Proceedings of the National Academy of Sciences of the United States of America最新文献

{"title":"Synaptic Gα12/13 signaling establishes hippocampal PV inhibitory circuits","authors":"Krassimira Garbett, Baris Tosun, Jaybree M. Lopez, Cassandra M. Smith, Kelly Honkanen, Richard C. Sando","doi":"10.1073/pnas.2407828121","DOIUrl":"https://doi.org/10.1073/pnas.2407828121","url":null,"abstract":"Combinatorial networks of cell adhesion molecules and cell surface receptors drive fundamental aspects of neural circuit establishment and function. However, the intracellular signals orchestrated by these cell surface complexes remain less understood. Here, we report that the Gα12/13 pathway lies downstream of several GPCRs with critical synaptic functions. Impairment of the Gα12/13 pathway in postnatal hippocampal neurons diminishes inhibitory inputs without altering neuronal morphology or excitatory transmission. Gα12/13 signaling in hippocampal CA1 neurons in vivo selectively regulates PV interneuron synaptic connectivity, supporting an inhibitory synapse subtype-specific function of this pathway. Our studies establish Gα12/13 as a signaling node that shapes inhibitory hippocampal circuitry.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"23 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging of tumor-associated macrophage dynamics during immunotherapy using a CD163-specific nanobody-based immunotracer","authors":"Yoline Lauwers, Timo W. M. De Groof, Cécile Vincke, Jolien Van Craenenbroeck, Neema Ahishakiye Jumapili, Romina Mora Barthelmess, Guillaume Courtoy, Wim Waelput, Tessa De Pauw, Geert Raes, Nick Devoogdt, Jo A. Van Ginderachter","doi":"10.1073/pnas.2409668121","DOIUrl":"https://doi.org/10.1073/pnas.2409668121","url":null,"abstract":"Immunotherapies have emerged as an effective treatment option for immune-related diseases, such as cancer and inflammatory diseases. However, variations in patient responsiveness limit the broad applicability and success of these immunotherapies. Noninvasive whole-body imaging of the immune status of individual patients during immunotherapy could enable the prediction and monitoring of the patient’s response, resulting in more personalized treatments. In this study, we developed a nanobody-based immunotracer targeting CD163, a receptor specifically expressed on macrophages. This anti-CD163 immunotracer bound to human and mouse CD163 with high affinity and specificity without competing for ligand binding. Furthermore, the tracer showed no unwanted immune cell activation and was nonimmunogenic. Upon radiolabeling of the anti-CD163 immunotracer, specific imaging of CD163 <jats:sup>+</jats:sup> macrophages using micro-single-photon emission computerized tomography/computed tomography or micro-positron emission tomography/CT was performed. The anti-CD163 immunotracer was able to stratify immunotherapy responders from nonresponders (NR) by visualizing differences in the intratumoral CD163 <jats:sup>+</jats:sup> TAM distribution in Lewis lung carcinoma-ovalbumin tumor-bearing mice receiving an anti-programmed cell death protein-1 (PD-1)/CSF1R combination treatment. Immunotherapy-responding mice showed a more homogeneous distribution of the PET signal in the middle of the tumor, while CD163 <jats:sup>+</jats:sup> TAMs were located at the tumor periphery in NR. As such, visualization of CD163 <jats:sup>+</jats:sup> TAM distribution in the tumor microenvironment could allow a prediction or follow-up of therapy response. Altogether, this study describes an immunotracer, specific for CD163 <jats:sup>+</jats:sup> macrophages, that allows same-day imaging and follow-up of these immune cells in the tumor microenvironment, providing a good basis for the prediction and follow-up of immunotherapy responses in cancer patients.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"52 6 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response","authors":"Heng Wang, Fang Xu, Chenlu Yao, Huaxing Dai, Jialu Xu, Bingbing Wu, Bo Tian, Xiaolin Shi, Chao Wang","doi":"10.1073/pnas.2412070121","DOIUrl":"https://doi.org/10.1073/pnas.2412070121","url":null,"abstract":"Inhibiting indoleamine 2,3 dioxygenase (IDO) for anticancer therapy has garnered significant attention in recent years. However, current IDO inhibitors face significant challenges which limit their clinical application. Here, we genetically engineered a high tryptophan-expressing <jats:italic>Clostridium butyricum</jats:italic> (L-Trp CB) strain that can colonize tumors strictly following systemic administration. We revealed that butyrate produced by L-Trp CB can inhibit IDO activity, preventing tryptophan catabolism and kynurenine accumulation in tumors. In addition, the large released tryptophan by L-Trp CB can provide discrete signals that support CD8+ T cell activation and energy metabolism within the tumor microenvironment. We observed that L-Trp CB significantly restored the proportion and function of CD8+ T cells, leading to significantly delayed tumor growth in both mouse and rabbit multiple tumor models with limited side effects. We here provide a synthetic biology treatment strategy for enhanced tumor immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response in tumors.