Biology subjects

Nguyen, V.

Publications and source records attributed to Nguyen, V..

At least 19 recordsLinked to original sources

bioRxiv2026

Salinity is associated with habitat use and mitochondrial lineage diversity in halophilic Ephydra flies (Diptera: Ephydridae)

Brine flies of the genus Ephydra (Diptera: Ephydridae) are ubiquitous extremophile animals whose larval forms are able to thrive in high-stress environments, including hypersaline and high carbonate waters. Despite their historical and ecological importance, little is known about their evolutionary history. Here, we focus on an understudied population of Ephydra living in former industrial salt evaporation ponds of the San Francisco Bay Area (SFBA), a region which has undergone significant environmental changes in the past century. We observed and collected Ephydra specimens and took salinity measurements of waters they inhabited during a 6-month period in 2024. We found that E. millbrae and E. gracilis demonstrate strong salinity preferences. We also analyzed DNA from Ephydra spp. specimens from distant sites and a timespan of ~40 years, generating the most comprehensive gene genealogy of the group to date based on a single mitochondrial locus. Our analysis of phylogenetic signals suggests that salinity envelopes are influenced by evolutionary relationships in Ephydra. This study provides new information about the natural history of extremophile flies in the SFBA and fills in current gaps in our knowledge about the evolutionary history of the genus more broadly.

evolutionary biology↗

bioRxiv2026

15-deoxy-Δ12,14-prostaglandin J2 limits Salmonella infection through regulation of host TLR4 signaling and inflammasome activation

Enteric infections caused by Salmonella enterica remain a major global health concern and are increasingly associated with antimicrobial resistance. Therefore, new strategies to combat this important pathogen are needed. The interactions between S. enterica and the human host have been the subject of intense investigation over the last several decades, yet new findings continue to emerge. We previously showed that 15-deoxy-{Delta}12,14-prostaglandin J2 (15d-PGJ2) reduces Salmonella colonization of macrophages, but the mechanisms underlying this protective effect were still unknown. Here, we demonstrate that 15d-PGJ2 limits Salmonella infection by suppressing TLR4 signaling and inflammasome activation. Treatment with 15d-PGJ2 reduced TLR4 expression, NF-{kappa}B activation, iNOS, COX-2, nitric oxide production, IL-1{beta} release, and inflammasome-related targets, including NLRP3 and caspase-1 activity, while only partially reversing macrophage polarization. Combined treatment with the TLR4 antagonist TAK-242 further reduced bacterial colonization of and IL-1{beta} release by macrophages, supporting the involvement of TLR4 signaling in the effects of 15d-PGJ2. During mouse infections, 15d-PGJ2 reduced bacterial burdens in a tissue-dependent manner. Together, these findings demonstrate that 15d-PGJ2 limits Salmonella infection through selective modulation of TLR4 signaling and inflammasome activation.

microbiology↗

bioRxiv2026

CALFP-MHC: Interpretable Pan-Allelic Prediction of Peptide-MHC Binding and Presentation Using Chemically Grounded Fingerprints and Contrastive Learning

Identifying which peptides bind major histocompatibility complex (MHC) molecules is central to vaccine design, neoantigen prioritization, and precision immunotherapy. Existing deep learning predictors largely encode amino acids as discrete symbols, thereby missing the residue-level chemistry driving molecular recognition. Performance also tends to degrade under class imbalance, for rare alleles, and on peptide- MHC combinations outside the training distribution. We developed CALFP-MHC, a framework that encodes each amino acid as a set of complementary cheminformatics fingerprints capturing functional groups, atomic connectivity, and substructural features, and combines positional encoding with supervised contrastive pre-training to organize the latent space by binding class before fine-tuning a binary classifier. Peptide-MHC interactions are modeled through a hybrid convolutional-transformer backbone. In a large-scale computational benchmark covering [~]18.7 million peptide-MHC pairs across 112 HLA class I and 53 class II alleles, CALFP-MHC achieved AUCs of 0.93-0.97 and PPVs of 0.66-0.94. Critically, performance remained above AUC 0.90 even at a 200:1 negative-to-positive ratio, where competing tools frequently collapsed toward chance. On independent experimental data containing 3,627 class I and 520 class II MS/MS-confirmed ligands and 570 validated neoantigens, the model maintained strong discrimination, correctly prioritizing immunogenic peptides and MHC-presented ligands. Attention and integrated-gradient analyses recovered established anchor positions (P2 and P{Omega} for class I, P1, P4, P6, and P9 for class II) and highlighted chemically interpretable functional groups consistent with known binding determinants. CALFP-MHC demonstrates that grounding residue representations in molecular chemistry, rather than sequence symbols alone, improves both robustness and interpretability in peptide-MHC binding prediction.

