Biology subjects

Sharma, A.

Publications and source records attributed to Sharma, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Revealing multiscale architecture of the intact human spine using hierarchical phase contrast tomography

Background: Computed tomography (CT) and magnetic resonance imaging (MRI) provide detailed clinical assessment of the human spine; however, their millimeter-scale spatial resolution limits direct visualization of tissue microarchitecture and interfaces. Hierarchical phase-contrast tomography (HiP-CT) enables ex vivo non-destructive, micron-resolution imaging of intact human organs without exogenous contrast agents, extending anatomical assessment to spatial scales inaccessible to conventional clinical imaging. Purpose: To evaluate the capability of HiP-CT to visualize macro- to microanatomy of an intact adult human spine ex vivo. Methods: An intact spine (C1-L5) from a 62-year-old male donor without known skeletal disease was formalin-fixed and imaged by HiP-CT at the European Synchrotron. Whole-spine imaging was performed at 16.26 m isotropic voxels, with selected regions of interest imaged using 2.2 m voxels. Ex vivo MRI using clinical sequences was performed for anatomical comparison. Three-dimensional segmentation and quantitative analyses included intervertebral disc (IVD) grading, annulus fibrosus fiber tracing, and vertebral trabecular micro-morphometry. Results: HiP-CT enabled high spatial-resolution, multiscale imaging of the intact human spine, simultaneously visualizing vertebral bone and endplate, IVDs, spinal cord and meninges, nerve roots and ganglia, vasculature, ligaments, and musculature. Three-dimensional segmentation and virtual sectioning mapped neurovascular anatomy and vertebral vascular supply, without exogenous contrast enhancement, while preserving their relationships with surrounding tissues. Whole-spine images enabled quantitative analysis of annulus fibrosus fiber organization and vertebral trabecular microarchitecture, permitting the detection of focal posterolateral fiber disruption at the L4-L5 IVD and regional differences in trabecular architecture between cervical and lumbar vertebral bodies. Local tomography resolved annulus fibrosus lamellae, vertebral endplate Haversian systems, and facet joint hyaline cartilage at micron resolution. Conclusions: HiP-CT enables non-destructive, multiscale three-dimensional imaging of the intact human spine while preserving tissue relationships across spatial scales and hard-soft tissue boundaries. HiP-CT could provide an ex vivo microanatomical reference for future correlation with clinical imaging investigations of spinal disease and in the development and validation of imaging biomarkers.

bioengineering↗

bioRxiv2026

Sex-specific dynamics of activity-dependent regulation of synaptic CaMKII

Similar behavioral outcomes in males and females can mask substantial differences in the mechanisms underlying neuronal function. However, to what extent sex influences the abundance and activity-dependent changes of proteins that govern neuronal plasticity remains poorly understood. Here we investigated sex-specific regulation of calcium/calmodulin-dependent protein kinase II (CaMKII), an evolutionarily conserved regulator of synaptic stability and plasticity in fruit fly Drosophila melanogaster. We find that the steady state levels and activity-driven changes in CaMKII protein differ between female and male at both third instar larval neuromuscular junction (NMJ) and in adult fly mushroom body (MB). These sex-specific differences are downstream of the sex determination pathway, implicating somatic sex identity in the regulation of CaMKII abundance and its activity-dependent dynamics. Despite the differences in CaMKII levels between female and male flies, we observed no impairment of plasticity in either sex. Overall, our findings reveal sex-dependent regulation of both steady-state and activity-dependent levels of a highly conserved neuronal plasticity-associated protein across distinct neuronal contexts and development stages. These results further support the idea that females and males can achieve similar behavioral outcomes through different molecular mechanisms. Growing evidence that sexually dimorphic molecular responses contribute directly to sex differences in vulnerability to stress and disease underscores the importance of identifying these mechanisms and understanding their consequences.

neuroscience↗

bioRxiv2026

Transcriptomic and lipidomic profiles reveal higher thermal adaptability in a tropical versus a temperate isolate of Chromera velia

