Physiological genomics最新文献

The aim of the present study was to investigate changes in the gut microbiome both during and after consumption of malted rice amazake (MR-Amazake), a fermented food from Japan, in-home healthcare patients with disabilities, including patients with severe motor and intellectual disabilities. We monitored 12 patients who consumed MR-Amazake for 6 wk and investigated them before and after the intervention as well as 6 wk after the end of intake to compare their physical condition, diet, type of their medication, constipation assessment scale, and analysis of their comprehensive fecal microbiome using 16S rRNA sequencing. Their constipation symptoms were significantly alleviated, and principal coordinate analysis revealed that 30% of patients showed significant changes in the gut microbiome after MR-Amazake ingestion. Furthermore, Bifidobacterium was strongly associated with these changes. These changes were observed only during MR-Amazake intake; the original gut microbiome was restored when MR-Amazake intake was discontinued. These results suggest that 6 wk is a reasonable period of time for MR-Amazake to change the human gut microbiome and that continuous consumption of MR-Amazake is required to sustain such changes.NEW & NOTEWORTHY The consumption of malted rice amazake (MR-Amazake) showed significant changes in the gut microbiome according to principal coordinate analysis in some home healthcare patients with disabilities, including those with severe motor and intellectual disabilities. After discontinuation of intake, the gut microbiome returned to its original state. This is the first pilot study to examine both the changes in the gut microbiome and their sustainability after MR-Amazake intake.

In this study, postsmolt male Atlantic salmon, previously identified as low responders (LRs) or high responders (HRs) based on poststress cortisol levels, had their head kidney and liver sampled at 12°C and 20°C before injection (time 0) and after injection (i.e., at 12- and 24-h postinjection, respectively) with either Forte Micro (a multivalent vaccine containing bacterin, to capture peak antibacterial responses) or an equal volume of PBS. Quantitative real-time PCR (qPCR) was then used to measure the expression of 15 biomarker genes in the head kidney and 12 genes in the liver at each temperature/sampling point. Target transcripts were chosen that were related to growth, stress, and innate antibacterial immune responses. Many temperature, phenotype, and injection effects were found for individual genes within these three broad categories, and multivariate statistical analyses (i.e., principal component analysis and permutational multivariate analysis of variance) were used to look for overall patterns in transcript expression. These analyses revealed that HR salmon at 20°C mounted a more robust response (P < 0.05) for the 10 head kidney immune-related transcripts when injected with Forte Micro than LR salmon. In contrast, the seven liver stress-related transcripts displayed a greater response (P = 0.057) in LR versus HR fish with Forte Micro at 12°C. Overall, although this research did find some differences between LR and HR fish, it does not provide strong (conclusive) evidence that the selection of a particular phenotype would have major implications for the health of salmon over the temperature range examined.NEW & NOTEWORTHY This is the first paper to describe the impact of both temperature and bacterial stimulation on head kidney and liver transcript expression in Atlantic salmon characterized as LRs versus HRs. Notably, we found that HR salmon at 20°C mounted a more robust innate antibacterial immune response than LR salmon. In addition, LR fish at 12°C may (P = 0.057) exhibit higher expression of stress-related transcripts in response to vaccine injection relative to HR fish.

