bioRxiv : the preprint server for biology最新文献

{"title":"Using a modular massively parallel reporter assay to discover context-dependent regulatory activity in type 2 diabetes-linked noncoding regions.","authors":"Adelaide Tovar, Yasuhiro Kyono, Kirsten Nishino, Maya Bose, Arushi Varshney, Stephen C J Parker, Jacob O Kitzman","doi":"10.1101/2023.10.08.561391","DOIUrl":"10.1101/2023.10.08.561391","url":null,"abstract":"<p><p>Most genome-wide association signals for complex disease reside in the noncoding genome, where defining function is nontrivial. MPRAs (massively parallel reporter assays) offer a scalable means to identify functional regulatory elements, but are typically conducted without regard to cell type, pairing cloned fragments with a generic housekeeping promoter. To explore the context-sensitivity of MPRAs, we screened enhancer activity across a panel of nearly 12,000 198-bp fragments spanning over 300 type 2 diabetes- and metabolic trait-associated regions in the 832/13 rat insulinoma beta cell line, a relevant model of pancreatic beta cells. We explored these fragments' context sensitivity by comparing their activities when placed up- or downstream of a reporter gene, and in combination with either a synthetic housekeeping promoter (SCP1) or a more biologically relevant promoter corresponding to the human insulin ( <i>INS</i> ) gene. We identified clear effects of MPRA construct design on enhancer activity. Specifically, a subset of fragments (n = 702/11,656) displayed positional bias, evenly distributed across up- and downstream preference. Promoter choice also influenced MPRA activity (n = 698/11,656), mostly biased towards the cell-specific <i>INS</i> promoter (73.4%). To identify sequence features associated with promoter preference, we used Lasso regression with 562 genomic annotations and discovered that fragments with <i>INS</i> promoter-biased activity are enriched for HNF1 motifs. HNF1 family transcription factors are key regulators of glucose metabolism disrupted in maturity onset diabetes of the young (MODY), suggesting genetic convergence between rare coding variants that cause MODY and common T2D-associated regulatory regions. We designed a follow-up MPRA containing HNF1 motif-enriched fragments and observed several instances where deletion or mutation of HNF1 motifs disrupted the <i>INS</i> promoter-biased enhancer activity, specifically in the beta cell model but not in a skeletal muscle cell line, another diabetes-relevant cell type. Together, our study suggests that cell-specific regulatory activity is partially influenced by enhancer-promoter compatibility and indicates that careful attention should be paid when designing MPRA libraries to capture context-specific regulatory processes at disease-associated genetic signals.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694757","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}

{"title":"KRAS Inhibition Activates an Actionable CD24 \"Don't Eat Me\" Signal in Pancreatic Cancer.","authors":"Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Zhenzhen Xun, Phuoc T Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Ching-Fei Li, Madelaine S Theardy, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Elizabeth M Park, David H Peng, Yong Zhou, Hong Zhao, Timothy P Heffernan, Andrea Viale, Huamin Wang, Stephanie S Watowich, Han Liang, Dan Zhao, Ronald A DePinho, Wantong Yao, Haoqiang Ying","doi":"10.1101/2023.09.21.558891","DOIUrl":"10.1101/2023.09.21.558891","url":null,"abstract":"<p><p>KRAS ^G12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the function of KRAS ^G12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRAS ^G12C - driven PDAC model. Compared to the classical KRAS ^G12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRAS ^G12C tumors produced modest impact despite stimulating a 'hot' tumor immune microenvironment. Immunoprofiling revealed that CD24, a 'don't eat me' signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRAS ^G12D -driven PDAC. Together, this study reveals common and distinct oncogenic <i>KRAS</i> allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC.</p><p><strong>Significance: </strong>Generation of an autochthonous KRAS ^G12C -driven pancreatic cancer model enabled elucidation of specific effects of KRAS ^G12C during tumor development, revealing CD24 as an actionable adaptive mechanism in cancer cells induced upon KRAS ^G12C inhibition.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10542501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41166803","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}

