region. Protected areas in the Sonoran and Mojave Deserts are projected to experience mean losses of up to 5.8 species, whereas protected areas at higher elevations and transition zones may gain up to 7.8 species. Outside protected areas, bee diversity is threatened by urbanization and USSE development. Areas prioritized for future USSE development have an average species richness of 4.2 species higher than the study area average, and lower priority areas have 8.2 more species. USSE zones are expected to experience declines of 2.7 to 8.0 species by 2050 due to climate change alone. Despite the importance of solitary bees for pollination, their diversity is often overlooked in land management decisions. Our results show the utility of JSDMs for extending the usability of existing data-limited bee species records, easing the inclusion of these species in conservation and land management decision-making. The multiple threats from global change drivers underscore the importance of including ecologically vital, though often data-limited, species in land-use decisions.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643611","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 : 2024-07-16DOI: 10.1101/2024.07.15.603581
Charles A. Stockman, Alain Goriely, E. Kuhl
Alzheimer’s disease is a neurodegenerative disorder characterized by the presence of amyloid-β plaques and the accumulation of misfolded tau proteins and neurofibrillary tangles in the brain. A thorough understanding of the local accumulation of tau is critical to develop effective therapeutic strategies. Tau pathology has traditionally been described using reaction-diffusion models, which succeed in capturing the global spread, but fail to accurately describe the local aggregation dynamics. Current mathematical models enforce a single-peak behavior in tau aggregation, which does not align well with clinical observations. Here we identify a more accurate description of tau aggregation that reflects the complex patterns observed in patients. We propose an innovative approach that uses constitutive neural networks to autonomously discover bell-shaped aggregation functions with multiple peaks from clinical positron emission tomography (PET) data of misfolded tau protein. Our method reveals previously overlooked two-stage aggregation dynamics by uncovering a twoterm ordinary differential equation that links the local accumulation rate to the tau concentration. When trained on data from amyloid-β positive and negative subjects, the neural network clearly distinguishes between both groups and uncovers a more subtle relationship between amyloid-β and tau than previously postulated. In line with the amyloid-tau dual pathway hypothesis, our results show that the presence of toxic amyloid-β influences the accumulation of tau, particularly in the earlier disease stages. We expect that our approach to autonomously discover the accumulation dynamics of pathological proteins will improve simulations of tau dynamics in Alzheimer’s disease and provide new insights into disease progression.
阿尔茨海默病是一种神经退行性疾病，其特征是大脑中存在淀粉样β斑块以及折叠错误的 tau 蛋白和神经纤维缠结的积累。透彻了解 tau 蛋白的局部积聚对于制定有效的治疗策略至关重要。传统上，人们使用反应扩散模型来描述 Tau 病理学，这些模型成功地捕捉到了全球扩散，但却无法准确描述局部聚集动态。目前的数学模型在 Tau 聚集过程中强制执行单峰行为，这与临床观察结果不符。在这里，我们确定了一种更准确的 tau 聚集描述方法，它能反映在患者身上观察到的复杂模式。我们提出了一种创新方法，利用构成神经网络从折叠错误的 tau 蛋白的临床正电子发射断层扫描（PET）数据中自主发现具有多个峰值的钟形聚集函数。我们的方法揭示了以前被忽视的两阶段聚集动力学，发现了一个将局部积累率与 tau 蛋白浓度联系起来的两元常微分方程。在对淀粉样蛋白-β阳性和阴性受试者的数据进行训练时，神经网络能清楚地区分这两组，并揭示出淀粉样蛋白-β和tau之间比以前推测的更微妙的关系。与淀粉样蛋白-tau 双通道假说一致，我们的研究结果表明，毒性淀粉样蛋白-β的存在会影响 tau 的积累，尤其是在疾病的早期阶段。我们希望我们这种自主发现病理蛋白积累动态的方法能改善对阿尔茨海默氏症中 tau 动态的模拟，并为疾病的进展提供新的见解。
