Biology subjects

Dong, J.

Publications and source records attributed to Dong, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Dual blockade of IL-18 and IL-4Rα by a bispecific antibody for improved treatment of atopic dermatitis

Background: Atopic dermatitis (AD) is a chronic inflammatory dermatosis primarily driven by type 2 immunity, with additional type 1 and type 3 components that may limit the benifit of ILRalpha blockade alone. Interleukin18 (IL18), an epithelial alarmin genetically associated with AD and correlated with disease severity, has been implicated as an upstream amplifier of this mixed inflammatory response. Objective: To assess whether concurrent IL18 neutralization and IL4Ralpha; blockade with a bispecific antibody provides broader and more balanced suppression of AD relevant type 1, type 2, and type 3 pathways than single target inhibition. Methods: We generated FJ0125, a bispecific antibody comprising human IL18 binding protein fused to a novel humanized anti IL4Ralpha antibody, and characterized its binding, signaling, and functional activity in vitro and in vivo. The activity was evaluated in human group 2 innate lymphoid cell and primed Th2 cell assays, a keratinocyte & dendritic cell & T cell coculture system, and an MC903/Staphylococcus aureus induced dermatitis model in human IL4/IL4Ralpha; knock in mice. Results: FJ0125 bound to IL18 and IL4Ralpha; with high affinity, engaged both targets, inhibited IL4/IL13 signaling with dupilumab comparable potency, and neutralized human and mouse IL18. In vitro, FJ0125 more effectively suppressed IL18 driven lymphocyte activation and type 1, type 2, and type 3 cytokine production than IL18BPFc or IL4Ralpha; monotherapy. In vivo, FJ0125 reduced multitype cytokines, improved dermatitis, lowered serum IgE, and abrogated the paradoxical IL22 increase observed with selective IL4Ralpha; blockade. Conclusion: Dual IL18/IL4Ralpha; blockade with FJ0125 achieves coordinated suppression of multitype inflammation and represents a mechanistically substantiated therapeutic strategy for AD.

immunology↗

bioRxiv2026

Diverse signaling proteins recruit RCC1-Like Domain proteins to the plasma membrane through a common structural framework.

Plants translate diverse environmental cues into spatially regulated growth responses through intracellular signaling mechanisms that remain incompletely understood. Here, we identify the BREVIS RADIX (BRX) domain of RCC1-LIKE DOMAIN (RLD) proteins as a versatile interaction module that recognizes multiple signaling proteins in Arabidopsis. We identified members of the PHYTOCHROME KINASE SUBSTRATE (PKS) and BIG GRAIN (BG) families as novel RLD interactors families, in addition to the previously characterized LAZY1-LIKE (LZY) proteins and BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL). Structural, biochemical, and cell-based analyses demonstrate that these diverse partners, despite having divergent interaction sequences, bind a common surface on the RLD BRX domain to recruit RLD to the plasma membrane. This interaction relies on a shared {beta}-strand-based recognition mode, in which distinct peptide conformations accommodate binding to the same BRX-domain surface. Furthermore, we show that RLD2 and RLD3 contribute to hypocotyl phototropism, and that disrupting the conserved PKS interaction motif abolishes PKS4 function in this response. Together, our findings identify the RLD BRX domain as a molecular platform for diverse protein interactions and establish a PKS-RLD module that operates in phototropism. Furthermore, these findings strongly suggest that RLD recruitment to the plasma membrane via PKS underlies phototropic signal transduction.

plant biology↗

bioRxiv2026

BioMINTREL expands biological problem solving through cross-disciplinary representations

Biological research agents often rely on familiar analytical methods, limiting the questions explored in existing data. We introduce BioMINTREL, an AI agent that finds methods from other disciplines and connects them to biological measurements. It can draw on relationships among datasets and complementary ideas from several methods to develop new questions and analyses. We evaluate it on BioMDC-Bench, which assesses 228 possible applications of computational methods to biological tasks. Compared with GPT-5.4 mini and Qwen3.6-35B, BioMINTREL improves F1 agreement with human experts by up to 45.3 percentage points and increases coverage of applications supported by studies published in subsequent years by up to 58.8 percentage points. Four case studies on real data go beyond previous analyses to reveal dose-specific variant effects, constraints on spatial cell communication and routes through perturbation-response states, and identify the sampling needed to test whether rare high-state cells predict later lineage size. These results highlight BioMINTREL's potential to expand questions in existing data and suggest directions for subsequent research.

