Biology subjects

Xiong, X.

Publications and source records attributed to Xiong, X..

At least 19 recordsLinked to original sources

bioRxiv2026

Cross-feeding reshapes interactions between antibiotic stressors through metabolic feedbacks

Stressors can combine to inhibit organismal growth or function more (synergy) or less (antagonism) strongly than expected from their individual effects, yet whether these interactions are intrinsic properties of cells or stressors, or emergent consequences of ecological interactions remains unclear. Antibiotic combinations provide a tractable model for studying stressor interactions, but have been characterized largely in bacterial monocultures. Here, we compared antibiotic stressor interactions in Escherichia coli growth in monoculture versus when cross-feeding with Salmonella enterica. Across 36 antibiotic pairs, cross-feeding frequently shifts interactions toward antagonism and away from synergy. In the sulfamethoxazole-trimethoprim pair, dual treatment increases carbon excretion by E. coli, promoting partner growth and attenuating stressor synergy through reciprocal metabolic feedback. Perturbing partner metabolite usage restores monoculture-like interaction outcomes across multiple drug pairs. Together, our results demonstrate that stressor interactions in microorganisms can emerge from ecological feedbacks mediated by metabolic excretion.

microbiology↗

bioRxiv2026

An L-threonine-inducible biosensor derived from the tryptophan-repressed trp promoter of Escherichia coli for high-throughput screening of L-threonine overproducers

L-Threonine is an essential amino acid widely used in the feed, food, and pharmaceutical industries, and microbial fermentation is now the dominant route for its production. Further increases in producer titers depend on random mutagenesis coupled with high-throughput screening (HTS), but progress has been limited by the lack of a biosensor with a broad operating range, high sensitivity, and target specificity. Here, we show that L-threonine induces the tryptophan-repressed trp promoter of Escherichia coli, a response that, to our knowledge, has not been described previously. Deletion analysis showed that both the trpO operator and the trpL attenuation element contribute to induction, and that the lowest basal expression occurs only when both elements are present. By optimizing the ribosome-binding site, the promoter -10 region, and TrpR expression, we constructed an L-threonine biosensor on a pACYC backbone. The sensor responded linearly to L-threonine from 0.1 to 30 g/L (R2 = 0.9895), with an induction ratio of up to 51.7-fold. Among the 20 proteinogenic amino acids tested, only L-threonine produced a detectable response. The biosensor distinguished strains with different L-threonine production capacities and guided the directed evolution of homoserine kinase (ThrB) at a conserved motif, yielding variants with brighter reporter fluorescence and increased L-threonine production. This work provides a high-performance biosensor based on native E. coli regulatory elements for screening L-threonine overproducers.

bioengineering↗

bioRxiv2026

Shared and idiosyncratic coding regimes coexist in macaque IT

Population-level measurements portray object representations in primate inferotemporal cortex (IT) as smooth, low-dimensional, and predictable by deep neural networks (DNNs). However, it remains unclear whether this structured population-level picture is representative of the full diversity of its constituent neurons. Here, we used Neuropixels 2.0 probes to record large populations of well-isolated units from an fMRI-localized face patch in macaque anterior IT while monkeys viewed more than 3,000 natural images. Single-unit responses were substantially sparser and more heterogeneous than multi-unit activity (MUA). Sparse neurons collectively formed a higher-dimensional code, supported efficient image identification, and responded later than broadly tuned neurons. Partly independently of sparseness, some neurons exhibited reliable feature randomness: their stimulus preferences were reproducible across repeated presentations but discontinuous across DNN feature spaces, rather than reflecting trial-to-trial response variability or noise. These neurons were virtually uncorrelated with the surrounding population despite being located within the same face patch. By contrast, MUA responses were denser, more correlated, lower-dimensional, and better predicted by DNNs. Together, these findings suggest a dual coding architecture in anterior IT: shared low-dimensional structure supports category generalization, whereas sparse and reliably feature-random single-neuron responses expand the representational space and support efficient identification of individual visual inputs. Response sparseness and reliable feature randomness may therefore constitute fundamental computational resources for object recognition.