immunology↗

bioRxiv2026

Reprogramming Cas9 PAM Recognition for Allele-Specific Editing

The therapeutic potential of CRISPR-Cas9 genome editing is fundamentally constrained by the requirement for specific short DNA sequences (PAMs) flanking the target site, limiting access to many clinically relevant genomic loci. This stringent PAM requirement is particularly problematic in applications which require precise positioning, such as base editing and allele-specific editing. Although PAM-relaxed variants have expanded the targetable genome, they incur trade-offs in on-target activity, off-target editing, and cleavage kinetics. This highlights an unmet need for variants that are re-targeted to alternative PAMs in order to maintain the specificity and enzymatic performance inherent to stringent dinucleotide PAM recognition. To overcome these limitations, we developed a yeast selection platform to engineering SpCas9 variants with re-specified PAM recognition. Using a clinically relevant Huntingtons disease gene (HTT) SNP as a proof-of-concept target, we engineered variants with reciprocal NGC and NGT PAM selectivity, as a step toward allele-specific editing in a large percentage of Huntingtons disease patients. These yeast-selected SpCas9 variants retained their modified activity across multiple endogenous HEK293T loci, demonstrating that this specificity is robust across diverse genomic contexts. The variants surpassed PAM-broadened variants on their respective on-target PAM while displaying broad loss of activity across alternative PAMs, effectively re-specifying PAM recognition toward a single dinucleotide sequence. Retargeted variants recovered on-target cleavage kinetics approaching that of wild-type SpCas9, even under competing substrate conditions, demonstrating that PAM re-specification can simultaneously restore catalytic efficiency and improve specificity. Beyond NGC and NGT, we leveraged our high-throughput platform to engineer Cas9 with re-specified activity across multiple additional non-canonical PAMs in yeast, further demonstrating its utility as a general and programmable framework for expanding the therapeutic reach of precision genome editing.

molecular biology↗

bioRxiv2026

Clusterin regulates microglial inflammation and cognitive function independent of amyloid pathology in Alzheimer's disease

Clusterin (CLU) is a major genetic risk factor for late-onset Alzheimers disease (AD), yet the mechanism underlying this risk remains unclear. This study investigated the role of CLU in regulating microglial inflammation, amyloid pathology, and cognitive function in CLU-deficient and AD models. CLU synthesis and secretion in microglia were highly dynamic, with minimal expression at rest but markedly increased expression upon pro-inflammatory stimulation. CLU deficiency amplified microglial activation and inflammatory responses, whereas introducing recombinant CLU protein reduced microglial inflammation. In a human mutant APP knock-in AD mouse model, loss of CLU impaired learning and memory despite a reduced amyloid burden. snRNA-seq analysis further revealed that CLU loss disrupted the balance between excitatory and inhibitory neurons. These findings provide novel insights indicating that CLU likely functions as a negative feedback regulator of microglial activation and inflammation, thereby promoting microglial resolution and neuronal homeostasis, and consequently, cognitive outcomes independent of amyloid pathology.

neuroscience↗

bioRxiv2026

Detection of Pancreatic Cancer Using a Methylation-Specific PCR-Based Multi-Cancer Early Detection Test

ContextPancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy often diagnosed at advanced stages due to the lack of early clinical symptoms. DNA methylation alterations arise early in PDAC tumorigenesis and may serve as promising biomarkers for blood-based cancer detection. ObjectiveTo evaluate the performance of EPISEEK, a laboratory-developed blood-based multi-cancer early detection (MCED) assay, for detecting PDAC across disease stages. DesignA retrospective cohort study included 97 patients with stage I-IV PDAC and 201 asymptomatic healthy controls. Sensitivity, specificity, area under the curve (AUC), and stage-specific performance were assessed. EPISEEK-MCED performance was also compared with CA 19-9 alone and in combination with CA 19-9. ResultsEPISEEK-MCED classified 65 of 97 PDAC cases as positive, corresponding to an observed sensitivity of 70.1% (95% CI, 60.3% - 78.3%) at 99.5% specificity. The assay demonstrated strong discrimination between PDAC cases and healthy controls, with an AUC of 0.916 (95% CI, 0.88 - 0.952). Sensitivity increased with advancing stage while remaining substantial in early-stage disease, measuring 53.6% for stage I and 65.1% for stage II PDAC, 100% for stage III and 94.7% for stage IV. Across stages, EPISEEK-MCED outperformed CA 19-9 alone, particularly in early-stage disease. Combined analysis of EPISEEK-MCED and CA 19-9 further improved detection performance, achieving sensitivity of 57.1% and 81.4% for stage I and II, respectively. ConclusionsEPISEEK-MCED demonstrated high specificity and sensitivity for PDAC detection across disease stages, including early-stage disease. Combining EPISEEK-MCED with CA19-9 further improved performance, supporting its clinical utility for PDAC detection.

molecular biology↗

bioRxiv2026

Domain-Specific Agonist Binding Affinities Explain Structural and Functional Regulation of TRPM2

TRPM2 is a Ca{superscript 2}-permeable cation channel activated by ADP-ribose (ADPR) and oxidative stress, yet the relative contributions of its two nucleotide-binding domains, MHR1/2 and NUDT9H, remain incompletely understood. Here, we quantitatively determine the affinities of the isolated human TRPM2 MHR1/2 and NUDT9H domains for ADPR, 2-deoxy-dADPR (dADPR), and 8-Br-cADPR using biophysical approaches. The MHR1/2 domain binds ADPR with high affinity (Kd {approx} 0.5 {micro}M), whereas the NUDT9H domain displays substantially lower affinity (Kd {approx} 192 {micro}M), revealing a difference of nearly three orders of magnitude. Mutational analysis demonstrates that alterations in MHR1/2 strongly affect ligand binding and channel activation, while mutations within NUDT9H that markedly reduce ligand affinity exert only modest effects on gating. In parallel, we quantify intracellular ADPR concentrations in resting and hydrogen peroxide-stimulated cells and find that they remain well below the affinity required for substantial NUDT9H occupancy. Together, our findings indicate that high-affinity binding to the MHR1/2 domain is sufficient to drive TRPM2 activation under physiological conditions, whereas the NUDT9H domain likely contributes to maintaining the structural integrity of the channel rather than directly mediating ligand-dependent activation. These results provide a quantitative framework for understanding ligand-dependent TRPM2 regulation in cells.

biophysics↗

bioRxiv2026

Mechano-activation of synovial fibroblasts and macrophages during OA progression in the dynamically stiffening synovial microenvironment

ObjectiveDuring osteoarthritis (OA) progression, the synovial membrane undergoes profound structural and compositional remodeling and fibrosis. We sought to elucidate how evolving synovial microenvironmental mechanics during fibrotic remodeling influence cell behavior and drive the progression of synovial pathology. MethodsSkeletally-mature male C57BL/6J mice were subjected to destabilization of the medial meniscus (DMM). To control for surgical confounders, both sham-operated and unoperated mice were included, with evaluation at 4- and 8-weeks. Synovial micromechanics were quantified via atomic force microscopy (AFM). Single-cell RNA sequencing (scRNA-seq), RNA fluorescence in situ hybridization (FISH), and flow cytometry were employed to investigate cellular heterogeneity, spatial organization, and crosstalk within fibrotic and non-fibrotic synovial niches. ResultsProgressive fibrotic remodeling and marked matrix stiffening were observed in DMM-operated synovium but absent in sham- and un-operated controls. While both sham and DMM joints mounted an acute stromal and immune response to surgery, these changes resolved over time in sham conditions but persisted in DMM synovium. During disease progression, distinct functional subsets of synovial fibroblasts and immune cells emerged, with mechanosignalling pathways and distinct immune cell-fibroblast crosstalk robustly activated within DMM-induced fibrotic microenvironments. ConclusionThis study demonstrates the complex cellular dynamics and crosstalk that differentiate the evolution of the pathological synovial response in the fibrotic DMM condition relative to surgical sham controls. Our findings highlight mechanotransduction as a central mechanism driving OA synovial pathogenesis and underscore the utility of the DMM model as a platform to dissect the molecular underpinnings of synovial fibrosis.

