Biology subjects

Yadav, A.

Publications and source records attributed to Yadav, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

ACSS2 mediates prenatal alcohol exposure-related morphological and behavioral phenotypes

The metabolic enzyme Acetyl-CoA Synthetase 2 (ACSS2) recently emerged as an unexpected regulator of molecular and behavioral changes associated with alcohol use. Its role during prenatal exposure, however, remains unknown. Here, we use a combination of proteomic, genomic and behavioral approaches to establish ACSS2 as a key mediator of prenatal alcohol exposure-related phenotypes. We define the developmental window during which ACSS2 translocates to nuclei in the mouse brain, and show that alcohol-derived acetate is incorporated into fetal brain histone acetylation in utero. Using genetically engineered mice not expressing ACSS2, we demonstrate that loss of this enzyme attenuates chronic prenatal alcohol exposure-induced craniofacial abnormalities, motor function deficits, cognitive impairments as well as associated chromatin and gene expression changes in the dorsal hippocampus and the cerebellar vermis. Our results outline a previously unknown mechanism underlying prenatal alcohol exposure-related phenotypes regulated by ACSS2, which will inform the development of future therapeutic interventions. HIGHLIGHTSO_LIACSS2 translocates to nuclei during in utero brain development C_LIO_LIAlcohol-derived acetate is incorporated into fetal brain histone acetylation C_LIO_LIPrenatal alcohol exposure results in long-lasting and ACSS2-dependent chromatin and gene expression changes in the hippocampus and cerebellar vermis C_LIO_LILoss of ACSS2 attenuates molecular changes, craniofacial abnormalities and cognitive impairments linked to prenatal alcohol exposure C_LI

neuroscience↗

bioRxiv2025

Quantum Deep Learning Pipeline for Next Generation Network Biology

PurposeModule discovery in omics networks is central to interpretation. Classical pipelines capture broad community structure, but exact search for small, connected, topology aware modules is combinatorial, making exhaustive solutions impractical at genome scale. Moreover, most quantum clique formulations to date optimize only maximal density on non biological graphs, which mismatches the heterogeneous shapes of real biological modules. MethodsWe trained a symmetric 10-dimensional autoencoder on GTEx normals (Heart Left Ventricle; Muscle Skeletal; UCSC Xena Toil) to obtain tissue-specific latent representations. For each tissue we built a 10*10 latent-node correlation graph and formulated a QUBO that rewards strong edges and penalizes isolated selections (edge threshold {tau}=0.80). QAOA (depth=3, COBYLA) generated high-probability bitstrings, which we post-filtered to retain connected, non-overlapping subsets; decoder triggered gene sets and multi-library enrichment provided functional interpretation. ResultsQAOA distilled the Heart graph to three dyads (2-node modules with strong-edge sums {approx}0.89/0.95), pairing conduction with mitochondria, conduction with ECM/adhesion, and two contractile nodes. In Muscle, QAOA returned one dominant 6-node module (edge-sum {approx}7.0) integrating contractile machinery, electrophysiology, mitochondrial metabolism, and translation; a weaker ECM leaning triplet was visible but fell below the top 10 threshold. ConclusionQAOA based quantum optimization yields discrete, testable modules from latent correlations that match tissue programs. Despite a 10-node demo (current limits), the scale-agnostic design extends to 10^3 10^5 nodes and multi omics via hierarchical compression and hybrid search supporting quantum modeling for next generation network biology.

bioinformatics↗

bioRxiv2025

MitoXRNet: Deep Learning-enabled 3D Segmentation of Mitochondria and Nucleus in Soft X-ray Tomograms