bioinformatics↗

bioRxiv2026

π-MNovo improves de novo peptide sequencing through microbial-domain adaptation and evidence-guided candidate selection

The high taxonomic and strain-level diversity of microbial communities makes it difficult for reference databases to fully represent the protein sequences present in metaproteomic samples, limiting database-dependent peptide identification. De novo peptide sequencing can recover peptide sequences directly from tandem mass spectra without relying on reference databases, providing complementary peptide evidence for metaproteomics. However, most existing de novo sequencing models were developed largely from non-microbial proteomic data and lack specific adaptation to microbial spectra. Here, we established a dedicated microbial spectral resource comprising more than 10 million annotated high-quality tandem mass spectra from 72 cultured microbial isolates, with peptide digests from each isolate separated into five high-pH reversed-phase fractions to increase the opportunity for deeper and more diverse peptide sampling. Using this resource, we developed {pi}-MNovo, which combines adaptation to microbial spectra with evidence-guided candidate selection to improve full-length peptide sequencing precision. On a seven-species external benchmark, {pi}-MNovo achieved 66.30% complete-peptide recall under the same residue-mass-based complete-peptide matching criterion applied to all models, exceeding four published models by 6.9-21.7% in relative recall, with consistent gains across species and peptide-length groups. In two independent metaproteomic datasets, {pi}-MNovo increased reference-supported taxonomic coverage, while synthetic-community analysis recapitulated the designed abundance ranking. From pFind-unidentified spectra, {pi}-MNovo recovered 1,587 pFind-unreported, reference-matched peptides that passed spectrum-evidence filtering. These results show that {pi}-MNovo expands recoverable peptide evidence and enhances the utility of de novo sequencing for metaproteomic analysis.

bioinformatics↗

bioRxiv2026

Speciesformer learns conserved cellular states for cross-species generative virtual cell modeling

Cells across species are governed by evolutionarily conserved biological programs, yet their molecular states and responses are reshaped by species, tissue and cellular context. A central challenge for virtual cell modeling is therefore to learn cellular states and state transitions that separate transferable biological principles from context-specific variation. Existing single-cell foundation models have advanced cellular representation learning, but most remain focused on single-species analysis, discriminative tasks or specialized forms of generation. Here we present Speciesformer, a cross-species generative single-cell foundation model that integrates evolutionary representation learning with virtual cell-state generation. Speciesformer is pretrained on SpeciesCorpus, comprising 131 million cells from 11 species, 154 tissues, and more than 923 cell types, and maps species-specific genes into a shared evolution-informed gene space. Its encoder learns transferable cell and gene representations that support biological representation probing and cross-species knowledge transfer, providing a common state space for resolving conserved and context-dependent cellular programs. Building on this shared representation, Speciesformer uses a unified generative architecture to model cellular states and state transitions under semantic and interventional conditions, enabling bidirectional generation between transcriptomic states and biological text descriptions, as well as prediction of post-perturbation transcriptomes from initial cell states and intervention descriptions, including in previously unobserved cellular contexts. By unifying evolutionary variation, biological semantics and conditional state transitions, Speciesformer extends cross-species foundation modeling toward a generative virtual cell framework for representing, describing and predicting cellular states across biological contexts.

systems biology↗

bioRxiv2026

Mammalian TMC Family Proteins are Mechanically Gated Ion Channels

Every known life form senses and reacts to mechanical forces. These mechanical stimuli can be converted into electrical signals by mechanically gated ion channels, a transduction cascade pivotal to numerous physiological functions including touch, hearing, mechanical pain, circulation, gastrointestinal function, and mechanical loading in various tissues. Despite continuous efforts, numerous mechanically gated ion channels with the mechanotransduction process underlying these physiological functions remain unidentified. Here, we focused on the transmembrane channel-like (TMC) protein family expressed in the cultured cells to identify those with potential mechanosensitive activity. Remarkably, in contrast to human TMC1/2 (HsTMC1/2), human TMC3-8 (HsTMC3-8) proteins are localized to the plasma membrane when heterologously expressed in the cultured cells. Further experiments revealed that mechanical poking stimuli can effectively activate HsTMC3-8. In addition, HsTMC3-8 induced stretch-activated currents and elicited well-resolved single-channel activities in response to negative pressure stimulation. The mutants near the putative pore region altered reversal potentials (Erev) of HsTMC3-8, suggesting that TMC3-8 are likely pore-forming subunits of ion channels. In summary, we proposed that TMC proteins are the largest mammalian mechanically gated ion channel family.

