Tissue-specific Effects Research Articles

Tissue-Specific Effects of Aging on Repeat-Mediated Mutation Hotspots In Vivo

Aging constitutes complex and dynamic alterations in molecular and physiological processes and is associated with numerous disorders, in part due to increased genetic instability. The aging population is projected to double by 2050, underscoring the urgent need to better understand the relationships between aging and age-related disorders. Repetitive DNA elements are intrinsic sources of genetic instability and have been found to co-localize with mutation hotspots in human cancer genomes. In this study, we explored the relationship between aging and DNA repeat-mediated genetic instability in vivo using an H-DNA-forming mirror-repeat sequence from the cancer-associated human c-MYC gene. Utilizing a unique mutation-reporter mouse model, we observed tissue-specific effects of aging on H-DNA-induced genetic instability, with mutation frequencies increasing in spleen tissues and remaining unchanged in testis tissues. Analysis of the mutation spectra revealed large deletion mutations as the primary contributor to increasing H-DNA-induced mutations, supported by increased cleavage activity of H-DNA structures in aged spleen tissues. Our findings demonstrate that aging has distinct tissue-specific effects on repeat-mediated, cancer-associated mutations, providing insights into the complex relationship between aging and cancer.

The impact of inactivation of the GH/IGF axis during aging on healthspan.

Several mouse lines with congenital growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis disruption have shown improved health and extended lifespan. The current study investigated how inactivating this axis, specifically during aging, impacts the healthspan. We used a tamoxifen-inducible global GH receptor (GHR) knockout mouse model starting at 12 months and followed the mice until 24 months of age (iGHRKO12-24 mice). We found sex- and tissue-specific effects, with some being pro-aging and others anti-aging. Measuring an array of cytokines in serum revealed that inactivation of the GH/IGF-1 axis at 12 months did not affect systemic inflammation during aging. On the other hand, hypothalamic inflammation was significantly reduced in iGHRKO12-24 mice, evidenced by GFAP+ (glial fibrillary acidic protein, a marker of astrocytes) and Iba-1+ (a marker for microglia). Liver RNAseq analysis indicated feminization of the male transcriptome, with significant changes in the expression of monooxygenase, sulfotransferase, and solute-carrier-transporter gene clusters. Finally, we found impaired bone morphology, more pronounced in male iGHRKO12-24 mice and correlated with GH/IGF-1 inactivation onset age. We conclude that inhibiting the GH/IGF-1 axis during aging only partially preserves the beneficial healthspan effects observed with congenital GH deficiency.

Deciphering the tissue-specific functional effect of Alzheimer risk SNPs with deep genome annotation.

Alzheimer's disease (AD) is a highly heritable brain dementia, along with substantial failure of cognitive function. Large-scale genome-wide association studies (GWASs) have led to a set of SNPs significantly associated with AD and related traits. GWAS hits usually emerge as clusters where a lead SNP with the highest significance is surrounded by other less significant neighboring SNPs. Although functionality is not guaranteed even with the strongest associations in GWASs, lead SNPs have historically been the focus of the field, with the remaining associations inferred to be redundant. Recent deep genome annotation tools enable the prediction of function from a segment of a DNA sequence with significantly improved precision, which allows in-silico mutagenesis to interrogate the functional effect of SNP alleles. In this project, we explored the impact of top AD GWAS hits around APOE region on chromatin functions and whether it will be altered by the genetic context (i.e., alleles of neighboring SNPs). Our results showed that highly correlated SNPs in the same LD block could have distinct impacts on downstream functions. Although some GWAS lead SNPs showed dominant functional effects regardless of the neighborhood SNP alleles, several other SNPs did exhibit enhanced loss or gain of function under certain genetic contexts, suggesting potential additional information hidden in the LD blocks.

