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Role of channels in the O₂ permeability of murine red blood cells. III. Mathematical modeling and simulations. 通道在小鼠红细胞o2通透性中的作用III。数学建模。
bioRxiv : the preprint server for biology Pub Date : 2025-05-19 DOI: 10.1101/2025.03.05.639964
Rossana Occhipinti, Pan Zhao, Fraser J Moss, Walter F Boron
{"title":"Role of channels in the O₂ permeability of murine red blood cells. III. Mathematical modeling and simulations.","authors":"Rossana Occhipinti, Pan Zhao, Fraser J Moss, Walter F Boron","doi":"10.1101/2025.03.05.639964","DOIUrl":"10.1101/2025.03.05.639964","url":null,"abstract":"<p><p>In this third of three papers, we develop a reaction-diffusion model for O <sub>2</sub> offloading from a red blood cell (RBC), treated as a sphere with diameter approximating RBC thickness. Stopped-flow (SF) analysis (paper #1) of hemoglobin/oxyhemoglobin (Hb/HbO <sub>2</sub> ) absorbance spectra during O <sub>2</sub> efflux from intact murine RBCs show that membrane-impermeant inhibitor p-chloromercuribenzenesulfonate (pCMBS) reduces the HbO <sub>2</sub> -deoxygenation rate constant (k <sub>HbO2</sub> ) by ~61%. SF experiments show that k <sub>HbO2</sub> falls by (1) 9% for aquaporin-1 knockouts (AQP1-KOs), (2) 17% for Rhesus A-glycoprotein knockouts (RhAG-KOs), (3) 30% for double knockouts (dKOs), and (4) ~78% in dKOs/pCMBS. Here, we simulate HbO <sub>2</sub> dissociation (rate constant, k <sub>HbO2</sub> → Hb); HbO <sub>2</sub> , Hb, and O <sub>2</sub> diffusion through RBC cytosol; transmembrane O <sub>2</sub> diffusion; and O <sub>2</sub> diffusion through extracellular unconvected fluid (EUF) to bulk extracellular fluid. Informed by automated-hematology data (paper #1) and imaging-flow-cytometry data (paper #2), simulations predict that observed k <sub>HbO2</sub> decreases cannot reflect changes in RBC size/shape or [Hb/HbO <sub>2</sub> ]. Instead, membrane O <sub>2</sub> permeability ( <i>P</i> <sub>M,O2</sub> ) must fall by (1) 22% to account for AQP1-KO data, (2) 36% for RhAG-KOs, (3) 55% for dKOs, and (4) 91% for dKOs/pCMBS. Exploring predicted k <sub>HbO2</sub> sensitivities to eight key parameters (e.g., [Hb/HbO <sub>2</sub> ], diffusion constants, k <sub>HbO2</sub> → Hb, thickness <sub>EUF</sub> , diameter <sub>Sphere</sub> ) shows that no reasonable changes explain the k <sub>HbO2</sub> data. We introduce a linear-combination approach to accommodate for the presence of poikilocytes. Finally, contrary to common beliefs, the model predicts that, in the absence of inhibitors, the RBC membrane represents >30% of total diffusive \"resistance\" to O <sub>2</sub> offloading, even for a WT mouse.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Solid tumor CAR T cells engineered with fusion proteins targeting PDL1 for localized IL-12 delivery. 靶向PDL1的融合蛋白工程化的实体瘤CAR - T细胞用于局部IL-12递送。
bioRxiv : the preprint server for biology Pub Date : 2025-05-19 DOI: 10.1101/2025.04.04.647304
John P Murad, Lea Christian, Reginaldo Rosa, Yuwei Ren, Eric Hee Jun Lee, Lupita S Lopez, Anthony K Park, Jason Yang, Candi Trac, Lauren N Adkins, Wen-Chung Chang, Catalina Martinez, Carl H June, Stephen J Forman, Jun Ishihara, John K Lee, Lawrence A Stern, Saul J Priceman
{"title":"Solid tumor CAR T cells engineered with fusion proteins targeting PDL1 for localized IL-12 delivery.","authors":"John P Murad, Lea Christian, Reginaldo Rosa, Yuwei Ren, Eric Hee Jun Lee, Lupita S Lopez, Anthony K Park, Jason Yang, Candi Trac, Lauren N Adkins, Wen-Chung Chang, Catalina Martinez, Carl H June, Stephen J Forman, Jun Ishihara, John K Lee, Lawrence A Stern, Saul J Priceman","doi":"10.1101/2025.04.04.647304","DOIUrl":"https://doi.org/10.1101/2025.04.04.647304","url":null,"abstract":"<p><p>CAR T cell efficacy in solid tumors is limited due in part to the immunosuppressive TME. To improve anti-tumor responses, we hypothesized that enabling CAR T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier (e.g., TGFβtrap, IL15, or IL12) combined with an immune checkpoint inhibitor (e.g., αPDL1) will provide tumor localized immunomodulation to improve CAR T cell functionality. To that end, we engineered CAR T cells to secrete TGFβtrap, IL15, or IL12 molecules fused to αPDL1 scFv, and assessed in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR T cells engineered with αPDL1-IL12 were superior in safety and efficacy compared to CAR T cells alone and to those engineered with αPDL1 fused with TGFβtrap or IL15. Further, αPDL1-IL12 engineered CAR T cells improved T cell trafficking and tumor infiltration, localized IFNγ production, TME modulation, and anti-tumor responses, with reduced systemic inflammation-associated toxicities. We believe our αPDL1-IL12 engineering strategy presents an opportunity to improve CAR T cell clinical efficacy and safety across multiple solid tumor types.