neuroscience↗

bioRxiv2026

IL-21-producing peripheral helper T cells associate with autoimmune bile duct injury in biliary atresia

BackgroundBiliary atresia (BA) is a severe neonatal liver disease characterized by progressive fibrosis and bile duct obliteration. ObjectiveAlthough immune dysregulation is implicated in the pathogenesis of BA, the specific mechanisms driving bile duct injury remain incompletely understood. This study aimed to characterize tertiary lymphoid structures (TLSs) within extrahepatic biliary remnants (EBRs), identify their cellular mediators, and evaluate the therapeutic potential of targeting IL-21 receptor signaling. DesignWe performed integrated bulk RNA sequencing, single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and flow cytometry on clinical samples from BA patients and non-BA cholestatic controls. TLS maturation was assessed by CD23 immunohistochemistry in EBRs from 148 BA patients and correlated with clinical parameters. Anti-IL-21R antibody treatment was evaluated in a rhesus rotavirus-induced BA mouse model, with treatment initiated on day 4 post-infection. ResultsTLSs were identified in BA EBRs with significantly higher prevalence than in matched liver tissues. Mature TLSs containing CD23 germinal centers were associated with elevated serum matrix metalloproteinase-7, more advanced hepatic fibrosis, and localized autoantibody deposition on injured bile ducts. Single-cell profiling revealed expanded CD4+ T peripheral helper (Tph) cells expressing IL-21 and CXCL13 within TLS-containing EBRs. Tph cells were enriched in peripheral blood of BA patients compared to non-BA cholestatic controls (P = 0.0025), and serum IL-21 was significantly elevated (P < 0.0001). Post-infection IL-21R blockade in the mouse model reduced jaundice incidence, improved weight gain, prevented extrahepatic biliary obstruction, and significantly improved long-term survival. ConclusionTLSs in BA extrahepatic biliary remnants harbor expanded Tph cells associated with IL-21-mediated B cell activation and bile duct injury. IL-21R blockade ameliorated disease in a murine BA model, identifying the IL-21/IL-21R axis as a potential therapeutic target warranting further investigation. Key MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSImmune dysregulation contributes to biliary atresia (BA), with documented lymphocyte infiltration and defective B cell tolerance. However, the cellular mechanisms linking local immune activation to bile duct injury are unclear, and the roles of organized lymphoid structures and specific CD4 T cell subsets in orchestrating local humoral responses have not been characterized. What this study addsThis study demonstrates that mature tertiary lymphoid structures in extrahepatic biliary remnants are associated with disease severity markers and localized bile duct injury in BA. We identify T peripheral helper cells as an expanded IL-21-producing CD4 T cell population within these structures, and show that post-infection IL-21 receptor blockade prevents biliary obstruction and improves survival in a murine BA model. How this study might affect research, practice or policyThese findings identify the IL-21/IL-21R signaling axis as a candidate therapeutic target in BA warranting further preclinical and translational investigation. TLS maturation status in biliary remnants and serum autoantibody levels may serve as potential biomarkers of disease severity, meriting prospective evaluation in clinical cohorts.

