Biology subjects

Yadav, N.

Publications and source records attributed to Yadav, N..

At least 19 recordsLinked to original sources

bioRxiv2026

Adenosylhomocysteinase drives epigenetic and metabolic reprogramming in ZFTA-RELA ependymoma

Supratentorial ependymomas (ST-EPNs) are aggressive pediatric brain tumors predominantly driven by the recurrent ZFTA-RELA fusion, an oncogenic chromatin regulator that establishes an aberrant transcriptional program. Although metabolic pathways modulate epigenetic regulation by controlling the availability of metabolic cofactors, how ZFTA-RELA coordinates metabolic reprogramming with epigenetic regulation is not well understood. Here, we show that ZFTA-RELA-positive ependymomas exhibit enhanced methionine dependency, elevated adenosyl homocysteinase (AHCY) expression, and epigenetically control aspartate metabolism for tumor growth. Mechanistically, ZFTA-RELA upregulates AHCY, increasing cellular methylation potential which promotes H3K4me3-dependent expression of CAD, the first enzyme complex of de novo pyrimidine biosynthesis, while simultaneously enforcing H3K27me3 mediated repression of ASNS, which encodes asparagine synthetase. Through this coordinated epigenetic program, aspartate utilization is directed toward pyrimidine biosynthesis while endogenous asparagine production is limited. Restricting S-adenosylmethionine availability or genetically or pharmacologically inhibiting AHCY reverses these epigenetic states, leading to CAD downregulation, ASNS upregulation, impaired nucleotide synthesis, and suppression of tumor growth in vitro and in vivo. Similarly, EZH2 inhibition also restores ASNS expression and suppresses tumor proliferation. These findings suggest that ZFTA-RELA EPN maintain ASNS-low phenotype which conditionally make them dependent on extracellular asparagine. We further show that enhanced de novo pyrimidine synthesis not only supports nucleotide production but also provides UDP-sugars required for N-glycosylation and stabilization of the asparagine transporter SLC1A5, thereby promoting extracellular asparagine uptake and tumor proliferation. Collectively, our findings identify AHCY as a critical metabolic regulator of epigenetic and metabolic reprogramming that drives pyrimidine synthesis and establishes extracellular asparagine dependency, revealing actionable metabolic vulnerabilities in ZFTA-RELA-positive ST-EPNs.

cancer biology↗

bioRxiv2026

FANCM restrains structural genome evolution and defines a synthetic lethal dependency in BRCA1-deficient breast cancer

BRCA1 deficient cancers experience persistent replication stress and structural genome instability yet retain the capacity for sustained proliferation, implying reliance on compensatory genome-maintenance mechanisms. Here, we establish BRCA1/FANCM synthetic lethality in human BRCA1 deficient breast cancer and exploit temporally controlled FANCM depletion to capture genome evolution over successive cell divisions before declining cellular fitness becomes limiting. We show that FANCM restrains genome wide structural variation in BRCA1 deficient breast cancer cells under endogenous replication stress. FANCM loss amplifies the characteristic BRCA1 associated short tandem duplication (TD) phenotype while permitting larger, including megabase-scale, TDs and diverse rearrangements to emerge. Newly emerged TDs preferentially associate with Pol II occupied regions, and FANCM depletion increases proximity between the replication machinery and elongating RNAPII in BRCA1 mutant breast cancer cells, linking FANCM-mediated genome protection to transcription replication encounters. BRCA1 altered human tumors with low FANCM expression recapitulate key features of this phenotype, while genome/transcriptome integration links newly emerged SVs to configuration dependent local transcriptional changes. Together, these findings establish FANCM as a replication stress safeguard coupling survival to restraint of structural genome evolution.

cancer biology↗

bioRxiv2026

Confluent growth state dependent transcriptomic adaptation in A549 lung cancer cells

