Biology subjects

Sarkar, A.

Publications and source records attributed to Sarkar, A..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Single Cell Transcriptome Signatures of Sarcoidosis in Lung Immune Cell Populations

RationaleTo identify cell specific molecular changes associated with sarcoidosis risk and progression, we aimed to characterize the cellular composition, gene expression patterns, and cell-cell interactions in BAL cells from patients with sarcoidosis (both progressive and non-progressive) and healthy controls. MethodsSingle cell RNA-seq data were collected on 12 sarcoidosis and 4 control participants. We combined scRNA-seq data from these participants with our previously collected data on 4 sarcoidosis and 10 control participants for a final sample size of 16 sarcoidosis cases (8 progressive and 8 non-progressive) and 14 controls. Following initial preprocessing in CellRanger, data were quality controlled, combined, and clustered in Seurat. We tested differences in cell proportions by disease group using F-tests on cell proportions and differences in gene expression using pseudobulk analysis. Cell to cell communication and pathway analysis were performed using CellChat. ResultsWe identified five macrophage populations: resident, high metallothionein (MT) resident, recruited, profibrotic recruited, and proliferating macrophages. Each subpopulation displayed unique gene expression profiles, with notable differential expression of genes and pathways linked to sarcoidosis in resident macrophages, recruited macrophages, and proliferating macrophages. We also observed changes in gene expression associated with disease progression in resident and recruited macrophages. In non-macrophages cells, we observed a significant reduction in the number of B cells in sarcoidosis patients compared to controls. Among T cell populations, we identified specific transcriptional alterations at gene and pathway level. Additionally, we observed distinct differences in cell-to-cell interactions of macrophages and T cells between sarcoidosis patients and healthy controls. ConclusionsThese findings underscore the complexity of immune cell involvement in sarcoidosis and highlight potential cellular and molecular targets for further investigation.

genomics↗

bioRxiv2025

Optimizing SARS-CoV-2 RBD Boundaries for Enhanced E. coli Expression

The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a significant risk to global health, warranting the formulation of efficient preventive and therapeutic measures to tackle its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein of coronaviruses plays a pivotal role in viral attachment and entry into host cells. The receptor-binding domain (RBD) of the SARS-CoV-2 S protein has demonstrated a robust binding affinity to ACE2 receptors in humans. Consequently, it has become a prime target for therapeutic interventions using antibodies, vaccines, or other designed inhibitors. This paper presents an optimized RBD sequence that can be efficiently expressed in Escherichia coli and refolded to yield a functional protein. Using optimized refolding procedures, we obtained 10-12 mg of active protein from a one-liter LB culture. The biological activity of the refolded RBD was confirmed by monitoring its interaction with the designed LCB1 miniprotein ligand by surface plasmon resonance, wherein they exhibited significant affinity levels as reflected by their dissociation constants (KDs < 10 nM). The resulting RBD could be an ideal target for designing potent COVID-19 antivirals. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/633331v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@14e13b4org.highwire.dtl.DTLVardef@efb1f8org.highwire.dtl.DTLVardef@8d155dorg.highwire.dtl.DTLVardef@75a591_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

De novo functional discovery of peptide-MHC restricted CARs from recombinase-constructed large-diversity monoclonal T cell libraries

Chimeric antigen receptors (CAR) that mimic T cell receptors (TCR) on eliciting peptide-major histocompatibility complex (pMHC) specific T cell responses hold great promise in the development of immunotherapies against solid tumors, infections, and autoimmune diseases. However, broad applications of TCR-mimic (TCRm) CARs are hindered to date largely due to lack of a facile approach for the effective isolation of TCRm CARs. Here, we establish a highly efficient process for de novo discovery of TCRm CARs from human naive antibody repertories by combining recombinase-mediated large-diversity monoclonal library construction with T cell activation-based positive and negative screenings. Panels of highly functional TCRm CARs with peptide-specific recognition, minimal cross-reactivity, and low tonic signaling were rapidly identified towards MHC-restricted intracellular tumor-associated antigens MAGE-A3, NY-ESO-1, and MART-1. Transduced TCRm CAR-T cells exhibited pMHC-specific functional avidity, potent cytokine release, and efficacious and persistent cytotoxicity. The developed approach could be used to generate safe and potent immunotherapies targeting MHC-restricted antigens.