Mitochondrial morphology is crucial for cellular function, but large-scale analysis is limited by challenges in high-resolution imaging and segmentation. MitoXRNet, a compact 3D deep-learning model, efficiently segments mitochondria and nuclei from Soft X-ray Tomography data using multi-axis slicing, Sobel-based boundary enhancement, and combined BCE-Robust Dice loss. With 1.4M parameters, it achieves a Dice score of 73.8% on INS-1E cells, outperforming existing models. Automated analysis indicated that glucose induced larger mitochondria and higher matrix density, and that GIP and GKA induced smaller and denser mitochondria, highlighting previously unreported {beta}-cell mitochondrial remodeling. MitoXRNet allows for scalable profiling of organelle-level morpho-biophysical data. HighlightsO_LIA data-efficient method for 3D segmentation of mitochondria and nucleus from Soft X-ray tomograms. C_LIO_LIIncorporates domain-specific Sobel filter-based preprocessing to improve segmentation accuracy and quality under imperfect or noisy labels. C_LIO_LIEnables rapid and automated analysis of mitochondrial morphology, facilitating quantitative assessment of pharmacological effects on cellular ultrastructure. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/682919v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@8600f6org.highwire.dtl.DTLVardef@1a9230eorg.highwire.dtl.DTLVardef@13c6f09org.highwire.dtl.DTLVardef@9dc9f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Decoding Rice Seed Storage Proteins: From Gene Identification to Structural Prediction

Rice seed storage proteins (SSPs) serve as the primary source of dietary protein, energy, and nutrition; however, our understanding of these proteins remains limited, hindering efforts aimed at enhancing grain nutritional quality. To address this, we conducted a comprehensive genome-wide analysis of rice SSPs, encompassing phylogenetic relationships, domain and motif characterization, promoter cis-element mapping, expression profiling, and 3D structural modeling. Through homology- and domain-based searches, we identified 65 SSP-encoding genes, including 19 previously uncharacterized members. Phylogenetic analysis and domain comparisons revealed evolutionary proximity between albumins and prolamins; and between globulins and glutelins. Albumins, glutelins and prolamins clustered tandemly implying that duplication has driven SSP expansion. Transcriptomic evidence indicated that albumins, globulins, and glutelins were transcriptionally active from S2 seed development stage, whereas prolamins initiated expression from S3 stage. Promoter analysis revealed several seed-specific cis-regulatory elements, with CAATBOX1, EBOXBNNAPA, and DOFCOREZM being the most prevalent. Structural modeling showed that albumins and prolamins predominantly adopted -helical conformations, whereas globulins and glutelins were enriched in {beta}-strands and coils. This integrated analysis offers valuable insights into the classification, evolution, regulation, and structure of rice SSPs, providing a foundational resource for advancing grain nutritional improvement strategies.

plant biology↗

bioRxiv2025

Tagging and harvesting of developing rice spikelets to demarcate grain developmental stages

PremiseIn rice, grain is the major sink for nutrient storage and is a rich source of carbohydrates, seed storage proteins, lipids, minerals, and vitamins, making it a principal food source for over half of the worlds population. Grain development in rice generally spans over a month and has been divided into five stages, S1-S5, depending upon various morphological and physiological changes occurring in the developing seed. To completely understand the process, rice grain development needs to be examined at each stage. However, there are no detailed protocols available to demarcate grain developmental stages. Methods and ResultsThis protocol describes how to tag and harvest the developing rice spikelets. The process starts with anthesis and continues till seed maturation, demarcating the five stages of rice grain development. Seeds are collected, labelled, and stored for use in molecular experiments. Using this protocol, we were able to identify and distinguish different seed developmental stages as observed by histochemical screening. ConclusionThis is an easy, efficient, and cost-effective method. This protocol ensures the collection of the entire panel of rice seed developmental stages. The stored tissue can later be used for various molecular biology based experiments.

plant biology↗

bioRxiv2025

Mapping Structural Aging across Human Tissues reveals tissue-specific trajectories, coordinated deterioration and genetic determinants