Cell confluency is a major determinant of cell-cell communication, protein interactions, access to nutrients, and signalling dynamics, thereby significantly impacting biological outcomes. Lung cancer cells like A549 are widely used as screening models for scientific studies wherein their growth in vitro progress from non-confluent to confluent growth. In this study, we investigated the transcriptomic adaptations associated with the transition of A549 cells from baseline non-confluent to confluent growth. Comparative transcriptomic analysis between confluent and cells at baseline identified 815 upregulated and 671 downregulated transcripts. Pathway enrichment analysis of deregulated transcripts in confluent cells revealed enhanced cholesterol and sterol biosynthetic pathways, along with suppression of chromosomal segregation and mitotic pathways. At confluency, an increased expression of glucose transporters (SLC2, SLC60, and SL37 families) and glycolytic pathways, and a decrease in amino acid transporters (SLC1, SLC7, SLC38, and SLC36) and amino acid metabolic pathways is observed. A reduced one-carbon metabolic signature (SHMT2, DHFR, and MTHFD2) and enhanced fatty acid precursor synthesis (HMGCLL1, ALDH6A1, and AASS) were also observed at confluency. 1H NMR profiling of culture media revealed higher glucose and glutamine utilisation with lactate accumulation during culture maturation. Collectively, the data suggest transcriptome-level rewiring in A549 cells with preferential biosynthesis of lipids and sterols at confluency and underscore the importance of considering culture maturity in cancer biology, metabolism, and therapeutic studies.

systems biology↗

bioRxiv2026

Development of the First Cytochrome Oxidase I Barcode and Evidence for a Single Haplotype Associated with the Recent United States Invasion of the Pasture Mealybug Heliococcus summervillei (Pseudococcidae, Hemiptera)

Heliococcus summervillei is an emerging invasive mealybug that causes severe dieback in grasses in pastures and turfgrass landscapes. It is widespread in Australia and has recently been detected across the Caribbean, Mexico, and the United States. Accurate identification of mealybugs is challenging due to cryptic morphology, overlapping diagnostic characters, and limited taxonomic expertise and literature, which makes molecular tools essential for regulatory diagnostics and management. We developed the first Cytochrome Oxidase I (COI) barcode for H. summervillei and used it to examine mitochondrial variation across available populations. COI sequences reveal approximately a 10.2% mitochondrial split between the Type A and Type B variants. Phylogenetic, haplotype network, and genetic distance analyses show that all invasive range populations share one haplotype associated with a recent invasion in the United States, Australia, Pakistan, and the Caribbean, whereas the Barbados lineage contains two closely related haplotypes that represent a historically stable mitochondrial variant. Together, these results establish the first COI reference library for H. summervillei, clarify mitochondrial lineage structure, and provide a practical barcode tool that enables rapid identification of invasive populations and supports timely regulatory and pest management responses. Recognizing mitochondrial variants also establishes a framework for resolving lineage-specific biological and management traits and strengthens reconstruction of introduction pathways central to regulatory decision-making and limiting further spread.

genetics↗

bioRxiv2026

Structural insights into the inhibition of sickle hemoglobin polymerization by asymmetric hemoglobin tetramer HbFS (α2γβS)

Sickle cell disease (SCD) is caused by a single amino acid substitution in the {beta}S globin chain at 6th position (6E[->]V). This results in polymerization of deoxy state of sickle hemoglobin (HbS), followed by its precipitation and subsequent sickling of erythrocytes. These deformed cells can block small capillaries (vaso-occlusion), causing cardiovascular complications, ultimately leading to ischemia-reperfusion injury, severe oxygen deficiency, and progressive systemic damage. Occasionally, patients with SCD have been observed to produce exorbitantly high levels of fetal hemoglobin (HbF), which has been linked with the inhibition of HbS polymerization. One of the effects of hydroxyurea, the most commonly used therapeutic for SCD, is to elevate HbF levels. However, the mechanism of inhibitory role of HbF on HbS polymerization is largely unknown. This study attempts to gain insights into the mechanisms involved in this process by means of native mass spectrometry, ion mobility mass spectrometry, and hydrogen deuterium exchange-based mass spectrometry (H/DX-MS). The conformational flexibility of asymmetric hemoglobin, HbFS (2{gamma}{beta}S), for the observed regions in the tetrameric molecule appears to be more in the deoxy state as compared to the oxy state, eventually leading to reduced polymerization of sickle hemoglobin in patients with SCD that express elevated HbF levels.

