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Lipid synthesis and transport are essential for energy, production of cell membrane, and cell signaling. Acyl-CoA thioesterases (ACOTs) function to regulate intracellular levels of fatty acyl-CoAs through hydrolysis. Two members of this family, ACOT11 and ACOT12, contain steroidogenic acute regulatory related lipid transfer domains, which typically function as lipid transport or regulatory domains. This work reviews ACOT11 and ACOT12 structures and functions, and the potential role of the START domains in lipid transfer activity and the allosteric regulation of catalytic activity.
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The motor features of Parkinson's disease result from loss of dopaminergic neurons in the substantia nigra with autophagy dysfunction being closely linked to this disease. While a large body of work focusing on protein effectors of autophagy has been reported, regulation of autophagy by lipids has garnered far less attention. Therefore, we sought to identify endogenous lipid molecules that act as signaling mediators of autophagy in differentiated SH-SY5Y cells, a commonly used dopaminergic neuron-like cell model. In order to accomplish this goal, we assessed the role of a fatty acid-binding protein (FABP) family member on autophagy due to its function as an intracellular lipid chaperone. We focused specifically upon FABP5 due to its heightened expression in dopaminergic neurons within the substantia nigra and SH-SY5Y cells. Here, we report that knockdown of FABP5 resulted in suppression of autophagy in differentiated SH-SY5Y cells suggesting the possibility of an autophagic role for an interacting lipid. A lipidomic screen of FABP5-interacting lipids uncovered hits that include 5-oxo-eicosatetraenoic acid (5OE) and its precursor metabolite, arachidonic acid (AA). Additionally, other long-chain fatty acids were found to bind FABP5, such as stearic acid (SA), hydroxystearic acid (HSA), and palmitic acid (PA). The addition of 5OE, SA, and HSA but not AA or PA, led to potent inhibition of autophagy in SH-SY5Y cells. To identify potential molecular mechanisms for autophagy inhibition by these lipids, RNA-Seq was performed which revealed both shared and divergent signaling pathways between the lipid-treated groups. These findings suggest a role for these lipids in modulating autophagy through diverse signaling pathways and could represent novel therapeutic targets for Parkinson's disease.
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Autofagia , Proteínas de Ligação a Ácido Graxo , Humanos , Proteínas de Ligação a Ácido Graxo/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Linhagem Celular Tumoral , Diferenciação Celular , Neurônios Dopaminérgicos/metabolismo , Transdução de SinaisRESUMO
Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we show profound sexual dimorphism in the scWAT of sedentary rats and in the dynamic response of this tissue to ExT. Specifically, the scWAT of sedentary females displays -omic signatures related to insulin signaling and adipogenesis, whereas the scWAT of sedentary males is enriched in terms related to aerobic metabolism. These sex-specific -omic signatures are preserved or amplified with ExT. Integration of multi-omic analyses with phenotypic measures identifies molecular hubs predicted to drive sexually distinct responses to training. Overall, this study underscores the powerful impact of sex on adipose tissue biology and provides a rich resource to investigate the scWAT response to ExT.
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Tecido Adiposo Branco , Condicionamento Físico Animal , Caracteres Sexuais , Gordura Subcutânea , Animais , Masculino , Feminino , Ratos , Tecido Adiposo Branco/metabolismo , Gordura Subcutânea/metabolismo , Adipogenia , Ratos Sprague-Dawley , MultiômicaRESUMO
Little is known about lipid changes that occur in the setting of metabolic-dysfunction-associated steatotic liver disease (MASLD) regression. We previously reported improvements in hepatic steatosis, de novo lipogenesis (DNL), and metabolomic profiles associated with oxidative stress, inflammation, and selected lipid metabolism in 40 adolescent boys (11-16 y) with hepatic steatosis ≥5% (98% meeting the definition of MASLD). Participants were randomized to a low-free-sugar diet (LFSD) (n = 20) or usual diet (n = 20) for 8 weeks. Here, we employed untargeted/targeted lipidomics to examine lipid adaptations associated with the LFSD and improvement of hepatic steatosis. Our LC-MS/MS analysis revealed decreased triglycerides (TGs), diacylglycerols (DGs), cholesteryl esters (ChE), lysophosphatidylcholine (LPC), and phosphatidylcholine (PC) species with the diet intervention (p < 0.05). Network analysis demonstrated significantly lower levels of palmitate-enriched TG species post-intervention, mirroring the previously shown reduction in DNL in response to the LFSD. Targeted oxylipins analysis revealed a decrease in the abundance of 8-isoprostane and 14,15-DiHET and an increase in 8,9-DiHET (p < 0.05). Overall, we observed reductions in TGs, DGs, ChE, PC, and LPC species among participants in the LFSD group. These same lipids have been associated with MASLD progression; therefore, our findings may indicate normalization of key biological processes, including lipid metabolism, insulin resistance, and lipotoxicity. Additionally, our targeted oxylipins assay revealed novel changes in eicosanoids, suggesting improvements in oxidative stress. Future studies are needed to elucidate the mechanisms of these findings and prospects of these lipids as biomarkers of MASLD regression.
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The biology of individual lipid species and their relevance in Alzheimer's disease (AD) remains incompletely understood. We utilized non-targeted mass spectrometry to examine brain lipids variations across 316 post-mortem brains from participants in the Religious Orders Study (ROS) or Rush Memory and Aging Project (MAP) cohorts classified as either control, asymptomatic AD (AAD), or symptomatic AD (SAD) and integrated the lipidomics data with untargeted proteomic characterization on the same individuals. Lipid enrichment analysis and analysis of variance identified significantly lower abundance of lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) species in SAD than controls or AAD. Lipid-protein co-expression network analyses revealed that lipid modules consisting of LPE and LPC exhibited a significant association to protein modules associated with MAPK/metabolism, post-synaptic density, and Cell-ECM interaction pathways and were associated with better antemortem cognition and with neuropathological changes seen in AD. Particularly, LPE 22:6 [sn-1] levels are significantly decreased across AD cases (SAD) and show the most influence on protein changes compared to other lysophospholipid species. LPE 22:6 may be a lipid signature for AD and could be leveraged as potential therapeutic or dietary targets for AD.
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Traditional cellular and live-virus methods for detection of SARS-CoV-2 neutralizing antibodies (nAbs) are labor- and time-intensive, and thus not suited for routine use in the clinical lab to predict vaccine efficacy and natural immune protection. Here, we report the development and validation of a rapid, high throughput method for measuring SARS-CoV-2 nAbs against native-like trimeric spike proteins. This assay uses a blockade of human angiotensin converting enzyme 2 (hACE-2) binding (BoAb) approach in an automated digital immunoassay on the Quanterix HD-X platform. BoAb assays using Wuhan-WT (vaccine strain), delta (B.1.167.2), omicron BA1 and BA2 variant viral strains showed strong correlation with cell-based pseudovirus neutralization activity (PNA) and live-virus neutralization activity. Importantly, we were able to detect similar patterns of delta and omicron variant resistance to neutralization in samples with paired vaccine strain and delta variant BoAb measurements. Finally, we screened clinical samples from patients with or without evidence of SARS-CoV-2 exposure by a single-dilution screening version of our assays, finding significant nAb activity only in exposed individuals. Importantly, this completely automated assay can be performed in 4 h to measure neutralizing antibody titers for 16 samples over 8 serial dilutions or, 128 samples at a single dilution with replicates. In principle, these assays offer a rapid, robust, and scalable alternative to time-, skill-, and cost-intensive standard methods for measuring SARS-CoV-2 nAb levels.
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The pairing of antibody genes IGHV2-5/IGLV2-14 is established as a public immune response that potently cross-neutralizes SARS-CoV-2 variants, including Omicron, by targeting class-3/RBD-5 epitopes in the receptor binding domain (RBD). LY-CoV1404 (bebtelovimab) exemplifies this, displaying exceptional potency against Omicron sub-variants up to BA.5. Here, we report a human antibody, 002-S21B10, encoded by the public clonotype IGHV2-5/IGLV2-14. While 002-S21B10 neutralized key SARS-CoV-2 variants, it did not neutralize Omicron, despite sharing >92% sequence similarity with LY-CoV1404. The structure of 002-S21B10 in complex with spike trimer plus structural and sequence comparisons with LY-CoV1404 and other IGHV2-5/IGLV2-14 antibodies revealed significant variations in light-chain orientation, paratope residues, and epitope-paratope interactions that enable some antibodies to neutralize Omicron but not others. Confirming this, replacing the light chain of 002-S21B10 with the light chain of LY-CoV1404 restored 002-S21B10's binding to Omicron. Understanding such Omicron evasion from public response is vital for guiding therapeutics and vaccine design.
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COVID-19 , SARS-CoV-2 , Humanos , Anticorpos Antivirais , Anticorpos Neutralizantes , EpitoposRESUMO
Rapid antigen tests (RATs) have become an invaluable tool for combating the COVID-19 pandemic. However, concerns have been raised regarding the ability of existing RATs to effectively detect emerging SARS-CoV-2 variants. We compared the performance of 10 commercially available, emergency use authorized RATs against the Delta and Omicron SARS-CoV-2 variants using both individual patient and serially diluted pooled clinical samples. The RATs exhibited lower sensitivity for Omicron samples when using PCR cycle threshold (CT) value (a rough proxy for RNA concentration) as the comparator. Interestingly, however, they exhibited similar sensitivity for Omicron and Delta samples when using quantitative antigen concentration as the comparator. We further found that the Omicron samples had lower ratios of antigen to RNA, which offers a potential explanation for the apparent lower sensitivity of RATs for that variant when using C T value as a reference. Our findings underscore the complexity in assessing RAT performance against emerging variants and highlight the need for ongoing evaluation in the face of changing population immunity and virus evolution.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , Pandemias , RNARESUMO
Hormones and receptors coevolve to generate species diversity in hormone action. We compared the structure and function of androgen receptors (ARs) across fishes, with a focus on ARs in ghost knifefishes (Apteronotidae). Apteronotids, like many other teleosts, have two ARs (ARα and ARß). ARß is largely conserved, whereas ARα sequences vary considerably across species. The ARα ligand binding domain (LBD) has evolved under positive selection, and differences in the LBD across apteronotid species are associated with diversity in androgenic regulation of behavior. The Apteronotus leptorhynchus ARα LBD differs substantially from that of the Apteronotus albifrons ARα or the ancestral AR. Structural modeling and transactivation assays demonstrated that A. leptorhynchus ARα cannot bind androgens. We propose a model whereby relative expression of ARα versus ARß in the brain, coupled with loss of androgen binding by ARα in A. leptorhynchus might explain reversals in androgenic regulation and sex differences in electrocommunication behavior.
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Androgênios , Peixe Elétrico , Animais , Feminino , Masculino , Androgênios/farmacologia , Androgênios/metabolismo , Peixe Elétrico/metabolismo , Receptores Androgênicos/metabolismo , Peixes/genética , Peixes/metabolismo , ComunicaçãoRESUMO
Nuclear receptors (NRs) are transcription factors that regulate essential biological processes in response to cognate ligands. An important part of NR function involves ligand-induced conformational changes that recruit coregulator proteins to the activation function surface (AFS), ~15 Å away from the ligand-binding pocket. Ligands must communicate with the AFS to recruit appropriate coregulators and elicit different transcriptional outcomes, but this communication is poorly understood. These studies illuminate allosteric communication networks underlying activation of liver receptor homolog-1 (LRH-1), a NR that regulates development, metabolism, cancer progression, and intestinal inflammation. Using >100 µs of all-atom molecular dynamics simulations involving 74 LRH-1 complexes, we identify distinct signaling circuits used by active and inactive ligands for AFS communication. Inactive ligands communicate via strong, coordinated motions along paths through the receptor to the AFS. Activating ligands disrupt the "inactive" circuit and induce connectivity with a second allosteric site. Ligand-contacting residues in helix 7 help mediate the switch between circuits, suggesting new avenues for developing LRH-1-targeted therapeutics. We also elucidate aspects of coregulator signaling, showing that localized, destabilizing fluctuations are induced by inappropriate ligand-coregulator pairings. These studies have uncovered novel features of LRH-1 allostery, and the quantitative approach used to analyze many simulations provides a framework to study allosteric signaling in other receptors.
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Receptores Citoplasmáticos e Nucleares , Fatores de Transcrição , Ligantes , Simulação de Dinâmica Molecular , Sítio Alostérico , Ligação ProteicaRESUMO
In this meet-the-author Q&A, Cell Press Community Review editor Leslie Nitsche speaks to Eric Ortlund as well as Eva Huber and Michael Groll from the Groll group about their recent Structure papers and their experiences publishing via Cell Press Community Review.
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DNA-dependent protein kinase (DNA-PK) plays a critical role in non-homologous end joining (NHEJ), the predominant pathway that repairs DNA double-strand breaks (DSB) in response to ionizing radiation (IR) to govern genome integrity. The interaction of the catalytic subunit of DNA-PK (DNA-PKcs) with the Ku70/Ku80 heterodimer on DSBs leads to DNA-PK activation; however, it is not known if upstream signaling events govern this activation. Here, we reveal a regulatory step governing DNA-PK activation by SIRT2 deacetylation, which facilitates DNA-PKcs localization to DSBs and interaction with Ku, thereby promoting DSB repair by NHEJ. SIRT2 deacetylase activity governs cellular resistance to DSB-inducing agents and promotes NHEJ. SIRT2 furthermore interacts with and deacetylates DNA-PKcs in response to IR. SIRT2 deacetylase activity facilitates DNA-PKcs interaction with Ku and localization to DSBs and promotes DNA-PK activation and phosphorylation of downstream NHEJ substrates. Moreover, targeting SIRT2 with AGK2, a SIRT2-specific inhibitor, augments the efficacy of IR in cancer cells and tumors. Our findings define a regulatory step for DNA-PK activation by SIRT2-mediated deacetylation, elucidating a critical upstream signaling event initiating the repair of DSBs by NHEJ. Furthermore, our data suggest that SIRT2 inhibition may be a promising rationale-driven therapeutic strategy for increasing the effectiveness of radiation therapy.
