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Abstract Whilst the exercise‐induced myokine interleukin‐6 (IL‐6) plays a beneficial role in cardiac structural adaptations, its influence on exercise‐induced functional cardiac outcomes remains unknown. We hypothesised that IL‐6 activity is required for exercise‐induced improvements in left ventricular global longitudinal strain (LV GLS). In an exploratory study 52 individuals with abdominal obesity were randomised to 12 weeks’ high‐intensity exercise or no exercise in combination with IL‐6 receptor inhibition (IL‐6i) or placebo. LV strain and volume measurements were assessed by cardiac magnetic resonance. Exercise improved LV GLS by −5.4% [95% CI: −9.1% to −1.6%] (P = 0.007). Comparing the change from baseline in LV GLS in the exercise + placebo group (−4.8% [95% CI: −7.4% to −2.2%]; P

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

In reinforcement learning (RL) tasks, decision makers learn the values of actions in a context-dependent fashion. Although context dependence has many advantages, it can lead to suboptimal preferences when choice options are extrapolated beyond their original encoding contexts. Here, we tested whether we could manipulate context dependence in RL by introducing a secondary task designed to bias attention toward either absolute or relative outcomes. Participants completed a learning phase that involved choices between two (Experiment 1; n = 111) or three (Experiment 2; n = 90) options per trial with complete feedback. Choice options were grouped in stable contexts so that only a small set of the possible combinations were encountered. One group of participants rated how they felt about particular options (Feelings condition), and another group reported how much they expected to win from particular options (Outcomes condition) at occasional points throughout the learning phase. A third group (Control condition) made no ratings. In the subsequent transfer test, participants chose between all possible pairs of options without feedback. The experimental manipulation had no effect on learning phase performance but a significant effect on transfer, with the Feelings and Control conditions exhibiting greater context dependence than the Outcomes condition. Further, rated feelings reflected relative valuation whereas expected outcomes were more sensitive to absolute option values. Hierarchical Bayesian modeling was used to summarize the findings from both experiments. Our results suggest that attending to affective reactions versus expected outcomes moderates the effects of encoding context on subsequent choices.

Abstract Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson’s disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.

Objective/Participants: In a large, diverse sample of college students (N = 2,230), this online study investigated racial/ethnic differences on type of discriminatory event experienced and perceived stress, and whether discrimination-related stress was associated with mental health symptoms. Methods: Prevalence of lifetime/past year discriminatory events was assessed and frequency of discrimination-related stress was compared across racial/ethnic groups. Correlations between discrimination-related stress and mental health symptoms were also examined. Results: All racial/ ethnic groups reported experiencing all types of discriminatory events, though prevalence was lowest for White students. Racial/ethnic minority (i.e., Asian, Black, Latinx) students reported greater discrimination-related perceived stress compared to White, non-Hispanics. Across all racial/ethnic groups, discrimination-related stress was positively associated with negative mental health outcomes (e.g., anxiety/depressive symptoms). Conclusions: These results highlight the need to continue efforts to reduce discriminatory experiences of racial/ethnic minority students and to incorporate antiracism interventions in universities to mitigate the pervasive negative experiences of minority students.

Little is known about the healthy aging of the circadian timing system under natural living conditions. This study explores changes in the circadian rhythm of distal skin temperature (DST) with aging and relates these changes to sleep–wake timing and environmental influences. DST, sleep–wake timing, 24-h light exposure, and physical activity were measured and averaged over seven consecutive days using temperature sensors, actigraphy with a light meter, and sleep diaries in 35 healthy older women (60–79 years) and 30 young women (20–34 years). Circadian rhythm characteristics, describing strength (amplitude) and timing (acrophase) of the DST rhythm, were calculated using cosinor analysis. The older adults displayed an 18–19% smaller amplitude and a 66–73 min earlier acrophase (peak time) for DST rhythm than the young adults, indicating a weaker and phase-advanced DST rhythm. The phase advance for DST was not due to an earlier evening increase, but to a shorter nocturnal plateau period. Daytime light exposure inversely affected strength (amplitude) but not phasing of the DST rhythm in older adults. The DST rhythm was 3.5 times more advanced than the sleep–wake rhythm, showing an altered phase relationship (phase angle) between both rhythms with aging. The phase angle was more heterogeneous among older adults, showing differential aging. The phase advance for DST rhythm and the altered and heterogeneous phase relationship between DST and sleep–wake rhythms were not related to ambient light exposure and the physical activity of older adults. This suggests that healthy aging of the circadian system might be due to endogenous mechanisms such as an internal rearrangement rather than external influences.