biochemistry↗

bioRxiv2026

Comprehensive Analysis Reveals Adaptive DNA Repair and Replication Stress Networks in Genomically Unstable Breast Cancer

Genomic instability is a defining hallmark of breast cancer, yet the mechanisms by which tumors tolerate persistent DNA damage remain poorly understood. We performed a comprehensive, multi-cohort analysis of breast cancer datasets to define how DNA damage response (DDR) and replication stress tolerance (RST) networks are rewired in genomically unstable tumors. Using fraction of genome altered (FGA) as a chromosomal instability metric, we show that BRCA-mutant tumors exhibit elevated genomic instability coupled with increased expression of homologous recombination, Fanconi anemia, mismatch repair, base excision repair, and alternative end-joining pathways. Strikingly, heightened pathway activity correlates with increased genome alteration, supporting a model of damage tolerance rather than repair restoration. RST programs, including fork remodeling, protection, and single strand DNA gap suppression, further contribute to tumor fitness under replication stress. These adaptive states are enriched in aggressive subtypes, intensified with progression, and associate with pathway-specific mutational burden. Co-occurrence and mutual exclusivity mapping uncovered non-random subtype-relevant genetic interactions states among major drivers and DDR genes, nominating context-specific synthetic lethal opportunities. Our findings identify compensatory genome-maintenance programs as central drivers of tumor resilience and highlight pathway-specific vulnerabilities for targeted therapeutic intervention.

cancer biology↗

bioRxiv2026

Saliva Metabolomics Reveals Distinct Metabolic Signatures in Patients with Chronic Obstructive Pulmonary Disease: A GC-MS-based approach.

Chronic obstructive pulmonary disease (COPD), a chronic lung disease, involves complex metabolic disturbances that remain poorly characterized using non-invasive matrices. The metabolic alterations associated with cigarette smoke (CS), one of the major drivers of disease progression in COPD patients, have not been explored in detail. This study primarily aimed to investigate the metabolic signatures in COPD patients categorized into smoker (n=15), ex-smoker (n=11), and non-smoker (n=3) subgroups. Utilizing saliva as a noninvasive sample, we identified 26 metabolites with differential expression in smokers and 31 in ex-smokers. However, no such significant alteration was observed in the non-smokers subgroup. The multivariate analysis distinctly separated the COPD subgroups from healthy controls. Additionally, pathway enrichment analysis revealed perturbations in key metabolic pathways, including unsaturated fatty acid biosynthesis, arginine biosynthesis, the tricarboxylic acid (TCA) cycle, and pyruvate metabolism. Moreover, univariate Random forest analysis identified four metabolites (cyclopentanone, tetradecane 4-methyl, acetophenone, and scyllo-inositol) as potential biomarkers distinguishing COPD subgroups from healthy controls. This study offers novel molecular insights into the association of smoking with disease progression and provides a mechanistic understanding of COPD in different subgroups for better management of the disease. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/717654v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1c3be84org.highwire.dtl.DTLVardef@10ce0aorg.highwire.dtl.DTLVardef@1470712org.highwire.dtl.DTLVardef@2163b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Early Blood Metabolome Remodeling Reveals Metabolic Signatures of Hypoxic-Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy (HIE) is a neonatal brain injury in which a definitive diagnosis within the first 6 hours of life is essential for initiating therapeutic hypothermia and improving neurological outcomes. However, early clinical evaluation and currently available biomarkers lack quantitative specificity during this narrow therapeutic window. We are providing insights into how rapid disturbances in systemic metabolites that regulate cerebral energy metabolism, neurotransmitter cycling, redox balance, and membrane integrity generate a definitive biochemical signature of HIE immediately after birth. We performed quantitative blood-based 1H NMR metabolomics on collected blood samples within [~]1 hour of birth from 81 neonates (HIE, n = 42; non-HIE, n = 39), under optimized handling conditions to preserve metabolic integrity. Metabolite analysis revealed a distinct HIE-associated profile characterized by elevated lactate, alanine, succinate, glutamate, taurine, glycine, choline, and pyroglutamate, alongside significant depletion of glucose and glutamine compared with non-HIE controls (p < 0.05). These coordinated metabolic shifts reflect impaired mitochondrial respiration, enhanced anaerobic glycolysis, excitotoxic amino acid accumulation, altered membrane phospholipid turnover, and oxidative stress. Multivariate analysis demonstrated clear separation between groups (PLS-DA accuracy = 0.83, R{superscript 2}Y = 0.46, Q{superscript 2} = 0.82), with glutamine, lactate, glutamate, and pyroglutamate as key discriminators. Pathway enrichment highlighted perturbations in glycolysis, the glucose-alanine cycle, glutamate-glutamine metabolism, Warburg effect like metabolic reprogramming, and redox homeostasis. Integration into supervised machine-learning models (Random Forest, XGBoost, SVM, KNN) achieved strong diagnostic performance (AUC = 0.97 {+/-} 0.03; sensitivity {approx} 87%). Collectively, this minimally invasive NMR-to-machine-learning framework enables early, mechanistically grounded risk stratification of neonatal HIE within the therapeutic window.

neuroscience↗

bioRxiv2025

Global phylogeography of Amrasca biguttula (Hemiptera: Cicadellidae) across eight countries reveals a single-haplotype incursion into the United States beyond its putative native range

Amrasca biguttula is a pest of cotton, ornamentals, and vegetables, and is invading the southeastern United States. We addressed five questions: (1) Are US populations genetically identical to those in the putative native range? (2) Does the southeastern US outbreak extend the recent Puerto Rico and Florida invasion or represent separate introductions? (3) Does the lineage infesting ornamentals match that on other crops? (4) What is the mitochondrial cytochrome oxidase subunit 1 (mtCOI) diversity of A. biguttula? (5) Which regions constitute its native versus invaded range? Adults were collected from Florida, Georgia, South Carolina, Texas, and Puerto Rico. Species identity was confirmed morphologically and by sequencing mtCOI, where possible, from five individuals per site, yielding consensus haplotypes. We analyzed 11 US, 20 Puerto Rican, and 342 sequences originating from publicly available databases (n = 373). Phylogenetic analysis confirmed monophyly of this species. A haplotype network recovered 70 unique haplotypes, including a star-like core of 68 radiating from Hap01 and two divergent singletons. The mainland US and Chinese populations were fixed for Hap01, indicating recent introductions. Puerto Rico exhibited Hap01, Hap52, and Hap70, reflecting multiple introductions, but could also result from haplotype diversity carried within a single introduction involving many individuals. Furthermore, southeastern US sites were fixed for Hap01, indicating extension from Puerto Rico and Florida. No haplotype was host-specific, confirming a lineage across crops. Diversity metrics indicate recent expansion in Iraq, Hong Kong, and Puerto Rico. South Asia, particularly Bangladesh, India, and Pakistan, showed the highest haplotype diversity, supporting its role as the putative native range. In contrast, low diversity in China and the US is consistent with recent invasion. Curation yielded 373 high-quality sequences, providing a unified database to support quarantine and management strategies.

genetics↗

bioRxiv2025

Methionine metabolism shapes immune response against Mycobacterium tuberculosis

The methionine metabolism is central to epigenetic reprogramming to produce pro-inflammatory cytokines. Disruptions in methionine metabolism contribute to complex disorders, providing an important target for nutrient interventions. Here, Mycobacterium tuberculosis (Mtb) H37Rv-infected C57BL/6 mice showed functional heterogeneity between alveolar and non-alveolar macrophage (AMs/Non-AMs) with major metabolic reprogramming in Non-AMs. Global metabolite and proteome analysis of Mtb-infected bone marrow-derived macrophages (BMDMs) showed a diversion of flux from methionine metabolism toward increased nucleotide salvage and glutathione (GSH) production. Carbon units of 13C5-methionine via isotopomer analysis contributed to polyamine synthesis, fuelling the nucleotide salvage node in Mtb-infected BMDMs. Methionine supplementation increased mycobacterial clearance in C57BL/6 mice and in BMDMs by promoting a pro-inflammatory response, as evident by increased IL-1{beta} and IFN-{gamma}. Increased IL-1{beta} production is mainly contributed to by increased H3K4 trimethylation in macrophages. These findings reveal an important strategy by which methionine supplementation in macrophages and mice remodels host metabolism to enhance acute pro-inflammatory responses and exploit dietary supplementation to improve nutritional immunity in TB. HighlightsO_LIMycobacterium tuberculosis (Mtb) infection decreases intracellular methionine levels and increases purine levels in primary macrophages. C_LIO_LIMethionine carbon units contribute to nucleotide salvage, and their restriction lowers IL-1 response and mycobacterial clearance. C_LIO_LIEx vivo methionine supplementation in Mtb-infected macrophages increases H3K4me3 at the Il-1b gene promoter and gene body, leading to an increased pro-inflammatory response and improved mycobacterial clearance. C_LIO_LIIn vivo methionine supplementation improved pro-inflammatory response in lungs, spleen and bone marrow, leading to accelerated mycobacterial clearance upon Mtb-H37Rv infection. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/680834v2_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1bf5corg.highwire.dtl.DTLVardef@ba4dbdorg.highwire.dtl.DTLVardef@145f23dorg.highwire.dtl.DTLVardef@122b2a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Tiger diet in Ranthambore Tiger Reserve: how do metabarcoding and mechanical sorting compare?

Accurately describing large carnivore diets is critical for understanding trophic interactions and identifying targeted conservation strategies. Most studies have relied on traditional dietary analysis based on mechanical sorting and identification of undigested prey remains, a method known to be error-prone and ecologically biased. Here, we compare the diet of tigers using non-invasively collected scats from Ranthambore Tiger Reserve in India, analysed using mechanical sorting and DNA metabarcoding. We found that DNA metabarcoding outperformed mechanical sorting in detecting higher overall prey and rare prey species occurrences, uncovering higher prey diversity. The study revealed that tigers were subsisting mainly on wild prey such as sambar and chital. However, domestic cattle contributed the highest relative prey biomass to their diet. Our findings demonstrate that DNA metabarcoding is an efficient, effective and powerful approach that overcomes several of the previously identified biases of the mechanical sorting approach and provides an accessible and particularly useful tool for carnivore dietary studies based on non-invasive samples. The increased frequency of livestock depredation relative to previous studies highlights the need for active mitigation measures to secure this population.

ecology↗

bioRxiv2025

Whom Do We Prefer to Learn From in Observational Reinforcement Learning?

Learning by observing others experiences is a hallmark of human intelligence. While the neurocomputational mechanisms underlying observational learning are well understood, less is known about whom people prefer to learn from in the context of observational learning. One hypothesis posits that learners prefer individuals who exhibit a high degree of decision noise (randomness in action selection), free riding on the costly exploration of others. An alternative hypothesis suggests that learners prefer individuals with low decision noise, and imitate consistent and reliable behavior. In a preregistered experiment, we found that most participants preferred to learn from low-noise individuals. Furthermore, exploratory analyses revealed that participants who preferred lownoise individuals tended to rely on imitation of others actions, whereas those who preferred high-noise individuals relied more on learning from others reward outcomes. These findings offer a potential computational account of how learning styles shape partner selection in social learning. Author SummaryIn our daily lives, we often learn by watching others. For example, when starting a new job, we might watch an experienced colleague to learn effective strategies, or an inexperienced coworker to avoid common mistakes. While previous studies have examined how people learn by observing others, less is known about how we decide whom to observe. This study explored whether people prefer to learn from individuals who make consistent choices or those who behave more randomly. At first glance, the answer seems obvious: we would naturally prefer to learn from those who make consistent, reliable decisions. However, there can also be value in learning from someone who behaves unpredictably. For example, when searching for a good restaurant, observing an adventurous friend who tries unfamiliar places might help us discover hidden gems. Despite this potential advantage, we found that most participants preferred consistent decision-makers. Further analysis revealed that participants who favored reliable partners tended to imitate their actions, while those who chose more exploratory partners focused more on outcomes. Our findings suggest that personal learning styles shape partner preferences. These insights could help us understand how people choose whom to learn from in everyday settings like classrooms, or workplaces.