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Quebras de DNA de Cadeia Dupla , Proteínas Quinases , DNA/genética , DNA/metabolismo , Reparo do DNA por Junção de Extremidades , Reparo do DNA , Proteína Quinase Ativada por DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Autoantígeno Ku/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Quinases/genética , Sirtuína 2/genética , Sirtuína 2/metabolismo , HumanosRESUMO
Steroidogenic factor-1 (SF-1) is a phospholipid-sensing nuclear receptor expressed in the adrenal glands, gonads, and hypothalamus which controls steroidogenesis and metabolism. There is significant therapeutic interest in SF-1 because of its oncogenic properties in adrenocortical cancer. Synthetic modulators are attractive for targeting SF-1 for clinical and laboratory purposes due to the poor pharmaceutical properties of its native phospholipid ligands. While small molecule agonists targeting SF-1 have been synthesized, no crystal structures have been reported of SF-1 in complexes with synthetic compounds. This has prevented the establishment of structure-activity relationships that would enable better characterization of ligand-mediated activation and improvement in current chemical scaffolds. Here, we compare the effects of small molecules in SF-1 and its close homolog, liver receptor homolog-1 (LRH-1), and identify several molecules that specifically activate LRH-1. We also report the first crystal structure of SF-1 in complex with a synthetic agonist that displays low nanomolar affinity and potency for SF-1. We use this structure to explore the mechanistic basis for small molecule agonism of SF-1, especially compared to LRH-1, and uncover unique signaling pathways that drive LRH-1 specificity. Molecular dynamics simulations reveal differences in protein dynamics at the pocket mouth as well as ligand-mediated allosteric communication from this region to the coactivator binding interface. Our studies, therefore, shed important insight into the allostery driving SF-1 activity and show potential for modulation of LRH-1 over SF-1.
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Modelos Moleculares , Simulação de Dinâmica Molecular , Receptores Citoplasmáticos e Nucleares , Bibliotecas de Moléculas Pequenas , Fator Esteroidogênico 1 , Ligantes , Fosfolipídeos/química , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/química , Bibliotecas de Moléculas Pequenas/química , Fator Esteroidogênico 1/agonistas , Fator Esteroidogênico 1/química , Humanos , Cristalografia por Raios XRESUMO
Understanding the molecular features of neutralizing epitopes is important for developing vaccines/therapeutics against emerging SARS-CoV-2 variants. We describe three monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during the first wave of the pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, poorly neutralized Beta, and failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these mAbs in complex with trimeric spike protein showed that all three mAbs bivalently bind spike with two mAbs targeting class 1 and one targeting a class 4 receptor binding domain epitope. The immunogenetic makeup, structure, and function of these mAbs revealed specific molecular interactions associated with the potent multi-variant binding/neutralization efficacy. This knowledge shows how mutational combinations can affect the binding or neutralization of an antibody, which in turn relates to the efficacy of immune responses to emerging SARS-CoV-2 escape variants.
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Anticorpos Neutralizantes , COVID-19 , Humanos , SARS-CoV-2/genética , Anticorpos Monoclonais , Epitopos , Testes de NeutralizaçãoRESUMO
Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer's disease risk factor apolipoprotein E (APOE) and other secretome components. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.