Augmented vagal signaling may be therapeutic in hypertension. Most studies to date have used stimulation of the cervical vagal branches. Here, we investigated the effects of chronic intermittent electric stimulation of the ventral subdiaphragmatic vagal nerve branch (sdVNS) on long-term blood pressure, immune markers, and gut microbiota in the spontaneously hypertensive rat (SHR), a rodent model of hypertension characterized by vagal dysfunction, gut dysbiosis, and low-grade inflammation. We evaluated the effects of sdVNS on transcriptional networks in the nucleus of the solitary tract (NTS), a major cardioregulatory brain region with direct gut vagal projections. Male juvenile SHRs were implanted with radiotelemetry transmitters and vagal nerve cuffs for chronic intermittent electric sdVNS, applied three times per day for 7 consecutive weeks followed by 1 wk of no stimulation. Blood pressure was measured once a week using telemetry in the sdVNS group as well as age-matched sham-stimulated SHR controls. At the endpoint, colonic and circulating inflammatory markers, corticosterone, and circulating catecholamines were investigated. Bacterial 16 s sequencing measured gut bacterial abundance and composition. RNA sequencing evaluated the effects of sdVNS on transcriptional networks in the NTS. SHRs that received sdVNS exhibited attenuated development of hypertension compared with sham animals. No changes in peripheral inflammatory markers, corticosterone, or catecholamines and no major differences in gut bacterial diversity and composition were observed following sdVNS, apart from decreased abundance of Defluviitaleaceale bacterium detected in sdVNS SHRs compared with sham animals. RNA sequencing revealed significant sdVNS-dependent modulation of select NTS transcriptional networks, including catecholaminergic and corticosteroid networks.NEW & NOTEWORTHY We show that stimulation of the ventral subdiaphragmatic vagal nerve branch may be a promising potential approach to treating hypertension. The data are especially encouraging given that rodents received only 30 min per day of intermittent stimulation therapy and in view of the potential of long-term blood pressure effects that are not stimulus-locked.

Lysine is an essential amino acid that serves as a building block in protein synthesis. Beside this, the metabolic activity of lysine has only recently been unraveled. Lysine metabolism is tissue specific and is linked to several renal, cardiovascular, and endocrinological diseases through human metabolomics datasets. As a free molecule, lysine takes part in the antioxidant response and engages in protein modifications, and its chemistry shapes both proteome and metabolome. In the proteome, it is an acceptor for a plethora of posttranslational modifications. In the metabolome, it can be modified, conjugated, and degraded. Here, we provide an update on integrative physiology of mammalian lysine metabolites such as α-aminoadipic acid, saccharopine, pipecolic acid, and lysine conjugates such as acetyl-lysine, and sugar-lysine conjugates such as advanced glycation end products. We also comment on their emerging associative and mechanistic links to renal disease, hypertension, diabetes, and cancer.

Congenital heart disease (CHD) is one of the most prevalent neonatal congenital anomalies. To catalog the putative candidate CHD risk genes, we collected 16,349 variants [single-nucleotide variants (SNVs) and Indels] impacting 8,308 genes in 3,166 CHD cases for a comprehensive meta-analysis. Using American College of Medical Genetics (ACMG) guidelines, we excluded the 0.1% of benign/likely benign variants and the resulting dataset consisted of 83% predicted loss of function variants and 17% missense variants. Seventeen percent were de novo variants. A stepwise analysis identified 90 variant-enriched CHD genes, of which six (GPATCH1, NYNRIN, TCLD2, CEP95, MAP3K19, and TTC36) were novel candidate CHD genes. Single-cell transcriptome cluster reconstruction analysis on six CHD tissues and four controls revealed upregulation of the top 10 frequently mutated genes primarily in cardiomyocytes. NOTCH1 (highest number of variants) and MYH6 (highest number of recurrent variants) expression was elevated in endocardial cells and cardiomyocytes, respectively, and 60% of these gene variants were associated with tetralogy of Fallot and coarctation of the aorta, respectively. Pseudobulk analysis using the single-cell transcriptome revealed significant (P < 0.05) upregulation of both NOTCH1 (endocardial cells) and MYH6 (cardiomyocytes) in the control heart data. We observed nine different subpopulations of CHD heart cardiomyocytes of which only four were observed in the control heart. This is the first comprehensive meta-analysis combining genomics and CHD single-cell transcriptomics, identifying the most frequently mutated CHD genes, and demonstrating CHD gene heterogeneity, suggesting that multiple genes contribute to the phenotypic heterogeneity of CHD. Cardiomyocytes and endocardial cells are identified as major CHD-related cell types.NEW & NOTEWORTHY Congential heart disease (CHD) is one of the most prevalent neonatal congenital anomalies. We present a comprehensive analysis combining genomics and CHD single-cell transcriptome. Our study identifies 90 potential candidate CHD risk genes of which 6 are novel. The risk genes have heterogenous expression suggestive of multiple genes contributing to the phenotypic heterogeneity of CHD. Cardiomyocytes and endocardial cells are identified as major CHD-related cell types.

