Tracking smell loss to identify healthcare workers with SARS-CoV-2 infection

Introduction Healthcare workers (HCW) treating COVID-19 patients are at high risk for infection and may also spread infection through their contact with vulnerable patients. Smell loss has been associated with SARS-CoV-2 infection, but it is unknown whether monitoring for smell loss can be used to identify asymptomatic infection among high risk individuals. In this study we sought to determine if tracking smell sensitivity and loss using an at-home assessment could identify SARS-CoV-2 infection in HCW. Methods and findings We performed a prospective cohort study tracking 473 HCW across three months to determine if smell loss could predict SARS-CoV-2 infection in this high-risk group. HCW subjects completed a longitudinal, behavioral at-home assessment of olfaction with household items, as well as detailed symptom surveys that included a parosmia screening questionnaire, and real-time quantitative polymerase chain reaction testing to identify SARS-CoV-2 infection. Our main measures were the prevalence of smell loss in SARS-CoV-2-positive HCW versus SARS-CoV- 2-negative HCW, and timing of smell loss relative to SARS-CoV-2 test positivity. SARS-CoV-2 was identified in 17 (3.6%) of 473 HCW. HCW with SARS-CoV-2 infection were more likely to report smell loss than SARS-CoV-2-negative HCW on both the at-home assessment and the screening questionnaire (9/17, 53% vs 105/456, 23%, P < .01). 6/9 (67%) of SARS-CoV-2-positive HCW reporting smell loss reported smell loss prior to having a positive SARS-CoV-2 test, and smell loss was reported a median of two days before testing positive. Neurological symptoms were reported more frequently among SARS-CoV-2-positive HCW who reported smell loss compared to those without smell loss (9/9, 100% vs 3/8, 38%, P < .01). Conclusions In this prospective study of HCW, self-reported changes in smell using two different measures were predictive of SARS-CoV-2 infection. Smell loss frequently preceded a positive test and was associated with neurological symptoms

p97/UBXD1 Generate Ubiquitylated Proteins That Are Sequestered into Nuclear Envelope Herniations in Torsin-Deficient Cells

DYT1 dystonia is a debilitating neurological movement disorder that arises upon Torsin ATPase deficiency. Nuclear envelope (NE) blebs that contain FG-nucleoporins (FG-Nups) and K48-linked ubiquitin are the hallmark phenotype of Torsin manipulation across disease models of DYT1 dystonia. While the aberrant deposition of FG-Nups is caused by defective nuclear pore complex assembly, the source of K48-ubiquitylated proteins inside NE blebs is not known. Here, we demonstrate that the characteristic K48-ubiquitin accumulation inside blebs requires p97 activity. This activity is highly dependent on the p97 adaptor UBXD1. We show that p97 does not significantly depend on the Ufd1/Npl4 heterodimer to generate the K48-ubiquitylated proteins inside blebs, nor does inhibiting translation affect the ubiquitin sequestration in blebs. However, stimulating global ubiquitylation by heat shock greatly increases the amount of K48-ubiquitin sequestered inside blebs. These results suggest that blebs have an extraordinarily high capacity for sequestering ubiquitylated protein generated in a p97-dependent manner. The p97/UBXD1 axis is thus a major factor contributing to cellular DYT1 dystonia pathology and its modulation represents an unexplored potential for therapeutic development

Facile Protein Immobilization Using Engineered Surface-Active Biofilm Proteins

Immobilization of enzymes and other biomolecules to surfaces is critically important for biotechnology, with important applications in sensing and controlled delivery of molecular species for analytical or biomedical purposes. The presentation of protein recognition elements in a way that avoids denaturation and nonspecific interactions while maintaining the accessibility of the active site is a challenge for which no general solution has been found. Here we present a robust, facile method for immobilization of any protein to a surface using engineered protein building blocks. By functionalizing an interfacial protein, BslA, with peptides (SpyTag and SnoopTag) that spontaneously react with their cognate protein partners (SpyCatcher and SnoopCatcher), we are able to create patterned surfaces of protein monolayers displaying reactive tags. We demonstrate that these surfaces can be functionalized rapidly, spontaneously, and specifically with proteins of interest attached to SpyCatcher or SnoopCatcher. This method both protects the surface from nonspecific adsorption and also presents the recognition element in a uniform, active conformation. We envision that this method will have widespread applications, including immobilization of therapeutically relevant proteins for diagnostic applications

[In Press] Estimating flying-fox mortality associated with abandonments of pups and extreme heat events during the austral summer of 2019-20

Abstract. Mass mortalities in flying-foxes occur in summers that reach extremely hot temperatures. In this study, we examine the spatiotemporal distributions of mortality from pup abandonments and extreme heat events in Australian flying-fox camps during the 2019–20 summer. We recorded data on flying-fox mortality in known affected camps and applied a standard method to estimate the number of deaths. Pup mortalities from abandonments were recorded in 10 camps in New South Wales. A minimum estimate of 2612 flying-foxes died in pup abandonments, the majority of which occurred in one camp in Bomaderry. Die-offs from extreme heat events were recorded in 40 camps associated with eight separate heat events in south-eastern Australia. A minimum estimate of 72 175 flying-foxes died during these heat events, which all occurred within the range of the threatened grey-headed flying-fox (Pteropus poliocephalus). Further, 409 and 2251 live flying-foxes were taken into care from pup abandonments and heat events respectively. The minimum mortality estimated represents the highest recorded mortality of Australian flying-foxes within a single summer. This highlights a need to restore vegetation in flying-fox foraging areas and camps, address anthropogenic climate change and gather more empirical data to inform heat stress interventions to minimise flying-fox mortalities

Sex differences in immune responses that underlie COVID-19 disease outcomes

There is increasing evidence that coronavirus disease 2019 (COVID-19) produces more severe symptoms and higher mortality among men than among women1,2,3,4,5. However, whether immune responses against severe acute respiratory syndrome coronavirus (SARS-CoV-2) differ between sexes, and whether such differences correlate with the sex difference in the disease course of COVID-19, is currently unknown. Here we examined sex differences in viral loads, SARS-CoV-2-specific antibody titres, plasma cytokines and blood-cell phenotyping in patients with moderate COVID-19 who had not received immunomodulatory medications. Male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. By contrast, female patients had more robust T cell activation than male patients during SARS-CoV-2 infection. Notably, we found that a poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients. By contrast, higher levels of innate immune cytokines were associated with worse disease progression in female patients, but not in male patients. These findings provide a possible explanation for the observed sex biases in COVID-19, and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19