bioengineering↗

bioRxiv2026

CD14-deficiency protects against osteoarthritic subchondral bone sclerosis via enhanced osteoclastogenesis following joint injury

Aberrant bone remodeling is a hallmark of osteoarthritis, the most common arthritis affecting over 27 million US adults. Subchondral bone sclerosis, one sign of aberrant bone remodeling observable by routine x-rays, occurs as the trabeculae thicken, leading to increased bone volume. Toll-like receptors, pattern-recognition receptors of the innate immune system, have been implicated in OA pathogenesis, with TLR ligands, receptors, and co-receptors shown to mediate the severity and progression of OA. We have previously shown that CD14-deficiency protects mice against post-traumatic OA, and specifically reduces subchondral sclerosis post-injury. We hypothesized that depletion of CD14 protects against TLR4-dependent inhibition of osteoclastogenesis and therefore increases OC density in the SCB after injury, mitigating aberrant bone deposition in a murine model of OA. To determine how cellular changes correlate with bone structure derangements post-DMM, we performed MicroCT, Tartrate-resistant acid phosphatase staining, and alkaline phosphatase staining. To establish mechanistic changes in cellular signaling, we isolated WT and CD14-deficient osteoclast precursors and subjected them to LPS, an osteoarthritis-relevant TLR ligand, during differentiation. CD14-deficient mice, as well as WT mice treated with an anti-CD14 monoclonal antibody, show protection from post-injury increases in both bone volume fraction and bone mineral density. CD14-deficient mice had an increased osteoclast presence in the SCB two weeks post-injury, potentially protecting them from increases in bone volume and density. In vitro, CD14-deficient OCPs differentiated faster than WT OCPs, due to reduced Type I Interferon (IFN-I) signaling. In the presence of an LPS challenge, CD14-deficient OCPs were protected against LPS and TLR4-mediated inhibition, likely due to decreased MyD88-dependent TLR4 signaling. This work opens up new potential pathways to therapeutically target aberrant bone remodeling in the setting of joint injury and PTOA. Lay SummaryOsteoarthritis is one of the leading causes of disability worldwide. One of the hallmarks is subchondral sclerosis, or thickening of the bone in and around the joint. In this work, we used a mouse model of osteoarthritis to show that decreasing inflammatory signaling, through removal of CD14, protects against subchondral sclerosis, due to an increased presence of osteoclasts, cells that combat bone thickening. Osteoclasts without CD14 differentiate faster than osteoclasts with CD14, due to decreased Type I Interferon, an inflammatory cytokine. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/705094v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@176bdd5org.highwire.dtl.DTLVardef@a914bborg.highwire.dtl.DTLVardef@902748org.highwire.dtl.DTLVardef@2f9b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Transient signaling of free ADP-ribose monitored with an intracellular biosensor

We have developed a biosensor enabling the dynamic, compartmentalized, and longitudinal measurements of intracellular ADP-ribose (ADPR) in live cells. Free ADPR is a critical signaling metabolite derived from nicotinamide adenine dinucleotide (NAD+). As an agonist for Transient Receptor Potential Melastatin 2 (TRPM2), ADPR levels can regulate immune responses during infection, as well as nociception and adjustment of core body temperature. The study of ADPR signaling has been limited, however, by a lack of methods to measure this metabolite in situ. Using the biosensor and its paired non-responsive control, we determine that intracellular ADPR accumulation was transient and tunable. We found that basal concentrations were in the nanomolar range and could be stimulated [~]30-fold to activate TRPM2. We identified that TRPM2 activation, measured by calcium influx, required an intracellular ADPR threshold concentration between 2 - 4 {micro}M at physiological temperature. We observed that the timing of the ADPR rise coincided with TRPM2 activation, thus providing support for ADPR fluctuations being a critically regulated aspect for channel activation. Notably, transient fluctuations of ADPR were not accurately reflected by measurements of intracellular NAD+ loss or calcium levels. Significance StatementWe have developed a unique real-time biosensor for free ADP-ribose that is tuned to physiological concentrations and capable of intracellular measurements in individual cells. Using a calibrated system we determined that concentrations and timing of induced intracellular ADPR aligned with the thermosensitive TRPM2 activity. The data support ADPR as a critical component whose intracellular levels are regulated to control TRPM2 channel opening in cells.

