Two-step phosphorylation of Ana2 by Plk4 is required for the sequential loading of Ana2 and Sas6 to initiate procentriole formation.

The conserved process of centriole duplication requires Plk4 kinase to recruit and promote interactions between Sas6 and Sas5/Ana2/STIL (respective nomenclature of worms/flies/humans). Plk4-mediated phosphorylation of Ana2/STIL in its conserved STAN motif has been shown to promote its interaction with Sas6. However, STAN motif phosphorylation is not required for recruitment of Ana2 to the centriole. Here we show that in Drosophila, Ana2 loads onto the site of procentriole formation ahead of Sas6 in a process that also requires Plk4. However, whereas Plk4 is first recruited to multiple sites around the ring of zone II at the periphery of the centriole, Ana2 is recruited to a single site in telophase before Plk4 becomes finally restricted to this same single site. When we over-ride the auto-destruction of Plk4, it remains localized to multiple sites in the outer ring of the centriole and, if catalytically active, recruits Ana2 to these sites. Thus, it is the active form of Plk4 that promotes Ana2's recruitment to the centriole. We now show that Plk4 phosphorylates Ana2 at a site other than the STAN motif, which lies in a conserved region we term the ANST (ANa2-STil) motif. Mutation of this site, S38, to a non-phosphorylatable residue prevents the procentriole loading of Ana2 and blocks centriole duplication. Thus the initiation of procentriole formation requires Plk4 to first phosphorylate a single serine residue in the ANST motif to promote Ana2's recruitment and, secondly, to phosphorylate four residues in the STAN motif enabling Ana2 to recruit Sas6. We discuss these findings in light of the multiple Plk4 phosphorylation sites on Ana2

Signatures of the disk-jet coupling in the Broad-line Radio Quasar 4C+74.26

Here we explore the disk-jet connection in the broad-line radio quasar 4C+74.26, utilizing the results of the multiwavelength monitoring of the source. The target is unique in that its radiative output at radio wavelengths is dominated by a moderately-beamed nuclear jet, at optical frequencies by the accretion disk, and in the hard X-ray range by the disk corona. Our analysis reveals a correlation (local and global significance of 96\% and 98\%, respectively) between the optical and radio bands, with the disk lagging behind the jet by $250 \pm 42$ days. We discuss the possible explanation for this, speculating that the observed disk and the jet flux changes are generated by magnetic fluctuations originating within the innermost parts of a truncated disk, and that the lag is related to a delayed radiative response of the disk when compared with the propagation timescale of magnetic perturbations along relativistic outflow. This scenario is supported by the re-analysis of the NuSTAR data, modelled in terms of a relativistic reflection from the disk illuminated by the coronal emission, which returns the inner disk radius $R_{\rm in}/R_{\rm ISCO} =35^{+40}_{-16}$. We discuss the global energetics in the system, arguing that while the accretion proceeds at the Eddington rate, with the accretion-related bolometric luminosity $L_{\rm bol} \sim 9 \times 10^{46}$ erg s$^{-1}$ $\sim 0.2 L_{\rm Edd}$, the jet total kinetic energy $L_\textrm{j} \sim 4 \times 10^{44}$ erg s$^{-1}$, inferred from the dynamical modelling of the giant radio lobes in the source, constitutes only a small fraction of the available accretion power.Comment: 9 pages and 6 figures, ApJ accepte

The Role of SGLT2 Inhibitors in Heart Failure: A Systematic Review and Meta-Analysis.

AIMS: Recent randomised controlled trials (RCTs) have shown a significant prognostic benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors in the cardiovascular (CV) profile of patients with diabetes. This systematic review and meta-analysis aim to provide a concise evaluation of all the available evidence for the use of these agents in patients with heart failure (HF) regardless of their baseline diabetes status. METHODS AND RESULTS: PubMed, Web of Science, and Cochrane library databases were systematically searched from inception until November 20th 2020. Eight studies consisting of 13,275 patients were included in the meta-analysis. For the total population, SGLT2 inhibitors reduced the risk of all-cause mortality (HR: 0.83; 95% CI: 0.75-0.91; I 2 0%), hospitalisation for HF (HR: 0.68; 95% CI: 0.61-0.75; I 2: 0%), CV death (HR: 0.82; 95% CI: 0.74-0.92; I 2: 0%), and hospitalisation for HF or CV death (HR: 0.72; 95% CI: 0.66-0.78; I 2: 0%). Subgroup analyses of the total population according to the diabetes status showed that SGLT2 inhibitors significantly reduced the risk of hospitalisation for HF (HR: 0.68; 95% CI: 0.61, 0.75; I 2: 0%), as well as the risk of hospitalisation for HF or CV death (HR: 0.72; 95% CI: 0.66, 078; I 2: 0%) and CV death (HR: 0.82; 95% CI: 0.74, 0.91; I 2: 0%). CONCLUSIONS: The results of this meta-analysis confirm the growing evidence in the literature of the favourable profile of SGLT2 inhibitors in cardiovascular outcomes and mortality in patients with heart failure regardless of the baseline diabetes status. This systematic review has been registered with PROSPERO (CRD42021224777)