1.Tissue structure, the organization of cells, vasculature and extracellular matrix, underpins organ function. Yet how it deteriorates with age remains largely uncharacterized. Current aging research focuses primarily on molecular changes, missing this structural dimension. Here we present PathStAR (Pathology-based Structural Aging Rate), a computational framework that quantifies tissue structural aging from histopathology images without training on chronological age. Applying PathStAR to 25,306 postmortem biopsies spanning 40 tissue types from 970 individuals aged 21-70, we show that structural aging unfolds through non-linear phases rather than gradual decline. We identify three distinct temporal programs: early-aging tissues (vascular system, peaking in the 30s), late-aging tissues (uterus and vagina, peaking around menopause) and biphasic-aging tissues (digestive and male reproductive organs, with two acceleration periods). During accelerated phases, tissues exhibit common molecular signature of increased inflammation, decreased energy production, regeneration and quality control alongside tissue-specific pathway disruptions related to its function: Artery-specific decline of peroxisomal function, responsible for fatty acid breakdown and testis-specific decline of spermatogenesis. Cross-organ analysis reveals coordinated deterioration within individuals, not only within expected organ systems but also unexpectedly between digestive and reproductive tissues, traced to shared sex hormone signaling. This reveals a role for sex hormones in maintaining structural integrity of non-reproductive organs during aging. Genome-wide association analysis identifies 123 germline variants associated with organ-specific accelerated structural aging, including variants in the longevity regulator SIRT6 linked specifically to vascular structural decline. As proof of concept, PathStAR captures the established non-linear functional decline of the ovary, fertility loss in the 30s and menopause in the 50s, that bulk transcriptomic and methylation profiles from matched samples fail to detect. PathStAR provides a systematic map of structural aging across the human body: when tissues structure decline, what molecular programs define each phase, and how organs deteriorate in coordination.

bioinformatics↗

bioRxiv2025

PathQC: Determining Molecular and Physical Integrity of Tissues from Histopathological Slides

Quantifying tissue molecular and physical integrity is essential for biobank development. However, current assessment methods either involve destructive testing that depletes valuable biospecimens or rely on manual evaluations, which are not scalable and lead to interindividual variation. To overcome these challenges, we present PathQC, a deep learning framework that directly predicts the tissue RNA Integrity Number (RIN) and the extent of autolysis from hematoxylin and eosin (H&E)-stained whole-slide images of normal tissue biopsies. PathQC first extracts morphological features from the slide using a recently developed digital pathology foundation model (UNI), followed by a supervised model that learns to predict RNA Integrity Number and autolysis scores from these morphological features. PathQC is trained on and applied to the Genotype-Tissue Expression (GTEx) cohort, which comprises 25,306 non-diseased post-mortem samples across 29 tissues from 970 donors, where paired ground truth RIN and autolysis scores were available. Here, PathQC predicted RIN with an average correlation of 0.47 and an autolysis score of 0.45, with notably high performance in Adrenal Gland tissue (R=0.82) for RIN and in Colon tissue (R=0.83) for autolysis. We provide a pan-tissue model for the prediction of RIN and autolysis score for a new slide from any tissue type (GITHUB). Overall, PathQC will enable scalable measurement of molecular and physical integrity from routine H&E images, thereby enhancing the quality of both biobank generation and its retrospective analysis.

bioinformatics↗

bioRxiv2025

Mitochondrial Dysfunction and Senescence Accompany Glioblastoma Cell Death Triggered by a Putative Metabolic Inhibitor

Glioblastoma (GBM) is a fatal cancer with a dismal prognosis and a dire need for novel chemotherapeutics. Metabolic reprogramming is an established hallmark of cancer. In our previous study on GBM, we aimed at targeting the metabolic reprogramming of cancer by using stiripentol (STP), a putative lactate dehydrogenase (LDH) inhibitor and an FDA-approved anti-epileptic drug. However, the precise mechanism of STPs anti-cancer activity remains unclear. We aimed to elucidate the mechanism of action of STP in GBM to further develop STP as a therapeutic. We employed a multiomic approach followed by metabolic and cellular assays. STP treatment induced genetic and metabolic alterations in GBM cells. Inhibition of LDH by STP was moderate but not potent. The cellular changes were accompanied by an increase in reactive oxygen species, a decrease in mitochondrial membrane potential, and induction of senescence in GBM cells. Our research indicates that further research in senescence-inducing agents and novel LDH inhibitors can provide novel therapeutics for GBM.

pharmacology and toxicology↗

bioRxiv2025

Beta Desynchronization Mediates The Impact Of Internally Directed Attention In A Dual-Task Working Memory Paradigm