neuroscience↗

bioRxiv2026

Inorganic Nitrogen Availability Drives Metabolic Specialization and Adaptive Strategies in Vibrio harveyi and Vibrio parahaemolyticus

Nitrogen availability is a key factor shaping microbial metabolism, ecological adaptation, and nitrogen cycling in aquatic environments. Members of the genus Vibrio are ubiquitous heterotrophic bacteria in marine and aquaculture ecosystems, yet their responses to different inorganic nitrogen sources remain poorly understood. Here, we systematically compared the growth characteristics, nitrogen transformation capacity, and molecular responses of Vibrio harveyi and Vibrio parahaemolyticus under ammonium (NH4+), nitrate (NO3-), and nitrite (NO2-) conditions using physiological assays, comparative genomic analysis, and transcriptomic profiling. V. harveyi exhibited broader nitrogen utilization capacity and was able to grow under all three nitrogen conditions, whereas V. parahaemolyticus showed a strong preference for NH4+ and limited growth under NO3- and NO2- conditions. Moreover, V. harveyi displayed rapid population expansion accompanied by reduced long-term viability, while V. parahaemolyticus maintained greater population stability. Both species showed NO3- accumulation during growth despite lacking canonical nitrification genes under NH4+ condition, suggesting the potential involvement of non-canonical heterotrophic nitrification processes. Transcriptomic analysis revealed nitrogen source-dependent metabolic specialization in V. harveyi. NH4+ availability promoted motility-associated responses and metabolic overflow, whereas NO3- induced iron acquisition-related pathways and NO2- activated assimilatory nitrite reduction coupled with oxidative stress adaptation. These findings demonstrate that inorganic nitrogen availability drives divergent metabolic and adaptive strategies in Vibrio, providing new insights into their nitrogen metabolic potential and ecological roles in aquatic environments.

microbiology↗

bioRxiv2026

The S1B-Targeting PEDV Neutralizing Antibody C62 Prematurely Activates S-trimer and Mimics Receptor Function

Porcine epidemic diarrhea virus (PEDV) causes devastating enteric disease in piglets, yet the mechanistic basis of antibody-mediated neutralization remains poorly understood. Here, we determined the structure of PEDV HNXX-strain spike domain B (S1B) simultaneously bound by C62, a neutralizing porcine monoclonal antibody against PEDV G2 strains, and N34, a non-neutralizing porcine PEDV antibody. The structure reveals that C62 targets a conserved, cryptic epitope that is accessible only when S1B adopts an "up" conformation. Functionally, we showed that C62 has substantially stronger activity than N34 in triggering S-trimer disassembly and inducing the formation of proteinase K-resistant, post-fusion-like S2 structures. Despite the weaker triggering activity of N34, both C62 and N34 can function as artificial receptors. Notably, although the C62 epitope is conserved across both G1 and G2 strains, C62 exhibits G2-strain-biased neutralizing activity. We further showed that differences in cell-surface membrane fusion activity among PEDV spikes correlate with distinct viral entry pathways and are jointly determined by the S1A and S1B sequences. Together, our findings identify a strain-specific vulnerable site on the PEDV S-trimer and provide insight into how cell-surface membrane fusion activity may influence viral entry pathway selection and antibody neutralization efficacy.

microbiology↗

bioRxiv2026

Lineage recording reveals hijacked hepatic progenitor states as a common origin of HCC and ICC

