Biology subjects

Peng, L.

Publications and source records attributed to Peng, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Hidden grassland productivity from overlooked herbivore impacts

Grasslands cover approximately 40% of Earth's land surface and contribute substantially to terrestrial primary production. Despite widespread grazing, field estimates of grassland aboveground net primary productivity commonly overlook two grazing-related processes: biomass consumed by herbivores and post-grazing compensatory growth. The magnitude and direction of the resulting biases remain unclear. Here we quantified these biases using a 3-year yak grazing experiment on the Tibetan Plateau, a meta-analysis of 152 grazing experiments across China, and a global synthesis of 212 paired observations from 58 studies. Overlooking biomass consumed by herbivores consistently underestimated productivity by 34-51%. By contrast, overlooking grazing-induced compensation generated smaller but more variable biases, ranging from 29% underestimation to 19% overestimation, mainly reflecting contrasting compensatory responses under rotational versus continuous grazing. These findings show that overlooking grazing-mediated processes introduces substantial, process-dependent biases in grassland productivity estimates, underscoring the need to incorporate these processes into ecosystem and climate assessments.

ecology↗

bioRxiv2026

Autophagosome-tethering compounds selectively lower mutant ataxin-3 in preclinical models of spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is most common subtype of autosomal dominant spinocerebellar ataxia worldwide and the most prevalent CAG expansion disorder in the east Asian population, but disease-modifying therapies remain unavailable. SCA3 is caused by the accumulation of polyglutamine- (polyQ-) expanded mutant ataxin-3 (mAtxn3), while the wild-type ataxin-3 (wtAtxn3) plays an important cellular role. Thus, allele-selective clearance of mAtxn3 without affecting wtAtxn3 is highly desired for SCA3 treatment. To achieve this goal, we tested previously reported compounds that have been shown to selectively degrade the Huntingtons disease causing mutant HTT protein by tethering the expanded polyQ to the autophagosome protein LC3. Here, we demonstrated that two of these compounds, AN2 and GW5074, selectively reduced both soluble and aggregated mAtxn3 with expanded polyQ (84Q), but not wtAtxn3, in both cellular and mouse models of SCA3. Mechanistically, both compounds lowered mAtxn3 by enhancing its autophagic degradation without obvious activation of global autophagy. At the molecular level, both compounds increased mAtxn3-LC3 interaction and colocalization to enhance the allele-selectively autophagic degradation of mAtxn3. Phenotypically, both compounds rescued cell viability and ATP content of SCA3 cellular models. In SCA3 patient pluripotent stem cells (iPSCs) derived cortical neurons, both compounds allele-selectively reduced mAtxn3 and partially rescued neurite shortening. Importantly, in a well-established SCA3 transgenic mouse model (MJD84.2), intracerebroventricular, intraperitoneal, and oral administration allele-selectively reduced mAtxn3 in multiple brain regions and rescued motor function deficits. Oral dosing achieved nanomolar cerebellar exposure and showed no overt liver, kidney, or glial toxicity over 28 days. Analyses of 1303 Chinese patients with SCA3 and ATXN3 constructs of different polyglutamine lengths further supported the compounds polyQ length-dependent activity with relative sparing of normal-length ataxin-3. Together, these findings provide preclinical proof of concept that utilizing orally available small molecule compounds to allele-selectively enhance mAtxn3 autophagic degradation for SCA3 treatment. One-sentence summarySmall-molecule autophagosome-tethering compounds selectively lower mutant ataxin-3 through an LC3- and autophagy-dependent mechanism and improve disease-related phenotypes in preclinical models of SCA3.

neuroscience↗

bioRxiv2026

Deep reinforcement learning-driven discovery of a MsbA-targeted small-molecule antibiotic for the treatment of Acinetobacter baumannii infection