bioengineering↗

bioRxiv2024

Potassium ferric oxalate nanoparticles prevent human blood clotting and thrombosis in a mouse model

Blood clot creates occlusion in the veins and arteries, which leads to pernicious effects. Here, the anticoagulation properties of potassium ferric oxalate nanoparticles (KFeOx-NPs) in human blood were demonstrated for blood clot management. The mechanism involves the chelation of calcium ions from the blood by the oxalate present in the KFeOx-NPs. Various commercial assays were used to determine the clotting time for the KFeOx-NPs and identified the hindrance in activating factor XII in the intrinsic pathway. We used animal models to show toxicity and biodistribution profiles and determined the safety and efficacy. Intravenously injected KFeOx-NPs increased clotting time and thrombosis prevention in a mouse model confirmed by ultrasound and the power Doppler images. Coating catheters with KFeOx-NPs prevents clot formation with reduced protein attachment when incubated with blood, enhancing blood flow properties. In biological applications, KFeOx-NPs may improve the long-term prevention of blood clot formation and enhance the efficiency of medical devices. TOC O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/621820v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1292afeorg.highwire.dtl.DTLVardef@1c5ba81org.highwire.dtl.DTLVardef@576f23org.highwire.dtl.DTLVardef@4186e9_HPS_FORMAT_FIGEXP M_FIG C_FIG PVP-stabilized novel potassium ferric oxalate nanoparticles were synthesized for the application of blood clot management and thrombosis prevention.

pathology↗

bioRxiv2024

Glioblastoma Treatment by Systemic Actinium-225 alpha-particle Dendrimer-radioconjugates is Improved by Chemotherapy

RATIONALEThe poor prognosis of glioblastoma is largely due to drug resistance and tumor location that, together, make it difficult to treat aggressively without affecting the rest of the brain. METHODOLOGYHigh-energy, short-range (40-80{micro}m) dendrimer-delivered -particles could address both challenges, because (1) they cause complex, highly cytotoxic double-strand DNA breaks, and (2) irradiation of the neighboring brain is minimal, since dendrimers selectively delivers them to tumors. Since cancer cells that are not directly hit by -particles will likely not be killed, the patterns of tumor irradiation affect efficacy. Systemically injected dendrimers extensively accumulate in glioblastomas, where they are taken up by tumor associated macrophages (TAMs), which tend to infiltrate tumors. We hypothesized that dendrimers labeled with -particle emitters, when being carried by TAMs, could more evenly irradiate glioblastomas, improving survival. In this study, the efficacy of dendrimers radiolabeled with the -particle emitter actinium-225 (dendrimer-radioconjugates) was evaluated when administered alone and/or after temozolomide, in a syngeneic immune-competent orthotopic GL261-C57BL/6 mouse model. RESULTSSystemically-administered dendrimer-radioconjugates, at activities that did not result in long-term toxicities, prolonged survival of mice with orthotopic GL261 tumors, compared to standard-of-care temozolomide (39 vs 31 days mean survival, p=0.0061) and non-treated animals (30 days, p=0.0009). Importantly, injection of temozolomide 24 hours before administration of dendrimer-radioconjugates further improved survival remarkably (44 days). This improvement in efficacy was attributed to: (1) the significant increase (by 33%) in tumor absorbed doses delivered by dendrimer-radioconjugates when injected after chemotherapy, without altering normal organ dosimetry, while sparing the tumor-surrounding healthy brain; (2) the potentially deeper tumor penetration of dendrimer-radioconjugates, suggested by the enhancement of dendrimer penetration within GL261-spheroids, employed as model tumor-avascular regions and/or TAM-free regions; and/or (3) the formation of a more lethal cocktail when both modalities acted on same cancer cells, that was correlated with increased levels of dendrimer-radioconjugates associating with GL261 cells in vitro and with greater incidences of karyomegaly in vivo. CONCLUSIONSThis study demonstrates the potential of a brain tumor targeted systemic actinium-225 radiopharmaceutical therapy that inhibits growth of glioblastoma cells and prolongs survival of mice with orthotopic brain tumors, further improved by standard-of-care temozolomide, without notable toxicities.

bioengineering↗

bioRxiv2024

Cav3.1 is a leucine sensor in POMC neurons mediating appetite suppression and weight loss

