Biology subjects

Yin, L.

Publications and source records attributed to Yin, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Hypothalamic plasticity for alloparenting in male mice

Repeated exposure to young can induce caregiving in virgin female mice, a phenomenon known as pup sensitization, but whether virgin males can similarly acquire parental behavior and the neural mechanisms underlying this transition remain unclear. We show that 7 days of continuous pup exposure reliably converts virgin adult male mice to a parental state. This transition requires calcitonin receptor (CalcR)-expressing neurons in the medial preoptic area (MPOA): silencing MPOACalcR neurons disrupts both the acquisition and expression of paternal behavior, whereas optogenetic activation of GABAergic MPOACalcR neurons promotes caregiving in virgin males. Longitudinal two-photon calcium imaging reveals that MPOACalcR neurons develop enhanced pup-selective responses as males transition to a parental state. Moreover, CalcR signaling in the MPOA promotes synaptic potentiation and facilitates the emergence of parental behavior. These results identify an experience-dependent hypothalamic plasticity mechanism that enables parental behavior in non-father males.

neuroscience↗

bioRxiv2026

Temporal RNA splicing dysregulation in a human multicellular model of C9orf72 ALS

Amyotrophic lateral sclerosis (ALS) is a complex and heterogenous disease, comprising of familial and sporadic forms, numerous genetic mutations, and a wide range of affected cell types and proposed dysregulated processes. While the usage of in vitro cell cultures, mouse models, and postmortem patient tissue have advanced our understanding of ALS disease mechanisms, the temporal progression of the disease and how early molecular changes evolve remain poorly understood. Here, we establish human spinal cord organoids (hSpO) derived from C9orf72 patient induced pluripotent stem cells (C9-ALS hiPSCs) as a platform to model longitudinal changes across the disease trajectory. We show that C9-ALS hSpO recapitulate hallmark C9orf72-related pathologies, increased cell death, and progressive neuronal dysfunction. We further identify RNA splicing dysregulation as an early and persistent feature of C9-ALS, with splicing signatures in hSpO closely mirroring those observed in postmortem patient tissue. Finally, prediction of RNA binding proteins (RBPs) that induce early splicing changes in C9-ALS reveals signatures consistent with a broad RBP network dysfunction. Together, this work establishes hSpO as an in vitro system for investigating early disease mechanisms of ALS in a human multicellular context and highlights dysregulated events that precede cell death.

neuroscience↗

bioRxiv2026

Test-Retest Reproducibility of Single- and Cross-Population White Matter Atlases in Diffusion MRI Tractography

Diffusion MRI tractography enables noninvasive mapping of white matter fiber tracts. Atlas-based white matter parcellation supports automated tract identification by assigning individual streamlines to atlas-defined clusters and anatomical tract labels. Because clustering-based white matter atlases are constructed from cohort-specific tractography data, they capture common white matter organization represented in the atlas-construction population. Although major white matter anatomy is shared across populations, subtle population-related anatomical variability may influence atlas representation and test-retest correspondence. Therefore, the reproducibility and cross-population generalizability of tractography-based white matter atlases are important considerations for quantitative neuroimaging studies. In this study, we evaluated whether incorporating cross-population anatomical variability during atlas construction improves test-retest reproducibility. To do so, we compared a single-population ORG atlas constructed from a Western cohort with the cross-population East-West White Matter Atlas constructed from both Eastern and Western cohorts. Test-retest diffusion MRI scans from the Human Connectome Project Young Adult (HCP-YA) dataset and the Connectivity-based Brain Imaging Research Database (C-BIRD) were analyzed as independent Western and Eastern test-retest cohorts, respectively. Whole-brain tractography was reconstructed for each dMRI scan and parcellated using both atlases. Reproducibility was assessed using tract detection rate at both cluster level and anatomical tract level, weighted Dice coefficient, and the relative difference of mean fractional anisotropy (FA). Both atlases showed stable tract detection across test-retest scans in both cohorts. Compared with the ORG atlas, the East-West White Matter Atlas achieved higher overall spatial overlap and lower test-retest variability in mean FA, although atlas performance varied across individual tracts. These findings suggest that integrating cross-population information during atlas construction improves the reproducibility and generalizability of white matter atlas mapping across independent populations and imaging protocols.