ApoE Receptor-2 R952Q Variant in Macrophages Elevates Soluble LRP1 to Potentiate Hyperlipidemia and Accelerate Atherosclerosis in Mice.

apoER2 (apolipoprotein E receptor-2) is a transmembrane receptor in the low-density lipoprotein receptor (LDLR) family with unique tissue expression. A single-nucleotide polymorphism that encodes the R952Q sequence variant has been associated with elevated plasma cholesterol levels and increased myocardial infarction risk in humans. The objective of this study was to delineate the mechanism underlying the association between the apoER2 R952Q variant and increased atherosclerosis risk. An apoER2 R952Q mouse model was generated using a CRISPR/Cas9 strategy, intercrossed with LDLR knockout mice, followed by feeding a Western-type high-fat high-cholesterol diet for 16 weeks. Atherosclerosis was investigated by immunohistology. Plasma lipids and lipid distributions among the various lipoprotein classes were analyzed by colorimetric assay. Tissue-specific effects of the R952Q sequence variant on atherosclerosis were analyzed by bone marrow transplant studies. sLRP1 (soluble low-density lipoprotein receptor-related protein 1) was measured in plasma and conditioned media from bone marrow-derived macrophages by ELISA and GST-RAP (glutathione S-transferase-receptor-associated protein) pull-down, respectively. P38 MAPK (mitogen-activated protein kinase) phosphorylation in VLDL (very-low-density lipoprotein)-treated macrophages was determined by Western blot analysis. Consistent with observations in humans with this sequence variant, the apoER2 R952Q mutation exacerbated diet-induced hypercholesterolemia, via impediment of plasma triglyceride-rich lipoprotein clearance, to accelerate atherosclerosis in Western diet-fed LDLR knockout mice. Reciprocal bone marrow transplant experiments revealed that the apoER2 R952Q mutation in bone marrow-derived cells instead of non-bone marrow-derived cells was responsible for the increase in hypercholesterolemia and atherosclerosis. Additional data showed that the apoER2 R952Q mutation in macrophages promotes VLDL-induced LRP1 (low-density lipoprotein receptor-related protein 1) shedding in a p38 MAPK-dependent manner. The apoER2 R952Q mouse model recapitulates characteristics observed in human disease. The underlying mechanism is that the apoER2 R952Q mutation in macrophages exacerbates VLDL-stimulated sLRP1 production in a p38 MAPK-dependent manner, resulting in its competition with cell surface LRP1 to impede triglyceride-rich lipoprotein clearance, thereby resulting in increased hypercholesterolemia and accelerated atherosclerosis.

Acute kidney injury after catheter ablation of atrial fibrillation: comparison between different energy sources

Abstract Introduction Pulsed field ablation (PFA) is an innovative technology recently adopted for the treatment of atrial fibrillation (AF). Preclinical and clinical studies have reported a reassuring safety profile, because of its tissue specific effect, sparing adjacent tissues. However, two cases of acute kidney injury (AKI) secondary to hemolysis after PFA have recently been reported. Purpose To compare the incidence of AKI and hemolysis after catheter ablation of AF using radiofrequency energy (RFA), cryo-balloon energy (CBA) and PFA using a pentaspline catheter. Method Patients undergoing catheter ablation of AF were consecutively enrolled in a prospective registry in a tertiary referral center between April 2010 and January 2024. Blood samples including renal parameters and hemolysis indicators were obtained prior to the procedure and the day after the procedure. AKI was defined as an increase in serum creatinine by 26.5 µmol/L within up to 10 days after the procedure . Results A total of 2602 patients (median age 64 years, 29.4% female) underwent catheter ablation for AF. 1707 (66.4%) were treated with RFA, 557 (21.7%) using CBA and 306 (11.9%) using PFA. Median net duration of ablation was 1669 (IQR 1207, 2164) seconds for RFA, 1046 (IQR 840, 1451) seconds for CBA and, 80 (IQR 48, 85) seconds (32 (IQR 19, 34) applications) for PFA. AKI was found in 21 (0.012%), 1 (0.002%) and 1 (0.003%) patients treated with RFA, CBA and PFA, respectively, p=0.245. The case with AKI after PFA received a total of 86 PFA applications. There was a significant positive correlation for the RFA group between the ablation duration and the creatinine level after the procedure, while there was no positive correlation for the CBA and PFA group (Figure). At least one hemolysis indicator (Bilirubin, LDH or Urea levels) was elevated the day after the procedure in 53.1%, 50.1% and 46.5% in the RFA, CBA and PFA group, respectively, p=0.12. Conclusion AKI appears to be very rare after PFA and comparable to thermal energy forms. Hemolysis does not seem to be dependent on the used energy source for pulmonary vein isolation. Minimal hemolysis occurs when PFA is applied as recommended by the manufacturer.Graphical Abstract

