RESUMO
Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.
Assuntos
COVID-19 , SepseRESUMO
Atomically-thin two-dimensional (2D) nanostructure, an emerging class of nanomaterials, has achieved tremendous progress in the past decade and will remain a significant research topic in the near future. Apart from the discoveries of various 2D nanomaterials, remarkable attentions have been paid to the rational design and alteration of architectures based on pristine 2D materials to meet demands of next-generation functional applications in the near term. Herein, this review intends to provide an instant survey over the recent key advances on the structural engineering strategies of 2D nanomaterial-based architectures for new sensing capabilities and opportunities. Through intrinsic or extrinsic alterations, the pristine 2D nanostructures of some unique intrinsic properties could be modified and functionalized in a predictable pattern to overcome existing drawbacks and obtain synergistic abilities, demonstrating a great potential in promoting sensing device performance. In parallel with the review of latest development of structural engineering strategies and related highly functionalized sensor devices including sensing capabilities towards Covid-19 antigens, the underlying mechanisms of these designs are revealed to offer a unique insight in understandings of architecture design and property tailoring for boosting new sensing capabilities and performances.
RESUMO
The virus replication and lung inflammation are basic targets for COVID-19 treatment. To effectively treat COVID-19, the best chemical drug should combine inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokine expression together. Our SARS-CoV-2 main protease (Mpro) crystal structure studies revealed Au(I), derived from auranofin (AF) or gold cluster (GA), could specifically bind thiolate of Cys145 of SARS-CoV-2 Mpro. GA or AF could well inhibit Mpro activity and significantly decrease SARS-CoV-2 replication in cell. Cell studies showed that either AF or GA could down-regulate NF{kappa}B pathway, therefore significantly inhibit inflammatory cytokine level of IL-6, IL-1{beta}, TNF- in macrophage and bronchial epithelial cell, respectively. The lung viral load in GA treated COVID-19 mice (15mg/kg.bw) is significantly lower than that in normal saline (NS, 0.9% NaCl) treated COVID-19 mice, and pathological studies revealed GA treatment (score ~1.8) significantly reduced lung inflammatory injury compared with NS treated COVID-19 mice (score ~3). After normal mice were treated by GA (15mg/kg), the Au ingredient well distributed into lungs and there are no pathological changes in main organs when compared with control mice. The toxicity results revealed GA is more safety than auranofin for cell/mice/rat. The rat pharmacokinetics studies show GA is with high bioavailability (> 90%) in vivo.