neuroscience↗

bioRxiv2026

Prenatal 3i-0777 treatment attenuates left ventricular hypertrabeculation and dysfunction in a retinoic acid-induced mouse model

Excessive left ventricular trabeculation and thinning of the compacted myocardium arise during cardiac development and may be accompanied by myocardial dysfunction. Gestational exposure to all-trans retinoic acid (ATRA) induces a comparable phenotype in mice, providing a model for evaluating prenatal pharmacological intervention. We examined whether 3i-0777, a small-molecule enhancer of GATA4-NKX2-5 transcriptional synergy, could attenuate these structural and functional abnormalities. Pregnant C57BL/6NCrl dams were randomly assigned to untreated control, vehicle control, ATRA, or ATRA plus 3i-0777 groups (12 independent litters per group). Both ATRA-exposed groups received ATRA (50 mg/kg) on embryonic day (E)12.5. In the ATRA plus 3i-0777 group, 3i-0777 (15 mg/kg) was administered as a separate injection concurrently with ATRA at E12.5, followed by 5 mg/kg every 8 h (three doses per day) on E13.5-E15.5. At postnatal day 1, one pup was randomly selected from each litter for echocardiography and subsequent histomorphometry. The echocardiographic and histomorphometric ratios of non-compacted to compacted myocardial layer thickness (N/C ratios) were higher, and the absolute magnitude of global longitudinal strain (|GLS|) was lower, in the ATRA group than in either control group (all adjusted P < 0.001). Compared with the ATRA group, the ATRA plus 3i-0777 group had lower echocardiographic and histomorphometric N/C ratios (0.58 {+/-} 0.19 vs 2.19 {+/-} 0.18 and 0.90 {+/-} 0.33 vs 2.46 {+/-} 0.48, respectively), higher |GLS| (25.9 {+/-} 2.5% vs 15.3 {+/-} 2.7%), and a smaller left ventricular internal diameter at end-diastole (1.15 {+/-} 0.06 vs 1.42 {+/-} 0.10 mm; all adjusted P < 0.001). These findings provide proof of concept that ATRA-induced left ventricular hypertrabeculation and dysfunction can be pharmacologically attenuated in utero.

developmental biology↗

bioRxiv2026

A hypothalamic dynorphin-KOR pathway that orchestrates male sexual behavior under sexual competition

In nature, males often attack rivals before mating, yet how aggression shapes mating strategies remains unclear. Using a laboratory sexual competition model with optogenetics, calcium imaging, and pharmacology, we found that aggressive male mice attack competitors before mating, whereas social males mate promptly. This delay is mediated by Gi-coupled kappa-opioid receptor-expressing GABAergic interneurons in the medial preoptic area (MPOAKOR), recruited by estrogen receptor 1-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvlEsr1), which inhibit MPOAEsr1 mating neurons. VMHvlEsr1 neurons activate MPOAKOR neurons through direct glutamatergic transmission and indirect disinhibition by suppressing dynorphin release from prodynorphin-expressing arcuate nucleus terminals (ArcPdyn). During rival encounters, aggressive males show a greater MPOA dynorphin decline and stronger MPOAKOR activity than social males. Thus, a VMHvlEsr1/ArcPdyn[->]MPOAKOR[->]MPOAEsr1 circuit gates mating according to prior aggressive experience, explaining how social competition shapes reproductive strategies.

neuroscience↗

bioRxiv2026

Glutamine Metabolism Supports α cell Mass and Glucagon Secretion

The liver- cell axis is a finely tuned biological rheostat that regulates whole body amino acid availability. Pancreatic cells secrete glucagon that regulates amino acid catabolism through gluconeogenesis and ureagenesis, yet the mechanisms linking amino acid levels to cell growth and function are not fully understood. Here, we identify glutaminase, the enzyme that catalyzes glutamine catabolism, as a critical cell regulator. Glutaminase is highly enriched in cells across species. cell expression of glutaminase is required for nutrient-dependent mTORC1 activation, suppression of AMPK signaling, and sustained expression of the glutamine transporter SLC38A5. This establishes a feed-forward loop linking glutamine metabolism to amino acid sensing and growth. Reduced glutaminase activity impairs dynamic glucagon secretion in response to low glucose and amino acids. Together, these findings highlight the importance of glutamine metabolism in cell growth and hormone secretion and suggest it may play a role in cell adaptation to hyperaminoacidemia.