Inclusion of a decoy alternative dominated by a target option, but not its competitor, typically leads to increased choice for the target over the competitor, known as the attraction effect. However, the reverse sometimes occurs, known as the repulsion effect. This research tested factors that moderate the repulsion effect in preferential choice scenarios with numerical attributes. Experiment 1 used a between-subjects design with a small set of consumer products and demonstrated robust repulsion effects that did not depend on the relative similarity of the decoy and target. Experiments 2 and 4 used a more powerful within-subjects design along with an expanded set of products and showed that repulsion effects were generally enhanced when the decoy and target had more similar attributes; however, the moderating effect of decoy–target similarity appeared to be fragile and sensitive to stimulus presentation factors. These findings provided mixed support for the hypothesis that the target is tainted by its proximity to the decoy. Experiments 3 and 5 tested whether the extremity of values on the attribute favoring the target moderates the repulsion effect. The results demonstrated that repulsion is more likely when all the alternatives have extremely high values on the target’s better attribute. Extremity of attribute values on the dimension favoring the target may result in a categorical assessment along that dimension and shift focus to the attribute favoring the competitor as one way to foster the repulsion effect.

Abstract Aims Transthyretin amyloid cardiomyopathy (ATTR CM) is a progressive and severe heart disease with physical and psychological implications. The Nordic PROACT study was conducted to investigate the health‐related quality of life (HRQoL) in ATTR CM patients. Methods and results The Nordic PROACT study was a cross‐sectional non‐interventional study conducted in 12 cardiology hospital clinics across Norway, Sweden, Finland and Denmark. Men and women aged ≥18 years diagnosed with symptomatic ATTR CM were included. The investigator provided information on medical history, biomarkers, current treatment, co‐morbidities and disease severity according to the New York Heart Association (NYHA) class and the National Amyloidosis Centre (NAC) staging. Patients completed the HRQoL questionnaires in the form of the Kansas City Cardiomyopathy Questionnaire (KCCQ), the EQ‐5D‐5L index with Visual Analog Scale (VAS), and the Major Depression Inventory (MDI). A total of 169 patients (mean ± SD age 77.7 ± 6.2 years) were included. Ninety‐two per cent were men. Seventy‐six per cent had wildtype ATTR CM (ATTRwt CM) and 15% had a hereditary form of ATTR CM (ATTRv CM) while 9% were genetically unclassified. Most patients were in NYHA class II (54%) and NAC stage 1 (53%). Participation in randomized clinical trials (RCT) was noted in 58% of the patients. The 169 ATTR CM patients had a mean ± SD KCCQ score of 64.3 ± 23.1 for total symptom score, 64.8 ± 20.9 for overall summary score (OSS) and 65.1 ± 21.5 for clinical summary score. The EQ‐5D‐5L total utility score was 0.8 ± 0.2 and the EQ‐5D‐5L VAS score was 62.9 ± 20.6. The vast majority (89%) did not report any signs of depression. Patients with ATTRv CM had a higher KCCQ OSS as compared with ATTRwt CM, while EQ‐5D‐5L utility score, EQ‐5D‐5L VAS and MDI were similar. Non‐RCT participants had a poorer HRQoL as compared with RCT participants as reflected in lower KCCQ OSS and EQ‐5D‐5L VAS scores and a higher MDI score. Patients with higher NYHA classes and NAC disease stages had a poorer HRQoL as demonstrated by lower KCCQ and EQ‐5D‐5L scores and higher MDI scores. Correlation between KCCQ, EQ‐5D‐5L and MDI and the covariate NYHA class remained significant (P