HighlightsCERAMIC enables continuous and high-capacity lineage tracing of liver tumor initiation Fatty liver-associated hepatocytes acquire regenerative and premalignant cell states before malignant transformation Lineage reconstruction identifies Hep_Bi-zonal cells as the cellular origin of liver tumor initiation Transcriptional and regulatory programs distinguish tumor-fated hepatocytes from failed-to-transform lineages Peroxisomal metabolism is required for progenitor-state formation and liver tumor initiation Spatial remodeling identifies a macrophage niche associated with tumor-fated hepatocytes Dual ontogenies and functional specialization of lipid-associated macrophages shape the tumor-fated hepatocyte niche Fatty liver disease predisposes to primary liver cancer, yet the lineage routes and niche mechanisms that select rare tumor-fated hepatocytes remain unclear. Here we developed CERAMIC, a high-capacity CRISPR-Cas9 lineage recorder that co-recovers editing scars and transcriptomes from single cells, and applied it to an AKT/NRAS-driven model of MASLD-associated liver tumor initiation. Longitudinal lineage, single-cell and spatial analyses revealed a hierarchical trajectory in which bipotential bi-zonal hepatocytes (Hep_Bi-zonal), rather than pericentral-like hepatocytes (Hep_CVlike), generated regenerative and neoplastic hepatocyte progenitor states that progressed toward both hepatocellular carcinoma and intrahepatic cholangiocarcinoma lineages. Tumor-fated cells preferentially expanded along a remodeled midlobular-periportal axis and depended on ACOX1-mediated peroxisomal beta-oxidation to withstand lipotoxic and oxidative stress. Spatial and lineage analyses further identified a sequential lipid-associated macrophage niche, in which monocyte-derived LAMs engaged tumor-fated hepatocytes through an LGALS9-P4HB axis, and P4HB inhibition suppressed tumor expansion. These findings define liver tumor initiation as a lineage-restricted process licensed by peroxisomal metabolic adaptation and macrophage-derived niche signals.

cancer biology↗

bioRxiv2026

Circadian Clock Control of Muscle Stem Cells Through Temporal Coordination of Notch and Wnt Signaling

The circadian clock regulates stem cell responses during tissue remodeling and repair. In skeletal muscle regeneration, successful regenerative myogenesis requires a temporally coordinated transition from Notch- to Wnt-driven signaling. However, the mechanisms governing this timing event remain poorly understood. Here, we show that circadian clock activity marks the cycling population of regeneration-activated myogenic progenitors that is induced in concert with Notch signaling. We identify key components of the Notch pathway as direct circadian clock targets and demonstrate that the clock coordinates Notch and Wnt signaling to drive myogenic progression. Genetic activation of the clock in satellite cells, as well as pharmacological clock stimulation, enhanced both proliferative expansion and subsequent differentiation of myogenic progenitors during regeneration. These effects were mediated by early activation of Notch signaling followed by increased Wnt pathway activity at later regenerative stages. Notably, both clock-dependent mechanisms remained functional in dystrophin-deficient mouse muscle and human myoblasts. Furthermore, clock-activating compounds enhanced regenerative myogenesis following acute injury and improved regeneration in dystrophic muscle. Collectively, these findings establish the circadian clock as a temporal regulator of regenerative signaling programs that orchestrate muscle repair with potential for targeted interventions.

cell biology↗

bioRxiv2026

Enhanced Target Binding by Leritrelvir Restores Dimerization of Mpro Mutants and Mitigates Drug Resistance

The SARS-CoV-2 main protease (Mpro) has been a major target of antiviral drug development, leading to the development of inhibitors such as nirmatrelvir, the antiviral component of the COVID-19 drug Paxlovid. However, resistance-associated mutations that reduce the efficacy of current Mpro inhibitors, particularly nirmatrelvir, have emerged. Here, we evaluated the inhibitory activity of leritrelvir (RAY1216), an Mpro inhibitor approved in China for COVID-19 monotherapy, against a panel of Mpro variants carrying mutations at 12 resistance-associated residues distributed across four catalytic subsites. Using integrated biochemical, biophysical, structural, and cellular analyses, we demonstrate that leritrelvir retains stronger inhibitory activity against most tested resistant mutants compared with nirmatrelvir. Most of the tested mutations promote Mpro dimer dissociation, with E166V showing a particularly pronounced effect and markedly compromising nirmatrelvir binding. In contrast, thermal shift and size-exclusion chromatography assays demonstrate that leritrelvir binding restores dimerization of these Mpro mutants. Sixteen high-resolution crystal structures reveal that leritrelvir binding re-instates key dimer-interface interactions disrupted by resistance mutations. Mini-replicon assays further confirm leritrelvir to possess enhanced cellular antiviral efficacy compared with nirmatrelvir. Our findings indicate that tighter leritrelvir binding enables more effective inhibition of dissociation-prone Mpro mutants than nirmatrelvir, supporting its use as a more resilient antiviral agent for SARS-CoV-2 treatment.