physiology↗

bioRxiv2026

Proton FLASH preserves neurocognition across delivery techniques: implications for clinical translation in pediatric brain tumors

BackgroundRadiation therapy is integral to the curative treatment of childhood brain tumors but contributes to late neurocognitive impairment in survivors. FLASH (ultra-high dose rate, >40Gy/s) reduces normal-tissue toxicity in preclinical models, and proton-FLASH is currently the only modality capable of delivering ultra-high dose rates to the deep targets, such as pediatric brain tumors. However, two questions remain unresolved before clinical translation: (1) whether the FLASH effect can be achieved on synchrotron-based proton systems, which deliver protons in discrete spills that may be insufficient to cover a clinical target within a single delivery, and (2) which dose-rate metric, among the multiple definitions currently used in the field, best predicts the biological FLASH effect. MethodsC57BL/6 mice (7-8 weeks) received 10 Gy whole-brain RT via a clinical Hitachi ProBEAT synchrotron with CBCT-guided delivery, using three transmission-beam techniques: single-spill pencil beam scanning (SS PBS), multi-spill PBS with [~]2-second inter-spot delay (MS PBS), and passive scatter (PS), compared to conventional (CONV) delivery and unirradiated controls (n=24-28/group, equal sex distribution). Dose rate was quantified using three frameworks: field dose rate (FDR), PBS dose rate (PBSDR), and dose-averaged dose rate (DADR). Recognition memory was assessed by novel object recognition (NOR) at 6 weeks post-RT, and cognitive flexibility was assessed via touchscreen visual discrimination and reversal learning at 14 weeks. Hippocampal neuroinflammation was evaluated by immunofluorescence and immunohistochemistry for Iba1, NeuN, and GFAP. ResultsFLASH conditions were met by SS PBS and PS under all three dose-rate definitions, but MS PBS qualified as FLASH only by DADR. Despite this, neuroprotection was preserved across all three FLASH techniques: discrimination index was significantly higher for SS PBS (P=0.021), MS PBS (P=0.008), and PS (P<0.001) versus CONV, with no significant difference between FLASH techniques. On touchscreen testing, FLASH-treated females demonstrated preserved cognitive flexibility (P=0.047 vs. CONV on reversal learning correct trials). Iba1+ microglia were reduced in FLASH compared to CONV mice, with morphology suggestive of preserved homeostatic state. ConclusionsSynchrotron-based proton FLASH preserves neurocognitive function across all delivery techniques, including under multi-spill delivery essential for treating clinical-scale pediatric brain tumors. Critically, this neuroprotection was observed even for deliveries that qualified as FLASH only by DADR, identifying DADR as the dose-rate metric most relevant to the biological FLASH effect with direct implications for clinical trial design and dose-rate reporting standards.

cancer biology↗

bioRxiv2026

Microglia-derived IL-18 remodels hippocampal plasticity to constrain traumatic fear memory

Post-traumatic stress disorder (PTSD) involves complex neuroimmune-synaptic crosstalk in the hippocampus. Here we show that interleukin-18 (IL-18), an extensively studied pro-inflammatory cytokine, serves a protective role against traumatic fear memory through a microglia-to-neuron signaling axis. Traumatic stress induces sustained upregulation of IL-18 in the hippocampus. Exogenous IL-18 administration attenuates fear memory, whereas blockade of IL-18 signaling exacerbates it. Mechanistically, microglial-derived IL-18 acts on neuronal IL-18R1 to restore stress-impaired synaptic plasticity and reduce perineuronal net density, thereby facilitating structural synaptic remodeling. In addition, IL-18 modulates the synaptic organization of fear memory-encoding engram cells within hippocampal ensembles. Together, these findings redefine IL-18 as a homeostatic regulator of post-trauma hippocampal synaptic function and identify the hippocampal IL-18 pathway as a potential therapeutic target for PTSD.

