Effect of COVID-19 vaccination on viral clearance and antibody production in older patients with SARS-CoV-2 infection

Whether coronavirus disease 2019 (COVID-19) vaccination promotes viral clearance in older patients has not been reported. We performed a retrospective review of patients hospitalized with COVID-19. This study included 24 patients with COVID-19 admitted to Hiroshima City Funairi Citizens Hospital between June 1 and July 10, 2021. Nine patients who were vaccinated (median age: 72 years) were compared with 15 patients who were not vaccinated (median age: 70 years). Viral clearance was confirmed by SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR). Antibody titers were measured to assess vaccination efficacy. The vaccinated group had a higher negative conversion rate than that in the non-vaccinated group on RT-PCR testing before discharge (83% vs. 36%, P = 0.064). Antibody titers on admission and 10 ± 2 days after onset were significantly higher in the vaccinated group than those in the non-vaccinated group (35 vs. 0 binding antibody units (BAU)/mL, P = 0.012; and 114 vs. 7 BAU/mL, P = 0.032, respectively). Stimulating antibody production by vaccination may promote faster viral clearance in older patients who develop COVID-19.This research was funded by “Advanced study aim to contribute creating new evidence in COVID-19 based on the local government-academia collaboration research system in Hiroshima”: AMED Research Program on Emerging and Re-emerging Infectious Diseases, Grant Number JP20fk0108453

High-Performance Drug Discovery: Computational Screening by Combining Docking and Molecular Dynamics Simulations

Virtual compound screening using molecular docking is widely used in the discovery of new lead compounds for drug design. However, this method is not completely reliable and therefore unsatisfactory. In this study, we used massive molecular dynamics simulations of protein-ligand conformations obtained by molecular docking in order to improve the enrichment performance of molecular docking. Our screening approach employed the molecular mechanics/Poisson-Boltzmann and surface area method to estimate the binding free energies. For the top-ranking 1,000 compounds obtained by docking to a target protein, approximately 6,000 molecular dynamics simulations were performed using multiple docking poses in about a week. As a result, the enrichment performance of the top 100 compounds by our approach was improved by 1.6–4.0 times that of the enrichment performance of molecular dockings. This result indicates that the application of molecular dynamics simulations to virtual screening for lead discovery is both effective and practical. However, further optimization of the computational protocols is required for screening various target proteins

All-atom molecular dynamics simulations of entire virus capsid reveal the role of ion distribution in capsid’s stability

Present experimental methods do not have sufficient resolution to investigate all processes in virus particles at atomistic details. We report the results of molecular dynamics simulations and analyze the connection between the number of ions inside an empty capsid of PCV2 virus and its stability. We compare the crystallographic structures of the capsids with unresolved N-termini and without them in realistic conditions (room temperature and aqueous solution) and show that the structure is preserved. We find that the chloride ions play a key role in the stability of the capsid. A low number of chloride ions results in loss of the native icosahedral symmetry, while an optimal number of chloride ions create a neutralizing layer next to the positively charged inner surface of the capsid. Understanding the dependence of the capsid stability on the distribution of the ions will help clarify the details of the viral life cycle that is ultimately connected to the role of packaged viral genome inside the capsid

A pre-metazoan origin of the CRK gene family and co-opted signaling network.

CRK and CRKL adapter proteins play essential roles in development and cancer through their SRC homology 2 and 3 (SH2 and SH3) domains. To gain insight into the origin of their shared functions, we have investigated their evolutionary history. We propose a term, crk/crkl ancestral (crka), for orthologs in invertebrates before the divergence of CRK and CRKL in the vertebrate ancestor. We have isolated two orthologs expressed in the choanoflagellate Monosiga brevicollis, a unicellular relative to the metazoans. Consistent with its highly-conserved three-dimensional structure, the SH2 domain of M. brevicollis crka1 can bind to the mammalian CRK/CRKL SH2 binding consensus phospho-YxxP, and to the SRC substrate/focal adhesion protein BCAR1 (p130(CAS)) in the presence of activated SRC. These results demonstrate an ancient origin of the CRK/CRKL SH2-target recognition specificity. Although BCAR1 orthologs exist only in metazoans as identified by an N-terminal SH3 domain, YxxP motifs, and a C-terminal FAT-like domain, some pre-metazoan transmembrane proteins include several YxxP repeats in their cytosolic region, suggesting that they are remotely related to the BCAR1 substrate domain. Since the tyrosine kinase SRC also has a pre-metazoan origin, co-option of BCAR1-related sequences may have rewired the crka-dependent network to mediate adhesion signals in the metazoan ancestor

