Physiological genomics最新文献

The etiology of fetal growth restriction (FGR) is multifactorial, although many cases often involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion, resulting in high resistance to blood flow, decreased availability of nutrients, and increased hypoxia. We have developed a nonviral, polymer-based nanoparticle that facilitates delivery and transient gene expression of human insulin-like 1 growth factor (hIGF1) in placental trophoblast for the treatment of placenta insufficiency and FGR. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, the aim of the study was to identify novel pathways in the subplacenta/decidua that provide insight into the underlying mechanism driving placental insufficiency and may be corrected with hIGF1 nanoparticle treatment. Pregnant guinea pigs underwent ultrasound-guided sham or hIGF1 nanoparticle treatment at midpregnancy, and subplacenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. The MNR subplacenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion, and downregulation of genelists involved in the regulation of cell migration. hIGF1 nanoparticle treatment resulted in marked changes to transporter activity in the MNR + hIGF1 subplacenta/decidua when compared with sham MNR. Under normal growth conditions however, hIGF1 nanoparticle treatment decreased genelists enriched for kinase signaling pathways and increased genelists enriched for proteolysis, indicative of homeostasis. Overall, this study identified changes to the subplacenta/decidua transcriptome that likely result in inadequate trophoblast invasion and increases our understanding of pathways that hIGF1 nanoparticle treatment acts on to restore or maintain appropriate placenta function.NEW & NOTEWORTHY Placental insufficiency at midpregnancy, established through moderate maternal nutrient restriction, is characterized with fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion, and downregulation of genelists involved in the regulation of cell migration. Treatment of placenta insufficiency with a hIGF1 nanoparticle results in marked changes to transporter activity and increases our mechanistic understanding of how therapies designed to improve fetal growth may impact the placenta.

Low carbohydrate availability during recovery from aerobic exercise alters skeletal muscle microRNA (miRNA) profiles, which may mechanistically regulate exercise recovery. However, its impact on circulating miRNA (c-miRNA) profiles remains unclear. This study aimed to determine the effects of low versus adequate carbohydrate availability on c-miRNA profiles during recovery from aerobic exercise. Nine males (22 ± 4 yr, 1.81 ± 0.09 m, 83.9 ± 11.9 kg, 25.7 ± 2.3 kg/m², means ± SD) completed this randomized, crossover study comprising two glycogen depletion trials, followed by 24 h of isocaloric refeeding to induce low (LOW; 1.5 g/kg carbohydrate, 3.0 g/kg fat) or adequate (AD; 6.0 g/kg carbohydrate, 1.0 g/kg fat) carbohydrate availability. Total c-miRNA was extracted from serum 24 h following glycogen depletion exercise. Data were log-transformed and analyzed as fold change relative to AD. Bioinformatics was conducted on significant c-miRNA and associated pathways (miRTarBase/KEGG). Follow-up transfection of miR-375-3p mimic or inhibitor into C2C12 cells assessed metabolic, inflammatory, and catabolic pathways at the gene and protein levels. Of the 84 miRNAs assessed, miR-335-5p (-0.49 ± 0.60; P = 0.04) and miR-375-3p (-1.57 ± 1.25; P = 0.01) were significantly lower, and miR-214-3p (1.76 ± 1.85; P = 0.02) was significantly higher in AD versus LOW. In vitro experiments indicated that miR-375-3p regulates catabolic pathways at the gene and protein level. Low carbohydrate availability alters c-miRNA profiles, particularly miR-375-3p, which targets proteostasis and metabolism 24 h into recovery from aerobic exercise. These findings identify unique c-miRNA targets as potential biomarkers for the mechanistic effects of low carbohydrate availability on exercise recovery.NEW & NOTEWORTHY Low carbohydrate consumption (LOW) 24 h in recovery from aerobic exercise elicits a distinct circulating miRNA profile compared with adequate carbohydrate consumption (AD). MicroRNA 375-3p was the most significantly different between the LOW and AD treatments. Follow-up in vitro experiments suggest that AD carbohydrate availability blunts catabolic signaling during postexercise recovery.