neuroscience↗

bioRxiv2026

Benchmarking SNP-Calling Accuracy Against Known Citrus Pedigrees Reveals Pangenome Advantages Over Linear References

BackgroundPangenomes are a promising new approach to genomics that can reduce reference bias in genotyping, but the reliability of such a data model remains unclear in tracking variation across species. To test the utility of graph-based pangenomes for interspecific breeding, we developed a Minigraph-Cactus super-pangenome representing four Citrus species derived from the founder lines of a citrus breeding program. To benchmark SNP calling accuracy using graph and linear-based approaches, we performed whole genome short read sequencing for two sets of pedigreed progeny: 30 F1 hybrids and 244 advanced hybrids from an F1 crossed with a parent not included in the pangenome. ResultsThe linear approach yielded more SNP calls than the graph-based approach, however, both methods exhibited similar Mendelian Inheritance Error Rates (MIER) in a tool-dependent manner. Reconstruction of parental haplotype blocks in the advanced hybrids revealed a striking improvement in performance in the pangenome graph-based calls, suggesting MIER is vulnerable to error when reference bias influences both parental and progeny genotype calls. Masking of regions diverged from the reference path improved MIER accuracy metrics and haplotype block reconstruction in both the linear and graph-based SNP calls. ConclusionsIn non-model systems, inheritance patterns observed from pedigreed hybrids provide a framework for benchmarking variant-calling accuracy using pangenomes. SNP miscalls originating from diverged regions can falsely satisfy MIER filters, thus we recommend haplotype blocks. The inherent structure of the pangenome graph has promising applications for removing regions of unreliable mapping quality, which cannot otherwise be reliably removed using traditional filtering metrics.

genomics↗

bioRxiv2026

Co-evolution of Oncogenic KRAS Signaling and LILRBhigh Macrophages Drives Pancreatic Cancer Recurrence

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after surgical resection, indicating that residual disease is sustained by coordinated tumor-microenvironment interactions. To define the biological basis of recurrence, we leverage large-scale clinical data from 2,710 patients, deeply characterized multi-omics profiling (whole-exome, bulk RNA, and single-nucleus sequencing) of 36 matched primary and locally recurrent PDACs, an in-house multiplex spatial imaging cohort of 190 patients, and extensive public datasets. Recurrent tumors were characterized by increased KRAS mutant allele dosage and reinforced KRAS signaling, accompanied by expansion of basal-like malignant cell states. In parallel, we identified an immunosuppressive macrophage population marked by high LILRB expression that spatially co-localized with KRAS-activated tumor cells. Functional studies showed that LILRB4+ macrophages enhanced tumor cell plasticity and progression, whereas inhibition of macrophage LILRB4 suppressed these phenotypes. Notably, a first-in-class human anti-LILRB4 antibody reduced macrophage-driven tumor traits, and dual targeting of KRAS signaling and LILRB4 achieved superior tumor control in macrophage-containing mouse models. These findings reveal a co-evolved tumor-immune niche underlying PDAC recurrence and nominate the KRAS-LILRB4 axis as a therapeutic vulnerability.

cancer biology↗

bioRxiv2026

Transcriptomic evaluation of immune-infiltrated patient-derived tumor organoids as preclinical models in renal cell carcinoma

Patient-derived tumor organoids (PDTOs) have emerged as valuable preclinical models for studying tumor biology and therapeutic responses. However, despite the development of protocols for tumor dissociation and immune cell infiltration, their fidelity in representing clear cell renal cell carcinoma (ccRCC) tumors remains poorly characterized. To address this, we established matched samples, including tumor tissue, enzymatically dissociated tumor, formed PDTOs, and immune-infiltrated PDTOs from three ccRCC patients, and performed bulk RNA sequencing to capture dynamic molecular changes across the experimental workflow. Our analyses revealed that tumor dissociation triggered stress-related transcriptional changes, marked by the upregulation of heat shock genes (e.g., HSPA1A) and the downregulation of the hypoxia pathway, while PDTOs recapitulated hypoxic signaling. Immune-infiltrated PDTOs retained critical immune signatures including T-effector, and exhibited an enhanced pro-inflammatory phenotype (CXCL10, JAK-STAT). Furthermore, predictive gene signatures and immunotherapy response scores further underscored the clinical relevance of immune-infiltrated PDTOs consistent with the original tumor tissue. Collectively, these findings validate immune-infiltrated PDTOs as robust, patient-specific models for personalized therapeutic exploration, offering a platform to optimize immunotherapy strategies in ccRCC.

