Biology subjects

Kumar, S.

Publications and source records attributed to Kumar, S..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Bioenergetic responses to β-adrenergic stimulation in beige adipocyte depend on actomyosin driven forces

Beige (BeAT) and white adipoctyes (WAT) reside within the same fat depots but differ in their responses to {beta}-adrenergic stimulation. While both activate classical PKA-mediated pathways, only beige adipocytes show induction of UCP1 expression and enhanced mitochondrial respiration, suggesting additional mechanisms that distinguish their responses. Here we uncover a parallel, non-canonical biomechanical pathway specific to beige adipocytes that is essential for thermogenic activation. Mechanistically, {beta}-AR stimulation induces a rapid Myh9-mediated actomyosin contraction and stiffening in beige, but not white, adipocytes that activates focal adhesion kinase (FAK), which we show to be critical for the expression of oxidative and thermogenic genes including UCP1 and PLIN5. These findings reveal a new biomechanical Myh9-FAK signaling arm downstream of b-adrenergic activation that differentiates thermogenic from white adipocytes.

cell biology↗

bioRxiv2025

Immunological Differences in Atopic Dermatitis Across Age Groups: Insights from Single-Cell Multi-Omics

BackgroundAtopic dermatitis (AD) occurs across all ages but presents distinct clinical and immunologic features between children, adults, and older adults. The molecular programs underlying these age-specific immune differences remain poorly understood. MethodsWe performed single-cell multi-omics profiling of peripheral blood mononuclear cells (PBMCs) from 29 AD patients and 29 matched healthy controls (HC), spanning pediatric (0-17 years), adult (18-59 years), and geriatric ([≥]60 years) groups. Using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we simultaneously quantified transcriptomic (RNA) and surface proteomic (ADT) profiles across [~]280,000 immune cells. Integrated analyses identified 30 immune subsets for cell-type proportion and differential expression analyses. Machine-learning classifiers were trained on significant gene and protein features to distinguish AD subgroups by age. ResultsCompared with HC, AD blood showed enrichment of CD14+ monocytes, plasmacytoid dendritic cells, and CD4+ proliferating T cells. Within AD, pediatric patients had increased {gamma}{delta} T cells, naive CD4+, and naive CD8+ T cells, while geriatric patients exhibited more CD4+ cytotoxic and CD8+ central memory T cells, indicating a shift from naive to effector predominance with aging. Transcriptomic and proteomic analyses revealed distinct programs: pediatric AD was enriched for IL-10 and cytokine-cytokine receptor signaling; adult AD demonstrated activation of metabolic and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B)/Th1/Th17 pathways; and geriatric AD exhibited reduced adaptive immune activity but increased innate signaling. Machine-learning models based on differentially expressed genes and proteins accurately classified AD age groups (transcript-based F1 = 0.70, AUC = 0.79), identifying stable markers such as IRF2, PDK4, ZFP90, CD21, CD94, and CD122. ConclusionsSingle-cell multi-omics profiling revealed immune differences across the AD lifespan, transitioning from developmental tolerance in children to inflammatory and metabolic activation in adults to enhanced innate signaling in geriatric individuals. These findings highlight molecular signatures that could support age-specific diagnostics and therapeutic strategies for AD across the lifespan.