animal behavior and cognition↗

bioRxiv2025

Pre-exposure to time-restricted feeding reduces tissue CD4+ T cells with limited effect on Mycobacterium tuberculosis clearance

Time-restricted feeding (TRF) in human and animal models positively impacts metabolic health by improving glucose homeostasis and reducing adiposity. However, limited studies have investigated the impact of TRF on the host immune response and upon bacterial infection. In this study, C57BL/6 mice (6-8 weeks old, male) were subjected to 8 hours of dark-phase TRF for 30 days, and aerosol infected with a low dose (100-400 colony-forming units) of Mycobacterium tuberculosis (Mtb) H37Rv. The body weight gain, multi-tissue metabolome, and proteome changes and distribution of immune cells in these study groups were monitored. In the first 15 days of TRF, mice showed better glucose tolerance with marginal weight loss. The serum and liver metabolome of TRF mice demonstrated perturbed fatty acid biosynthesis and degradation, steroid hormone biosynthesis pathways and tyrosine metabolism. Liver proteome data of TRF mice indicated an increased fatty acid oxidation which might affect the host immune cell frequency and functionality. The Mtb-infected TRF and control mice had similar tissue (lung, spleen and liver) bacterial burden at 21 days post-infection. The bone marrow of Mtb-infected TRF mice had significantly lower CD3+ T cells, and CD4+ T cells were low both in the bone marrow and lungs. This study reports that mice undergoing 8 hours of TRF had an improved metabolic phenotype, and discontinuing TRF limits its positive impact on handling Mtb infection at an early point.

immunology↗

bioRxiv2025

Inflammasome activation dictates the efficacy of antimycobacterial activity of frontline TB drugs

Recent developments in TB treatment have identified an enormous potential of host targeting entities (host directed therapies-HDT) in achieving better and faster control of infection. We have previously demonstrated the synergistic effect of sertraline with frontline TB drugs in clearing infection in murine tissues. We surmised that understanding the mechanism of sertraline mediated enhancement of antibiotic efficacy would help identify novel pathways of pathogen control. Here, we have used sertraline as a probe to identify host signaling pathways that are important for bacterial control. We identify a role for sertraline mediated modulation of macrophage mitochondrial physiology in this process. We show that the resultant ROS generated in cells acts as the secondary signal for host cell inflammasome activation catalyzing the greater release of IL1beta; and significant efflux of K+ from the SRT treated macrophages. We thus highlight an important relationship between mitochondrial physiology in regulating the activation of the inflammasome to achieve better control of Mtb by infected macrophages.

microbiology↗

bioRxiv2025

Macrophages of diabetes and tuberculosis co-morbid conditions show perturbed differentiation and metabolic signatures

Diabetes negatively impacts the host immune system, leading to allergies, recurring infections, and lameness. Its impact on the distribution and molecular phenotypes of the bone marrow-derived macrophages (BMDMs) needs attention and, more importantly, in co-morbid conditions like diabetes and tuberculosis (DM-TB). In this study, total bone marrow cells were harvested at 3 w.p.i., from the low aerosol dose (100-120 CFU) of Mycobacterium tuberculosis H37Rv infected control and NA-STZ induced diabetic C57BL/6 mice. The bone marrow cells were differentiated into BMDMs, and CD11c, CD11b and F4/80 marker expressions were monitored using flow cytometry. BMDMs stimulated with Mtb H37Rv lysate were subjected to global transcriptome profiling to identify the perturbed metabolic and molecular landscape. The BMDMs of the DM-TB comorbid mice showed low CD11c, CD11b and higher F4/80 expression. The macrophages of the DM group showed a skewed pro-inflammatory response, characterized by perturbed complement response, NF-kB pathway and fatty acid metabolism, whereas macrophages of the DM-TB group showed deregulated ceramide and amino acid metabolism. Macrophages from the DM and DM-TB group stimulated with Mtb H37Rv lysate, showed a deregulated transcript signature that impacts humoral response. The dampened immune response observed in the DM-TB group macrophages highlights the importance of identifying novel targets for developing tailored drugs for comorbid conditions.

