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Introduction: The idea behind the presentation of this case relates to utilizing space technology in earth applications with mutual benefit for both patients confined to bed and astronauts. Deconditioning and the progressiveness of skeletal muscle loss in the absence of adequate gravity stimulus have been of physiological concern. A robust countermeasure to muscle disuse is still a challenge for both immobilized patients and astronauts in long duration space missions. Researchers in the space medicine field concluded that artificial gravity (AG) produced by short-radius centrifugation on a passive movement therapy device, combined with exercise, has been a robust multi-system countermeasure as it re-introduces an acceleration field and gravity load.Methods: A short-arm human centrifuge (SAHC) alone or combined with exercise was evaluated as a novel, artificial gravity device for an effective rehabilitation strategy in the case of a stroke patient with disability. The results reveal valuable information on an individualized rehabilitation strategy against physiological deconditioning. A 73-year-old woman was suddenly unable to speak, follow directions or move her left arm and leg. She could not walk, and self-care tasks required maximal assistance. Her condition was getting worse over the years, also she was receiving conventional rehabilitation treatment. Intermittent short-arm human centrifuge individualized protocols were applied for 5 months, three times a week, 60 treatments in total.Results: It resulted in significant improvement in her gait, decreased atrophy with less spasticity on the left body side, and ability to walk at least 100 m with a cane. Balance and muscle strength were improved significantly. Cardiovascular parameters improved responding to adaptations to aerobic exercise. Electroencephalography (EEG) showed brain reorganization/plasticity evidenced through functional connectivity alterations and activation in the cortical regions, especially of the precentral and postcentral gyrus. Stroke immobility-related disability was also improved.Discussion: These alterations were attributed to the short-arm human centrifuge intervention. This case study provides novel evidence supporting the use of the short-arm human centrifuge as a promising therapeutic strategy in patients with restricted mobility, with application to astronauts with long-term muscle disuse in space.

The Human Leukocyte Antigen (HLA) is a critical genetic system for different outcomes after solid organ and hematopoietic cell transplantation. Its polymorphism is usually determined by molecular technologies at the DNA level. A potential role of HLA allelic expression remains under investigation in the context of the allogenic immune response between donors and recipients. In this study, we quantified the allelic expression of all three HLA class I loci (HLA-A, B and C) by RNA sequencing and conducted an analysis of expression quantitative traits loci (eQTL) to investigate whether HLA expression regulation could be associated with non-coding gene variations. HLA-B alleles exhibited the highest expression levels followed by HLA-C and HLA-A alleles. The max fold expression variation was observed for HLA-C alleles. The expression of HLA class I loci of distinct individuals demonstrated a coordinated and paired expression of both alleles of the same locus. Expression of conserved HLA-A~B~C haplotypes differed in distinct PBMC's suggesting an individual regulated expression of both HLA class I alleles and haplotypes. Cytokines TNFα /IFNβ, which induced a very similar upregulation of HLA class I RNA and cell surface expression across alleles did not modify the individually coordinated expression at the three HLA class I loci. By identifying cis eQTLs for the HLA class I genes, we show that the non-coding eQTLs explain 29%, 13%, and 31% of the respective HLA-A, B, C expression variance in unstimulated cells, and 9%, 23%, and 50% of the variance in cytokine-stimulated cells. The eQTLs have significantly higher effect sizes in stimulated cells compared to unstimulated cells for HLA-B and HLA-C genes expression. Our data also suggest that the identified eQTLs are independent from the coding variation which defines HLA alleles and thus may be influential on intra-allele expression variability although they might not represent the causal eQTLs.