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibitory and disinhibitory VIP IN-mediated circuits in neocortex. 新皮层VIP in介导的抑制和去抑制回路。
bioRxiv : the preprint server for biology Pub Date : 2025-05-17 DOI: 10.1101/2025.02.26.640383
Shlomo Dellal, Hector Zurita, Ilya Kruglikov, Manuel Valero, Pablo Abad-Perez, Erez Geron, John Hongyu Meng, Alvar Pronneke, Jessica L Hanson, Ema Mir, Marina Ongaro, Xiao-Jing Wang, Gyorgy Buzsaki, Robert P Machold, Bernardo Rudy
{"title":"Inhibitory and disinhibitory VIP IN-mediated circuits in neocortex.","authors":"Shlomo Dellal, Hector Zurita, Ilya Kruglikov, Manuel Valero, Pablo Abad-Perez, Erez Geron, John Hongyu Meng, Alvar Pronneke, Jessica L Hanson, Ema Mir, Marina Ongaro, Xiao-Jing Wang, Gyorgy Buzsaki, Robert P Machold, Bernardo Rudy","doi":"10.1101/2025.02.26.640383","DOIUrl":"10.1101/2025.02.26.640383","url":null,"abstract":"<p><p>Cortical GABAergic interneurons (INs) expressing the neuropeptide vasoactive-intestinal peptide (VIP) predominantly function by inhibiting dendritic-targeting somato-statin (SST) expressing INs, thereby disinhibiting pyramidal cells (PCs) and facilitating cortical circuit plasticity. VIP INs are a molecularly heterogeneous group, but the physiological significance of this diversity is unclear at present. Here, we have characterized the functional diversity of VIP INs in the primary somatosensory cortex (vS1) using intersectional genetic approaches. We found that VIP INs are comprised of four primary populations that exhibit different laminar distributions, axonal and dendritic arbors, intrinsic electrophysiological properties, and efferent connectivity. Furthermore, we observe that these populations are differentially activated by long-range inputs, and display distinct responses to neuromodulation by endocannabinoids, acetylcholine and noradrenaline. Stimulation of VIP IN subpopulations in vivo results in differential effects on the cortical network, thus providing evidence for specialized modes of VIP IN-mediated regulation of PC activity during cortical information processing.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Yes-associated Protein Induces Age-dependent Inflammatory Signaling in the Pulmonary Endothelium. 是相关蛋白诱导肺内皮细胞年龄依赖性炎症信号转导
bioRxiv : the preprint server for biology Pub Date : 2025-05-16 DOI: 10.1101/2025.02.26.640349
Memet T Emin, Alexandra M Dubuisson, Prisha Sujin Kumar, Carsten Knutsen, Cristina M Alvira, Rebecca F Hough
{"title":"Yes-associated Protein Induces Age-dependent Inflammatory Signaling in the Pulmonary Endothelium.","authors":"Memet T Emin, Alexandra M Dubuisson, Prisha Sujin Kumar, Carsten Knutsen, Cristina M Alvira, Rebecca F Hough","doi":"10.1101/2025.02.26.640349","DOIUrl":"10.1101/2025.02.26.640349","url":null,"abstract":"<p><p>Acute Lung Injury (ALI) causes the highly lethal Acute Respiratory Distress Syndrome (ARDS) in children and adults, for which therapy is lacking. Children with Pediatric ARDS (PARDS) have a mortality rate that is about half of adults with ARDS. Improved ALI measures can be reproduced in rodent models with juvenile animals, suggesting that physiologic differences may underlie these outcomes. Here, we show that pneumonia-induced ALI caused inflammatory signaling in the endothelium of adult mice which depended on Yes-associated protein (YAP). This signaling was not present in 21-day-old weanling mice. Transcriptomic analysis of lung endothelial responses revealed nuclear factor kappa-B (NF-κB) as significantly increased with ALI in adult versus weanling mice. Blockade of YAP signaling protected against inflammatory response, hypoxemia, and NF-κB nuclear translocation in response to Pseudomonas aeruginosa pneumonia in adult mice. Our results demonstrate an important signaling cascade in the lung endothelium of adult mice that is not present in weanlings. We suggest other pathways may also exhibit age-dependent signaling, which would have important implications for ARDS therapeutics in the adult and pediatric age groups.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Iron Metalloproteome of Pseudomonas aeruginosa Under Oxic and Anoxic Conditions. 铜绿假单胞菌铁蛋白超配合物的天然金属蛋白质组学检测。