biochemistry↗

bioRxiv2025

Enterocloster citroniae and related gut microbiome species modulate Vibrio cholerae biofilm formation through the production of bioactive small molecules

Cholera is a diarrheal disease that affects millions of people globally. Although the causative agent, Vibrio cholerae, has been extensively studied in isolation, investigation of its interactions with the gut microbiota started relatively recently. We and others previously showed that microbiota-derived metabolites significantly influence V. cholerae behavior. By investigating how an organic extract of human feces affects V. cholerae gene expression, we showed that gut metabolites strongly suppress swimming motility, a trait important for host colonization. Interestingly, extracts of pure cultures of a gut commensal, Enterocloster citroniae, recapitulated this inhibition. Here, we present a comprehensive examination of the effect of small molecules produced by E. citroniae and related species on V. cholerae behavior. We show that E. citroniae small molecules inhibit motility by various V. cholerae strains, and that several phylogenetically related species produce this activity, although the magnitude of the effect varies between strains. Using biofilm formation assays in static and flow conditions, we show that V. cholerae strongly induces biofilm formation in response to E. citroniae metabolites. Transcriptome and reporter analyses showed that several genes involved in synthesis of an extracellular polysaccharide are induced by E. citroniae metabolites. Lastly, we show that V. cholerae interactions with host cells are also modulated by this commensal. These findings advance our understanding of microbiome-pathogen interactions and how commensal bacteria influence V. cholerae virulence through the production of small molecules. In the future, this knowledge may be used to design novel microbiome-based therapeutic approaches to combat cholera and other infections. ImportanceThe human gut is home to a dense and rich community of microbes termed microbiota. This community has critical functions for host health, including protection against enteric pathogens. Despite this important role, we have only recently scratched the surface of the interactions that occur between members of the microbiota and pathogenic invaders. Cholerae is a disease that still causes significant morbidity and mortality worldwide. Studying how the causative agent, Vibrio cholerae, interacts with the microbiota will have implications not only for our understanding of this important microbial community, but may also lead to the development of new therapeutic strategies against cholera and potentially other infectious diseases.

microbiology↗

bioRxiv2025

Charting the Undiscovered Metabolome with Synthetic Multiplexing

Most molecular features detected in untargeted metabolomics remain uncharacterized due to the limited scope of existing spectral reference libraries. We synthesized >100,000 biologically inspired compounds using multiplexed reactions, of which 91% were absent from existing structural databases, and searched the resulting MS/MS library across >1.7 billion public spectra, increasing annotation rates by 17.4%. This approach revealed previously undescribed exposure-derived metabolites, including ibuprofen-carnitine. Because ibuprofen has been linked to rhabdomyolysis, reduced mitochondrial function, and impaired muscle recovery in carnitine-limited contexts, we investigated the functional relevance of this conjugate. Ibuprofen-carnitine reduced carnitine transport via the OCTN2 transporter, and in a postpartum mouse muscle injury model, ibuprofen delayed muscle repair that could be rescued by carnitine supplementation, with urinary ibuprofen-carnitine:carnitine ratios tracking this effect. These findings support a hypothesis whereby NSAID-carnitine conjugates compete for carnitine transport, impairing energy metabolism and muscle recovery in susceptible individuals. Synthetic multiplexing thus provides a scalable route to annotate the dark metabolome and generate experimentally testable biological hypotheses.

biochemistry↗

bioRxiv2025

QuickStainer: a rapid negative staining device for improved preservation of molecular structure

Negative staining is a widely used technique for observing macromolecules and their assemblies by transmission electron microscopy. It is commonly employed to optimize specimens for cryo-EM. The stain, typically a uranyl salt, surrounds the structure, providing an outline view at about 20 [A] resolution. Many macromolecules are relatively stable and rigid, and negative stain images provide a good representation of their structure. However, some are labile or flexible and their structure or assembly state is altered by binding to the carbon substrate on the grid before specimen staining. In these cases, the negatively stained appearance does not faithfully represent the structure in solution. This problem is reduced when samples are incubated on the carbon surface for short times (5 s) rather than typical times (30-60 s) before staining. To reduce disruption to a minimum, we have developed a rapid negative staining device (QuickStainer) using 3D-printed components, a stepper motor for precisely timed movements, and an Arduino-controlled interface to execute commands. QuickStainer produces consistent, reproducible results, achieving sample incubation times as low as 10 ms before staining. Tests show rapid adherence of molecules to the grid and greatly improved structural preservation of labile specimens compared with standard preparation protocols. The design of QuickStainer can accommodate inclusion of additional steps, such as timed incubation with enzyme substrate, before staining.