The apicomplexan alga Chromera velia is the closest known phototrophic relative of apicomplexan parasites (Sporozoa). Despite its scientific importance as a model for the evolution of parasitic Apicomplexa, only two strains are available in culture. The first isolate (SH), obtained from stony coral in the cold waters of Sydney Harbour, was used for the original species description. The second isolate (OTI) originates from tropical corals at One Tree Island in the Great Barrier Reef. In this study, we compare their growth, transcriptomic, and lipidomic profiles at 20{degrees}C and 26{degrees}C. Both strains grew faster at 26{degrees}C, yet they responded differently to higher temperature. In SH, warming downregulated nearly 85% of its thermally responsive genes, with motility-, cytoskeleton-, and lipid-associated genes most strongly affected, while at 26{degrees}C, SH retained higher expression of translation and nitrogen, amide, and peptide biosynthesis genes than OTI. OTI, by contrast, mounted a smaller, more balanced response and maintained stable expression of cilium, axoneme, and microtubule genes across both temperatures. The lipidomes of the two strains showed both shared and divergent responses. Both isolates sense and respond to increasing temperature in the same basic way, but OTI stabilizes its membranes, whereas SH redirects lipid synthesis from membrane lipids to storage lipids. OTI membranes were also constitutively less unsaturated than those of SH at both temperatures, consistent with a membrane already suited to warmer water that needs less remodeling. Our data show that two isolates of the same species, originating from different thermal environments, respond to elevated temperature through distinct transcriptomic and lipidomic programs. This suggests that the tropical OTI isolate is adapted to higher temperatures and demonstrates how reef-associated algae respond to rising ocean temperatures.

evolutionary biology↗

bioRxiv2026

The interactome of the receptor kinase THESEUS1 reveals how cell wall integrity is linked to hormone signalling in Arabidopsis

The receptor kinase THESEUS1 (THE1) activates responses to impairment of cell wall integrity (CWI). However, the interaction partners enabling THE1 to mediate the responses remain underexplored, impeding a mechanistic understanding of THE1. We produced a set of THE1 GFP fusion constructs in which THE1 is either wild type, mutated in its kinase domain, has a loss of function mutation in its ectodomain, or lacks the kinase or extracellular domain. We used these constructs to perform localization studies and immunoprecipitation liquid chromatography tandem mass spectrometry under control and stress conditions (isoxaben induced cell wall damage and sorbitol induced hyperosmotic stress) to identify the THE1 interactome. The interactome of THE1 changed in a context dependent manner, linking THE1 to known signaling components in CWI maintenance and phytohormone response (such as proton pumps, calcium pumps, other receptor kinases or cellulose synthesis regulators). Moreover, we identified novel interactors, associating THE1 with hitherto unexplored signaling pathways in response to CWI impairment. Our results also suggest that the THE1G37D protein (corresponding to the the1 1 allele) is retained in the endoplasmic reticulum, explaining its loss of function phenotype. The THE1 interactome and localization data provide the foundation to build a mechanistic understanding of THE1 mediated CWI maintenance.