molecular biology↗

bioRxiv2026

Immunometabolic Remodeling of Perivascular Adipose Tissue in Murine Lupus: Implications for Lupus Vasculopathy

BackgroundPatients with systemic lupus erythematosus (SLE) face markedly increased cardiovascular disease (CVD) risk driven by mechanisms beyond traditional risk factors. Thoracic aortic perivascular adipose tissue (tPVAT) is dysfunctional in lupus and exacerbates endothelial dysfunction, yet the molecular basis of this dysfunction remains poorly defined. MethodsIntegrated multi-omics profiling, including bulk RNA-seq, untargeted proteomics, lipidomics, and high-dimensional spectral flow cytometry, was performed on tPVAT from 15-week-old MRL/lpr mice (active lupus, n = 4-6) and MRL control mice (n = 5-6). Adipogenic differentiation capacity of tPVAT adipose stromal and progenitor cells (ASPCs) from MRL/lpr was assessed by Oil Red O staining at 5 (pre-dieasea) and 15 weeks (active disease), with subcutaneous ASPCs used as depot controls. ResultsTranscriptomic profiling of tPVAT from MRL/lpr mice identified 2,742 upregulated and 1,494 downregulated genes (adjusted p < 0.001, |log2FC| > 1), with strong activation of interferon, IL6-JAK-STAT3, and TNFA signaling pathways together with suppression of fatty acid metabolism, oxidative phosphorylation, and adipogenic pathways. Proteomic and lipidomic analyses were concordant, revealing broad downregulation of mitochondrial bioenergetic machinery, depletion of cardiolipin and acylcarnitines, and enrichment of ceramide phosphoinositols and lysophosphatidylcholines. Cardiolipin strongly correlated with the mitochondrial/metabolic protein module (r = 0.95) and inversely with the immune/inflammatory protein module (r = -0.92). Spectral flow cytometry confirmed marked CD45+ leukocyte infiltration dominated by T cells, together with a significantly reduced Treg/CD4+ ratio indicating loss of local immunoregulatory balance. ASPCs derived from PVAT of 15-week-old MRL/lpr mice exhibited impaired white and beige adipogenic differentiation, while APCs from PVAT of 5-week-old MRL/lpr mice, and from subcutaneous adipose tissues of 15-week-old MRL/lpr mice, had normal white and beige differentiation, consistent with an acquired, depot-specific, disease-stage-dependent progenitor defect in PVAT of MRL/lpr mice. ConclusionsLupus tPVAT undergoes a concordant cross-platform molecular reprogramming of mitochondrial bioenergetic genes coupled with establishment of an interferon-dominant immune niche and acquired loss of ASPC adipogenic capacity. These findings provide a molecular framework for lupus PVAT dysfunction and identify restoration of mitochondrial function, suppression of interferon-driven inflammation, and renewal of progenitor differentiation as potential therapeutic strategies for lupus vasculopathy.