The purpose of this study was to elucidate the skeletal muscle transcriptomic response unique to rest duration during high-intensity interval exercise. Thoroughbred horses performed three 1-min bouts of exercise at their maximal oxygen uptake (10.7-12.5 m/s), separated by 15 min (long) or 2 min (short) walking at 1.7 m/s. Gluteus medius muscle was collected before and at 4 h after the exercise and used for RNA sequencing. We identified 1,756 and 1,421 differentially expressed genes in response to the long and short protocols, respectively, using DEseq2 analysis [false discovery rate (FDR) cutoff = 0.05, minimal fold change = 1.5]. The overall transcriptional response was partially aligned, with 43% (n = 949) of genes altered in both protocols, whereas no discordant directional changes were observed. K-means clustering and gene set enrichment analyses based on Gene Ontology biological process terms showed that genes associated with muscle adaptation and development were upregulated regardless of exercise conditions; genes related to immune and cytokine responses were more upregulated following the long protocol, and protein folding and temperature response were highly expressed after the short protocol. We found that 11 genes were upregulated to a greater extent by the short protocol and one was by the long protocol, with GNA13, SPART, PHAF1, and PTX3 identified as potential candidates for skeletal muscle remodeling. Our results suggest that altered metabolic fluctuations dependent on the intermittent pattern of interval exercise modulate skeletal muscle gene expression, and therefore, rest interval length could be an important consideration in optimizing skeletal muscle adaptation.NEW & NOTEWORTHY This is the first study to address the comparison of transcriptional responses to high-intensity interval exercise with two different rest periods in skeletal muscle. The expression of genes related to metabolic adaptations altered in both conditions, while genes associated with immune and cytokine responses and protein folding and temperature response were varied with the length of the rest period. These results provide evidence for rest duration-specific transcriptional response to high-intensity interval training.

Glioblastoma multiforme (GBM) is one of the most common and aggressive type of malignant glioma with an average survival time of 12-18 mo. Despite the utilization of extensive surgical resections using cutting-edge neuroimaging, and advanced chemotherapy and radiotherapy, the prognosis remains unfavorable. The heterogeneity of GBM and the presence of the blood-brain barrier further complicate the therapeutic process. It is crucial to adopt a multifaceted approach in GBM research to understand its biology and advance toward effective treatments. In particular, omics research, which primarily includes genomics, transcriptomics, proteomics, and epigenomics, helps us understand how GBM develops, finds biomarkers, and discovers new therapeutic targets. The availability of large-scale multiomics data requires the development of computational models to infer valuable biological insights for the implementation of precision medicine. Artificial intelligence (AI) refers to a host of computational algorithms that is becoming a major tool capable of integrating large omics databases. Although the application of AI tools in GBM-omics is currently in its early stages, a thorough exploration of AI utilization to uncover different aspects of GBM (subtype classification, prognosis, and survival) would have a significant impact on both researchers and clinicians. Here, we aim to review and provide database resources of different AI-based techniques that have been used to study GBM pathogenesis using multiomics data over the past decade. We summarize different types of GBM-related omics resources that can be used to develop AI models. Furthermore, we explore various AI tools that have been developed using either individual or integrated multiomics data, highlighting their applications and limitations in the context of advancing GBM research and treatment.

