Sleep disturbance mediates the link between both self-compassion and self-criticism and psychological distress during prolonged periods of stress

Poor sleep and subsequent decline in mental health often occur during times of prolonged stress, such as a pandemic. Self-compassion is linked with improved sleep and better mental health, while self-criticism is linked with poorer sleep and psychological distress. Given there is little evidence of the interrelationships of these constructs, we examined whether higher self-compassion or lower levels of self-criticism can reduce psychological distress directly and indirectly via sleep during times of prolonged stress. Structural equation modelling was used to analyse two samples (N = 722, Study 1, and N = 622, Replication Study) of university students during different stages of the pandemic. An aggregate psychological distress construct was calculated using depression, anxiety and stress measures. We created models that showed insomnia symptoms mediated the relationship between self-compassion/self-criticism and psychological distress. Sleep partially mediated both relationships, and this was the strongest effect in both samples. This suggests that improving self-compassion and reducing self-criticism will improve sleep, leading to reduced psychological distress. As our findings are robust and held at two time points, future research should investigate broader demographics and differing stress responses

Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients

Background: 8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50 %. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). Methods: SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing. Results: High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y419) and FAK (Y861) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. Conclusions: Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism

Targeting of Early Endosomes by Autophagy Facilitates EGFR Recycling and Signalling

Despite recently uncovered connections between autophagy and the endocytic pathway, the role of autophagy in regulating endosomal function remains incompletely understood. Here, we find that the ablation of autophagy-essential players disrupts EGFinduced endocytic trafficking of EGFR. Cells lacking ATG7 or ATG16L1 exhibit increased levels of phosphatidylinositol-3-phosphate (PI(3)P), a key determinant of early endosome maturation. Increased PI(3)P levels are associated with an accumulation of EEA1-positive endosomes where EGFR trafficking is stalled. Aberrant early endosomes are recognised by the autophagy machinery in a TBK1- and Gal8-dependent manner and are delivered to LAMP2-positive lysosomes. Preventing this homeostatic regulation of early endosomes by autophagy reduces EGFR recycling to the plasma membrane and compromises downstream signalling and cell survival. Our findings uncover a novel role for the autophagy machinery in maintaining early endosome function and growth factor sensing

The impact of deliberate reflection with WISE-MDTM modules on critical thinking of nurse practitioner students: A prospective, randomized controlled pilot study

Objective: Nurse practitioner (NP) students at our graduate school of nursing use WISE-MDTM simulation modules in the curriculum. This prospective randomized controlled pilot study was undertaken to evaluate critical-thinking outcomes associated with adding metacognitive deliberate-reflection guidance to the learning strategy with WISE-MDTM simulation modules. Methods: Of 33 NP students randomly assigned to intervention and control groups, 16 completed the study. The intervention group received WISE-MDTM learning modules with specific guidance or deliberate reflection. Controls used the modules with instructions for periodic free-thought reflections. Students’ tape-recorded reflections were categorized according to author-developed critical-thinking categories. Data were analyzed using NVIVOTM. Students’ feedback was collected by post-intervention anonymous survey. Results: Critical thinking outcomes (student responses to exercises after free-thinking or deliberate-reflection guidance) did not differ between groups. However, the intervention group demonstrated a higher level of critical thought after deliberate-reflection guidance. Post-intervention quantitative and qualitative feedback from both groups endorsed the value of the WISE-MDTM modules for NP education. Conclusions: Despite no difference in unprompted outcomes between groups, the intervention group often verbalized more thoughtful clinical decision-making. We speculate that the deliberate-reflection guidance intervention utilized with students throughout only two modules was insufficient for them to internalize the critical-thinking process. We propose using free-thought reflections with one or two WISE-MDTM modules to identify struggling students’ clinical decision-making process. These students’ remediation plan could include recording their deliberate-reflection process while viewing WISE-MDTM modules. Students would be guided to verbalize and record their critical-thinking processes for faculty review until students sufficiently integrate the process into their clinical decision-making

Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer's disease mutants

<p>Abstract</p> <p>Background</p> <p>Amyloid precursor protein (APP) is enzymatically cleaved by γ-secretase to form two peptide products, either Aβ40 or the more neurotoxic Aβ42. The Aβ42/40 ratio is increased in many cases of familial Alzheimer's disease (FAD). The transmembrane domain (TM) of APP contains the known dimerization motif GXXXA. We have investigated the dimerization of both wild type and FAD mutant APP transmembrane domains.</p> <p>Results</p> <p>Using synthetic peptides derived from the APP-TM domain, we show that this segment is capable of forming stable transmembrane dimers. A model of a dimeric APP-TM domain reveals a putative dimerization interface, and interestingly, majority of FAD mutations in APP are localized to this interface region. We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.</p> <p>Conclusion</p> <p>The dissociation constants are correlated to both the Aβ42/Aβ40 ratio and the mean age of disease onset in AD patients. We also show that these TM-peptides reduce Aβ production and Aβ42/Aβ40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and γ-secretase components, potentially revealing a new class of γ-secretase inhibitors.</p

