Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Marion I. Stunault, Hao Zhang, Xiangfeng Niu, Marissa A. Laramie, Jasmin Sponagel, Leah P. Shriver, Gary J. Patti, Vitaly A. Klyachko, Ghazaleh Ashrafi
Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval—functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals.
长期以来，葡萄糖一直被认为是大脑的主要燃料来源。然而，在睡眠或电路活动期间，大脑中的葡萄糖水平会发生波动，从而造成重大的代谢压力。在这里，我们证明哺乳动物大脑使用丙酮酸作为燃料来源，并且丙酮酸可以在缺乏葡萄糖的情况下支持神经元的活力。神经末梢是代谢脆弱的部位，我们发现线粒体摄取丙酮酸是海马末梢产生氧化 ATP 的关键步骤。我们发现线粒体丙酮酸载体通过赖氨酸乙酰化进行翻译后修饰，进而调节线粒体丙酮酸摄取。我们的数据揭示了线粒体丙酮酸载体调节神经传递的不同步骤，即突触囊泡释放的时空模式和囊泡回收的效率--这些功能对突触可塑性具有深远影响。总之，我们发现丙酮酸是一种有效的神经元燃料，线粒体丙酮酸摄取是海马终端神经传递代谢控制的关键节点。
{"title":"Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission","authors":"Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Marion I. Stunault, Hao Zhang, Xiangfeng Niu, Marissa A. Laramie, Jasmin Sponagel, Leah P. Shriver, Gary J. Patti, Vitaly A. Klyachko, Ghazaleh Ashrafi","doi":"10.1126/sciadv.adp7423","DOIUrl":"10.1126/sciadv.adp7423","url":null,"abstract":"<div >Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval—functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp7423","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Geological storage and mineralization of CO2 in mafic/ultramafic reservoirs faces challenges including limited effective porosity, permeability, and rock reactivity; difficulties in using seawater for CO2 capture; and uncontrolled carbonation. This study introduces a CO2 capture, storage, and mineralization approach with the utilization of biobased biodegradable chelating agents and seawater. An acidic chelating agent solution is used to increase effective porosity and permeability through enhanced mineral dissolution. For instance, applying an acidic N,N-Bis(carboxymethyl)-L-glutamate solution to a porous basalt increased effective porosity by 16% and permeability by 26-fold in 120 hours. Subsequently, alkaline chelating agent–containing seawater improves CO2 capture and storage by inhibiting mineralization, thus maintaining injectivity while providing ions for mineralization and further expanding storage space. Last, controlled mineralization is achieved by adjusting chelating agent biodegradation. Promising CO2 storage and mineralization capacities two orders higher than current techniques, this approach reduces required reservoir volume while enhancing efficiency.
岩浆岩/超岩浆岩储层中二氧化碳的地质封存和矿化面临着各种挑战，包括有限的有效孔隙度、渗透率和岩石反应性；利用海水捕获二氧化碳的困难；以及不受控制的碳化。本研究介绍了一种利用生物基可生物降解螯合剂和海水进行二氧化碳捕获、封存和矿化的方法。酸性螯合剂溶液可通过提高矿物溶解度来增加有效孔隙率和渗透性。例如，在多孔玄武岩中使用酸性 N , N -双（羧甲基）- L -谷氨酸溶液，可在 120 小时内将有效孔隙率提高 16%，渗透性提高 26 倍。随后，含有碱性螯合剂的海水通过抑制矿化作用提高了二氧化碳的捕获和储存能力，从而在为矿化作用提供离子的同时保持了注入能力，并进一步扩大了储存空间。最后，通过调整螯合剂的生物降解，实现可控矿化。这种方法有望使二氧化碳的封存和矿化能力比现有技术高出两个数量级，从而在提高效率的同时减少所需的储层容积。
{"title":"CO2 capture, geological storage, and mineralization using biobased biodegradable chelating agents and seawater","authors":"Jiajie Wang, Ryota Sekiai, Ryota Tamura, Noriaki Watanabe","doi":"10.1126/sciadv.adq0515","DOIUrl":"10.1126/sciadv.adq0515","url":null,"abstract":"<div >Geological storage and mineralization of CO<sub>2</sub> in mafic/ultramafic reservoirs faces challenges including limited effective porosity, permeability, and rock reactivity; difficulties in using seawater for CO<sub>2</sub> capture; and uncontrolled carbonation. This study introduces a CO<sub>2</sub> capture, storage, and mineralization approach with the utilization of biobased biodegradable chelating agents and seawater. An acidic chelating agent solution is used to increase effective porosity and permeability through enhanced mineral dissolution. For instance, applying an acidic <i>N</i>,<i>N</i>-Bis(carboxymethyl)-<i>L</i>-glutamate solution to a porous basalt increased effective porosity by 16% and permeability by 26-fold in 120 hours. Subsequently, alkaline chelating agent–containing seawater improves CO<sub>2</sub> capture and storage by inhibiting mineralization, thus maintaining injectivity while providing ions for mineralization and further expanding storage space. Last, controlled mineralization is achieved by adjusting chelating agent biodegradation. Promising CO<sub>2</sub> storage and mineralization capacities two orders higher than current techniques, this approach reduces required reservoir volume while enhancing efficiency.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq0515","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Manuel Santos Gutiérrez, Mickaël David Chekroun, Ilan Koren
