Our findings suggest that IFN- γ , alongside TNF- α , might be a key driver of this abundant inflammatory macrophage phenotype in severe COVID-19 and other inflammatory diseases, which may be targeted by existing immunomodulatory therapies.Vaccine efforts against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the current COVID-19 pandemic are focused on SARS-CoV-2 spike glycoprotein, the primary target for neutralizing antibodies. Here, we performed cryo-EM and site-specific glycan analysis of one of the leading subunit vaccine candidates from Novavax based on a full-length spike protein formulated in polysorbate 80 (PS 80) detergent. Our studies reveal a stable prefusion conformation of the spike immunogen with slight differences in the S1 subunit compared to published spike ectodomain structures. Interestingly, we also observed novel interactions between the spike trimers allowing formation of higher order spike complexes. This study confirms the structural integrity of the full-length spike protein immunogen and provides a basis for interpreting immune responses to this multivalent nanoparticle immunogen.Infection and replication of SARS CoV-2 (the virus that causes COVID-19) requires entry to the interior of host cells. In humans, a Protein-Protein Interaction (PPI) between the SARS CoV-2 Receptor-Binding Domain (RBD) and the extracellular peptidase domain of ACE2, on the surface of cells in the lower respiratory tract, is an initial step in the entry pathway. Inhibition of the SARS CoV-2 RBD / ACE2 PPI is currently being evaluated as a target for therapeutic and/or prophylactic intervention. However, relatively little is known about the molecular underpinnings of this complex. Employing multiple computational platforms, we predicted hot-spot residues in a positive control PPI (PMI / MDM2) and the CoV-2 RBD/ACE2 complex. Computational alanine scanning mutagenesis was performed to predict changes in Gibbs free energy that are associated with mutating residues at the positive control (PMI/MDM2) or SARS RBD/ACE2 binding interface to alanine. Additionally, we used the Adaptive Poisson-Boltzmann Solver to calculate macromolecular electrostatic surfaces at the interface of the positive control PPI and SARS CoV-2 / ACE2 PPI. Collectively, this study illuminates predicted hot-spot residues, and clusters, at the SARS CoV-2 RBD / ACE2 binding interface, potentially guiding the development of reagents capable of disrupting this complex and halting COVID-19.Efficient translation of human induced pluripotent stem cells (hiPSCs) depends on implementing scalable cell manufacturing strategies that ensure optimal self-renewal and functional differentiation. Currently, manual culture of hiPSCs is highly variable and labor-intensive posing significant challenges for high-throughput applications. Here, we established a robotic platform and automated all essential steps of hiPSC culture and differentiation under chemically defined conditions. This streamlined approach allowed rapid and standardized manufacturing of billions of hiPSCs that can be produced in parallel from up to 90 different patient-and disease-specific cell lines. Moreover, we established automated multi-lineage differentiation to generate primary embryonic germ layers and more mature phenotypes such as neurons, cardiomyocytes, and hepatocytes. To validate our approach, we carefully compared robotic and manual cell culture and performed molecular and functional cell characterizations (e.g. bulk culture and single-cell transcriptomics, mass cytometry, metabolism, electrophysiology, Zika virus experiments) in order to benchmark industrial-scale cell culture operations towards building an integrated platform for efficient cell manufacturing for disease modeling, drug screening, and cell therapy. Combining stem cell-based models and non-stop robotic cell culture may become a powerful strategy to increase scientific rigor and productivity, which are particularly important during public health emergencies (e.g. opioid crisis, COVID-19 pandemic).We report the identification of three structurally diverse compounds – compound 4, GC376, and MAC-5576 – as inhibitors of the SARS-CoV-2 3CL protease. Structures of each of these compounds in complex with the protease revealed strategies for further development, as well as general principles for designing SARS-CoV-2 3CL protease inhibitors. These compounds may therefore serve as leads for the basis of building effective SARS-CoV-2 3CL protease inhibitors.BackgroundSARS-CoV-2 and its associated disease, COVID-19, has infected over seven million people world-wide, including two million people in the United States. While many people recover from the virus uneventfully, a subset of patients will require hospital admission, some with intensive care needs including intubation, and mechanical ventilation. To date there is no cure and no vaccine is available. Passive immunotherapy by the transfusion of convalescent plasma donated by COVID-19 recovered patients might be an effective option to combat the virus, especially if used early in the course of disease. Here we report our experience of using convalescent plasma at a tertiary care center in a mid-size, midwestern city that did not experience an overwhelming patient surge.MethodsHospitalized COVID-19 patients categorized as having Severe or Life-Threatening disease according to the Mayo Clinic Emergency Access Protocol were screened, consented, and treated with convalescent plasma collected from local donors recovered from COVID-19 infection. Clinical data and outcomes were collected retrospectively.Results31 patients were treated, 16 severe patients and 15 life-threatened patients. Overall mortality was 27% (4/31) but only patients with life-threatening disease died. 94% of transfused patients with severe disease avoided escalation to ICU care and mechanical ventilation. 67% of patients with life-threatening disease were able to be extubated. Most transfused patients had a rapid decrease in their respiratory support requirements on or about day 7 following convalescent plasma transfusion.ConclusionOur results demonstrate that convalescent plasma is associated with reducing ventilatory requirements in patients with both severe and life-threatening disease, but appears to be most beneficial when administered early in the course of disease when patients meet the criteria for severe illness.We describe the establishment and current content of the ImmuneCODE™ database, which includes hundreds of millions of T-cell Receptor (TCR) sequences from over 1,400 subjects exposed to or infected with the SARS-CoV-2 virus, as well as over 135,000 high-confidence SARS-CoV-2-specific TCRs. This database is made freely available, and the data contained in it can be downloaded and analyzed online or offline to assist with the global efforts to understand the immune response to the SARS-CoV-2 virus and develop new interventions.Mimicry is exhibited in multiple scales, ranging from molecular, to organismal, and then to human society. 'Batesian’ type mimicry entails a conflict of interest between sender and receiver, reflected in a deceptive mimic signal. 'Mullerian’ type mimicry occurs when there is perfect common interest between sender and receiver, manifested by an honest co-mimic signal. Using a signaling games approach, simulations show that invasion by Batesian mimics will make Mullerian mimicry unstable, in a coevolutionary chase. We use these results to better understand the deceptive strategies of SARS-CoV-2 and their key role in the COVID-19 pandemic. At the biomolecular level, we explain how cellularization promotes Mullerian molecular mimicry, and discourages Batesian molecular mimicry. A wide range of processes analogous to cellularization are presented; these might represent a manner of reducing oscillatory instabilities. Lastly, we identify examples of mimicry in human society, that might be addressed using a signaling game approach.