Migratory songbirds undertake challenging journeys to reach their breeding grounds each spring. They accomplish these nonstop flapping feats of endurance through a suite of physiological changes, including the development of substantial fat stores and flight muscle hypertrophy and an increased capacity for fat catabolism. In addition, migratory birds may show large reductions in organ masses during flight, including the flight muscle and liver, which they must rapidly rebuild during their migratory stopover before replenishing their fat stores. However, the molecular basis of this capacity for rapid tissue remodeling and energetic output has not been thoroughly investigated. We performed RNA-sequencing analysis of the liver and pectoralis flight muscle of captive white-throated sparrows in experimentally photostimulated migratory and nonmigratory condition to explore the mechanisms of seasonal change to metabolism and tissue mass regulation that may facilitate these migratory journeys. Based on transcriptional changes, we propose that tissue-specific adjustments in preparation for migration may alleviate the damaging effects of long-duration activity, including a potential increase to the inflammatory response in the muscle. Furthermore, we hypothesize that seasonal hypertrophy balances satellite cell recruitment and apoptosis, while little evidence appeared in the transcriptome to support myostatin-, insulin-like growth factor 1-, and mammalian target of rapamycin-mediated pathways for muscle growth. These findings can encourage more targeted molecular studies on the unique integration of pathways that we find in the development of the migratory endurance phenotype in songbirds.NEW & NOTEWORTHY Migratory songbirds undergo significant physiological changes to accomplish their impressive migratory journeys. However, we have a limited understanding of the regulatory mechanisms underlying these changes. Here, we explore the transcriptomic changes to the flight muscle and liver of white-throated sparrows as they develop the migratory condition. We use these patterns to develop hypotheses about metabolic flexibility and tissue restructuring in preparation for migration.

Chronic hypercapnia (CH) is a hallmark of respiratory-related diseases, and the level of hypercapnia can acutely or progressively become more severe. Previously, we have shown time-dependent adaptations in steady-state physiology during mild (arterial Pco₂ ∼55 mmHg) and moderate (∼60 mmHg) CH in adult goats, including transient (mild CH) or sustained (moderate CH) suppression of acute chemosensitivity suggesting limitations in adaptive respiratory control mechanisms as the level of CH increases. Changes in specific markers of glutamate receptor plasticity, interleukin-1ß, and serotonergic modulation within key nodes of cardiorespiratory control do not fully account for the physiological adaptations to CH. Here, we used an unbiased approach (bulk tissue RNA sequencing) to test the hypothesis that mild or moderate CH elicits distinct gene expression profiles in important brain stem regions of cardiorespiratory control, which may explain the contrasting responses to CH. Gene expression profiles from the brain regions validated the accuracy of tissue biopsy methodology. Differential gene expression analyses revealed greater effects of CH on brain stem sites compared with the medial prefrontal cortex. Mild CH elicited an upregulation of predominantly immune-related genes and predicted activation of immune-related pathways and functions. In contrast, moderate CH broadly led to downregulation of genes and predicted inactivation of cellular pathways related to the immune response and vascular function. These data suggest that mild CH leads to a steady-state activation of neuroinflammatory pathways within the brain stem, whereas moderate CH drives the opposite response. Transcriptional shifts in immune-related functions may underlie the cardiorespiratory network's capability to respond to acute, more severe hypercapnia when in a state of progressively increased CH.NEW & NOTEWORTHY Mild chronic hypercapnia (CH) broadly upregulated immune-related genes and a predicted activation of biological pathways related to immune cell activity and the overall immune response. In contrast, moderate CH primarily downregulated genes related to major histocompatibility complex signaling and vasculature function that led to a predicted inactivation of pathways involving the immune response and vascular endothelial function. The severity-dependent effect on immune responses suggests that neuroinflammation has an important role in CH and may be important in the maintenance of proper ventilatory responses to acute and chronic hypercapnia.

Although there are more than 10,000 reptile species, and reptiles have historically contributed to our understanding of biology, genetics research into class Reptilia has lagged compared with other animals. Here, we summarize recent progress in genetics of coloration in reptiles, with a focus on the leopard gecko, Eublepharis macularius. We highlight genetic approaches that have been used to examine variation in color and pattern formation in this species as well as to provide insights into mechanisms underlying skin cancer. We propose that their long breeding history in captivity makes leopard geckos one of the most promising emerging reptilian models for genetic studies. More broadly, technological advances in genetics, genomics, and gene editing may herald a golden era for studies of reptile biology.