plant biology↗

bioRxiv2026

Glycoconjugates tune the viscoelastic signature of mammary tumor progression

Breast cancer progression involves extensive remodeling of the tumor extracellular matrix (ECM), resulting in changes in mechanical properties. Tumors are viscoelastic, exhibiting both an initial elastic response to loading and a time-dependent viscous response. While it is well established that tumor elasticity or stiffness is elevated, changes in tissue viscoelasticity during breast cancer progression remain poorly characterized. Here, using a mouse model that recapitulates stages of human breast cancer progression (mouse mammary tumor virus-polyoma middle T antigen, MMTV-PyMT), we show that tumors from both early and late disease time points were significantly more viscoelastic than normal mammary glands. Spatial microindentation revealed that while local stiffness and viscoelasticity are strongly coupled in soft regions of normal tissue, this relationship weakens in late carcinoma. Compared to normal glands, carcinoma tissues also exhibited marked upregulation of glycosaminoglycans (GAGs) and glycoproteins. Selective enzymatic degradation of sulfated GAGs, mucins, or O/N-linked glycans reduced viscoelasticity without altering stiffness, establishing glycoconjugates as major contributors to tumor viscoelasticity. In vitro, increasing matrix viscoelasticity drove non-transformed mammary epithelial cells (MCF10A) toward a malignant phenotype through focal adhesion kinase mechanosignaling. Our work establishes increased viscoelasticity as a defining mechanical feature of breast cancer progression, driven in part by the accumulation of glycoconjugates. These findings provide a fuller picture of tumor mechanical evolution and a benchmark for recapitulating matrix viscoelasticity in engineered models of breast cancer.

cancer biology↗

bioRxiv2026

Evolutionarily Conserved Plasmodium falciparum HSP70-3 Enhances the Immunogenicity of the Established Malaria Vaccine Antigen Circumsporozoite Protein through Cross-Presentation

Background: Clinically approved P. falciparum circumsporozoite protein (PfCSP)-based pre-erythrocytic stage malaria vaccines suffer from sub-optimal efficacy and rapidly waning memory. By decoding these limitations, we fast-tracked vaccine optimization by correcting CSPs fragile immunogenicity using a parasite-derived chaperone. Unlike other orthologues of P. falciparum heat shock protein 70 (PfHSP70), substrate-binding domain (SBD) of PfHSP70-3 is an evolutionarily conserved internal mitochondrial matrix chaperone. We demonstrate that PfHSP70-3-SBD hydrophobic region complexes with PfCSP and targets host CD91 on antigen-presenting cells to trigger cross-presentation, resulting in enhanced immune responses to PfCSP. Methods: In silico analyses predicted interactions among PfHSP70-3-SBD, PfCSP, and CD91 receptor. Recombinant PfHSP70-3-SBD and PfCSP proteins were purified and assessed for in vitro interaction using ELISA and far-western dot blot assays. BALB/c mice were immunized with alum-formulated PfCSP, with or without PfHSP70-3-SBD. PfCSP-specific IgG and IFN-{gamma} expression were evaluated by ELISA and RT-qPCR, respectively. Functional activity was assessed using transgenic Plasmodium berghei expressing PfCSP (Pb/Pf CSP), by sporozoite neutralization assay. Findings: PfHSP70-3-SBD demonstrated a specific interaction with PfCSP. The complex primarily engages CD91 receptor cluster IV, providing a potential mechanistic basis for antigen cross-presentation. Incorporation of PfHSP70-3-SBD enhanced PfCSP-specific total IgG responses and increased IFN-gamma expression in BALB/c mice, indicating improved immunogenicity upon co-formulation. Notably, immune sera neutralized Pb/Pf CSP sporozoites, delaying blood-stage patency until day 12 in 40% of C57BL/6 mice, with no detectable parasitemia in surviving mice for up to 2 months, indicating sustained efficacy against the sporozoite stage. Interpretation: Molecular chaperones, including HSPs, are currently under intense investigation for their immune-potentiating activity, leading to next-generation vaccine development. By utilizing chaperonic domains derived directly from the pathogenic agent itself to serve an essential adjuvant function, this approach reduces reliance on heterologous adjuvants while enhancing antigen-specific immunity. Funding: This work was supported by funding from Indian Council of Medical Research (IIRPSG-2024-01-03940). Keywords: Substrate-binding domain, PfHSP70-3, Adjuvant, Cross-presentation, Pre-erythrocytic stage, Plasmodium falciparum

microbiology↗

bioRxiv2026

HIV-1 envelope glycan loss links receptor adaptation and innate immune escape in SHIVs

