Functional consequences of subunit diversity in RNA polymerases II and V

SummaryMultisubunit RNA polymerases IV and V (Pol IV and Pol V) evolved as specialized forms of Pol II that mediate RNA-directed DNA methylation (RdDM) and transcriptional silencing of transposons, viruses, and endogenous repeats in plants. Among the subunits common to Arabidopsis thaliana Pols II, IV, and V are 93% identical alternative ninth subunits, NRP(B/D/E)9a and NRP(B/D/E)9b. The 9a and 9b subunit variants are incompletely redundant with respect to Pol II; whereas double mutants are embryo lethal, single mutants are viable, yet phenotypically distinct. Likewise, 9a or 9b can associate with Pols IV or V but RNA-directed DNA methylation is impaired only in 9b mutants. Based on genetic and molecular tests, we attribute the defect in RdDM to impaired Pol V function. Collectively, our results reveal a role for the ninth subunit in RNA silencing and demonstrate that subunit diversity generates functionally distinct subtypes of RNA polymerases II and V

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

Engagement in research: an innovative three-stage review of the benefits for health-care performance

Background: There is a widely held assumption that research engagement improves health-care performance at various levels, but little direct empirical evidence. Objectives: To conduct a theoretically and empirically grounded synthesis to map and explore plausible mechanisms through which research engagement might improve health services performance. A review of the effects on patients of their health-care practitioner's or institution's participation in clinical trials was published after submission of the proposal for this review. It identified only 13 relevant papers and, overall, suggested that the evidence that research engagement improves health-care performance was less strong than some thought. We aimed to meet the need for a wider review. Methods: An hourglass review was developed, consisting of three stages: (1) a planning and mapping stage; (2) a focused review concentrating on the core question of whether or not research engagement improves health care; and (3) a wider (but less systematic) review of papers identified during the two earlier stages. Studies were included in the focused review if the concept of ‘engagement in research’ was an input and some measure of ‘performance’ an output. The search strategy covered the period 1990 to March 2012. MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science and other relevant databases were searched. A total of 10,239 papers were identified through the database searches, and 159 from other sources. A further relevance and quality check on 473 papers was undertaken, and identified 33 papers for inclusion in the review. A standard meta-analysis was not possible on the heterogeneous mix of papers in the focused review. Therefore an explanatory matrix was developed to help characterise the circumstances in which research engagement might improve health-care performance and the mechanisms that might be at work, identifying two main dimensions along which to categorise the studies: the degree of intentionality and the scope of the impact. Results: Of the 33 papers in the focused review, 28 were positive (of which six were positive/mixed) in relation to the question of whether or not research engagement improves health-care performance. Five papers were negative (of which two were negative/mixed). Seven out of 28 positive papers reported some improvement in health outcomes. For the rest, the improved care took the form of improved processes of care. Nine positive papers were at a clinician level and 19 at an institutional level. The wider review demonstrated, for example, how collaborative and action research can encourage some progress along the pathway from research engagement towards improved health-care performance. There is also evidence that organisations in which the research function is fully integrated into the organisational structure out-perform other organisations that pay less formal heed to research and its outputs. The focused and wider reviews identified the diversity in the mechanisms through which research engagement might improve health care: there are many circumstances and mechanisms at work, more than one mechanism is often operative, and the evidence available for each one is limited. Limitations: To address the complexities of this evidence synthesis of research we needed to spend significant time mapping the literature, and narrowed the research question to make it feasible. We excluded many potentially relevant papers (though we partially addressed this by conducting a wider additional synthesis). Studies assessing the impact made on clinician behaviour by small, locally conducted pieces of research could be difficult to interpret without full knowledge of the context. Conclusions: Drawing on the focused and wider reviews, it is suggested that when clinicians and health-care organisations engage in research there is the likelihood of a positive impact on health-care performance. Organisations that have deliberately integrated the research function into organisational structures demonstrate how research engagement can, among other factors, contribute to improved health-care performance. Further explorations are required of research networks and schemes to promote the engagement of clinicians and managers in research. Detailed observational research focusing on research engagement within organisations would build up an understanding of mechanisms

Coronal Heating as Determined by the Solar Flare Frequency Distribution Obtained by Aggregating Case Studies

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counter-intuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfv\'en waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, $\alpha=2$ as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed $>$600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: pre-flare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that $\alpha = 1.63 \pm 0.03$. This is below the critical threshold, suggesting that Alfv\'en waves are an important driver of coronal heating.Comment: 1,002 authors, 14 pages, 4 figures, 3 tables, published by The Astrophysical Journal on 2023-05-09, volume 948, page 7

Risk of COVID-19 after natural infection or vaccinationResearch in context

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health