👤 Julia F Charles

Following their domestication, chickens were translocated around the world to novel environments. Through a combination of natural and artificial selection, chickens adapted to these local conditions, creating significant genetic diversity across populations worldwide. Studying this diversity in the context of local environmental conditions may offer insights into mechanisms of adaptation to environmental stressors. In this study, we analyzed genomic data from the Chicken Genomic Diversity Consortium, applying multiple statistical approaches, including fixation index (F The online version contains supplementary material available at 10.1038/s41598-026-41813-8. Show less

The potential causal effects of perinatal exposure to polyunsaturated fatty acids (PUFAs) on child neurodevelopment remains controversial. To infer causation, we assessed the association of perinatal PUFA patterns and child neurodevelopment by using conventional regression analyses and 1-sample Mendelian randomization (MR). Among 1096 mother-child pairs from the French Etude des Déterminants Pré- et Postnatals du Développement de la Santé de L'enfant cohort, patterns of perinatal exposure to PUFAs were previously identified combining PUFA levels from maternal and cord erythrocytes, and colostrum. Child verbal, performance, and full-scale intelligence quotients (IQs) were assessed at ages 5-6 y. Among maternal fatty acid desaturase (FADS) variants genotyped, 2 candidates, rs174546 (FADS1) and rs174634 (FADS3), were selected, as instrumental variables, for the MR analysis. The association of PUFA patterns with child IQ was examined by conventional multivariable linear regression and 2-stage least-squares MR regression. In the conventional approach, the first pattern "high omega-3 long-chain PUFAs (LC-PUFAs), low omega-6 LC-PUFAs" was positively associated with verbal IQ [β (95% confidence interval) = 1.24 (0.27, 2.21) points per 1 standard deviation (SD) increase in pattern] and full-scale IQ [1.11 (0.18, 2.05)]. This pattern was independent of FADS variants, rendering MR analysis inapplicable. The third pattern, "colostrum LC-PUFAs," was positively associated with verbal [1.11 (0.19, 2.02)], performance [1.01 (0.09, 1.93)], and full-scale IQ [1.13 (0.25, 2.01)]. The MR approach, based on genetic instruments strongly associated with the third pattern, supported the beneficial effect on performance IQ [2.93 (0.05, 5.81) points per 1 SD increase in genetically predicted pattern]. The MR also suggested a deleterious effect of the fourth pattern "linoleic acid (LA) and dihomo-gamma-linolenic acid (DGLA)" on performance IQ [-1.66 (-3.22, -0.09)]. These findings supported the potential beneficial effects of perinatal exposure to LC-PUFAs on child neurodevelopment while highlighting possible adverse effects associated with exposure to LA and DGLA. Show less

White adipose tissue dysfunction has emerged as a critical factor in cardiometabolic disease development, yet the cellular microstructure and genetic architecture of adipocyte morphology remain poorly explored. We introduce Adipocyte U-Net 2.0, an advanced deep learning method for the semantic segmentation of adipose tissue histology, enabling analysis of over 27 million adipocytes from 2,667 individuals. Our approach revealed that adipocyte hypertrophy associates with metabolic dysfunction, including increased fasting glucose, glycated hemoglobin, leptin, and triglycerides, with decreased adiponectin and HDL cholesterol levels. Through the largest genome-wide association study of adipocyte size to date (N Our findings demonstrate the utility of deep learning for adipocyte phenotyping at scale and provide novel insights into the genetic basis of adipocyte morphology and its relationship to metabolic disease. Show less

BACKGROUND Acute decompensated heart failure (ADHF) is associated with deterioration in renal function-an important risk factor for poor outcomes. Whether ADHF results in permanent kidney damage/dysfunction is unknown. METHODS AND RESULTS We investigated for the first time the renal responses to the development of, and recovery from, ADHF using an ovine model. ADHF development induced pronounced hemodynamic changes, neurohormonal activation, and decline in renal function, including decreased urine, sodium and urea excretion, and creatinine clearance. Following ADHF recovery (25 days), creatinine clearance reductions persisted. Kidney biopsies taken during ADHF and following recovery showed widespread mesangial cell prominence, early mild acute tubular injury, and medullary/interstitial fibrosis. Renal transcriptomes identified altered expression of 270 genes following ADHF development and 631 genes following recovery. A total of 47 genes remained altered post-recovery. Pathway analysis suggested gene expression changes, driven by a network of inflammatory cytokines centered on IL-1β (interleukin 1β), lead to repression of reno-protective eNOS (endothelial nitric oxide synthase) signaling during ADHF development, and following recovery, activation of glomerulosclerosis and reno-protective pathways and repression of proinflammatory/fibrotic pathways. A total of 31 dysregulated genes encoding proteins detectable in urine, serum, and plasma identified potential candidate markers for kidney repair (including Show less