Antibiotics with new mechanisms are highly pursued to address the threat of infections caused by drug-resistant Gram-negative bacteria. Targeting MsbA, a key protein of the lipopolysaccharide biosynthesis pathway, represents a promising strategy to discover new classes of antibiotics. However, currently available MsbA-targeted molecules either lack sufficient potency or have unfavorable properties, necessitating expansion of chemical space. In this study, we chose the most promising cerastecin Cpd 4 as the template, and used two Artificial Intelligence (AI)-based tools, i.e. Link-INVENT and AutoMolDesigner for molecular design, performed chemical derivatization and antibacterial activity evaluation, which led to the discovery of Y-11 (MIC for A. baumannii: 0.5 g/mL). Encouragingly, Y-11 showed equivalent potency to Cpd4 for carbapenem-resistant A. baumannii, and less cytotoxicity and hemolysis as well as lower spontaneous resistance frequency. In vivo efficacy study demonstrated that Y-11 could effectively reduce bacterial loads in the mice infected by A. baumannii. The following mechanism study including molecular dynamics simulation, biochemical assay, and transmission electron microscope (TEM) analysis suggested that Y-11 inhibited the transport of lipooligosaccharide and impaired the formation of outer membrane, probably by competitively binding to the substrate binding site of MsbA and modulating ATPase activity. Taken together, we have discovered a MsbA-targeted small molecule Y-11 via AI-driven drug design, which provides a foundation for future antibiotic development.

biochemistry↗

bioRxiv2026

Targeting fibroblast activation suppresses chemotherapy-induced pro-invasive remodeling of the extracellular matrix

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that accounts for nearly 20% of breast cancer diagnoses. Despite recent approvals of novel therapeutic agents for TNBC, neoadjuvant chemotherapy remains part of standard of care treatment for TNBC patients. However, approximately 60% of TNBC patients who received neoadjuvant chemotherapy fail to achieve pathological complete response and face significantly elevated risks of recurrence and distant metastasis. We have shown that chemotherapy can induce significant changes in TNBC tumor extracellular matrix (ECM) that drive tumor cell invasion and may contribute to recurrence. Here, we investigate how chemotherapy drugs can impact resident fibroblasts, the major generators of ECM in the breast tissue. We find that chemotherapy activates fibroblasts and that doxorubicin specifically induces the production of pro-invasive ECM by fibroblasts via TGF-{beta}/Smad3 signaling. An FDA-approved tyrosine kinase inhibitor nintedanib suppressed doxorubicin-induced fibroblast activation and pro-invasive ECM production by fibroblasts in vitro. Additionally, in a TNBC mouse model, nintedanib reduced fibroblast activation markers in tumors, suppressed tumor cell motility in the tumor ECM, and reduced lung metastasis. These findings demonstrate a novel mechanism by which chemotherapy can induce fibroblast activation and imply that targeting fibroblast activation reduces chemotherapy-induced metastasis in TNBC.

cancer biology↗

bioRxiv2026

Differential LncRNA expression profile in the plasma of preeclampsia and normal pregnancies

Background: Early detection of preeclampsia with noninvasive and reliable biomarkers is the foremost step for minimizing adverse effects during pregnancy. However, none maternal serum analyte evaluated so far is sufficiently accurate to allow recommending their routine use. Methods: Microarray was used to first identify differentially expressed LncRNA and mRNA. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to determine bio-functions and signaling pathways. Quantitative real-time polymerase chain reaction was used to validate the results of microarray. Finally, the lncRNA-mRNA co-expression network was constructed to find the interaction of genes. Result: A total of 1476 differentially expressed lncRNAs and 594 mRNAs were identified. Both RNA-seq and RT-qPCR showed the expression of T241171,T338586, uc002ywy.3 was up-regulated, and the expression of ENST00000524858, T131416, T357032, uc.335+ was down regulated in the plasma of patients with preeclampsia. Pathway analysis showed the targeted mRNAs were enriched in apoptosis, sulfur metabolism, starch and sucrose metabolism. ceRNA network found that LncRNA-uc002ywy.3 might be the upstream regulator of miRNA-4498. LncRNA-uc002ywy.3/miRNA-4498 was predicted to interplay with genes involved in programmed cell death-1and its ligand (PD-1/PD-L1) pathway by KEGG analysis. Conclusion s PD-1/PD-L1 signaling pathway may be involved in the development of preeclampsia. The dysregulated LncRNA-uc002ywy.3/miRNA-4498 shed light on a new layer involved in the regulatory network of preeclampsia.

