Accelerated molecular dynamics to explore the binding of transition metals to amyloid-β

We report the accelerated molecular dynamics (aMD) simulation of amyloid-β (Aβ) peptides of four different lengths (16, 28, 40, and 42 residues) and their complexes when bound to Cu(II), Fe(II), or Zn(II). 600 ns equilibrated trajectory data were analyzed for each structure from three independent 200 ns aMD simulations, generating 16 aMD trajectories. We show that the presence of a metal ion leads to reduced size and decreased mobility relative to the free peptide due to the anchoring effect of the ions. The reduced mobility was shown largely to be due to the restricted movement in N-terminal residues, most notably Asp1 and His6 that are involved in the metal-ion coordination in all cases. Significant disruption of the secondary structure and patterns of salt bridge interactions arise on the coordination of metal ions. In this regard, similarities were noted between results for Zn(II) and Fe(II), whereas results for Cu(II) are more comparable to that of the free peptides. Reweighting of free energy surfaces was carried out from aMD data to identify the properties and descriptions of local minima structures

Replica exchange molecular dynamics simulation of the coordination of Pt(ii)-Phenanthroline to amyloid-β†

We report replica exchange molecular dynamics (REMD) simulations of the complex formed between amyloid-β peptides and platinum bound to a phenanthroline ligand, Pt(phen). After construction of an AMBER-style forcefield for the Pt complex, REMD simulation employing temperatures between 270 and 615 K was used to provide thorough sampling of the conformational freedom available to the peptide. We find that the full length peptide Aβ42, in particular, frequently adopts a compact conformation with a large proportion of α- and 3,10-helix content, with smaller amounts of β-strand in the C-terminal region of the peptide. Helical structures are more prevalent than in the metal-free peptide, while turn and strand conformations are markedly less common. Non-covalent interactions, including salt-bridges, hydrogen bonds, and π-stacking between aromatic residues and the phenanthroline ligand, are common, and markedly different from those seen in the amyloid-β peptides alone

Molecular dynamics simulation of aluminum binding to amyloid-β and its effect on peptide structure

Multiple microsecond-length molecular dynamics simulations of complexes of Al(III) with amyloid-β (Aβ) peptides of varying length are reported, employing a non-bonded model of Al-coordination to the peptide, which is modelled using the AMBER ff14SB forcefield. Individual simulations reach equilibrium within 100 to 400 ns, as determined by root mean square deviations, leading to between 2.1 and 2.7 μs of equilibrated data. These reveal a compact set of configurations, with radius of gyration similar to that of the metal free peptide but larger than complexes with Cu, Fe and Zn. Strong coordination through acidic residues Glu3, Asp7 and Glu11 is maintained throughout all trajectories, leading to average coordination numbers of approximately 4 to 5. Helical conformations predominate, particularly in the longer Al-Aβ40 and Al-Aβ42 peptides, while β-strand forms are rare. Binding of the small, highly charged Al(III) ion to acidic residues in the N-terminus strongly disrupts their ability to engage in salt bridges, whereas residues outside the metal binding region engage in salt bridges to similar extent to the metal-free peptide, including the Asp23-Lys28 bridge known to be important for formation of fibrils. High helical content and disruption of salt bridges leads to characteristic tertiary structure, as shown by heat maps of contact between residues as well as representative clusters of trajectories

No straight lines – young women’s perceptions of their mental health and wellbeing during and after pregnancy: a systematic review and meta-ethnography

Background: Young mothers face mental health challenges during and after pregnancy including increased rates of depression compared to older mothers. While the prevention of teenage pregnancy in countries such as the United States and the United Kingdom has been a focus for policy and research in recent decades, the need to understand young women’s own experiences has been highlighted. The aim of this meta-ethnography was to examine young women’s perceptions of their mental health and wellbeing during and after pregnancy to provide new understandings of those experiences. Methods: A systematic review and meta-ethnographic synthesis of qualitative research was conducted. Seven databases were systematically searched and forward and backward searching conducted. Papers were included if they were from Organisation for Economic Co-operation and Development countries and explored mental health and wellbeing experiences of young mothers (age under 20 in pregnancy; under 25 at time of research) as a primary research question – or where evidence about mental health and wellbeing from participants was foregrounded. Nineteen papers were identified and the Critical Appraisal Skills Programme checklist for qualitative research used to appraise the evidence. Following the seven-step process of meta-ethnography, key constructs were examined within each study and then translated into one another. Results: Seven translated themes were identified forming a new line of argument wherein mental health and wellbeing was analysed as relating to individual bodily experiences; tied into past and present relationships; underpinned by economic insecurity and entangled with feelings of societal surveillance. There were ‘no straight lines’ in young women’s experiences, which were more complex than dominant narratives around overcoming adversity suggest. Conclusions: The synthesis concludes that health and social care professionals need to reflect on the operation of power and stigma in young women’s lives and its impact on wellbeing. It adds to understanding of young women’s mental health and wellbeing during and after pregnancy as located in physical and structural factors rather than individual capacities alone

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Blood pressure and blood glucose concentration amongst middle-aged men conceived and/or born on Guernsey during the 1940-45 German occupation

Session - Obesity, diet and exercisepublished_or_final_versio

Efficacy, safety, and immunogenicity of a booster regimen of Ad26.COV2.S vaccine against COVID-19 (ENSEMBLE2) : results of a randomised, double-blind, placebo-controlled, phase 3 trial

Background Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose. Methods ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe–critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing. Findings Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36·0 (15·0–62·0) days. Vaccine efficacy was 75·2% (adjusted 95% CI 54·6–87·3) against moderate to severe–critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55·6%] of 3015 vs 896 [57·5%] of 1559, respectively; systemic adverse events, 1764 [58·5%] of 3015 vs 821 [52·7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1–2 in severity. Interpretation A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe–critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed