The ongoing COVID-19 pandemic has clearly established how vital rapid, widely accessible diagnostic tests are in controlling infectious diseases and how difficult and slow it is to scale existing technologies. Here, we demonstrate the use of the rapid affinity pair identification via directed selection (RAPIDS) method to discover multiple affinity pairs for SARS-CoV-2 nucleocapsid protein (N-protein), a biomarker of COVID-19, from in vitro libraries in 10 weeks. The pair with the highest biomarker sensitivity was then integrated into a 10-minute, vertical-flow cellulose paper test. Notably, the as-identified affinity proteins were compatible with a roll-to-roll printing process for large-scale manufacturing of tests. The test achieved 40 pM and 80 pM limits of detection in 1×PBS (mock swab) and saliva matrices spiked with cell-culture generated SARS-CoV-2 viruses and is also capable of detection of N-protein from characterized clinical swab samples. Hence, this work paves the way towards the mass production of cellulose paper-based assays which can address the shortages faced due to dependence on nitrocellulose and current manufacturing techniques. Further, the results reported herein indicate the promise of RAPIDS and engineered binder proteins for the timely and flexible development of clinically relevant diagnostic tests in response to emerging infectious diseases.
Subnanometer-sized metal clusters often feature a molecule-like electronic structure, which makes their physical and chemical properties significantly different from those of nanoparticles and bulk material. Considering potential applications, there is a major concern about their thermal stability and susceptibility towards oxidation. Cu clusters of only 5 atoms (Cu 5 clusters) are first synthesized in high concentration using a new-generation wet chemical method. Next, it is shown that, contrary to what is currently assumed, Cu 5 clusters display nobility, beyond resistance to irreversible oxidation, at a broad range of temperatures and oxygen pressures. The outstanding nobility arises from an unusual reversible oxidation which is observed by in situ X-ray Absorption Spectroscopy and X-ray Photoelectron Spectroscopy on Cu 5 clusters deposited onto highly oriented pyrolitic graphite at different oxygen pressures and up to 773 K. This atypical property is explained by a theoretical approach combining different state-of-the-art first principles theories. It reveals the essential role of collective quantum effects in the physical mechanism responsible for the nobility of Cu 5 clusters, encompassing a structural ‘breathing’ through concerted Cu–Cu elongations/contractions upon O 2 uptake/release, and collective charge transfer as well. A predictive phase diagram of their reversible oxidation states is also delivered, agreeing with the experimental observations. The collective quantum effects responsible of the observed nobility are expected to be general in subnanometer-sized metal clusters, pushing this new generation of materials to an upper level.
The global Coronavirus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of co-existing medical conditions while the underlying mechanisms remain unclear. Furthermore, there are no proven effective therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, diseases manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus-host protein-protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measure revealed underlying pathogenesis for broad COVID-19-associated manifestations. Multi-modal analyses of single-cell RNA-sequencing data showed that co-expression of ACE2 and TMPRSS2 was elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn's disease patients compared to uninflamed tissues, revealing shared pathobiology by COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicated that COVID-19 shared intermediate inflammatory endophenotypes with asthma (including IRAK3 and ADRB2 ). To prioritize potential treatment, we combined network-based prediction and propensity score (PS) matching observational study of 18,118 patients from a COVID-19 registry. We identified that melatonin (odds ratio (OR) = 0.36, 95% confidence interval (CI) 0.22-0.59) was associated with 64% reduced likelihood of a positive laboratory test result for SARS-CoV-2. Using PS-matching user active comparator design, melatonin was associated with 54% reduced likelihood of SARS-CoV-2 positive test result compared to angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (OR = 0.46, 95% CI 0.24-0.86).
Severe cases of coronavirus disease 2019 (COVID-19), caused by infection with SARS-CoV-2, are characterized by a hyperinflammatory immune response that leads to numerous complications. Production of proinflammatory neutrophil extracellular traps (NETs) has been suggested to be a key factor in inducing a hyperinflammatory signaling cascade, allegedly causing both pulmonary tissue damage and peripheral inflammation. Accordingly, therapeutic blockage of neutrophil activation and NETosis, the cell death pathway accompanying NET formation, could limit respiratory damage and death from severe COVID-19. Here, we demonstrate that synthetic glycopolymers that activate signaling of the neutrophil checkpoint receptor Siglec-9 suppress NETosis induced by agonists of viral toll-like receptors (TLRs) and plasma from patients with severe COVID-19. Thus, Siglec-9 agonism is a promising therapeutic strategy to curb neutrophilic hyperinflammation in COVID-19.
With the current trajectory of the 2019-nCoV outbreak unknown, public health and medicinal measures will both be needed to contain spreading of the virus and to optimize patient outcomes. While little is known about the virus, an examination of the genome sequence shows strong homology with its more well-studied cousin, SARS-CoV. The spike protein used for host cell infection shows key nonsynonymous mutations which may hamper efficacy of previously developed therapeutics but remains a viable target for the development of biologics and macrocyclic peptides. Other key drug targets, including RdRp and 3CLpro, share a strikingly high (>95%) homology to SARS-CoV. Herein, we suggest 4 potential drug candidates (an ACE2-based peptide, remdesivir, 3CLpro-1 and a novel vinylsulfone protease inhibitor) that can be used to treat patients suffering with the 2019-nCoV. We also summarize previous efforts into drugging these targets and hope to help in the development of broad spectrum anti-coronaviral agents for future epidemics.
