ABSTRACT
The causative pathogen of Coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an enveloped virus assembled by a lipid envelope and multiple structural proteins. In this study, by integrating experimental data, structural modeling, and coarse-grained molecular dynamics simulations, we constructed multiscale models of SARS-CoV-2. Our 500-ns coarse-grained simulation of the intact virion allowed us to investigate the dynamic behavior of the membrane-embedded proteins and the surrounding lipid molecules in situ. Our results indicated that the membrane-embedded proteins are highly dynamic, and certain types of lipids exhibit various binding preferences to specific sites of the membrane-embedded proteins. The equilibrated virion model was transformed into atomic resolution, which provided a 3D structure for scientific demonstration and can serve as a framework for future exascale all-atom MD simulations.
ABSTRACT
Objective:To evaluate the survival outcome and toxicity of hypofractionated radiotherapy (45 Gy/15f) in patients with locally advanced/advanced non-small cell lung cancer (NSCLC) who are ineligible for conventional fractionated radiotherapy.Methods:The early efficacy, survival and toxicity of inoperable patients ( n=64) with locally advanced/advanced NSCLC patients admitted to Cancer Hospital of Tianjin Medical University from 2014 to 2018 were retrospectively analyzed. Hypofractionated radiotherapy (45 Gy/15f) were performed by using intensity-modulated radiotherapy or volumetric-modulated arc therapy technologies on Pinnacle 9 planning system. Results:The median follow-up time was 26 months. The early efficacy was available in 58 patients: complete response for 2 cases (3%), partial response for 22(38%), stable disease for 28(44%) and progressive disease for 6(9%), respectively. The local control rate was 90%. The median time to progression (TTP) and the median overall survival (OS) for all patients was 8.2 months and 21.0 months, respectively. The 1-, 2-and 3-year TTP rate was 37%, 28%, 14% and the OS rate was 66%, 43% and 27%, respectively. The incidence of esophagitis was 17%( n=11), 19%( n=12) for radiation pneumonitis and 20%( n=13) for myelosuppression. No grade ≥3 esophagitis or pneumonia was found. Conclusion:Hypofractionated radiotherapy (45 Gy/15f) is efficacious and safe for patients with locally advanced/advanced NSCLC, which yields controllable adverse events.
ABSTRACT
Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus (SARS-CoV-2) and represents the causative agent of a potentially fatal disease that is of public health emergency of international concern. Coronaviruses, including SARS-CoV-2, encode an envelope (E) protein, which is a small, hydrophobic membrane protein; the E protein of SARS-CoV-2 has high homology with that of severe acute respiratory syndrome coronavirus. (SARS-CoV) In this study, we provide insights into the function of the SARS-CoV-2 E protein channel and the ion and water permeation mechanisms on the basis of combined in silico methods. Our results suggest that the pentameric E protein promotes the penetration of monovalent ions through the channel. Analysis of the potential mean force (PMF), pore radius and diffusion coefficient reveals that Leu10 and Phe19 are the hydrophobic gates of the channel. In addition, the pore demonstrated a clear wetting/dewetting transition with monovalent cation selectivity under transmembrane voltage, which indicates that it is a hydrophobic voltage-dependent channel. Overall, these results provide structural-basis insights and molecular-dynamic information that are needed to understand the regulatory mechanisms of ion permeability in the pentameric SARS-CoV-2 E protein channel.