Objective: Studies regarding health effects of religious fasting have been increased during the last decade. Our aim was to investigate the impact of adherence to the periodic Christian Orthodox Church (COC) fasting on nutrient intake, body composition, and risk factors for metabolic syndrome (MetS). Methods: Four-hundred individuals aged 42.6 ± 17.0 years participated in this cross-sectional study. Two-hundred subjects followed the COC fasting since childhood or at least the last twelve consecutive years, and two-hundred subjects did not follow the COC fasting regimes or any other restrictive dietary pattern. Socioeconomic data, lifestyle habits, and physical activity data were collected. Nutritional assessment was performed via two 24 h recalls and a food frequency questionnaire. Anthropometric data and biochemical parameters were also measured. Results: Fasters had a significantly lower daily intake of calories (1547 vs. 1662 kcals, p = 0.009), protein (52 vs. 59 g, p = 0.001), fat (82 vs. 89 g, p = 0.012), and cholesterol (147 vs. 178 g, p = 0.001) compared with non-fasters. Furthermore, fasters reported a healthier way of living, with lower rates of smoking and alcohol consumption (p < 0.001 and 0.002, respectively). Insulin and magnesium levels were significantly higher, whereas levels of urea, transaminases, glucose, and phosphorus were significantly lower, as was DBP in fasters versus non-fasters. Furthermore, MetS prevalence was non-significantly higher in non-faster compared with fasters. Conclusion: During a non-fasting period, individuals following the COC fasting recommendations reported lower intake of calories, protein, fat, and cholesterol compared with non-fasters. Fasters tended to have a healthier lifestyle pattern and a lower risk for MetS versus non-fasters. Some biochemical parameters also significantly differed between the two study groups. Further research is warranted to establish the long-term clinical impact of these findings.

Religious fasting that involves abstinence from specific food(s) is part of many religions worldwide and has been gaining attention by the research community during the last years. The study aimed to investigate whether the periodic Christian Orthodox fasting mitigates the changes in body composition, dietary intake, and metabolic syndrome (MetS) in postmenopausal women. One hundred and thirty-four postmenopausal women aged 57.3 ± 6.7 years participated in this study. The Christian Orthodox fasting was followed by 68 postmenopausal women since their childhood, whereas 66 postmenopausal women were non-fasters. Data collection involved anthropometric, biochemical, clinical, and dietary information. Postmenopausal women who fasted according to Christian Orthodox Church recommendations had significantly higher mean fat free mass (45 vs. 44 kg, p = 0.002), hip circumference (104 vs. 99 cm, p = 0.001), and diastolic blood pressure (79 vs. 82 mmHg, p = 0.024). No other differences were found with regards to anthropometric data. Fasters also consumed significantly less fat (78 vs. 91 g, p = 0.006), as well as saturated (19 vs. 23 g, p = 0.015), monounsaturated (41 vs. 47 g, p = 0.018), and polyunsaturated fat (8.5 vs. 10 g, p = 0.023), trans fatty acids (0.5 vs. 2.3 g, p = 0.035), and cholesterol (132 vs. 176 g, p = 0.011). In terms of MetS features, non-fasters had more frequently elevated fasting blood glucose (11.8 vs. 24.2%, p = 0.039) and elevated blood pressure (13.2 vs. 36.4%, p = 0.041) compared with fasters. MetS was more common in non-fasters versus fasters with a marginal level of significance (30.3 vs. 23.5%, p = 0.052). Postmenopausal women who follow the Christian Orthodox fasting regime had lower fat intake, and no other difference in nutrient intake, compared with non-fasters. The latter were more likely to have MetS and some of its components. Overall, periodic abstinence from meat, dairy products, and eggs might play a protective role in postmenopausal women with regard to MetS.

Objective: Studies regarding health effects of religious fasting have been increased during the last decade. Our aim was to investigate the effects of Christian Orthodox Church (COC) fasting on metabolic syndrome in young adults. Methods: Participants were 224 men and women, of whom 111 had been following the COC fasting regime and 113 were non-fasters, all aged 18 to 49 years (mean age 29.23 ± 8.78 years). Anthropometric measurements, including the Bioelectrical Impedance Analysis, were performed on individuals, and they also completed food intake questionnaires, and provided blood samples for biochemical analysis. Metabolic syndrome was defined according to criteria of the National Cholesterol Education Program-Adult Treatment Panel III and all variables were checked. Results: Fasters did not statistically differ in anthropometric measurements when comparing to non-fasters. Differences were found in terms of biochemical variables, and more specific in HDL cholesterol, LDL cholesterol and total blood cholesterol, and in systemic and diastolic blood pressure, although non statistically significant. Statistically significant differences were only noticed in heart pulses and insulin levels, with fasters having lower heart pulses (69.44 ± 9.84 versus 72.63 ± 10.74) and greater mean values of insulin levels (4.16 ± 4.66 versus 3.12 ± 2.35). When analysis was carried to identify which variables were met for metabolic syndrome, it was found that fasters had statistically significant lower values of blood pressure when compared to non-fasters. In more details mean systolic blood pressure was 121.67 ± 12.21 versus 123.41 ± 11.73 for fasters and non-fasters respectively, and mean diastolic blood pressure was 75.77 ± 8.82 versus 78.27 ± 10.07 for fasters and non-fasters. Furthermore, the mean energy intake was higher in non-fasters (1698.25 ± 515.99 kcals) when compared to fasters (1590.24 ± 404.19 kcals) but not statistically significant different. Conclusions: Young adults aged 18 to 49 years who fast according to the COC fasting regimes do not have different metabolic syndrome prevalence when comparing to non-fasters, but there was a statistically significant difference in the prevalence of elevated blood pressure with fasters having lower values.

Abstract Individuals experiencing socioeconomic disadvantage in childhood have a higher rate of inflammation-related diseases decades later. Little is known about the mechanisms linking early life experiences to the functioning of the immune system in adulthood. To address this, we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (78% and 26%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than cis DNA methylation may regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of gene regulation that cannot fully be explained by differential cis DNA methylation.

Abstract Background The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D. Methods Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts. Results We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling. Conclusions Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.

Leydig cells (LC) are the main testicular androgen-producing cells. In eutherian mammals, two types of LCs emerge successively during testicular development, fetal Leydig cells (FLCs) and adult Leydig cells (ALCs). Both display significant differences in androgen production and regulation. Using bulk RNA sequencing, we compared the transcriptomes of both LC populations to characterize their specific transcriptional and functional features. Despite similar transcriptomic profiles, a quarter of the genes show significant variations in expression between FLCs and ALCs. Non-transcriptional events, such as alternative splicing was also observed, including a high rate of intron retention in FLCs compared to ALCs. The use of single-cell RNA sequencing data also allowed the identification of nine FLC-specific genes and 50 ALC-specific genes. Expression of the corticotropin-releasing hormone 1 (Crhr1) receptor and the ACTH receptor melanocortin type 2 receptor (Mc2r) specifically in FLCs suggests a dual regulation of steroidogenesis. The androstenedione synthesis by FLCs is stimulated by luteinizing hormone (LH), corticotrophin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH) whereas the testosterone synthesis by ALCs is dependent exclusively on LH. Overall, our study provides a useful database to explore LC development and functions.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning.Methods and findingsWe utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n = 795) or at high risk of developing the disease (n = 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (ConclusionsIn this study, we developed several models with different combinations of clinical and omics data and identified biological features that appear to be associated with liver fat accumulation. In general, the clinical variables showed better prediction ability than the complex omics variables. However, the combination of omics and clinical variables yielded the highest accuracy. We have incorporated the developed clinical models into a web interface (see: https://www.predictliverfat.org/) and made it available to the community.Trial registrationClinicalTrials.gov NCT03814915.