Cloud microphysics studies include how tiny cloud droplets grow and become rain. This is crucial for understanding cloud properties like size, life span, and impact on climate through radiative effects. Small weak-updraft clouds near the haze-to-cloud transition are especially difficult to measure and understand. They are abundant but hard to capture by satellites. Köhler’s theory explains initial droplet growth but struggles with large particle groups. Here, we present a stochastic, analytical framework building on Köhler’s theory to account for (monodisperse) aerosols and cloud droplet interaction through competitive growth in a limited water vapor field. These interactions are modeled by sink terms, while fluctuations in supersaturation affecting droplet growth are modeled by nonlinear white noise terms. Our results identify hysteresis mechanisms in the droplet activation and deactivation processes. Our approach allows for multimodal cloud’s droplet size distributions supported by laboratory experiments, offering a different perspective on haze-to-cloud transition and small cloud formation.
{"title":"Gibbs states and Brownian models for coexisting haze and cloud droplets","authors":"Manuel Santos Gutiérrez, Mickaël David Chekroun, Ilan Koren","doi":"10.1126/sciadv.adq7518","DOIUrl":"10.1126/sciadv.adq7518","url":null,"abstract":"<div >Cloud microphysics studies include how tiny cloud droplets grow and become rain. This is crucial for understanding cloud properties like size, life span, and impact on climate through radiative effects. Small weak-updraft clouds near the haze-to-cloud transition are especially difficult to measure and understand. They are abundant but hard to capture by satellites. Köhler’s theory explains initial droplet growth but struggles with large particle groups. Here, we present a stochastic, analytical framework building on Köhler’s theory to account for (monodisperse) aerosols and cloud droplet interaction through competitive growth in a limited water vapor field. These interactions are modeled by sink terms, while fluctuations in supersaturation affecting droplet growth are modeled by nonlinear white noise terms. Our results identify hysteresis mechanisms in the droplet activation and deactivation processes. Our approach allows for multimodal cloud’s droplet size distributions supported by laboratory experiments, offering a different perspective on haze-to-cloud transition and small cloud formation.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq7518","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Runye Shi, Xiao Chang, Tobias Banaschewski, Gareth J. Barker, Arun L. W. Bokde, Sylvane Desrivières, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Rüdiger Brühl, Jean-Luc Martinot, Marie-Laure Paillère Martinot17,, Eric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Luise Poustka, Sarah Hohmann, Nathalie Holz, Michael N. Smolka, Nilakshi Vaidya, Henrik Walter, Robert Whelan, Gunter Schumann, Xiaolei Lin, Jianfeng Feng, IMAGEN Consortium
Maternal education was strongly correlated with adolescent brain morphology, cognitive performances, and mental health. However, the molecular basis for the effects of maternal education on the structural neurodevelopment remains unknown. Here, we conducted gene-environment–wide interaction study using the Adolescent Brain Cognitive Development cohort. Seven genomic loci with significant gene-environment interactions (G×E) on regional gray matter volumes were identified, with enriched biological functions related to metabolic process, inflammatory process, and synaptic plasticity. Additionally, genetic overlapping results with behavioral and disease-related phenotypes indicated shared biological mechanism between maternal education modified neurodevelopment and related behavioral traits. Finally, by decomposing the multidimensional components of maternal education, we found that socioeconomic status, rather than family environment, played a more important role in modifying the genetic effects on neurodevelopment. In summary, our study provided analytical evidence for G×E effects regarding adolescent neurodevelopment and explored potential biological mechanisms as well as social mechanisms through which maternal education could modify the genetic effects on regional brain development.