Simian-human immunodeficiency viruses (SHIVs) are widely used to model HIV-1 infection in macaques, yet most SHIVs encoding circulating HIV-1 envelope glycoproteins (Env) replicate poorly because of inefficient use of macaque CD4 and sensitivity to host antiviral responses. During adaptation to macaques, Env is therefore subject to multiple selective pressures to improve receptor utilization while maintaining function in the face of host immune restriction. Type I interferon (IFN) is a major component of the host antiviral response during acute infection, and IFN resistance increases during SHIV adaptation to macaques through serial passage. However, the viral determinants of this resistance have remained unclear. Here, we show that serial passage of a lineage of SHIVs in macaques selected Env variants with markedly increased resistance to IFN- and enhanced replication in macaque CD4+ T lymphocytes. IFN- resistance mapped principally to loss of two highly conserved N-linked glycans at N197 and N276 near the CD4-binding site. Glycan loss altered the conformational landscape of virus-associated Env, enhanced macaque CD4-dependent entry and membrane fusion without increasing human CD4-dependent entry, and reduced incorporation of the IFN-inducible restriction factors IFITM3 and IFITM3A into progeny virions. Depletion of IFITM3/3A rendered the parental SHIV highly resistant to IFN- and abolished differential IFN- sensitivity among parental, adapted, and glycan-loss viruses. These findings reveal that loss of receptor-proximal Env glycans can simultaneously improve utilization of a heterologous CD4 receptor and promote escape from IFN-mediated restriction, linking receptor adaptation and innate immune evasion during lentiviral adaptation to a new host.

microbiology↗

bioRxiv2026

The chemosensory system of the clonal raider ant larva

Ant larvae are blind and immobile, depending heavily on the adults for care in the form of feeding, grooming, and transport. However, they are not inactive colony members but play a central role in the organization of ant societies by modulating adult behavior and physiology. While adult ants have been studied extensively, we still know little about what sensory modalities larvae use to perceive their environment. Here, we provide a molecular and circuit-level characterization of the chemosensory system of the clonal raider ant larva. Combining scanning electron microscopy and confocal imaging, we show that dome sensilla in the maxillary and labial palps are innervated by odorant receptor (OR) neurons. A larger population of ionotropic receptor (IR) neurons innervate papilla sensilla across various regions of the larval head: the antennae, the labrum, the maxillary palps and galeae, as well as the labial palps and the ventral labium. This suggests that IRs, which can have various functions, from taste and olfaction to temperature and humidity sensing, constitute the predominant chemosensory modality in ant larvae. To investigate projections into the central brain, we imaged transgenic lines that fluorescently label OR- and IR-expressing neurons. We found that OR- and IR-expressing neurons in the labium and maxilla project along the labial and maxillary nerves through the subesophageal ganglion to the deutocerebrum, whereas IR-expressing neurons from the labrum project to the tritocerebrum and those from the antenna project to the posterior deutocerebrum. Together, our findings establish a structural and molecular framework to study larval chemosensation in ants.

evolutionary biology↗

bioRxiv2026

Physical Basis Of pKa Shift For Ionizable Lipids In An LNP-like Environment

Lipid nanoparticles (LNPs) are a leading drug delivery platform for mRNA or other nucleic acid-based therapeutics. LNP platforms are typically composed of ionizable aminolipids, phospholipids, sterols, and lipids tagged with polyethylene glycol. The ionizable aminolipids are typically cationic at low pH, allowing them to encapsulate negatively charged mRNA. The pH at which the ionizable head groups change charge states, the apparent pKa, is crucial to understand the characteristics and formulation of LNP. However, this is difficult to measure as the apparent pKa differs from the pKa of the aminolipids in bulk solution due to the complex chemical and charge environment. In this study, we use molecular dynamics (MD) simulations with alchemical free energy perturbation to calculate the pKa shift as a function of lipid composition, treating LNP-like and vesicle-like environments. Our results show that the pH-dependent structure of the systems affects the trends in pKa shifts in complex ways, driven by factors including surface electrostatics and lipid internalization. Our all-atom simulation protocol allows us to efficiently estimate the apparent pKa of LNP-like models formed with novel ionizable aminolipids and estimate how it will change with composition.