A multi-omics study of brain tissue transcription and DNA methylation revealing the genetic pathogenesis of ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disease that often affects a patient's whole life. Research has found that genetics plays an important role in the development of ADHD. However, there is still a lack of knowledge about the tissue-specific causal effects of biological processes beyond gene expression, such as alternative splicing (AS) and DNA methylation (DNAm), on ADHD. In this paper, a multi-omics study was conducted to investigate the causal effects of the transcription and the DNAm on ADHD, by integrating ADHD genome-wide association data with quantitative trait loci data of gene expression, AS, and DNAm across 14 different brain tissues. The causal effects were estimated using four different two-sample Mendelian randomization methods. Finally, we also prioritized the expression of 866 genes showing significant causal effects, including COMMD5, ENSG00000271904, HYAL3, etc., within at least one brain tissue. We prioritized 966 unique genes that have statistically significant causal AS events, within at least one of the 14 different brain tissues. These genes include PPP1R16A, GGT7, TREM2, etc. Furthermore, through mediation analysis, 106 regulatory pathways were inferred where DNAm influences ADHD through gene expression or AS processes. Our research findings provide guidance for future experimental studies on the molecular mechanisms of ADHD development, and also put forward valuable knowledge for the prevention, diagnosis, and treatment of ADHD.

Insights on estetrol, the native estrogen: from contraception to hormone replacement therapy.

Estetrol (E4) is a natural estrogen that has recently emerged as new option for contraception and hormone replacement therapy (HRT). Unlike other estrogens, E4 primarily stimulates nuclear estrogen receptor alpha (ERα) and does not activate membrane ERα. For this reason, this novel estrogen has tissue-specific effects across various organs such as liver, vascular endothelium, mammary glands, brain, vagina, and uterus. The selective activation of the nuclear ERα results in distinct pharmacological properties that contribute to its unique therapeutic profile. Moreover, E4 shows minimal interaction with the hepatic cytochrome P450 enzyme system, leading to a favorable pharmacokinetic profile and a reduced potential for drug-drug interactions. Currently, E4 is commercially available in combination with drospirenone as a combined oral contraceptive and its application in HRT is undergoing late-stage clinical development. Many studies have demonstrated that E4 has a lower impact on hemostatic and metabolic parameters compared to other estrogens, potentially reducing the risk of adverse effects commonly associated with hormonal therapies such as thromboembolic events or dyslipidemia. Beyond its role in contraception and HRT, E4 shows promising therapeutic potential in other medical fields, including neuroprotection in neonatal hypoxic-ischemic encephalopathy, enhancement of hematopoietic stem cell transplantation outcomes and prostate cancer management. This review synthesizes the latest evidence on E4 primarily focusing on its pharmacological characteristics and clinical applications. The findings suggest that E4 versatility and peculiar mechanism of action may represent an important therapeutic option for a broad spectrum of medical conditions.

Recruitment of CXCR4+ type 1 innate lymphoid cells distinguishes sarcoidosis from other skin granulomatous diseases.

Sarcoidosis is a multiorgan granulomatous disease that lacks diagnostic biomarkers and targeted treatments. Using blood and skin from patients with sarcoid and non-sarcoid skin granulomas, we discovered that skin granulomas from different diseases exhibit unique immune cell recruitment and molecular signatures. Sarcoid skin granulomas were specifically enriched for type 1 innate lymphoid cells (ILC1s) and B cells and exhibited molecular programs associated with formation of mature tertiary lymphoid structures (TLSs), including increased CXCL12/CXCR4 signaling. Lung sarcoidosis granulomas also displayed similar immune cell recruitment. Thus, granuloma formation was not a generic molecular response. In addition to tissue-specific effects, patients with sarcoidosis exhibited an 8-fold increase in circulating ILC1s, which correlated with treatment status. Multiple immune cell types induced CXCL12/CXCR4 signaling in sarcoidosis, including Th1 T cells, macrophages, and ILCs. Mechanistically, CXCR4 inhibition reduced sarcoidosis-activated immune cell migration, and targeting CXCR4 or total ILCs attenuated granuloma formation in a noninfectious mouse model. Taken together, our results show that ILC1s are a tissue and circulating biomarker that distinguishes sarcoidosis from other skin granulomatous diseases. Repurposing existing CXCR4 inhibitors may offer a new targeted treatment for this devastating disease.

Spermidine supplementation influence on protective enzymes of Apis mellifera (Hymenoptera: Apidae).