bioRxiv : the preprint server for biology Pub Date : 2025-05-15 DOI: 10.1101/2025.01.15.633287
Mak Saito, Matthew R McIlvin
{"title":"The Iron Metalloproteome of Pseudomonas aeruginosa Under Oxic and Anoxic Conditions.","authors":"Mak Saito, Matthew R McIlvin","doi":"10.1101/2025.01.15.633287","DOIUrl":"10.1101/2025.01.15.633287","url":null,"abstract":"<p><p>Pseudomonas aeruginosa is a major contributor to human infections and is widely distributed in the environment. Its ability for growth under aerobic and anaerobic conditions provides adaptability to environmental changes and in confronting immune responses. We applied native 2-dimensional metalloproteomics to P. aeruginosa to examine how use of iron within the metallome responds to oxic and anoxic conditions. Analyses revealed four iron peaks comprised of metalloproteins with synergistic functions, including: 1) respiratory and metabolic enzymes, 2) oxidative stress response enzymes, 3) DNA synthesis and nitrogen assimilation enzymes, and 4) denitrification enzymes and related copper enzymes. Fe peaks were larger under anoxic conditions, consistent with increased iron demand due to anaerobic metabolism and with the denitrification peak absent under oxic conditions. Three ferritins co-eluted with the first and third iron peaks, localizing iron storage with these functions. Several enzymes were more abundant at low oxygen, including alkylhydroperoxide reductase C that deactivates organic radicals produced by denitrification, all three classes of ribonucleotide reductases (including monomers and oligomer forms), ferritin (increasing in ratio relative to bacterioferritin), and denitrification enzymes. Superoxide dismutase and homogentisate 1,2-dioxygenase were more abundant at high oxygen. Several Fe peaks contained iron metalloproteins that co-eluted earlier than their predicted size, implying additional protein-protein interactions and suggestive of cellular organization that contributes to iron prioritization in Pseudomonas with its large genome and flexible metabolism. This study characterized the iron metalloproteome of one of the more complex prokaryotic microorganisms, attributing enhanced iron use under anaerobic denitrifying metabolism to its specific metalloprotein constituents.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11760780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
DNMT3A Stability Is Maintained by Ubiquitin-Specific Peptidase 11 (USP11) and Sumoylation Countering Degradation. DNMT3A的稳定性通过泛素特异性肽酶11 (USP11)和Sumoylation对抗降解来维持。
bioRxiv : the preprint server for biology Pub Date : 2025-05-15 DOI: 10.1101/2025.03.05.641683
Taishi Yonezawa, Justine Rutter, Raghav Ramabadran, Venkatasubramaniam Sundaramurthy, Gandhar Datar, Mikolaj Slabicki, Margaret A Goodell
{"title":"DNMT3A Stability Is Maintained by Ubiquitin-Specific Peptidase 11 (USP11) and Sumoylation Countering Degradation.","authors":"Taishi Yonezawa, Justine Rutter, Raghav Ramabadran, Venkatasubramaniam Sundaramurthy, Gandhar Datar, Mikolaj Slabicki, Margaret A Goodell","doi":"10.1101/2025.03.05.641683","DOIUrl":"10.1101/2025.03.05.641683","url":null,"abstract":"<p><p>DNA methyltransferase 3A (DNMT3A) plays crucial roles in hematopoiesis and mammalian development. DNMT3A protein instability has been associated with several diseases such as MDS, AML and Tatton-Brown-Rahman syndrome. Here we report, DNMT3A stability is maintained by deubiquitinating enzyme USP11 countering degradation by CUL4-DCAF8 E3 ligase. DNMT3A localization changes caused by certain unstable DNMT3A mutations, which could be considered one of the losses of function of DNMT3A. The mislocalization is partially rescued by E1 enzyme inhibition or stable USP11 expression lines. Interestingly, we show that USP11 enhances DNMT3A SUMOylation by promoting the interaction between DNMT3A and SUMO E3 Ligases, and DNMT3A SUMOylation also essential for maintaining DNMT3A protein stability and DNMT3A DNA Mtase activity. Our results reveal the mechanism for DNMT3A protein turnover through USP11, and the mechanism essential for DNMT3A function, as well as a therapeutic approach for several diseases causing DNMT3A protein instability.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A RUNX2 GFP reporter is expressed prior to osteochondral differentiation and models Metaphyseal Dysplasia with Maxillary Hypoplasia and Brachydactyly (MDMHB). RUNX2 GFP报告基因在骨软骨分化前表达,并模拟干骺端发育不良伴上颌发育不全和短指畸形(MDMHB)。