immunology↗

bioRxiv2026

Unlocking Your Programmable and Creative RNA Sequence Designer with RDiffusion

RNA, a pillar of the central dogma, has shaped three billion years of evolution. Despite cataloging tens of millions of non-coding RNAs and annotating millions, we have barely scratched the surface of the vast, unexplored RNA sequence space. Here, we introduce RDiffusion, a discrete-diffusion-based generative transformer model for RNA sequence design. Conditioned on diverse biological features, such as desired function, family type, secondary and tertiary structure, or binding protein partners, it can guide the generation of novel RNA sequences tailored to specific design specifications. We evaluate RDiffusion across a broad spectrum of RNA design tasks and find that it not only surpasses all baseline methods in design success rate and sequence diversity but also achieves advanced performance on downstream tasks. To demonstrate its translational potential, we applied RDiffusion with a customized seed-screening pipeline to de novo design therapeutic MicroRNA(miRNA) mimics in osteoarthritis (OA). This strategy identified mimic 0-4 as a lead candidate targeting SDC4 to preserve ECM homeostasis and cartilage integrity, with robust efficacy validated in clinical OA samples. Altogether, RDiffusion holds strong potential to serve as a cornerstone for RNA generation and representation learning, establishing a generalizable AI-driven paradigm for RNA therapeutic discovery.

bioengineering↗

bioRxiv2026

Dynamic Gating Mechanism of the b0,+AT-Mediated Arg Transport: Insights from ASMD Simulations

Heteromeric amino acid transporters (HATs) mediate essential amino acid flux across membranes, but the molecular dynamics of substrate translocation remain poorly defined for many family members. Here, using conventional and adaptive steered molecular dynamics (cMD and ASMD) simulations, we identify residue W230 in the b0,+AT transport channel as a dynamic gate that regulates arginine (Arg) influx through side chain flipping. By integrating dynamic network analysis with dynamical cross-correlation of residue motions, we show that regulatory signals propagate from the Arg binding site through transmembrane helix 5 (TM5), a connecting loop, and TM6 to reach W230. We propose a dynamic gating mechanism for b0,+AT - mediated amino acid transport. Arg binding at V186 triggers signal propagation that enhances cooperative interactions between W230 and Arg, driving the side chain flipping of W230. Our findings reveal a dynamic gating mechanism underlying b0,+AT - dependent Arg transport and suggest that residue-triggered side chain reorientation may represent a conserved and efficient strategy in transporter function. Author SummaryAmino acids are the essential building blocks of life, and their transport across cell membranes is vital for nutrition and cellular signaling. Heteromeric amino acid transporters (HATs) mediate this process, yet how they physically move substrates through the protein at the atomic level remains poorly understood. In this study, we used advanced computer simulations to observe, in unprecedented detail, how b0,+AT--a key HAT member--transports the amino acid arginine. Our simulations revealed that a single residue, tryptophan 230 (W230), functions as a molecular gate: its side chain flips open to allow arginine to pass and then closes behind it, ensuring one-way traffic into the cell. We further discovered that the initial binding of arginine sends a signal through specific structural elements (helices and loops) to trigger this gate opening. This work not only uncovers a dynamic gating mechanism for b0,+AT but also suggests that similar side-chain flipping events may represent a common and efficient strategy used by other transporters to control substrate movement. Our findings provide a new framework for understanding transporter function and could inform future drug design targeting these critical membrane proteins.

biophysics↗

bioRxiv2026

Multimodal physical evidence uncovers interpretable gene regulatory networks for perturbation prediction

Gene regulatory networks govern cell fate transitions through dynamic causal mechanisms1. Since exhaustively mapping this vast perturbation space experimentally is prohibitive2, scalable computational models are essential. Yet, current frameworks fall short because they infer statistical co-expression rather than physical mechanisms, remain blind to non-canonical regulators lacking classical DNA-binding motifs, and fail to generalize across unseen perturbation factors or cell lines. Here we show that a multimodal biophysical framework, VitaGRN, overcomes these barriers by constructing a biophysical regulatory scaffold from multimodal evidence and propagating interactions to capture non-canonical regulators. By leveraging structurally aligned protein embeddings, VitaGRN predicts zero-shot perturbation responses and uncovers non-canonical translational control programs. Notably, VitaGRN demonstrates robust generalization across unseen factors, cell lines, and developmental transitions. Ultimately, VitaGRN generates a confidence-calibrated virtual perturbation atlas spanning over a thousand factors. This resource reframes gene regulatory networks from static correlation graphs into dynamically generalizable and mechanistically trans-parent models, streamlining wet-lab candidate prioritization.