Dietary supplementation has been proposed as a sustainable way to improve the health and resilience of honey bees (Apis mellifera, L.), as the decline in their numbers in recent decades has raised scientific, environmental, and economic concerns. Spermidine, a natural polyamine, has been shown to be a promising substance for honey bee supplementation, as its health-promoting effects have been demonstrated in numerous studies and in different organisms. As already shown, supplementation with spermidine at a certain concentration prolonged lifespan, reduced oxidative stress, and increased antioxidative capacity in honey bees. The aim of the present study was to investigate whether spermidine supplementation affects gene expression and/or enzyme activity of antioxidative and detoxification enzymes and immune response markers in honey bee workers. The different gene expression and enzyme activity patterns observed in abdominal and head tissues in response to spermidine supplementation suggest tissue-specific and concentration-dependent effects. In addition, the immune response markers suggest that spermidine has the ability to boost honey bee immunity. The observed changes make a valuable contribution to understanding the molecular mechanisms by which spermidine may exert its beneficial effects on the bee's health and lifespan. These results support the idea of the use of spermidine supplementation to promote bee health and resilience to environmental stressors, emphasizing that the dose must be carefully chosen to achieve a balance between the pro- and antioxidant effects of spermidine.

Adipose ADM2 ameliorates NAFLD via promotion of ceramide catabolism

The adipose tissue of mammals represents an important energy-storing and endocrine organ, and its dysfunction is relevant to the onset of several health problems, including non-alcoholic fatty liver disease (NAFLD). However, whether treatments targeting adipose dysfunction could alleviate NAFLD has not been well-studied. Adrenomedullin 2 (ADM2), belonging to the CGRP superfamily, is a protective peptide that has been shown to inhibit adipose dysfunction. To investigate the adipose tissue-specific effects of ADM2 on NAFLD, adipose-specific ADM2-overexpressing transgenic (aADM2-tg) mice were developed. When fed a high-fat diet, aADM2-tg mice displayed decreased hepatic triglyceride accumulation compared to wild-type mice, which was attributable to the inhibition of hepatic de novo lipogenesis. Results from lipidomics studies showed that ADM2 decreased ceramide levels in adipocytes through the upregulation of ACER2, which catalyzes ceramide catabolism. Mechanically, activation of adipocyte HIF2α was required for ADM2 to promote ACER2-dependent adipose ceramide catabolism as well as to decrease hepatic lipid accumulation. This study highlights the role of ADM2 and adipose-derived ceramide in NAFLD and suggests that its therapeutic targeting could alleviate disease symptoms.

Activation of Nrf2 at Critical Windows of Development Alters Tissue-Specific Protein S-Glutathionylation in the Zebrafish (Danio rerio) Embryo.

Activation of Nrf2-the master regulator of antioxidative response-at different stages of embryonic development has been shown to result in changes in gene expression, but the tissue-specific and downstream effects of Nrf2 activation during development remain unclear. This work seeks to elucidate the tissue-specific Nrf2 cellular localization and the downstream changes in protein S-glutathionylation during critical windows of zebrafish (Danio rerio) development. Wild-type and mutant zebrafish embryos with a loss-of-function mutation in Nrf2a were treated with two canonical activators, sulforaphane (SFN; 40 µM) or tert-butylhydroquinone (tBHQ; 1 µM), for 6 h at either pharyngula, hatching, or the protruding-mouth stage. Nrf2a protein and S-glutathionylation were visualized in situ using immunohistochemistry. At the hatching stage, Nrf2a protein levels were decreased with SFN, but not tBHQ, exposure. Exposure to both activators, however, decreased downstream S-glutathionylation. Stage- and tissue-specific differences in Nrf2a protein and S-glutathionylation were identified in the pancreatic islet and liver. Protein S-glutathionylation in Nrf2a mutant fish was increased in the liver by both activators, but not the islets, indicating a tissue-specific and Nrf2a-dependent dysregulation. This work demonstrates that critical windows of exposure and Nrf2a activity may influence redox homeostasis and highlights the importance of considering tissue-specific outcomes and sensitivity in developmental redox biology.

