Biology subjects

Varlamov, O.

Publications and source records attributed to Varlamov, O..

8 recordsLinked to original sources

bioRxiv2026

Efficacy of postmenopausal estrogen replacement in SIV-infected female macaques on antiretroviral therapy.

The success of modern antiretroviral therapy (ART) has increased the life expectancy of people living with HIV to levels approaching that of uninfected individuals. For women living with HIV (WLWH), this means that more will survive to undergo menopause and experience the consequences of decreased ovarian hormone levels, particularly estrogen (E2). The recent change in federal guidance for use of postmenopausal hormone therapy is increasing demand for both E2-alone and E2+progestogen formulations to control adverse symptoms of menopause. The consequences and efficacy of hormone therapy in WLWH are thus an important issue for WLWH and their healthcare providers. The role of E2 replacement in postmenopausal WLWH is a significant issue because of its potential effects on control the viral reservoir and its demonstrated beneficial metabolic effects in uninfected postmenopausal women. To address these questions, we employed a novel nonhuman primate model of postmenopausal WLWH undergoing E2 replacement. Reproductively competent female rhesus macaques were infected with simian immunodeficiency virus (SIV) and then subjected to a daily ART regimen. After complete suppression of plasma viremia, all animals were ovariectomized (OVX) and then implanted with Silastic capsules containing either cholesterol vehicle or sufficient E2 to restore pre-OVX plasma levels. Plasma and cell-associated viral dynamics, immune responses, body composition, systemic and tissue-specific metabolic parameters, cytokine profiles, and parameters of bone health were followed longitudinally from baseline through 34 weeks of E2 deficiency or replacement. We found that E2 status did not significantly affect plasma or tissue viral dynamics or overall metabolic homeostasis. However, E2 replacement exerted beneficial effects on several aspects of bone health in spite of a chronic inflammatory state that persisted following effective ART suppression of the SIV reservoir. Our findings suggest that hormone therapy, specifically E2 replacement, offers benefit to WLWH, particularly with respect to bone loss.

physiology↗

bioRxiv2026

Spontaneous Pregravid Obesity Reshapes Fetal Immune Ontogeny in a Nonhuman Primate Model

Pregravid obesity is associated with longterm immune alterations in the offspring; however, the mechanisms remain poorly defined. To address this gap, we investigated the impact of spontaneous pregravid obesity, independent of obesogenic diet, on fetal immune ontogeny in a rhesus macaque model. Using spectral flow cytometry, multiplex cytokine profiling, functional stimulation assays, and singlecell RNA sequencing, we profiled immune composition, function, transcriptional profiles, and intercellular communication in umbilical cord blood as well as fetal spleen and lung. Pregravid obesity was associated with altered fetal organ growth, elevated inflammatory mediators, altered frequencies of immune cell populations, and hyperresponsiveness to stimulation by splenic and lung leukocytes. Singlecell transcriptomic analyses revealed tissuespecific reprogramming of innate immune cells, including heightened inflammatory, migratory, and metabolic signatures with impaired antigen presentation. Moreover, there was evidence of impaired T cell differentiation, premature effector differentiation, and B cell dysfunction. Cell-cell communication analysis identified loss of tolerogenic signaling and enhanced proinflammatory pathways across spleen and lung myeloid cells. These findings demonstrate that spontaneous pregravid obesity fundamentally reshapes fetal circulating and tissueresident immune cells, providing mechanistic insight into the increased susceptibility to infection, respiratory diseases, and immune dysregulation observed in offspring of mothers with obesity.

immunology↗

bioRxiv2026

Maternal Obesity Reprograms Differentiation Trajectories of Fetal Hematopoietic Stem and Progenitor Cells Through Altered Inflammatory Signaling

BackgroundMaternal obesity is a global health challenge with profound consequences for offspring health. While its impact on metabolic programming has been widely studied, far less is known about how maternal obesity shapes the fetal immune system. The fetal bone marrow (FBM) is the central site of hematopoietic stem and progenitor cell (HSPC) development, and disruptions in this niche can have lifelong effects on immunity, infection susceptibility, and inflammatory disease risk. In this study, we examined FBM hematopoiesis in a nonhuman primate model of spontaneous maternal obesity. MethodsUsing spectral flow cytometry, single-cell RNA sequencing, and functional differentiation assays, we mapped progenitor composition, lineage trajectories, and immune function in offspring exposed to maternal obesity compared with lean controls. These complementary approaches allowed us to capture cellular frequencies and transcriptional programs, while trajectory and signaling analyses provided insight into how progenitor maturation and intercellular communication are disrupted by maternal obesity. ResultsOur findings reveal that maternal obesity decreases CD34+ HSPCs and common lymphoid progenitor populations, while expanding megakaryocyte-erythroid and granulocyte-monocyte progenitors. Pseudotime analysis demonstrated altered maturation, with cells accumulating at early differentiation states. Transcriptional profiling uncovered a strong inflammatory bias, with myeloid progenitors upregulating alarmins, interferon-stimulated genes, and proinflammatory mediators. Functionally, monocytes derived from obese FBM showed impaired migratory and colony-stimulating capacity, coupled with exaggerated TNF responses to LPS stimulation. ConclusionTogether, these results demonstrate that maternal obesity, even in the absence of obesogenic diet, disrupts fetal bone marrow hematopoiesis by altered HSPC maturation, reprogramming lineage trajectories, and inducing inflammatory bias.