{"title":"The coarse mental map of the breast is anchored on the nipple.","authors":"Katie H Long, Emily E Fitzgerald, Ev I Berger-Wolf, Amani Fawaz, Stacy T Lindau, Sliman J Bensmaia, Charles M Greenspon","doi":"10.1101/2022.09.14.507974","DOIUrl":"10.1101/2022.09.14.507974","url":null,"abstract":"<p><p>Touch plays a key role in our perception of our body and shapes our interactions with the world, from the objects we manipulate to the people we touch. While the tactile sensibility of the hand has been extensively characterized, much less is known about touch on other parts of the body. Despite the important role of the breast in lactation as well as in affective and sexual touch, relatively little is known about its sensory properties. To fill this gap, we investigated the spatial acuity of the breast and compared it to that of the hand and back, body regions that span the range of tactile spatial acuity. First, we found that the tactile acuity of the breast was even lower than that of the back, heretofore the paragon of poor acuity. Second, acuity was lower for larger breasts, consistent with the hypothesis that innervation capacity does not scale with body size. Third, touches to different regions of the nipple were largely indistinguishable, suggesting that the nipple is a sensory unit. Fourth, localization errors were systematically biased toward the nipple.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"103 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12440013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89309274","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}

{"title":"Benchmarking large language models for genomic knowledge with GeneTuring.","authors":"Xinyi Shang, Xu Liao, Zhicheng Ji, Wenpin Hou","doi":"10.1101/2023.03.11.532238","DOIUrl":"10.1101/2023.03.11.532238","url":null,"abstract":"<p><p>Large language models (LLMs) show promise in biomedical research, but their effectiveness for genomic inquiry remains unclear. We developed GeneTuring, a benchmark consisting of 16 genomics tasks with 1,600 curated questions, and manually evaluated 48,000 answers from ten LLM configurations, including GPT-4o (via API, ChatGPT with web access, and a custom GPT setup), GPT-3.5, Claude 3.5, Gemini Advanced, GeneGPT (both slim and full), BioGPT, and BioMedLM. A custom GPT-4o configuration integrated with NCBI APIs, developed in this study as SeqSnap, achieved the best overall performance. GPT-4o with web access and GeneGPT demonstrated complementary strengths. Our findings highlight both the promise and current limitations of LLMs in genomics, and emphasize the value of combining LLMs with domain-specific tools for robust genomic intelligence. GeneTuring offers a key resource for benchmarking and improving LLMs in biomedical research.</p><p><strong>Biographical note: </strong>Dr. Wenpin Hou is an Assistant Professor (tenure-track) in the Department of Biostatistics at Columbia University and member of its Data Science Institute, developing AI and statistical methods for decoding gene regulatory programs from single-cell and spatial multiomics data.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/79/09/nihpp-2023.03.11.532238v1.PMC10054955.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9335674","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}

{"title":"Combatting nonidentifiability to infer motor cortex inputs yields similar encoding of initial and corrective movements.","authors":"Peter J Malonis, Ankit Vishnubhotla, Nicholas G Hatsopoulos, Jason N MacLean, Matthew T Kaufman","doi":"10.1101/2021.10.18.464704","DOIUrl":"10.1101/2021.10.18.464704","url":null,"abstract":"<p><p>Primary motor cortex (M1) plays a central role in voluntary movement, but how it integrates sensory-driven corrective instructions is unclear. We analyzed population activity recorded from M1 of macaques during a sequential arm movement task with target updates requiring online adjustments to the motor plan. Using Latent Factor Analysis via Dynamical Systems (LFADS), we separated neural activity into two components: intrinsic dynamics and inferred external inputs influencing those dynamics. Inferred input timing was more strongly locked to target appearance than to movement onset, suggesting that variable reaction times reflect interactions between inputs and ongoing dynamics. Inferred inputs were tuned similarly for both initial and corrective movements, suggesting a shared input encoding across visually-instructed and corrective movements that was previously obscured by M1 dynamics. Because input inference can suffer from the challenge of nonidentifiability, where different models fit the data indistinguishably, we used ensembles of models with varied hyperparameters to diagnose when inputs are identifiable or nonidentifiable. In the monkey data, ensembles produced consistently similar results, suggesting that inputs could be meaningfully inferred and that their encoding was not simply a result of model bias. These results highlight the challenges of nonidentifiability and the potential of model ensembles to identify inputs in ongoing dynamics, at least in some cases.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89555048","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}