{"title":"Two for tau: Automated model discovery reveals two-stage tau aggregation dynamics in Alzheimer’s disease","authors":"Charles A. Stockman, Alain Goriely, E. Kuhl","doi":"10.1101/2024.07.15.603581","DOIUrl":"https://doi.org/10.1101/2024.07.15.603581","url":null,"abstract":"Alzheimer’s disease is a neurodegenerative disorder characterized by the presence of amyloid-β plaques and the accumulation of misfolded tau proteins and neurofibrillary tangles in the brain. A thorough understanding of the local accumulation of tau is critical to develop effective therapeutic strategies. Tau pathology has traditionally been described using reaction-diffusion models, which succeed in capturing the global spread, but fail to accurately describe the local aggregation dynamics. Current mathematical models enforce a single-peak behavior in tau aggregation, which does not align well with clinical observations. Here we identify a more accurate description of tau aggregation that reflects the complex patterns observed in patients. We propose an innovative approach that uses constitutive neural networks to autonomously discover bell-shaped aggregation functions with multiple peaks from clinical positron emission tomography (PET) data of misfolded tau protein. Our method reveals previously overlooked two-stage aggregation dynamics by uncovering a twoterm ordinary differential equation that links the local accumulation rate to the tau concentration. When trained on data from amyloid-β positive and negative subjects, the neural network clearly distinguishes between both groups and uncovers a more subtle relationship between amyloid-β and tau than previously postulated. In line with the amyloid-tau dual pathway hypothesis, our results show that the presence of toxic amyloid-β influences the accumulation of tau, particularly in the earlier disease stages. We expect that our approach to autonomously discover the accumulation dynamics of pathological proteins will improve simulations of tau dynamics in Alzheimer’s disease and provide new insights into disease progression.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643949","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 : 2024-07-16DOI: 10.1101/2024.07.12.603230
J. Duchoslavová
Nitrogen is often a limiting factor for plant growth, and its availability is a major determinant of level of competition. In clonal plants, patterns of nitrogen translocation between ramets may be part of plant nitrogen economics, and, as such, may also be related to the typical availability of nitrogen. In nutrient-poor habitats, extensive nutrient sharing balancing resource availability may be important, whereas nutrient sharing between established ramets may not be beneficial in productive habitats. I tested the proposed nutrient sharing strategies on nitrogen translocation in six stoloniferous species that occur in habitats of varying productivity. Mother and daughter ramets of each species were grown either in a homogeneous nutrient-poor treatment or in a “nutrient-poor to nutrient-rich” treatment. I traced the translocation of nitrogen in both directions using stable isotope labelling when the daughter ramets were one month old. Surprisingly, I found no effect of nutrient treatment on nitrogen translocation. Instead, each species translocated nitrogen either acropetally, basipetally, or equally in both directions. There was no relationship between the direction of translocation and the productivity of the species’ habitats. However, net translocation seemed to be related to the relative size of daughters across species, and within Veronica officinalis. The results suggest that the relative size of plant parts is an important determinant of the strength of the sink for nitrogen they form, and that the growth habit of a species can affect its nitrogen translocation. Under certain conditions, such internally induced source-sink relationships may dominate over external nitrogen heterogeneity. I speculate that growth habit, together with nitrogen translocation patterns, may be part of adaptive growth strategies.
{"title":"Nitrogen sharing strategies in six clonal species","authors":"J. Duchoslavová","doi":"10.1101/2024.07.12.603230","DOIUrl":"https://doi.org/10.1101/2024.07.12.603230","url":null,"abstract":"Nitrogen is often a limiting factor for plant growth, and its availability is a major determinant of level of competition. In clonal plants, patterns of nitrogen translocation between ramets may be part of plant nitrogen economics, and, as such, may also be related to the typical availability of nitrogen. In nutrient-poor habitats, extensive nutrient sharing balancing resource availability may be important, whereas nutrient sharing between established ramets may not be beneficial in productive habitats. I tested the proposed nutrient sharing strategies on nitrogen translocation in six stoloniferous species that occur in habitats of varying productivity. Mother and daughter ramets of each species were grown either in a homogeneous nutrient-poor treatment or in a “nutrient-poor to nutrient-rich” treatment. I traced the translocation of nitrogen in both directions using stable isotope labelling when the daughter ramets were one month old. Surprisingly, I found no effect of nutrient treatment on nitrogen translocation. Instead, each species translocated nitrogen either acropetally, basipetally, or equally in both directions. There was no relationship between the direction of translocation and the productivity of the species’ habitats. However, net translocation seemed to be related to the relative size of daughters across species, and within Veronica officinalis. The results suggest that the relative size of plant parts is an important determinant of the strength of the sink for nitrogen they form, and that the growth habit of a species can affect its nitrogen translocation. Under certain conditions, such internally induced source-sink relationships may dominate over external nitrogen heterogeneity. I speculate that growth habit, together with nitrogen translocation patterns, may be part of adaptive growth strategies.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640437","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 : 2024-07-16DOI: 10.1101/2024.07.11.603175
Xin Li, Robert J. Huebner, Margot Kossmann Williams, Jessica Sawyer, M. Peifer, John B. Wallingford, D. Thirumalai
Cells undergo dramatic changes in morphology during embryogenesis, yet how these changes affect the formation of ordered tissues remains elusive. Here we find that the emergence of a nematic liquid crystal phase occurs in cells during gastrulation in the development of embryos of fish, frogs, and fruit flies. Moreover, the spatial correlations in all three organisms are long-ranged and follow a similar power-law decay (y∼x−α) with α less than unity for the nematic order parameter, suggesting a common underlying physical mechanism unifies events in these distantly related species. All three species exhibit similar propagation of the nematic phase, reminiscent of nucleation and growth phenomena. Finally, we use a theoretical model along with disruptions of cell adhesion and cell specification to characterize the minimal features required for formation of the nematic phase. Our results provide a framework for understanding a potentially universal features of metazoan embryogenesis and shed light on the advent of ordered structures during animal development.
{"title":"Emergence of cellular nematic order is a conserved feature of gastrulation in animal embryos","authors":"Xin Li, Robert J. Huebner, Margot Kossmann Williams, Jessica Sawyer, M. Peifer, John B. Wallingford, D. Thirumalai","doi":"10.1101/2024.07.11.603175","DOIUrl":"https://doi.org/10.1101/2024.07.11.603175","url":null,"abstract":"Cells undergo dramatic changes in morphology during embryogenesis, yet how these changes affect the formation of ordered tissues remains elusive. Here we find that the emergence of a nematic liquid crystal phase occurs in cells during gastrulation in the development of embryos of fish, frogs, and fruit flies. Moreover, the spatial correlations in all three organisms are long-ranged and follow a similar power-law decay (y∼x−α) with α less than unity for the nematic order parameter, suggesting a common underlying physical mechanism unifies events in these distantly related species. All three species exhibit similar propagation of the nematic phase, reminiscent of nucleation and growth phenomena. Finally, we use a theoretical model along with disruptions of cell adhesion and cell specification to characterize the minimal features required for formation of the nematic phase. Our results provide a framework for understanding a potentially universal features of metazoan embryogenesis and shed light on the advent of ordered structures during animal development.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643111","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 : 2024-07-16DOI: 10.1101/2024.07.12.603345
Parham Peyda, Chia-Ho Lin, Kelechi Onwuzurike, Douglas L. Black
The Rbfox proteins regulate alternative pre-mRNA splicing by binding to the RNA element GCAUG. In the nucleus, most of Rbfox is bound to LASR, a complex of RNA-binding proteins that recognize additional RNA motifs. However, it remains unclear how the different subunits of the Rbfox/LASR complex act together to bind RNA and regulate splicing. We used a nuclease-protection assay to map the transcriptome-wide footprints of Rbfox1/LASR on nascent cellular RNA. In addition to GCAUG, Rbfox1/LASR binds RNA containing motifs for LASR subunits hnRNPs M, H/F, C, and Matrin3. These elements are often arranged in tandem, forming multi-part modules of RNA motifs. To distinguish contact sites of Rbfox1 from the LASR subunits, we analyzed a mutant Rbfox1(F125A) that has lost RNA binding but remains associated with LASR. Rbfox1(F125A)/LASR complexes no longer interact with GCAUG but retain binding to RNA elements for LASR. Splicing analyses reveal that in addition to activating exons through adjacent GCAUG elements, Rbfox can also stimulate exons near binding sites for LASR subunits. Mini-gene experiments demonstrate that these diverse elements produce a combined regulatory effect on a target exon. These findings illuminate how a complex of RNA-binding proteins can decode combinatorial splicing regulatory signals by recognizing groups of tandem RNA elements.
{"title":"The Rbfox1/LASR complex controls alternative pre-mRNA splicing by recognition of multi-part RNA regulatory modules","authors":"Parham Peyda, Chia-Ho Lin, Kelechi Onwuzurike, Douglas L. Black","doi":"10.1101/2024.07.12.603345","DOIUrl":"https://doi.org/10.1101/2024.07.12.603345","url":null,"abstract":"The Rbfox proteins regulate alternative pre-mRNA splicing by binding to the RNA element GCAUG. In the nucleus, most of Rbfox is bound to LASR, a complex of RNA-binding proteins that recognize additional RNA motifs. However, it remains unclear how the different subunits of the Rbfox/LASR complex act together to bind RNA and regulate splicing. We used a nuclease-protection assay to map the transcriptome-wide footprints of Rbfox1/LASR on nascent cellular RNA. In addition to GCAUG, Rbfox1/LASR binds RNA containing motifs for LASR subunits hnRNPs M, H/F, C, and Matrin3. These elements are often arranged in tandem, forming multi-part modules of RNA motifs. To distinguish contact sites of Rbfox1 from the LASR subunits, we analyzed a mutant Rbfox1(F125A) that has lost RNA binding but remains associated with LASR. Rbfox1(F125A)/LASR complexes no longer interact with GCAUG but retain binding to RNA elements for LASR. Splicing analyses reveal that in addition to activating exons through adjacent GCAUG elements, Rbfox can also stimulate exons near binding sites for LASR subunits. Mini-gene experiments demonstrate that these diverse elements produce a combined regulatory effect on a target exon. These findings illuminate how a complex of RNA-binding proteins can decode combinatorial splicing regulatory signals by recognizing groups of tandem RNA elements.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640236","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 : 2024-07-16DOI: 10.1101/2024.07.11.603079
Paul Hoffman, Matthew Bair
Identifying the brain systems that process concrete and abstract concepts is key to understanding the neural architecture of thought, memory and language. We review current theories of concreteness effects and test their neural predictions in a meta-analysis of 72 neuroimaging studies. Concrete concepts preferentially activated visual and action processing regions, particularly when presented in sentences, while abstract concepts preferentially activated networks for language, social cognition and semantic control. Specialisation for both concept types was present in the default mode network (DMN), with effects dissociating along a social-spatial axis. Concrete concepts generated greater activation in a medial temporal DMN component, implicated in constructing mental models of spatial contexts and scenes. Abstract concepts showed greater activation in frontotemporal DMN regions involved in theory-of-mind and language. These results support claims that generating models of situations and events is a core DMN function and indicate specialisation within DMN for different aspects of these models.
{"title":"Neural specialisation for concrete and abstract concepts revealed through meta-analysis","authors":"Paul Hoffman, Matthew Bair","doi":"10.1101/2024.07.11.603079","DOIUrl":"https://doi.org/10.1101/2024.07.11.603079","url":null,"abstract":"Identifying the brain systems that process concrete and abstract concepts is key to understanding the neural architecture of thought, memory and language. We review current theories of concreteness effects and test their neural predictions in a meta-analysis of 72 neuroimaging studies. Concrete concepts preferentially activated visual and action processing regions, particularly when presented in sentences, while abstract concepts preferentially activated networks for language, social cognition and semantic control. Specialisation for both concept types was present in the default mode network (DMN), with effects dissociating along a social-spatial axis. Concrete concepts generated greater activation in a medial temporal DMN component, implicated in constructing mental models of spatial contexts and scenes. Abstract concepts showed greater activation in frontotemporal DMN regions involved in theory-of-mind and language. These results support claims that generating models of situations and events is a core DMN function and indicate specialisation within DMN for different aspects of these models.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640554","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 : 2024-07-16DOI: 10.1101/2024.07.13.603403
Ingileif B. Hallgrímsdóttir, M. Carilli, L. Pachter
We describe a coordinate system and associated hypothesis testing framework for determining whether cis or trans regulation is responsible for differences in gene expression between two homozygous strains or species.
{"title":"Estimating cis and trans contributions to differences in gene regulation","authors":"Ingileif B. Hallgrímsdóttir, M. Carilli, L. Pachter","doi":"10.1101/2024.07.13.603403","DOIUrl":"https://doi.org/10.1101/2024.07.13.603403","url":null,"abstract":"We describe a coordinate system and associated hypothesis testing framework for determining whether cis or trans regulation is responsible for differences in gene expression between two homozygous strains or species.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640942","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 : 2024-07-16DOI: 10.1101/2024.07.15.602703
Julia Kleniuk, A. G. Nadadhur, Emily Wolfenden, Catherine Rodger, Eliska Zlamalova, Evan Reid
Protrudin binds ER-localised VAPs and endosomal phosphoinositides to form ER-endosome contacts that promote endosomal tubule fission and endosome-to-Golgi traffic. Protrudin recruits KIF5 to provide a FYCO1-independent force to fission endosomal tubules in neurons and non-polarised cells. Abstract Fission of transport tubules from early endosomes is required for endosomal sorting, but mechanisms of endosomal tubule fission (ETF) are incompletely understood. We show protrudin acts at ER-endosome contacts to promote ETF and endosome-to-Golgi traffic. Protrudin-mediated ETF required its ability to interact with ER-localised VAP proteins, endosomal phosphoinositides and KIF5. These properties also regulated the distance between protrudin and endosomal tubules. The defective ETF phenotype of increased endosomal tubulation in cells lacking protrudin was phenocopied by depletion of KIF5, but not FYCO1, a motor protein adaptor implicated in protrudin-dependent late endosome motility. It also required intact microtubules and dynein, consistent with a model where protrudin facilitates a tug-of-war between KIF5 and dynein to fission tubules. In addition to its direct role, protrudin links many other machineries involved in ETF, thus our findings elucidate how ETF is co-ordinated. These machineries are enriched for proteins implicated in hereditary motor neuron disorders, and protrudin or KIF5 depletion caused defective ETF in human neurons.
{"title":"Protrudin acts at ER-endosome contacts to promote KIF5-mediated endosomal fission and endosome-to-Golgi transport","authors":"Julia Kleniuk, A. G. Nadadhur, Emily Wolfenden, Catherine Rodger, Eliska Zlamalova, Evan Reid","doi":"10.1101/2024.07.15.602703","DOIUrl":"https://doi.org/10.1101/2024.07.15.602703","url":null,"abstract":"Protrudin binds ER-localised VAPs and endosomal phosphoinositides to form ER-endosome contacts that promote endosomal tubule fission and endosome-to-Golgi traffic. Protrudin recruits KIF5 to provide a FYCO1-independent force to fission endosomal tubules in neurons and non-polarised cells. Abstract Fission of transport tubules from early endosomes is required for endosomal sorting, but mechanisms of endosomal tubule fission (ETF) are incompletely understood. We show protrudin acts at ER-endosome contacts to promote ETF and endosome-to-Golgi traffic. Protrudin-mediated ETF required its ability to interact with ER-localised VAP proteins, endosomal phosphoinositides and KIF5. These properties also regulated the distance between protrudin and endosomal tubules. The defective ETF phenotype of increased endosomal tubulation in cells lacking protrudin was phenocopied by depletion of KIF5, but not FYCO1, a motor protein adaptor implicated in protrudin-dependent late endosome motility. It also required intact microtubules and dynein, consistent with a model where protrudin facilitates a tug-of-war between KIF5 and dynein to fission tubules. In addition to its direct role, protrudin links many other machineries involved in ETF, thus our findings elucidate how ETF is co-ordinated. These machineries are enriched for proteins implicated in hereditary motor neuron disorders, and protrudin or KIF5 depletion caused defective ETF in human neurons.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641858","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 : 2024-07-16DOI: 10.1101/2024.07.10.602985
Dominique Armstrong, Cheng-Yen Chang, Monica J. Hong, Linda Green, William Hudson, Yichao Shen, Li-Zhen Song, Sheetal Jammi, Benjamin Casal, Chad J. Creighton, Alexandre Carisey, X. Zhang, Neil J. McKenna, Sung Wook Kang, Hyun-Sung Lee, D. Corry, F. Kheradmand
Adaptive immunity is critical to eliminate malignant cells, while multiple tumor-intrinsic factors can alter this protective function. Melanoma antigen-A4 (MAGE-A4), a cancer-testis antigen, is expressed in several solid tumors and correlates with poor survival in non-small cell lung cancer (NSCLC), but its role in altering antitumor immunity remains unclear. We found that expression of MAGE-A4 was highly associated with the loss of PTEN, a tumor suppressor, in human NSCLC. Here we show that constitutive expression of human MAGE-A4 combined with the loss of Pten in mouse airway epithelial cells results in metastatic adenocarcinoma enriched in CD138+ CXCR4+ plasma cells, predominantly expressing IgA. Consistently, human NSCLC expressing MAGE-A4 showed increased CD138+ IgA+ plasma cell density surrounding tumors. The abrogation of MAGE-A4-responsive plasma cells (MARPs) decreased tumor burden, increased T cell infiltration and activation, and reduced CD163+CD206+ macrophages in mouse lungs. These findings suggest MAGE-A4 promotes NSCLC tumorigenesis, in part, through the recruitment and retention of IgA+ MARPs in the lungs.
{"title":"MAGE-A4-Responsive Plasma Cells Promote Non-Small Cell Lung Cancer","authors":"Dominique Armstrong, Cheng-Yen Chang, Monica J. Hong, Linda Green, William Hudson, Yichao Shen, Li-Zhen Song, Sheetal Jammi, Benjamin Casal, Chad J. Creighton, Alexandre Carisey, X. Zhang, Neil J. McKenna, Sung Wook Kang, Hyun-Sung Lee, D. Corry, F. Kheradmand","doi":"10.1101/2024.07.10.602985","DOIUrl":"https://doi.org/10.1101/2024.07.10.602985","url":null,"abstract":"Adaptive immunity is critical to eliminate malignant cells, while multiple tumor-intrinsic factors can alter this protective function. Melanoma antigen-A4 (MAGE-A4), a cancer-testis antigen, is expressed in several solid tumors and correlates with poor survival in non-small cell lung cancer (NSCLC), but its role in altering antitumor immunity remains unclear. We found that expression of MAGE-A4 was highly associated with the loss of PTEN, a tumor suppressor, in human NSCLC. Here we show that constitutive expression of human MAGE-A4 combined with the loss of Pten in mouse airway epithelial cells results in metastatic adenocarcinoma enriched in CD138+ CXCR4+ plasma cells, predominantly expressing IgA. Consistently, human NSCLC expressing MAGE-A4 showed increased CD138+ IgA+ plasma cell density surrounding tumors. The abrogation of MAGE-A4-responsive plasma cells (MARPs) decreased tumor burden, increased T cell infiltration and activation, and reduced CD163+CD206+ macrophages in mouse lungs. These findings suggest MAGE-A4 promotes NSCLC tumorigenesis, in part, through the recruitment and retention of IgA+ MARPs in the lungs.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643954","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}