Hypothalamic leucine sensing promotes satiety and weight loss but an understanding of how leucine regulates neuronal activity is lacking. Here we show that Cacna1g, encoding the T-type voltage-gated calcium channel Cav3.1, is enriched in hypothalamic leucine-sensing neurons and mediates leucine sensing. Pharmacological inhibition of Cav3.1 blunts leucine-induced activation of POMC neurons as well as the anorectic response to leucine in vivo. In addition, genetic deletion of Cacna1g in POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding. Mechanistically, we show that leucine binds to the voltage-sensing segment of Cav3.1, thereby reducing its threshold for voltage-dependent activation. Last, pharmacological activation of hypothalamic Cav3.1 promotes weight loss in diet-induced obese mice and potentiates the weight loss response to GLP-1 receptor agonism. These results reveal that Cav3.1 is a neuronal leucine sensor and a relevant weight loss target.

neuroscience↗

bioRxiv2024

SARS-CoV-2 protein ORF3a induces Atg8ylation of lysosomal membranes

Atg8ylation is an autophagy associated response to membrane damage that recruits mammalian ATG8 proteins (mATG8s) to damaged membranes to promote their repair or removal. Here, we show that the SARS-CoV-2 protein ORF3a induces lysosomal membrane atg8ylation and that this response protects cells from death. mATG8s interact with ORF3a and are required for lysosomal damage induced by ORF3a. ORF3a targets mTOR in an Atg8ylation dependent manner and promotes lysophagy through mATG8 mediated coordination of TRIM16 and Galectin-3. ORF3a triggers apoptosis, necroptosis, and pyroptosis, whereas atg8ylation limits ORF3a- induced cell death. Together, our findings identify mATG8s and the autophagy conjugation machinery as key regulators of lysosomal atg8ylation and lysophagy in response to the SARS-CoV-2 virulence factor ORF3a.

cell biology↗

bioRxiv2024

Evidencing the role of a conserved polar signaling channel in the activation mechanism of the u-opioid receptor

The activity of G protein-coupled receptors has been generally linked to dynamically interconverting structural and functional states and the process of activation was proposed to be controlled by an interconnecting network of conformational switches in the transmembrane domain. However, it is yet to be uncovered how ligands with different extent of functional effect exert their actions. According to our recent hypothesis, the transmission of the external stimulus is accompanied by the shift of macroscopic polarization in the transmembrane domain, furnished by concerted movements of conserved polar amino acids and the rearrangement of polar species. Previously, we have examined the -opioid, {beta}2-adrenergic and type 1 cannabinoid receptors by performing molecular dynamics simulations. Results revealed correlated dynamics of a polar signaling channel connecting the orthosteric binding pocket and the intracellular G protein-binding surface in all three class A receptors. In the present study, the interplay of this polar signaling channel in the activation mechanism was evidenced by systematic mutation of the channel residues of the -opioid receptor. Mutant receptors were analyzed utilizing molecular dynamics simulations and characterized in vitro by means of radioligand receptor binding and G protein stimulation assays. Apart from one exception, all mutants failed to bind the endogenous agonist endomorphin-2 and to stimulate the Gi protein complex. Furthermore, mutation results confirmed strong allosteric coupling between the binding pocket and the intracellular surface. The strong association and optimal bioactive orientation of the bound agonist was found to be crucial for the initiation of correlated motions and consequent signaling.

molecular biology↗

bioRxiv2024

Cyclin A/B RxL Macrocyclic Inhibitors to Treat Cancers with High E2F Activity

Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC). Mechanistically, cyclin A/Bi hyperactivate E2F1 and cyclin B by blocking their RxL-interactions with cyclin A and Myt1, respectively, ultimately leading to SAC activation and mitotic cell death. Base editor screens identified cyclin B variants that confer cyclin A/Bi resistance including several variants that disrupted cyclin B:Cdk interactions. Unexpectedly but consistent with our base editor and knockout screens, cyclin A/Bi induced the formation of neo-morphic Cdk2-cyclin B complexes that promote SAC activation and apoptosis. Finally, orally-bioavailable cyclin A/Bi robustly inhibited tumor growth in chemotherapy-resistant patient-derived xenograft models of SCLC. This work uncovers gain-of-function mechanisms by which cyclin A/Bi induce apoptosis in cancers with high E2F activity, and suggests cyclin A/Bi as a therapeutic strategy for SCLC and other cancers driven by high E2F activity.