bioinformatics↗

bioRxiv2026

Microinjection-based Single-Cell Toxicological Assessment Reveals How Physiological Levels of PFOS Impair Oocyte Maturation and Developmental Competence

Perfluorooctanesulfonic acid (PFOS) is a persistent environmental contaminant widely detected in human serum and follicular fluid and has been associated with reduced implantation rates and female fertility. However, its direct effects on mammalian oocyte maturation remain poorly understood. Here, we developed a microinjection-based single-oocyte toxicological assay to directly evaluate how physiologically relevant PFOS concentrations affect mouse oocyte maturation and early embryonic development. Microinjection of PFOS at follicular-fluid level (5.6 nM) and occupational exposure level (60 nM) significantly reduced germinal vesicle breakdown (GVBD) and polar body extrusion (PBE) rates compared with water-injected controls. Notably, all tested concentrations (2.4 nM serum level, 5.6 nM, and 60 nM) induced abnormal polar-body formation, disrupted meiotic spindle morphology, and increased the proportion of unhealthy oocytes. PFOS exposure also significantly elevated intracellular reactive oxygen species (ROS) levels and mitochondrial membrane potential at 5.6 nM, indicating oxidative stress and mitochondrial dysfunction. Cytological analyses revealed chromosome misalignment and widened metaphase I plates, suggesting chromosome missegregation and subsequent prometaphase II arrest with defective polar bodies. Single-cell RNA sequencing of PFOS-treated oocytes exhibiting abnormal small polar bodies identified distinct transcriptional signatures, including dysregulation of genes involved in mRNA processing, chromosome segregation, mitochondrial function, and cell division. Functionally, these oocytes failed to progress beyond the 2-cell stage following in vitro fertilization, indicating loss of developmental competence. Collectively, these findings demonstrate that PFOS directly disrupts meiotic progression through spindle defects, oxidative stress, and transcriptional dysregulation, ultimately compromising oocyte quality even at environmentally relevant exposure levels. Environmental ImplicationPFOS is a persistent environmental contaminant widely detected in human serum and follicular fluid. Our findings demonstrate that PFOS at physiologically relevant levels can impair oocyte maturation, disrupt meiotic chromosome segregation, and compromise early embryonic development. By using a single-oocyte toxicological assay, we reveal that even low-dose PFOS exposure can induce oxidative stress and transcriptional dysregulation. These results highlight the potential reproductive risks of chronic PFOS exposure and underscore the importance of stricter environmental monitoring and regulation to protect female reproductive health and fertility. This novel assay also has the potential to redefine safety thresholds for other environmental toxicants.

cell biology↗

bioRxiv2026

Gene-Specific Analysis of Clonal Hematopoiesis Identifies ASXL1 as a Risk Factor for Lung Cancer

IntroductionClonal hematopoiesis of indeterminate potential (CHIP) is a recognized risk factor for hematologic malignancies, but its contribution to different types of solid cancers remains incompletely defined. MethodsHere, we performed a systematic, gene-specific analysis of CHIP across 19 common solid cancer types using two large population-based cohorts, the UK Biobank and All of Us with Cox proportional hazards models and nested case-control logistic models. ResultsWe demonstrate that the relationship between CHIP and solid tumors is highly cancer-type specific, with lung cancer exhibiting the strongest association. In lung cancer, this association is largely driven by ASXL1-mutant clones. Specifically, high variant allele fraction (high-VAF) ASXL1 conferring a significantly increased risk (hazard ratio = 3.2), and the associations remained robust after adjustment for age, sex, body mass index (BMI), smoking status, and genetic ancestry. Notably, ASXL1 CHIP was substantially enriched among smokers, and its association with lung cancer risk was restricted to ever-smokers, highlighting a key interaction between CHIP and environmental exposure. The enrichment of ASXL1 CHIP in lung cancer was further validated in two independent cancer-only cohorts, including MSK-IMPACT and TCGA. In addition, rare germline variant association analysis revealed that germline variation in ASXL1 had the strongest association with lung cancer susceptibility among all solid tumors. ConclusionsCollectively, our findings support a model in which smoking-associated expansion of ASXL1-mutant clones contributes to lung cancer development and suggest that gene-specific CHIP metrics may enhance risk stratification and early detection strategies.