immunology↗

bioRxiv2024

Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex

Adipogenin (Adig) is an evolutionarily conserved microprotein and is highly expressed in adipose tissues and testis. Here, we identify Adig as a critical regulator for lipid droplet formation in adipocytes. We determine that Adig interacts directly with seipin, leading to the formation of a rigid complex. We solve the structure of the seipin/Adig complex by Cryo-EM at 2.98[A] overall resolution. Surprisingly, seipin can form two unique oligomers, undecamers and dodecamers. Adig selectively binds to the dodecameric seipin complex. We further find that Adig promotes seipin assembly by stabilizing and bridging adjacent seipin subunits. Functionally, Adig plays a key role in generating lipid droplets in adipocytes. In mice, inducible overexpression of Adig in adipocytes substantially increases fat mass, with enlarged lipid droplets. It also elevates thermogenesis during cold exposure. In contrast, inducible adipocyte-specific Adig knockout mice manifest aberrant lipid droplet formation in brown adipose tissues and impaired cold tolerance.

cell biology↗

bioRxiv2023

Adipose Tissue Analysis Toolkit (ATAT) for Automated Analysis of Adipocyte Size and Extracellular Matrix in White Adipose Tissue

ObjectiveThe pathological expansion of white adipose tissue (WAT) in obesity involves adipocyte hypertrophy accompanied by expansion of collagen-rich pericellular extracellular matrix (ECM) and the development of crown-like structures (CLS). Traditionally, WAT morphology is assessed through immunohistochemical analysis of WAT sections. However, manual analysis of large histological sections is time-consuming, and available digital tools for analyzing adipocyte size and pericellular ECM are limited. To address this gap, we developed the Adipose Tissue Analysis Toolkit (ATAT), an ImageJ plugin facilitating analysis of adipocyte size, WAT ECM and CLS. Methods and ResultsATAT utilizes local and image-level differentials in pixel intensity to independently threshold background, distinguishing adipocyte-free tissue without user input. It accurately captures adipocytes in histological sections stained with common dyes and automates the analysis of adipocyte cross-sectional area, total-field, and localized region-of-interest ECM. ATAT allows fully automated batch analysis of histological images using default or user-defined adipocyte detection parameters. ConclusionsATAT provides several advantages over existing WAT image analysis tools, enabling high-throughput analyses of adipocyte-specific parameters and facilitating the assessment of ECM changes associated with WAT remodeling due to weight changes and other pathophysiological alterations that affect WAT function. Study Importance Questions What is already known about this subject?The manual analysis of large WAT histological sections is very time-consuming, while digital tools for the analysis of WAT are limited. What are the new findings in your manuscript?- ATAT enables fully automated analysis of batches of histological images using either default or user-defined adipocyte detection parameters - ATAT allows high-throughput analyses of adipocyte-specific parameters and pericellular extracellular matrix - ATAT enables the assessment of fibrotic changes associated with WAT remodeling and crown-like structures How might your results change the direction of research or the focus of clinical practice?- ATAT is designed to work with histological sections and digital images obtained using a slide scanner or a microscope. - This tool will help basic and clinical researchers to conduct automated analyses of adipose tissue histological sections.