bioRxiv : the preprint server for biology Pub Date : 2025-05-15 DOI: 10.1101/2025.05.15.654100
Dimitrios V Bikas, Sara Vardabasso, Gabrielle Quickstad, Karl B Shpargel
{"title":"A RUNX2 GFP reporter is expressed prior to osteochondral differentiation and models Metaphyseal Dysplasia with Maxillary Hypoplasia and Brachydactyly (MDMHB).","authors":"Dimitrios V Bikas, Sara Vardabasso, Gabrielle Quickstad, Karl B Shpargel","doi":"10.1101/2025.05.15.654100","DOIUrl":"https://doi.org/10.1101/2025.05.15.654100","url":null,"abstract":"<p><p>SOX9 and RUNX2 are lineage defining transcription factors that drive differentiation of chondrocyte and osteoblast lineages respectively from osteochondral progenitors. In limb development, these progenitors are specified first by SOX9 expression required for mesenchymal stem cell (MSC) condensation prior to RUNX2 activation and osteochondral differentiation to chondrocyte and osteoblast lineages. Unlike limb development, the anterior craniofacial skeleton arises from cranial neural crest (cNCC) stem cells. To examine the temporal activation of SOX9 and RUNX2 within cNCCs, we utilized a combination of immunofluorescence to detect endogenous proteins and genetic reporters to label SOX9 and RUNX2 expressing cells. We find that RUNX2 is expressed broadly throughout cNCC stem cells of the first branchial arch that will give rise to developing mandibular tissue at a timepoint prior to osteochondral lineage determination. Substantial SOX9 expression is activated subsequently within differentiating chondrocytes. These findings were validated by fluorescent reporters inserted in the 3' untranslated regions (3'UTRs) of <i>Sox9</i> and <i>Runx2</i> . Although the GFP based <i>Runx2</i> reporter did not delete any 3'UTR sequences, homozygous <i>Runx2 <sup>GFP/GFP</sup></i> pups develop postnatal deficiencies in intramembranous and endochondral ossification that correlate with enhanced expression of RUNX2 protein in osteoblasts and hypertrophic chondrocytes. <i>Runx2 <sup>GFP/GFP</sup></i> phenotypes model the human disorder, Metaphyseal Dysplasia with Maxillary Hypoplasia and Brachydactyly (MDMHB), resulting from RUNX2 enhanced activity due to intragenic duplications. Altogether, this reporter model provides a valuable tool for studying RUNX2 function in early cNCC-derived stem cell lineages and highlights the high sensitivity of ossification pathways to RUNX2 dosage.</p><p><strong>Summary: </strong>We have developed a novel mouse model for a human disorder resulting from excessive RUNX2, a transcription factor required for bone formation. We find that RUNX2 turns on early within facial stem cells in a pattern unique from limb development. Excessive RUNX2 is particularly detrimental to bone growth in juvenile development after birth.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Overcoming myeloid-driven resistance to CAR T therapy by targeting SPP1. 通过靶向SPP1克服CAR - T治疗的骨髓驱动耐药。
bioRxiv : the preprint server for biology Pub Date : 2025-05-15 DOI: 10.1101/2025.04.01.646202
Sharareh Gholamin, Heini M Natri, Yuqi Zhao, Shengchao Xu, Maryam Aftabizadeh, Begonya Comin-Anduix, Supraja Saravanakumar, Christian Masia, Robyn A Wong, Lance Peter, Mei-I Chung, Evan D Mee, Brenda Aguilar, Renate Starr, Davis Y Torrejon, Darya Alizadeh, Xiwei Wu, Anusha Kalbasi, Antoni Ribas, Stephen Forman, Behnam Badie, Nicholas Banovich, Christine Brown
{"title":"Overcoming myeloid-driven resistance to CAR T therapy by targeting SPP1.","authors":"Sharareh Gholamin, Heini M Natri, Yuqi Zhao, Shengchao Xu, Maryam Aftabizadeh, Begonya Comin-Anduix, Supraja Saravanakumar, Christian Masia, Robyn A Wong, Lance Peter, Mei-I Chung, Evan D Mee, Brenda Aguilar, Renate Starr, Davis Y Torrejon, Darya Alizadeh, Xiwei Wu, Anusha Kalbasi, Antoni Ribas, Stephen Forman, Behnam Badie, Nicholas Banovich, Christine Brown","doi":"10.1101/2025.04.01.646202","DOIUrl":"10.1101/2025.04.01.646202","url":null,"abstract":"<p><p>Chimeric antigen receptor CAR T cell therapy faces notable limitations in treatment of solid tumors. The suppressive tumor microenvironment TME, characterized by complex interactions among immune and stromal cells, is gaining recognition in conferring resistance to CAR T cell therapy. Despite the abundance and diversity of macrophages in the TME, their intricate involvement in modulating responses to CAR T cell therapies remains poorly understood. Here, we conducted single-cell RNA sequencing scRNA seq on tumors from 41 glioma patients undergoing IL13Ra2-targeted CAR T cell therapy, identifying elevated suppressive SPP1 signatures predominantly in macrophages from patients who were resistant to treatment. Further integrative scRNA seq analysis of high-grade gliomas as well as an interferon-signaling deficient syngeneic mouse model both resistant to CAR T therapy demonstrated the role of congruent suppressive pathways in mediating resistance to CAR T cells and a dominant role for SPP1+ macrophages. SPP1 blockade with an anti-SPP1 antibody abrogates the suppressive TME effects and substantially prolongs survival in IFN signaling-deficient and glioma syngeneic mouse models resistant to CAR T cell therapy. These findings illuminate the role of SPP1+ macrophages in fueling a suppressive TME and driving solid tumor resistance to CAR cell therapies. Targeting SPP1 may serve as a universal strategy to reprogram immune dynamics in solid tumors mitigating resistance to CAR T therapies.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Unpacking the V1 map: Differential covariation of visual properties across spatial dimensions. 人类初级视觉皮层的首选空间频率随皮层放大而变化。
bioRxiv : the preprint server for biology Pub Date : 2025-05-14 DOI: 10.1101/2025.03.19.644195
Marc M Himmelberg, Yuna Kwak, Marisa Carrasco, Jonathan Winawer
{"title":"Unpacking the V1 map: Differential covariation of visual properties across spatial dimensions.","authors":"Marc M Himmelberg, Yuna Kwak, Marisa Carrasco, Jonathan Winawer","doi":"10.1101/2025.03.19.644195","DOIUrl":"10.1101/2025.03.19.644195","url":null,"abstract":"<p><p>Primary visual cortex (V1) has played a key role in understanding the organization of cerebral cortex. Both structural and functional properties vary sharply throughout the human V1 map. Despite large variation, underlying constancies computed from the covariation pattern of V1 properties have been proposed. Such constancies would imply that V1 is composed of multiple identical units whose visual properties differ only due to differences in their inputs. To test this, we used fMRI to investigate how V1 cortical magnification and preferred spatial frequency covary across eccentricity and polar angle, measured in 40 observers. V1 cortical magnification and preferred spatial frequency were strongly correlated across eccentricity and around polar angle, however their relation differed between these dimensions: they were proportional across eccentricity but not polar angle. The constant ratio of cortical magnification to preferred spatial frequency when measured as a function of eccentricity suggests a shared underlying cause of variation in the two properties, e.g., the gradient of retinal ganglion cell density across eccentricity. In contrast, the deviation from proportionality around polar angle implies that cortical variation differs from that in retina along this dimension. Thus, a constancy hypothesis is supported for one of the two spatial dimensions of V1, highlighting the importance of examining the full 2D-map to understand how V1 is organized.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Activity of human-specific Interlaminar Astrocytes in a Chimeric Mouse Model of Fragile X Syndrome. 人类特异性层间星形细胞在脆性X综合征嵌合小鼠模型中的活性。
bioRxiv : the preprint server for biology Pub Date : 2025-05-14 DOI: 10.1101/2025.02.26.640426
Alexandria Anding, Baiyan Ren, Ragunathan Padmashri, Maria Burkovetskaya, Anna Dunaevsky
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