Internally directed attention (IDA), whether spontaneous or intentional, has been associated with impaired performance on externally directed cognitive tasks. Yet, the neurophysiological mechanisms underpinning this disruption remain poorly understood. In the present study, we characterized the neural correlates of IDA and identified how they impact on performance in a color-recall working memory task using electroencephalography (EEG). Participants performed a novel dual-task paradigm involving either self-referential (IDA) or perceptual processing of adjectives, involving externally directed attention (EDA) followed by a color-recall task. IDA enhanced late positive potentials (LPP) in EEG over medial-frontal electrodes as a marker of sustained affective and self-referential engagement. Time-frequency analyses further revealed increased event-related desynchronization in alpha and beta bands during stimulus encoding in the IDA condition, as well as increased alpha synchronization during the delay period, consistent with internal attention maintenance. To capture trial-level variability in task performance, we applied conditional quantile regression on the single trial data. Results showed that beta desynchronization in interaction with condition type during encoding influenced performance significantly in trials with low errors, whereas trials with high error in color recall were better explained by increased reaction times. These findings provide converging electrophysiological evidence for distinct neural signatures of internally directed attention and highlight their behavioral consequences in working memory performance.

neuroscience↗

bioRxiv2025

Ultrasound imaging of in situ transcriptional activity in opaque tissue

Ultrasound imaging and acoustic reporter genes provide unique capabilities for in vivo biological imaging by leveraging ultrasounds ability to visualize opaque tissues with high spatiotemporal resolution. But until now, the expression of acoustic reporter genes - based on gas vesicle (GV) proteins - has been limited to ex vivo-modified cells due to the complexity of the GV gene cluster, precluding valuable in situ applications. Here, we develop a system capable of introducing GV genes directly into native tissues via stoichiometric multi-AAV delivery. We validate this system in the mouse brain, demonstrating well-tolerated in situ gene expression and repeated ultrasound imaging over more than a month in the same animal. Furthermore, by placing GV genes under the control of immediate early gene promoters, we demonstrate the ability to track in vivo gene expression changes arising from elevated neural activity during epileptic seizures. This work connects ultrasound to in situ transcriptional dynamics happening inside the opaque tissues of living creatures.

bioengineering↗

bioRxiv2025

Increased Synapse Elimination by Inflammatory Cells Contributes to Long-lasting Post-Stroke Memory Dysfunction in Old Mice

Old patients are more likely to experience memory dysfunction than young patients after a stroke. It has been reported that brain astrocytes and microglia cause excessive removal of synapses at the acute and subacute stages of stroke, and inhibition of their phagocytosis improved neurobehavioral outcomes. We hypothesized that memory dysfunction in old subjects is associated with increased synapse removal by inflammatory cells. Ischemic stroke was induced in young (2-month-old) and old (15-18-month-old) mice. Memory functions were analyzed by the Y-maze test weekly for 8 weeks and the novel object recognition (NOR) test at 7 days before and 8 weeks post-stroke. We have also created a tibia fracture 6 hours before stroke injury in young mice, to test if the activation of 7-nicotinic acetylcholine receptor (nAchRs) reduces inflammatory cells and synapse elimination. Brains were collected 8 weeks after the induction of ischemic stroke. Transcriptome changes, neuronal injuries, neuroinflammation, synapse removal, and neurite outgrowth were analyzed. We found that old mice developed long-term memory dysfunction after ischemic stroke, which was not seen in young mice. Old mice showed larger infarct volume, higher neuroinflammation, and more synapses engulfed by microglia/macrophages and astrocytes in the peri-atrophic region and hippocampi than young mice. More synapse-engulfing astrocytes than microglia/macrophages were present in the peri-atrophic region and the ipsilateral hippocampi, suggesting that reactive astrocytes contributed more than activated microglia/macrophages in synapse removal. Activation of 7-nAchRs in mice subjected to tibia fracture 6 hours before ischemic injury reduced synapse removal by microglia/macrophages and astrocytes in the hippocampi. Our study indicated that an increase in synaptic elements by inflammatory cells contributes to the long-lasting memory deficit after stroke in old mice. Astrocytes may contribute more than microglia/macrophages in synapse removal. Inhibition of neuroinflammation by activating 7-nAchRs can reduce synapse loss and thus may improve post-stroke memory function.

