Biology subjects

Hou, S.

Publications and source records attributed to Hou, S..

At least 19 recordsLinked to original sources

bioRxiv2026

SVC: A Vision Transformer-based Spatially and Virtually Embedded Cell Model for Deciphering Subcellular Spatial Transcriptomic Heterogeneity

Subcellular transcript localization shapes gene regulation and cellular function, yet profiling it at scale remains difficult, limiting our ability to study subcellular heterogeneity across tissues and disease. Here, we present SVC, a Vision Transformer-based spatially and virtually embedded cell model that learns subcellular transcript organization within native tissue context directly from subcellular-resolution spatial transcriptomics. SVC represents each gene's subcellular localization as an image patch and uses other genes within the same cell as context, enabling subcellular contextual learning of spatial dependencies that govern intracellular organization. By integrating gene-function priors, cell morphology, spatial context, and, when available, cell identity, SVC captures unified, spatially grounded representations across genes and cells that connect subcellular organization to cellular state and tissue microenvironment. Across diverse subcellular-resolution spatial transcriptomics datasets, SVC accurately predicts cell-specific subcellular transcript localization and co-organization, generalizes across tissues and technical platforms, and supports subcellular imputation of unmeasured genes and in silico perturbation. Leveraging these capabilities, SVC highlights disease-associated patterns of intracellular transcript reorganization and spatially heterogeneous responses to gene perturbations. Beyond prediction, SVC reveals systematic variation in subcellular transcript organization associated with gene function, cellular states, and tissue microenvironments, uncovering de novo spatial biology that is not accessible by cell-level analysis. SVC's learned representations further transfer to cell- and tissue-level tasks, including cell-level expression imputation, cell clustering, and spatial domain detection. Together, SVC provides a general framework for modeling and interrogating subcellular transcript organization in situ, enabling scalable discovery of subcellular spatial biology.

bioinformatics↗

bioRxiv2026

A genome-scale ORF screen for resilience factors that protect the RPE and restore vision in aged mice

Aging is a complex phenomenon, yet therapeutic discovery has largely relied on testing individual hypothesis-driven targets. Here, we performed a genome-scale open reading frame (ORF) screen for oxidative-stress resistance in retinal pigment epithelium (RPE) cells, which are vulnerable to oxidative damage during aging. The screen identified nine protective ORFs including antioxidant factors and an epithelial-to-mesenchymal transition regulator. Notably, we also identified three factors that reduce transcriptomic age including the cardiac transcription factor NKX2-5. NKX2-5 conferred robust oxidative resilience in vitro and in vivo. Domain dissection revealed that its homeodomain is dispensable for resilience, enabling development of NKX2-5{Delta}HD, which retained protective activity without detectable toxicity over 14 months. In middle-aged mice, subretinal NKX2-5{Delta}HD restored visual and electrophysiological function, and its systemic delivery improved grip strength and reduced frailty in late-aged mice. These findings highlight the value of unbiased, genome-scale gain-of-function screening, as resilience factors normally expressed in other contexts can be reengineered as potential therapeutics for age-related decline in other tissues.

genetics↗

bioRxiv2026

Neuronal and astrocytic adaptations in the lateral habenula during withdrawal from chronic ethanol

The lateral habenula (LHb) encodes aversive states and negative affect, positioning it as a candidate region for the negative reinforcement that drives alcohol withdrawal. However, little is known about how chronic ethanol exposure affects LHb neuronal function and glial biology during withdrawal. Here, we used chronic intermittent ethanol (CIE) vapor exposure, a well-established model of alcohol dependence that reliably produces somatic and affective signs of withdrawal, to examine LHb physiology and astrocytic markers during acute withdrawal in male and female rats. Whole-cell and cell-attached recordings revealed that withdrawal reduced evoked and spontaneous firing in LHb neurons, with rebound firing following a crossover pattern between males and females. Despite these excitability changes, the overall distribution of firing phenotypes was unchanged, suggesting a shift in gain rather than a reorganization of cell types. Immunofluorescence revealed increased Sox9+ and GFAP labeling in the LHb during withdrawal at the same time point when electrophysiology experiments uncovered impaired astrocytic regulation of glutamate clearance. Together, these findings reveal that withdrawal from chronic ethanol exposure produces neuronal and glial adaptations in the LHb, pointing to impaired glutamate regulation as a candidate mechanism relevant to the negative affective state of alcohol withdrawal. These findings position the LHb as a potential node linking astrocyte-neuron dynamics to withdrawal symptoms and relapse vulnerability in alcohol use disorder.

neuroscience↗

bioRxiv2026

Active non-redundancy and viral orchestration sustain diel microbial successions in the coastal ocean

Ecosystem resilience in dynamic coastal oceans is conventionally ascribed to functional redundancy, where taxonomically distinct microbes buffer environmental fluctuations through interchangeable metabolic roles. In this study, we reveal a deterministic succession architecture sustained by active non redundancy and temporal metabolic coupling, uncovered via autonomous drone array metatranscriptomic sampling in Daya Bay, China. By resolving the transcriptional landscape into six chronometrically phased modules rather than simple time points, we demonstrate a near total renewal of the active gene pool, with greater than 90% of transcribed clusters showing phase exclusivity within approximatively a two-hour window. This radical functional reshaping exposes a tight, scale dependent taxonomic functional coupling where community composition is a strong, linear predictor of metabolic output, peaking at the genus level (p < 0.0001). Functional continuity is maintained not by redundant generalists, but by a precisely sequential relay of specialists, each optimized for transient microniches with minimal overlap between successive phases. Deep learning structural adjudication of the psbA gene pool further reveals viral orchestration of this temporal coupling, where incoming cyanophages introduce structurally distinct protein variants that sustain photosynthetic electron flow under peak irradiance. These findings redefine coastal microbiome stability as a fine-tuned rapid succession of temporal specialists rather than a redundant backdrop. We propose a fundamental revision of marine ecosystem models, shifting from passive buffering frameworks to deterministic, clock driven architectures, which may prove to be critical for forecasting microbiome responses to accelerating short term climate variability.

microbiology↗

bioRxiv2026

Functional bipartition of medial prefrontal cortex into salience detection and movement gain

Reward prediction error (RPE) is a key function putatively realized by brain-wide neural states to drive learning and adaptive responding. The medial prefrontal cortex (mPFC) is among the many areas canonically implicated in RPE computation. Yet, whether mPFC RPE processing differs as a function of valence, value, and sign is not well-understood. Here, we performed in vivo mPFC calcium imaging in male and female rats engaged in an appetitive or aversive Pavlovian task designed to elicit RPE, along with continuous, unbiased behavioral monitoring. We found that short-latency bulk mPFC activity reports salience independent of valence, value, or RPE. Surprisingly, as subsequently validated with in vivo bidirectional optogenetics, we show that salience-null mPFC activity modulates generalized movement in a valence- and task-agnostic fashion. Together, these results challenge the pervasive notion of a unitary, region-wide representation of cognitive processes, including RPE signaling, by bulk mPFC activity, and instead, support a functional bipartition schema combining reactive detection of integrated salience and dynamic modulation of movement gain.

neuroscience↗

bioRxiv2026

Super-resolution single-cell spatial atlas of plant de novo regeneration

Plant de novo regeneration, a capacity absent in animals, relies on stem-cell-niche formation rather than pre-existing reservoirs. Growth hormones such as auxin and cytokinin, together with numerous genetic regulators, participate in regeneration, but the architectural principles coordinating extensive cellular reprogramming at the individual-cell scale remain elusive. Using super-resolution multimodal spatial transcriptomics to 1.16 million cells, we tracked tomato regeneration across temporal intervals from wounding to organogenesis. Datasets are available at http://www.single-cell-spatial.com.

cell biology↗

bioRxiv2026

Taxonomy-aware, disorder-matched benchmarking of phase-separating protein predictors