AimSubclasses of different glycaemic disturbances could explain the variation in characteristics of individuals with type 2 diabetes (T2D). We aimed to examine the association between subgroups based on their glucose curves during a five-point mixed-meal tolerance test (MMT) and metabolic traits at baseline and glycaemic deterioration in individuals with T2D.MethodsThe study included 787 individuals with newly diagnosed T2D from the Diabetes Research on Patient Stratification (IMI-DIRECT) Study. Latent class trajectory analysis (LCTA) was used to identify distinct glucose curve subgroups during a five-point MMT. Using general linear models, these subgroups were associated with metabolic traits at baseline and after 18 months of follow up, adjusted for potential confounders.ResultsAt baseline, we identified three glucose curve subgroups, labelled in order of increasing glucose peak levels as subgroup 1-3. Individuals in subgroup 2 and 3 were more likely to have higher levels of HbA1c, triglycerides and BMI at baseline, compared to those in subgroup 1. At 18 months (n = 651), the beta coefficients (95% CI) for change in HbA1c (mmol/mol) increased across subgroups with 0.37 (-0.18-1.92) for subgroup 2 and 1.88 (-0.08-3.85) for subgroup 3, relative to subgroup 1. The same trend was observed for change in levels of triglycerides and fasting glucose.ConclusionsDifferent glycaemic profiles with different metabolic traits and different degrees of subsequent glycaemic deterioration can be identified using data from a frequently sampled mixed-meal tolerance test in individuals with T2D. Subgroups with the highest peaks had greater metabolic risk.

In this study the authors examine the allelic imbalance (AI) landscape of colorectal cancer, reporting loss of TP53 as a driver of AI. They use CRISPR-Cas9 screens to identify 79 genes (within AI regions) regulating cell growth and identify a network of transcription factors that may contribute to colorectal tumorigenesis.

Lifestyle choices significantly influence mental health in later life. In this study we investigated the effects of the Christian Orthodox Church (COC) fasting diet, which includes long-term regular abstinence from animal-based products for half the calendar year, on cognitive function and emotional wellbeing of healthy adults. Two groups of fasting and non-fasting individuals were evaluated regarding their cognitive performance and the presence of anxiety and depression using the Mini Mental Examination Scale, the Hamilton Anxiety Scale, and the Geriatric Depression Scale (GDS), respectively. Data on physical activity, smoking, and vitamin levels were collected and correlated with mental health scoring. Negative binomial regression was performed to examine differences in the GDS scores between the two groups. Significantly lower levels of anxiety (7.48 ± 4.98 vs. 9.71 ± 5.25; p < 0.001) and depression (2.24 ± 1.77 vs. 3.5 ± 2.52; p < 0.001), along with better cognitive function (29.15 ± 0.79 vs. 28.64 ± 1.27; p < 0.001), were noticed in fasting compared to non-fasting individuals. GDS score was 31% lower (Incidence Rate Ratio: 0.69, 95% Confidence Interval: 0.56–0.85) in the fasting group compared to the control, while vitamin and ferrum levels did not differ. The COC fasting diet was found to have an independent positive impact on cognition and mood in middle-aged and elderly individuals.

It is well established that lncRNAs are aberrantly expressed in cancer where they have been shown to act as oncogenes or tumor suppressors. RNA profiling of 314 colorectal adenomas/adenocarcinomas and 292 adjacent normal colon mucosa samples using RNA‐sequencing demonstrated that the snoRNA host gene 16 (SNHG16) is significantly up‐regulated in adenomas and all stages of CRC. SNHG16 expression was positively correlated to the expression of Wnt‐regulated transcription factors, including ASCL2, ETS2, and c‐Myc. In vitro abrogation of Wnt signaling in CRC cells reduced the expression of SNHG16 indicating that SNHG16 is regulated by the Wnt pathway. Silencing of SNHG16 resulted in reduced viability, increased apoptotic cell death and impaired cell migration. The SNHG16 silencing particularly affected expression of genes involved in lipid metabolism. A connection between SNHG16 and genes involved in lipid metabolism was also observed in clinical tumors. Argonaute CrossLinking and ImmunoPrecipitation (AGO‐CLIP) demonstrated that SNHG16 heavily binds AGO and has 27 AGO/miRNA target sites along its length, indicating that SNHG16 may act as a competing endogenous RNA (ceRNA) “sponging” miRNAs off their cognate targets. Most interestingly, half of the miRNA families with high confidence targets on SNHG16 also target the 3′UTR of Stearoyl‐CoA Desaturase (SCD). SCD is involved in lipid metabolism and is down‐regulated upon SNHG16 silencing. In conclusion, up‐regulation of SNHG16 is a frequent event in CRC, likely caused by deregulated Wnt signaling. In vitro analyses demonstrate that SNHG16 may play an oncogenic role in CRC and that it affects genes involved in lipid metabolism, possible through ceRNA related mechanisms.