bioinformatics↗

bioRxiv2025

Rovaca: A highly optimized variant caller for rapid and robust germline DNA analysis

The Genome Analysis Toolkit (GATK) HaplotypeCaller is the gold standard for germline variant detection, but its computational intensity presents a significant bottleneck in large-scale genomic analyses. While accelerated solutions exist, they often require specialized hardware or are proprietary, limiting accessibility. We present Rovaca, a novel, pure software variant caller implemented in C++ that dramatically accelerates germline analysis on standard CPU hardware. By preserving the core mathematical models of GATK HaplotypeCaller, Rovaca achieves nearly identical output, ensuring high concordance and facilitating adoption. Performance gains are achieved through a sophisticated producer-consumer multi-threading architecture and targeted micro-architectural optimizations of the PairHMM algorithm using AVX-512 instructions. Benchmarks on standard GIAB datasets show Rovaca is 57-76x faster for Whole-Genome Sequencing and 30x faster for Whole-Exome Sequencing compared to GATK. The F1-scores for both SNPs and INDELs consistently differ by less than 0.01%, demonstrating exceptional accuracy. Rovaca is a deterministic, robust, and cost-efficient tool that removes the computational barrier for high-throughput germline variant analysis. Rovaca is open-source and available at https://github.com/ZephyRoy/Rovaca.

bioinformatics↗

bioRxiv2025

UHRF1 restricts HCoV-229E infection through epigenetic silencing of the viral receptor APN

The emergence of SARS-CoV-2 has posed significant threats to global health, particularly for the older population. Similarly, common human coronaviruses, such as HCoV-229E, which typically cause mild cold-like symptoms, have also been linked to severe diseases, underscoring the need to understand virus-host interactions and identify host factors contributing to viral pathogenesis and disease progression. In this study, we performed a genome-wide CRISPR knockout screen using HCoV-229E and identified Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) as a potent restriction factor. Mechanistically, UHRF1 suppressed HCoV-229E infection by downregulating the expression of its cell entry receptor, aminopeptidase N (APN), through promoter hypermethylation. Focused CRISPR activation screens of UHRF1-downregulated genes confirmed the critical role of APN in HCoV-229E infection and identified additional genes (e.g., SIGLEC1, PLAC8, and heparan sulfate biosynthesis genes) contributing to the restrictive functions of UHRF1. Transcriptomic and single-cell RNA sequencing analysis revealed that UHRF1 expression decreases with age, negatively correlating with increased APN expression. This age-related decline in UHRF1 was further validated in primary alveolar macrophages isolated from elderly individuals, which exhibited heightened susceptibility to HCoV-229E infection compared to those from younger individuals. Our findings highlight UHRF1 as a key age-related host defense factor against coronavirus infection and provide novel insights into the epigenetic regulation of viral entry receptors.

microbiology↗

bioRxiv2025

High glucose levels impair the body's renal protective function during water deprivation by blunting the FXR-TonEBP axis

BackgroundDehydration often leads to kidney-related complications, yet its impact on diabetic patients remains underexplored. This study aimed to investigate the effects of dehydration on diabetic nephropathy(DN) and the underlying mechanisms of injury. MethodsWe analyzed clinical outcomes in 81 dehydration-induced acute kidney injury patients (35 with diabetes) and validated findings in streptozotocin-induced diabetic mice subjected to intermittent water deprivation (WD). Renal function, histopathology, and molecular markers (FXR, TonEBP, AQP2, gp91, apoptosis regulators) were assessed. ResultsKidney injury was aggravated after water deprivation in patients with diabetics and it is difficult to recover after water supplementation, with poor prognosis. Animal experiments have shown that compared with mice in a normal state, dehydration challenge aggravated renal damage in diabetic mice with increased serum creatinine, pathological damage, and renal interstitial cell apoptosis. Mechanistically, in a normal state FXR-TonEBP axis was enhanced to protect the kidney after water deprivation challenge, but this compensatory protective response was blunted in the diabetic state. ConclusionHyperglycemia blunts the FXR-TonEBP-osmolyte pathway during dehydration, compromising renal medullary protection. Targeting this axis may mitigate dehydration risks in diabetic nephropathy.