biophysics↗

bioRxiv2026

An AI-powered cloud biofoundry for autonomous biological research

Autonomous experimentation, where an automated system designs, performs, analyzes, and iteratively improves experiments with minimal human intervention represents a transformative scientific research paradigm. However, it remains hampered by the disconnect between computational design and experimental execution. Here we present iCloudBiofoundry, a cloud-accessible, scalable, and self-evolving platform that bridges this divide. A scientific multi-agent system, iBioGenie, plans research workflows by converting natural language research objectives into testable hypotheses and experimentally grounded protocols using literature, databases, and computational tools. A physical AI layer, BiofoundryAI, translates them into executable workflows that run autonomously on distributed robotic biofoundries, and collects the data for iterative design. We demonstrate the end-to-end capabilities of iCloudBiofoundry across three representative case studies spanning enzyme retrieval, protein engineering, and metabolic engineering. By integrating agentic AI with physical AI, iCloudBiofoundry provides a cloud accessible platform that unifies computational design and robotic execution, enabling autonomous biological research.

synthetic biology↗

bioRxiv2026

Multi-Lab Testing of Early Preclinical Discoveries Identifies Promising Treatments

A fundamental challenge in drug development is the frequent failure of early laboratory research to translate into clinical benefit. One promising solution is to confirm findings from exploratory single-laboratory studies across multiple laboratories before clinical testing. We investigated this approach following the conduct of preclinical multi-laboratory studies across different fields of medicine. For this, we evaluated effect sizes, experimental rigor, and a set of criteria to identify determinants of confirmation success. When tested under increased rigor, only a fraction of multi-laboratory studies confirmed the initial results. The underlying effect size reduction was associated with outcome-relevant experimental differences between exploratory and confirmatory stages. In summary, multi-laboratory studies proved highly informative and served as an effective filter for promising treatments.

scientific communication and education↗

bioRxiv2026

Articular calcified cartilage microarchitecture has a predictive role in abnormal osteochondral strain distributions in murine age-related osteoarthritis

Even though osteoarthritis is considered a disease of the whole joint, integrated analysis of articular calcified cartilage (ACC) behaviour with adjacent tissues remains a persistent limitation. Herein, we performed synchrotron X-ray computed tomography in intact loaded joints and coupled anatomical analysis with digital volume correlation to examine whether microarchitectural ACC features serve as predictive mechano-biomarkers of osteoarthritis. We reveal that male osteoarthritis-prone STR/Ort mice have thicker yet more porous ACC that contains larger but less spherical chondrocyte lacunae than their healthy parental-control CBA mice. This was linked to asymmetrical distribution of tensile and compressive strains generated under physiological loads in the ACC and underlying subchondral bone in tibial epiphyses of STR/Ort mice. Together these data suggest that murine ACC microarchitecture has a mechano-predictive role in age-related osteoarthritis.

physiology↗

bioRxiv2026

Extracellular CIRP induces neurotoxic astrocytes via TREM-1 in Alzheimer's disease

Extracellular cold-inducible RNA-binding protein (eCIRP) is a crucial neuroinflammatory mediator in ischemic stroke and alcohol-induced memory impairment. We have recently discovered that amyloid{beta} causes microglia to release eCIRP, prompting us to investigate its role in Alzheimer's disease (AD). We found that eCIRP levels were significantly elevated in the cerebrospinal fluid (CSF) and plasma of AD patients compared with age-matched non-AD subjects, as well as in hTau.P301S mice (a model of AD tauopathy) compared with wildtype control mice. Plasma eCIRP strongly correlated with astrocyte activation marker glial fibrillary acidic protein (GFAP) in AD patients. eCIRP induced neurotoxic astrocyte-specific genes and astrocyte release of proinflammatory and neurotoxic factors in C8-D1a cells, primary murine astrocytes and intracerebroventricular eCIRP-injected C57BL/6 mice brains. In particular, eCIRP increased Complement 3, an astrocytic marker involved in neuroinflammation-associated neurodegeneration. Primary astrocytes from TREM-1 knockout mice were resistant to eCIRP induction of neurotoxic astrocytes. eCIRP increased TREM-1 expression and activation in astrocytes. Blocking CIRP/TREM-1 interaction using peptide M3, effectively attenuated eCIRP's induction of neurotoxic astrocytes. Thus, eCIRP strongly correlates with astrocyte reactivity in AD patients, and eCIRP induces neurotoxic astrocytes via TREM-1, which is attenuated by M3, suggesting a novel therapeutic opportunity to target neurotoxic astrocytes in AD.

neuroscience↗

bioRxiv2026

Scalable Computational Phenomics of Nuclear Morphology

Interpretable computational pathology is constrained by a trade-off between scalable learned representations and biologically explicit phenotypes. Here we present NucXplore, a nuclear phenomics framework that converts each hematoxylin-and-eosin (H&E)-stained nucleus into 129 explicitly defined features spanning morphology, chromatin, intensity, texture, color, and spatial context. A Rust-based implementation accelerates extraction 17.6-fold over the Python reference implementation. Across three histopathology cohorts, NucXplore outperformed classical descriptors and larger deep-learning embeddings while retaining feature attribution. Applied to human skin, hierarchical multiple-instance models resolved eight cellular compartments and decoded age and sun-exposure states, revealing a largely shared aging program with age and cell-specific exposure-dependent recalibration. Conditional flow matching and neural ODE integration transformed cross-sectional phenotypes into model-implied trajectories, uncovering a midlife velocity minimum, late-life re-acceleration, and cell-specific changes in trajectory magnitude and direction. Source-free domain adaptation enabled preliminary transfer of age-associated predictions to an independent hospital cohort. NucXplore thus unifies interpretable representation, high-performance computing, and dynamical modeling for cellular phenotyping from routine histology.

pathology↗

bioRxiv2026

Optimising digital volume correlation across materials: a practical framework for accuracy and spatial resolution

Digital volume correlation (DVC) provides full-field three-dimensional measurements of internal deformation, but its accuracy and effective spatial resolution depend on image-processing and analysis choices. Here, we use fibrous, cartilaginous and mineralised tissues within a rat intervertebral disc (IVD) as a controlled multi-material case study, combining virtual compression with experimentally loaded synchrotron computed tomography images. We systematically evaluate phase retrieval and image filtering, bit-depth conversion, point-cloud design, subvolume size and strain-field smoothing. Stronger phase retrieval reduced correlation residuals while increasing displacement and strain errors, showing that residual minimisation alone can select poorer parameters. Image filtering sensitivity was greatest in fibrous tissue, which had the smallest characteristic image feature size, whereas inappropriate intensity mapping during 16-bit to 8-bit conversion preferentially degraded low-contrast cartilage. Increasing subvolume size, point spacing or strain-window size improved measurement robustness but progressively smoothed local strain heterogeneity. We demonstrate that the spatial resolution of strain measurement must be matched across tissue types in order to compare strain magnitude; in the IVD, matching DVC spatial resolution changed the apparent ratio of compressive strain among fibrous, cartilaginous and mineralised tissues from 3.1:1.9:1 to 14:7.7:1. These findings establish a sequential, deformation-based optimisation framework in which image characteristics guide processing, known deformations validate accuracy and strain fields are compared at matched measurement scales. The framework supports more reproducible and mechanically interpretable DVC analyses in heterogeneous biological and engineered materials.

bioengineering↗

bioRxiv2026

Xanthomonas pateli sp. nov. and X. hingoranii sp. nov. reveal a community of non-pathogenic Xanthomonas species complex in citrus