physiology↗

bioRxiv2026

Profiling Siglec-7 and Siglec-9 ligands across the LuCaP PDX series: Implications for glyco-immune checkpoint inhibition in advanced prostate cancer

Advanced prostate cancer exhibits profound cellular and molecular heterogeneity, frequently becoming resistant to androgen receptor (AR) targeting through lineage plasticity and neuroendocrine differentiation. Immunotherapies have shown limited efficacy in prostate cancer, largely due to its immunosuppressive tumour microenvironment. Hypersialylation contributes to immune evasion by engaging sialic acid-binding immunoglobulin-like lectins (Siglecs) on immune cells, forming glyco-immune checkpoints. Although this pathway represents a promising therapeutic target, the distribution of Siglec ligands across diverse prostate cancer phenotypes and their response to standard-of-care hormone therapy remain poorly understood. Here, we utilised high-affinity engineered sialoglycan-binding reagents (HYDRA) to perform comprehensive immunohistochemical profiling of Siglec-7 and Siglec-9 ligands across a panel of 40 Washington Carcinoma of the Prostate (LuCaP) patient-derived xenograft (PDX) models. Ligand expression was evaluated in relation to AR status and neuroendocrine phenotype. To determine the impact of androgen deprivation on the tumour glycome, ligand expression was compared between matched PDX lines grown in intact and castrated mice. Our findings reveal widespread but heterogeneous expression of Siglec-7 and Siglec-9 ligands across the LuCaP cohort. Expression levels were comparable between AR-positive adenocarcinoma models and AR-negative neuroendocrine variants, demonstrating that this glyco-immune checkpoint is maintained across distinct prostate cancer lineages. Under castration conditions, glycan remodelling occurred in a model-dependent manner. A subset of PDX models exhibited reduced Siglec ligand expression following castration, suggesting partial AR dependence. In contrast, other models displayed increased ligand expression, consistent with adaptive immune evasion in response to therapeutic stress, while a third group remained largely unchanged. Collectively, our study demonstrates that the Siglec-7/9 glyco-immune checkpoint axis is broadly maintained across the spectrum of prostate cancer lineage plasticity but is dynamically remodelled by androgen deprivation in a patient-specific manner. These findings support the sialoglycan-Siglec axis as a lineage-independent immunotherapeutic target and suggest that strategies aimed at disrupting Siglec-mediated immune suppression, such as tumour desialylation, may be most effective when combined with androgen deprivation therapy to enhance anti-tumour immunity.

cancer biology↗

bioRxiv2026

Correlative MIMS-EM imaging reveals metabolic turnover from organelle to organismal scales in C. elegans during dietary restriction