BackgroundBiomolecular condensates formed via liquid-liquid phase separation (LLPS) play vital roles in cellular organization and function. Computational prediction of phase-separating proteins (PSPs) is increasingly used to prioritize candidates at proteome scale, making robust, well-designed benchmarks essential for fair evaluation and iterative improvement of PSP predictors. ResultsWe first show that a recently released PSP benchmark is substantially confounded by the imbalances in taxonomic origin and intrinsic-disorder compositions between positive and negative sets, allowing predictors to achieve high apparent performance by exploiting non-LLPS shortcuts and obscuring their true ability to distinguish PSPs. To minimize these effects, we construct a taxonomy-aware, disorder-matched PSP benchmark. Using this benchmark, we find that absolute sequence and biophysical feature values of PSPs differ markedly across taxa, whereas LLPS-associated feature shifts relative to taxon-specific proteome backgrounds are comparatively conserved. Benchmarking twenty PSP predictors under this framework reveals pronounced taxon-dependent variation in performance. Moreover, PSPs lacking IDRs consistently constitute a more challenging regime across methods, motivating routine disorder-stratified evaluation. ConclusionsOur taxonomy-aware, disorder-matched benchmarking framework reduces shortcut-driven biases, enables more interpretable evaluation of PSP predictors, and provides guidance for developing models that capture transferable LLPS-associated signals rather than dataset- or taxon-specific shortcuts.

bioinformatics↗

bioRxiv2026

A unified framework enables accessible deployment and comprehensive benchmarking of single-cell foundation models

Single-cell foundation models (scFMs) have been widely promoted as a unifying paradigm for transcriptomic analysis, yet whether large-scale pretraining translates into reproducible biological advantages remains unclear. Their adoption is further hindered by heterogeneous implementations, preprocessing requirements, and computational environments. Here we develop a unified, automated, and reproducible framework for standardized deployment and controlled evaluation of scFMs across datasets, computational environments, training regimes, and downstream analyses, substantially lowering the technical barriers to their use. Leveraging this framework, we systematically investigate thirteen scFMs alongside established methods across nearly one hundred datasets spanning diverse biological contexts. Our analyses reveal clear practical boundaries to scFM utility. First, increased model scale, architectural complexity, pretraining corpus size, or input encoding does not consistently translate into superior downstream performance. Instead, measurable properties of embedding geometry provide a model-agnostic, representation-level explanation for differences in zero-shot performance across diverse model families. Second, the benefits of pretrained representations depend strongly on the biological and supervision regime: scFMs provide their clearest advantages under extremely limited supervision, particularly for rare-cell annotation and open-set detection of source-absent cell states, whereas established methods remain competitive or preferable in most other settings. Task-matched analyses further show that scFM representations transfer inconsistently to spatial-domain recovery, while their gene embeddings capture broad functional relatedness without reliably recovering context-specific regulatory relationships. Together, these results establish that scFM utility is neither universal nor determined simply by model scale alone, but varies with learned representation geometry, biological context, and supervision. By combining reproducible deployment with large-scale empirical and mechanistic investigation, our framework provides a principled foundation for determining when foundation-model pretraining offers genuine practical value and when simpler approaches remain sufficient.

bioinformatics↗

bioRxiv2025

Copper-Free Click Chemistry Enables High-Fidelity Engineering of Mitochondria Targeted Brain-Derived Exosomes

Mitochondrial dysfunction is a hallmark of neurodegenerative and neuroinflammatory disorders, including hypertension and cardiovascular disease, yet strategies for safe and precise mitochondrial-targeted delivery remain limited. Here, we establish strain-promoted azide-alkyne cycloaddition (SPAAC) as a biocompatible, high-fidelity chemical platform for engineering mitochondria-targeted brain-derived exosomes (BR-EVs). Copper-free click conjugation of a mitochondrial-targeting ligand (e.g. Cy5-DBCO) under mild aqueous conditions preserved vesicle morphology (30-150 nm core; 120-200 nm hydrodynamic), proteomic composition, and uptake dynamics. Time-course imaging and fluorescence recovery after photobleaching (FRAP) revealed unaltered endocytic kinetics, >75 % mitochondrial colocalization, and intact organelle architecture. In vivo neuroinflammation and biodistribution analyses demonstrated immunological neutrality, strong central nervous system retention, and minimal peripheral dispersion following intracerebroventricular administration. Proteomic profiling of unlabeled Sprague-Dawley (SD) and hypertensive Dahl salt-sensitive (DSS) BR-EVs uncovered hypertension-driven enrichment of oxidative and complement pathways correlating with mitochondrial fragmentation and reactive oxygen species generation in neuronal cultures. These findings establish SPAAC-mediated ligand conjugation as a biocompatible and chemically precise approach for generating mitochondria-targeted exosomes that preserve exosomal identity, biodistribution, and signaling fidelity--advancing a foundational platform for organelle-specific delivery and mechanistic imaging in the central nervous system.