{"title":"Gene-environment interactions in the influence of maternal education on adolescent neurodevelopment using ABCD study","authors":"Runye Shi, Xiao Chang, Tobias Banaschewski, Gareth J. Barker, Arun L. W. Bokde, Sylvane Desrivières, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Rüdiger Brühl, Jean-Luc Martinot, Marie-Laure Paillère Martinot17,, Eric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Luise Poustka, Sarah Hohmann, Nathalie Holz, Michael N. Smolka, Nilakshi Vaidya, Henrik Walter, Robert Whelan, Gunter Schumann, Xiaolei Lin, Jianfeng Feng, IMAGEN Consortium","doi":"10.1126/sciadv.adp3751","DOIUrl":"10.1126/sciadv.adp3751","url":null,"abstract":"<div >Maternal education was strongly correlated with adolescent brain morphology, cognitive performances, and mental health. However, the molecular basis for the effects of maternal education on the structural neurodevelopment remains unknown. Here, we conducted gene-environment–wide interaction study using the Adolescent Brain Cognitive Development cohort. Seven genomic loci with significant gene-environment interactions (G×E) on regional gray matter volumes were identified, with enriched biological functions related to metabolic process, inflammatory process, and synaptic plasticity. Additionally, genetic overlapping results with behavioral and disease-related phenotypes indicated shared biological mechanism between maternal education modified neurodevelopment and related behavioral traits. Finally, by decomposing the multidimensional components of maternal education, we found that socioeconomic status, rather than family environment, played a more important role in modifying the genetic effects on neurodevelopment. In summary, our study provided analytical evidence for G×E effects regarding adolescent neurodevelopment and explored potential biological mechanisms as well as social mechanisms through which maternal education could modify the genetic effects on regional brain development.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Morphological features of organismal body plans are often highly conserved within large taxa. For example, segmentation is a shared and defining feature of all insects. Screens in Drosophila identified genes responsible for the development of body segments, including the “pair-rule” genes (PRGs), which subdivide embryos into double-segment units in a previously unexpected pre-patterning step. Here we show that the milkweed bug Oncopeltus fasciatus also uses a pair rule for embryo subdivision but Oncopeltus employs different genes for this process. We identified the gene Blimp1 as an Oncopeltus PRG based on its expression pattern, tested its function with RNA interference and CRISPR-Cas9, and generated the first PR mutant in this species. Although it does not have PR function in Drosophila, like Drosophila PRGs, Blimp1 encodes a transcription factor required for embryonic viability. Thus, pair-rule subdivision of the insect body plan is more highly conserved than the factors mediating this process, suggesting a developmental constraint on this pre-patterning step.
