Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19 (preprint)

The most common cause of death due to COVID-19 remains respiratory failure. Yet, our understanding of the precise cellular and molecular changes underlying lung alveolar damage is limited. Here, we integrate single cell transcriptomic data of COVID-19 donor lungs with spatial transcriptomic data stratifying histopathological stages of diffuse alveolar damage (DAD). We identify changes in cellular composition across progressive DAD, including waves of molecularly distinct macrophages and depleted epithelial and endothelial populations throughout different types of tissue damage. Predicted markers of pathological states identify immunoregulatory signatures, including IFN-alpha and metallothionein signatures in early DAD, and fibrosis-related collagens in organised DAD. Furthermore, we predict a fibrinolytic shutdown via endothelial upregulation of SERPINE1/PAI-1. Cell-cell interaction analysis revealed macrophage-derived SPP1/osteopontin signalling as a key regulator during early DAD. These results provide the first comprehensive, spatially resolved atlas of DAD stages, highlighting the cellular mechanisms underlying pro-inflammatory and pro-fibrotic pathways across alveolar damage progression.

Non-Muscle Myosin ⅡA (NM-ⅡA) Boosts PEDV Infection Through its Interaction with the Viral S Protein (preprint)

Porcine epidemic diarrhea virus (PEDV) is a serious coronavirus that has caused huge economic losses to the swine industry. Understanding the host factors and their interactions with PEDV is crucial for revealing the pathogenicity of PEDV. This study provided robust evidence that PEDV utilized non-muscle myosin IIA (NM-ⅡA) as an essential host factor to facilitate its infection. The expression of NM-ⅡA was found to be significantly up-regulated by PEDV infection in vitro and in vivo. Intriguingly, suppressing NM-ⅡA activity or expression inhibited PEDV proliferation, while overexpressing NM-ⅡA or even its tail domain had the opposite action. Importantly, the co-localization of PEDV with NM-ⅡA in cells, and the interaction between the PEDV S protein and NM-ⅡA, was validated by IFA and Co-IP, respectively. Mechanistically, NM-IIA achieved this function by interacting with the S protein via its tail domain. These findings reveal an essential role of NM-ⅡA in PEDV infection.

Protocol for Alberta Societal Health Integration Program (ABSHIP): Community- based Complementary & Alternative Medicine (CAM) Services Model for Social Recovery and Improve Economic Participation (preprint)

Background Mental health problems and chronic health conditions cause significant productivity loss in the workplace. Chronic pain and mental health care needs in Canada that existed before COVID-19 remain unmet and have been exacerbated by the pandemic. The Alberta Societal Health Integration Program (ABSHIP) proposes an innovative community-based model in which Complementary and Alternative Medicine (CAM) services are provided to help achieve social recovery and improve economic participation. Methods Participants will receive CAM treatment in two modes: a minimum of two acupuncture treatment sessions per week for up to a total of 12 treatments, and voluntary Qigong exercise. The study will recruit 150 participants between the ages of 14 and 55 who are suffering from pain or mental health issues that are causing severe productivity loss. Primary outcome indicators are productivity (WPAI), pain (BPI), quality of sleep (PSQI), depression (PHQ-9), anxiety (GAD-7), anger (DAR-5), quality of life (EQ-5D-5L) and substance use (DAST-10 & CAGE). Secondary outcome indicators include general health care utilization, which will be measured by patients’ self-reported inpatient, outpatient, emergency department, and prescription drug utilization. Data will be collected at baseline (before treatment) and after the sixth and twelfth session (post-treatment) to measure short-term outcomes of the study. To understand the long-term impact of ABSHIP, participants will be invited to take the same survey three and six months after completing the program. Discussion ABSHIP is a first-of-its-kind study that provides CAM integrated interventions to enhance pain management, as well as protecting and fostering psychosocial well-being and resilience in children, adolescents, and seniors. The successful completion of the project will result in cost savings as well as significant evidence to aid instrument policy in the short and long run. Trial Registration This interventional study involving human participants, has been approved by the University of Calgary (UofC) Conjoint Health Research Ethics Board (CHREB) (ethics ID: REB 21-2050).

Loss of Anti-Spike Antibodies Following mRNA Vaccination for COVID-19 Among Patients with Multiple Myeloma (preprint)

Background: Multiple myeloma (MM) patients have variable responses to mRNA vaccination to COVID-19. Little is known regarding their vaccine-induced antibody levels over time. Methods: We monitored spike IgG antibody levels over 24 weeks among a subset of 18 MM patients who showed a full response after two mRNA vaccinations. MM patients had a more rapid decline in antibody levels as compared to 8 healthy controls, with power law half-lives of 72 days (versus 107 days) and exponential half-lives of 37 days (versus 51 days). Results: The patients with longer SARS-CoV-2 antibody half-lives were more likely to have undetectable monoclonal protein than those with shorter half-lives, suggesting better disease control may correlate with longer duration of vaccine-induced antibodies. Regardless, by 16 weeks post-second dose of mRNA vaccination, the majority of patients had antibody levels below 250 binding arbitrary units per milliliter, which would be unlikely to contribute significantly to preventing COVID-19. Conclusions: Thus, even MM patients who respond adequately to vaccination are likely to require more frequent booster doses than the general population.

A persistent neutrophil-associated immune signature characterises post-COVID19 pulmonary sequelae (preprint)

Persistent interstitial lung changes with associated symptoms occur in a proportion of individuals that have recovered from severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) infection through unknown mechanisms. We studied individuals with severe COVID-19 longitudinally following recovery from acute illness. Subjects with interstitial lung changes at 3-6 months post-recovery had an upregulated neutrophil-associated immune signature including increased chemokines, proteases and markers of neutrophil extracellular traps detectable systemically. Similar pathways were enriched in the upper airway with a concomitant augmentation of antiviral type-I interferon signalling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Repeat sampling indicated that full normalisation of radiological and functional changes has not yet been reached in many individuals by 12 months post-recovery. These data provide functional insight into mechanisms driving pulmonary sequelae of COVID-19 and provide a rational basis for development of future targeted approaches to prevent long-term complications.

First-principles DFT investigations of the vibrational spectra of chloro-quine and hydroxychloroquine

Since the COVID-19 pandemic began, two drugs, chloroquine (CQ) and hydroxychloroquine (HCQ), have received renewed attention. Using the density functional theory method in the CASTEP and DMol3 packages, we calculated both molecules’ infrared spectra and the partial phonon density of states of the hydroxyl group to identify the origin of the differences between the two spectra. Some characteristic vibrational modes of the hydroxyl group in HCQ were analysed individually. We also compared their Fukui functions and found that the oxygen atom in HCQ possesses electrophilic properties. This finding may be related to the large difference in toxicity between these two drugs. The method herein presents a new pathway to investigate organic molecules from the view of physics.