DNA methylation correlates of chronological age in diverse human tissue types

BackgroundWhile the association of chronological age with DNA methylation (DNAm) in whole blood has been extensively studied, the tissue-specificity of age-related DNAm changes remains an active area of research. Studies investigating the association of age with DNAm in tissues such as brain, skin, immune cells, fat, and liver have identified tissue-specific and non-specific effects, thus, motivating additional studies of diverse human tissue and cell types.ResultsHere, we performed an epigenome-wide association study, leveraging DNAm data (Illumina EPIC array) from 961 tissue samples representing 9 tissue types (breast, lung, colon, ovary, prostate, skeletal muscle, testis, whole blood, and kidney) from the Genotype-Tissue Expression (GTEx) project. We identified age-associated CpG sites (false discovery rate < 0.05) in 8 tissues (all except skeletal muscle, n = 47). This included 162,002 unique hypermethylated and 90,626 hypomethylated CpG sites across all tissue types, with 130,137 (80%) hypermethylated CpGs and 74,703 (82%) hypomethylated CpG sites observed in a single tissue type. While the majority of age-associated CpG sites appeared tissue-specific, the patterns of enrichment among genomic features, such as chromatin states and CpG islands, were similar across most tissues, suggesting common mechanisms underlying cellular aging. Consistent with previous findings, we observed that hypermethylated CpG sites are enriched in regions with repressed polycomb signatures and CpG islands, while hypomethylated CpG sites preferentially occurred in non-CpG islands and enhancers. To gain insights into the functional effects of age-related DNAm changes, we assessed the correlation between DNAm and local gene expression changes to identify age-related expression quantitative trait methylation (age-eQTMs). We identified several age-eQTMs present in multiple tissue-types, including in the CDKN2A, HENMT1, and VCWE regions.ConclusionOverall, our findings will aid future efforts to develop biomarkers of aging and understand mechanisms of aging in diverse human tissue types.

Pervasive tissue-, genetic background-, and allele-specific gene expression effects in Drosophila melanogaster.

The pervasiveness of gene expression variation and its contribution to phenotypic variation and evolution is well known. This gene expression variation is context dependent, with differences in regulatory architecture often associated with intrinsic and environmental factors, and is modulated by regulatory elements that can act in cis (linked) or in trans (unlinked) relative to the genes they affect. So far, little is known about how this genetic variation affects the evolution of regulatory architecture among closely related tissues during population divergence. To address this question, we analyzed gene expression in the midgut, hindgut, and Malpighian tubule as well as microbiome composition in the two gut tissues in four Drosophila melanogaster strains and their F1 hybrids from two divergent populations: one from the derived, European range and one from the ancestral, African range. In both the transcriptome and microbiome data, we detected extensive tissue- and genetic background-specific effects, including effects of genetic background on overall tissue specificity. Tissue-specific effects were typically stronger than genetic background-specific effects, although the two gut tissues were not more similar to each other than to the Malpighian tubules. An examination of allele specific expression revealed that, while both cis and trans effects were more tissue-specific in genes expressed differentially between populations than genes with conserved expression, trans effects were more tissue-specific than cis effects. Despite there being highly variable regulatory architecture, this observation was robust across tissues and genetic backgrounds, suggesting that the expression of trans variation can be spatially fine-tuned as well as or better than cis variation during population divergence and yielding new insights into cis and trans regulatory evolution.

An integrative multi-context Mendelian randomization method for identifying risk genes across human tissues

Mendelian randomization (MR) provides valuable assessments of the causal effect of exposure on outcome, yet the application of conventional MR methods for mapping risk genes encounters new challenges. One of the issues is the limited availability of expression quantitative trait loci (eQTLs) as instrumental variables (IVs), hampering the estimation of sparse causal effects. Additionally, the often context- or tissue-specific eQTL effects challenge the MR assumption of consistent IV effects across eQTL and GWAS data. To address these challenges, we propose a multi-context multivariable integrative MR framework, mintMR, for mapping expression and molecular traits as joint exposures. It models the effects of molecular exposures across multiple tissues in each gene region, while simultaneously estimating across multiple gene regions. It uses eQTLs with consistent effects across more than one tissue type as IVs, improving IV consistency. A major innovation of mintMR involves employing multi-view learning methods to collectively model latent indicators of disease relevance across multiple tissues, molecular traits, and gene regions. The multi-view learning captures the major patterns of disease relevance and uses these patterns to update the estimated tissue relevance probabilities. The proposed mintMR iterates between performing a multi-tissue MR for each gene region and joint learning the disease-relevant tissue probabilities across gene regions, improving the estimation of sparse effects across genes. We apply mintMR to evaluate the causal effects of gene expression and DNA methylation for 35 complex traits using multi-tissue QTLs as IVs. The proposed mintMR controls genome-wide inflation and offers insights into disease mechanisms.