neuroscience↗

bioRxiv2025

Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis

ObjectiveSkeletal muscle myogenesis, during development and regeneration, are primarily facilitated by the progeny of resident muscle stem cells, the muscle progenitor cells (MPCs). Intriguingly, extracellular glutamine (Gln) is required by MPCs. Disruptions in Gln availability or metabolism, impair MPC function and hinder skeletal muscle regeneration. Gln, a nutritionally non-essential amino acid (NEAA), which is most abundant in skeletal muscle, becomes conditionally essential during advancing age and catabolic states like sepsis, trauma, and strenuous situations. The intracellular mechanisms through which extracellular Gln availability affects MPC proliferation are poorly understood. Therefore, this study was aimed to examine how extracellular supply of Gln influences myogenesis through the spatial distribution of TCA-cycle enzymes. MethodsHuman primary muscle myoblasts (HSKM2) and murine MPCs (C2C12) were utilized for in-vitro experiments. To investigate the impact of Gln availability on MPC proliferation, proliferation assays, confocal imaging, succinyl-proteomics, and single-cell nuclei ATAC sequencing were used. ResultsGln (2 mM) significantly enhanced MPC viability and cell cycle progression, while Gln depletion (0 mM) reduced cell number and induced G0/G1 arrest. Gln deficiency downregulated MyoD expression, impairing myogenic potential. Inhibiting intracellular Gln metabolism also limited proliferation, indicating the necessity of Gln catabolism for cell proliferation. Gln deficiency increased nuclear localization of TCA cycle enzymes (DLST, OGDH), elevated histone succinylation, and restricted chromatin accessibility of the myogenic regulatory factor, MyoD1, highlighting a Gln dependent metabolic-epigenetic nexus in myogenic regulation. ConclusionThese findings demonstrate that extracellular Gln availability is a key regulator of myogenesis through its influence on metabolism, epigenetic modifications, and chromatin accessibility.

developmental biology↗

bioRxiv2025

Alleviation of Drought Stress and Plant Growth Promotion in Mungbean through Rhizospheric Actinobacteria

Drought is a major cause for decreasing in crop yield and agricultural productivity around the Globe. The application of drought tolerance Actinobacteria to agroecosystem improves the growth and protect from water scarcity and they can be better alternative for natural farming and sustainable agriculture for aride and semi-aride regions. Herein, we isolated ten morphologically different actinobacteria from the rhizospheric soil of Datura and Khejri plants which are surviving in the nature without any special treatment provided. All the isolated bacteria were screened in-vitro for their drought tolerance capability for different time intervals against polyethylene glycol 8000 (PEG8000) with 5%, 10% and 10% concentration to media which produce moisture stress in which medium bacteria were growing. Among them best five bacterial isolates were selected and named RADM1 to RADM5 for further experimentation. Physiological characterizations were done through their ability to grow in different temperature, pH ranges and NaCl concentration supplemented with the 5% PEG8000. Morphology of the bacteria was Grams positive and mycelium producing same as typical Actinobacterial species and for biochemical diversity stains were able to IMVIC test and carbohydrate utilization through IMVIC test. Enzymatic observations of isolates were resulted positive for nitrate reduction, catalase production and negative for starch hydrolysis. PCR amplification and 16S rRNA gene sequencing in BlastN found maximum similarity of three species with Streptomyces clavuligerus and two species with Rhodococcus erythropolis and submitted to NCBI gene bank database with accession number PQ114139 (RADM1), PQ120343 (RADM2), PQ114109 (RADM3), PQ120390 (RADM4), PQ039766 (RADM5). In pot trial of mungbean, all the isolates showed better performance in bacterial treatments with an average increase in physiological parameters like, seedlings shoot length (52.70% and 9.62%), root length (35.63% and 17.25%), fresh weight (42.8% and 13.76%) dry weight (45.25% and 21.24%) in compared to uninoculated induced drought and watered treatments. Stress features of seedlings revealed significant increase in proline and chlorophyll contents whereas decrease in MDA contents than the untreated plants which indicates actinobacteria reduced water scarcity and damage of plant membrane. IMPORTANCERhizosphere of plant contains diversity of microbes with different abilities to support the plant growth. The role of plant growth promoting bacteria in soil presented and their association with plant can be the one reason for survive of the plant against the abiotic stress conditions like drought, salinity, temperature or pH. The actinobacteria found in the rhizosphere have evolved multiple strategies to assist plants in managing the adverse effects of drought. These strategies may include alterations in phytohormones, which play a vital role in enabling plants to withstand environmental stresses, modifications to root structures, accumulation of osmolytes, enhancements in the plants antioxidant defense mechanisms, synthesis of exopolysaccharides, and the identification of particular genes that support plant growth and improve drought resilience. These actinobacteria as bioinoculant can be the better alternative for the chemical fertilizers use and protect from the water scarcity.