{"title":"Same rule, different genes: Blimp1 is a pair-rule gene in the milkweed bug Oncopeltus fasciatus","authors":"Katie Reding, Matthew Chung, Abigail Heath, Julie Dunning Hotopp, Leslie Pick","doi":"10.1126/sciadv.adq9045","DOIUrl":"10.1126/sciadv.adq9045","url":null,"abstract":"<div >Morphological features of organismal body plans are often highly conserved within large taxa. For example, segmentation is a shared and defining feature of all insects. Screens in <i>Drosophila</i> identified genes responsible for the development of body segments, including the “pair-rule” genes (PRGs), which subdivide embryos into double-segment units in a previously unexpected pre-patterning step. Here we show that the milkweed bug <i>Oncopeltus fasciatus</i> also uses a pair rule for embryo subdivision but <i>Oncopeltus</i> employs different genes for this process. We identified the gene <i>Blimp1</i> as an <i>Oncopeltus</i> PRG based on its expression pattern, tested its function with RNA interference and CRISPR-Cas9, and generated the first PR mutant in this species. Although it does not have PR function in <i>Drosophila</i>, like <i>Drosophila</i> PRGs, <i>Blimp1</i> encodes a transcription factor required for embryonic viability. Thus, pair-rule subdivision of the insect body plan is more highly conserved than the factors mediating this process, suggesting a developmental constraint on this pre-patterning step.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adq9045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyun-Kyu Choi, Stefano Travaglino, Matthias Münchhalfen, Richard Görg, Zhe Zhong, Jintian Lyu, David M. Reyes-Aguilar, Jürgen Wienands, Ankur Singh, Cheng Zhu
B cell maturation depends on cognate interactions between the T and B cells. Upon interaction with CD40 ligand (CD40L) on T cells, CD40 delivers costimulatory signals alongside B cell antigen receptor (BCR) signaling to regulate affinity maturation and antibody class switch. Mutations affecting CD40-CD40L interactions cause abnormal antibody responses in immunodeficiencies known as X-linked hyper-IgM syndrome (X-HIgM). Here, we study the CD40-mediated mechanotransduction in B cells, which likely occurs during their physical contacts with T cells. We found that CD40 forms catch bond with CD40L that lasts longer at larger forces, both B and T cells exert tension on CD40-CD40L bonds, and force enhances CD40 signaling and antibody class switch. X-HIgM CD40L mutations impair catch bond formation, suppress endogenous tension, and reduce force-enhanced CD40 signaling, leading to deficiencies in antibody class switch. Our findings highlight the role of mechanotransduction in CD40 function and provide insights into the mechanisms underlying X-HIgM syndrome.
B 细胞的成熟取决于 T 细胞和 B 细胞之间的同源相互作用。在与 T 细胞上的 CD40 配体（CD40L）相互作用时，CD40 与 B 细胞抗原受体（BCR）信号一起传递成本刺激信号，以调节亲和力成熟和抗体类别转换。影响 CD40-CD40L 相互作用的突变会导致异常抗体反应，这种免疫缺陷被称为 X 连锁高 IgM 综合征（X-HIgM）。在这里，我们研究了 CD40 介导的 B 细胞机械传导，这种传导可能发生在 B 细胞与 T 细胞的物理接触过程中。我们发现，CD40与CD40L形成的捕捉键在较大的力作用下会持续更长时间，B细胞和T细胞都会对CD40-CD40L键施加张力，力会增强CD40信号转导和抗体类别转换。X-HIgM CD40L 基因突变会损害捕捉键的形成，抑制内源性张力，减少受力增强的 CD40 信号传导，从而导致抗体类别转换的缺陷。我们的研究结果突显了机械传导在 CD40 功能中的作用，并为 X-HIgM 综合征的内在机制提供了见解。
{"title":"Mechanotransduction governs CD40 function and underlies X-linked hyper-IgM syndrome","authors":"Hyun-Kyu Choi, Stefano Travaglino, Matthias Münchhalfen, Richard Görg, Zhe Zhong, Jintian Lyu, David M. Reyes-Aguilar, Jürgen Wienands, Ankur Singh, Cheng Zhu","doi":"10.1126/sciadv.adl5815","DOIUrl":"10.1126/sciadv.adl5815","url":null,"abstract":"<div >B cell maturation depends on cognate interactions between the T and B cells. Upon interaction with CD40 ligand (CD40L) on T cells, CD40 delivers costimulatory signals alongside B cell antigen receptor (BCR) signaling to regulate affinity maturation and antibody class switch. Mutations affecting CD40-CD40L interactions cause abnormal antibody responses in immunodeficiencies known as X-linked hyper-IgM syndrome (X-HIgM). Here, we study the CD40-mediated mechanotransduction in B cells, which likely occurs during their physical contacts with T cells. We found that CD40 forms catch bond with CD40L that lasts longer at larger forces, both B and T cells exert tension on CD40-CD40L bonds, and force enhances CD40 signaling and antibody class switch. X-HIgM CD40L mutations impair catch bond formation, suppress endogenous tension, and reduce force-enhanced CD40 signaling, leading to deficiencies in antibody class switch. Our findings highlight the role of mechanotransduction in CD40 function and provide insights into the mechanisms underlying X-HIgM syndrome.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adl5815","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Damian Kovalovsky, Satish Noonepalle, Manasa Suresh, Dileep Kumar, Michael Berrigan, Nithya Gajendran, Sumit Upadhyay, Anelia Horvath, Allen Kim, David Quiceno-Torres, Karthik Musunuri, Alejandro Villagra