Metabolism is spatially compartmentalized across scales, from distinct tissues to cells and orga-nelles. However, most approaches for studying metabolic activity obscure spatial organization and intra-compartment heterogeneity within bulk biochemical measurements. On the other hand, multi-isotope mass spectrometry coupled with scanning electron microscopy (MIMS-EM) maps the fates of labeled nutrients in situ at nanometer-scale resolution, preserving ultrastructural con-text. Here we adapt MIMS-EM for Caenorhabditis elegans, where the compact metazoan body plan uniquely enables visualization of virtually all tissue types and their resident organelles within a single cross-sectional image. Using pulse-chase labeling of dietary carbon and nitrogen, we apply this approach to understanding the metabolic program induced in early stages of dietary restriction (DR). While DR is widely proposed to enhance organismal healthspan by enhancing broadscale turnover, proteomic studies have suggested more nuanced models. MIMS-EM across intact animals reveals that DR induces non-uniform effects between tissues and car-bon/nitrogen resources, accelerating carbon turnover in the muscle and hypodermis, but not in-testine. At the organelle scale, MIMS-EM revealed heterogeneity within mitochondrial networks that was independent of diet and stable over time. Spatial analysis of isotope signatures within intestinal mitochondrial networks also indicated greater similarity between neighboring mitochon-dria than distal mitochondria, supporting models of local mitochondrial mixing. Collectively, these results reveal that DR induces compartment- and resource-specific remodeling strategies across an intact animal while establishing C. elegans MIMS-EM as a powerful platform for multi-scale, integrative models of nutrient handling.

physiology↗

bioRxiv2026

Base-and-Sugar Dual-Frame Flow Matching for RNA Co-Design

Current frame-based RNA generative models represent each nucleotide with a single rigid coordinate frame. However, our analysis of seven nucleotide frame constructions across 11,497 static RNA chains and 31,432 multi-state relation groups reveals a clear trade-off: base-centered frames better preserve base-mediated relations, whereas sugar-centered frames better support sugar-phosphate backbone reconstruction. Motivated by this complementarity, we introduce DuetRNA, a joint sequence-structure generation model for RNA co-design that performs SE(3) flow matching over coupled base-and-sugar frames. Empirically, we evaluate DuetRNA under both the inverse-folded (IF) backbone-design protocol and generated-sequence (GS) co-design protocol. DuetRNA improves scTM-validity over the strongest matched baselines by 7.67 and 4.33 % under IF and GS, respectively. Controlled ablations further support the necessity of the dual-frame modeling in DuetRNA. The official DuetRNA repository is https://github.com/XjunLi/DuetRNA.

bioinformatics↗

bioRxiv2026

Photoreceptor-derived FGF2 mediates a protective stress response without driving pathological retinal neovascularization in ischemic retinopathy

Fibroblast growth factor 2 (FGF2) is frequently induced during ischemic retinal injury and has traditionally been considered a pro-angiogenic factor based largely on studies using exogenous FGF2 administration. However, its endogenous cellular origin and physiological role remain incompletely understood. Here, we used single-cell transcriptomic analysis combined with spatial validation and rod photoreceptor-specific genetic approaches to define the endogenous role of FGF2 during oxygen-induced retinopathy (OIR). We identify rod photoreceptors as a major cellular source of ischemia-induced FGF2. Notably, Fgf2 expression remained elevated during the regression of pathological neovascularization, revealing a temporal dissociation between neuronal stress responses and vascular remodeling. Single-cell analysis further showed that Fgf2 induction occurred within a coordinated photoreceptor stress-response program involving endothelin 2 (Edn2) and B-cell lymphoma 3 (Bcl3). This transcriptional signature was independently reproduced in the N-methyl-N-nitrosourea (MNU)-induced photoreceptor degeneration model. Rod-specific deletion of Fgf2 markedly increased photoreceptor apoptosis, indicating that endogenous FGF2 contributes to photoreceptor survival under ischemic stress. In contrast, neither genetic depletion nor overexpression of FGF2 altered pathological neovascularization or vaso-obliteration. Bidirectional manipulation of FGF2 further modulated the expression of representative stress-associated genes Edn2 and Bcl3, supporting FGF2 involvement in this injury-response program. Finally, receptor expression analysis revealed relatively limited endothelial expression of Fgfr1-Fgfr4 compared with VEGF receptors, suggesting a cellular basis for the distinct effects of endogenous FGF2 and VEGF signaling. Together, these findings identify endogenous retinal FGF2 as a photoreceptor-derived survival factor that is induced during stress but is insufficient to drive pathological angiogenesis. These results support a model in which neuronal adaptation and vascular remodeling represent partially distinct responses during ischemic retinal injury.