neuroscience↗

bioRxiv2025

A Reversible Mitochondrial ROS Probe for Monitoring Mitophagy Dynamics: Development and Application of MitoFlare

Mitochondrial dysfunction and defective mitophagy are defining features of numerous neurodegenerative and metabolic disorders, yet existing tools provide limited ability to quantify mitophagy dynamics in real time within living, post-mitotic cells. Here we present MitoFlare, a mitochondria-targeted, reversible mtROS-responsive fluorogenic probe that enables continuous, non-genetic visualization of mitochondrial oxidative activation and turnover. MitoFlare incorporates dual TEMPO nitroxide quenchers into a long-wavelength rhodamine scaffold, producing >95% basal quenching and rapid, fully reversible fluorescence activation in response to mitochondrial superoxide, hydroxyl radicals, lipid-derived peroxyl species, and peroxynitrite. When combined with LysoTracker Green, MitoFlare forms a dual-probe imaging platform that resolves the entire mitophagy cascade with high spatial and temporal fidelity in intact PC12 neuronal cells. Using this platform, we established a quantitative framework comprising three mechanistically distinct metrics: (i) a proximity index that reports early mitochondrial engagement with lysosomes, (ii) Manders M1 coefficient that captures mid-stage mitochondria-lysosome fusion and mitophagosome formation, and (iii) a quenching/swelling index that resolves terminal lysosomal degradation. Nutrient deprivation induced a complete, temporally ordered mitophagy program, including mtROS priming, Parkin-OPTN-associated fusion, and efficient acidification-dependent cargo degradation. In contrast, inhibition of v-ATPase with bafilomycin A1 arrested mitophagy at the fusion stage, resulting in persistent redox-active mitochondrial cargo that failed to undergo lysosomal digestion. Importantly, MitoFlares reversible redox chemistry uniquely revealed accumulation of undegraded, oxidatively active mitochondrial remnants within non-acidified vesicles--pathological intermediates that are undetectable using irreversible ROS dyes or genetically encoded reporters. These findings demonstrate that mitophagy proceeds through discrete, redox-regulated and lysosome-dependent phases that can be quantitatively mapped in real time. By enabling synchronized measurement of oxidative activation, organelle trafficking, fusion, and degradation, the MitoFlare-LysoTracker system establishes a new benchmark for dynamic mitophagy analysis in physiologically relevant models. This platform provides a powerful foundation for mechanistic interrogation of mitochondrial quality control and for accelerating the discovery of therapeutic strategies aimed at restoring mitophagic fidelity in neurodegenerative, cardiovascular, and metabolic diseases.

neuroscience↗

bioRxiv2025

A newly identified Duck orbivirus as the etiological agent of egg-production decline in Chinese breeder ducks

The genus Orbivirus comprises double-stranded RNA viruses, many of which are transmitted by arthropods and cause febrile, hemorrhagic, or reproductive diseases in animals. In recent years, unexplained outbreaks characterized by marked egg-production decline have occurred in breeder duck flocks in China. To identify the causative agent, samples were collected from affected farms in multiple regions across China between 2022 and 2025. Representative samples were analyzed by high-throughput sequencing, followed by phylogenetic analysis, transmission electron microscopy, host cell infection assays, and animal challenge experiments. A previously unreported Orbivirus, designated Duck orbivirus (DORV), was identified. Epidemiological investigation indicated that outbreaks mainly affected breeder ducks during the peak laying period (21-55 weeks of age), with higher incidence in summer and autumn. The DORV genome contains ten double-stranded RNA segments encoding seven structural and five nonstructural proteins. Phylogenetic analysis showed that DORV is closely related to Parrys Lagoon virus (PLV) and Corriparta virus (CORV). Electron microscopy revealed icosahedral particles 30-40 nm in diameter. DORV replicated efficiently in DEF, DEL and C6/36 cells but not in MDCK and LMH cells, suggesting a restricted host range with potential arthropod-borne features. Infection of breeder ducks with DORV-SD01 reduced egg production by 30-40% and caused lesions in the ovary, liver, and spleen. This study describes a novel duck-origin Orbivirus linked to egg-production decline, offering new etiological insights and extending the host spectrum of Orbivirus. The results provide a foundation for future surveillance and prevention of emerging waterfowl diseases.