immunology↗

bioRxiv2025

VDR-calcium axis regulates the diet-driven metabolic shift during weaning

Weaning in mammals is associated with a shift in the metabolism, driven by the differences in the macronutrient composition of milk and post-weaning diet. Milk has a higher fat content compared with the carbohydrate-enriched solid food. Malnutrition during this stage could affect this transition with long-term adverse effects. The role of micronutrients during this transition is not well understood. Mice lacking a functional vitamin D receptor (VDR) progressively develop severe skeletal muscle and adipose atrophy after weaning, suggesting a role for vitamin D signaling in the metabolic transition during weaning. Here, we demonstrate that after weaning, VDR knock-out mice exhibit systemic energy deprivation and higher lipolysis in inguinal white adipose tissue, probably due to increased norepinephrine signaling via protein kinase A (PKA) and extracellular signalling-regulated kinase (ERK) pathways. Energy deprivation in vdr-/- mice is associated with defective liver glycogenolysis, characterized by increased expression of protein phosphatase-1 and decreased phosphorylation of glycogen phosphorylase. However, restoration of serum calcium levels by a rescue diet is sufficient to restore energy metabolism in vdr-/- mice. Interestingly, maintaining a high-fat-containing milk-based diet post-weaning could prevent the onset of energy deprivation, liver glycogen storage defect, and adipose atrophy in these mice without restoring serum calcium levels. Our data show that the vitamin D-calcium axis is essential for the adaptation of mice to the dietary shift from high-fat-containing milk to post-weaning carbohydrate-enriched diets. It also reveals a novel macronutrient-micronutrient interaction that shapes the metabolic flexibility of the individual based on the dietary composition of nutrients.

physiology↗

bioRxiv2024

Effect of p-benzoquinone, a cigarette smoke-derived component, on the architecture and function of human RBC

p-benzoquinone (pBQ), a cigarette smoke-derived component, stands as one of the lethal oxidants of cigarette smoke. Health hazards caused by cigarette smoking are a profound global health concern. It has been reported to contribute significantly to several health disorders, such as lung cancer, chronic obstructive pulmonary disease (COPD), cardiovascular diseases, etc. These adverse health effects might be attributed to the complex mixture of approximately 4,000 chemicals present in cigarette smoke, such as nicotine, tar, nitric oxide, and p-benzosemiquinone (pBSQ). pBSQ, ranging from 100-200 {micro}g per cigarette, gets oxidized to pBQ in the lungs of smokers and subsequently enters into the bloodstream. In the present study, we investigated the detrimental effect of pBQ on the architecture of human RBCs. Previously, we showed that the covalent modification of human hemoglobin with pBQ results in an alteration in its structure and function. In addition, we explored the potential neutralizing role of N-acetyl cysteine (NAC) in the reactivity of pBQ. Our results demonstrated that pBQ exposure to human red blood cells (RBCs), ex vivo, significantly decreases the reduced glutathione (GSH) content of RBCs, leading to the elevation of reactive oxygen species (ROS) and consequently causing oxidative damage to cellular components. pBQ exposure resulted in increased RBC sedimentation, altered membrane fluidity, enhanced lipid peroxidation, and significant morphological changes, such as bulging and distortion on the surface of RBCs, which eventually compromise membrane integrity. In addition, the coexistence of NAC with pBQ was found to be effective in neutralizing pBQ, thereby restoring GSH levels and RBC membrane architecture. These findings highlight the potential of NAC in mitigating the harmful effects of cigarette smoke on RBCs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/619387v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@8c3d58org.highwire.dtl.DTLVardef@10f7655org.highwire.dtl.DTLVardef@21d140org.highwire.dtl.DTLVardef@30d65c_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Periventricular and Deep White Matter Hyperintensity Thresholds in Aging: Exponential Progression, Cognitive Decline, and Neuroanatomic Atrophy