The impact of exercise on pediatric tumor biology is essentially unknown. We explored the effects of regular exercise on tumor proteome profile (as assessed with liquid chromatography with tandem mass spectrometry) in a mouse model of one of the most aggressive childhood malignancies, high-risk neuroblastoma (HR-NB). Tumor samples of 14 male mice (aged 6-8 wk) that were randomly allocated into an exercise (5-wk combined aerobic and resistance training) or nonexercise control group (6 and 8 mice/group, respectively) were analyzed. The Search Tool for the Retrieval of Interacting Genes/Proteins database was used to generate a protein-protein interaction (PPI) network and enrichment analyses. The Systems Biology Triangle (SBT) algorithm was applied for analyses at the functional category level. Tumors of exercised mice showed a higher and lower abundance of 101 and 150 proteins, respectively, than controls [false discovery rate (FDR) < 0.05]. These proteins were enriched in metabolic pathways, amino acid metabolism, regulation of hormone levels, and peroxisome proliferator-activated receptor signaling (FDR < 0.05). The SBT algorithm indicated that 184 and 126 categories showed a lower and higher abundance, respectively, in the tumors of exercised mice (FDR < 0.01). Categories with lower abundance were involved in energy production, whereas those with higher abundance were related to transcription/translation, apoptosis, and tumor suppression. Regular exercise altered the abundance of hundreds of intratumoral proteins and molecular pathways, particularly those involved in energy metabolism, apoptosis, and tumor suppression. These findings provide preliminary evidence of the molecular mechanisms underlying the potential effects of exercise in HR-NB.NEW & NOTEWORTHY We used liquid chromatography with tandem mass spectrometry to explore the impact of a 5-wk exercise intervention on the tumor proteome profile in a mouse model of one of the most aggressive childhood malignancies, high-risk neuroblastoma. Exercise altered the abundance of hundreds of proteins and pathways, particularly those involved in energy metabolism and tumor suppression. These molecular changes could mediate, at least partly, the potential antitumorigenic effects of exercise.

This study intended to analyze the effects of body weight control by the diet, training adaptation, and gut microbiota metabolites of wrestlers in the week leading up to competition. According to the weight difference of wrestlers from the target weight 1 wk before the competition, those whose weight control effectiveness is less than 2 kg were classified as the CW group, whereas more than 2 kg were classified as the CnW group. The body weight, body composition, and diet of wrestlers were recorded; urine samples were taken for standard urine testing, and stool samples were collected for the analysis of gut microbiota and metabolites. The data showed that the relative values of carbohydrate and fat energy in the CnW group were significantly higher than those of the CW group, but the relative values of protein energy were significantly lower. The white blood cells, occult blood, and protein appeared in urine in the CnW group. The microbiota with higher abundance values in the CnW group were positively correlated with the relative value of carbohydrate energy, while the abundance value of Streptococcus was negatively correlated, and the functional prediction of differential bacteria was related to riboflavin and selencompound metabolism. The differential metabolites of CW/CnW group were functionally enriched in the processes of lipid and amino acid metabolism. Overall, the extent of weight control in wrestlers was correlated with sensible dietary patterns, adaptability to training load, and distinct gut microbiota and metabolites.NEW & NOTEWORTHY The purpose of this study is to observe the differences in precompetition diet structure, adaptability to training, gut microbiota, and metabolites of wrestlers with different weight control effects and analyze the correlation between them, aiming to provide scientific guidance and advice on weight control for wrestlers.

The rat, Rattus norvegicus, has provided an important model for investigation of a range of characteristics of biomedical importance. Here we survey the origins of this species, its introduction into laboratory research, and the emergence of genetic and genomic methods that utilize this model organism. Genomic studies have yielded important progress and provided new insight into several biologically important traits. However, some studies have been impeded by the lack of a complete and accurate reference genome for this species. New sequencing and genome assembly methods applied to the rat have resulted in a new reference genome assembly, GRCr8, which is a near telomere-to-telomere assembly of high base-level accuracy that incorporates several elements not captured in prior assemblies. As genome assembly methods continue to advance and production costs become a less significant obstacle, genome assemblies for multiple inbred rat strains are emerging. These assemblies will allow a rat pangenome assembly to be constructed that captures all the genetic variations in strains selected for their utility in research and will overcome reference bias, a limitation associated with reliance on a single reference assembly. By this means, the full utility of this model organism to genomic studies will begin to be revealed.

