Sex differences in functional limitations and the role of socioeconomic factors: a multi-cohort analysis

Background: Women are more likely to have functional limitations than are men, partly because of greater socioeconomic disadvantage. However, how sex differences vary by severity of functional limitations remains unclear. We examined sex differences in functional limitations, with attention to socioeconomic factors and severity of limitations. Methods: Longitudinal data on limitations in basic activities of daily living (ADL) and instrumental activities of daily living (IADL) and mobility activities were drawn from 62 375 participants from 14 countries. For ADL, IADL, and mobility, participants were categorised based on number of limited activities (0, 1, 2, or ≥3). Sex differences in limitations in four birth cohorts (1895–1929, 1930–38, 1939–45, and 1946–60) were analysed before and after adjustment for socioeconomic factors (education and labour force status). Findings: The prevalence of IADL and ADL limitations was higher in women than in men. After adjustment for socioeconomic factors, this sex difference was attenuated. The sex difference in IADL limitations at age 75 years (in the 1895–1929 cohort) was 3·7% before adjustment for socioeconomic factors (95% CI 2·6–4·7) and 1·7% (1·1–2·2) after adjustment. For ADL, the sex difference in limitations at age 75 years (in the 1895–1929 cohort) was 3·2% (2·3–4·1) before adjustment for socioeconomic factors and 1·4% (0·9–1·8) after adjustment. Sex differences in mobility limitations (16·1%, 95% CI 14·4–17·7) remained after adjustment for socioeconomic factors (14·3%, 12·7–15·9). After age 85 years, women were more likely to have three or more IADL or mobility limitations and men were more likely to have one or two limitations. Interpretation: Socioeconomic factors largely explain sex differences in IADL and ADL limitations but not mobility. Sex differences in mobility limitations in midlife are important targets for future research and interventions. Funding: National Institute on Aging, UK National Institute for Health Research, European Commission, and US Social Security Administration

On the asymptotic giant branch star origin of peculiar spinel grain OC2

Microscopic presolar grains extracted from primitive meteorites have extremely anomalous isotopic compositions revealing the stellar origin of these grains. The composition of presolar spinel grain OC2 is different from that of all other presolar spinel grains. Large excesses of the heavy Mg isotopes are present and thus an origin from an intermediate-mass (IM) asymptotic giant branch (AGB) star was previously proposed for this grain. We discuss the isotopic compositions of presolar spinel grain OC2 and compare them to theoretical predictions. We show that the isotopic composition of O, Mg and Al in OC2 could be the signature of an AGB star of IM and metallicity close to solar experiencing hot bottom burning, or of an AGB star of low mass (LM) and low metallicity suffering very efficient cool bottom processing. Large measurement uncertainty in the Fe isotopic composition prevents us from discriminating which model better represents the parent star of OC2. However, the Cr isotopic composition of the grain favors an origin in an IM-AGB star of metallicity close to solar. Our IM-AGB models produce a self-consistent solution to match the composition of OC2 within the uncertainties related to reaction rates. Within this solution we predict that the 16O(p,g)17F and the 17O(p,a)14N reaction rates should be close to their lower and upper limits, respectively. By finding more grains like OC2 and by precisely measuring their Fe and Cr isotopic compositions, it may be possible in the future to derive constraints on massive AGB models from the study of presolar grains.Comment: 10 pages, 8 figures, accepted for publication on Astronomy & Astrophysic

Cyclophilin40 isomerase activity is regulated by a temperature-dependent allosteric interaction with Hsp90

Cyclophilin 40 (Cyp40) comprises an N-terminal cyclophilin domain with peptidyl-prolyl isomerase (PPIase) activity and a C-terminal tetratricopeptide repeat (TPR) domain that binds to the C-terminal–EEVD sequence common to both heat shock protein 70 (Hsp70) and Hsp90. We show in the present study that binding of peptides containing the MEEVD motif reduces the PPIase activity by ∼30%. CD and fluorescence assays show that the TPR domain is less stable than the cyclophilin domain and is stabilized by peptide binding. Isothermal titration calorimetry (ITC) shows that the affinity for the–MEEVD peptide is temperature sensitive in the physiological temperature range. Results from these biophysical studies fit with the MD simulations of the apo and holo (peptide-bound) structures which show a significant reduction in root mean square (RMS) fluctuation in both TPR and cyclophilin domains when–MEEVD is bound. The MD simulations of the apo-protein also highlight strong anti-correlated motions between residues around the PPIase-active site and a band of residues running across four of the seven helices in the TPR domain. Peptide binding leads to a distortion in the shape of the active site and a significant reduction in these strongly anti-correlated motions, providing an explanation for the allosteric effect of ligand binding and loss of PPIase activity. Together the experimental and MD results suggest that on heat shock, dissociation of Cyp40 from complexes mediated by the TPR domain leads to an increased pool of free Cyp40 capable of acting as an isomerase/chaperone in conditions of cellular stress