biophysics↗

bioRxiv2025

Single-vessel transcriptome map pathological landscapes and reveal NR2F2-mediated smooth muscle cell phenotype acquisition in capillary malformations

BackgroundCapillary malformation (CM) is a congenital vascular anomaly affecting the skin, mucosa, and brain, yet the understanding of its vascular pathogenesis remains limited. MethodsWe applied spatial whole-transcriptome profiling (GeoMx) and gene set enrichment analysis within CM lesions at single vasculature level. Differentially expressed genes were validated by immunofluorescence staining. Phosphoproteomics was profiled to uncover lesion- wide phosphorylation sites on proteins. Single-cell RNA sequencing was performed on CM- derived induced pluripotent stem cells (iPSCs) to determine differentiation trajectories of lesional vascular lineages. In silico gene perturbation was used to predict candidate genes for modulating vascular pathological progression, followed by functional validation in CM iPSC-derived endothelial cells (ECs) using a Tet-on system. ResultsA spatial transcriptomic atlas was constructed, and pathological landscape of individual CM vasculature was delineated. CM vessels exhibited hallmarks of endothelial-to-mesenchymal transition (EndMT), including disruption of adherens junctions (AJs), vascular identity transitions, and metabolic remodeling. Phosphoproteomics confirmed that differentially phosphorylated proteins were enriched in EndMT- and AJ-related pathways. Aberrant expression of venous transcriptional factor NR2F2 was observed in lesional ECs and correlated with progressive enlargement from capillaries to larger-caliber vessels containing multiple layers of smooth muscle cells (SMCs). In CM iPSCs, differentiation course yielded reduced ECs but increased SMCs. In silico knockout simulation predicted NR2F2 as a crucial regulator of facilitating SMC phenotype in CM. Consistently, enforced NR2F2 expression during iPSC differentiation suppressed endothelial markers while inducing SMC-associated genes. ConclusionsSingle CM vasculature displays pathological hallmarks characterized by EndMT and AJ disruption, leading to progressive vascular remodeling. NR2F2 functions as a central regulatory factor orchestrating the acquisition of the SMC phenotype, thereby representing a potential therapeutic target in CM.

pathology↗

bioRxiv2025

Receptor-tethered orthogonal IL-2 enhances regulatory T cell therapy

Regulatory T cell (Treg) therapy is an emerging platform for controlling immune overactivation. Efficacy of Treg therapy is limited by the poor persistence of infused Tregs due to insufficient IL-2, which is essential for Treg survival and function. IL-2 activates many immune cells besides Tregs, imposing a challenge for the selective provision of IL-2 to infused Tregs. In this study, we found infusions of orthogonal (ortho) IL-2 failed to enhance Tregs engineered with a corresponding orthoIL-2 receptor (IL-2R) in a mouse model of autoimmune diabetes. We then developed a receptor-tethered orthoIL-2 by optimizing the combination of IL-2, IL-2R, and the linker connecting them to achieve autocrine signaling selectively in engineered Tregs. Tregs expressing the tethered orthoIL-2 showed autocrine IL-2 signaling in vitro, enhanced CD25, CTLA-4, and Foxp3 expression, persisted without exogenous IL-2 in vivo, and prevented autoimmune diabetes using as few as 2,000 Tregs. Knocking the tethered orthoIL-2 construct into the Foxp3 locus enabled Treg-specific expression, with the additional benefit of positively reinforcing tethered orthoIL-2 expression through the activation of the Foxp3 gene by enhanced IL-2 signaling. Together, these results illustrate a safe and effective cell-engineering solution for overcoming Tregs dependency on exogenous IL-2, thereby achieving superior therapeutic efficacy.