microbiology↗

bioRxiv2025

Cell type-specific associations with Alzheimer's Disease conserved across racial and ethnic groups

Genomic studies at single-cell resolution have implicated multiple cell types associated with clinical and pathological traits in Alzheimers Disease (AD), but have not examined common features across broad, multi-ethnic populations, and across multiple regions. To bridge this gap, we performed single-nucleus RNA-seq and ATAC-seq profiling of cortical and subcortical brain regions from post-mortem samples across Non-Latin White, African American, and Latin donors (the latter of any race). Using discrete and continuous dissection of molecular programs, we elucidate cell-type-specific glial and neuronal signatures associated with AD across multiple population groups. Notably, we found that multiple microglial (GPNMB+, CD74+, and CR1+ subgroups) and astrocyte (SERPINH1+ and WIF1+ subgroups) signatures are associated with worse clinical and pathological phenotypes across all three population groups. We also report continuous gene expression factors in oligodendrocytes that are not captured by discrete clusters, yet still show strong associations with disease phenotypes. Finally, we observe these discrete cellular identities and continuous gene programs separate cognitively impaired donors into 6 molecularly distinct subgroups that span racial and ethnic population groups. Overall, our study identifies key cell types and gene programs implicated in AD that are shared across population groups, and provides an initial data set that underscores how representative sampling can capture conserved signatures as well as disease heterogeneity, leading to better prioritization of key cell types for further investigation.

neuroscience↗

bioRxiv2025

Ontogeny of the spinal cord dorsal horn

The dorsal horn of the mammalian spinal cord is an exquisite example of form serving function. It is comprised of diverse neuronal populations stacked into laminae, each of which receives different circuit connections and plays specialized roles in behavior. An outstanding question is how this organization emerges during development from an apparently homogeneous pool of neural progenitors. Here, we found that dorsal neurons are diversified by time, with families of related cell types born as temporal cohorts, and by a spatial-molecular gradient that specifies the full array of individual cell types. Excitatory dorsal neurons then settle in a chronotopic arrangement that transforms their progressive birthdates into anatomical order. This establishes the dorsal horn laminae, as these neurons are also required for spatial organization of inhibitory neurons and sensory axons. This work reveals essential ontogenetic principles that shape dorsal progenitors into the diverse cell types and architecture that subserve sensorimotor behavior. Highlights- Temporal cohorts of late-born dorsal neurons give rise to neuronal families - Sequentially-born excitatory neuron families form adjacent laminae - Laminar structure specifically requires excitatory (but not inhibitory or sensory) neurons - Graded expression of Zic transcription factors directs fine neuronal identity

neuroscience↗

bioRxiv2025

Priming of retrograde signaling in wheat across multiple natural environments reveal how responses to dynamic stimuli can be integrated to alter yield, yield stability and water productivity

O_LIChloroplast-to-nucleus retrograde signaling enables rapid stress responses in plants, but whether these signals accumulate to affect crop performance across entire growing seasons under field conditions remains unknown. C_LIO_LIWe generated wheat mutants with targeted deletions in specific SAL gene copies from two distinct homeologous groups (TaSAL1 and TaSAL2), creating lines with enhanced stress signal responsiveness. We tested these lines across 15 field trials spanning diverse Australian environments with varying temperatures, rainfall, and irrigation regimes, measuring physiological responses, yield, biomass, and water productivity. C_LIO_LILines with TaSAL2 gene deletions showed 4-8% yield improvements with enhanced water productivity, while TaSAL1 deletions reduced yields. The TaSAL2 mutants maintained superior photosynthetic function under drought stress, showed improved relative water content, and demonstrated enhanced yield stability across environments. Canopy temperature measurements revealed dynamic stomatal regulation, with increased closure during midday stress periods but normal aperture under benign conditions. Significantly, specific SAL modifications enhanced photosynthetic efficiency and stress resilience without traditional yield penalties. C_LIO_LITargeted modification of specific SAL homeologous groups can simultaneously improve both yield and stress tolerance in wheat. This demonstrates that retrograde signaling integrates environmental information across the plant lifecycle, and highlights the importance of locus-specific targeting and multi-environment field validation for crop modifications. C_LI