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"23 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corticosteroids reduce pathological angiogenesis yet compromise reparative vascular remodeling in a model of retinopathy","authors":"Masayuki Hata, Maki Hata, Agnieszka Dejda, Frédérique Pilon, Roberto Diaz-Marin, Frédérik Fournier, Jean-Sebastien Joyal, Gael Cagnone, Yotaro Ochi, Sergio Crespo-Garcia, Ariel M. Wilson, Przemyslaw Sapieha","doi":"10.1073/pnas.2411640121","DOIUrl":"https://doi.org/10.1073/pnas.2411640121","url":null,"abstract":"Tissue inflammation is often broadly associated with cellular damage, yet sterile inflammation also plays critical roles in beneficial tissue remodeling. In the central nervous system, this is observed through a predominantly innate immune response in retinal vascular diseases such as age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. Here, we set out to elucidate the dynamics of the immune response during progression and regression of pathological neovascularization in retinopathy. In a mouse model of oxygen-induced retinopathy, we report that dexamethasone, a broad-spectrum corticosteroid, suppresses initial formation of pathological preretinal neovascularization in early stages of disease, yet blunts reparative inflammation by impairing distinct myeloid cell populations, and hence reduces beneficial vascular remodeling in later stages of disease. Using genetic depletion of distinct components of the innate immune response, we demonstrate that CX3C chemokine receptor 1-expressing microglia contribute to angiogenesis. Conversely, myeloid cells expressing lysozyme 2 are recruited to sites of damaged blood vessels and pathological neovascularization where they partake in a reparative process that ultimately restores circulatory homeostasis to the retina. Hence, the Janus-faced properties of anti-inflammatory drugs should be considered, particularly in stages associated with persistent neovascularization.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"58 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GSK3β phosphorylation catalyzes the aggregation of tau into Alzheimer's disease-like filaments","authors":"Pijush Chakraborty, Alain Ibáñez de Opakua, Jeffrey A. Purslow, Simon A. Fromm, Debdeep Chatterjee, Milan Zachrdla, Shannon Zhuang, Sambhavi Puri, Benjamin Wolozin, Markus Zweckstetter","doi":"10.1073/pnas.2414176121","DOIUrl":"https://doi.org/10.1073/pnas.2414176121","url":null,"abstract":"The pathological deposition of proteins is a hallmark of several devastating neurodegenerative diseases. These pathological deposits comprise aggregates of proteins that adopt distinct structures named strains. However, the molecular factors responsible for the formation of distinct aggregate strains are unknown. Here, we show that the serine/threonine kinase GSK3β catalyzes the aggregation of the protein tau into Alzheimer’s disease (AD)-like filaments. We demonstrate that phosphorylation by GSK3β, but not by several other kinases, promotes the aggregation of full-length tau as well as enhances phase separation into gel-like condensate structures. Cryoelectron microscopy further reveals that the fibrils formed by GSK3β-phosphorylated tau adopt a fold comparable to that of paired helical filaments isolated from the brains of AD patients. Our results elucidate the intricate relationship between posttranslational modification and the formation of tau strains in neurodegenerative diseases.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"12 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complement C3d enables cell-mediated immunity capable of distinguishing spontaneously transformed from nontransformed cells","authors":"Jeffrey L. Platt, Chong Zhao, Jeffrey Chicca, Matthew J. Pianko, Joshua Han, Stephanie The, Arvind Rao, Evan T. Keller, Mayara Garcia de Mattos Barbosa, Lwar Naing, Tracy Pasieka-Axenov, Lev Axenov, Simon Schaefer, Evan Farkash, Marilia Cascalho","doi":"10.1073/pnas.2405824121","DOIUrl":"https://doi.org/10.1073/pnas.2405824121","url":null,"abstract":"Immune surveillance depends in part on the recognition of peptide variants by T cell antigen receptors. Given that both normal B cells and malignant B cells accumulate mutations we chose a murine model of multiple myeloma to test conditions to induce cell-mediated immunity targeting malignant plasma cell (PC) clones but sparing of normal PCs. Revealing a previously unknown function for intracellular C3d, we found that C3d engaged T cell responses against malignant PC in the bone marrow of mice that had developed multiple myeloma spontaneously. Our results show that C3d internalized by cells augments immune