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Apolipoproteína E4 , Mitocôndrias , Animais , Humanos , Camundongos , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Astrócitos/metabolismo , Genótipo , Mitocôndrias/metabolismo , Mitocôndrias/patologiaRESUMO
Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid-binding protein that transports phosphatidylcholine (PC) between cellular membranes. To better understand the protective metabolic effects associated with hepatic PC-TP, we generated a hepatocyte-specific PC-TP knockdown (L-Pctp-/-) in male mice, which gains less weight and accumulates less liver fat compared to wild-type mice when challenged with a high-fat diet. Hepatic deletion of PC-TP also reduced adipose tissue mass and decreases levels of triglycerides and phospholipids in skeletal muscle, liver and plasma. Gene expression analysis suggest that the observed metabolic changes are related to transcriptional activity of peroxisome proliferative activating receptor (PPAR) family members. An in-cell protein complementation screen between lipid transfer proteins and PPARs uncovered a direct interaction between PC-TP and PPARδ that was not observed for other PPARs. We confirmed the PC-TP- PPARδ interaction in Huh7 hepatocytes, where it was found to repress PPARδ-mediated transactivation. Mutations of PC-TP residues implicated in PC binding and transfer reduce the PC-TP-PPARδ interaction and relieve PC-TP-mediated PPARδ repression. Reduction of exogenously supplied methionine and choline reduces the interaction while serum starvation enhances the interaction in cultured hepatocytes. Together our data points to a ligand sensitive PC-TP- PPARδ interaction that suppresses PPAR activity.
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Fígado Gorduroso , PPAR delta , Masculino , Animais , Camundongos , PPAR delta/genética , Fosfatidilcolinas/metabolismo , Ligantes , Fígado Gorduroso/genética , Fígado Gorduroso/prevenção & controle , Fígado Gorduroso/metabolismo , Fígado/metabolismo , DietaRESUMO
Cancer cells use acetate to support the higher demand for energy and lipid biosynthesis during uncontrolled cell proliferation, as well as for acetylation of regulatory proteins. Acyl-CoA thioesterase 12 (Acot12) is the enzyme that hydrolyzes acetyl-CoA to acetate in liver cytosol and is downregulated in hepatocellular carcinoma (HCC). A mechanistic role for Acot12 in hepatocarcinogenesis was assessed in mice in response to treatment with diethylnitrosamine(DEN)/carbon tetrachloride (CCl4) administration or prolonged feeding of a diet that promotes non-alcoholic steatohepatitis (NASH). Relative to controls, Acot12-/- mice exhibited accelerated liver tumor formation that was characterized by the hepatic accumulation of glycerolipids, including lysophosphatidic acid (LPA), and that was associated with reduced Hippo signaling and increased yes-associated protein (YAP)-mediated transcriptional activity. In Acot12-/- mice, restoration of hepatic Acot12 expression inhibited hepatocarcinogenesis and YAP activation, as did knockdown of hepatic YAP expression. Excess LPA produced due to deletion of Acot12 signaled through LPA receptors (LPARs) coupled to Gα12/13 subunits to suppress YAP phosphorylation, thereby promoting its nuclear localization and transcriptional activity. These findings identify a protective role for Acot12 in suppressing hepatocarcinogenesis by limiting biosynthesis of glycerolipids including LPA, which preserves Hippo signaling.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Via de Sinalização Hippo , Neoplasias Hepáticas/patologia , Fatores de Transcrição/genética , Proteínas de Sinalização YAP/metabolismoRESUMO
The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.
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COVID-19 , Humanos , Criança , Adulto , SARS-CoV-2 , Estado Terminal , Citocinas , FibrinogênioRESUMO
Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training and sex on its molecular landscape has not been fully established. Utilizing an integrative multi-omics approach with data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we identified profound sexual dimorphism in the dynamic response of rat scWAT to endurance exercise training. Despite similar cardiorespiratory improvements, only male rats reduced whole-body adiposity, scWAT adipocyte size, and total scWAT triglyceride abundance with training. Multi-omic analyses of adipose tissue integrated with phenotypic measures identified sex-specific training responses including enrichment of mTOR signaling in females, while males displayed enhanced mitochondrial ribosome biogenesis and oxidative metabolism. Overall, this study reinforces our understanding that sex impacts scWAT biology and provides a rich resource to interrogate responses of scWAT to endurance training.
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Rapid Antigen Tests (RAT) have become an invaluable tool for combating the COVID-19 pandemic. However, concerns have been raised regarding the ability of existing RATs to effectively detect emerging SARS-CoV-2 variants. We compared the performance of eight commercially available, emergency use authorized RATs against the Delta and Omicron SARS-CoV-2 variants using individual patient and serially diluted pooled clinical samples. The RATs exhibited lower sensitivity for Omicron samples when using PCR Cycle threshold (C T ) value (a proxy for RNA concentration) as the comparator. Interestingly, however, they exhibited similar sensitivity for Omicron and Delta samples when using quantitative antigen concentration as the comparator. We further found that the Omicron samples had lower ratios of antigen to RNA, which offers a potential explanation for the apparent lower sensitivity of RATs for that variant when using C T value as a reference. Our findings underscore the complexity in assessing RAT performance against emerging variants and highlight the need for ongoing evaluation in the face of changing population immunity and virus evolution.