Repeated Remote Ischemic Conditioning Protects Against Doxorubicin Cardiotoxicity: Never Too Much of a Good Thing.
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ABSTRACT:
SUBMITTER: Hausenloy DJ
PROVIDER: S-EPMC8352202 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Copper is a micronutrient essential for growth due to its role as a cofactor in enzymes involved in respiration, defense against oxidative damage, and iron uptake. Yet too much of a good thing can be lethal, and yeast cells typically do not have tolerance to copper levels much beyond the concentration in their ancestral environment. Here, we report a short-term evolutionary study of Saccharomyces cerevisiae exposed to levels of copper sulfate that are inhibitory to the initial strain. We isolated and identified adaptive mutations soon after they arose, reducing the number of neutral mutations, to determine the first genetic steps that yeast take when adapting to copper. We analyzed 34 such strains through whole-genome sequencing and by assaying fitness within different environments; we also isolated a subset of mutations through tetrad analysis of four lines. We identified a multilayered evolutionary response. In total, 57 single base-pair mutations were identified across the 34 lines. In addition, gene amplification of the copper metallothionein protein, CUP1-1, was rampant, as was chromosomal aneuploidy. Four other genes received multiple, independent mutations in different lines (the vacuolar transporter genes VTC1 and VTC4; the plasma membrane H+-ATPase PMA1; and MAM3, a protein required for normal mitochondrial morphology). Analyses indicated that mutations in all four genes, as well as CUP1-1 copy number, contributed significantly to explaining variation in copper tolerance. Our study thus finds that evolution takes both common and less trodden pathways toward evolving tolerance to an essential, but highly toxic, micronutrient.
| S-EPMC4317662 | biostudies-literature
Project description:There is growing evidence of risks associated with excessive technology use, especially among teens and young adults. However, little is known about the characteristics of those who are at elevated risk of being problematic users. Using data from the 2012 Current Population Survey Internet Use Supplement and Educational Supplement for teens and young adults, this study developed a conceptual framework for modeling technology use. A three-part categorization of use was posited for utilitarian, social and entertainment purposes, which fit observed data well in confirmatory factor analysis. Seemingly unrelated regression was used to examine the demographic characteristics associated with each of the three categories of use. Exploratory factor analysis uncovered five distinct types of users, including one user type that was hypothesized to likely be at elevated risk of problematic use. Regression results indicated that females in their twenties who are in school and have greater access to technology were most likely to fall into this higher-risk category. Young people who live with both parents were less likely to belong to this category. This study highlighted the importance of constructing models that facilitate identification of patterns of use that may characterize a subset of users at high risk of problematic use. The findings can be applied to other contexts to inform policies related to technology and society as well.Supplementary informationThe online version of this article (10.1007/s11293-020-09683-1) contains supplementary material, which is available to authorized users.
| S-EPMC7610009 | biostudies-literature
Project description:BackgroundInsulin shares a limited physiological concentration range with other endocrine hormones. Not only too low, but also too high systemic insulin levels are detrimental for body functions.Main bodyThe physiological function and clinical relevance of insulin are usually seen in association with its role in maintaining glucose homeostasis. However, insulin is an anabolic hormone which stimulates a large number of cellular responses. Not only too low, but also excess insulin concentrations are detrimental to the physiological balance. Although the glucoregulatory activity of insulin is mitigated during hyperinsulinemia by dampening the efficiency of insulin signaling ("insulin resistance"), this is not the case for most other hormonal actions of insulin, including the promotion of protein synthesis, de novo lipogenesis, and cell proliferation; the inhibition of lipolysis, of autophagy-dependent cellular turnover, and of nuclear factor E2-related factor-2 (Nrf2)-dependent antioxidative; and other defense mechanisms. Hence, there is no general insulin resistance but selective impairment of insulin signaling which causes less glucose uptake from the blood and reduced activation of endothelial NO synthase (eNOS). Because of the largely unrestricted insulin signaling, hyperinsulinemia increases the risk of obesity, type 2 diabetes, and cardiovascular disease and decreases health span and life expectancy. In epidemiological studies, high-dose insulin therapy is associated with an increased risk of cardiovascular disease. Randomized controlled trials of insulin treatment did not observe any effect on disease risk, but these trials only studied low insulin doses up to 40 IU/day. Proof for a causal link between elevated insulin levels and cardiovascular disease risk comes from Mendelian randomization studies comparing individuals with genetically controlled low or high insulin production.ConclusionsThe detrimental actions of prolonged high insulin concentrations, seen also in cell culture, argue in favor of a lifestyle that limits circadian insulin levels. The health risks associated with hyperinsulinemia may have implications for treatment regimens used in type 2 diabetes.
| S-EPMC7441661 | biostudies-literature
Project description:The opportunity to receive individual research results (IRRs) in accordance with personal preferences may incentivize biobank participation and maximize perceived benefit. This trial investigated the relationship between parents' preferences and intent to participate (ITP) in biobank research utilizing their child's genetic information. We randomized parents of pediatric patients to four hypothetical biobanks, one of which employed a preference-setting model for return of results regarding their child. ITP was highest among those desiring all types of IRRs (93.3%) and decreased as participants became increasingly selective with their preferences ( p < .0001). We demonstrated that most parents would participate in a biobank that allows for preference setting; however, those who set preferences to receive a narrower set of IRRs are less likely to participate.
| S-EPMC8793343 | biostudies-literature
Project description:OBJECTIVES:Prior studies investigating hospital mechanical ventilation volume-outcome associations have had conflicting findings. Volume-outcome relationships within contemporary mechanical ventilation practices are unclear. We sought to determine associations between hospital mechanical ventilation volume and patient outcomes. DESIGN:Retrospective cohort study. SETTING:The California Patient Discharge Database 2016. PATIENTS:Adult nonsurgical patients receiving mechanical ventilation. INTERVENTIONS:The primary outcome was hospital death with secondary outcomes of tracheostomy and 30-day readmission. We used multivariable generalized estimating equations to determine the association between patient outcomes and hospital mechanical ventilation volume quartile. MEASUREMENTS AND MAIN RESULTS:We identified 51,689 patients across 274 hospitals who required mechanical ventilation in California in 2016. 38.2% of patients died in the hospital with 4.4% receiving a tracheostomy. Among survivors, 29.5% required readmission within 30 days of discharge. Patients admitted to high versus low volume hospitals had higher odds of death (quartile 4 vs quartile 1 adjusted odds ratio, 1.40; 95% CI, 1.17-1.68) and tracheostomy (quartile 4 vs quartile 1 adjusted odds ratio, 1.58; 95% CI, 1.21-2.06). However, odds of 30-day readmission among survivors was lower at high versus low volume hospitals (quartile 4 vs quartile 1 adjusted odds ratio, 0.77; 95% CI, 0.67-0.89). Higher hospital mechanical ventilation volume was weakly correlated with higher hospital risk-adjusted mortality rates (? = 0.16; p = 0.008). These moderately strong observations were supported by multiple sensitivity analyses. CONCLUSIONS:Contrary to previous studies, we observed worse patient outcomes at higher mechanical ventilation volume hospitals. In the setting of increasing use of mechanical ventilation and changes in mechanical ventilation practices, multiple mechanisms of worse outcomes including resource strain are possible. Future studies investigating differences in processes of care between high and low volume hospitals are necessary.
| S-EPMC7245578 | biostudies-literature
Project description:Microbial sequencing revealed progressive reduction of gut microbiota that showed some differences in the two ABX groups compared to untreated controls. Interestingly, duration of ABX was associated with a gradual disappearance of the CD4+ and CD4+CD8+ subset of gut intraepithelial lymphocytes (IELs). This IEL subset is microbiota-dependent and is absent in germ-free mice. Relative abundance of Lactobacillus reuteri correlated with frequencies of CD4+CD8+ IELs and reduced EAU. Notably, IELs in culture suppressed antigen-specific activation of autoreactive T cells.
2023-11-17 | GSE236922 | GEO
Project description:Provisioning of abundant food resources in human-altered landscapes can have profound effects on wildlife ecology, with important implications for pathogen transmission. While empirical studies have quantified the effects of provisioning on host behaviour and immunology, the net interactive effect of these components on host-pathogen dynamics is unknown. We use simple compartmental models to investigate how provisioning-induced changes to host demography, contact behaviour and immune defence influence pathogen invasion and persistence. We show that pathogen invasion success and equilibrium prevalence depend critically on how provisioning affects host immune defence and that moderate levels of provisioning can lead to drastically different outcomes of pathogen extinction or maximizing prevalence. These results highlight the need for further empirical studies to fully understand how provisioning affects pathogen transmission in urbanized environments.
| S-EPMC4126624 | biostudies-literature
Project description: Not available
| S-EPMC10643586 | biostudies-literature
Project description:OBJECTIVE:Can having too much self-control make people unhappy? Researchers have increasingly questioned the unilateral goodness of self-control and proposed that it is beneficial only up to a certain point, after which it becomes detrimental. The little empirical research on the issue shows mixed results. Hence, we tested whether a curvilinear relationship between self-control and subjective well-being exists. METHOD:We used multiple metrics (questionnaires, behavioral ratings), sources (self-report, other-report), and methods (cross-sectional measurement, dayreconstruction method, experience sampling method) across six studies (Ntotal ?=?5,318). RESULTS:We found that self-control positively predicted subjective well-being (cognitive and affective), but there was little evidence for an inverted U-shaped curve. The results held after statistically controlling for demographics and other psychological confounds. CONCLUSION:Our main finding is that self-control enhances subjective well-being with little to no apparent downside of too much self-control.
| S-EPMC5677575 | biostudies-literature
Project description:Bacteria that synthesize c-di-AMP also encode several mechanisms for controlling c-di-AMP levels within the cytoplasm. One major class of phosphodiesterases comprises GdpP and DhhP homologs, which degrade c-di-AMP into the linear molecule 5'-pApA or AMP by the DHH-DHHA1 domain. The other major class comprises PgpH homologs, which degrade c-di-AMP by the HD domain. Both GdpP and PgpH harbor sensory domains, likely to regulate c-di-AMP hydrolysis activity in response to signal input. As another possible mechanism for controlling cytoplasmic c-di-AMP levels, bacteria also secrete c-di-AMP via multidrug resistance transporters, as demonstrated for Listeria monocytogenes. Mutants that accumulate high c-di-AMP levels, by deletion of phosphodiesterases or multidrug resistance transporters, exhibit aberrant physiology, growth defects, and attenuated virulence in infection.
| S-EPMC4821758 | biostudies-literature