Histone deacetylase 6 (HDAC6) inhibition is associated with an increased pro-inflammatory tumor microenvironment and antitumoral immune responses. Here, we show that the HDAC6 inhibitor AVS100 (SS208) had an antitumoral effect in SM1 melanoma and CT26 colon cancer models and increased the efficacy of anti–programmed cell death protein 1 treatment, leading to complete remission in melanoma and increased response in colon cancer. AVS100 treatment increased pro-inflammatory tumor-infiltrating macrophages and CD8 effector T cells with an inflammatory and T cell effector gene signature. Acquired T cell immunity and long-term protection were evidenced as increased immunodominant T cell clones after AVS100 treatment. Last, AVS100 showed no mutagenicity, toxicity, or adverse effects in preclinical good laboratory practice studies, part of the package that has led to US Food and Drug Administration clearance of an investigational new drug application for initiating clinical trials. This would be a first-in-human combination therapy of pembrolizumab with HDAC6 inhibition for locally advanced or metastatic solid tumors.
组蛋白去乙酰化酶6（HDAC6）抑制与促炎性肿瘤微环境和抗肿瘤免疫反应的增加有关。在这里，我们发现 HDAC6 抑制剂 AVS100（SS208）在 SM1 黑色素瘤和 CT26 结肠癌模型中具有抗肿瘤作用，并提高了抗程序性细胞死亡蛋白 1 治疗的疗效，导致黑色素瘤完全缓解和结肠癌反应增强。AVS100 治疗增加了促炎性肿瘤浸润巨噬细胞和 CD8 效应 T 细胞，并具有炎症和 T 细胞效应基因特征。AVS100 治疗后，免疫优势 T 细胞克隆增加，证明了获得性 T 细胞免疫和长期保护。最后，AVS100 在临床前良好实验室实践研究中未显示出诱变性、毒性或不良反应。这将是人类首次将 pembrolizumab 与 HDAC6 抑制剂联合治疗局部晚期或转移性实体瘤。
{"title":"The HDAC6 inhibitor AVS100 (SS208) induces a pro-inflammatory tumor microenvironment and potentiates immunotherapy","authors":"Damian Kovalovsky, Satish Noonepalle, Manasa Suresh, Dileep Kumar, Michael Berrigan, Nithya Gajendran, Sumit Upadhyay, Anelia Horvath, Allen Kim, David Quiceno-Torres, Karthik Musunuri, Alejandro Villagra","doi":"10.1126/sciadv.adp3687","DOIUrl":"10.1126/sciadv.adp3687","url":null,"abstract":"<div >Histone deacetylase 6 (HDAC6) inhibition is associated with an increased pro-inflammatory tumor microenvironment and antitumoral immune responses. Here, we show that the HDAC6 inhibitor AVS100 (SS208) had an antitumoral effect in SM1 melanoma and CT26 colon cancer models and increased the efficacy of anti–programmed cell death protein 1 treatment, leading to complete remission in melanoma and increased response in colon cancer. AVS100 treatment increased pro-inflammatory tumor-infiltrating macrophages and CD8 effector T cells with an inflammatory and T cell effector gene signature. Acquired T cell immunity and long-term protection were evidenced as increased immunodominant T cell clones after AVS100 treatment. Last, AVS100 showed no mutagenicity, toxicity, or adverse effects in preclinical good laboratory practice studies, part of the package that has led to US Food and Drug Administration clearance of an investigational new drug application for initiating clinical trials. This would be a first-in-human combination therapy of pembrolizumab with HDAC6 inhibition for locally advanced or metastatic solid tumors.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp3687","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Morphogen gradients instruct cells to pattern tissues. Although the mechanisms by which morphogens transduce chemical signals have been extensively studied, the roles and regulation of the physical communication between morphogen-receiver cells remain unclear. Here, we show that the Wnt/β-catenin–morphogen gradient, which patterns the embryonic anterior-posterior (AP) axis, generates intercellular tension gradients along the AP axis by controlling membrane cadherin levels in zebrafish embryos. This “mechano-gradient” is used for the cell competition–driven correction of noisy morphogen gradients. Naturally and artificially generated unfit cells, producing noisy Wnt/β-catenin gradients, induce local deformation of the mechano-gradients that activate mechanosensitive calcium channels in the neighboring fit cells, which then secrete annexin A1a to kill unfit cells. Thus, chemo-mechanical interconversion–mediated competitive communication between the morphogen-receiver cells ensures precise tissue patterning.
{"title":"Mechano-gradients drive morphogen-noise correction to ensure robust patterning","authors":"Kana Aoki, Taiki Higuchi, Yuki Akieda, Kotone Matsubara, Yasuyuki Ohkawa, Tohru Ishitani","doi":"10.1126/sciadv.adp2357","DOIUrl":"10.1126/sciadv.adp2357","url":null,"abstract":"<div >Morphogen gradients instruct cells to pattern tissues. Although the mechanisms by which morphogens transduce chemical signals have been extensively studied, the roles and regulation of the physical communication between morphogen-receiver cells remain unclear. Here, we show that the Wnt/β-catenin–morphogen gradient, which patterns the embryonic anterior-posterior (AP) axis, generates intercellular tension gradients along the AP axis by controlling membrane cadherin levels in zebrafish embryos. This “mechano-gradient” is used for the cell competition–driven correction of noisy morphogen gradients. Naturally and artificially generated unfit cells, producing noisy Wnt/β-catenin gradients, induce local deformation of the mechano-gradients that activate mechanosensitive calcium channels in the neighboring fit cells, which then secrete annexin A1a to kill unfit cells. Thus, chemo-mechanical interconversion–mediated competitive communication between the morphogen-receiver cells ensures precise tissue patterning.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp2357","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tobias Zachs, Jessie James L. Malit, Jingwei Xu, Alexandra Schürch, Shamphavi Sivabalasarma, Phillip Nußbaum, Sonja-Verena Albers, Martin Pilhofer
Microbial communities are shaped by cell-cell interactions. Although archaea are often found in associations with other microorganisms, the mechanisms structuring these communities are poorly understood. Here, we report on the structure and function of haloarchaeal contractile injection systems (CISs). Using a combination of functional assays and time-lapse imaging, we show that Halogeometricum borinquense exhibits antagonism toward Haloferax volcanii by inducing cell lysis and inhibiting proliferation. This antagonism is contact-dependent and requires a functional CIS, which is encoded by a gene cluster that is associated with toxin-immunity pairs. Cryo–focused ion beam milling and imaging by cryo–electron tomography revealed that these CISs are bound to the cytoplasmic membrane, resembling the bacterial type six secretion systems (T6SSs). We show that related T6SS gene clusters are conserved and expressed in other haloarchaeal strains, which exhibit antagonistic behavior. Our data provide a mechanistic framework for understanding how archaea may shape microbial communities and affect the food webs they inhabit.
{"title":"Archaeal type six secretion system mediates contact-dependent antagonism","authors":"Tobias Zachs, Jessie James L. Malit, Jingwei Xu, Alexandra Schürch, Shamphavi Sivabalasarma, Phillip Nußbaum, Sonja-Verena Albers, Martin Pilhofer","doi":"10.1126/sciadv.adp7088","DOIUrl":"10.1126/sciadv.adp7088","url":null,"abstract":"<div >Microbial communities are shaped by cell-cell interactions. Although archaea are often found in associations with other microorganisms, the mechanisms structuring these communities are poorly understood. Here, we report on the structure and function of haloarchaeal contractile injection systems (CISs). Using a combination of functional assays and time-lapse imaging, we show that <i>Halogeometricum borinquense</i> exhibits antagonism toward <i>Haloferax volcanii</i> by inducing cell lysis and inhibiting proliferation. This antagonism is contact-dependent and requires a functional CIS, which is encoded by a gene cluster that is associated with toxin-immunity pairs. Cryo–focused ion beam milling and imaging by cryo–electron tomography revealed that these CISs are bound to the cytoplasmic membrane, resembling the bacterial type six secretion systems (T6SSs). We show that related T6SS gene clusters are conserved and expressed in other haloarchaeal strains, which exhibit antagonistic behavior. Our data provide a mechanistic framework for understanding how archaea may shape microbial communities and affect the food webs they inhabit.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp7088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jonathan Lagos, Ursula Holder, Sara Sagadiev, Andrea Montiel-Armendariz, Lucy Z. Li, Chandrashekhar Pasare, Baidong Hou, Jessica A. Hamerman, Mridu Acharya
B cell adapter for PI 3-kinase (BCAP) is an adaptor molecule associated with signaling through multiple immune receptors, including the B cell receptor (BCR). However, B cell–intrinsic role of BCAP in antibody responses is unclear. We investigated the role of BCAP in B cell response to viral particles and found a previously unidentified mechanism by which BCAP regulates antigen-specific responses. B cell–specific deletion of BCAP in mice leads to decreases in antigen-specific responses through defects in BCR-antigen endocytosis. BCAP is necessary to orchestrate actin reorganization around the antigen for efficient endocytosis through BCR and intracellular processing of antigens. Therefore, loss of BCAP from B cells leads to defects in antigen endocytosis, hampering the propagation of antigen-derived signals and decreasing the ability of B cells to present antigens to T cells. Thus, our study clarifies how BCAP regulates B cell responses to complex antigens and elucidates that antigen positioning inside B cells determines different B cell activation outcomes.
PI 3-激酶的 B 细胞适配器（BCAP）是一种与通过包括 B 细胞受体（BCR）在内的多种免疫受体发出信号有关的适配器分子。然而，BCAP 在抗体反应中的 B 细胞内在作用尚不清楚。我们研究了 BCAP 在 B 细胞对病毒颗粒的反应中的作用，发现了 BCAP 调节抗原特异性反应的一种以前未发现的机制。小鼠B细胞特异性缺失BCAP会导致BCR-抗原内吞缺陷，从而降低抗原特异性反应。BCAP 是协调抗原周围肌动蛋白重组的必要条件，以便通过 BCR 进行有效的内吞，并在细胞内处理抗原。因此，B细胞中 BCAP 的缺失会导致抗原内吞缺陷，阻碍抗原衍生信号的传播，降低 B 细胞向 T 细胞展示抗原的能力。因此，我们的研究阐明了 BCAP 如何调节 B 细胞对复杂抗原的反应，并阐明了 B 细胞内的抗原定位决定了 B 细胞活化的不同结果。
{"title":"B cell adapter for PI 3-kinase (BCAP) coordinates antigen internalization and trafficking through the B cell receptor","authors":"Jonathan Lagos, Ursula Holder, Sara Sagadiev, Andrea Montiel-Armendariz, Lucy Z. Li, Chandrashekhar Pasare, Baidong Hou, Jessica A. Hamerman, Mridu Acharya","doi":"10.1126/sciadv.adp1747","DOIUrl":"10.1126/sciadv.adp1747","url":null,"abstract":"<div >B cell adapter for PI 3-kinase (BCAP) is an adaptor molecule associated with signaling through multiple immune receptors, including the B cell receptor (BCR). However, B cell–intrinsic role of BCAP in antibody responses is unclear. We investigated the role of BCAP in B cell response to viral particles and found a previously unidentified mechanism by which BCAP regulates antigen-specific responses. B cell–specific deletion of BCAP in mice leads to decreases in antigen-specific responses through defects in BCR-antigen endocytosis. BCAP is necessary to orchestrate actin reorganization around the antigen for efficient endocytosis through BCR and intracellular processing of antigens. Therefore, loss of BCAP from B cells leads to defects in antigen endocytosis, hampering the propagation of antigen-derived signals and decreasing the ability of B cells to present antigens to T cells. Thus, our study clarifies how BCAP regulates B cell responses to complex antigens and elucidates that antigen positioning inside B cells determines different B cell activation outcomes.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"10 46","pages":""},"PeriodicalIF":11.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adp1747","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号