cancer biology↗

bioRxiv2024

Nuclease-Resistant L-DNA Tension Probes Enable Long-TermForce Mapping of Single Cells and Cell Consortia

DNA-based tension probes with precisely programmable force response provide important insights into cellular mechanosensing. However, their degradability in cell culture limits their use for long-term imaging, for instance, when cells migrate, divide, and differentiate. This is a critical limitation for providing insights into mechanobiology for these longer-term processes. Here, we present DNA-based tension probes that are entirely designed based on the stereoisomer of biological D-DNA, i.e., L-DNA. We demonstrate that L-DNA tension probes are essentially indestructible by nucleases and provide days-long imaging without significant loss in image quality. We also show their superiority already for short imaging times commonly used for classical D-DNA tension probes. We showcase the potential of these resilient probes to image minute movements, and for generating long term force maps of single cells and for the first time, of collectively migrating cell populations.

biophysics↗

bioRxiv2024

Multiple clustered centrosomes in antigen-presenting cells foster T cell activation without MTOC polarization

Cellular polarization plays a pivotal role in regulating immunological processes and is often associated with centrosome reorientation. During immune synapse (IS) formation centrosome repositioning in lymphocytes assists in T cell activation. While a single centrosome, consisting of two centrioles, is present in T cells, antigen-presenting cells (APCs) such as dendritic cells (DCs) amplify centrioles during maturation leading to increased centrosome numbers upon immune activation. How centrosome amplification in DCs affects IS formation and T cell activation is unclear. In this study, we combine experimental data with mathematical and computational modelling to provide evidence that centrosome amplification in DCs enhances antigen-specific T cell activation. Extra centrioles in DCs form active centrosomes, which cluster during DC-T cell interactions and unlike in T cells, localize close to the cell center. Perturbing either centriole numbers or centrosome configuration in DCs results in impaired T cell activation. Collectively, our results highlight a crucial role for centrosome amplification and optimal centrosome positioning in APCs for controlling T cell responses.

cell biology↗

bioRxiv2024

Spectrally Resolved Single Molecule Orientation Imaging Reveals Direct Correspondence between Polarity and Order Experienced by Nile Red in Supported Lipid Bilayer Membrane

Molecular level interaction among lipids, cholesterol and water dictates nanoscale membrane organization of lipid bilayers into liquid ordered (Lo) and liquid disordered (Ld) phases, characterized by different polarity and order. Generally, solvatochromic dyes easily discriminate polarity difference between Lo and Ld phases, whereas molecular flippers and rotors show distinct photophysics depending on membrane order. In spite of progress in single molecule spectral imaging and single molecule orientation mapping, still direct experimental proof linking polarity with order sensed by the same probe eludes us. Here, we demonstrate spectrally resolved single molecule orientation localization microscopy to connect nanoscopic localization of probe on bilayer membrane with its emission spectra, three-dimensional dipole orientation and rotational constraint offered by the local microenvironment and highlights the beautiful correspondence between polarity and order. This technique has the potential to addres nanoscale heterogeneity and dynamics, especially in biology as well as material sciences. TOC GRAPHICS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/600028v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@d3aa13org.highwire.dtl.DTLVardef@42e184org.highwire.dtl.DTLVardef@e3a244org.highwire.dtl.DTLVardef@b25a50_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2024

A comprehensive multi-omics study reveals potential prognostic and diagnostic biomarkers for colorectal cancer

BackgroundColorectal cancer (CRC) is a complex disease with diverse genetic alterations and causes 10% of cancer-related deaths worldwide. Understanding its molecular mechanisms is essential for identifying potential biomarkers and therapeutic targets for its effective management. MethodWe integrated copy number alterations (CNA) and mutation data via their differentially expressed genes termed as candidate genes (CGs) computed using bioinformatics approaches. Then, using the CGs, we perform Weighted correlation network analysis (WGCNA) and utilise several hazard models such as Univariate Cox, Least Absolute Shrinkage and Selection Operator (LASSO) Cox and multivariate Cox to identify the key genes involved in CRC progression. We used different machine-learning models to demonstrate the discriminative power of selected hub genes among normal and CRC (early and late-stage) samples. ResultsThe integration of CNA with mRNA expression identified over 3000 CGs, including CRC-specific driver genes like MYC and APC. In addition, pathway analysis revealed that the CGs are mainly enriched in endocytosis, cell cycle, wnt signalling and mTOR signalling pathways. Hazard models identified four key genes, CASP2, HCN4, LRRC69 and SRD5A1, that were significantly associated with CRC progression and predicted the 1-year, 3-years, and 5-years survival times. WGCNA identified seven hub genes: DSCC1, ETV4, KIAA1549, NOP56, RRS1, TEAD4 and ANKRD13B, which exhibited strong predictive performance in distinguishing normal from CRC (early and late-stage) samples. ConclusionsIntegrating regulatory information with gene expression improved early versus latestage prediction. The identified potential prognostic and diagnostic biomarkers in this study may guide us in developing effective therapeutic strategies for CRC management.

bioinformatics↗

bioRxiv2024

Protein Sequence Domain Annotation using Language Models

Protein domain annotation underlies large-scale functional inference and is commonly performed by scanning sequences against libraries of profile hidden Markov models (profile HMMs). We describe PSALM, a protein domain annotation method that combines (i) a pretrained protein language model (ESM-2) with (ii) a per-residue domain-state classifier and (iii) a structured probabilistic decoder that produces a single, non-overlapping set of domain calls with explicit boundaries and scores. On a benchmark of 89M protein sequences with 107M annotated domains, PSALM attains a domain-detection sensitivity-specificity tradeoff comparable to HMMER. We characterize sequence and residue-level coverage on UniProtKB, observing higher coverage for HMMER at stringent expected false positive counts (E-values) and higher coverage for PSALM at relaxed E-values. We release code for data processing, training, and inference, along with the model weights and datasets used for training, validation, and benchmarking.

bioinformatics↗

bioRxiv2024

Designing DNA With Tunable Regulatory Activity Using Discrete Diffusion

Designing regulatory DNA with tunable and context-specific activity is a major goal in biotechnology and medicine. Deep generative models offer a promising route for sequence design, yet it remains unclear whether synthetic sequences faithfully recapitulate the motif organization and functional specificity of natural regulatory DNA. Here we present DNA Discrete Diffusion (D3), a generative model that designs regulatory DNA through an iterative nucleotide-substitution process. Across computational benchmarks, D3 improves regulatory sequence generation relative to matched diffusion baselines, producing sequences that more closely match target activity, activity distributions, and sequence composition. In K562 lentiMPRA experiments, D3-designed sequences retained measurable regulatory activity and more closely recapitulated the activity distribution of genomic regulatory sequences than matched diffusion baselines. D3 performs robustly with limited training data and generates sequences informative enough to improve predictive models when labeled data are scarce. When trained without activity labels on task-specific regulatory sequence sets, D3 learns frozen sequence representations that are predictive of enhancer activity and compare favorably to several off-the-shelf genomic language model embeddings. Analysis of the sampling process identifies reproducible phases of sequence exploration, compositional refinement, and motif-associated convergence, providing an interpretable view of how D3 constructs regulatory sequences. These results establish D3 as a practical framework for designing synthetic regulatory DNA and studying sequence features associated with context-specific regulatory activity.

genomics↗

bioRxiv2024

Phagocytosis-driven neurodegeneration through opposing roles of an ABC transporter in neurons and phagocytes

Lipid homeostasis is critical to the survival of neurons. Lipid transporters from the ATP-binding cassette A (ABCA) subfamily are important regulators of lipid trafficking and are associated with multiple neurodegenerative diseases. How ABCA transporters regulate specific aspects of lipid homeostasis to impact neurodegeneration is an outstanding question. Here we report that the Drosophila ABCA protein Engulfment ABC Transporter in the ovary (Eato) contributes to phagocytosis-dependent neurodegeneration by playing two opposing roles in neurons and nearby phagocytes: In neurons, Eato prevents dendrites and axons from being attacked and engulfed by neighboring phagocytes; in phagocytes, however, Eato enhances the ability of these cells to detect neurons as engulfment targets. Thus, Eato deficiency in neurons alone results in severe phagocytosis-dependent dendrite and axon degeneration, whereas removing Eato from both neurons and phagocytes completely rescues the neurite degeneration. Surprisingly, Eato exerts its functions in both neurons and phagocytes by suppressing the effects of the eat-me signal phosphatidylserine (PS) exposed on the cell surface. Interestingly, multiple human and C. elegans ABCA homologs can compensate for the loss of Eato in phagocytes but not in neurons, suggesting both conserved and cell type-specific activities of these ABCA proteins. These results reveal how ABCA proteins participate in neurodegeneration by regulating PS homeostasis and imply possible mechanisms of neuron-phagocyte interactions in neurodegenerative diseases.