The accumulation of visceral adipose tissue (VAT) is strongly associated with cardiovascular disease and diabetes. In contrast, individuals with increased subcutaneous adipose tissue (SAT) without corresponding increases in VAT are associated with a metabolic healthy obese phenotype. These observations implicate dysfunctional VAT as a driver of disease processes, warranting investigation into obesity-induced alterations of distinct adipose depots. To determine the effects of obesity on adipose gene expression, male mice (n = 4) were fed a high-fat diet to induce obesity or a normal laboratory diet (lean controls) for 12-14 mo. Mesenteric VAT and inguinal SAT were isolated for bulk RNA sequencing. AT from lean controls served as a reference to obesity-induced changes. The long-term high-fat diet induced the expression of 169 and 814 unique genes in SAT and VAT, respectively. SAT from obese mice exhibited 308 differentially expressed genes (164 upregulated and 144 downregulated). VAT from obese mice exhibited 690 differentially expressed genes (262 genes upregulated and 428 downregulated). KEGG pathway and GO analyses revealed that metabolic pathways were upregulated in SAT versus downregulated in VAT while inflammatory signaling was upregulated in VAT. We next determined common genes that were differentially regulated between SAT and VAT in response to obesity and identified four genes that exhibited this profile: elovl6 and kcnj15 were upregulated in SAT/downregulated in VAT while trdn and hspb7 were downregulated in SAT/upregulated in VAT. We propose that these genes in particular should be further pursued to determine their roles in SAT versus VAT with respect to obesity.NEW & NOTEWORTHY A long-term high-fat diet induced the expression of more than 980 unique genes across subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). The high-fat diet also induced the differential expression of nearly 1,000 AT genes. We identified four genes that were oppositely expressed in SAT versus VAT in response to the high-fat diet and propose that these genes in particular may serve as promising targets aimed at resolving VAT dysfunction in obesity.

Cancer remains a leading cause of death worldwide and although prognosis and survivorship after therapy have improved significantly, current cancer treatments have long-term health consequences. For decades telomerase-mediated telomere maintenance has been an attractive anti-cancer therapeutic target due to its abundance and role in telomere maintenance, pathogenesis, and growth in neoplasms. Telomere maintenance-specific cancer therapies, however, are marred by off-target side effects that must be addressed before they reach clinical practice. Regular exercise training is associated with telomerase-mediated telomere maintenance in normal cells, which is associated with healthy aging. A single bout of endurance exercise training dynamically, but temporarily, increases TERT mRNA and telomerase activity, as well as several molecules that control genomic stability and telomere length (i.e., shelterin and TERRA). Considering the epidemiological findings and accumulating research highlighting that exercise significantly reduces the risk of many types of cancers and the anti-carcinogenic effects of exercise on tumor growth in vitro, investigating the governing molecular mechanisms of telomerase control in context with exercise and cancer may provide important new insights to explain these findings. Specifically, the molecular mechanisms controlling telomerase in both healthy cells and tumors after exercise could reveal novel therapeutic targets for tumor-specific telomere maintenance and offer important evidence that may refine current physical activity and exercise guidelines for all stages of cancer care.

Hypertension affects 1 in 2 U.S. adults and hypertension prevalence increases with aging. Both hypertension and aging can cause arterial remodeling. We investigated the hypothesis that aortic remodeling contributes to age-dependent hypertension in male Sprague Dawley (SD) rats. Compared to young 3-month-old rats 16-month-old male SD rats developed age-dependent hypertension that associated with increased sympathetic tone to the vasculature, elastin disarray and blood pressure variability. Our quantitative proteomic/phosphoproteomic workflow of the aorta identified 2366 proteins and 226 phosphoproteins, from which 58 proteins and 39 phosphoproteins were differentially expressed or phosphorylated respectively between young normotensive controls and aged hypertensive animals. Analysis of the proteome highlighted significant changes in the extracellular matrix, actin cytoskeleton and inflammatory pathways. Analysis of the differential phosphoproteome revealed significant differences in synapse and neuron projection and vascular smooth muscle cell (VSMC) function including actin remodeling and focal adhesions. STRING hypertension network analysis identified 13 differentially expressed and 10 differentially phosphorylated proteins associated with hypertension. Within the STRING analysis we observed 2 major areas of correlation of alterations in the aorta proteome with increased hypertension risk score - vascular inflammation and VSMC function. The majority of the identified phosphorylation sites (78.57%) in hypertension-relevant hyperphosphorylated proteins were located at serine residues. Collectively, we report that arterial remodeling in age-dependent hypertension is associated with an altered extracellular matrix and actin cytoskeleton and modulation of VSMC focal adhesion networks and neuron/synapse interactions.