No abstract

Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) may hold promise as a treatment for coronavirus disease 2019 (COVID-19). We compared the mortality and clinical outcome of patients with COVID-19 who received 200 mL of CCP with a spike protein IgG titer ≥ 1:2430 (median 1:47,385) within 72 hours of admission with propensity score–matched controls cared for at a medical center in the Bronx, between April 13 and May 4, 2020. Matching criteria for controls were age, sex, body mass index, race, ethnicity, comorbidities, week of admission, oxygen requirement, D-dimer, lymphocyte counts, corticosteroid use, and anticoagulation use. There was no difference in mortality or oxygenation between CCP recipients and controls at day 28. When stratified by age, compared with matched controls, CCP recipients less than 65 years had 4-fold lower risk of mortality and 4-fold lower risk of deterioration in oxygenation or mortality at day 28. For CCP recipients, pretransfusion spike protein IgG, IgM, and IgA titers were associated with mortality at day 28 in univariate analyses. No adverse effects of CCP were observed. Our results suggest CCP may be beneficial for hospitalized patients less than 65 years, but data from controlled trials are needed to validate this finding and establish the effect of aging on CCP efficacy.

The causes of coagulopathy associated with coronavirus disease 2019 (COVID-19) are poorly understood. We aimed to investigate the relationship between von Willebrand factor (VWF) biomarkers, intravascular hemolysis, coagulation, and organ damage in COVID-19 patients and study their association with disease severity and mortality. We conducted a retrospective study of 181 hospitalized COVID-19 patients randomly selected with balanced distribution of survivors and nonsurvivors. Patients who died had significantly lower ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity, significantly elevated lactate dehydrogenase levels, significantly increased shistocyte/RBC fragment counts, and significantly elevated VWF antigen and activity levels compared with patients discharged alive. These biomarkers correlate with markedly elevated D-dimers. Additionally, only 30% of patients who had an ADAMTS13 activity level of less than 43% on admission survived, yet 60% of patients survived who had an ADAMTS13 activity level of greater than 43% on admission. In conclusion, COVID-19 may present with low ADAMTS13 activity in a subset of hospitalized patients. Presence of schistocytes/RBC fragment and elevated D-dimer on admission may warrant a work-up for ADAMTS13 activity and VWF antigen and activity levels. These findings indicate the need for future investigation to study the relationship between endothelial and coagulation activation and the efficacy of treatments aimed at prevention and/or amelioration of microangiopathy in COVID-19.

Significance Cardiovascular diseases remain the leading cause of death worldwide, with atherosclerosis being the most common source of clinical events. Metabolic changes with aging associate with concurrent increased risk of both type 2 diabetes and cardiovascular disease, with the former further raising the risk of the latter. The activity of a selective type of autophagy, chaperone-mediated autophagy (CMA), decreases with age or upon dietary excesses. Here we study whether reduced CMA activity increases risk of atherosclerosis in mouse models. We have identified that CMA is up-regulated early in response to proatherogenic challenges and demonstrate that reduced systemic CMA aggravates vascular pathology in these conditions. We also provide proof-of-concept support that CMA up-regulation is an effective intervention to reduce atherosclerosis severity and progression.

The causes of coagulopathy associated with COVID-19 disease are poorly understood. We aimed to investigate the relationship between markers of endothelial activation, intravascular hemolysis, coagulation, and organ damage in COVID-19 patients and study their association with disease severity and mortality. We conducted a retrospective study of 181 hospitalized COVID-19 patients randomly selected with equal distribution of survivors and non-survivors. Patients who died had significantly lower ADAMTS13 activity, significantly higher LDH, schistocytes and von Willebrand Factor levels compared to patients discharged alive. Only 30% of patients with an initial ADAMTS13 activity <43% survived vs. 60% with ADAMTS13 >43% who survived. In conclusion, COVID-19 may manifest as a TMA-like illness in a subset of hospitalized patients. Presence of schistocytes on admission may warrant a work-up for TMA. These findings indicate the need for future investigation to study the relationship between endothelial and coagulation activation and the efficacy of TMA treatments in COVID-19.

Olfactory sensory axons target well-defined intermediate targets in the zebrafish olfactory bulb called protoglomeruli well before they form odorant receptor-specific glomeruli. A subset of olfactory sensory neurons are labeled by expression of the or111-7:IRES: GAL4 transgene whose axons terminate in the central zone (CZ) protoglomerulus. Previous work has shown that some of these axons misproject to the more dorsal and anterior dorsal zone (DZ) protoglomerulus in the absence of Netrin 1/Dcc signaling. In search of additional cues that guide these axons to the CZ, we found that Semaphorin 3D (Sema3D) is expressed in the anterior bulb and acts as a repellent that pushes them towards the CZ. Further analysis indicates that Sema3D signaling is mediated through Nrp1a, while Nrp2b also promotes CZ targeting but in a Sema3D-independent manner. nrp1a, nrp2b and dcc transcripts are detected in or111-7 transgene-expressing neurons early in development and both Nrp1a and Dcc act cell-autonomously in sensory neurons to promote accurate targeting to the CZ. dcc and nrp1a double mutants have significantly more DZ misprojections than either single mutant, suggesting that the two signaling systems act independently and in parallel to direct a specific subset of sensory axons to their initial protoglomerular target.

No abstract

Circadian rhythms align physiological functions with the light-dark cycle through oscillatory changes in the abundance of proteins in the clock transcriptional program. Timely removal of these proteins by different proteolytic systems is essential to circadian strength and adaptability. Here we show a functional interplay between the circadian clock and chaperone-mediated autophagy (CMA), whereby CMA contributes to the rhythmic removal of clock machinery proteins (selective chronophagy) and to the circadian remodeling of a subset of the cellular proteome. Disruption of this autophagic pathway in vivo leads to temporal shifts and amplitude changes of the clock-dependent transcriptional waves and fragmented circadian patterns, resembling those in sleep disorders and aging. Conversely, loss of the circadian clock abolishes the rhythmicity of CMA, leading to pronounced changes in the CMA-dependent cellular proteome. Disruption of this circadian clock/CMA axis may be responsible for both pathways malfunctioning in aging and for the subsequently pronounced proteostasis defect.