Rocaglates induce gain-of-function alterations to eIF4A and eIF4F

Rocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities in pre-clinical cancer studies. As a result, this family of compounds has been significantly expanded through the development of efficient synthetic schemes. However, it is unknown whether all of the members of the rocaglate family act through similar mechanisms of action. Here, we present a comprehensive study comparing the biological activities of >200 rocaglates to better understand how the presence of different chemical entities influences their biological activities. Through this, we find that most rocaglates preferentially repress the translation of mRNAs containing purine-rich 5' leaders, but certain rocaglates lack this bias in translation repression. We also uncover an aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to the sequestration of the complex onto RNA.P50 GM067041 - NIGMS NIH HHS; R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HHSPublished versio

Acceptability and feasibility of continuous glucose monitoring in people with diabetes : protocol for a mixed-methods systematic review of quantitative and qualitative evidence

BACKGROUND: Good glycaemic control is a crucial part of diabetes management. Traditional assessment methods, including HbA1c checks and self-monitoring of blood glucose, can be unreliable and inaccurate. Continuous glucose monitoring (CGM) offers a non-invasive and more detailed alternative. Availability of this technology is increasing worldwide. However, there is no current comprehensive evidence on the acceptability and feasibility of these devices. This is a protocol for a mixed-methods systematic review of qualitative and quantitative evidence about acceptability and feasibility of CGM in people with diabetes. METHODS: We will search MEDLINE, Embase, CINAHL, and CENTRAL for qualitative and quantitative evidence about the feasibility and acceptability of CGM in all populations with diabetes (any type) using search terms for "continuous glucose monitoring" and "diabetes". We will not apply any study-type filters. Searches will be restricted to studies conducted in humans and those published from 2011 onwards. We will not restrict the search by language. Study selection and data extraction will be carried out by two reviewers independently using Rayyan and Eppi-Reviewer, respectively, with disagreements resolved by discussion. Data extraction will include key information about each study, as well as qualitative evidence in the form of participant quotes from primary studies and themes and subthemes based on the authors' analysis. Quantitative data relating to acceptability and feasibility including data loss, adherence, and quantitative ratings of acceptability will be extracted as means and standard deviations or n/N as appropriate. Qualitative evidence will be analysed using framework analysis informed by the Theoretical Framework of Acceptability. Where possible, quantitative evidence will be combined using random-effects meta-analysis; otherwise, a narrative synthesis will be performed. The most appropriate method for integrating qualitative and quantitative findings will be selected based on the data available. DISCUSSION: Ongoing assessment of the acceptability of interventions has been identified as crucially important to scale-up and implementation. This review will provide new knowledge with the potential to inform a programme theory of CGM as well as future roll-out to potentially vulnerable populations, including those with severe mental illness. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021255141

A core outcome set for trials evaluating self-management interventions in people with severe mental illness and coexisting type 2 diabetes

BACKGROUND: People with severe mental illness (SMI), such as schizophrenia, have higher rates of type 2 diabetes and worse outcomes, compared to those without SMI and it is not known whether diabetes self-management interventions are effective for people who have both conditions. Research in this area has been impeded by a lack of consensus on which outcomes to prioritise in people with co-existing SMI and diabetes.AIMS: To develop a core outcome set (COS) for use in effectiveness trials of diabetes self-management interventions in adults with both type 2 diabetes and SMI.METHODS: The COS was developed in three stages: (i) identification of outcomes from systematic literature review of intervention studies, followed by multi-stakeholder and service user workshops; (ii) rating of outcomes in a two-round online Delphi survey; (iii) agreement of final 'core' outcomes through a stakeholder consensus workshop.RESULTS: Seven outcomes were selected: glucose control, blood pressure, body composition (body weight, BMI, body fat), health-related quality of life, diabetes self-management, diabetes-related distress and medication adherence.CONCLUSIONS: This COS is recommended for future trials of effectiveness of diabetes self-management interventions for people with SMI and type 2 diabetes. Its use will ensure trials capture important outcomes and reduce heterogeneity so findings can be readily synthesised to inform practice and policy.</p

Francisella tularensis Transmission by Solid Organ Transplantation, 20171.

In July 2017, fever and sepsis developed in 3 recipients of solid organs (1 heart and 2 kidneys) from a common donor in the United States; 1 of the kidney recipients died. Tularemia was suspected only after blood cultures from the surviving kidney recipient grew Francisella species. The organ donor, a middle-aged man from the southwestern United States, had been hospitalized for acute alcohol withdrawal syndrome, pneumonia, and multiorgan failure. F. tularensis subsp. tularensis (clade A2) was cultured from archived spleen tissue from the donor and blood from both kidney recipients. Whole-genome multilocus sequence typing indicated that the isolated strains were indistinguishable. The heart recipient remained seronegative with negative blood cultures but had been receiving antimicrobial drugs for a medical device infection before transplant. Two lagomorph carcasses collected near the donor's residence were positive by PCR for F. tularensis subsp. tularensis (clade A2). This investigation documents F. tularensis transmission by solid organ transplantation

Prevalence, risk factors, and treatments for post-COVID breathlessness:a systematic review and meta-analysis

Persistent breathlessness >28 days after acute COVID-19 infection has been identified as a highly debilitating post-COVID symptom. However, the prevalence, risk factors, mechanisms and treatments for post-COVID breathlessness remain poorly understood. We systematically searched PubMed and Embase for relevant studies published from 1 January 2020 to 1 November 2021 (PROSPERO registration number: CRD42021285733) and included 119 eligible papers. Random-effects meta-analysis of 42 872 patients with COVID-19 reported in 102 papers found an overall prevalence of post-COVID breathlessness of 26% (95% CI 23-29) when measuring the presence/absence of the symptom, and 41% (95% CI 34-48) when using Medical Research Council (MRC)/modified MRC dyspnoea scale. The pooled prevalence decreased significantly from 1-6 months to 7-12 months post-infection. Post-COVID breathlessness was more common in those with severe/critical acute infection, those who were hospitalised and females, and was less likely to be reported by patients in Asia than those in Europe or North America. Multiple pathophysiological mechanisms have been proposed (including deconditioning, restrictive/obstructive airflow limitation, systemic inflammation, impaired mental health), but the body of evidence remains inconclusive. Seven cohort studies and one randomised controlled trial suggested rehabilitation exercises may reduce post-COVID breathlessness. There is an urgent need for mechanistic research and development of interventions for the prevention and treatment of post-COVID breathlessness

John squire and endothelial glycocalyx structure: an unfinished story

John Squire did not only produce leading works in the muscle field, he also significantly contributed to the vascular permeability field by ultrastructural analysis of the endothelial glycocalyx. Presented here is a review of his involvement in the field by his main collaborator C.C. Michel and his last postdoctoral researcher KP Arkill. We end on a reinterpretation of his work that arguably links to our current understanding of endothelial glycocalyx structure and composition predicting 6 glycosaminoglycans fibres per syndecan core protein, only achieved in the endothelium by dimerization

Structure in the Magnetic Field of the Milky Way Disk and Halo traced by Faraday Rotation

Magnetic fields in the ionized medium of the disk and halo of the Milky Way impose Faraday rotation on linearly polarized radio emission. We compare two surveys mapping the Galactic Faraday rotation, one showing the rotation measures of extragalactic sources seen through the Galaxy (from Hutschenreuter et al 2022), and one showing the Faraday depth of the diffuse Galactic synchrotron emission from the Global Magneto-Ionic Medium Survey. Comparing the two data sets in 5deg x 10deg bins shows good agreement at intermediate latitudes, 10 < |b| < 50 deg, and little correlation between them at lower and higher latitudes. Where they agree, both tracers show clear patterns as a function of Galactic longitude: in the Northern Hemisphere a strong sin(2 x longitude) pattern, and in the Southern hemisphere a sin(longitude + pi) pattern. Pulsars with height above or below the plane |z| > 300 pc show similar longitude dependence in their rotation measures. Nearby non-thermal structures show rotation measure shadows as does the Orion-Eridanus superbubble. We describe families of dynamo models that could explain the observed patterns in the two hemispheres. We suggest that a field reversal, known to cross the plane a few hundred pc inside the solar circle, could shift to positive z with increasing Galactic radius to explain the sin(2xlongitude) pattern in the Northern Hemisphere. Correlation shows that rotation measures from extragalactic sources are one to two times the corresponding rotation measure of the diffuse emission, implying Faraday complexity along some lines of sight, especially in the Southern hemisphere.Comment: 37 pages, 26 figures, Ap. J. accepte

An annotated cDNA library of juvenile Euprymna scolopes with and without colonization by the symbiont Vibrio fischeri

BACKGROUND: Biologists are becoming increasingly aware that the interaction of animals, including humans, with their coevolved bacterial partners is essential for health. This growing awareness has been a driving force for the development of models for the study of beneficial animal-bacterial interactions. In the squid-vibrio model, symbiotic Vibrio fischeri induce dramatic developmental changes in the light organ of host Euprymna scolopes over the first hours to days of their partnership. We report here the creation of a juvenile light-organ specific EST database. RESULTS: We generated eleven cDNA libraries from the light organ of E. scolopes at developmentally significant time points with and without colonization by V. fischeri. Single pass 3' sequencing efforts generated 42,564 expressed sequence tags (ESTs) of which 35,421 passed our quality criteria and were then clustered via the UIcluster program into 13,962 nonredundant sequences. The cDNA clones representing these nonredundant sequences were sequenced from the 5' end of the vector and 58% of these resulting sequences overlapped significantly with the associated 3' sequence to generate 8,067 contigs with an average sequence length of 1,065 bp. All sequences were annotated with BLASTX (E-value < -03) and Gene Ontology (GO). CONCLUSION: Both the number of ESTs generated from each library and GO categorizations are reflective of the activity state of the light organ during these early stages of symbiosis. Future analyses of the sequences identified in these libraries promise to provide valuable information not only about pathways involved in colonization and early development of the squid light organ, but also about pathways conserved in response to bacterial colonization across the animal kingdom

Determinants of Physical Health Self-Management Behaviours in Adults With Serious Mental Illness:A Systematic Review

Behavioural interventions can support the adoption of healthier lifestyles and improve physical health outcomes, but it is unclear what factors might drive success of such interventions in people with serious mental illness (SMI). We systematically identified and reviewed evidence of the association between determinants of physical health self-management behaviours in adults with SMI. Data about American Association of Diabetes Educator’s Self-Care Behaviours (AADE-7) were mapped against the novel Mechanisms of Action (MoA) framework. Twenty-eight studies were included in the review, reporting evidence on 104 determinant-behaviour links. Beliefs about capabilities and beliefs about consequences were the most important determinants of behaviour, especially for being physically active and healthy eating. There was some evidence that emotion and environmental context and resources played a role in determining reducing risks, being active, and taking medications. We found very limited evidence associated with problem solving, and no study assessed links between MoAs and healthy coping. Although the review predominantly identified evidence about associations from cross-sectional studies that lacked validated and objective measures of self-management behaviours, these findings can facilitate the identification of behaviour change techniques with hypothesised links to determinants to support self-management in people with SMI