Tissue-specific effects of temperature and salinity on the cell cycle and apoptosis in the Nile Tilapia (Oreochromis niloticus)

The Nile Tilapia (Oreochromis niloticus) evolved in warm, freshwater rivers, but possesses a broad physiological tolerance to a range of environmental conditions. Due to this hardiness and resilience, this species has been successfully introduced to regions widely outside of its native range. Here, we examine the impact of temperature and salinity variation on this species at the sub-lethal level. Specifically, Nile Tilapia were exposed to two temperatures (21 °C or 14 °C) and three salinities (0, 16, 34 ppt) for 1-h. Given their native habitat, the 21 °C / 0 ppt exposure was considered the control condition. Both cell cycle arrest and apoptosis represent sub-lethal but deleterious responses to environmental stress. Flow cytometry was used to assess the percentage of cells in a given stage of the cell cycle as a metric of cell cycle arrest in spleen and liver. Percentage of apoptotic cells were also quantified. Spleen was more sensitive to cold stress, demonstrating an increase in cells in the G2/M phase after experimental treatment. Liver, however, was more sensitive to salinity stress, with a significant increase in cells stalled in G2/M phase at higher salinities, which is in keeping with the freshwater evolutionary history of the species. A modest apoptotic signal was observed in liver but not in spleen. Together, these findings demonstrate that even short, acute exposures to cold temperatures and elevated salinity can cause sub-lethal damage in a species that is otherwise tolerant of environmental stress at the whole organism level.

Pleiotropic effects of an eQTL in the CELSR2/PSRC1/SORT1 cluster that associates with LDL-C and resting metabolic rate.

The locus CELSR2-PSRC1-SORT1, a primary genetic signal for lipids, has recently been implicated in different metabolic processes. Our investigation identified its association with energy metabolism. To determine biological mechanisms that govern diverse functions of this locus. Genotypes for 491,265 variants in 7,000 clinically characterized American Indians were previously determined using a custom-designed array specific for this longitudinally studied American Indian population. Among the genotyped individuals, 5,205 had measures of fasting lipid levels and 509 had measures of resting metabolic rate (RMR) and substrate oxidation rate assessed through indirect calorimetry. A genome-wide association study (GWAS) for LDL-C levels identified a variant in CELSR2 and the molecular impact of this variant on gene expression was assessed in skeletal muscle biopsies from 207 participants, followed by functional validation in mouse myoblasts using a luciferase assay. A GWAS in American Indians identified rs12740374 in CELSR2 as the top signal for LDL-C levels (P = 1 × 10-22); further analysis of this variant identified an unexpected correlation with reduced RMR (effect = -44.3 kcal/day/minor-allele) and carbohydrate oxidation rate (effect = -5.21 mg/hour/kg-EMBS). Tagged variants showed a distinct linkage disequilibrium architecture in American Indians, highlighting a potential functional variant, rs6670347 (minor-allele frequency = 0.20). Positioned in the glucocorticoid receptor's core binding motif, rs6670347 is part of a skeletal muscle-specific enhancer. Human skeletal muscle transcriptome analysis showed CELSR2 as the most differentially expressed gene (P = 1.9 × 10-7), with the RMR-lowering minor allele elevating gene expression. Experiments in mouse myoblasts confirmed enhancer-based regulation of CELSR2 expression, dependent on glucocorticoids. Rs6670347 also associated with increased oxidative phosphorylation gene expression; CELSR2 as a regulator of these genes, suggests potential influence on energy metabolism through muscle oxidative capacity. Variants in the CELSR2/PSRC1/SORT1 locus exhibit tissue-specific effects on metabolic traits, with an independent role in muscle metabolism through glucocorticoid signaling.

Clinical Spectrum of Long COVID: Effects on Female Reproductive Health.

