Interferon-γ-induced Regulation of Peroxisome Proliferator-activated Receptor γ and STATs in Adipocytes

Interferon-γ (IFN-γ) is known primarily for its roles in immunological responses but also has been shown to affect fat metabolism and adipocyte gene expression. To further investigate the effects of IFN-γ on fat cells, we examined the effects of this cytokine on the expression of adipocyte transcription factors in 3T3-L1 adipocytes. Although IFN-γ regulated the expression of several adipocyte transcription factors, IFN-γ treatment resulted in a rapid reduction of both peroxisome proliferator-activated receptor (PPAR) protein and mRNA. A 48-h exposure to IFN-γ also resulted in a decrease of both CCAAT/enhancer-binding α and sterol regulatory element binding protein (SREBP-1) expression. The short half-life of both the PPARγ mRNA and protein likely contributed to the rapid decline of both cytosolic and nuclear PPARγ in the presence of IFN-γ. Our studies clearly demonstrated that the IFN-γ-induced loss of PPARγ protein is partially inhibited in the presence of two distinct proteasome inhibitors. Moreover, IFN-γ also inhibited the transcription of PPARγ, which was accompanied by a decrease in PPARγ mRNA accumulation. In addition, exposure to IFN-γ resulted in a substantial increase in STAT I expression and a small increase in STAT 3 expression. IFN-γ treatment of 3T3-L1 adipocytes (48-96 h) resulted in a substantial inhibition of insulin-sensitive glucose uptake. These data clearly demonstrate that IFN-γ treatment results in the development of insulin resistance, which is accompanied by the regulation of various adipocyte transcription factors, in particular the synthesis and degradation of PPARγ

Student voice in work integrated learning scholarship: a review of teacher education and geographical sciences

Work integrated learning is an umbrella term that refers to the opportunities provided to university students to integrate knowledge of theory and practice as part of their degree program. As the role of students in higher education is evolving, we sought to develop our understanding of the role of students in the work integrated learning (WIL) space through exploring current literature on student voice. In this paper, we consider what has been reported about WIL in relation to student voice, how it has been represented, and how this has influenced practice. We undertook a systematic literature review for two different disciplines, one which represented an example of a professionally accredited undergraduate degree program (teacher education), and the other an example of a program with no professional accreditation (geographical sciences). The teacher education literature demonstrated more clearly the use of student voice to inform WIL within curriculum design. However, the geographical sciences literature did include examples of student voice being incorporated within the design of collaborative community-based forms of WIL. A role for students as researchers, who lead research and initiate curriculum change into WIL, was noticeably absent in both disciplinary sets of literature. The lack of evidence of the inclusion of students in the design, conduct, and analysis of WIL provides an invitation for SoTL scholars to redefine the role of students in this space

Student voice in work integrated learning scholarship: A review of teacher education and geographical sciences

Work integrated learning is an umbrella term that refers to the opportunities provided to university students to integrate knowledge of theory and practice as part of their degree program. As the role of students in higher education is evolving, we sought to develop our understanding of the role of students in the work integrated learning (WIL) space through exploring current literature on student voice. In this paper, we consider what has been reported about WIL in relation to student voice, how it has been represented, and how this has influenced practice. We undertook a systematic literature review for two different disciplines, one which represented an example of a professionally accredited undergraduate degree program (teacher education), and the other an example of a program with no professional accreditation (geographical sciences). The teacher education literature demonstrated more clearly the use of student voice to inform WIL within curriculum design. However, the geographical sciences literature did include examples of student voice being incorporated within the design of collaborative community-based forms of WIL. A role for students as researchers, who lead research and initiate curriculum change into WIL, was noticeably absent in both disciplinary sets of literature. The lack of evidence of the inclusion of students in the design, conduct, and analysis of WIL provides an invitation for SoTL scholars to redefine the role of students in this space

The role of metacognition in self-critical rumination: an investigation in individuals presenting with low self-esteem

Background: No research, to date, has directly investigated the role of metacognition in self-critical rumination and low self-esteem. Aim: To investigate the presence of metacognitive beliefs about self-critical rumination; the goal of self-critical rumination and its stop signal; and the degree of detachment from intrusive self-critical thoughts. Method: Ten individuals reporting both a self-acknowledged tendency to judge themselves critically and having low self-esteem were assessed using metacognitive profiling, a semi-structured interview. Results: All participants endorsed both positive and negative metacognitive beliefs about self-critical rumination. Positive metacognitive beliefs concerned the usefulness of self-critical rumination as a means of improving cognitive performance and enhancing motivation. Negative metacognitive beliefs concerned the uncontrollability of self-critical rumination and its negative impact on mood, motivation and perception of self-worth. The primary goal of engaging in self-critical rumination was to achieve a better or clearer understanding of a given trigger situation or to feel more motivated to resolve it. However, only four participants were able to identify when this goal had been achieved, which was if the trigger situation were not to occur again. Participants unanimously stated that they were either unable to detach from their self-critical thoughts or could do so some of the time with varying degrees of success. More often than not, though, self-critical thoughts were viewed as facts, would rarely be seen as distorted or biased, and could take hours or days to dissipate. Conclusions: These findings provide preliminary evidence that specific facets of metacognition play a role in the escalation and perseveration of self-critical rumination

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570