Mortality of Migratory Birds from Marine Commercial Fisheries and Offshore Oil and Gas Production in Canada

There is an imminent need for conservation and best-practice management efforts in marine ecosystems where global-scale declines in the biodiversity and biomass of large vertebrate predators are increasing and marine communities are being altered. We examine two marine-based industries that incidentally take migratory birds in Canada: (1) commercial fisheries, through bycatch, and (2) offshore oil and gas exploration, development, and production. We summarize information from the scientific literature and technical reports and also present new information from recently analyzed data to assess the magnitude and scope of mortality. Fisheries bycatch was responsible for the highest levels of incidental take of migratory bird species; estimated combined take in the longline, gillnet, and bottom otter trawl fisheries within the Atlantic, including the Gulf of St. Lawrence, and Pacific regions was 2679 to 45,586 birds per year. For the offshore oil and gas sector, mortality estimates ranged from 188 to 4494 deaths per year due to the discharge of produced waters resulting in oil sheens and collisions with platforms and vessels; however these estimates for the oil and gas sector are based on many untested assumptions. In spite of the uncertainties, we feel levels of mortality from these two industries are unlikely to affect the marine bird community in Canada, but some effects on local populations from bycatch are likely. Further research and monitoring will be required to: (1) better estimate fisheries-related mortality for vulnerable species and populations that may be impacted by local fisheries, (2) determine the effects of oil sheens from produced waters, and attraction to platforms and associated mortality from collisions, sheens, and flaring, so that better estimates of mortality from the offshore oil and gas sector can be obtained, and (3) determine impacts associated with accidental spills, which are not included in our current assessment. With a better understanding of the direct mortality of marine birds from industry, appropriate mitigation and management actions can be implemented. Cooperation from industry for data collection, research to fill knowledge gaps, and implementation of mitigation approaches will all be needed to conserve marine birds in Canada

Transcript specific regulation of expression influences susceptibility to multiple sclerosis.

Genome-wide association studies (GWAS) have identified over 100 loci containing single nucleotide variants (SNVs) that influence the risk of developing multiple sclerosis (MS). Most of these loci lie in non-coding regulatory regions of the genome that are active in immune cells and are therefore thought to modify risk by altering the expression of key immune genes. To explore this hypothesis we screened genes flanking MS-associated variants for evidence of allele specific expression (ASE) by quantifying the transcription of coding variants in linkage disequilibrium with MS-associated SNVs. In total, we were able to identify and successfully analyse 200 such coding variants (from 112 genes) in both CD4+ and CD8+ T cells from 106 MS patients and 105 controls. Fifty-six of these coding variants (from 43 genes) showed statistically significant evidence of ASE in one or both cell types. In the Lck interacting transmembrane adaptor 1 gene (LIME1), for example, we were able to show that in both cell types, the MS-associated variant rs2256814 increased the expression of some transcripts while simultaneously reducing the expression of other transcripts. In CD4+ cells from an additional independent set of 96 cases and 93 controls we were able to replicate the effect of this SNV on the balance of alternate LIME1 transcripts using qPCR (p = 5 × 10-24). Our data thus indicate that some of the MS-associated SNVs identified by GWAS likely exert their effects on risk by distorting the balance of alternate transcripts rather than by changing the overall level of gene expression

Inflamation and oxidative stress : The molecular connectivity between insulin resistance, obesity and Alzheimer\u27s disease

Type 2 diabetes (T 2 DM), Alzheimer’s disease (AD), and insulin resistance are age-related conditions and increased prevalence is of public concern. Recent research has provided evidence that insulin resistance and impaired insulin signalling may be a contributory factor to the progression of diabetes, dementia, and other neurological disorders. Alzheimer’s disease (AD) is the most common subtype of dementia. Reduced release (for T 2 DM) and decreased action of insulin are central to the development and progression of both T 2 DM and AD. A literature search was conducted to identify molecular commonalities between obesity, diabetes, and AD. Insulin resistance affects many tissues and organs, either through impaired insulin signalling or through aberrant changes in both glucose and lipid (cholesterol and triacylglycerol) metabolism and concentrations in the blood. Although epidemiological and biological evidence has highlighted an increased incidence of cognitive decline and AD in patients with T 2 DM, the common molecular basis of cell and tissue dysfunction is rapidly gaining recognition. As a cause or consequence, the chronic in flammatory response and oxidative stress associated with T 2 DM, amyloid- ! (A ! ) protein accumulation, and mitochondrial dysfunction link T 2 DM and AD