physiology↗

bioRxiv2025

Structural and temporal dynamics analysis on PANoptosis in sepsis: a bibliometric analysis

PANoptosis, as a new type of programmed cell death, is characterized by pyroptosis, apoptosis and necroptosis, and is a key mechanism causing a variety of inflammatory diseases. Despite the growing number of studies indicating the crucial role of PANoptosis in sepsis, there has been no bibliometric analysis of the research hotspots and trends in this field. Therefore, this study aims to explore the history, research hotspots and emerging trends of PANoptosis in sepsis related research in the past 20 years from the perspective of structure and temporal dynamics. The articles related to PANoptosis in sepsis were retrieved from the Web of Science Core Collection (WoSCC) database from 2000 to 2024. CiteSpace and HistCite were used to analyse the historical features, the evolution of active topics, and emerging trends about PANoptosis in sepsis. 6165 original articles and reviews on PANoptosis in sepsis were included in the bibliometric analysis. In the last 20 years, the number of published documents is increasing year by year and reaches a peak in 2022. At the same time, many activation themes have emerged at different times, as evidenced by a total of 96 categories, 865 keywords and 629 reference bursts. Keyword clustering anchored eight emerging research subfields, namely 0# oxidative stress, 1#pyroptosis, 2#sepsis-associated encephalopathy, 3#acute kidney injury, 4#immunosuppression, 5#necroptosis, 7#lung injury and 8#extracellular vesicles. The keyword alluvial map shows that the most persistent research concepts in this field are phosphatase. And the emerging keywords are toll_like_receptors, regulatory T cells, recognition, etc. In a timeline visualization based on the time span of the citations, we find five relevant emerging topics, namely 1# immunosuppression, 2# sepsis-induced cardiomyopathy, 3# pyroptosis, 4# acute kidney injury, and 13# COVID-19. Our study provides a comprehensive bibliometric analysis and summary about the current status and trends on PANoptosis in sepsis, which will aid researchers in conducting further scientific research in this field.

bioinformatics↗

bioRxiv2025

The interplay of membrane tension and FtsZ filament condensation on the initiation and progression of cell division in B. subtilis

The first step of cell division is deforming the planar cell membrane inward towards the cytoplasm. As deforming membranes is energetically costly, biology has developed various protein systems to accomplish this task. The mechanisms providing the force to deform bacterial membranes to initiate division remain unknown. In vivo studies have shown the condensation of FtsZ filaments into a sharp ring is required to initiate cell division, an observation mirrored in vitro with FtsZ filaments encapsulated inside liposomes. Similarly, the force for membrane deformation in many eukaryotic deforming systems arises from the local crowding of proteins on the membrane surface. As any membrane deforming system works against the membrane tension, here we modulated the amount of lipid synthesis and thus membrane tension in Bacillus subtilis to examine: 1) if the condensation of FtsZ filaments by FtsZ bundling proteins serves to overcome the cellular membrane tension to deform the membrane inward and 2) how changes to the membrane tension affect the subsequent invagination of the septum. First, we developed methods to simultaneously measure and modulate membrane tension in live cells. Next, we determined how altering the membrane tension affected the cells ability to initiate division with reduced levels of FtsZ bundling proteins. While cells depleted of 2 FtsZ bundling proteins were unable to divide, reducing membrane tension to a given threshold restored their ability to initiate division. Likewise, cells with intermediate levels of FtsZ bundling proteins required a lesser decrease in membrane tension to initiate division. We also found that reductions in membrane tension increase the rate of Z ring constriction, with the constriction rate scaling linearly with the membrane tension. Interestingly, while the constriction rate in wild-type B. subtilis is limited by FtsZ treadmilling, the rate of constriction becomes independent of FtsZs treadmilling rate when membrane tension is reduced. These experiments give two major insights: First, the filament condensation caused by FtsZ bundling proteins works to overcome membrane tension and deform the membrane inward to initiate division. Second, the rate of septal constriction is limited by membrane tension, suggesting that membrane fluctuations at the tip of the growing septa limit the rate of cell wall synthesis. Finally, our measurements allow the estimation of several physical values of cell division, such as the force required to bend the membrane, but also that the cell membrane provides only 0.1%, a small amount of surface tension relative to the entire cell envelope, indicating 99.9% of the pressure drop occurs across the cell wall. These calculations also indicate that cell division occurs via comparatively very small membrane tension fluctuations relative to the high turgor pressure that exists across the entire cell envelope.