molecular biology↗

bioRxiv2026

An Essential Role of the AMPK-Related Kinase SNRK in Regulating Drosophila Sleep

Protein kinases are important regulators of sleep in animals, but their loss-of-function mutations usually show moderate phenotypes. We report here that sucrose non-fermenting related kinase (SNRK), a member of the AMP-activated protein kinase-related kinase (ARK) family, plays an essential role in sleep regulation: Snrk gene knockout resulted in a profound loss of night-time sleep phenotype, much stronger than that of the well-known ARK member Sik3. This phenotype was completely rescued by neuronal SNRK expression. SNRK in adulthood was required for sleep. Catalytic and regulatory sites in SNRK were important for sleep. A chemoconnectomic (CCT) screen revealed SNRK functioning in cholinergic neurons whose activation is known to inhibit sleep. Sleep loss in SNRK mutants was rescued by pharmacological blockade of nicotinic acetylcholine receptors. Our findings have uncovered a fundamental role for SNRK in cholinergic neurons to regulate sleep.

neuroscience↗

bioRxiv2026

Quercetin and Fisetin activate circadian clock via RORα and inhibit adipocyte growth

The circadian clock maintains temporal control of metabolic processes and exerts a key role in adipocyte development. Discovery of clock-modulatory compounds may provide new avenues for metabolic disease therapy. Here we report the identification of flavonoid compounds, Quercetin and Fisetin, as clock-activating molecules with direct inhibitory action on adipogenesis and adipocyte lipid metabolism. Quercetin and Fisetin displayed robust ROR agonism that promoted clock oscillation with induction of clock genes. Treating preadipocytes with these compounds blocked their adipogenic differentiation. In mature adipocytes, Quercetin and Fisetin suppressed lipid accumulation by inhibiting lipogenic enzymes. Furthermore, activation of ROR by a synthetic agonist or ectopic expression were sufficient to inhibit adipogenesis. In mice treated with Quercetin or Fisetin, ROR was markedly induced in adipose depots with strong suppression of the adipogenic and lipogenic programs. While quercetin significantly attenuated lipid storage in adipose tissue in vivo accompanied with lowering of free fatty acids and improved insulin sensitivity, fisetin displayed a less robust effect with differential regulation of lipolytic pathway. Collectively, these findings uncovered the clock-activating properties of quercetin and fisetin that prevent adipocyte maturation and hypertrophy to limit adipose tissue expansion. These actions contribute, at least in part, to their beneficial effects on metabolic disorders.

cell biology↗

bioRxiv2026

CellPulse: A Foundation Model of Coordinated Gene Dynamics Simulating Viral Infectious Diseases

Understanding how cells respond to perturbations like viral infections requires models capturing coordinated gene dynamics. However, current gene expression foundation models are predominantly reliant on single-cell data and static gene expression, limiting their applicability in real clinical scenarios. We present CellPulse, a direction-aware foundation model trained on the Virus Stimulated Atlas (VISTA), a newly curated atlas of over 23 million bulk RNA-sequencing differential expression profiles from viral infections. CellPulse models the direction and magnitude of gene expression changes via a structured representation of differential expression and a direction-aware attention mechanism, enabling the learning of coherent regulatory programs. It shows powerful diagnosing capability by accurately classifying 31 distinct virus types across diverse clinical and laboratory samples, solely from host transcriptional signatures. Crucially, without prior knowledge injection, CellPulses interpretability reveals virus-associated host factors that mediate infection. Using a selection of host factors for in silico drug screening yielded numerous compounds with confirmed efficacies in wet-lab assays, while cell-based and animal experiments further verified the causal relationship between host targets and viral infections. Overall, CellPulse represents a generalizable foundation model for deciphering coordinated gene dynamics from bulk transcriptomics, bridging host response modeling with clinical relevance and therapeutic discovery for infectious diseases and beyond.

bioinformatics↗

bioRxiv2026

TopicVI: A Knowledge-guided deep interpretable model for resolving context-specific gene programs