bioinformatics↗

bioRxiv2026

Effects of Phthalate Metabolite Mixture Exposure on Mouse Oocyte Development

Phthalates are pervasive endocrine-disrupting chemicals widely used in consumer products. The wide use of many phthalates results in chronic human exposure to complex mixtures rather than single compounds. Despite extensive studies on individual compounds, the combined effects of phthalate metabolites on oogenesis remain poorly understood. Here, we developed a precise microinjection-based single-oocyte toxicological assay to examine the impact of a defined phthalate metabolite mixture on meiotic progression. Phthalate mixture exposure markedly impaired oocyte maturation, as most oocytes failed to extrude the first polar body. Mechanistic analyses revealed severe meiotic defects, including disrupted spindle morphology, chromosome misalignment, disorganized actin cytoskeleton, and impaired mitochondrial function, accompanied by excessive reactive oxygen species (ROS) accumulation and DNA damage. Single-cell transcriptomic profiling further identified differentially expressed genes enriched in biological processes related to exocytosis, secretory pathway regulation, and cytoskeletal organization, as well as in MAPK, JAK-STAT, cGMP-PKG, and GnRH signaling pathways that are essential for follicular development and oocyte maturation. Together, these findings demonstrate that combined phthalate exposure directly compromises female gamete quality and underscore the importance of evaluating mixture effects when assessing risks to womens reproductive health.

cell biology↗

bioRxiv2026

Orai1 is required for Ca2+-dependent plasma membrane repair and mechanoadaptation

Ca2+-dependent repair of plasma membrane breaches is essential for animal cell viability. An initial passive influx of extracellular Ca2+ triggers the formation of a protein plug that rapidly seals breaches. However, the mechanism of extracellular Ca2+ requirement for subsequent repair remains undefined. EHD2 protein stabilizes the plasma membrane caveolae, which sustain membrane repair, and maintains high surface levels of the caveolae-resident Ca2+ channel Orai1. We establish the requirement of both Orai1 and EHD2 for repair of plasma membrane lesions induced by mechanical injury or by a model bacterial pore-forming toxin. We demonstrate rapid EHD2 recruitment and Orai1-mediated Ca2+ entry at plasma membrane sites of localized mechanical stimulus, the latter requiring EHD2 and CAV1. EHD2 and Orai1 are necessary for mechanosensitive YAP/TAZ-TEAD activation and positive feedback for CAV1 expression that promotes membrane repair. Our studies establish EHD2 and Orai1 as novel components of mammalian plasma membrane repair and mechanoadaptation.

cell biology↗

bioRxiv2026

BiomniBench: Process-level Evaluation of LLM Agents for Real-world Biomedical Research

LLM agents now perform real biomedical research, but evaluating them rigorously is hard. Outcome-only benchmarks fail in two ways. First, a correct final answer can come from memorization, reward hacking, or wrong reasoning that produces the right number by chance. Second, valid alternative analyses are marked wrong simply because they differ from the reference. We introduce BiomniBench, a process-level evaluation framework that scores the full agent trajectory against expert-designed, task-specific rubrics. Our first release, BiomniBench-DA, contains 100 data-analysis tasks across 17 task types, 5 disease areas, and a general-biology category, each based on a paper from journals such as Nature, Cell, and Science and co-developed with an original author or a domain expert. Benchmarking frontier and open-weight models across four agent harnesses reveals three findings. Frontier and open-weight bases cluster within a few points of each other, with substantial headroom for all models. The agent harness shifts scores by more than the gap between successive model generations. Agents reliably ground claims in real sources yet consistently fall short on method selection, biological interpretation, and scientific reasoning. BiomniBench is the first process-level benchmark for LLM agents in biomedical research, providing the dimension-level diagnostics that outcome scoring cannot. Datasethuggingface.co/datasets/phylobio/BiomniBench-DA

bioinformatics↗

bioRxiv2026

Serine Stabilizes SLC7A11 and Enhances Cystine Influx to Protect Against Acute Pancreatitis