microbiology↗

bioRxiv2025

Diel rhythms shape viral community structure and activity across the host domains of life

Circadian rhythms, driven by endogenous clocks and synchronized with environmental cues, are fundamental to life on Earth. While extensively studied in diverse organisms, their influence on viral ecology remains largely unexplored. This study takes the temporal dynamics of viruses in Daya Bay as an example to uncover the rhythmic control of viral replication and activity. Using a high-resolution time-series dataset collected every 2 hours over a 3-day period, we identified a total of 22,151 viral operational taxonomic units (vOTUs) and 414 Nucleocytoplasmic Large DNA Virus (NCLDV) genomes. Our analysis revealed significant diel fluctuations, with 14.48% of vOTUs exhibiting diel patterns in metagenomic abundance and 1.97% showing diel transcriptional activity. We found that these abundant diel viruses infect hosts across the domains of life, including cyanobacteria, pelagibacteria, Marine Group II (MGII) archaea and protists, all known for their diel metabolism. The expanded spectrum of host diversity with diel viral interactions significantly broadens our understanding of virus-host rhythmic dynamics in natural environmental settings. A strong positive correlation was detected between the transcriptional activities of these diel viruses and their respective hosts. Contrary to bacteriophages, which mostly peaked during the day, we demonstrated that NCLDVs showed nocturnal diel abundance with a co-fluctuating diel transcriptomic activity pattern tightly hitched to their hosts, peaking at night and declining during the day. Furthermore, we identified a rich compendium of viral genes with significant diel expression patterns, including those related to structural protein production, DNA replication, and stress response. Notably, several essential viral genes involved in stress response and repair were found to be diel transcribed for the first time, including UV-endonuclease (UvdE), peroxidase, chaperones, and early light-induced protein (ELIP). Our findings suggest that viruses across host domains actively synchronize with environmental cues to optimize their replication and transmission, despite their dependence on host metabolism. This study provides novel insights into the rhythmic control of viral communities and their intricate interactions with hosts, with profound implications for microbial community succession and biogeochemical cycles.

ecology↗

bioRxiv2025

Optimal transport modeling uncovers spatial domain dynamics in spatiotemporal transcriptomics studies

Spatiotemporal transcriptomics is an emerging and powerful approach that adds a temporal dimension to spatial transcriptomics, enabling the characterization of dynamic changes in tissue architecture during development or disease progression. Here, we present SpaDOT (Spatial Domain Transition detection), a computational method designed to identify spatial domains and infer their temporal dynamics across time points for spatiotemporal transcriptomics studies. SpaDOT employs a variational autoencoder (VAE) framework to capture a low-dimensional representation of the data, incorporating hidden clustering variables to define distinct spatial domains. In the process, SpaDOT integrates a Gaussian Process prior and graph neighbor information to explicitly model both global spatial continuity and local structural heterogeneity among spatial locations within each time point, while using optimal transport (OT) to derive time-varying embeddings and infer the relationships between spatial domains across time points. Through simulation and real data applications, we demonstrate the superiority of SpaDOT in spatial domain detection, latent space preservation, and domain transition tracking over time. In real data applications, SpaDOT accurately captures dynamic domain transitions, including the disappearance and re-emergence of domains due to technical variation. Notably, SpaDOT uncovers key aspects of valvulogenesis in the developing heart, revealing the splitting of a single valve structure into two distinct functional valves -- the atrioventricular valve and the semilunar valve.