{"title":"Bifurcation in space: Emergence of functional modularity in the neocortex.","authors":"Xiao-Jing Wang, Junjie Jiang, Roxana Zeraati, Aldo Battista, Julien Vezoli, Henry Kennedy, Ulises Pereira-Obilinovic","doi":"10.1101/2023.06.04.543639","DOIUrl":"10.1101/2023.06.04.543639","url":null,"abstract":"<p><p>Recent studies have shown that neural representation and processing are widely distributed in the brains of behaving animals [1, 2, 3, 4]. These observations challenge functional specialization as a central tenet of Neuroscience, which refers to the notion that distinct brain regions are dedicated to specific aspects of cognition such as working memory or subjective decision-making. Here we develop the concept of <i>bifurcation in space</i> to mechanistically account for the emergence of functional specialization that is compatible with distributed neural coding in a large-scale neo-cortex. Our theory starts with a departure from the canonical local circuit principle [5] by highlighting differences between cortical areas in the form of experimentally quantified heterogeneities of synaptic excitation and inhibition. We investigated connectome-based modelling of a multiregional cortex for both macaque monkeys and mice, as well as a generative model of a spatially embedded neocortex. During working memory in a simulated delayed response task, surprisingly, we found an inverted-V-shaped pattern of neuronal timescales across the cortical hierarchy as a signature of functional modularity, in sharp contrast to an increasing pattern of timescales during the resting state, as reported previously [6]. Furthermore, our model cortex simultaneously and robustly displays a plethora of bifurcations in space and their associated rich repertoire of timescale profiles across a large-scale cortex; the corresponding functionally defined modules (spatial attractors) could potentially subserve various internal mental processes. This work yields several specific experimentally testable predictions, including an inverted-V pattern of timescales, a measure of comparison between functional modules and structural modules defined by the graph theory, and a new plot for revealing bifurcation in space in neural activity recorded from animals performing different tasks that engage various functional modules. We propose that bifurcation in space, resulting from the connectome and macroscopic gradients of neurobiological properties across the cortex, represents a fundamental principle for understanding the brain's functional specialization and modular organization.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6a/80/nihpp-2023.06.04.543639v1.PMC10274618.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9798813","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}

{"title":"Dissociating instructive from permissive roles of brain circuits with reversible neural activity manipulations.","authors":"Daniel Quintana, Hayley A Bounds, Jennifer Brown, May Wang, J Simon Wiegert, Hillel Adesnik","doi":"10.1101/2023.05.11.540397","DOIUrl":"10.1101/2023.05.11.540397","url":null,"abstract":"<p><p>Recent work has demonstrated that both permanent lesions and acute inactivation experiments can lead to erroneous conclusions about the causal role of brain areas in specific behaviors, casting serious doubt on major avenues by which neuroscientists study the brain. To overcome this challenge, we developed a three-stage optogenetic approach which leverages the ability to precisely control the temporal period of regional inactivation with either brief or sustained illumination, enabling investigators to dissociate between putative 'permissive' and 'instructive' roles of brain areas in behavior. We applied this approach to the mouse primary visual cortex (V1) to probe whether V1 is permissive or instructive for the detection low contrast stimuli. Acute inactivation of V1 drastically suppressed performance, but during persistent inactivation, the animals' contrast detection recovered to pre-silencing levels. This recovery was itself reversible, as returning the animals to intermittent V1 inactivation reinstated the behavioral deficit. These results argue that V1 is the default circuit mice use to detect visual stimuli, but in its absence, other regions can compensate for it. This novel, temporally controllable optogenetic perturbation paradigm should be useful in other brain circuits to assess whether they are instructive or permissive in a brain function or behavior.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a3/bd/nihpp-2023.05.11.540397v1.PMC10197619.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9541186","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}

{"title":"Asymmetric cortical projections to striatal direct and indirect pathways distinctly control actions.","authors":"Jason R Klug, Xunyi Yan, Hilary A Hoffman, Max D Engelhardt, Fumitaka Osakada, Edward M Callaway, Xin Jin","doi":"10.1101/2023.10.02.560589","DOIUrl":"10.1101/2023.10.02.560589","url":null,"abstract":"<p><p>The striatal direct and indirect pathways constitute the core for basal ganglia function in action control. Although both striatal D1- and D2-spiny projection neurons (SPNs) receive excitatory inputs from the cerebral cortex, whether or not they share inputs from the same cortical neurons, and how pathway-specific corticostriatal projections control behavior remain largely unknown. Here using a G-deleted rabies system in mice, we found that more than two-thirds of excitatory inputs to D2-SPNs also target D1-SPNs, while only one-third do so <i>vice versa</i>. Optogenetic stimulation of striatal D1- vs. D2-SPN-projecting cortical neurons differently regulate locomotion, reinforcement learning and sequence behavior, implying the functional dichotomy of pathway-specific corticostriatal subcircuits. These results reveal the partially segregated yet asymmetrically overlapping cortical projections on striatal D1- vs. D2-SPNs, and that the pathway-specific corticostriatal subcircuits distinctly control behavior. It has important implications in a wide range of neurological and psychiatric diseases affecting cortico-basal ganglia circuitry.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694453","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}