Previously, we found that the incidence of kidney injury in patients with chronic hypoxia was related to the partial pressure of arterial oxygen. However, at oxygen concentrations that contribute to kidney injury, the changes in the relationship between microRNAs (miRNAs) and the hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) axis and the key miRNAs involved in this process have not been elucidated. Therefore, we elucidated the relationship between VEGF and kidney injury at different oxygen concentrations and the mechanisms mediated by miRNAs. Sprague-Dawley rats were exposed to normobaric hypoxia and categorized into six groups based on the concentration of the oxygen inhaled and injection of the angiogenesis inhibitor bevacizumab, a humanized anti-VEGF monoclonal antibody. Renal tissue samples were processed to determine pathological and morphological changes and HIF-1α, VEGF, and miRNA expression. We performed a clustering analysis of high-risk pathways and key hub genes. The results were validated using two Gene Expression Omnibus datasets (GSE94717 and GSE30718). As inhaled oxygen concentration decreased, destructive changes in the kidney tissues became more severe. Although the kidney possesses a self-protective mechanism under an intermediate degree of hypoxia (10% O₂), bevacizumab injections disrupted this mechanism, and VEGF expression was associated with the ability of the kidney to repair itself. rno-miR-124-3p was identified as a crucial miRNA; a key gene target, Mapk14, was identified during this process. VEGF plays an important role in kidney protection from injury under different hypoxia levels. Specific miRNAs and their target genes may serve as biomarkers that provide new insights into kidney injury treatment.NEW & NOTEWORTHY Renal tolerance to hypoxic environments is limited, and the degree of hypoxia does not show a linear relationship with angiogenesis. VEGF plays an important role in the kidney's self-protective mechanism under different levels of hypoxia. miR-124-3p may be particularly important in kidney repair, and it may modulate VEGF expression through the miR-124-3p/Mapk14 signaling pathway. These microRNAs may serve as biomarkers that provide new insights into kidney injury treatment.

Submaximal exercise capacity is an indicator of cardiorespiratory fitness with clinical and public health implications. Submaximal exercise capacity and its response to exercise programs are characterized by heritability levels of about 40%. Using physical working capacity (power output) at a heart rate of 150 beats/min (PWC150) as an indicator of submaximal exercise capacity in subjects of the HERITAGE Family Study, we have undertaken multi-omics and in silico explorations of the underlying biology of PWC150 and its response to 20 wk of endurance training. Our goal was to illuminate the biological processes and identify panels of genes associated with human variability in intrinsic PWC150 (iPWC150) and its trainability (dPWC150). Our bioinformatics approach was based on a combination of genome-wide association, skeletal muscle gene expression, and plasma proteomics and metabolomics experiments. Genes, proteins, and metabolites showing significant associations with iPWC150 or dPWC150 were further queried for the enrichment of biological pathways. We compared genotype-phenotype associations of emerging candidate genes with reported functional consequences of gene knockouts in mouse models. We investigated the associations between DNA variants and multiple muscle and cardiovascular phenotypes measured in HERITAGE subjects. Two panels of prioritized genes of biological relevance to iPWC150 (13 genes) and dPWC150 (6 genes) were identified, supporting the hypothesis that genes and pathways associated with iPWC150 are different from those underlying dPWC150. Finally, the functions of these genes and pathways suggested that human variation in submaximal exercise capacity is mainly driven by skeletal muscle morphology and metabolism and red blood cell oxygen-carrying capacity.NEW & NOTEWORTHY Multi-omics and in silico explorations of the genes and underlying biology of submaximal exercise capacity and its response to 20 wk of endurance training were undertaken. Prioritized genes were identified: 13 genes for variation in submaximal exercise capacity in the sedentary state and 5 genes for the response level to endurance training, with no overlap between them. Genes and pathways associated with submaximal exercise capacity in the sedentary state are different from those underlying trainability.