bioinformatics↗

bioRxiv2022

Impact of pregravid obesity on anti-microbial fetal monocyte response

Maternal pre-pregnancy (pregravid) obesity is associated with adverse outcomes for both mother and offspring. Amongst the complications for the offspring is increased susceptibility and severity of neonatal infections necessitating admission to the intensive care unit, notably bacterial sepsis and enterocolitis. Previous studies have reported aberrant responses to LPS and polyclonal stimulation by umbilical cord blood monocytes that were mediated by alterations in the epigenome. In this study, we show that pregravid obesity dysregulates umbilical cord blood monocyte responses to bacterial and viral pathogens. Specifically, interferon-stimulated gene expression and inflammatory responses to E. coli and respiratory syncytial virus (RSV) were significantly dampened. Although upstream signaling events were comparable, translocation of the key transcription factor NF-{kappa}B and chromatin accessibility at pro- inflammatory gene promoters following TLR stimulation was significantly attenuated. Using a rhesus macaque model of western style diet induced obesity, we further demonstrate that this defect is detected in fetal peripheral monocytes and tissue-resident macrophages during gestation. Collectively, these data indicate that maternal obesity and high-fat diet present metabolic, signaling, and epigenetic impediments to pathogen recognition in fetal innate immune cells that result in a state of immune paralysis during gestation and at birth.

immunology↗

bioRxiv2021

Maternal Obesity Dysregulates Fetal Hematopoietic Stem and Progenitor Cell Development in Rhesus Macaques

BackgroundMaternal obesity adversely impacts the in utero metabolic environment and offsprings health, but its effect on fetal hematopoiesis and immune cell development remains incompletely understood, particularly in models that resemble human development. MethodsWe studied gestational day 130-135 fetuses derived from rhesus macaque dams chronically exposed to a high-fat Western-style diet (WSD) or a low-fat control diet. Fetal immune cell phenotypes and fetal bone marrow architecture and hematopoietic stem and progenitor cell (FBM HSPC) function were examined using bone computed tomography, histology, flow cytometry, single-cell RNA-sequencing, and HSPC transplantation assays. FindingsMaternal WSD induced premature FBM cavity opening and a codominant increase in the number of FBM adipocytes. Furthermore, a maternal WSD induced a proinflammatory transcriptional response in FBM HSPCs. FBM macrophages from the WSD group exhibited heightened proinflammatory responses to toll-like receptor agonist stimulation. Maternal WSD exposure suppressed the expression of genes required for B-cell development and decreased the frequencies of FBM B-cells. Finally, maternal WSD led to poor engraftment of FBM HSPCs in nonlethally irradiated immunodeficient NOD/SCID/IL2r{gamma}-/- mice. InterpretationsMaternal WSD impairs FBM development, drives a hyperinflammatory phenotype, and induces functional and differentiation impairment in FBM HSPCs in a translationally relevant nonhuman primate model. FundingNational Institute of Health RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSMaternal obesity is associated with increased risk of infections and proinflammatory disease in offspring. The translationally-relevant rhesus macaque model was utilized to address the effects of maternal obesogenic diet on fetal hematopoietic and immune cell development. Added value of this studyWe assessed changes in fetal immune cell phenotypes and fetal hematopoietic stem and progenitor cell function using immunohistochemistry, flow cytometry, single-cell RNA sequencing, and transplantation assays. We determined that chronic consumption of a maternal obesogenic diet induced the development of adipogenic and proinflammatory environments in the fetal bone marrow. Additionally, we detected the impairment in B-cell differentiation program in fetal hematopoietic stem and progenitor cells. Implications of all the available evidenceThese data demonstrate that maternal obesogenic diet modulates fetal hematopoietic development and could impact the offsprings immune system, including proinflammatory phenotype and a decline in B-cell function.

immunology↗

bioRxiv2020

Regulatory diversity contributes to a divergent transcriptional response to dietary changes in mammals

BACKGROUNDRegulatory innovation is central to the evolution of species. Different nutritional sources are one environmental pressure that can lead to selection for novel regulatory elements. Dietary composition changes, including exposure to "western" diets with excess fat and sugar content, can lead to transcriptional regulatory changes in the liver. In order to investigate how transcriptional regulatory changes in response to a high fat diet diverge across species, we profiled chromatin accessibility, histone modifications and the transcriptome in livers of rhesus macaques and mice fed high fat and normal diets. RESULTSWhile the majority of elements exhibiting changes in chromatin accessibility in response to a high fat diet are enriched for similar transcription factors across species, the loci that change are mostly species specific. These unique responsive regulatory elements are largely derived from transposable elements and are enriched for liver-specific transcription factors, such as HNF4. Furthermore, the majority of genes that respond to a high fat diet in rhesus macaques do not have a shared response in mice and are proximal to regulatory elements that display changes in chromatin accessibility only in rhesus macaques. CONCLUSIONSOur study demonstrates that most of the liver regulatory elements that exhibit changes in chromatin accessibility in response to a high fat diet do so in a species-specific manner. These findings illustrate how a similar environmental stimulus can drive a divergent chromatin and transcriptional responses in evolutionary distinct mammalian species.

genomics↗