neuroscience↗

bioRxiv2024

G6b-B antibody-based cis-acting platelet receptor inhibitors (CAPRIs) as a new family of anti-thrombotic therapeutics

Key PointsO_LIBispecific cis-acting platelet receptor inhibitors (CAPRIs) mediate hetero-clustering of the ITIM receptor G6B with ITAM receptors. C_LIO_LIG6B-GPVI and G6B-CD32A CAPRIs specifically inhibit collagen- and immune complex-induced thrombus formation, respectively. C_LI Platelets are highly reactive fragments of megakaryocytes that play a fundamental role in thrombosis and hemostasis. Predictably, all conventional anti-platelet therapies elicit bleeding, raising the question whether the thrombotic activity of platelets can be targeted separately. In this study, we describe a novel approach of inhibiting platelet activation through the use of bispecific single-chain variable fragments (bi-scFvs), termed cis-acting platelet receptor inhibitors (CAPRIs) that harness the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing co-inhibitory receptor G6b-B (G6B) to suppress immunoreceptor tyrosine-based (ITAM)-containing receptor-mediated platelet activation. CAPRI-mediated hetero-clustering of G6B with either the ITAM-containing GPVI-FcR {gamma}-chain complex or Fc{gamma}RIIA (CD32A) inhibited collagen- or immune complex-induced platelet aggregation. G6B-GPVI CAPRIs strongly and specifically inhibited thrombus formation on collagen under arterial shear, whereas G6B-CD32A CAPRI strongly and specifically inhibited thrombus formation to heparin-induced thrombocytopenia, vaccine-induced thrombotic thrombocytopenia and antiphospholipid syndrome complexes on Von Willebrand Factor-coated surfaces and photochemical-injured endothelial cells under arterial shear. Our findings provide proof-of-concept that CAPRIs are highly effective at inhibiting ITAM receptor-mediated platelet activation, laying the foundation for a novel family of anti-thrombotic therapeutics with potentially improved efficacy and fewer bleeding outcomes compared with current anti-platelet therapies.

cell biology↗

bioRxiv2024

Gestational exposure to high heat-humidity conditions impairs mouse embryonic development

Unprecedented rates of global warming have created an existential challenge for the sustainable survival of species on this planet. Tropical conditions of high ambient temperature and relative humidity are extremely vulnerable to maternal-child health. Emerging epidemiological studies depict that exposure to extremely hot weather conditions during pregnancy leads to an array of adverse pregnancy outcomes, such as low birth weight, stillbirth, preterm delivery, congenital abnormalities and adult-onset disorders. A lack of understanding of the underlying molecular pathophysiology limits us from developing an effective combat strategy in terms of targeted therapeutics to improvise the combined teratogenic effects of high heat-humidity in pregnancy. To address this, it is important to delineate the effect of hot-humid weather conditions on the process of embryogenesis. However, working with human embryos is technically and ethically challenging. In this study, we have established a mouse model of heat-humidity stress during pregnancy, which essentially recapitulates the adverse pregnancy outcomes observed in humans. Importantly, we have profiled the impact of high heat-humidity exposure during gestation at different stages of embryogenesis using this mouse model. Our results indicate that the teratogenicity of heat-humidity stress gets manifested in a cumulative manner, starting from the pre-implantation stage and becomes severe at the mid-gestation, culminating in significantly higher embryonic deaths and malformations at the late gestational stage of mouse embryogenesis. Overall, our study paves the path for exploring the underlying molecular players that get dysregulated under gestational exposure to hot and humid conditions, resulting in severe embryonic defects.

developmental biology↗