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Published By American Physiological Society

1531-2267, 1094-8341
Updated Saturday, 16 October 2021

Author(s):  
Theresa Casey ◽  
Aridany M Suarez-Trujillo ◽  
Conor McCabe ◽  
Linda Beckett ◽  
Rebecca Klopp ◽  
...  

Circadian disruption increased insulin resistance and decreased mammary development in late gestation, non-lactating (dry) cows. The objective was to measure the effect of circadian disruption on transcriptomes of the liver and mammary gland. At 35 d before expected calving (BEC) multiparous dry cows were assigned to either control (CON) or phase-shifted treatments (PS). CON was exposed to 16 h light and 8 h of dark. PS was exposed to 16 h light to 8 h dark, but phase of the light-dark cycle was shifted 6 h every 3 d. On d 21 BEC, liver and mammary were biopsied. RNA was isolated (n=6 CON, n=6 PS per tissue), libraries prepared and sequenced using paired end reads. Reads mapping to bovine genome averaged 27 M ± 2 M, and aligned to 14,222 protein coding genes in liver and 15,480 in mammary analysis. In the liver, 834 genes, and in the mammary gland, 862 genes were different (nominal P < 0.05) between PS and CON. In the liver, genes upregulated in PS functioned in cholesterol biosynthesis, endoplasmic reticulum stress, wound healing, and inflammation. Genes downregulated in liver function in cholesterol efflux. In the mammary gland, genes upregulated functioned in mRNA processing and transcription, downregulated genes encoded extracellular matrix proteins and proteases, cathepsins and lysosomal proteases, lipid transporters and regulated oxidative phosphorylation. Increased cholesterol synthesis and decreased efflux suggests circadian disruption potentially increases the risk of fatty liver in cows. Decreased remodeling and lipid transport in mammary may decrease milk production capacity during lactation.


Author(s):  
Yuling Chi ◽  
Dou Yeon Youn ◽  
Alus M. Xiaoli ◽  
Li Liu ◽  
Yunping Qiu ◽  
...  

Excessive long-term consumption of dietary carbohydrates, including glucose, sucrose or fructose, has been shown to have significant impact on genome-wide gene expression, which likely results from changes in metabolic substrate flux. However, there has been no comprehensive study on the acute effects of individual sugars on the genome wide gene expression that may reveal the genetic changes altering signaling pathways, subsequent metabolic processes and ultimately physiological/pathological responses. Considering that gene expressions in response to acute carbohydrate ingestion might be different in nutrient sensitive and insensitive mammals, we conducted comparative studies of genome wide gene expression by deep mRNA sequencing of the liver in nutrient sensitive C57BL/6J and nutrient insensitive BALB/cJ mice. Further to determine the temporal responses, we compared livers from mice in the fasted state and following ingestion of standard laboratory mouse chow supplemented with plain drinking water or water containing 20% glucose, sucrose or fructose. Supplementation with these carbohydrates induced unique extents and temporal changes in gene expressions in a strain specific manner. Fructose and sucrose stimulated gene changes peaked at 3 h postprandial, whereas glucose effects peaked at 12 h and 6 h postprandial in C57BL/6J and BABL/cJ mice, respectively. Network analyses revealed that fructose changed genes were primarily involved in lipid metabolism and were more complex in C57BL/6J than in BALB/cJ mice. These data demonstrate that there are qualitative and quantitative differences in the normal physiological responses of the liver between these two strains of mice and C57BL/6J is more sensitive to sugar intake than BALB/cJ.


Author(s):  
Nidhi Shukla ◽  
Anchita Prasad ◽  
Uma Kanga ◽  
Renuka Suravajhala ◽  
Vinod Kumar Nigam ◽  
...  

SARS-CoV-2 harbors many known unknown regions in the form of hypothetical open reading frames (ORFs). While the mechanisms underlying the disease pathogenesis are not clearly understood, molecules such as long noncoding RNAs (lncRNAs) play a key regulatory role in the viral pathogenesis from endocytosis. We asked whether or not the lncRNAs in the host are associated with the viral proteins and argue that lncRNA-mRNA molecules related to viral infection may regulate SARS-CoV-2 pathogenesis. Towards the end of the perspective, we provide challenges and insights into investigating these transgression pathways.


Author(s):  
Theun de Groot ◽  
Rosalinda Doty ◽  
Lars Damen ◽  
Ruben Baumgarten ◽  
Steffi Bressers ◽  
...  