bioinformatics↗

bioRxiv2025

Type one protein phosphatases (TOPPs) catalyze EIN2 dephosphorylation to regulate ethylene signaling in Arabidopsis

TOPPs (Type one protein phosphatases) widely modulate plant hormone signaling and stress responses in plants, but their roles in ethylene signal transduction remain unknown. This study reveals a reciprocal regulatory relationship between TOPPs and EIN2 (Ethylene insensitive 2)-mediated ethylene signaling. We identified that ethylene can induce TOPPs expression, and topp1/4/5 triple mutants exhibited partial ethylene insensitivity with reduced EIN3 protein levels and ERF1 (Ethylene response factor 1) expression. Mechanistically, TOPPs genetically act upstream of EIN2, physically interacting with its carboxyl-terminal domain (EIN2-C) to dephosphorylate the critical S655 residue. This site-specific dephosphorylation promotes EIN2 stability and EIN2-C nuclear accumulation, thereby activating ethylene responses. Notably, transgenic plants expressing phosphorylation-deficient EIN2S655A displayed constitutive ethylene responses and improved salt tolerance. Further investigation showed that EIN3/EIL1 (EIN3 like 1) transcriptionally activates TOPPs expression by binding to their promoter, amplifying ethylene signaling accordingly. Together, our finding establishes TOPPs play an important regulatory role in ethylene signal transduction and elucidate a dephosphorylation-switch mechanism in controlling EIN2 function, providing critical insight into the role of EIN2 post-translational modifications in plant stress adaptation.

plant biology↗

bioRxiv2025

Clathrin-mediated endocytosis of ERECTA family receptors is essential for proper stomatal development in Arabidopsis

Stomata, specialized structures of plant epidermis, are crucial for gas (e.g. CO2, O2 and H2O) exchange between plants and the environment. Stomatal density and pattern are governed by ERECTA Family (ERf) receptor-like kinases (RLKs)-controlled signaling. Clathrin-mediated endocytosis (CME) is a new mechanism for the internalization of receptor to activate the downstream signaling in animals. Here, we found that mutation of CME components resulted in formation of stomatal clusters and thus increased stomatal index. The adaptor protein 2 {sigma} (AP2{sigma}) subunit of CME interacted with ERf. ERf receptor internalization required CME. Furthermore, the ERf receptor motifs were identified to be recognized by AP2{sigma}. Genetic analysis showed that CME components CHC2, CLC2, and CLC3 acted downstream of EPIDERMAL PATTERNING FACTOR 1/2 (EPF1/2) while upstream of YODA, and worked together with ERf to regulate stomatal development. Consistently, EPF2-induced MAPK activation was significantly reduced in chc2-2 clc2 clc3 and ap2 clc2 clc3 mutants or when the ERf endocytic motifs were mutated, leading to stabilized SPEECHLESS protein and misregulated stomatal lineage progression. Overall, our findings demonstrate that activation of the ERf receptors via internalization is essential for stomatal development, establishing a novel mechanism of CME-mediated receptor internalization activation in plants. Significance StatementStomatal development in Arabidopsis is well characterized, but how EPF-ERf signals activate the MAPK cascade remains unclear. While animals employ clathrin-mediated endocytosis (CME) for receptor internalization and signaling, this mechanism was unknown in plants. We identified CME as a novel regulator of stomatal development. The ERf receptors represent the first identified cargo proteins for AP2{sigma} in plants, undergoing internalization through CME. Clathrin acts downstream of EPF but upstream of YODA, and blocking ERf internalization impairs MAPK activation. Thus, ERf internalization is essential for downstream signaling, revealing a novel CME-dependent activation mechanism in plants.

cell biology↗

bioRxiv2025

Cell-resolved high-dimensional imaging analysis, therapeutic modeling, and a Phase Ib clinical study validate BCL-2 as a target across heterogeneous CRPC subtypes