cell biology↗

bioRxiv2026

Rule-dependent transformation of observed into self-actions in macaque ventral premotor cortex

The ventral premotor cortex (PMv) has been implicated in both action selection and the perception of observed actions, but it remains unclear whether PMv activity during action observation reflects the observed action itself, or variables related to the observers own action when the observed action becomes behaviourally relevant. Here, we recorded neural activity in macaque PMv during a task that dissociated observed action, rule context, and the subsequently selected self-action. Population activity during observation was already biased toward the upcoming self-action and became increasingly aligned with it. At the level of single neurons, subsets showed modulation by rule and required self-action beyond the observed action. Task-related variables coexisted during observation, rather than being organized into distinct sequential stages. These findings indicate that PMv activity during action observation is not solely determined by the observed action, but instead reflects variables related to the selection of the agents own action, consistent with a transformation from observed action to self-action.

neuroscience↗

bioRxiv2026

A Variant-Resistant Linear Epitope in the SARS-CoV-2 Nucleocapsid Protein for Antigen Detection

We previously generated a mouse monoclonal antibody, N179, against the SARS-CoV-2 nucleocapsid (N) protein and developed a colloidal gold-based immunochromatographic test strip. This assay achieved a detection limit of 2 ng/mL and displayed 98% concordance with RT-qPCR results. However, the precise epitope recognized by mAb N179 had not been defined. Using a panel of GST-fused N protein truncation fragments, we mapped the linear B-cell epitope recognized by mAb N179 to the flexible C-terminal tail of the N protein by Western blotting and ELISA. The minimal binding motif required for mAb N179 recognition was identified as 390QTVTLL395. Multiple sequence alignment of 11 representative SARS-CoV-2 lineages, including Alpha, Beta, Gamma, Delta, and Omicron subvariants BA.1, BA.2, and BA.3.2, revealed that this epitope was completely conserved across all variants analyzed. Stringent local pairwise alignment analysis using EMBOSS WATER further showed that the 390QTVTLL395 motif achieved a perfect 6/6 match exclusively in SARS-CoV-2; no identical sequence was detected in the seven common human coronaviruses, four influenza viruses, or five bat coronaviruses examined. Structural prediction analyses indicated that this region is surface-exposed and possesses a strong linear B-cell epitope propensity. Together, these findings identify 390QTVTLL395 as a specific molecular signature of SARS-CoV-2 among the viruses analyzed. Our results provide an epitope-level explanation for the sustained diagnostic reliability of the mAb N179-based assay against emerging variants, clarify the molecular basis for its lack of cross-reactivity, and may inform the rational design of SARS-CoV-2 diagnostics targeting conserved, mutation-resistant epitopes. ImportanceWe identified the exact nucleocapsid protein epitope recognized by monoclonal antibody N179, a diagnostic antibody used in a colloidal gold rapid assay. The identified 390QTVTLL395 motif at residues 390 to 395 was conserved among the SARS-CoV-2 variants analyzed and was not present as an identical continuous sequence in the related respiratory viruses examined. This work supports precise epitope mapping as a useful strategy for evaluating and revalidating diagnostic antibodies as respiratory viruses evolve.