immunology↗

bioRxiv2025

Myeloperoxidase impairs mucociliary transport on human airway epithelium

Dampening neutrophil-driven inflammation in the airways remains a challenge in treating cystic fibrosis (CF) lung disease. Myeloperoxidase (MPO) is a neutrophilic enzyme that produces reactive oxygen species and is highly concentrated in CF sputum samples. Greater MPO concentrations have been previously correlated with increased mucus plugging in bronchiectasis, suggesting that the enzyme could impair mucociliary transport. MPO reacts competitively with either thiocyanate (SCN-) or chloride (Cl-) in the airways to catalyze the production of hypothiocyanous acid (HOSCN) or hypochlorous acid (HOCl), respectively. HOCl has proved in prior studies to be extremely cytotoxic, while HOSCN can drastically reduce cytotoxicity. The concentration of SCN- in the airways is largely dependent on transport by the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is dysfunctional in individuals with CF and causes low SCN- concentrations. CFTR modulator therapies likely raise the concentration of SCN- and enhance the production of HOSCN in the airways. We found that MPO inhibits mucociliary transport in vitro in regardless of SCN- concentrations primarily due to increasing the macromolecular components and effective viscosity of airway surface liquid. The impairment of mucus clearance by MPO was similar to neutrophil elastase (NE), another neutrophilic granular enzyme that damages the host tissues and induces the secretion of mucin proteins by the airway epithelium. Overall, these findings identify MPO as a therapeutic target to resolve deficits in airway clearance function in CF and other related muco-obstructive lung diseases.

cell biology↗

bioRxiv2025

A painless nerve growth factor variant uncouples nociceptive and neurotrophic TrkA signaling

Nerve growth factor (NGF) binding to the receptor tyrosine kinase, TrkA, drives neurotrophic signaling essential for neuronal development and survival. This interaction simultaneously drives peripheral pain, making this pathway an attractive but complicated therapeutic target for chronic pain. By integrating single-molecule microscopy, structural and electrophysiology analyses, with a human NGF variant, NGFpainless, which retains neurotrophic effects but abolishes pain, we delineate the molecular mechanisms that bias TrkA signaling towards neurotrophic functions without triggering nociception. We show that, unlike wild-type NGF, NGFpainless fails to sensitize TRPV1 channels to capsaicin, thus disengaging TrkA from the nociceptive pathway. We further show that this selective loss of nociceptive TrkA signaling by NGFpainless results from its reduced ability to activate PLC{gamma}1 and trigger calcium release compared to NGF, while still preserving the ERK and AKT signaling essential for neurotrophic functions. This biased signaling arises from reduced electrostatic complementarity at the TrkA:NGFpainless complex interface, which shortens the lifetime of this functional complex on native membranes. Mutations in TrkA that restore the electrostatic complementarity at the TrkA:NGFpainless interface eliminate biased signaling. This mechanistic understanding of TrkA binding by NGFpainless, and how it differs from NGF, will spur the development of two therapeutic classes of molecules - one that selectively suppresses nociceptive signaling while preserving neurotrophic functions in chronic pain, and another that enhances neurotrophic activity without evoking peripheral pain in neurodegenerative conditions.

neuroscience↗

bioRxiv2025

Insights into the mechanism of succinimide formation in an archaeal glutaminase.

Succinimide (SNN), an intermediate formed during asparaginyl deamidation or aspartyl dehydration in proteins, is generally hydrolysis-prone, leading to isomerization to L/D /{beta}-aspartyl residue, with the latter being considered deleterious to protein structure and function. An unusually stable SNN-mediated conformational rigidity through restriction of the backbone dihedral angle, {psi}, enhances the thermostability of glutamine amidotransferase (GATase) from Methanocaldococcus jannaschii (Mj). Although several structural features involved in maintaining a stable SNN and imparting SNN-mediated thermostability have been identified in MjGATase, the residues in the protein that catalyse the rapid and complete conversion of Asn109 to SNN remain unknown. Here, we investigated several site-directed mutants of MjGATase for their ability to retain Asn109 side chain in the unmodified form. Mass spectrometric analysis of 10 single mutants enabled the identification of residues that impacted the proportion of SNN and Asn population in the protein sample. This led to the generation of two double mutants that retained intact Asn109 side chain as observed in the mass spectra and crystal structures. These mutants with intact Asn residue at position 109, displayed lower thermal stability than the protein with the SNN modification. Further understanding of the deprotonation mechanism was addressed using QM/MM MD metadynamics simulations. HighlightsO_LIStable succinimide (SNN) arising from deamidation of Asn109 residue imparts hyperthermostability to MjGATase. C_LIO_LIExamination of the structure of MjGATase suggests neighbouring residues playing possible roles in deamidation and cyclization. C_LIO_LIExamination by LC-MS of single site-directed mutants of residues contacting SNN revealed varied levels of intact Asn109 enabling generation of double mutants with complete absence of deamidation. C_LIO_LIPresence of intact Asn109 confirmed by X-ray crystallography highlights the role of Y158, D110, and K151 in mediating SNN formation. C_LIO_LIQM/MM MD metadynamics simulations support experimental findings. C_LI