{"title":"Preventing trogocytosis by cathepsin B inhibition augments CAR T cell function.","authors":"Kenneth A Dietze, Kiet Nguyen, Aashli Pathni, Frank Fazekas, Wenxiang Sun, Ethan Rosati, Jillian M Baker, Maday Galeana Figueroa, Etse Gebru, Daniel Yamoah, Rediet Mulatu, Alexander Wang, Aaron P Rapoport, David Lum, Xiaoxuan Fan, Sabarinath V Radhakrishnan, Djordje Atanackovic, Arpita Upadhyaya, Tim Luetkens","doi":"10.1101/2024.06.11.598379","DOIUrl":"10.1101/2024.06.11.598379","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy in cancer treatment. Still, most patients receiving CAR T cells relapse within 5 years of treatment. CAR-mediated trogocytosis (CMT) is a potential tumor escape mechanism in which cell surface proteins transfer from tumor cells to CAR T cells. CMT results in the emergence of antigen-negative tumor cells, which can evade future CAR detection, and antigen-positive CAR T cells, which has been suggested to cause CAR T cell fratricide and exhaustion. Whether CMT indeed causes CAR T cell dysfunction and the molecular mechanisms conferring CMT remain unknown. Using a selective degrader of trogocytosed antigen in CAR T cells, we show that the presence of trogocytosed antigen on the CAR T cell surface directly causes CAR T cell fratricide and exhaustion. By performing a small molecule screening using a custom high throughput CMT-screening assay, we found that the cysteine protease cathepsin B is essential for CMT and that inhibition of cathepsin B is sufficient to prevent CAR T cell fratricide and exhaustion, leading to improved long-term CAR T cell persistence and anti-tumor activity. Our data demonstrate that it is feasible to separate CMT from cytotoxic activity, that CAR T cell persistence, a key factor associated with clinical CAR T cell efficacy, is directly linked to cathepsin B activity in CAR T cells, and that it is possible to improve CAR T cell function through selective inhibition of CMT. One sentence summary: CAR-mediated trogocytosis is mediated by the cysteine protease cathepsin B and directly causes CAR T cell exhaustion and fratricide.</p><p><strong>Abstract figure: </strong></p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11195252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141447740","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}

{"title":"Single cell RNA-sequencing suggests a novel lipid-associated mast cell population following weight cycling.","authors":"Munira Kapadia, Alexa M Betjemann, Matthew A Cottam, Mona Mashayekhi, Heidi J Silver, Alyssa H Hasty, Heather L Caslin","doi":"10.1101/2023.11.12.566786","DOIUrl":"10.1101/2023.11.12.566786","url":null,"abstract":"<p><p>We previously demonstrated that weight cycled mice have increased adipose mast cells compared to obese mice by single cell RNA-sequencing. Here, we aimed to confirm and elucidate these changes. Interestingly, we did not detect an increase in total mast cell numbers in weight cycled mice by Toluidine blue or flow cytometry, however, further subcluster analysis of our dataset showed that our initial mast cell cluster consisted of two unique populations. One population had very high expression of classical mast cell markers and another had elevated lipid handling and antigen presentation genes with a concomitant reduction in classical mast cell genes. This new \"lipid-associated\" mast cell cluster accounted for most of the mast cells in the weight cycled group. We induced a similar phenotype <i>in vitro</i> using repeated exposure to adipose tissue conditioned media to mimic weight gain and weight regain. Upon repeated exposure to adipose tissue conditioned media, bone marrow-derived mast cells had increased lipid droplets and reduced expression of cKit and FcεR1 compared to control cells. Moreover, we analyzed mast cells in a pilot study of subcutaneous adipose tissue from four obese, prediabetic women. We found two mast cell populations that appear similar to the murine populations detected by sequencing. The population with reduced cKit and FcεR1 was significantly correlated with weight variance. Together, these data suggest that weight cycling may induce a unique population of mast cells similar to lipid- associated macrophages, which have been shown to play a role in diverse diseases from obesity and atherosclerosis to Alzheimer's disease. Future studies will focus on isolation of these cells from mice and humans to better determine their lineage, differentiation, and functional roles.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10680619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138447388","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}