Objectives: IL-13 is a cytokine classically produced by anti-inflammatory T-helper-2 lymphocytes; it is decreased in the circulation of type 2 diabetic patients and impacts positively on liver and skeletal muscle. Although IL-13 can exert positive effects on beta-cell lines, its impact and mode of action on primary beta-cell function and survival remain largely unexplored. Methods: Beta-cells were cultured for 48 h in the presence of IL-13 alone or in combination with IL-1β or cytokine cocktail (IL-1β, IFNγ, TNFα). Results: IL-13 protected human and rat beta-cells against cytokine induced death. However, IL-13 was unable to protect from IL-1β impaired glucose stimulated insulin secretion and did not influence NFκB nuclear relocalization induced by IL-1β. IL-13 induced phosphorylation of Akt, increased IRS2 protein expression and counteracted the IL-1β induced regulation of several beta-cell stress response genes. Conclusions: The prosurvival effects of IL-13 thus appear to be mediated through IRS2/Akt signaling with NFκB independent regulation of gene expression. In addition to previously documented beneficial effects on insulin target tissues, these data suggest that IL-13 may be useful for treatment of type 2 diabetes by preserving beta-cell mass or slowing its rate of decline. Keywords: Beta-cells, Apoptosis, Cytokines, Gene expression, Akt

Objective: We have previously shown the existence of a muscle–pancreas intercommunication axis in which CX3CL1 (fractalkine), a CX3C chemokine produced by skeletal muscle cells, could be implicated. It has recently been shown that the fractalkine system modulates murine β-cell function. However, the impact of CX3CL1 on human islet cells especially regarding a protective role against cytokine-induced apoptosis remains to be investigated. Methods: Gene expression was determined using RNA sequencing in human islets, sorted β- and non-β-cells. Glucose-stimulated insulin secretion (GSIS) and glucagon secretion from human islets was measured following 24 h exposure to 1–50 ng/ml CX3CL1. GSIS and specific protein phosphorylation were measured in rat sorted β-cells exposed to CX3CL1 for 48 h alone or in the presence of TNFα (20 ng/ml). Rat and human β-cell apoptosis (TUNEL) and rat β-cell proliferation (BrdU incorporation) were assessed after 24 h treatment with increasing concentrations of CX3CL1. Results: Both CX3CL1 and its receptor CX3CR1 are expressed in human islets. However, CX3CL1 is more expressed in non-β-cells than in β-cells while its receptor is more expressed in β-cells. CX3CL1 decreased human (but not rat) β-cell apoptosis. CX3CL1 inhibited human islet glucagon secretion stimulated by low glucose but did not impact human islet and rat sorted β-cell GSIS. However, CX3CL1 completely prevented the adverse effect of TNFα on GSIS and on molecular mechanisms involved in insulin granule trafficking by restoring the phosphorylation (Akt, AS160, paxillin) and expression (IRS2, ICAM-1, Sorcin, PCSK1) of key proteins involved in these processes. Conclusions: We demonstrate for the first time that human islets express and secrete CX3CL1 and CX3CL1 impacts them by decreasing glucagon secretion without affecting insulin secretion. Moreover, CX3CL1 decreases basal apoptosis of human β-cells. We further demonstrate that CX3CL1 protects β-cells from the adverse effects of TNFα on their function by restoring the expression and phosphorylation of key proteins of the insulin secretion pathway.