Mechanistic insights from single-cell and spatial transcriptomics largely rely on cell clustering, differential expression analysis, and interpretation through prior biological knowledge. However, this approach is often limited by the reliance on curated biological priors that fail to capture context-specific gene programs, particularly in complex disease states. To address this gap, we introduce TopicVI, a deep interpretable model that integrates established biological knowledge with data-driven refinement to discover context-dependent gene programs in single-cell and spatial transcriptomic data. TopicVI jointly infers cell clusters and gene topics using optimal transport to flexibly align prior gene programs with observed data while permitting context-specific refinements. Comprehensive benchmarking demonstrates that TopicVI outperforms existing methods in biological conservation, batch correction, topic coherence, and rare cell identification. TopicVI effectively disentangles multiple sources of biological variation, such as separating anatomy-specific expression patterns from disease-associated signatures in spatial transcriptomics. Applying TopicVI to glioblastoma datasets, we identify gene topics related to cell cycle regulation and EGFR signaling that reveal convergent tumor states across distinct drug perturbations. By integrating prior knowledge with data-driven discovery, TopicVI enables identification of interpretable gene programs that illuminate biological processes and therapeutic mechanisms in complex transcriptomics data.

bioinformatics↗

bioRxiv2026

Polyclonal-Monoclonal Transition in Lung Squamous Cell Carcinoma Evolution

The evolutionary trajectory of lung squamous cell carcinoma (LUSC) remains poorly defined, hindering the development of effective therapies. By integrating genomic and transcriptomic sequencing from human LUSC specimens, we delineated a polyclonal-to-monoclonal evolutionary trajectory during LUSC progression. This evolutionary pattern was corroborated by single-cell RNA sequencing, which revealed consistent tumor cell heterogeneity. Specifically, the SBS5 mutational signature was enriched and correlated with poor prognosis independent of tumor stage. By further utilizing the spontaneous LUSC mouse model to identify key genomic and genetic events in LUSC progression, we observed that the JNK pathway was inhibited and that cytoskeleton-related pathways were dysregulated during LUSC development, and identified the mutations in the JNK pathway (e.g., DACT1) and cytoskeletal regulators (e.g., KIF26A). Collectively, these findings established a polyclonal-monoclonal evolution paradigm for LUSC, potentially regulated by JNK pathways, which could benefit LUSC precision therapeutics.

genomics↗

bioRxiv2026

A synonymous mutation in MSMEG_4729 occurs at a high frequency in spontaneous D29-resistant mutants of Mycobacterium smegmatis

Compassionate use of mycobacteriophage therapy highlights the promising potential of phage therapy as an alternative treatment option for antibiotic-resistant infections when conventional treatments fail. However, realizing the full potential of phage therapy requires addressing key challenges, including host immune responses, the limited arsenal of therapeutically-useful mycobacteriophages, and the emergence of phage resistance. Dissecting the mechanisms of phage resistance is critical for ensuring the effectiveness and sustainability of phage therapy. In this study, we demonstrate that exposure to the lytic mycobacteriophage D29 triggers diverse genetic changes in Mycobacterium smegmatis. A synonymous mutation in MSMEG_4729 arises frequently but is insufficient to confer D29 resistance on its own. Instead, we identified possible Lsr2-independent activation of the lipooligosaccharide (LOS) biosynthesis cluster in a D29-resistant mutant harboring this mutation. We have also detected the possible activity of MSMEG_3213, a type II methyltransferase associated with m6A modifications in M. smegmatis. Finally, we isolated defense escape mutants (DEMs) of D29 capable of overcoming resistance in a strain with the MSMEG_4729 synonymous mutation. This profiling of M. smegmatiss likely defensive arsenal against the therapeutically-useful mycobacteriophage D29 provides a roadmap for further investigations and rational engineering of next-generation mycobacteriophages to combat drug-resistant mycobacterial infections. Impact statementInterest in phage therapy has been gaining traction recently, which is largely due to the serious threat of antimicrobial resistance. However, the efficacy and sustainability of phage therapy is threatened by certain challenges, which includes the ever existent threat of phage resistance. In this study, we identified several likely factors involved in D29 interaction with the model mycobacterium M. smegmatis. These findings set a roadmap for future investigations that would guide rational phage engineering to expand the currently limited arsenal of therapeutically useful mycobacteriophages as well as improve the efficiency of existing ones.

microbiology↗

bioRxiv2026

Likely role of promoter reconstitution in Mpr-mediated D29 resistance by Mycobacterium smegmatis

The multi-copy phage resistance gene (mpr) of M. smegmatis is a major factor in resistance to the lytic mycobacteriophage D29. Mpr is a membrane-bound exonuclease that cleaves phage DNA post injection, hence blocking downstream stages in the phage infection cycle. The mechanism of resistance allows for adsorption, is non-abortive and independent of any mutation in the gene. Rather, it depends on overexpression of a wild type copy of the gene. However, the underlying factor behind mpr overexpression in spontaneous D29-resistant mutants of M. smegmatis remained elusive. Here, we report that D29 infection triggers insertion sequence (IS) rearrangements, including the transposition and integration of IS6120 directly upstream of mpr. Mutants with IS6120 integration upstream of mpr show highly elevated Mpr expression. Whole genome sequence analysis reveals that IS6120 introduced a putative transcription factor-binding site and a canonical -35 promoter element at the integration site, hence reconstituting a fuller promoter (rcp) than the original promoter (wtp) at the site. Promoter reporter assays suggest that rcp is a far stronger promoter than wtp, implying that elevated mpr expression in D29-resistant mutants with this transposition event could be due to promoter reconstitution. While strains with this transposition event appear to grow normally, rcp-driven, vector-borne Mpr overexpression appears to be toxic as it barely allows for colony formation on agar plates. This study reports a previously unknown factor likely behind mpr regulation in M. smegmatis, adding to the existing knowledge of mycobacterial anti-phage defense mechanisms and guiding rational phage engineering efforts for therapeutic applications.

microbiology↗

bioRxiv2026

Z-RNA-ZBP1 axis drives Tau-mediated neurodegeneration

Although the causes of Tau aggregates vary, once Tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimers disease (AD) being the most well-known example. Despite its central pathogenic role, however, effective therapeutic strategies targeting neurotoxicity of Tau remain poor. Here we demonstrate the pathogenic role of neuronal cell death in Tau-related neurodegeneration. Tau-expressing neurons undergo cell death through Z-DNA-binding protein 1 (ZBP1) activation triggered by endogenous Z-RNAs. These Z-RNAs are derived from reactivated transposable elements (TEs) that are typically silenced within heterochromatin. Tau aggregates show a strong affinity for H3K9me3-modified chromatin, effectively sequestering these epigenetic marks from Heterochromatin Protein 1 (HP1), thereby disrupting the condensation of constitutive heterochromatin. Clinically, an inverse correlation between ZBP1 expression levels in excitatory neurons and cognitive performance in AD patients was observed. Importantly, Zbp1 haploinsufficiency significantly ameliorated cognitive deficits in aged Tau-transgenic mice (24-month-old), highlighting the therapeutic potential of ZBP1 inhibition to strive against neurodegeneration in tauopathies.

neuroscience↗

bioRxiv2026

Unravelling genome-wide mosaic microsatellite mutations at single-cell resolution

Short tandem repeats (STRs), or microsatellites, are highly mutable genomic elements that modulate gene regulations and are implicated in a range of human diseases. However, detecting mosaic STR mutations at single-cell resolution remains challenging due to both technical and biological complexities. To address this, we developed BayesMonSTR, a robust algorithm that enables accurate detection of mosaic STR mutations. Using this tool in single-cell analysis of human tissues, we reveal an accumulation of longer mosaic STR insertions and deletions (indels) in aging mitotic and post-mitotic cells. Strikingly, prefrontal cortex (PFC) neurons accumulate a higher burden of STR mutations than B cells or lung epithelium, with aged neurons exhibiting a particularly pronounced increase in longer STR deletions. These mutations are enriched at transcription start sites (TSSs) and active enhancers of highly expressed genes. Our work establishes a foundation for genome-wide, hypothesis-free discovery of disease-associated mosaic STR mutations and reveals a previously unexplored landscape of mosaic STR variation in development and aging.

bioinformatics↗