Association Between Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in Patients With COVID-19:A Systematic Review and Meta-analysis

Importance: The chronic receipt of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been assumed to exacerbate complications associated with COVID-19 and produce worse clinical outcomes. Objective: To conduct an updated and comprehensive systematic review and meta-analysis comparing mortality and severe adverse events (AEs) associated with receipt vs nonreceipt of ACEIs or ARBs among patients with COVID-19. Data Sources: PubMed and Embase databases were systematically searched from December 31, 2019, until September 1, 2020. Study Selection: The meta-analysis included any study design, with the exception of narrative reviews or opinion-based articles, in which COVID-19 was diagnosed through laboratory or radiological test results and in which clinical outcomes (unadjusted or adjusted) associated with COVID-19 were assessed among adult patients (≥18 years) receiving ACEIs or ARBs. Data Extraction and Synthesis: Three authors independently extracted data on mortality and severe AEs associated with COVID-19. Severe AEs were defined as intensive care unit admission or the need for assisted ventilation. For each outcome, a random-effects model was used to compare the odds ratio (OR) between patients receiving ACEIs or ARBs vs those not receiving ACEIs or ARBs. Main Outcomes and Measures: Unadjusted and adjusted ORs for mortality and severe AEs associated with COVID-19. Results: A total of 1788 records from the PubMed and Embase databases were identified; after removal of duplicates, 1664 records were screened, and 71 articles underwent full-text evaluation. Clinical data were pooled from 52 eligible studies (40 cohort studies, 6 case series, 4 case-control studies, 1 randomized clinical trial, and 1 cross-sectional study) enrolling 101949 total patients, of whom 26 545 (26.0%) were receiving ACEIs or ARBs. When adjusted for covariates, significant reductions in the risk of death (adjusted OR [aOR], 0.57; 95% CI, 0.43-0.76; P <.001) and severe AEs (aOR, 0.68; 95% CI, 0.53-0.88; P <.001) were found. Unadjusted and adjusted analyses of a subgroup of patients with hypertension indicated decreases in the risk of death (unadjusted OR, 0.66 [95% CI, 0.49-0.91]; P =.01; aOR, 0.51 [95% CI, 0.32-0.84]; P =.008) and severe AEs (unadjusted OR, 0.70 [95% CI, 0.54-0.91]; P =.007; aOR, 0.55 [95% CI, 0.36-0.85]; P =.007). Conclusions and Relevance: In this systematic review and meta-analysis, receipt of ACEIs or ARBs was not associated with a higher risk of multivariable-adjusted mortality and severe AEs among patients with COVID-19 who had either hypertension or multiple comorbidities, supporting the recommendations of medical societies. On the contrary, ACEIs and ARBs may be associated with protective benefits, particularly among patients with hypertension. Future randomized linical trials are warranted to establish causality

The quest for companions to post-common envelope binaries. II. NSVS14256825 and HS0705+6700

We report new mid-eclipse times of the two close binaries NSVS14256825 and HS0705+6700, harboring an sdB primary and a low-mass main-sequence secondary. Both objects display clear variations in the measured orbital period, which can be explained by the action of a third object orbiting the binary. If this interpretation is correct, the third object in NSVS14256825 is a giant planet with a mass of roughly 12 M_Jup. For HS0705+6700, we provide evidence that strengthens the case for the suggested periodic nature of the eclipse time variation and reduces the uncertainties in the parameters of the brown dwarf implied by that model. The derived period is 8.4 yr and the mass is 31 M_Jup, if the orbit is coplanar with the binary. This research is part of the PlanetFinders project, an ongoing collaboration between professional astronomers and student groups at high schools.Comment: Accepted by Astron. and Astrophy

Risk factors associated with post-COVID-19 condition: A systematic review and meta-analysis

IMPORTANCE: Post-COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support. OBJECTIVE To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC. DATA SOURCES: Medline and Embase databases were systematically searched from inception to December 5, 2022. STUDY SELECTION: The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients. DATA EXTRACTION AND SYNTHESIS: Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023. MAIN OUTCOMES AND MEASURES: The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19. RESULTS: The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76). CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination