Two-Dimensional Electrophoresis of Tau Mutants Reveals Specific Phosphorylation Pattern Likely Linked to Early Tau Conformational Changes

The role of Tau phosphorylation in neurofibrillary degeneration linked to Alzheimer's disease remains to be established. While transgenic mice based on FTDP-17 Tau mutations recapitulate hallmarks of neurofibrillary degeneration, cell models could be helpful for exploratory studies on molecular mechanisms underlying Tau pathology. Here, “human neuronal cell lines” overexpressing Wild Type or mutated Tau were established. Two-dimensional electrophoresis highlights that mutated Tau displayed a specific phosphorylation pattern, which occurs in parallel to the formation of Tau clusters as visualized by electron microscopy. In fact, this pattern is also displayed before Tau pathology onset in a well established mouse model relevant to Tau aggregation in Alzheimer's disease. This study suggests first that pathological Tau mutations may change the distribution of phosphate groups. Secondly, it is possible that this molecular event could be one of the first Tau modifications in the neurofibrillary degenerative process, as this phenomenon appears prior to Tau pathology in an in vivo model and is linked to early steps of Tau nucleation in Tau mutants cell lines. Such cell lines consist in suitable and evolving models to investigate additional factors involved in molecular pathways leading to whole Tau aggregation

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Data from: Steller’s jays assess and communicate about predator risk using detection cues and identity

Predators can vary in the risk they pose, depending upon the factors such as body size, maneuverability, hunting strategy, and diet. Prey can also detect predators with different senses, such as seeing, hearing, or smelling them. We presented wild Steller’s jays (Cyanocitta stelleri annectens) with visual cues (robotic raptors) or acoustic cues (call playbacks) of 4 different raptors to test how they assess risk and how this influences their alarm calls. The assessment of risk from different predator cues varied with different species of raptors: Jays responded to sharp-shinned hawks (Accipiter striatus) with an increase in latency to resume foraging regardless of whether they were seen or heard, whereas latency responses to northern goshawks (Accipiter gentilis) were longer if they were seen versus if they were heard. Furthermore, Steller’s jays altered the acoustic structure of their alarm calls depending on the species of raptor and whether they saw or heard them. These results demonstrate that Steller’s jay’s assessment of risk involves an interaction between predator identity and predator detection cue and in response, they alter their acoustically-simple alarm calls in surprisingly nuanced ways

Data from: Male courtship behaviors and female choice reduced during experimental starvation stress

Mating behaviors may exhibit trade-offs with survival because the energy allocated and time devoted to survival may reduce those available for mating behaviors that are important for reproduction. Long-term selection experiments for survival in stressful conditions are valuable for understanding how survival traits may trade-off with other traits, such as reproduction. We investigated how courtship behaviors and female choice may vary under stressful conditions in Drosophila melanogaster by mating females and males from starvation–selected lines with unselected-control lines. Males from starvation-selected lines had reduced courtship behaviors with fewer wing bouts per minute and shorter duration of wing bouts compared to control males, regardless of female pairing. These results are consistent with increased survival in starvation conditions showing trade-offs in males. Female mate selectivity also showed significant evolutionary changes with unselected-control females exhibiting differential courtship durations: shorter courtship durations when paired with males from unselected-control lines and longer courtship durations with males from starvation-selected lines. In contrast, starvation-selected females showed no significant differences in courtship duration between unselected-control and starvation-selected males despite the reduction in starvation–selected male courtship behaviors. We discuss how these results may indicate that starvation selection altered the interaction between females and males for mating ability and preferences in a complex manner consistent with life-history trade-off models

Survey of Vineyard Insects and Plants to Identify Potential Insect Vectors and Noncrop Reservoirs of Grapevine Red Blotch Virus

Grapevine red blotch virus (GRBV) is a DNA virus in the family Geminiviridae. This pathogen is the causal agent of grapevine red blotch disease, which affects cultivated grapevines and leads to negative effects on crop quality and yield. GRBV is present in commercial vineyards across North America, indicating that spread might have been largely human mediated. That said, recent surveys have demonstrated that there appears to be secondary transmission, most likely by an insect vector. In this study, vineyard insects and plants were surveyed to identify potential candidate vectors and noncrop plants that could act as reservoirs for this pathogen. Results reconfirm that GRBV is limited to Vitis spp., including both cultivated and wild grapevines. Eleven insect genera or species, field collected in vineyards, tested positive for GRBV using quantitative polymerase chain reaction. These insect taxa include unknown Aphididae, the cicadellids Aceratagallia spp., Acinopterus angulatus, Caladonus coquilleti, Colladonus montanus reductus, Colladonus sp., Empoasca spp., Erythroneura elegantula, and Scaphytopius graneticus, along with the membracid Spissistilus festinus and an unknown delphacid. Of these organisms, S. festinus is already known to be capable of transmitting GRBV, and Scaphytopius graneticus may merit closer evaluation as a candidate vector. [Graphic: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license