plant biology↗

bioRxiv2025

TLPath predicts telomere length in human tissues from histopathology images

Telomere dysfunction is a key hallmark of aging linked to numerous age-related diseases including cardiovascular disorders, pulmonary fibrosis, and metabolic syndromes. Despite decades of research yielding strong evidence linking telomere biology to aging processes, the field faces a critical bottleneck: current telomere measurement methods require specialized molecular techniques that prevent large-scale studies and clinical implementation. Here we present TLPath, a novel deep learning framework that extracts normal tissue architecture from routine histopathology (H&E) images to predict bulk-tissue telomere length. Trained on the Genotype-Tissue Expression cohort comprising >7.3 million patch images from >5,000 whole-slide images across 919 individuals, TLPath makes a remarkable discovery: the extracted morphological features spontaneously separate young, middle-aged, and elderly individuals within most tissue types-- demonstrating for the first time that aging causes substantial architectural changes in tissues detectable without explicit age supervision. These extracted features can predict bulk-telomere length with significant accuracy (>0.51 in well-represented tissues), outperforming chronological age as a predictor (correlation = 0.20) and identifying age-discordant cases - detecting both accelerated telomeres shortening in young individuals and preserved telomeres in older individuals. Mechanistic interpretation reveals that TLPath leverages established senescence morphological markers, including nuclear-to-cytoplasmic ratio and nuclear shape variation, for its predictions. We applied TLPath in [~]2,800 new GTEx biopsies where concordant with known association, the predicted telomere length is shorter across most tissues from individuals with Type 1/2 diabetes. Overall, we demonstrate that aging substantially alters tissue morphology, which TLPath captures and uses to predict telomere length, enabling large-scale telomere biology studies using existing tissue archives.

bioinformatics↗

bioRxiv2025

Regulation of lipid dysmetabolism and neuroinflammation linked with Alzheimer's disease through modulation of Dgat2

Alzheimers disease (AD), an age-associated neurodegenerative disorder, is characterized by progressive cognitive decline, amyloid-{beta} (A{beta}) deposition, lipid dysregulation, and neuroinflammation. Although mutations in the amyloid precursor protein (APP) and accumulation of A{beta}42 are established drivers of pathology, the mechanisms connecting amyloid toxicity with lipid metabolism and inflammatory responses remain poorly understood. Here, we employed complementary Drosophila and mouse models to dissect these relationships. Expression of AppNLG and A{beta}42 in Drosophila resulted in locomotor deficits, disrupted sleep-circadian rhythms, memory impairments, lipid accumulation, synaptic loss, and neuroinflammatory signatures. Comparable lipid metabolic disturbances and inflammatory alterations were detected in the AppNLG-F knock-in mouse model, underscoring their conserved relevance to AD pathogenesis. We further identified diacylglycerol O-acyltransferase 2 (Dgat2), a key enzyme catalyzing the final step of triglyceride synthesis, as a critical modulator of AD-related phenotypes. Dgat2 expression was altered in both animal models and human AD tissues. Notably, panneuronal knockdown of Dgat2 in Drosophila attenuated lipid accumulation, restored synaptic integrity, and ameliorated locomotor and cognitive deficits, while also reducing neuroinflammation. Dgat2 suppression additionally improved sleep and circadian behavior, highlighting its pleiotropic protective effects. Together, these findings demonstrate a mechanistic link between amyloid pathology, lipid dysregulation, and neuroinflammatory processes. Targeting Dgat2 may therefore represent a novel therapeutic strategy to counteract AD-associated metabolic and neuronal dysfunction. The conservation of lipid homeostasis mechanisms across species underscores the translational potential of this approach for delaying or mitigating AD progression.

physiology↗