Torsin ATPases: Harnessing Dynamic Instability for Function

Torsins are essential, disease-relevant AAA+ (ATPases associated with various cellular activities) proteins residing in the endoplasmic reticulum and perinuclear space, where they are implicated in a variety of cellular functions. Recently, new structural and functional details about Torsins have emerged that will have a profound influence on unraveling the precise mechanistic details of their yet-unknown mode of action in the cell. While Torsins are phylogenetically related to Clp/HSP100 proteins, they exhibit comparatively weak ATPase activities, which are tightly controlled by virtue of an active site complementation through accessory cofactors. This control mechanism is offset by a TorsinA mutation implicated in the severe movement disorder DYT1 dystonia, suggesting a critical role for the functional Torsin-cofactor interplay in vivo. Notably, TorsinA lacks aromatic pore loops that are both conserved and critical for the processive unfolding activity of Clp/HSP100 proteins. Based on these distinctive yet defining features, we discuss how the apparent dynamic nature of the Torsin-cofactor system can inform emerging models and hypotheses for Torsin complex formation and function. Specifically, we propose that the dynamic assembly and disassembly of the Torsin/cofactor system is a critical property that is required for Torsins' functional roles in nuclear trafficking and nuclear pore complex assembly or homeostasis that merit further exploration. Insights obtained from these future studies will be a valuable addition to our understanding of disease etiology of DYT1 dystonia

Single-Dilution COVID-19 Antibody Test with Qualitative and Quantitative Readouts

The coronavirus disease 2019 (COVID-19) global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to place an immense burden on societies and health care systems. A key component of COVID-19 control efforts is serological testing to determine the community prevalence of SARS-CoV-2 exposure and quantify individual immune responses to prior SARS-CoV-2 infection or vaccination. Here, we describe a laboratory-developed antibody test that uses readily available research-grade reagents to detect SARS-CoV-2 exposure in patient blood samples with high sensitivity and specificity. We further show that this sensitive test affords the estimation of viral spike-specific IgG titers from a single sample measurement, thereby providing a simple and scalable method to measure the strength of an individual's immune response. The accuracy, adaptability, and cost-effectiveness of this test make it an excellent option for clinical deployment in the ongoing COVID-19 pandemic.IMPORTANCE Serological surveillance has become an important public health tool during the COVID-19 pandemic. Detection of protective antibodies and seroconversion after SARS-CoV-2 infection or vaccination can help guide patient care plans and public health policies. Serology tests can detect antibodies against past infections; consequently, they can help overcome the shortcomings of molecular tests, which can detect only active infections. This is important, especially when considering that many COVID-19 patients are asymptomatic. In this study, we describe an enzyme-linked immunosorbent assay (ELISA)-based qualitative and quantitative serology test developed to measure IgG and IgA antibodies against the SARS-CoV-2 spike glycoprotein. The test can be deployed using commonly available laboratory reagents and equipment and displays high specificity and sensitivity. Furthermore, we demonstrate that IgG titers in patient samples can be estimated from a single measurement, enabling the assay's use in high-throughput clinical environments

Treatment of severe COVID-19 with convalescent plasma in Bronx, NYC

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