Lethal sterile inflammatory diseases are linked to amino acid metabolism, but the role of serine remains unclear. Here, we show that dysregulated serine metabolism and reduced plasma serine levels correlate with disease severity of acute pancreatitis (AP) in patients and mouse models. Elevating serine levels via exogenous serine supplementation or pancreatic phosphoglycerate dehydrogenase (PHGDH) overexpression mitigates pancreatic injury, whereas a serine deprivation diet or pancreatic PHGDH knockdown exacerbates AP. Serine prevents cell death and oxidative stress in pancreatic acinar cells, human induced pluripotent stem cells-derived pancreatic organoids and mouse pancreatic tissue. Serine enhances cysteine and glutathione biosynthesis primarily by promoting solute carrier family 7 member 11 (SLC7A11)-dependent cystine uptake rather than by serving as a direct substrate. Mechanistically, the E3 ubiquitin ligase NEDD4 mediates ubiquitination and degradation of SLC7A11, whereas serine binds to NEDD4 and thereby inhibits SLC7A11 degradation. Similarly to serine, pharmacological inhibition of NEDD4 alleviates lipid peroxidation and pancreatic injury. These findings identify serine as a critical signaling regulator of SLC7A11 stability and oxidative stress, and provides a new therapeutic strategy for AP and associated sterile inflammatory disorders. HighlightsAcute pancreatitis (AP) is linked to abnormal serine metabolism and serine depletion. Serine prevents cell death in AP acinar cells, human pancreatic organoids and mice. Serine promotes SLC7A11-dependent cystine uptake and glutathione levels in acinar cells. Serine reduces NEDD4-mediated ubiquitination of SLC7A11. In briefSerine protects against cell death and pancreatic injury in acute pancreatitis by stabilizing SLC7A11 through disruption of NEDD4-mediated ubiquitination in acinar cells.

pharmacology and toxicology↗

bioRxiv2026

Heterogeneous signaling pathways are critical for the persistence of memory T cells in spleen and bone marrow

Persistence of memory T lymphocytes, in the apparent absence of antigen, is a hallmark of immune memory and key to adaptive immunity to recurrent infections. The signaling pathways ensuring survival and quiescence of the memory T cells are largely enigmatic. Here we show, by inhibition in vivo, that persistence of surface CD69+KLF2-tissue-resident memory T cells of murine bone marrow and spleen is blocked by antibodies to the integrins VLA-4 and LFA-1, connecting the memory T cells to VCAM1 and ICAM1 of stromal cells. Persistence requires the PI3K/AKT signaling pathway, since it is blocked by Wortmannin, and it involves PI3K-dependent survival genes. Surface CD69-KLF2+ memory T cells of the bone marrow are also dependent on integrin-mediated contact to stromal cells. Their persistence critically depends on the NF-kB pathway, their PI3K signaling pathway is not relevant. Blocking Jak1 and 3 of the interleukin-7 and -15 signaling pathways does affect memory T cells of the spleen, but not those of the bone marrow. Thus, tissue-resident KLF2+ and KLF2-memory T cells, and memory T cells of spleen and bone marrow, use different signaling pathways, adapting them to their respective tissues and reflecting an unexpected heterogeneity in the molecular mechanisms of persistence.

immunology↗

bioRxiv2026

Hopx expression marks Aβ clearance astrocytes in Alzheimers disease

SUMMERYAstrocytic dysfunction is closely associated with nearly all types of neurological diseases. Targeting astrocyte regulation has thus emerged as an important potential therapeutic strategy for neurological disorders. However, mechanisms that induce astrocyte dysfunction under pathological conditions have not been fully elucidated. In this study, we identified that Homeodomain-only protein X (Hopx) is downregulated in astrocytes across inflammatory models, Alzheimers disease (AD) mouse models, and brain tissues from AD patients. In the brains of AD mice, Hopx-positive astrocytes exhibit efficient {beta}-amyloid (A{beta}) plaque clearance, while knockout of Hopx leads to astrocytic dysfunction. Conversely, astrocyte-specific overexpression of Hopx not only significantly enhances their A{beta} phagocytic function but also effectively reduces the generation of neurotoxic astrocytes while increasing protective astrocytes. In summary, this study demonstrates the core regulatory mechanism underlying astrocytic dysfunction under AD pathological conditions and provides important potential targets for developing therapeutic strategies for AD by targeting astrocyte regulatory pathways.

neuroscience↗