Background Chronic lithium treatment for bipolar disease causes mainly side effects in the kidney. A subset of lithium users develops nephrogenic diabetes insipidus (NDI), a urinary concentrating disorder, and chronic kidney disease (CKD). Age, lithium dose and duration of treatment are important risk factors, while genetic background might also play an important role. Methods In order to investigate the role of genetics, female mice of 29 different inbred strains were treated for one year with control or lithium chow and urine, blood and kidneys were analysed. Results Chronic lithium treatment increased urine production and/or reduced urine osmolality in 21 strains. Renal histology showed that lithium increased interstitial fibrosis and/or tubular atrophy in eight strains, while in none of the strains glomerular injury was induced. Interestingly, lithium did not elevate urinary albumin-creatinine ratio (ACR) in any strain, while eight strains even demonstrated a lowered ACR. The protective effect on ACR coincided with a similar decrease in urinary IgG levels, a marker of glomerular function, while the adverse effect of lithium on interstitial fibrosis/tubular atrophy coincided with a severe increase in urinary β2-microglobulin (B2M) levels, an indicator of proximal tubule damage. Conclusion Genetic background plays an important role in the development of lithium-induced NDI and chronic renal pathology in female mice. The strong correlation of renal pathology with urinary B2M levels indicates B2M as a promising biomarker for chronic renal damage induced by lithium.


Author(s):  
Michael Schwarzer ◽  
Annika Molis ◽  
Christina Schenkl ◽  
Andrea Schrepper ◽  
Steven L. Britton ◽  
...  

Introduction: Aerobic exercise capacity is inversely related to morbidity and mortality as well as to insulin resistance. However, exercising in patients has led to conflicting results, presumably because aerobic exercise capacity consists of intrinsic (genetically determined) and extrinsic (environmentally determined) parts. The contribution of both parts to insulin sensitivity is also not clear. We investigated sedentary and exercised (aerobic interval training) high (HCR) and low capacity runners (LCR) differing in their genetically determined aerobic exercise capacity to determine the contribution of both parts to insulin sensitivity. Methods and Results: LCR and HCR differed in their untrained exercise capacity and body weight. Sedentary LCR displayed a diabetic phenotype with higher random glucose, lower glucose infusion rate during hyperinsulinemic euglycemic clamping than HCR. Echocardiography showed equal morphological and functional parameters and no change with exercise. Four weeks of exercise caused significant improvements in aerobic exercise capacity, which was more pronounced in LCR. However, with respect to glucose use, exercise affected HCR only. In these animals, exercise increased 2-deoxyglucose uptake in gastrocnemius (+58.5 %, p= 0.1) and in epididymal fat (+106 %; p<0.05). Citrate synthase activity also increased in these tissues (gastrocnemius 69 % epididymal fat 63 %). Conclusion: In our model of HCR and LCR, genetic predisposition for low exercise capacity is associated with impaired insulin sensitivity and impedes exercise-induced improvements in insulin response. Our results suggest that genetic predisposition for low aerobic exercise capacity impairs insulin response, which may not be overcome by exercise.


Author(s):  
Jayasri Nanduri ◽  
Ning Wang ◽  
Benjamin L Wang ◽  
Nanduri R. Prabhakar

Intermittent hypoxia (IH) is a hallmark manifestation of Obstructive Sleep Apnea (OSA). Rodents treated with IH exhibit hypertension. Hypoxia-inducible factor (HIF)-1-dependent transcriptional activation of NADPH oxidases (Nox) and the resulting increase in reactive oxygen species (ROS) levels is a major molecular mechanism underlying IH/OSA-induced hypertension. Jumanji C (JmjC)-containing histone lysine demethylases (JmjC-KDMs) are coactivators of HIF-1-dependent transcriptional activation. In the present study, we tested the hypothesis that JmjC-KDMs are required for IH-evoked HIF-1 transcriptional activation of Nox4 and the ensuing hypertension. Studies were performed on pheochromocytoma (PC)12 cells and rats. IH increased KDM6B protein and enzyme activity in PC12 cells in a HIF-1-independent manner as evidenced by unaltered KDM6B activation by IH in HIF-1α shRNA treated cells. Cells treated with IH showed increased HIF-1-dependent Nox4 transcription as indicated by increased HIF-1α binding to hypoxia responsive element (HRE) sequence of the Nox4 gene promoter demonstrated by chromatin immunoprecipitation (ChiP) assay. Pharmacological blockade of KDM6B with GSKJ4, a specific KDM6 inhibitor, or genetic silencing of KDM6B with shRNA abolished IH-induced Nox4 transcriptional activation by blocking HIF-1α binding to the promoter of the NOX4 gene. Treating IH exposed rats with GSKJ4 showed: a) absence of KDM6B activation and HIF-1-dependent Nox4 transcription in the adrenal medullae, as well as b) absence of elevated plasma catecholamines and hypertension. Collectively, these findings indicate that KDM6B functions as a coactivator of HIF-1-mediated Nox4 transactivation and demonstrate a hitherto uncharacterized role for KDM's in IH-induced hypertension by HIF-1.


Author(s):  
Luke R Perreault ◽  
Thanh T Le ◽  
Madeleine J Oudin ◽  
Lauren Deems Black

Background: Cardiac fibroblasts are responsible for extracellular matrix turnover and repair in the cardiac environment and serve to help facilitate immune responses. However, it is well established that they have significant phenotypic heterogeneity with respect to location, physiological conditions, and developmental age. The goal of this study was to provide an in-depth transcriptomic profile of cardiac fibroblasts derived from rat hearts at fetal, neonatal, and adult developmental ages to ascertain variations in gene expression that may drive functional differences in these cells at these specific stages of development. Results: We performed RNA-seq of cardiac fibroblasts isolated from fetal, neonatal, and adult rats and compared to the rat genome. Principal component analysis of RNA-seq data suggested data variance was predominantly due to developmental age. Differential expression and Gene set enrichment analysis against Gene Ontology and Kyoto Encyclopedia of Genes and Genomes datasets indicated an array of differences across developmental ages, including significant decreases in cardiac development and cardiac function-associated genes with age, and a significant increase in immune and inflammatory-associated functions - particularly immune cell signaling, and cytokine and chemokine production - with respect to increasing developmental age. Conclusion: These results reinforce established evidence of diverse phenotypic heterogeneity of fibroblasts with respect to developmental age. Further, based on our analysis of gene expression, age-specific alterations in cardiac fibroblasts may play a crucial role in observed differences in cardiac inflammation and immune response observed across developmental ages.


Author(s):  
Jonquil Marie Poret ◽  
Jessie J Guidry ◽  
Liz Simon ◽  
Patricia E. Molina

Effective antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH), and the prevalence of at-risk alcohol use is higher among PLWH. Increased survival and aging of PLWH is associated with increased prevalence of metabolic comorbidities especially among menopausal women, and adipose tissue metabolic dysregulation may be a significant contributing factor. We examined the differential effects of chronic binge alcohol (CBA) administration and ovariectomy (OVX) on the omental adipose tissue (OmAT) proteome in a subset of simian immunodeficiency virus (SIV)-infected macaques of a longitudinal parent study. Quantitative discovery-based proteomics identified 1429 differentially expressed proteins. Ingenuity Pathway Analysis (IPA) was used to calculate z-scores, or activation predictions, for functional pathways and diseases. Results revealed protein changes associated with functional pathways centered around the "OmAT metaboproteome profile". Based on z-scores, CBA did not affect functional pathways of metabolic disease but dysregulated proteins involved in AMPK signaling and lipid metabolism. OVX-mediated proteome changes were predicted to promote pathways involved in glucose- and lipid-associated metabolic disease. Proteins involved in apoptosis, necrosis, and reactive oxygen species (ROS) pathways were also predicted to be activated by OVX, and these were predicted to be inhibited by CBA. These results provide evidence for the role of ovarian hormone loss in mediating OmAT metaboproteome dysregulation in SIV and suggest that CBA modifies OVX-associated changes. In the context of OVX, CBA administration produced larger metabolic and cellular effects, which we speculate may reflect a protective role of estrogen against CBA-mediated adipose tissue injury in female SIV-infected macaques.


Author(s):  
Amal Elfatih ◽  
Idris Mohammed ◽  
Doua Abdelrahman ◽  
Borbala Mifsud

The application of whole genome/exome sequencing technologies in clinical genetics and research has resulted in the discovery of incidental findings unrelated to the primary purpose of genetic testing. The American College of Medical Genetics and Genomics published guidelines for reporting pathogenic and likely pathogenic variants that are deemed to be medically actionable, which allowed us to learn about the epidemiology of incidental findings in different populations. However, consensus guidelines for variant reporting and classification are still lacking. We conducted a systematic literature review of incidental findings in whole genome/exome sequencing studies to obtain a comprehensive understanding of variable reporting and classification methods for variants that are deemed to be medically actionable across different populations. The review highlights the elements that demand further consideration or adjustment.


Author(s):  
Na Jiao ◽  
Rohit Loomba ◽  
Zi-Huan Yang ◽  
Dingfeng Wu ◽  
Sa Fang ◽  
...  

Multiple mechanisms for the gut microbiome contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) have been implicated. Here, weaim to investigate the contribution and potential application for altered bile acids (BA) metabolizing microbesin NAFLD by post-hoc analysis of whole metagenome sequencing (WMS) data. The discovery cohort consisted of 86 well-characterized biopsy-proven NAFLD patients and 38 healthy controls. Assembly-based analysis was performed to identify BA-metabolizing microbes. Statistical tests, feature selection and microbial co-abundance analysis were integrated to identify microbial alterations and markers in NAFLD. An independent validation cohort was subjected to similar analyses. NAFLD microbiota exhibited decreased diversity and microbial associations. We established a classifier model with 53 differential species exhibiting a robust diagnostic accuracy (AUC=0.97) for dectecting NAFLD. Next, eight important differential pathway markers including secondary BA biosynthesis were identified. Specifically, increased abundance of 7α-HSDH, baiA and baiB were detected in NAFLD. Further, 10 of 50 BA-metabolizing metagenome-assembled genomes (MAGs) from Bacteroides ovatusand Eubacterium biforme, were dominant in NAFLD and interplayed as a synergetic ecological guild. Importantly, two subtypes of NAFLD patients were observed according to secondary BA metabolism potentials. Elevated capability for secondary BA biosynthesis was also observed in the validation cohort. These bacterial BA-metabolizing genes and microbes identified in this study may serve as disease markers. Microbial differences in BA-metabolism and strain-specific differences among patients highlight the potential for precision medicine in NAFLD treatment.


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