microbiology↗

bioRxiv2025

From cognition to compensation: Neurocomputational mechanisms of guilt-driven and shame-driven altruistic behavior

Guilt and shame are key moral emotions that influence mental health and regulate social behavior. Although prior research has examined the psychological and neural correlates of these emotions, the cognitive antecedents that trigger them, as well as their transformation into social behavior, remain insufficiently understood. In this study, we developed a novel task to investigate how two crucial cognitive antecedents, harm and responsibility, elicit guilt and shame, and how these emotions subsequently drive compensatory behavior, by combining functional magnetic resonance imaging (fMRI) with computational modeling. Behaviorally, we found that harm had a stronger impact on guilt than on shame, whereas responsibility had a stronger impact on shame than guilt, which supports the functionalist theory of emotion. Moreover, compared to shame, guilt exerted a greater effect on compensation. Computational modeling results indicated that the integration of harm and responsibility by individuals is consistent with the phenomenon of responsibility diffusion. The fMRI results revealed that brain regions associated with inequity representation (posterior insula) and value computation (striatum) encode this integrated measure. Furthermore, individual differences in responsibility-driven shame sensitivity were associated with activity in theory-of-mind regions (temporoparietal junction and superior temporal sulcus). Guilt- and shame-driven compensatory behavior recruited distinct neural substrates, with shame-driven compensatory sensitivity being more strongly linked to activity in the lateral prefrontal cortex, a region implicated in cognitive control. Our findings provide computational, algorithmic, and neural accounts of guilt and shame.

neuroscience↗

bioRxiv2025

Peritoneal cavity-derived GATA6+ macrophages inhibit fibrosis through IL33 in endometrium

Macrophages exhibit a high degree of plasticity and play pivotal roles both in the normal physiological cycle of the endometrium and in its regeneration following injury. Although some new subsets of endometrial macrophages have been identified, their origins and functions remain to be further explored. In this study, we employed single-cell sequencing to analyze the endometrium of patients with normal endometrium and intrauterine adhesion (IUA) caused by injury. We identified a unique subset of macrophages distinguished by the expression of GATA6, a marker indicative of cavity macrophages. We verified that these GATA6+ macrophages were large peritoneal macrophages (LPMs) that migrated from the peritoneal cavity to the injured endometrium. Upon activation by injured endometrium, these LPMs demonstrated increased expression of Interleukin-33 (IL33), mediated by the Lars-Fos signaling axis, which interacts with the IL33 enhancer. Moreover, our studies revealed that IL33 derived from LPMs inhibited the differentiation of endometrial stromal cells (ESCs) into myofibroblasts, a critical step in the development of endometrial fibrosis. Furthermore, we confirmed the inhibitory effect occurred through the binding of IL33 to the ST2 receptor on ESCs, leading to the upregulation of JMJD3 and subsequent suppression of myofibroblast differentiation. Our findings highlight the essential role of LPMs in promoting endometrial repair and inhibiting fibrosis in IUA. Significance StatementThis study reveals the presence of a unique population of macrophages within the endometrium, originating from large peritoneal macrophages (LPMs), that are pivotal in endometrial repair. This finding offers new insights into the plasticity of macrophages and their potential therapeutic applications in treating endometrial fibrotic disorders.

immunology↗