BCL-2 has been implicated in prostate cancer (PCa) progression and development of castration-resistant disease (CRPC). However, it remains unclear how the BCL-2- and AR-expressing PCa cell populations evolve across the PCa continuum, how AR molecularly regulates BCL-2 and whether BCL-2 represents a common therapeutic target in heterogeneous CRPC. Importantly, BCL-2 inhibitors have yet to be approved for treating PCa patients. Here we first show the selective induction of BCL-2 by AR pathway inhibitors (ARPIs) in both patient specimens and xenograft models. Vectra-based quantitative multiplex immunofluorescence (qmIF) and image mass cytometry (IMC) analyses with single-cell resolution reveal markedly expanded BCL-2+ (AR+ or AR-) PCa cell populations in CRPC. Mechanistically, AR represses BCL-2 transcription through genomic binding via several AR binding sites and ARPIs relieve this repression, leading to BCL-2 upregulation. Comprehensive therapeutic studies in cells, organoids and xenografts establish that castration-induced BCL-2 is not merely associated with resistance but represents a shared and actionable vulnerability as the BCL-2 inhibitor ABT-199 potently suppressed the growth of multiple subtypes of CRPC. A Phase Ib clinical trial (NCT03751436) combining enzalutamide and BCL-2 inhibitor venetoclax demonstrated reduced circulating tumor cells in responding patients. Together, our findings elucidate the AR+/-BCL-2+/- PCa cell subpopulation dynamics during PCa progression, reveal a direct mechanistic link between AR inhibition and BCL-2-mediated resistance, and provide a strong rationale for targeting BCL-2 from the outset to eliminate emerging resistant subpopulations, inhibit treatment-induced cellular heterogeneity and plasticity, and improve therapeutic outcomes in CRPC.

cancer biology↗

bioRxiv2025

Transposable elements drive species-specific and tissue-specific transcriptomes in human development

BackgroundTransposable elements (TEs) are an abundant and crucial regulatory resource in the human genome. Serving as alternative promoters, TEs can be reactivated and produce TE-initiated transcripts, which play importance roles in early development and differentiated tissues. However, the prevalence and function of TE-initiated transcription in human development are poorly characterized. ResultsWe identified 12,918 TE-initiated transcripts across 40 human body sites and embryonic stem cells. Among TE-initiated transcripts, 80% were activated in a tissue-specific manner. TEs with tissue-specific transcription factor binding motifs were enriched in particular tissues. Additionally, approximately half of TE-derived TSSs were primates-specific. Notably, 375 primates-specific TE-derived TSSs were found to create novel tissue-specific gene expression patterns during evolution. ConclusionsOur results characterize the global profile of TE-initiated transcription and enhance our understanding of TE contribution to the primate-specific gene regulatory networks in human development.

bioinformatics↗

bioRxiv2025

Environmental NaCl affects C. elegans development and aging

Sodium is an essential nutrient, but is toxic in excess. In humans, excessive dietary sodium can cause high blood pressure, which contributes to age-related diseases including stroke and heart disease. We used C. elegans to elucidate how sodium levels influence animal aging. Most experiments on this animal are conducted in standard culture conditions: Nematode Growth Medium (NGM) agar with a lawn of E. coli. Here, we report that the supplemental NaCl in standard NGM, 50 mM, accelerates aging and decreases lifespan. For comparison, we prepared NGM with reduced NaCl or excess NaCl. Considering reduced NaCl as a baseline, wild-type worms on standard NGM displayed normal development and fertility but reduced lifespan and health span, indicating toxicity in old animals. The long-lived mutants daf-2, age-1, and nuo-6, cultured on standard NGM, also displayed reduced lifespan. Thus, NaCl in standard NGM accelerates aging in multiple genetic backgrounds. Wild-type worms on excess NaCl displayed delayed development and reduced fertility, and reduced lifespan and health span, indicating toxicity in both young and old animals. These results suggest that young animals are relatively resistant to NaCl toxicity, but that aging causes progressive sensitivity, such that old animals display toxicity to both standard and excess NaCl. We investigated pathways that respond to NaCl. Young animals cultured with excess NaCl activated gpdh-1, a specific response to NaCl stress. Old animals cultured with excess NaCl activated gpdh-1 and hsp-6, a reporter for the mitochondrial unfolded protein response. Thus, excess NaCl activates multiple stress response pathways in older animals.

developmental biology↗