Transcutaneous Vagus Nerve stimulation (tVNS) has been proposed as a prospective treatment for clinical conditions with altered GABAergic transmission. While possible effects of tVNS on behavioral performance in inhibitory control tasks have been previously reported, neurophysiological evidence showing its effects on GABA-mediated inhibition in the motor cortex is limited. Concurrently, the possible influence of participant’s gender and state conditions remains unexplored. Here, we applied, single- and paired-pulse TMS to the right or the left primary motor in two different groups of participants. We measured corticospinal excitability (CSE), short and long intracortical inhibition (SICI and LICI), cortical silent period (cSP) and intracortical facilitation (ICF) indexes. The measures were taken, in separated sessions of a within-subject design, at baseline prior to tVNS and after delivering active and sham tVNS in the Cymba conchae of the left ear. To exploit state dependent effects and assess the role of tVNS in motor learning, tVNS was applied, during the execution of a computerized visuomotor task. In the left TMS group, we observed better visuomotor performance during active than sham tVNS, regardless of participant’s gender. Interestingly, in both groups, we found a specific increase of SICI, which is mediated by GABAa activity, after active compared to sham-tVNS and baseline evaluations, which was specifically limited to female participants. No effects on CSE, ICF or GABAb-mediated intracortical inhibition indexes were observed. The results show specific effects of tVNS on motor learning and GABAa-mediated motor inhibition, providing supportive evidence for the application of tVNS as an alternative and coadjuvant treatment for disorders featured by altered inhibition mechanisms.
{"title":"Investigating the effects of transcutaneous Vagus Nerve Stimulation on motor cortex excitability and inhibition through paired-pulse Transcranial Magnetic Stimulation","authors":"Boscarol Sara, Turchi Letizia, Oldrati Viola, Urgesi Cosimo, Finisguerra Alessandra","doi":"10.1101/2024.07.12.603338","DOIUrl":"https://doi.org/10.1101/2024.07.12.603338","url":null,"abstract":"Transcutaneous Vagus Nerve stimulation (tVNS) has been proposed as a prospective treatment for clinical conditions with altered GABAergic transmission. While possible effects of tVNS on behavioral performance in inhibitory control tasks have been previously reported, neurophysiological evidence showing its effects on GABA-mediated inhibition in the motor cortex is limited. Concurrently, the possible influence of participant’s gender and state conditions remains unexplored. Here, we applied, single- and paired-pulse TMS to the right or the left primary motor in two different groups of participants. We measured corticospinal excitability (CSE), short and long intracortical inhibition (SICI and LICI), cortical silent period (cSP) and intracortical facilitation (ICF) indexes. The measures were taken, in separated sessions of a within-subject design, at baseline prior to tVNS and after delivering active and sham tVNS in the Cymba conchae of the left ear. To exploit state dependent effects and assess the role of tVNS in motor learning, tVNS was applied, during the execution of a computerized visuomotor task. In the left TMS group, we observed better visuomotor performance during active than sham tVNS, regardless of participant’s gender. Interestingly, in both groups, we found a specific increase of SICI, which is mediated by GABAa activity, after active compared to sham-tVNS and baseline evaluations, which was specifically limited to female participants. No effects on CSE, ICF or GABAb-mediated intracortical inhibition indexes were observed. The results show specific effects of tVNS on motor learning and GABAa-mediated motor inhibition, providing supportive evidence for the application of tVNS as an alternative and coadjuvant treatment for disorders featured by altered inhibition mechanisms.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641127","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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