Cholesterol-Amino-Phosphate (CAP) Derived Lipid Nanoparticles for Delivery of Self-Amplifying RNA and Restoration of Spermatogenesis in Infertile Mice.

Male infertility caused by genetic mutations is an important type of infertility. Currently, there is no reliable method in the clinic to address this medical need. The emergence of mRNA therapy provides a possible strategy for restoring mutant genes in the reproductive system. However, effective delivery of mRNA to spermatocytes remains a formidable challenge. Here a series of cholesterol-amino-phosphate (CAP) lipids are reported by integrating three bioactive moieties into a geometric structure, which is favorable for mRNA delivery. The results demonstrate that CAP-derived lipid nanoparticles (CAP LNPs) can deliver RNA including traditional mRNA and self-amplifying RNA (saRNA) encoding DNA Meiotic Recombinase 1 (Dmc1) protein in spermatocytes and treat male infertility caused by the Dmc1 gene mutation. Notably, the delivery efficiency of CAP LNPs is significantly higher than that of the MC3 and ALC-0315 LNPs, which is consistent with the design of CAP molecules. More importantly, a single injection of CAP LNPs-saRNA can produce Dmc1 protein for an extended period, which restores the spermatogenesis in the Dmc1 gene knockout mouse model. Overall, this study proves the concept of LNPs for the delivery of mRNA to spermatocytes, which provides a unique method to probe male infertility caused by the genetic mutation.

Refinement of SARS-CoV-2 envelope protein structure in a native-like environment by molecular dynamics simulations

COVID-19 has become an unprecedented threat to human health. The SARS-CoV-2 envelope (E) protein plays a critical role in the viral maturation process and pathogenesis. Despite intensive investigation, its structure in physiological conditions remains mysterious: no high-resolution full-length structure is available and only an NMR structure of the transmembrane (TM) region has been determined. Here, we present a refined E protein structure, using molecular dynamics (MD) simulations to investigate its structure and dynamics in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer system. Our initial homology model based upon the SARS-CoV E protein structure is shown to be unstable in the lipid bilayer, and the H3 helices tend to move away from the membrane center to the membrane-water interface. A more stable model was developed by replacing all H3 helices with the fully equilibrated H3 structure sampled in the MD simulations. This refined model exhibited more favorable contacts with lipids and water than the original homology model and induced local membrane curvature, decreasing local lipid order. Interestingly, the pore radius profiles showed that the channel in both homology and refined models remained in a closed state throughout the simulations. We also demonstrated the utility of this structure to develop anti-SARS-CoV-2 drugs by docking a library of FDA-approved, investigational, and experimental drugs to the refined E protein structure, identifying 20 potential channel blockers. This highlights the power of MD simulations to refine low-resolution structures of membrane proteins in a native-like membrane environment, shedding light on the structural features of the E protein and providing a platform for the development of novel antiviral treatments.

Investigation of the Psychological disorders in the healthcare nurses during a coronavirus disease 2019 outbreak in China.

The first case of atypical pneumonia caused by coronavirus disease 2019 (COVID-19) was reported in Wuhan, China in December 2019. Since then, cases of novel coronavirus-infected pneumonia (NCIP) have been reported throughout China as well as in 25 other countries. With the rapid growth of this global outbreak, psychological disorders or impact among the healthcare nurses caused by the COVID-19 pandemic is of great importance and worth to be evaluated. Here, we aimed to determine the levels of stress and psychological disorders of nurses who provided nursing care during the COVID-19 outbreak. A total of 159 nurses who provided healthcare work for COVID-19 patients were enrolled in our study. The psychological disorders and stress level were assessed via a questionnaire implemented by the mobile app. The results showed that the nurses who worked in the non-critical care ward (general ward in which the invasive medical procedure such as mechanical ventilation is absent) scored significantly higher on the traumatization condition (P < .05) and stress level (P < .01) as well as the impact of event scale -revised level (P < .01) compared with those worked in the critical care ward. In contrast to the previous report, our findings revealed that the future intervention for preventing the mental crisis among the healthcare nurses needs to be focusing on the individuals in the non-critical care ward instead of those in the critical care ward under the spreading of COVID-19.