Syphilis and gonorrhea reached an all-time high in 2018. The resurgence of syphilis and gonorrhea requires innovative methods of sexual contact tracing that encourage disclosure of same-sex sexual contacts that might otherwise be suppressed. Over 75% of Grindr mobile phone application users report seeking „friendship,” so this study asked people diagnosed with syphilis and gonorrhea to identify their friends.

Patients at the two Baltimore sexually transmitted infection (STI) clinics and the Baltimore City Health Department were asked 12 questions to elicit members of their friendship networks before eliciting sexual networks. The study included 353 index cases and 172 friendship contacts, yielding a friendship network of 331 non-isolates (n=331) and sexual-only network of 140 non-isolates. The data were plotted and analyzed using exponential family random graph analysis.

Eliciting respondents’ in-person social contacts yielded 12 syphilis cases and 6 gonorrhea cases in addition to the 16 syphilis cases t.

Eliciting friendship networks of people diagnosed with syphilis and gonorrhea may find members of their sexual networks, drug use networks, or people of similar STI risk. Friendship networks include more diagnosed cases of syphilis and gonorrhea than sexual networks alone, especially among populations with many non-disclosing men who have sex with men (MSM) and women who have sex with women (WSW). Future research should evaluate whether this friendship network method of contact tracing can be implemented by adapting automated mobile phone COVID-19 contact tracing protocols, if these COVID-19 contact tracing methods are able to maintain anonymity and public trust.

The COVID-19 pandemic has swiftly and remarkably altered community mental health service delivery and evidence-based practice (EBP) implementation. This study reports provider perspectives on the impact that COVID-19 had on their work and EBP implementation.

Providers (

= 93) completed online surveys with quantitative measures and open-ended items targeting their responses and/or reactions to COVID-19, and to the transition to providing services via telehealth.

Perceptions of personal risk and rumination around COVID-19 were low, while telehealth was viewed positively by providers. Three major themes emerged regarding the major impacts of COVID-19 on work 1) the altered nature of interactions between patient/client and provider, 2) changes in provider expectations regarding productivity, and 3) challenges maintaining work-life balance. In regard to the major impacts of COVID-19 on EBP implementation, three themes emerged 1) increased difficulty delivering certain therapies via telehealth, 2) potential limitations to session confidentiality, and 3) challenge of engaging children in telehealth.

In the context of the COVID-19 pandemic, community mental health providers continued to engage with clients and implement EBPs while navigating a number of changes related to the transition to telehealth. This study highlights the need for further work on what supports providers need to effectively engage with clients and deliver EBPs via telehealth and has implications for how telehealth is sustained or de-implemented in response to COVID-19.

In the context of the COVID-19 pandemic, community mental health providers continued to engage with clients and implement EBPs while navigating a number of changes related to the transition to telehealth. This study highlights the need for further work on what supports providers need to effectively engage with clients and deliver EBPs via telehealth and has implications for how telehealth is sustained or de-implemented in response to COVID-19.