The COVID-19 pandemic caused by SARS-CoV-2 has presented numerous health challenges, including long-term COVID, which affects female reproductive health. This review consolidates the current research on the impact of SARS-CoV-2 on the menstrual cycle, ovarian function, fertility, and overall gynecological health. This study emphasizes the role of angiotensin-converting enzyme receptors in viral entry and the subsequent tissue-specific pathological effects. It also explores the potential influence of long COVID on hormonal balance and immune responses, contributing to menstrual irregularities and impaired ovarian function. The findings indicate a higher prevalence of long-term COVID-19 among women, highlighting the substantial implications for reproductive health and the need for sex-sensitive longitudinal studies. Enhanced surveillance and targeted research are essential to develop effective interventions that prioritize women's reproductive well-being following SARS-CoV-2 infection. This review advocates for a sex-informed approach to ongoing COVID-19 research and healthcare strategies, aiming to provide up-to-date and pertinent data for healthcare providers and the general public, ultimately improving outcomes for females affected by long COVID.

Modulation of gene expression in immune-related organs by in ovo stimulation with probiotics and prophybiotics in broiler chickens.

In ovo stimulation has been studied intensively as an alternative to antibiotic use in poultry production. We investigated the potential use of a probiotic in combination with a phytobiotic as a prophybiotic for in ovo stimulation and reported its beneficial effects on the gut microbiome of broiler chickens. The current study further investigates the gene expression in the immune-related organs of these chickens to understand the tissue-specific immunomodulatory effects of the treatments. The selected prophybiotic (Leuconostoc mesenteroides with garlic aqueous extract) and its probiotic component alone were injected into ROSS308 chicken eggs on the 12th day of incubation, and gene expression in cecal tonsils, spleen, and liver at 35 days of age was determined using qPCR method. The relative expression of each treatment was compared to the positive control, chickens injected with physiological saline in ovo. The results displayed a downregulation of pro- and anti-inflammatory cytokines in the cecal tonsils of the probiotic group and the liver of the prophybiotic group. The spleen displayed upregulated AVBD1 in both groups and upregulated IL1-β in the probiotic group. The probiotic group displayed increased expression of genes related to metabolism of energy (COX16), protein (mTOR), and lipids (CYP46A1) whereas the prophybiotic group displayed reduced expression of genes related to cholesterol synthesis (SREBP1) and glucose transportation (SLC2A2) in the liver. In conclusion, Leuconostoc mesenteroides differentially modulated gene expression in chickens when administered in ovo in combination with garlic aqueous extract. Further in ovo studies with different prophybiotic combinations are required to optimize the benefits in broiler chickens.

Partitioning and aggregating cross-tissue and tissue-specific genetic effects to identify gene-trait associations

TWAS have shown great promise in extending GWAS loci to a functional understanding of disease mechanisms. In an effort to fully unleash the TWAS and GWAS information, we propose MTWAS, a statistical framework that partitions and aggregates cross-tissue and tissue-specific genetic effects in identifying gene-trait associations. We introduce a non-parametric imputation strategy to augment the inaccessible tissues, accommodating complex interactions and non-linear expression data structures across various tissues. We further classify eQTLs into cross-tissue eQTLs and tissue-specific eQTLs via a stepwise procedure based on the extended Bayesian information criterion, which is consistent under high-dimensional settings. We show that MTWAS significantly improves the prediction accuracy across all 47 tissues of the GTEx dataset, compared with other single-tissue and multi-tissue methods, such as PrediXcan, TIGAR, and UTMOST. Applying MTWAS to the DICE and OneK1K datasets with bulk and single-cell RNA sequencing data on immune cell types showcases consistent improvements in prediction accuracy. MTWAS also identifies more predictable genes, and the improvement can be replicated with independent studies. We apply MTWAS to 84 UK Biobank GWAS studies, which provides insights into disease etiology.

Calorie restriction activates a gastric Notch-FOXO1 pathway to expand ghrelin cells.

Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice. This effect was accompanied by increased Notch target Hes1 and Notch ligand Jag1 and was reversed by blocking Notch with DAPT, a gamma-secretase inhibitor. Primary cultures and genetically modified reporter mice show that increased endocrine cell abundance is due to altered Lgr5+ stem and Neurog3+ endocrine progenitor cell proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch. The Notch inhibitor PF-03084014 or ghrelin receptor antagonist GHRP-6 reversed the phenotypic effects of calorie restriction in mice. Tirzepatide additionally expanded ghrelin+ cells in mice. In summary, calorie restriction promotes Notch-dependent, FOXO1-regulated gastric endocrine cell differentiation.