13 results on '"James W. MacDonald"'
Search Results
2. Modeling cellular responses to serum and vitamin D in microgravity using a human kidney microphysiological system
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Kevin A. Lidberg, Kendan Jones-Isaac, Jade Yang, Jacelyn Bain, Lu Wang, James W. MacDonald, Theo K. Bammler, Justina Calamia, Kenneth E. Thummel, Catherine K. Yeung, Stefanie Countryman, Paul Koenig, Jonathan Himmelfarb, and Edward J. Kelly
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Biotechnology ,TP248.13-248.65 ,Physiology ,QP1-981 - Abstract
Abstract The microgravity environment aboard the International Space Station (ISS) provides a unique stressor that can help understand underlying cellular and molecular drivers of pathological changes observed in astronauts with the ultimate goals of developing strategies to enable long- term spaceflight and better treatment of diseases on Earth. We used this unique environment to evaluate the effects of microgravity on kidney proximal tubule epithelial cell (PTEC) response to serum exposure and vitamin D biotransformation capacity. To test if microgravity alters the pathologic response of the proximal tubule to serum exposure, we treated PTECs cultured in a microphysiological system (PT-MPS) with human serum and measured biomarkers of toxicity and inflammation (KIM-1 and IL-6) and conducted global transcriptomics via RNAseq on cells undergoing flight (microgravity) and respective controls (ground). Given the profound bone loss observed in microgravity and PTECs produce the active form of vitamin D, we treated 3D cultured PTECs with 25(OH)D3 (vitamin D) and monitored vitamin D metabolite formation, conducted global transcriptomics via RNAseq, and evaluated transcript expression of CYP27B1, CYP24A1, or CYP3A5 in PTECs undergoing flight (microgravity) and respective ground controls. We demonstrated that microgravity neither altered PTEC metabolism of vitamin D nor did it induce a unique response of PTECs to human serum, suggesting that these fundamental biochemical pathways in the kidney proximal tubule are not significantly altered by short-term exposure to microgravity. Given the prospect of extended spaceflight, more study is needed to determine if these responses are consistent with extended (>6 months) exposure to microgravity.
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- 2024
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3. Challenges and Opportunities for the Clinical Translation of Spatial Transcriptomics Technologies
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Kelly D. Smith, David K. Prince, James W. MacDonald, Theo K. Bammler, and Shreeram Akilesh
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kidney biopsy ,kidney pathology ,spatial transcriptomics ,gene expression ,clinical translation ,glomerular diseases ,precision medicine ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Background: The first spatially resolved transcriptomics platforms, GeoMx (Nanostring) and Visium (10x Genomics) were launched in 2019 and were recognized as the method of the year by Nature Methods in 2020. The subsequent refinement and expansion of these and other technologies to increase -plex, work with formalin-fixed paraffin-embedded tissue, and analyze protein in addition to gene expression have only added to their significance and impact on the biomedical sciences. In this perspective, we focus on two platforms for spatial transcriptomics, GeoMx and Visium, and how these platforms have been used to provide novel insight into kidney disease. The choice of platform will depend largely on experimental questions and design. The application of these technologies to clinically sourced biopsies presents the opportunity to identify specific tissue biomarkers that help define disease etiology and more precisely target therapeutic interventions in the future. Summary: In this review, we provide a description of the existing and emerging technologies that can be used to capture spatially resolved gene and protein expression data from tissue. These technologies have provided new insight into the spatial heterogeneity of diseases, how reactions to disease are distributed within a tissue, which cells are affected, and molecular pathways that predict disease and response to therapy. Key Message: The upcoming years will see intense use of spatial transcriptomics technologies to better define the pathophysiology of kidney diseases and develop novel diagnostic tests to guide personalized treatments for patients.