surveillance by several mechanisms. In one, C3d induces a master transcription regulator, E2f1, to increase the expression of long noncoding (lnc) RNAs, to generate peptides for MHC-I presentation, and increase MHC-I expression. In another, C3d increases expression of RNAs encoding ribosomal proteins linked to processing of defective ribosomal products that arise from noncanonical translation and known to promote immunosurveillance. Cancer cells are uniquely susceptible to increased expression and presentation of mutant peptides given the extent of protein misfolding and accumulation of somatic mutations. Accordingly, although C3d can be internalized by any cell, C3d preferentially targets malignant clones by evoking specific T cell–mediated immunity and sparing most nontransformed polyclonal B cells and PC with lower mutation loads. Malignant PC deletion was blocked by cyclosporin or by CD8 depletion confirming that endogenous T cells mediated malignant clone clearance. Besides the potential for therapeutic application our results highlight how intracellular C3d modifies cellular metabolism to augment immune surveillance.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"260 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic analysis of the sponge Aggregation Factor implicates an ancient toolkit for allorecognition and adhesion in animals","authors":"Fabian Ruperti, Monika Dzieciatkowska, M. Sabrina Pankey, Cedric S. Asensio, Dario Anselmetti, Xavier Fernàndez-Busquets, Scott A. Nichols","doi":"10.1073/pnas.2409125121","DOIUrl":"https://doi.org/10.1073/pnas.2409125121","url":null,"abstract":"The discovery that sponges (Porifera) can fully regenerate from aggregates of dissociated cells launched them as one of the earliest experimental models to study the evolution of cell adhesion and allorecognition in animals. This process depends on an extracellular glycoprotein complex called the Aggregation Factor (AF), which is composed of proteins thought to be unique to sponges. We used quantitative proteomics to identify additional AF components and interacting proteins in the classical model, <jats:italic>Clathria prolifera</jats:italic> , and compared them to proteins involved in cell interactions in Bilateria. Our results confirm MAFp3/p4 proteins as the primary components of the AF but implicate related proteins with calx-beta and wreath domains as additional components. Using AlphaFold, we unveiled close structural similarities of AF components to protein domains in other animals, previously masked by the mutational decay of sequence similarity. The wreath domain, believed to be unique to the AF, was predicted to contain a central beta-sandwich of the same organization as the vWFD domain (also found in extracellular, gel-forming glycoproteins in other animals). Additionally, many copurified proteins share a conserved C-terminus, containing divergent immunoglobulin (Ig) and Fn3 domains predicted to serve as an AF–interaction interface. One of these proteins, MAF-associated protein 1, resembles Ig superfamily cell adhesion molecules and we hypothesize that it may function to link the AF to the surface of cells. Our results highlight the existence of an ancient toolkit of conserved protein domains regulating cell–cell and cell–extracellular matrix protein interactions in all animals, and likely reflect a common origin of cell adhesion and allorecognition.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"12 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ecological dynamics explain modular denitrification in the ocean","authors":"Xin Sun, Pearse J. Buchanan, Irene H. Zhang, Magdalena San Roman, Andrew R. Babbin, Emily J. Zakem","doi":"10.1073/pnas.2417421121","DOIUrl":"https://doi.org/10.1073/pnas.2417421121","url":null,"abstract":"Microorganisms in marine oxygen minimum zones (OMZs) drive globally impactful biogeochemical processes. One such process is multistep denitrification (NO <jats:sub>3</jats:sub> <jats:sup>–</jats:sup> →NO <jats:sub>2</jats:sub> <jats:sup>–</jats:sup> →NO→N <jats:sub>2</jats:sub> O→N <jats:sub>2</jats:sub> ), which dominates OMZ bioavailable nitrogen (N) loss and nitrous oxide (N <jats:sub>2</jats:sub> O) production. Denitrification-derived N loss is typically measured and modeled as a single step, but observations reveal that most denitrifiers in OMZs contain subsets (“modules”) of the complete pathway. Here, we identify the ecological mechanisms sustaining diverse denitrifiers, explain the prevalence of certain modules, and examine the implications for N loss. We describe microbial functional types carrying out diverse denitrification modules by their underlying redox chemistry, constraining their traits with thermodynamics and pathway length penalties, in an idealized OMZ ecosystem model. Biomass yields of single-step modules increase along the denitrification pathway when organic matter (OM) limits growth, which explains the viability of populations