Evidence Map of Pancreatic Surgery–A living systematic review with meta-analyses by the International Study Group of Pancreatic Surgery (ISGPS)

Background: Pancreatic surgery is associated with considerable morbidity and, consequently, offers a large and complex field for research. To prioritize relevant future scientific projects, it is of utmost importance to identify existing evidence and uncover research gaps. Thus, the aim of this project was to create a systematic and living Evidence Map of Pancreatic Surgery. Methods: PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science were systematically searched for all randomized controlled trials and systematic reviews on pancreatic surgery. Outcomes from every existing randomized controlled trial were extracted, and trial quality was assessed. Systematic reviews were used to identify an absence of randomized controlled trials. Randomized controlled trials and systematic reviews on identical subjects were grouped according to research topics. A web-based evidence map modeled after a mind map was created to visualize existing evidence. Meta-analyses of specific outcomes of pancreatic surgery were performed for all research topics with more than 3 randomized controlled trials. For partial pancreatoduodenectomy and distal pancreatectomy, pooled benchmarks for outcomes were calculated with a 99% confidence interval. The evidence map undergoes regular updates. Results: Out of 30, 860 articles reviewed, 328 randomized controlled trials on 35, 600 patients and 332 systematic reviews were included and grouped into 76 research topics. Most randomized controlled trials were from Europe (46%) and most systematic reviews were from Asia (51%). A living meta-analysis of 21 out of 76 research topics (28%) was performed and included in the web-based evidence map. Evidence gaps were identified in 11 out of 76 research topics (14%). The benchmark for mortality was 2% (99% confidence interval: 1%–2%) for partial pancreatoduodenectomy and <1% (99% confidence interval: 0%–1%) for distal pancreatectomy. The benchmark for overall complications was 53% (99%confidence interval: 46%–61%) for partial pancreatoduodenectomy and 59% (99% confidence interval: 44%–80%) for distal pancreatectomy. Conclusion: The International Study Group of Pancreatic Surgery Evidence Map of Pancreatic Surgery, which is freely accessible via www.evidencemap.surgery and as a mobile phone app, provides a regularly updated overview of the available literature displayed in an intuitive fashion. Clinical decision making and evidence-based patient information are supported by the primary data provided, as well as by living meta-analyses. Researchers can use the systematic literature search and processed data for their own projects, and funding bodies can base their research priorities on evidence gaps that the map uncovers. © 2021 The Author

METALLIC ION DEVELOPMENTS AT GANIL

Radioactive ion beams (RIB) are routinely produced at GANIL by fragmentation of the projectile. A possible way to improve the RIB intensity is to increase the primary beam intensity impinging the target. Although high intensities can be obtained with an ECR ion source for gaseous elements, it is more difficult for metallic elements due to the poor ionization efficiency of the source. This report deals with metallic ion beam production at high intensity. Experimental results for Ca, Ni and Fe are presented. The oven and the MIVOC methods are compared

Protein–Protein Interactions Modulate the Docking-Dependent E3-Ubiquitin Ligase Activity of Carboxy-Terminus of Hsc70-Interacting Protein (CHIP)

CHIP is a tetratricopeptide repeat (TPR) domain protein that functions as an E3-ubiquitin ligase. As well as linking the molecular chaperones to the ubiquitin proteasome system, CHIP also has a docking-dependent mode where it ubiquitinates native substrates, thereby regulating their steady state levels and/or function. Here we explore the effect of Hsp70 on the docking-dependent E3-ligase activity of CHIP. The TPR-domain is revealed as a binding site for allosteric modulators involved in determining CHIP's dynamic conformation and activity. Biochemical, biophysical and modeling evidence demonstrate that Hsp70-binding to the TPR, or Hsp70-mimetic mutations, regulate CHIP-mediated ubiquitination of p53 and IRF-1 through effects on U-box activity and substrate binding. HDX-MS was used to establish that conformational-inhibition-signals extended from the TPR-domain to the U-box. This underscores inter-domain allosteric regulation of CHIP by the core molecular chaperones. Defining the chaperone-associated TPR-domain of CHIP as a manager of inter-domain communication highlights the potential for scaffolding modules to regulate, as well as assemble, complexes that are fundamental to protein homeostatic control.Published versio