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- 2024
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4. Epigenome-wide analysis of long-term air pollution exposure and DNA methylation in monocytes: results from the Multi-Ethnic Study of Atherosclerosis
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Gloria C. Chi, Yongmei Liu, James W. MacDonald, Lindsay M. Reynolds, Daniel A. Enquobahrie, Annette L. Fitzpatrick, Kathleen F. Kerr, Matthew J. Budoff, Su-In Lee, David Siscovick, and Joel D. Kaufman
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air pollution ,fine particulate matter ,oxides of nitrogen ,dna methylation ,gene expression ,Genetics ,QH426-470 - Abstract
Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals and cis-gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM2.5) and oxides of nitrogen (NOX) were estimated at participants’ homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals and cis-gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or near SDHAP3, ZFP57, HOXA5, and PRM1, respectively) were associated with PM2.5. The DMRs on chromosomes 5 and 6 also associated with NOX. The DMR on chromosome 5 had the smallest p-value for both PM2.5 (p = 1.4×10−6) and NOX (p = 7.7×10−6). Three differentially methylated CpGs were identified for PM2.5, and cg05926640 (near TOMM20) had the smallest p-value (p = 5.6×10−8). NOX significantly associated with cg11756214 within ZNF347 (p = 5.6×10−8). Several differentially methylated signals were also associated with cis-gene expression. The DMR located on chromosome 7 was associated with the expression of HOXA5, HOXA9, and HOXA10. The DMRs located on chromosomes 5 and 16 were associated with expression of MRPL36 and DEXI, respectively. The CpG cg05926640 was associated with expression of ARID4B, IRF2BP2, and TOMM20. We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.
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- 2022
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5. Spiny mice activate unique transcriptional programs after severe kidney injury regenerating organ function without fibrosis
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Daryl M. Okamura, Chris M. Brewer, Paul Wakenight, Nadia Bahrami, Kristina Bernardi, Amy Tran, Jill Olson, Xiaogang Shi, Szu-Ying Yeh, Adrian Piliponsky, Sarah J. Collins, Elizabeth D. Nguyen, Andrew E. Timms, James W. MacDonald, Theo K. Bammler, Branden R. Nelson, Kathleen J. Millen, David R. Beier, and Mark W. Majesky
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Animal physiology ,Molecular biology ,Developmental biology ,Science - Abstract
Summary: Fibrosis-driven solid organ failure is an enormous burden on global health. Spiny mice (Acomys) are terrestrial mammals that can regenerate severe skin wounds without scars to avoid predation. Whether spiny mice also regenerate internal organ injuries is unknown. Here, we show that despite equivalent acute obstructive or ischemic kidney injury, spiny mice fully regenerate nephron structure and organ function without fibrosis, whereas C57Bl/6 or CD1 mice progress to complete organ failure with extensive renal fibrosis. Two mechanisms for vertebrate regeneration have been proposed that emphasize either extrinsic (pro-regenerative macrophages) or intrinsic (surviving cells of the organ itself) controls. Comparative transcriptome analysis revealed that the Acomys genome appears poised at the time of injury to initiate regeneration by surviving kidney cells, whereas macrophage accumulation was not detected until about day 7. Thus, we provide evidence for rapid activation of a gene expression signature for regenerative wound healing in the spiny mouse kidney.
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- 2021
- Full Text
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6. Associations of prenatal exposure to NO2 and near roadway residence with placental gene expression
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Michael R. Hussey, Daniel A. Enquobahrie, Christine T. Loftus, James W. MacDonald, Theo K. Bammler, Alison G. Paquette, Carmen J. Marsit, Adam A. Szpiro, Joel D. Kaufman, Kaja Z. LeWinn, Nicole R. Bush, Frances Tylavsky, Qi Zhao, Catherine J. Karr, and Sheela Sathyanarayana
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Reproductive Medicine ,Obstetrics and Gynecology ,Developmental Biology - Published
- 2023