microbiology↗

bioRxiv2026

B3GNT7 regulates mucin glycosylation and protects against colitis and infection

Mucus covers and protects colonic epithelial cells. Mucus is mainly composed of heavily O-glycosylated proteins called mucins, and disruption of normal mucin glycosylation occurs in ulcerative colitis (UC). Mucin-2 (MUC2) is the major colonic mucin, and MUC2 O-glycans are often extended with sulfated polyLacNAc, also known as keratan sulfate (KS). The GlcNAc residues in KS are added by B3GNT family members. B3GNT7 is highly expressed in the colon, and B3GNT7 expression is dramatically reduced in UC. However, the function of B3GNT7 in colonic physiology is unexplored. Here we show that B3gnt7 is a key player in colonic physiology through its function in controlling the structure of mucus glycans. We found that B3GNT7 prefers to extend a sulfated acceptor substrate and is required for production of polyLacNAc-modified mucus in a human goblet cell model. In vivo, B3GNT7 regulates Muc2, Muc13, and Muc17 O-glycosylation. Intestinal B3GNT7 deficiency increases susceptibility to colitis and enteric infection in mice, showing that B3GNT7-dependent glycosylation confers protective properties to colonic mucus. Taken together, these results demonstrate that B3GNT7 has a function distinct from other B3GNT family members and is critical for maintaining colonic homeostasis. SIGNIFICANCE STATEMENTUlcerative colitis is a chronic inflammatory bowel disease that affects 5 million people globally. The colonic mucus layer forms a protective barrier over colonic epithelial cells and is disrupted in ulcerative colitis. Mucus is composed of mucin proteins decorated by carbohydrates, called glycans. Glycans confer protective properties to the mucus barrier, and mucin glycans change in ulcerative colitis. B3GNT7 is an enzyme that elongates glycans and is downregulated in ulcerative colitis. In this study, we use in vitro and in vivo models to demonstrate that B3GNT7 regulates colonic mucus glycans and protects mice against colitis and infection. Our findings provide molecular insight into the contributions of B3GNT7-dependent glycans to colonic homeostasis.

biochemistry↗

bioRxiv2026

Normobaric hypoxia alters the transcriptional response of healthy human skeletal muscles to a single session of high-intensity interval exercise

Given its well-documented effects on human physiology, hypoxia has garnered increasing interest for its potential to enhance specific adaptations to exercise. However, the molecular response of skeletal muscle to exercise under normobaric hypoxia remains poorly understood. To address this gap in knowledge, ten healthy young males completed a crossover study in which exercise in hypoxia was compared to exercise in normoxia matched by either absolute or relative intensity. This design allowed us to identify shared transcriptomic responses across all three conditions, as well as changes that were specific to exercise intensity or hypoxic exposure. Skeletal muscle biopsies were collected before, immediately after, and at 3 and 24 hours following each exercise session, with RNA sequencing performed to assess changes in gene expression. Following exercise, a greater number of differentially expressed genes were observed in hypoxia compared to normoxia at 24 h post-exercise. This hypoxia-specific response involved the downregulation of multiple mitochondrial pathways and appears to be regulated by a transcriptional network comprising both positive and negative regulators of HIF-1 activity. These findings highlight the ability of normobaric hypoxia to influence exercise-induced gene expression and suggests that it may promote distinct molecular adaptations in skeletal muscle following longer-term training.

physiology↗

bioRxiv2026

Spatiotemporal profiling reveals the role of inflammatory niche in driving prostate cancer

Prostate cancer (PCa) is a lethal malignancy that displays profound resistance to immune checkpoint blockade (ICB), via mechanisms that are poorly understood. Here, we investigate the causes of CD8 T cell exhaustion and mechanisms of tumor progression in a PCa animal model, by single cell and spatial profiling, along a time course, following orthotopic transplantation of RB1/TP53/PTEN-deficient mouse organoids, competent to express neoantigens. The resulting tumors were castration resistant, consisting of largely basal and L2 malignant cells with upregulated inflammatory gene programs, and a specific spatial distribution of macrophages, cancer associated fibroblast (CAF) subtypes, and CD8 T-cells that was not previously reported. Using Zman-seq, we demonstrate that the effector function of tumor-infiltrating CD8 T cells was rapidly impaired as early as 24hrs after their infiltration, likely driven by signals from proinflammatory macrophages, Ccl2-Jak2+ inflammatory CAFs, and malignant basal cells, thus driving resistance to ICB. Interestingly, dual blockade of JAK1/2 and PD1 induced potent anti-tumor effects in tumor epithelial cells, decreased malignant epithelial cells and pro-inflammatory macrophages, and increased the proportion of normal (Pi16+) fibroblasts in the TME. Our results underscore the therapeutic potential of targeting JAK1/2 to enhance the efficacy of ICB, providing a rationale for clinical investigation of this combination in PCa.