respiring NO <jats:sub>2</jats:sub> <jats:sup>–</jats:sup> and N <jats:sub>2</jats:sub> O in a NO <jats:sub>3</jats:sub> <jats:sup>–</jats:sup> -filled ocean. Results predict denitrifier community succession along environmental gradients: Pathway length increases as the limiting substrate shifts from OM to N, suggesting a niche for the short NO <jats:sub>3</jats:sub> <jats:sup>–</jats:sup> →NO <jats:sub>2</jats:sub> <jats:sup>–</jats:sup> module in free-living, OM-limited communities, and for the complete pathway in organic particle-associated communities, consistent with observations. The model captures and mechanistically explains the observed dominance and higher oxygen tolerance of the NO <jats:sub>3</jats:sub> <jats:sup>–</jats:sup> →NO <jats:sub>2</jats:sub> <jats:sup>–</jats:sup> module. Results also capture observations that NO <jats:sub>3</jats:sub> <jats:sup>–</jats:sup> is the dominant source of N <jats:sub>2</jats:sub> O. Our framework advances the mechanistic understanding of the relationship between microbial ecology and N loss in the ocean and can be extended to other processes and environments.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"87 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parallel mechanical computing: Metamaterials that can multitask","authors":"Mohamed Mousa, Mostafa Nouh","doi":"10.1073/pnas.2407431121","DOIUrl":"https://doi.org/10.1073/pnas.2407431121","url":null,"abstract":"Decades after being replaced with digital platforms, analogue computing has experienced a surging interest following developments in metamaterials and intricate fabrication techniques. Specifically, wave-based analogue computers which impart spatial transformations on an incident wavefront, commensurate with a desired mathematical operation, have gained traction owing to their ability to directly encode the input in its unprocessed form, bypassing analogue-to-digital conversion. While promising, these systems are inherently limited to single-task configurations. Their inability to concurrently perform multiple tasks, or compute in parallel, represents a major hindrance to advancing conceptual mechanical devices with broader computational capabilities. In here, we present a pathway to simultaneously process independent computational tasks within the same architected structure. By breaking time invariance in a set of metasurface building blocks, multiple frequency-shifted beams are self-generated which absorb notable energy amounts from the fundamental signal. The onset of these tunable harmonics enables distinct computational tasks to be assigned to different independent “channels,” effectively allowing an analogue mechanical computer to multitask.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"114 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nutrient colimitation is a quantitative, dynamic property of microbial populations","authors":"Noelle A. Held, Aswin Krishna, Donat Crippa, Rachana Rao Battaje, Alexander J. Devaux, Anastasia Dragan, Michael Manhart","doi":"10.1073/pnas.2400304121","DOIUrl":"https://doi.org/10.1073/pnas.2400304121","url":null,"abstract":"Resource availability dictates how fast and how much microbial populations grow. Quantifying the relationship between microbial growth and resource concentrations makes it possible to promote, inhibit, and predict microbial activity. Microbes require many resources, including macronutrients (e.g., carbon and nitrogen), micronutrients (e.g., metals), and complex nutrients like vitamins and amino acids. When multiple resources are scarce, as frequently occurs in nature, microbes may experience resource colimitation in which more than one resource simultaneously limits growth. Despite growing evidence for colimitation, the data are difficult to interpret and compare due to a lack of quantitative measures of colimitation and systematic tests of resource conditions. We hypothesize that microbes experience a continuum of nutrient limitation states and that nutrient colimitation is common in the laboratory and in nature. To address this, we develop a quantitative theory of resource colimitation that captures the range of possible limitation states and describes how they can change dynamically with resource conditions. We apply this approach to clonal populations of <jats:italic>Escherichia coli</jats:italic> to show that colimitation occurs in common laboratory conditions. We also show that growth rate and growth yield are colimited differently, reflecting the different underlying biology of these traits. Finally, we analyze environmental data to provide intuition for the continuum of limitation and colimitation conditions in nature. Altogether our results provide a quantitative framework for understanding and quantifying colimitation of microbes in biogeochemical, biotechnology, and human health contexts.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"23 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}