7. Mono(2-ethylhexyl) phthalate induces transcriptomic changes in placental cells based on concentration, fetal sex, and trophoblast cell type
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Samantha Lapehn, Scott Houghtaling, Kylia Ahuna, Leena Kadam, James W. MacDonald, Theo K. Bammler, Kaja Z. LeWinn, Leslie Myatt, Sheela Sathyanarayana, and Alison G. Paquette
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Health, Toxicology and Mutagenesis ,General Medicine ,Toxicology - Abstract
Phthalates are ubiquitous plasticizer chemicals found in consumer products. Exposure to phthalates during pregnancy has been associated with adverse pregnancy and birth outcomes and differences in placental gene expression in human studies. The objective of this research was to evaluate global changes in placental gene expression via RNA sequencing in two placental cell models following exposure to the phthalate metabolite mono(2-ethylhexyl) phthalate (MEHP). HTR-8/SVneo and primary syncytiotrophoblast cells were exposed to three concentrations (1, 90, 180 µM) of MEHP for 24 h with DMSO (0.1%) as a vehicle control. mRNA and lncRNAs were quantified using paired-end RNA sequencing, followed by identification of differentially expressed genes (DEGs), significant KEGG pathways, and enriched transcription factors (TFs). MEHP caused gene expression changes across all concentrations for HTR-8/SVneo and primary syncytiotrophoblast cells. Sex-stratified analysis of primary cells identified different patterns of sensitivity in response to MEHP dose by sex, with male placentas being more responsive to MEHP exposure. Pathway analysis identified 11 KEGG pathways significantly associated with at least one concentration in both cell types. Four ligand-inducible nuclear hormone TFs (PPARG, PPARD, ESR1, AR) were enriched in at least three treatment groups. Overall, we demonstrated that MEHP differentially affects placental gene expression based on concentration, fetal sex, and trophoblast cell type. This study confirms prior studies, as enrichment of nuclear hormone receptor TFs were concordant with previously published mechanisms of phthalate disruption, and generates new hypotheses, as we identified many pathways and genes not previously linked to phthalate exposure.
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- 2023
8. Temporal changes in the brain lipidome during neurodevelopment of Smith-Lemli-Opitz syndrome mice
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Amy Li, Kelly M. Hines, Dylan H. Ross, James W. MacDonald, and Libin Xu
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Oxidoreductases Acting on CH-CH Group Donors ,Brain ,Biochemistry ,Lipids ,Article ,Analytical Chemistry ,Smith-Lemli-Opitz Syndrome ,Mice ,Cholesterol ,Lipidomics ,Electrochemistry ,Environmental Chemistry ,Animals ,lipids (amino acids, peptides, and proteins) ,Spectroscopy - Abstract
Neurodevelopment is an intricately orchestrated program of cellular events that occurs with tight temporal and spatial regulation. While it is known that the development and proper functioning of the brain, which is the second most lipid rich organ behind adipose tissue, greatly rely on lipid metabolism and signaling, the temporal lipidomic changes that occur throughout the course of neurodevelopment have not been investigated. Smith-Lemli-Opitz syndrome is a metabolic disorder caused by genetic mutations in the DHCR7 gene, leading to defective 3β-hydroxysterol-Δ(7)-reductase (DHCR7), the enzyme that catalyzes the last step of cholesterol synthesis. Due to the close regulatory relationship between sterol and lipid homeostasis, we hypothesize that altered or dysregulated lipid metabolism beyond the primary defect of cholesterol biosynthesis is present in the pathophysiology of SLOS. Herein, we applied our HILIC-IM-MS method and LiPydomics Python package to streamline an untargeted lipidomics analysis of developing mouse brains in both wild-type and Dhcr7-KO mice. We compared relative lipid levels throughout development, from embryonic day 12.5 to postnatal day 0 and identified differentially expressed brain lipids between wild-type and Dhcr7-KO mice at specific developmental time points, revealing lipid metabolic pathways that are affected in SLOS beyond the cholesterol biosynthesis pathway, such as glycerolipid, glycerophospholipid, and sphingolipid metabolism. Implications of the altered lipid metabolic pathways in SLOS pathophysiology are discussed.