GPS and chemotherapy for elderly NSCLC

Background : Although platinum-combination chemotherapy is widely used to treat advanced non-small cell lung cancer (NSCLC), not all elderly patients benefit from this regimen. In this retrospective study, we aimed to evaluate whether the Glasgow Prognostic Score (GPS), an indicator of systemic inflammation and malnutrition, could predict the tolerability and efficacy of platinum-combination chemotherapy among elderly patients with NSCLC. Methods : The eligibility criteria included patients aged ≥ 70 years with NSCLC treated with first-line platinum-combination chemotherapy at Shimane University Hospital between January 2015 and December 2018. Results : Thirty-two patients with NSCLC (median age, 74 years) were included. The GPS scores were 0–1 for 19 patients and 2 for 13 patients. Four chemotherapy cycles were completed by 57.9% and 30.8% of patients in the GPS 0–1 and GPS 2 groups, respectively. The GPS 0–1 group experienced better outcomes than the GPS 2 group (response rate : 26% vs. 15%, P = 0.67 ; median progression-free survival : 4.1 vs. 2.1 months, P = 0.0026 ; median overall survival : 22.8 vs. 9.6 months, P = 0.0092). Conclusions : Platinum-combination chemotherapy demonstrated promising efficacy among elderly NSCLC patients with a GPS 0–1. Therefore, GPS may be crucial in determining whether treatments recommended for younger patients are suitable for older patients with NSCLC

Spectroscopic evidence for a charge-density-wave condensate in a charge-ordered manganite: Observation of collective excitation mode in Pr0.7_{\text{0.7}}Ca0.3_{\text{0.3}}MnO3_{\text{3}} by using THz time-domain spectroscopy

THz time-domain spectroscopy was used to directly probe the low-energy (0.5--5 meV) electrodynamics of the charge-ordered manganite Pr$_{0.7}$Ca$_{0.3}$MnO$_3$. We revealed the existence of a finite peak structure around 2--3 meV well below the charge gap $\sim300$ meV. In analogy to the low-energy optical properties of the well-studied low-dimensional materials, we attributed this observed structure to the collective excitation mode arising from the charge-density-wave condensate. This finding provides the importance role of the quasi-one dimensional nature of the charge and orbital ordering in Pr$_{0.7}$Ca$_{0.3}$MnO$_3$.Comment: REVTeX4, 8 pages including 7 figures and 2 table

Computational studies on prion proteins: effect of Ala(117)-->Val mutation.

Molecular dynamics calculations demonstrated the conformational change in the prion protein due to Ala(117)-->Val mutation, which is related to Gerstmann-Sträussler-Sheinker disease, one of the familial prion diseases. Three kinds of model structures of human and mouse prion proteins were examined: (model 1) nuclear magnetic resonance structures of human prion protein HuPrP (125-228) and mouse prion protein MoPrP (124-224), each having a globular domain consisting of three alpha-helices and an antiparallel beta-sheet; (model 2) extra peptides including Ala(117) (109-124 in HuPrP and 109-123 in MoPrP) plus the nuclear magnetic resonance structures of model 1; and (model 3) extra peptides including Val(117) (109-124 in HuPrP and 109-123 in MoPrP) plus the nuclear magnetic resonance structures of model 1. The results of molecular dynamics calculations indicated that the globular domains of models 1 and 2 were stable and that the extra peptide in model 2 tended to form a new alpha-helix. On the other hand, the globular domain of model 3 was unstable, and the beta-sheet region increased especially in HuPrP