biochemistry↗

bioRxiv2025

Chemical Dice Integrator (CDI): A Scalable Framework for Multimodal Molecular Representation Learning

The machine learning landscape for molecular property prediction is fragmented, with numerous Featurizers each capturing a narrow, specialized view of chemical structure. This heterogeneity forces a suboptimal choice of representation a priori, limiting model generalizability. We introduce the Chemical Dice Integrator (CDI), a hierarchical framework that unifies six orthogonal molecular representations, physicochemical (Mordred), topological (GROVER), visual (ImageMol), biological (Signaturizer), quantum-mechanical (MOPAC), and linguistic (ChemBERTa), into a single, coherent embedding. The framework consists of CDI-Basic, a two-tiered autoencoder that fuses these modalities, and CDI-Generalised, a Mamba State-Space Model (SSM) that learns a direct, efficient map from SMILES strings to the unified embedding space. Extensive benchmarking across 23 classification (171 tasks) and 10 regression datasets demonstrates that CDI embeddings consistently achieve superior predictive performance compared to individual Featurizers and standard feature aggregation methods. The CDI-Generalised model achieves this performance with exceptional computational efficiency, outperforming deep learning Featurizers in terms of speed and resource overhead. Furthermore, we demonstrate that the CDI embedding is chemically intuitive, allowing for the sensitive distinction of nuanced structural variants, such as chiral enantiomers and kekulized SMILES forms. By bridging multimodal chemical intelligence with scalable, sequence-based inference, CDI offers a strong foundation for molecular machine learning.

bioinformatics↗

bioRxiv2025

Biofuel-driven Adaptable n-type Supramolecular Wires: Mimicking Conducting Microbial Nano-filaments

We report the biofuel-driven self-assembly of a benzimidazole-pyridine platinum (II) complex into supramolecular nanowires. Phosphate promotes Pt{middle dot}{middle dot}{middle dot}Pt metallophilic stacking, whereas the pristine complex forms nanosheets dominated by {pi}-{pi} interactions. By varying phosphate denticity (adenosine/guanosine mono-, di-, and triphosphates), we tune the extent of Pt{middle dot}{middle dot}{middle dot}Pt interactions and the resulting electrical conductance of the nanowires, measured on graphene using a custom EGaIn setup. Triphosphate-templated nanowires exhibit nearly four orders of magnitude higher conductance than non-templated nanosheets. Thermopower measurements reveal a negative Seebeck coefficient, indicating LUMO-mediated electron transport and rare n-type behavior in these supramolecular assemblies. Temperature-dependent measurements show a transition from tunneling (non-templated nanosheets) to thermally activated hopping (triphosphate templated nanowires). The system is recyclable, apyrase hydrolysis disrupts the nanowires, and re-addition of phosphate restores assembly, enabling reversible conductance switching over multiple cycles. This study demonstrates a fuel-responsive, adaptive supramolecular electronic material, highlighting how controlled Pt{middle dot}{middle dot}{middle dot}Pt interactions can be exploited to program charge transport in soft, bioinspired electronic systems.

bioengineering↗

bioRxiv2025

Brain-wide single-neuron bases of working memory for sounds in humans

In order to understand the constantly changing acoustic world our brains must maintain elements of auditory scenes in memory. The neural mechanisms for this fundamental process remain unclear. Here, we report human intracranial recordings of 1269 single neurons while participants performed a non-verbal auditory working memory task that required adjustment of a tone frequency to match a target. We found neurons within hippocampus, insula and cingulate cortex, for which firing rates were modulated at different phases of the task, particularly during maintenance and adjustment. For the majority of the neurons modulated during maintenance there was a striking suppression of activity rather than increased activity. Across the entire neuronal population, state-space analysis demonstrated attractor-like states corresponding to different task phases. Behaviorally, more neurons were modulated at the beginning of the maintenance phase in trials when participants performed better. State-space analysis was consistent with greater attractor-like activity during the adjustment phase supporting better performance. These data support the existence of a widely distributed neural code for auditory working memory that determines related behavior based on attractor-like states.

neuroscience↗

bioRxiv2025

FcγRI is the key determinant of antibody-mediated Zika virus infection of human placental macrophages

Zika virus (ZIKV) can be vertically transmitted from a pregnant mother to the developing fetus, resulting in microcephaly and/or other congenital malformations. Dengue virus (DENV) cross-reactive antibodies can facilitate ZIKV placental transcytosis and enhance ZIKV infection of placenta macrophage-Hofbauer cells through binding to Fc-{gamma} receptors (Fc{gamma}Rs). To understand the role of individual Fc{gamma}R in antibody-mediated ZIKV placental infection, we generated a comprehensive panel of Fc-variants spanning a wide range of binding affinities to different Fc{gamma}Rs. We found that mutations with increased affinity to Fc{gamma}RI strongly correlated with an increased frequency of infected pro-monocytic U937 and Hofbauer cells. Next, we genetically deleted individual Fc{gamma}R in U937 cells, and found that the knockout of FCGR1A gene completely abolished ZIKV infection. In contrast, the deletion of FCGR2B gene showed no effect on ZIKV infection, and the deletion of FCGR2A gene had only a moderate impact on ZIKV infection. We further observed that Fc{gamma}RI was involved in both increased ZIKV internalization and replication. Collectively, our results establish Fc{gamma}RI as the key Fc receptor responsible for antibody-mediated ZIKV infection in both U937 and primary placental macrophages. These mechanistic findings not only provide insight into the importance of Fc{gamma}RI in ZIKV vertical transmission but also highlight Fc{gamma}RI as a potential therapeutic target, with significant implications for the development of strategies to prevent ZIKV transmission from mother to fetus.

immunology↗

bioRxiv2025

Uncertainty-Gated Min-Cost Flows for In Vivo NanoScale Synaptic Plasticity Tracking

Synapses are the fundamental unit of neural connectivity, exhibiting dynamic functional and structural changes that enable the brain to learn, adapt, and form memories. Recent advances in fluorescent labeling of endogenous proteins offer an opportunity to image synaptic strength in vivo and study mechanisms underlying adaptive neural computation. Studying synaptic dynamics requires tracking signals of small, densely packed synapses over days as they change in size, position, and intensity between imaging sessions, and may even appear or disappear. Associating >50,000 dynamic, submicrometer particles across time is difficult, even for state-of-the-art algorithms. Moreover, most algorithms assign equal weight to the lateral (XY) and noisier axial (Z) dimensions, reducing performance. To address these challenges and accurately track synapses in vivo, we developed SynTrack. We formulate tracking as a Maximum A Posteriori estimation problem that identifies the K most likely disjoint paths in a Hidden Markov Model, solved using min-cost circulation optimization. An anisotropic uncertainty model accounts for poorer axial resolution, and a fully temporally connected spatio-temporal graph overcomes long-term occlusions. SynTrack achieves a mean displacement of 0.50 {micro}m with a Multiple Object Tracking Accuracy (MOTA) score of 89.8%, on par with expert annotators but with substantially increased speed and scalability. In a large-scale volume imaged over two weeks, SynTrack reconstructed 74,000 synapse trajectories detected in 4.9 out of 8 imaging sessions on average, with 18,000 synapses tracked in at least seven sessions. We present a state-of-the-art algorithm capable of high-fidelity longitudinal tracking of individual synapses in behaving mice at an unprecedented scale.

neuroscience↗

bioRxiv2025

Prion protein-derived cell-penetrating peptide inhibits type II diabetes-associated islet amyloid polypeptide aggregation and cytotoxicity

Islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone co-packaged and co-secreted with insulin by pancreatic {beta}-cells. A pathological hallmark of type II diabetes is the self-assembly of IAPP into {beta}-sheet rich amyloid fibers, which is associated with {beta}-cell impairment. Previously, we showed that a cell-penetrating peptide (CPP) construct, consisting of a hydrophobic signal sequence coupled to a polycationic nuclear localization signal (NLS)-like sequence, exhibited potent anti-prion activity and antagonism of Alzheimers disease-associated amyloid-{beta} (A{beta}) peptide aggregation and neurotoxicity. Here, we have extended this approach towards type II diabetes by assessing the efficacy of the CPP construct, designated as NCAM1-PrP, in inhibiting IAPP oligomerization, fiber formation and associated cytotoxicity. Using complementary in vitro and in silico experiments, we show that NCAM1-PrP effectively modulates IAPPs toxic structures into non-toxic conformations. This study underlines the potential of our designed CPP-based therapeutic approach as a versatile tool in the battle against amyloid-associated pathologies.

biochemistry↗

bioRxiv2025

T-PGI: an engineered STITCHR system for scarless, programmable genome integration

Scarless, programmable insertion of defined DNA remains a central goal for therapeutic genome editing. We introduce T-PGI (Transposon-mediated programmable genomic integration), an engineered implementation of STITCHR that preserves target-primed reverse transcription (TPRT) while substantially improving efficiency, specificity, and modularity. T-PGI uses R2Tocc, a low-background ortholog that we further engineered through defined deletions, rational point mutations, and modular domain insertions to enhance performance. The system employs paired nCas9 nicks flanking homology arms and bicistronic co-expression with dual NLSs, together with optimized RNA donor designs. Using combinatorial guide-template screening, T-PGI achieves robust integration across diverse cargos, including precise cassette insertion following multi-kilobase deletions. Short- and long-read sequencing confirm high-fidelity insertion with minimal local indels or structural variants. Collectively, these advances establish T-PGI as a practical and adaptable platform for accurate, scarless genome integration and provide concise design principles spanning enzyme architecture, donor configuration, and guide pairing for next-generation therapeutic editing.

bioengineering↗

bioRxiv2025

Understanding the infection mechanism of {Phi}8 using infection method in Pseudomonas syringae pv. Phaseolicola strain: In-situ CryoET analysis

The Cystoviridae family strain {Phi}8 is an ideal model for studying the virus-host interactions and viral assembly mechanisms. In this study, we explored {Phi}8 infection kinetics in P. syringae pv. phaseolicola host cells using a combination of host lysis assays, transmission electron microscopy (TEM), cryo-focused ion beam (Cryo-FIB) milling, and in-situ cryo-electron tomography (Cryo-ET). Purified {Phi}8 was infected with host cells and observed at different time points. The host-pathogen infection was detected using TEM studies. The infected sample underwent Cryo-FIB milling. Our findings indicated that the infected host cell membrane changes its shape during infection. We were able to visualize the various stages of {Phi}8 assembly using subtomogram averaging. These stages included the unpackaged procapsid (PC) having a size of [~]41 nm and the double-stranded RNA (dsRNA)-packaged procapsid having a size of [~]54 nm. The packaged PC represented the most prevalent intermediate stages during viral assembly. Notably, the majority of complete virions isolated from the host cell were found outside the host cell, revealing the extracellular predominance of fully constructed particles. These findings emphasize the importance of stable intermediate stages in viral assembly and maturation of {Phi}8. This work advances our understanding of viral assembly and complex host-cell interactions. HighlightsO_LISuccessfully isolated and infected Pseudomonas syringae pv. phaseolicola (Pph) host cells with {Phi}8. C_LIO_LILysis assay performed to quantify host lysis to evaluate viral infection efficiency. C_LIO_LICryo-focused ion beam milling enabled precise preparation of cellular cross-sections for structural analysis. This allows identification of key stages of the {Phi}8 life cycle during the infection cycle. C_LIO_LIThe majority of complete virions were localized extracellularly, emphasizing the role of extracellular stages in the {Phi}8 lifecycle. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/678632v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@6ba760org.highwire.dtl.DTLVardef@1b99d2dorg.highwire.dtl.DTLVardef@fdfe72org.highwire.dtl.DTLVardef@14c077e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Multimodal Imaging and Logistic Weighted Cognitive Scores for Classification of MCI, AD, and FTD Subtypes

BackgroundDifferentiating between mild cognitive impairment (MCI), Alzheimers disease (AD), and frontotemporal dementia (FTD) subtypes remains a clinical challenge due to overlapping cognitive symptoms, structural atrophy, and metabolic patterns, especially in the early stages. Multimodal classification approaches integrating neuroimaging and cognitive scores may offer early and accurate characterization and subsequently improved diagnostic precision. MethodsIn this study, we included 100 participants (50 AD, 30 FTD, including 14 bvFTD and 16 PPA, and 20 MCI) who underwent simultaneous structural MRI and FDG-PET imaging. Cortical thickness (CTH) from anatomical MRI and standardized uptake values from FDG-PET were extracted using FreeSurfer and PETSurfer pipelines, respectively. CTH and FDG-PET features were combined into a single vector through a logistic weighting function derived from ACE-III scores, capturing the progressive nature of cognitive decline in dementia. A Naive Bayes classifier was then trained to differentiate diagnostic groups based on the merged features. ResultsThe model achieved classification accuracies of 83% for MCI vs. dementia (AD + FTD), 85% for MCI vs. FTD, 87% for MCI vs. PPA, 71% for MCI vs. bvFTD, 64% for MCI vs. AD, and 69% for AD vs. FTD. The overall classification accuracy was 68%, with the highest discriminative performance observed in separating MCI from FTD subtypes. ConclusionsThis study presents a novel, cognition-weighted multimodal approach combining structural and metabolic imaging to enhance the classification of neurodegenerative syndromes. Findings from this study, underscore the potential of integrating ACE-III scores with neuroimaging biomarkers for accurate characterization and, early-stage differentiation of MCI, AD, and FTD variants.

neuroscience↗

bioRxiv2025

Lower Airway Dysbiosis in NTM+ Bronchiectasis is Associated with NET-Predominant Severe Phenotypes

RationaleThe discoveries of neutrophilic inflammation and Pseudomonas-dominant pulmonary dysbiosis have helped pave the way for host-directed therapy in bronchiectasis. Substantial knowledge gaps remain about the interplay between neutrophilic signatures and microbes in non-tuberculous mycobacterial lung disease (NTM-LD), a phenotypically diverse lung infection that is increasingly prevalent in the United States and other parts of the world. ObjectivesEvaluate the lower airway microbiota and neutrophilic traits in NTM- and NTM+ bronchiectasis. Methods16S rRNA gene sequencing, cell counts and neutrophil extracellular trap (NET) immunoassays were performed on bronchoscopic lower airway samples in 200 bronchiectasis subjects (108 NTM-, 92 NTM+). A preclinical model of oral commensal micro-aspiration and NTM infection was used to profile the murine lower airways with flow cytometry and a NET assay. Measurements and Main ResultsLower airways of NTM+ bronchiectasis patients were enriched with Mycobacterium and oral commensals (e.g., Veillonella, Prevotella). NET levels were higher in NTM+ BAL. Mycobacterium and oral commensals co-occurred with NET and neutrophils in network studies. Distinct oral commensal taxa associated with severe disease phenotypes such as cavitary disease and exacerbators. In a murine micro-aspiration model, the combination of oral commensals and Mycobacterium led to a sustained pro-inflammatory immune response marked by an increase in Th17, {gamma}8T cells, PD-1+ T lymphocytes as well as higher NET levels. ConclusionsOur analyses showed that distinct microbiome features beyond the primary pathogen can contribute to neutrophilic inflammation and severe disease phenotypes in bronchiectasis/ NTM-LD.

immunology↗

bioRxiv2025

DNA shape and epigenomics distinguish the mechanistic origin of human genomic structural variations

The recent advent of long-read whole genome sequencing has enabled us to create an accurate telomere-to-telomere reference genome, construct pangenome graphs, and compile precise catalogs of genomic structural variations (SVs). These comprehensive SV repositories provide an excellent opportunity to explore the role of SVs in genotype-phenotype associations and examine the mechanisms by which SVs are introduced through double-strand break (DSB) repair. Here, we employed comprehensive SV catalogs identified through various short- and long-read whole genome sequencing efforts to infer the underlying mechanisms of SV introduction based on their genomic and epigenomic profiles. Our findings indicate that high local DNA methylation and DNA shape-related features, such as low variations in propeller twist, support the origins of homology-driven SVs. Subsequently, we utilized an active-learning-based unsupervised clustering approach, revealing that the homology-dependent SVs show greater evidence of retaining ancestral recombination patterns compared to their homology-independent counterparts. Finally, our comparison of inherited and de novo SVs from healthy populations and rare disease cohorts showed distinct upstream H3K27me3 levels in de novo SVs from individuals with ultra-rare disorders. These findings highlight genome-wide characteristics that may influence the choice of repair mechanisms linked to heritable SV origins.

genomics↗

bioRxiv2025

MicroNucML: A machine learning approach for micronuclei segmentation and the refinement of nuclei-micronuclei relationships

Micronuclei (MN) are structures containing small fragments of DNA, arising from mitotic errors or failed DNA repair attempts. Therefore, MN serve as markers of genomic instability and are typically quantified either manually or through threshold-based methods, which can be tedious and inaccurate, leading to varying degrees of success and throughput. By employing a two-phase labeling approach that utilizes polygon and brush segmentation, along with refinement using SAM2, we developed a high-quality MN segmentation tool. Subsequent data augmentation, which captured heterogeneity in image quality and color diversity, enabled us to train a generalizable Mask-RCNN model optimized for small object detection, achieving state-of-the-art performance in MN detection. Finally, we applied our model to immunofluorescence data obtained from cell lines exposed to DNA damage conditions to gain biological insights into MN dynamics and their role in inducing genome instability. In summary, this work establishes an accessible resource for systematically studying genome instability with significantly greater fidelity and sensitivity, enabling insights into damage biology that were previously unresolved.

bioinformatics↗

bioRxiv2025

Synaptic and neural pathway redundancy enables the robustness of a sensory-motor reflex and promotes predation escape in C. elegans

As a basic unit of the nervous system, the sensory-motor reflex circuit is fast and robust. However, it is not entirely clear how this robustness is achieved, given that various genetic perturbations can disrupt the function of the sensory neurons. By mapping the molecular basis of neuronal connections in the touch response circuit of Caenorhabditis elegans, we found prevalent genetic redundancy at neural pathway, synaptic, and molecular levels, which ensures that sensory signals can be relayed to command interneurons that control motor output. We also discovered developmental remodeling of the anterior circuit, which leads to the pruning of larval synapses, establishment of a second pathway that activates additional interneurons, and lateralization of the circuit. Finally, we found that the synapses that appeared to be functionally redundant in a simple touch assay contribute to the extent of reversal response in an additive manner, which may help the organism escape from predators.

neuroscience↗