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- 2023
9. Prolonged, Low-Level Exposure to the Marine Toxin, Domoic Acid, and Measures of Neurotoxicity in Nonhuman Primates
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Rebekah L. Petroff, Christopher Williams, Jian-Liang Li, James W. MacDonald, Theo K. Bammler, Todd Richards, Christopher N. English, Audrey Baldessari, Sara Shum, Jing Jing, Nina Isoherranen, Brenda Crouthamel, Noelle McKain, Kimberly S. Grant, Thomas M. Burbacher, and G. Jean Harry
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Macaca fascicularis ,Kainic Acid ,Health, Toxicology and Mutagenesis ,Public Health, Environmental and Occupational Health ,Animals ,Cytokines ,Female ,Marine Toxins ,Neurotoxicity Syndromes - Abstract
The excitotoxic molecule, domoic acid (DA), is a marine algal toxin known to induce overt hippocampal neurotoxicity. Recent experimental and epidemiological studies suggest adverse neurological effects at exposure levels near the current regulatory limit (20 ppm,This study aimed to identify adverse effects on the nervous system from prolonged, dietary DA exposure in adult, femaleMonkeys were orally exposed to 0, 0.075, andClinical blood counts, chemistry, and cytokine levels were not altered with DA exposure in nonhuman primates. Transcriptome analysis of the hippocampus yielded 748 differentially expressed genes (In the absence of overt hippocampal excitotoxicity, chronic exposure of
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- 2022
10. Ancestry-specific maps of GRCh38 linkage disequilibrium blocks for human genome research
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James W. MacDonald, Tabitha A. Harrison, Theo K. Bammler, Nicholas Mancuso, and Sara Lindström
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A map of approximately independent linkage disequilibrium (LD) blocks has many uses in statistical genetics. Current publicly available LD block maps are based on sparse recombination maps and are only available for GRCh37 (hg19) and prior genome assemblies. We generated LD blocks in GRCh38 coordinates for African (AFR), East Asian (EAS), European (EUR) and South Asian (SAS) ancestry populations. These new maps consist of 1,143 (EAS) - 1,604 (AFR) independent LD blocks across the 22 autosomal chromosomes and can be accessed athttps://github.com/jmacdon/LDblocks_GRCh38.
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- 2022
11. Maternal-fetal Stress and Dna Methylation Signatures in Neonatal Saliva: an Epigenome-wide Association Study
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Ritika, Sharma, Martin G, Frasch, Camila, Zelgert, Peter, Zimmermann, Bibiana, Fabre, Rory, Wilson, Melanie, Waldenberger, James W, MacDonald, Theo K, Bammler, Silvia M, Lobmaier, and Marta C, Antonelli
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Hydrocortisone ,Infant, Newborn ,Vesicular Transport Proteins ,Infant ,DNA Methylation ,Epigenome ,Fetal Diseases ,Pregnancy ,Prenatal Exposure Delayed Effects ,Genetics ,Humans ,Female ,Child ,Saliva ,Molecular Biology ,Biomarkers ,Genetics (clinical) ,Developmental Biology - Abstract
Background Maternal stress before, during and after pregnancy has profound effects on the development and lifelong function of the infant’s neurocognitive development. We hypothesized that the programming of the central nervous system (CNS), hypothalamic–pituitary–adrenal (HPA) axis and autonomic nervous system (ANS) induced by prenatal stress (PS) is reflected in electrophysiological and epigenetic biomarkers. In this study, we aimed to find noninvasive epigenetic biomarkers of PS in the newborn salivary DNA. Results A total of 728 pregnant women were screened for stress exposure using Cohen Perceived Stress Scale (PSS), 164 women were enrolled, and 114 dyads were analyzed. Prenatal Distress Questionnaire (PDQ) was also administered to assess specific pregnancy worries. Transabdominal fetal electrocardiograms (taECG) were recorded to derive coupling between maternal and fetal heart rates resulting in a ‘Fetal Stress Index’ (FSI). Upon delivery, we collected maternal hair strands for cortisol measurements and newborn’s saliva for epigenetic analyses. DNA was extracted from saliva samples, and DNA methylation was measured using EPIC BeadChip array (850 k CpG sites). Linear regression was used to identify associations between PSS/PDQ/FSI/Cortisol and DNA methylation. We found epigenome-wide significant associations for 5 CpG with PDQ and cortisol at FDR YAP1, TOMM20 and CSMD1, and two CpGs were located approximately lay at 50 kb from SSBP4 and SCAMP1. In addition, two differentiated methylation regions (DMR) related to maternal stress measures PDQ and cortisol were found: DAXX and ARL4D. Conclusions Genes annotated to these CpGs were found to be involved in secretion and transportation, nuclear signaling, Hippo signaling pathways, apoptosis, intracellular trafficking and neuronal signaling. Moreover, some CpGs are annotated to genes related to autism, post-traumatic stress disorder (PTSD) and schizophrenia. However, our results should be viewed as hypothesis generating until replicated in a larger sample. Early assessment of such noninvasive PS biomarkers will allow timelier detection of babies at risk and a more effective allocation of resources for early intervention programs to improve child development. A biomarker-guided early intervention strategy is the first step in the prevention of future health problems, reducing their personal and societal impact.