White matter hyperintensities (WMH), which are brain lesions associated with cerebral small vessel disease and aging, signify fiber loss and pruning. Analysis of T2-FLAIR MRI data from the NACC cohort, including cognitively normal (CN), cognitively impaired (CI), and Alzheimers disease (CI-AD) subjects, revealed that a significant subset of participants, even those classified as CN, harbor substantial periventricular (PVWMH) and deep white matter hyperintensity (DWMH) loads, while others displayed minimal or no PVWMH and DWMH, across ages 50-94 years. In this study, we quantified the thresholds and progression kinetics of PVWMH and DWMH and their impact on cognitive performance and neuroanatomic changes in the aging cohort (NCN = 521, NCI = 146, NCI-AD = 319). Our findings explore the impact of PVWMH and DWMH loads on global and specific cognitive domains to determine whether cognitive impairments are directly induced by PVWMH and DWMH loads, or mediated through distinct neuroanatomic structures. PV and DWMH loads are higher in CI and CI-AD subjects compared to CN but the PVWMH and DWMH loads are not discriminative of CI and CI-AD. The progression kinetics of PVWMH and DWMH volume with age indicate an exponential rate of increase, with PVWMH escalating approximately twice as fast as DWMH particularly around an inflection point at 61 years of age. PVWMH load presents with increased probability of occurrence in frontal horn compared to occipital horn while DWMH is diffused and accumulates significantly at later age than that observed for PVWMH. Multivariate global regression suggested significant effect (p<0.01) of PVWMH on Trail making tests (TMTs)-A and B (executive function), animal naming tests (semantic memory), with no significant effects observed for DWMH load. Indeed, beyond a threshold of PVWMH volume >2.3 mL, significant deficits in TMTs were observed compared to the subjects without PVWMH load. A PVWMH volume >2.3 mL and DWMH >2.75 mL is significantly associated with impairments in attention & working memory (Digit Span Tests), and semantic memory. Noticeably, significant neuroanatomic atrophy in the cerebral cortex, nucleus accumbens, RMFG, precentral, and paracentral gyrus is observed for PVWMH load >2.3 mL, while DWMH load was not significantly associated with neuroanatomic loss. Furthermore, a mediation model employing neuroanatomic volumes as mediator, PVWMH load as predictor and cognitive tests as outcome suggested that PVWMH volume contributes significantly to deficits in TMT-B mediated through atrophy in precentral gyrus (64%), accumbens (39%), paracentral gyrus (32%), rostral middle frontal gyrus (31%), and lingual gyrus (30%), each contributing distinct proportions, alongside the direct effect. DWMH load did not emerge as a significant predictor (direct or indirect) for the cognitive deficits. Further, no significant neuroanatomic mediations from PVWMH load were observed for other cognitive tests indicative of direct involvement of PVWMH load. Global cognition like MMSE was affected only at a higher PVWMH accumulation (>6 ml). HighlightsO_LIPVWMH escalates exponentially twice as fast as DWMH with age. C_LIO_LIPVWMH >2.3 mL is linked to cognitive deficits in executive function, semantic memory and neuroanatomic atrophy; DWMH less impactful. C_LIO_LIPVWMH, not DWMH, significantly affects cognitive decline via a unique set of brain structural loss. C_LIO_LIPVWMH and DWMH loads are not discriminative of CI and AD subjects. C_LI Overview O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/610993v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1ff66b2org.highwire.dtl.DTLVardef@af3852org.highwire.dtl.DTLVardef@19ab4c5org.highwire.dtl.DTLVardef@1d226a6_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