immunology↗

bioRxiv2025

Age-dependent tumor-immune interactions underlie immunotherapy response in pediatric cancer

Pediatric cancers originate in rapidly growing tissues within the context of a developing host. However, the interactions between cancer cells and the developing immune system are incompletely understood. Here, we established a suite of pediatric syngeneic mouse cancer models across diverse anatomical sites and compared their tumor immune microenvironment with that in adult mice. Tumors in pediatric mice exhibited significantly accelerated growth and diminished leukocyte infiltration, dominated by naive-like PD-1low/CD8+ T cells, and proliferative MHCIIlow/PD-L1hi/CD86low macrophages. Tumor-infiltrating leukocytes in pediatric mice were enriched for MYC targets, which was also observed in pediatric patient samples. Furthermore, pediatric mice displayed poor responses to anti-PD-1/PD-L1 or bispecific T cell engager antibodies, which could be reversed by inducing a proinflammatory microenvironment via MYC inhibition or inducing macrophage polarization to an MHCIIhi phenotype. These findings underscore the significant influence of young age on cancer immune responses and reveal potential new therapeutic opportunities for pediatric cancers. HIGHLIGHTSO_LIAllograft tumors exhibit markedly accelerated growth in pediatric hosts compared to adults. C_LIO_LITumors growing in pediatric mice have reduced leukocyte infiltration, dominated by naive-like PD-1low/CD8+ T cells, and MHCIIlow/M2-like macrophages. C_LIO_LIEnrichment of MYC target genes is observed in pediatric mouse tumors and confirmed in primary patient tumor samples. C_LIO_LIPediatric mice display reduced response to anti-PD-1/PD-L1 and BiTE immunotherapy, which can be reversed by remodeling the TIME, using either MYC inhibition or macrophage polarization. C_LI

cancer biology↗

bioRxiv2025

Asymmetric increase in episodic and procedural memory interference in older adults

In younger adults, newly formed procedural memories are weakened by the subsequent formation of episodic memories (E[->]P interference) and vice versa (P[->]E interference; "cross-memory interference"). Older adults experience significant decline in episodic memory but maintain relatively intact procedural memory. This asymmetric decline in memory may also cause an asymmetric change in cross-memory interference compared to younger adults. For example, older adults may experience a significant increase in one type of cross-memory interference while leaving the other unchanged. Additionally, decline in episodic memory may cause E[->]P interference to either increase or decrease depending on how the episodic and procedural memory systems interact. However, no study to our knowledge has compared cross-memory interference between younger and older adults. We investigated cross-memory interference in younger and older adults by measuring E[->]P (Exp. 1) and P[->]E (Exp. 2) interference in 40 younger (18-40 years old) and 40 older ([≥] 55 years old) adults. Compared to younger adults, the results show that older adults experience significantly stronger E[->]P interference while P[->]E interference was statistically indistinguishable between groups. These results confirm that older adults experience an asymmetric increase in cross-memory interference and suggest that the increase in E[->]P interference is related to the asymmetric decline in episodic memory relative to procedural memory.

neuroscience↗

bioRxiv2025

Two routes from the Fertile Crescent led to the introduction of common vetch into Europe.

Vicia sativa (common vetch, n=6) is an annual leguminous plant with high drought tolerance and high grain protein content. Historically and still today, vetches are important for nitrogen fixation to maintain cereal yields and feeding grazing livestock. In this study, we re-sequenced the genomes of 279 common vetch accessions from a wide geographic range covering western Eurasia and North Africa to construct a comprehensive nucleotide variation map. Population structure analyses indicate that the Middle Eastern region was the centre of origin of common vetch, which then entered Europe in two distinct waves. One wave propagated by humans through Turkey into the Carpathian Basin before spreading throughout Europe via "Danubian" and "Mediterranean" routes. Demographic inferences revealed a significant bottleneck for all common vetch groups initiated during the Last Glacial Maximum, followed by an expansion that coincides with the onset of the warm Holocene epoch and the Neolithic Revolution. Interestingly, we identified selective sweeps for the flowering time regulators VsSOC1 and VsFTb2 in northern latitude populations suggesting that both genes are important regulators of latitudinal adaptation. Overall, we provide valuable genomic resources for conservation and breeding programs to optimize food production in the face of population growth and reduced agricultural resources.

plant biology↗