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- 2022
12. Spiny mice activate unique transcriptional programs after severe kidney injury regenerating organ function without fibrosis
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Sarah J. Collins, Kristina Bernardi, Szu-Ying Yeh, Daryl M. Okamura, Elizabeth Dong Nguyen, Mark W. Majesky, Theo K. Bammler, Amy Tran, James W. MacDonald, Jill Olson, Adrian M. Piliponsky, David R. Beier, Xiaogang Shi, Branden R. Nelson, Nadia Bahrami, Andrew E. Timms, Kathleen J. Millen, Chris M. Brewer, and Paul Wakenight
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Kidney ,Pathology ,medicine.medical_specialty ,Multidisciplinary ,Molecular biology ,Regeneration (biology) ,Science ,Scars ,Biology ,medicine.disease ,biology.organism_classification ,Article ,medicine.anatomical_structure ,Spiny mouse ,Fibrosis ,Animal physiology ,Developmental biology ,medicine ,Renal fibrosis ,Solid organ ,medicine.symptom ,Wound healing - Abstract
Summary Fibrosis-driven solid organ failure is an enormous burden on global health. Spiny mice (Acomys) are terrestrial mammals that can regenerate severe skin wounds without scars to avoid predation. Whether spiny mice also regenerate internal organ injuries is unknown. Here, we show that despite equivalent acute obstructive or ischemic kidney injury, spiny mice fully regenerate nephron structure and organ function without fibrosis, whereas C57Bl/6 or CD1 mice progress to complete organ failure with extensive renal fibrosis. Two mechanisms for vertebrate regeneration have been proposed that emphasize either extrinsic (pro-regenerative macrophages) or intrinsic (surviving cells of the organ itself) controls. Comparative transcriptome analysis revealed that the Acomys genome appears poised at the time of injury to initiate regeneration by surviving kidney cells, whereas macrophage accumulation was not detected until about day 7. Thus, we provide evidence for rapid activation of a gene expression signature for regenerative wound healing in the spiny mouse kidney., Graphical abstract, Highlights • Acomys fully regenerate kidney structure and function without fibrosis after injury • Unique gene clusters rapidly activated in surviving cells align with regeneration • Acomys genome appears poised at the time of kidney injury to initiate regeneration, Animal physiology; Molecular biology; Developmental biology
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- 2021
13. Associations of plasma miRNAs with waist circumference and insulin resistance among women with polycystic ovary syndrome – Pilot study
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Pandora L. Wander, Daniel A. Enquobahrie, Theo K. Bammler, James W. MacDonald, Sengkeo Srinouanprachanh, Thanmai Kaleru, Dori Khakpour, and Subbulaxmi Trikudanathan
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MicroRNAs ,Endocrinology ,Obesity, Abdominal ,Humans ,Female ,Pilot Projects ,Obesity ,Insulin Resistance ,Waist Circumference ,Molecular Biology ,Biochemistry ,Epigenesis, Genetic ,Polycystic Ovary Syndrome - Abstract
Insulin resistance (IR) and central obesity are common in polycystic ovary syndrome (PCOS), but pathomechanisms for IR in PCOS are not established. Circulating microRNAs (miRNAs) are non-invasive biomarkers of epigenetic regulation that may contribute to the pathogenesis of IR and central adiposity in PCOS.We conducted a pilot study to examine associations of circulating miRNAs with IR and central adiposity among women with PCOS (n = 11) using high-throughput miRNA sequencing. We fit generalized linear models examining associations of waist circumference and HOMA-IR with plasma miRNAs. We used false discovery rate (FDR)-adjusted cutoff p 0.1 to correct for multiple testing. We used miRDB's Gene Ontology (GO) tool to identify predicted pathways for top hits.Mean age and BMI of participants were 27.9 years and 32.5 kg/mPlasma miR-1294 along with members of the miR-17/92 cluster and miRNAs involved in insulin signaling may be associated with central obesity and insulin resistance in PCOS. Larger studies among women with and without PCOS are needed to validate these findings.
- Published
- 2022
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