Initiation of NALT Organogenesis Is Independent of the IL-7R, LTβR, and NIK Signaling Pathways but Requires the Id2 Gene and CD3−CD4+CD45+ Cells

AbstractInitiation of nasopharyngeal-associated lymphoid tissue (NALT) development is independent of the programmed cytokine cascade necessary for the formation of Peyer's patches (PP) and peripheral lymph nodes (PLN), a cytokine cascade which consists of IL-7R, LTα1β2/LTβR, and NIK. However, the subsequent organization of NALT seems to be controlled by these cytokine signaling cascades since the maturation of NALT structure is generally incomplete in those cytokine cascade-deficient mice. NALT as well as PP and PLN are completely absent in Id2−/− mice. NALT organogenesis is initiated following the adoptive transfer of CD3−CD4+CD45+ cells into Id2−/− mice, constituting direct evidence that CD3−CD4+CD45+ inducer cells can provide an IL-7R-, LTα1β2/LTβR-, and NIK-independent tissue organogenesis pathway for secondary lymphoid tissue development

Population pharmacokinetic modeling of GS‐441524, the active metabolite of remdesivir, in Japanese COVID‐19 patients with renal dysfunction

腎障害患者におけるレムデシビルの薬物動態モデルを構築 --新型コロナウイルス感染症治療薬の適正使用に向けて--. 京都大学プレスリリース. 2021-11-25.Remdesivir, a prodrug of the nucleoside analog GS-441524, plays a key role in the treatment of coronavirus disease 2019 (COVID-19). However, owing to limited information on clinical trials and inexperienced clinical use, there is a lack of pharmacokinetic (PK) data in patients with COVID-19 with special characteristics. In this study, we aimed to measure serum GS-441524 concentrations and develop a population PK (PopPK) model. Remdesivir was administered at a 200 mg loading dose on the first day followed by 100 mg from day 2, based on the package insert, in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min. In total, 190 concentrations from 37 Japanese patients were used in the analysis. The GS-441524 trough concentrations were significantly higher in the eGFR less than 60 ml/min group than in the eGFR greater than or equal to 60 ml/min group. Extracorporeal membrane oxygenation in four patients hardly affected the total body clearance (CL) and volume of distribution (Vd) of GS-441524. A one-compartment model described serum GS-441524 concentration data. The CL and Vd of GS-441524 were significantly affected by eGFR readjusted by individual body surface area and age, respectively. Simulations proposed a dose regimen of 200 mg on day 1 followed by 100 mg once every 2 days from day 2 in patients with an eGFR of 30 ml/min or less. In conclusion, we successfully established a PopPK model of GS-441524 using retrospectively obtained serum GS-441524 concentrations in Japanese patients with COVID-19, which would be helpful for optimal individualized therapy of remdesivir

Review Article : Feudalism or Absolute Monarchism?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68809/2/10.1177_009770049001600304.pd

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Degradation of metamorphic InGaAs Esaki tunnel diodes due to electrode diffusion and impurity interdiffusion

We have investigated degradation of metamorphic In_Ga_As Esaki tunnel diodes. The degradation due to electrode diffusion and impurity interdiffusion is more prominent than that of lattice-matched In_Ga_As Esaki tunnel diodes.2005 International Conference on Indium Phosphide and Related Materials : May 8-12, 2005, Glasgow, Scotland

Symposium no. 06 Paper no. 77 Presentation: poster 77-1

On the basis of knowledge about P-adsorption by soils, we succeeded to synthesize very effective P adsorbent (high performance P adsorbent: HPA) which can effectively remove P from water for avoiding eutrification of water bodies such as ponds and rivers. The materials of the HPA were the soil, especially the volcanic ash soil with high P-adsorbing ability, and the various sludges. Generally, these materials were added with ferrous sulfate, pelletized and baked at 500 C for 15 min. The HPA had much higher abilities to adsorb P and to resist against mechanical disintegration in water than the volcanic ash soil. These abilities are prerequisite for cheap and simple removal of P from flowing water by percolation through the column of the P-adsorbent. The used and P-saturated HPA could be utilized as an amendment of P-deficient soils or could be regenerated with dilute sulfuric acid for further use as a P-adsorbent. Consequently, various users in Japan have welcomed the HPA. In addition, the HPA and its derivatives could strongly adsorb As (III), As (V), F and some toxic heavy metals as well and could be used for removing these pollutants from our environments

Initial central venous pressure could be a prognostic marker for hemodynamic improvement of polymyxin B direct hemoperfusion: a retrospective cohort study

Background;; Direct hemoperfusion with polymyxin B-immobilized fiber column (PMX-DHP) could improve the hemodynamic status of septic shock patients. As PMX-DHP is an invasive and costly procedure, it is desirable to estimate the therapeutic effect before performing the therapy. However, it is still unclear when this therapy should be started and what type of sepsis it should be employed for. In this study, we retrospectively examined the clinical effect of patients treated with PMX-DHP by using central venous pressure (CVP). Methods;; Seventy patients who received PMX-DHP for septic shock during the study period were recruited and divided into a low CVP group (n = 33, CVP < 12 mmHg) and a high CVP group (n = 37, CVP≧12 mmHg). The primary endpoint was vasopressor dependency index at 24 hours after starting PMX-DHP, and the secondary endpoint was the 28-day survival rate. Additionally, we performed a multivariate linear regression analysis on the difference in the vasopressor dependency index. Results;; The vasopressor dependency index significantly improved at 24 h in the low CVP group (0.33 to 0.16 mmHg[−1]; p < 0.01) but not in the high CVP group (0.43 to 0.34 mmHg[−1]; p = 0.41), and there was a significant difference between the two groups in the index at 24 h (p = 0.02). The 28-day survival rate was higher in the low CVP group (79 vs. 43 %; p < 0.01). Multivariate linear regression analysis showed that CVP (p = 0.04) was independently associated with the difference in the vasopressor dependency index. Conclusions;; Our study indicates that the clinical effect of PMX-DHP for septic shock patients with higher CVP (≧12 mmHg) might be limited and that the initial CVP when performing PMX-DHP could function as an independent prognostic marker for the hemodynamic improvement