The genus Xanthomonas comprises a phylogenetically and ecologically diverse group of bacteria, historically characterized by economically important plant-pathogenic members affecting a wide range of agricultural crops. However, an increasing number of non-pathogenic and endophytic lineages have been recognized within the genus, expanding understanding of its taxonomic and ecological breadth. While it has been known for the last 30 years that non-pathogenic Xanthomonas (NPX) are present in diverse plants, studies from our lab over the last decade on the rice microbiome have revealed the presence of multiple, diverse NPX species as a community associated with a particular plant host. In this study, we identify two novel citrus plant-associated NPX species and provide evidence for the existence of an NPX community composed of multiple, diverse species, as in rice. Biochemical analysis, along with phylogenomic and genome-based taxonomic investigations, revealed that these strains represent two novel species within the genus Xanthomonas, providing evidence for a citrus-associated NPX community composed of multiple, diverse species, analogous to that described in rice. The lack of a canonical type III secretion system, along with multiple antimicrobial biosynthetic loci, as in the rice NPX community, points to their importance in plant microbiomes. Hence, such systematic studies of the NPX community need to be extended to all other plants. Accordingly, we propose that strain LMG 8992 (DSM =122509T) be classified as a novel species, Xanthomonas pateli sp. nov., and strain LMG 8993 (DSM = 122444T) be classified as a novel species, Xanthomonas hingoranii sp. nov.

microbiology↗

bioRxiv2026

Temporal Indexing of Motor Memory

Humans must store and retrieve distinct implicit motor memories in different contexts. Recent research has revealed the motor adaptation system's sensitivity to contextual cues related to posture, spatial goals, and visual inputs. However, to date, the role of one critical variable in implicit motor memory retrieval - the passage of time - remains underexplored, even though it is arguably more fundamental. Here we ask if different temporal intervals can act as effective contextual cues for retrieving competing motor adaptation memories at the subsecond level. We combined a visuomotor dual adaptation paradigm with a 'set-go' task to link opposite perturbation contexts with different movement preparation intervals. The preparation intervals (and their associated perturbations) were randomly interleaved during training, leading to consistent interference. After training, a testing phase revealed robust contextual modulation effects, such that distinct implicit motor memories were retrieved based on the time elapsed during the pre-movement preparatory interval. These contextual memory effects generalized to novel preparatory intervals in a highly structured fashion. Contextual motor memory separation was seen both when elapsed time had to be internally tracked (high uncertainty) and when it was aided by visual and symbolic cues (low uncertainty). Learning and generalization data across experiments could be parsimoniously explained by a computational model that indexed motor memories via a cerebellar granule-cell-like temporal basis set that tiled the delay interval. Our findings suggest that intrinsic timing processes in the cerebellum may function to index motor memories and generalize those memories to new temporal contexts.

neuroscience↗

bioRxiv2026

A Distal Super-Enhancer Regulate CD47 Expression and Promotes Macrophage-Mediated Phagocytosis of Ovarian Cancer Cells

CD47 is an innate immune checkpoint that can protect tumor cells from macrophage-mediated clearance, but the regulatory mechanisms underlying its expression in ovarian cancer (OC) remain incompletely understood. Here, we investigated the epigenetic regulation of CD47 expression in OC. Single-cell and spatial transcriptomic analyses indicated preferential CD47 expression in malignant epithelial cells. Integration of publicly available epigenomic datasets revealed a distal regulatory region with enhancer-associated features across ovarian cancer models and HGSOC patient samples. A genome-wide CRISPR-Cas9 screen further implicated PITX2 and EP300 as regulators of CD47 expression. Chromatin immunoprecipitation assays showed PITX2 and EP300 occupancy at candidate enhancer elements within this CD47 regulatory region. Comparative epigenomic analyses suggested that features of this regulatory landscape are also present in fallopian tube epithelial cells and become more prominent in OC. Together, these findings support a PITX2-EP300 regulatory axis associated with CD47 expression and provide evidence for its potential contribution to tumor immune evasion.

cancer biology↗