Cholesteryl ester transfer protein (CETP) inhibitors are a new class of therapeutics for dyslipidemia that simultaneously improve two major cardiovascular disease (CVD) risk factors: elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol. However, the detailed molecular mechanisms underlying their efficacy are poorly understood, as are any potential mechanistic differences among the drugs in this class. Herein, we used electron microscopy (EM) to investigate the effects of three of these agents (Torcetrapib, Dalcetrapib and Anacetrapib) on CETP structure, CETP-lipoprotein complex formation and CETP-mediated cholesteryl ester (CE) transfer. We found that although none of these inhibitors altered the structure of CETP or the conformation of CETP-lipoprotein binary complexes, all inhibitors, especially Torcetrapib and Anacetrapib, increased the binding ratios of the binary complexes (e.g., HDL-CETP and LDL-CETP) and decreased the binding ratios of the HDL-CETP-LDL ternary complexes. The findings of more binary complexes and fewer ternary complexes reflect a new mechanism of inhibition: one distal end of CETP bound to the first lipoprotein would trigger a conformational change at the other distal end, thus resulting in a decreased binding ratio to the second lipoprotein and a degraded CE transfer rate among lipoproteins. Thus, we suggest a new inhibitor design that should decrease the formation of both binary and ternary complexes. Decreased concentrations of the binary complex may prevent the inhibitor was induced into cell by the tight binding of binary complexes during lipoprotein metabolism in the treatment of CVD. Show less

Osteoclasts are specialized secretory cells of the myeloid lineage important for normal skeletal homeostasis as well as pathologic conditions of bone including osteoporosis, inflammatory arthritis and cancer metastasis. Differentiation of these multinucleated giant cells from precursors is controlled by the cytokine RANKL, which through its receptor RANK initiates a signaling cascade culminating in the activation of transcriptional regulators which induce the expression of the bone degradation machinery. The transcription factor nuclear factor of activated T-cells c1 (NFATc1) is the master regulator of this process and in its absence osteoclast differentiation is aborted both in vitro and in vivo. Differential mRNA expression analysis by microarray is used to identify genes of potential physiologic relevance across nearly all biologic systems. We compared the gene expression profile of murine wild-type and NFATc1-deficient osteoclast precursors stimulated with RANKL and identified that the majority of the known genes important for osteoclastic bone resorption require NFATc1 for induction. Here, five novel RANKL-induced, NFATc1-dependent transcripts in the osteoclast are described: Nhedc2, Rhoc, Serpind1, Adcy3 and Rab38. Despite reasonable hypotheses for the importance of these molecules in the bone resorption pathway and their dramatic induction during differentiation, the analysis of mice with mutations in these genes failed to reveal a function in osteoclast biology. Compared to littermate controls, none of these mutants demonstrated a skeletal phenotype in vivo or alterations in osteoclast differentiation or function in vitro. These data highlight the need for rigorous validation studies to complement expression profiling results before functional importance can be assigned to highly regulated genes in any biologic process. Show less

Bardet-Biedl syndrome (BBS) is a rare developmental disorder with the cardinal features of abdominal obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, hypertension, and diabetes. BBS is genetically heterogeneous, with nine genes identified to date and evidence for additional loci. In this study, we performed mutation analysis of the coding and conserved regions of BBS1, BBS2, BBS4, and BBS6 in 48 French Caucasian individuals. Among the 36 variants identified, 12 were selected and genotyped in 1,943 French-Caucasian case subjects and 1,299 French-Caucasian nonobese nondiabetic control subjects. Variants in BBS2, BBS4, and BBS6 showed evidence of association with common obesity in an age-dependent manner, the BBS2 single nucleotide polymorphism (SNP) being associated with common adult obesity (P = 0.0005) and the BBS4 and BBS6 SNPs being associated with common early-onset childhood obesity (P = 0.0003) and common adult morbid obesity (0.0003 < P < 0.007). The association of the BBS4 rs7178130 variant was found to be supported by transmission disequilibrium testing (P = 0.006). The BBS6 variants also showed nominal evidence of association with quantitative components of the metabolic syndrome (e.g., dyslipidemia, hyperglycemia), a complication previously described in BBS patients. In summary, our preliminary data suggest that variations at BBS genes are associated with risk of common obesity. Show less

Recently a novel subfamily of closely related orphan G protein-coupled receptors (GPCRs) was identified, called GPRC5A, GPRC5B, GPRC5C and GPRC5D. Based on sequence homology, these receptors were classified as family C GPCRs, which include metabotropic GABA(B) receptors, metabotropic glutamate receptors, the calcium sensing receptor and a number of pheromone receptors. GPRC5 receptors share approximately 30-40% sequence homology to each other and 25% homology to the other family C members. It has been shown human GPRC5B mRNA is predominantly expressed in the central nervous system. In order to further characterise this receptor, we investigated both the mRNA and protein expression profiles in rodent tissues. Western blot analysis, using affinity-purified antisera specific to GPRC5B, identified a protein migrating at approximately 68 kDa, close to the predicted molecular weight for GPRC5B. Immunocytochemical analysis of GPRC5B-transfected cells revealed a cell surface localisation. In addition, immunohistochemical analysis of GPRC5B in rat brain and spinal cord demonstrated receptor expression in many areas, with highest levels of immunoreactivity in the neocortex, all subfields of the hippocampus, the granule cell layer of the cerebellum and throughout the spinal cord. Show less