Induction of the one-carbon cycle is an early hallmark of mitochondrial dysfunction and cancer metabolism. Vital intermediary steps are localized to mitochondria, but it remains unclear how one-carbon availability connects to mitochondrial function. Here, we show that the one-carbon metabolite and methyl group donor S-adenosylmethionine (SAM) is pivotal for energy metabolism. A gradual decline in mitochondrial SAM (mitoSAM) causes hierarchical defects in fly and mouse, comprising loss of mitoSAM-dependent metabolites and impaired assembly of the oxidative phosphorylation system. Complex I stability and iron-sulfur cluster biosynthesis are directly controlled by mitoSAM levels, while other protein targets are predominantly methylated outside of the organelle before import. The mitoSAM pool follows its cytosolic production, establishing mitochondria as responsive receivers of one-carbon units. Thus, we demonstrate that cellular methylation potential is required for energy metabolism, with direct relevance for pathophysiology, aging, and cancer.

In 2018, the A.S. Hornby Educational Trust launched its 'Decentring ELT' initiative, with the aim of identifying, publicizing, and supporting ways in which English language educators in low- and middle-income countries work locally and collaboratively to develop activities that respond to their particular circumstances. This article aims to explore the notion of 'decentring' in ELT by means of a provisional characterization and by presenting examples of activities carried out by ELT teacher associations in Africa, Latin America, and South Asia which involve: localization/devolution; encouragement of success-sharing; support for teacher research; investigation of members' needs and/or capabilities; and/or attempts to bring about wider change. On the basis of feedback received so far on our provisional characterization of decentring, we end by highlighting some ways in which this notion, and outside support for it, may need to be not only extended but also problematized and critiqued.

Objective: This study aimed to qualitatively examine how perceptions of cannabis differ among college students in an effort to better understand the changing landscape of cannabis on college campuses. Participants: Forty-six predominantly male (69.9%; M[subscript age] = 23.15, SD = 4.11) college students attending a border state university (i.e., a state that has not yet legalized cannabis but borders a state that has). Methods: Participants engaged in facilitated focus group discussions (N = 5) about cannabis-related issues. Results: Thematic analysis uncovered three primary themes and six subthemes. Main themes included: (1) User Heterogeneity and Identity, (2) Relative Benefits and Harms of Cannabis, and (3) Social Position of Cannabis on Campus Culture. Conclusions: Cannabis has quickly integrated into the college social environment, with social stigmatization and identification with cannabis impacting decisions to use. Findings inform existing college health programs on how to approach conversations about cannabis with students.

Abstract Background Hypospadias is a common inborn error of the male urethral development, for which the aetiology is still elusive. Polymorphic variants in genes involved in the masculinisation of male genitalia, such as the androgen receptor, have been associated with some cases of hypospadias. Co-regulators of the androgen receptor start being acknowledged as possible candidates for hormone-resistance instances, which could account for hypospadias. One such molecule, the protein FKBP52, coded by the FKBP4 gene, has an important physiological role in up-regulating androgen receptor activity, an essential step in the development of the male external genitalia. The presence of hypospadias in mice lacking fkbp52 encouraged us to study the sequence and the expression of FKBP4 in boys with isolated hypospadias. Patients and methods The expression of FKBP52 in the genital skin of boys with hypospadias and in healthy controls was tested by immunohistochemistry. Mutation screening in the FKBF4 gene was performed in ninety-one boys with non syndromic hypospadias. Additionally, two polymorphisms were typed in a larger cohort. Results Immunohistochemistry shows epithelial expression of FKBP52 in the epidermis of the penile skin. No apparent difference in the FKBP52 expression was detected in healthy controls, mild or severe hypospadias patients. No sequence variants in the FKBP4 gene have implicated in hypospadias in our study. Conclusion FKBP52 is likely to play a role in growth and development of the male genitalia, since it is expressed in the genital skin of prepubertal boys; however alterations in the sequence and in the expression of the FKBP4 gene are not a common cause of non-syndromic hypospadias.

Research has consistently linked social dominance orientation (SDO) and right-wing authoritarianism (RWA) to numerous forms of prejudice, but little research has examined how these personality and ideological variables interact in their associations with various attitudinal outcomes. The present study explored the interactions of SDO and RWA in predicting a wide range of social attitudes (i.e., modern racism, modern sexism, traditional gender role beliefs) and feeling thermometers toward racial/ethnic minorities, women, and other socially stigmatized groups in a cross-sectional survey of 1244 U.S. college students (M.sub.age = 21.54; SD = 5.17). Moderation analyses found significant independent associations of SDO, RWA, or both with all attitudinal or ideological outcome variables. We found a hypothesized synergistic interaction of SDO x RWA in predicting attitudes toward women scores, but the results did not support other hypothesized SDO x RWA interactions. Findings provide further support of the Dual Process Model and suggest that SDO and RWA may employ largely independent pathways in predicting attitudes toward marginalized groups., Author(s): Emma Wedell [sup.1] , Adrian J. Bravo [sup.1] Author Affiliations: (1) grid.264889.9, 0000 0001 1940 3051, Department of Psychological Sciences, William & Mary, , Williamsburg, VA, USA Introduction Although [...]

Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic conditions. Although mitochondrial disease patients are known to suffer from abnormal immune responses, how heteroplasmic mtDNA mutations affect the immune system at the molecular level is largely unknown. Here, in mice carrying pathogenic C5024T in mt-tRNAAla and in patients with mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome carrying A3243G in mt-tRNALeu, we found memory T and B cells to have lower pathogenic mtDNA mutation burdens than their antigen-inexperienced naive counterparts, including after vaccination. Pathogenic burden reduction was less pronounced in myeloid compared with lymphoid lineages, despite C5024T compromising macrophage OXPHOS capacity. Rapid dilution of the C5024T mutation in T and B cell cultures could be induced by antigen receptor–triggered proliferation and was accelerated by metabolic stress conditions. Furthermore, we found C5024T to dysregulate CD8+ T cell metabolic remodeling and IFN-γ production after activation. Together, our data illustrate that the generation of memory lymphocytes shapes the mtDNA landscape, wherein pathogenic variants dysregulate the immune response.

Abstract Background The majority of genetic epilepsies remain unsolved in terms of specific genotype. Phenotype‐based genomic analyses have shown potential to strengthen genomic analysis in various ways, including improving analytical efficacy. Methods We have tested a standardised phenotyping method termed ‘Phenomodels’ for integrating deep‐phenotyping information with our in‐house developed clinical whole exome/genome sequencing analytical pipeline. Phenomodels includes a user‐friendly epilepsy phenotyping template and an objective measure for selecting which template terms to include in individualised Human Phenotype Ontology (HPO) gene panels. In a pilot study of 38 previously solved cases of developmental and epileptic encephalopathies, we compared the sensitivity and specificity of the individualised HPO gene panels with the clinical epilepsy gene panel. Results The Phenomodels template showed high sensitivity for capturing relevant phenotypic information, where 37/38 individuals' HPO gene panels included the causative gene. The HPO gene panels also had far fewer variants to assess than the epilepsy gene panel. Conclusion We have demonstrated a viable approach for incorporating standardised phenotype information into clinical genomic analyses, which may enable more efficient analysis.

Hydrogen bonding between an amide group and the p-π cloud of an aromatic ring was first identified in a protein in the 1980s. Subsequent surveys of high-resolution X-ray crystal structures found multiple instances, but their preponderance was determined to be infrequent. Hydrogen atoms participating in a hydrogen bond to the p-π cloud of an aromatic ring are expected to experience an upfield chemical shift arising from a shielding ring current shift. We surveyed the Biological Magnetic Resonance Data Bank for amide hydrogens exhibiting unusual shifts as well as corroborating nuclear Overhauser effects between the amide protons and ring protons. We found evidence that Trp residues are more likely to be involved in p-π hydrogen bonds than other aromatic amino acids, whereas His residues are more likely to be involved in in-plane hydrogen bonds, with a ring nitrogen acting as the hydrogen acceptor. The p-π hydrogen bonds may be more abundant than previously believed. The inclusion in NMR structure refinement protocols of shift effects in amide protons from aromatic sidechains, or explicit hydrogen bond restraints between amides and aromatic rings, could improve the local accuracy of sidechain orientations in solution NMR protein structures, but their impact on global accuracy is likely be limited.