Virtual screening identifies a novel piperazine-based insect juvenile hormone agonist

Juvenile hormone (JH) agonists constitute a subclass of insect growth regulators and play important roles in insect pest management. In this work, a multi-step virtual screening program was executed to find novel JH agonists. A database of 5 million purchasable compounds was sequentially processed with three computational filters: (i) shape and chemical similarity as compared to known JH-active compounds; (ii) molecular docking simulations against a Drosophila JH receptor, methoprene-tolerant; and (iii) free energy calculation of ligand–receptor binding using a modified MM/PBSA (molecular mechanics/Poisson–Boltzmann surface area) protocol. The 11 candidates that passed the three filters were evaluated in a luciferase reporter assay, leading to the identification of a hit compound that contains a piperazine ring system (EC₅₀=870 nM). This compound is structurally dissimilar to known JH agonists and synthetically easy to access; therefore, it is a promising starting point for further structure optimization

A replication study confirmed the EDAR gene to be a major contributor to population differentiation regarding head hair thickness in Asia

Hair morphology is a highly divergent phenotype among human populations. We recently reported that a nonsynonymous SNP in the ectodysplasin A receptor (EDAR 1540T/C) is associated with head hair fiber thickness in an ethnic group in Thailand (Thai-Mai) and an Indonesian population. However, these Southeast Asian populations are genetically and geographically close, and thus the genetic contribution of EDAR to hair morphological variation in the other Asian populations has remained unclear. In this study, we examined the association of 1540T/C with hair morphology in a Japanese population (Northeast Asian). As observed in our previous study, 1540T/C showed a significant association with hair cross-sectional area (P = 2.7 × 10−6) in Japanese. When all populations (Thai-Mai, Indonesian, and Japanese) were combined, the association of 1540T/C was stronger (P = 3.8 × 10−10) than those of age, sex, and population. These results indicate that EDAR is the genetic determinant of hair thickness as well as a strong contributor to hair fiber thickness variation among Asian populations

Utility of robot‐assisted radical cystectomy with intracorporeal urinary diversion for muscle‐invasive bladder cancer

Radical cystectomy remains the gold standard for treatment of muscle‐invasive bladder cancer. Robot‐assisted radical cystectomy has technical advantages over laparoscopic radical cystectomy and has emerged as an alternative to open radical cystectomy. Despite the advancements in robotic surgery, experience with total intracorporeal reconstruction of urinary diversion remains limited. Most surgeons have carried out the hybrid approach of robot‐assisted radical cystectomy and extracorporeal reconstruction of urinary diversion, as intracorporeal reconstruction of urinary diversion remains technically challenging. However, intracorporeal reconstruction of urinary diversion might potentially proffer additional benefits, such as decreased fluid loss, reduction in estimated blood loss and a quicker return of bowel function. The adoption of intracorporeal ileal neobladder reconstruction has hitherto been limited to high‐volume academic institutions. In the present review, we compare the totally intracorporeal robot‐assisted radical cystectomy approach with open radical cystectomy and robot‐assisted radical cystectomy + extracorporeal reconstruction of urinary diversion in muscle‐invasive bladder cancer patients

Polymorphism Located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 Haplotype Confer Susceptibility to CNS Hypersomnias (Essential Hypersomnia)

Background: SNP rs5770917 located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype were previously identified as susceptibility loci for narcolepsy with cataplexy. This study was conducted in order to investigate whether these genetic markers are associated with Japanese CNS hypersomnias (essential hypersomnia: EHS) other than narcolepsy with cataplexy. Principal Findings: EHS was significantly associated with SNP rs5770917 (Pallele = 3.6610 23; OR = 1.56; 95 % c.i.: 1.12–2.15) and HLA-DRB1*1501-DQB1*0602 haplotype (Ppositivity = 9.2610 211; OR = 3.97; 95 % c.i.: 2.55–6.19). No interaction between the two markers (SNP rs5770917 and HLA-DRB1*1501-DQB1*0602 haplotype) was observed in EHS. Conclusion: CPT1B, CHKB and HLA are candidates for susceptibility to CNS hypersomnias (EHS), as well as narcolepsy with cataplexy

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy

Narcolepsy has genetic and environmental risk factors, but the specific genetic risk loci and interaction with environmental triggers are not well understood. Here, the authors identify genetic loci for narcolepsy, suggesting infection as a trigger and dendritic and helper T cell involvement. Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix (R). Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix (R)

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

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

Common variants in P2RY11 are associated with narcolepsy.

l e t t e r s Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genomewide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y 11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10 −10 , odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The diseaseassociated allele is correlated with reduced expression of P2RY11 in CD8 + T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases

Common variants in P2RY11 are associated with narcolepsy.

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.journal articleresearch support, n.i.h., extramuralresearch support, non-u.s. gov'tresearch support, u.s. gov't, p.h.s.2011 Jan2010 12 19importedErratum in : Nat Genet. 2011 Oct;43(10):1040