cancer biology↗

bioRxiv2026

HYPER-Net: Physics-Conditioned Self-Supervised Reconstruction for Fourier Light-Field Microscopy

The rapid convergence of optical innovation and machine intelligence is reshaping biological imaging by enabling platforms that jointly advance image formation and computational reconstruction for highspeed, high-resolution volumetric microscopy. However, broadly accessible three-dimensional imaging at high spatiotemporal resolution remains limited by the reliance of existing supervised methods on large modality-matched training datasets, the computational burden of conventional iterative reconstruction, and sensitivity to optical mismatch arising from small deviations in the spatial-angular point spread functions. Here, we introduce HYPER-Net, a physics-conditioned self-supervised framework for Fourier light-field microscopy that integrates scan-free volumetric acquisition with fast, robust three-dimensional reconstruction. HYPER-Net incorporates experiment-specific point-spread functions into the learning process in two complementary roles: as the forward operator that enforces measurement consistency and as a conditioning signal that adaptively modulates intermediate feature representations. This design reduces reliance on paired experimental ground-truth volumes, improves robustness to system variation, and enables generalizable reconstruction across diverse biological contexts. Using human colon organoids, embryonic Xenopus laevis hearts, hiPSC-derived cardiac spheroids, and freely moving Caenorhabditis elegans, we demonstrate high-fidelity volumetric imaging of tissue morphology, cardiac function, calcium-contraction coupling, and locomotion-associated neural and muscular dynamics. These results position HYPER-Net as a versatile framework for rapid volumetric imaging and quantitative analysis of dynamic biological systems across basic research and biomedical applications.

bioengineering↗

bioRxiv2026

Parasite defense covaries with reproductive timing, not with resistance

Defense is the ability of a host to minimize fitness loss to parasites. It is among the most variable phenotypes in host populations, and this variation facilitates rapid adaptation under parasite-mediated selection. We do not, however, know the underlying host traits that explain this variation in defense against parasites. A common assumption is that the most defended hosts are the most resistant, meaning they limit the establishment and growth of infecting parasites. Under this assumption, resistance traits should evolve readily under parasite selection. Resistance is, however, just one of many strategies hosts use to defend against parasites, and it does not consistently covary with fitness in the presence of parasites. We accordingly asked: which host traits covary with defense against parasites? We use controlled exposures to characterize genetic variation in defense of the nematode Caenorhabditis elegans against its natural microsporidian parasites. We report extensive variation in defense among wild strains of C. elegans: some strains lost 60% of fecundity under parasite exposure, while others were unaffected. We then tested the covariance of defense with two prominent host traits, resistance and reproductive timing. Our results did not support the hypothesis that resistance covaries with defense: strains with lower parasite burden did not have higher relative fecundity under exposure. Our results instead supported the hypothesis that life history covaries with defense: host strains that reproduced quickly had higher relative fecundity under exposure, consistent with the idea that parasites diminish future reproductive opportunities. The observed variation in defense among host strains indicates significant potential for wild C. elegans populations to evolve in response to their natural parasites. Because reproductive timing underpins this variation in defense, parasite-mediated selection could operate directly on host life history traits and should also be highly sensitive to shifts in life history driven by other biotic and abiotic factors. AUTHOR SUMMARYSome hosts fare much better than others in the face of parasite infection. What traits differentiate defended hosts from undefended hosts? The answer to this question is critical for identifying the strategies that best protect hosts from their parasites. It also allows us to predict and interpret the evolution of host populations over the course of epidemics. To address this question, we surveyed wild strains of a tractable model host, the nematode Caenorhabditis elegans, for their response to two species of microsporidian parasites. We found that, on average, parasite exposure substantially impaired the ability of hosts to reproduce. Host strains, however, varied widely: some experienced major losses in fecundity with exposure, while others were highly defended, showing little to no change. We identified reproductive timing as a key trait that differentiated defended hosts from undefended hosts. Our results suggest that reproducing quickly may have been protective, by allowing hosts to make most of their offspring before parasites impaired reproduction. We did not find evidence that resistance was protective: host strains with lower parasite burdens did not reproduce better than those with high parasite burdens. These findings give added weight to life history as a major component of host defense against parasites.

evolutionary biology↗

bioRxiv2026

Genomic insights into rapid diversification and adaptive introgression in the earthworm Amynthas aspergillum

How species diversify in highly fragmented landscapes while maintaining genetic connectivity remains a central question in evolutionary biology. The megascolecid earthworm Amynthas aspergillum exemplifies this paradox, showing deeply divergent mitochondrial lineages despite extensive nuclear gene flow across southern China. We conducted whole-genome resequencing across its core distribution in the Guangxi karst region to elucidate the population structure and processes underlying this cytonuclear discordance. Genome-wide analyses identified three genetically distinct groups shaped by fine-scale karst isolation, alongside pervasive historical and contemporary introgression. Demographic modeling revealed rapid diversification during the Late Pleistocene ([~]0.14LJMa) with pronounced fluctuations in effective population size. Although isolation increased inbreeding and mutational load in some lineages, introgression persisted even among deeply divergent mitochondrial clades. Notably, several introgressed regions showed strong signatures of positive selection, including genes involved in mitochondrial function and metabolism.Together, these results demonstrate that gene flow can simultaneously mitigate the genomic costs of isolation and promote functional innovation via adaptive introgression, providing a genomic framework for diversification with gene flow in subterranean invertebrates inhabiting fragmented karst landscapes.

genomics↗

bioRxiv2026

Single cell profiling reveals GSM-15606 attenuates air pollution-induced inflammation and preserves hippocampal neurogenesis

1.IntroductionAir pollution (AirPoll) is a major environmental risk factor for age-related cognitive decline and dementia, yet we poorly understood the cellular and molecular mechanisms underlying its effects and their potential attenuation. MethodsWe combined single cell RNA sequencing with immunohistochemistry to determine transcriptional responses in microglia, astrocytes, neurons and neural stem cells in the hippocampus of mice following exposure to chronic diesel exhaust particle (DEP). Differential gene expression profiles were compared between filtered-air and DEP exposed animals. The gamma secretase modulator GSM-15606 (BPN) was used to probe selective rescue of inflammatory signatures across distinct cell populations. ResultsDEP exposure triggered robust inflammatory programs in microglia and astrocytes, including upregulation of cytokine signaling components, innate immune receptors, stress-responsive transcription factors, and markers of reactive glial phenotypes. In neural stem cells, DEP induced activation of gliosis-associated pathways, including Il6st, Stat3, and Txnip, consistent with a pro-inflammatory state that may bias lineage decisions. Immunostaining confirmed a significant reduction in immature neurons in the neurogenic niche after AirPoll exposure. GSM-15606 attenuated many DEP-induced transcriptional alterations in microglia and astrocytes, reducing expression of inflammatory mediators and reactive gliosis markers, but did not modulate the inflammatory profile of neural stem cells. ConclusionsAirPoll activates divergent inflammatory pathways across hippocampal cell populations and suppresses neurogenesis. Targeting inflammation with GSM-15606 selectively reverses glial but not neural stem cell responses, highlighting cell-type-specific mechanisms and potential therapeutic pathways to mitigate pollution-related cognitive vulnerability. These results support GSM-15606 as a protective agent against AirPoll-induced hippocampal dysfunction and amyloidogenic stress.

neuroscience↗