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We conducted a Japanese GWAS for systemic sclerosis (SSc) comprising 1,428 cases and 112,599 controls, the largest Asian GWAS for SSc ever, and identified three novel signals. The lead SNP in FCGR/FCRL region had a strong effect size (OR 2.05, P = 4.9×10−11). The complete LD SNP, rs10917688, was found in a cis-regulatory element and a part of binding motifs for IRF8. IRF8 was a significant locus in the European GWAS and rs10917688 showed an association only in the presence of the risk allele of IRF8 in Japanese. rs10917688 was marked with H3K4me1 in primary B cells, and the heritability was enriched in active histone marks of primary B cells. A meta-analysis with the latest European GWAS found additional 30 significant loci including three novel signals. PRS constructed with the effect sizes of the meta-analysis indicated potential portability of genetic associations beyond populations (AUC: 0.593). The fitting of PRS was improved by further prioritizing the top 5% SNPs of IRF8 biding sites in B cells, underscoring common genetic architecture across populations and critical roles of B cells and IRF8 for SSc development.

Understanding the genetic effects on non-coding RNA (ncRNA) expression facilitates functional characterization of disease-associated genetic loci. Among several classes of ncRNAs, microRNAs (miRNAs) are key post-transcriptional gene regulators. Despite its biological importance, previous studies on the genetic architecture of miRNA expression focused mostly on the European individuals, underrepresented in other populations. Here, we mapped miRNA expression quantitative trait loci (miRNA-eQTL) for 343 miRNAs in 141 Japanese using small RNA sequencing and whole-genome sequencing, identifying 1275 cis-miRNA-eQTL variants for 40 miRNAs (false discovery rate < 0.2). Of these, 25 miRNAs having eQTL were unreported in the European studies, including 5 miRNAs with their lead variant monomorphic in the European populations, which demonstrates the value of miRNA-eQTL analysis in diverse ancestral populations. MiRNAs with eQTL effect showed allele-specific expression (ASE; e.g. miR-146a-3p), and ASE analysis further detected cis-regulatory variants not captured by the conventional miRNA-eQTL mapping (e.g. miR-933). We identified a copy number variation associated with miRNA expression (e.g. miR-570-3p, P = 7.2 × 10−6), which contributes to a more comprehensive landscape of miRNA-eQTLs. To elucidate a post-transcriptional modification in miRNAs, we created a catalog of miRNA-editing sites, including 10 canonical and 6 non-canonical sites. Finally, by integrating the miRNA-eQTLs and Japanese genome-wide association studies of 25 complex traits (mean n = 192 833), we conducted a transcriptome-wide association study, identifying miR-1908-5p as a potential mediator for adult height, colorectal cancer and type 2 diabetes (P < 9.1 × 10−5). Our study broadens the population diversity in ncRNA-eQTL studies and contributes to functional annotation of disease-associated loci found in non-European populations.

Background Despite evidence for the role of human leukocyte antigen (HLA) in the genetic predisposition to Parkinson's disease (PD), the complex haplotype structure and highly polymorphic feature of the major histocompatibility complex (MHC) region has hampered a unified insight on the genetic risk of PD. In addition, a majority of the reports focused on Europeans, lacking evidence on other populations. Objectives The aim of this study is to elucidate the genetic features of the MHC region associated with PD risk in trans-ethnic cohorts. Methods We conducted trans-ethnic fine-mapping of the MHC region for European populations (14,650 cases and 1,288,625 controls) and East Asian populations (7712 cases and 27,372 controls). We adopted a hybrid fine-mapping approach including both HLA genotype imputation of genome-wide association study (GWAS) data and direct imputation of HLA variant risk from the GWAS summary statistics. Results Through trans-ethnic MHC fine-mapping, we identified the strongest associations at amino acid position 13 of HLA-DRβ1 (P = 6.0 × 10-15 ), which explains the majority of the risk in HLA-DRB1. In silico prediction revealed that HLA-DRB1 alleles with histidine at amino acid position 13 (His13) had significantly weaker binding affinity to an α-synuclein epitope than other alleles (P = 9.6 × 10-4 ). Stepwise conditional analysis suggested additional independent associations at Ala69 in HLA-B (P = 1.0 × 10-7 ). A subanalysis in Europeans suggested additional independent associations at non-HLA genes in the class III MHC region (EHMT2; P = 2.5 × 10-7 ). Conclusions Our study highlights the shared and distinct genetic features of the MHC region in patients with PD across ethnicities. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Novel biomarkers of rheumatoid arthritis (RA), in addition to antibodies against cyclic citrullinated peptides, are required. Metabolome analysis is a promising approach to identify metabolite biomarkers for clinical diagnosis. We adopted a comprehensive non-targeted metabolomics approach combining capillary electrophoresis time-of-flight mass spectrometry (TOFMS) and liquid chromatography TOFMS. We constructed metabolomics profiling of 286 plasma samples of a Japanese population [92 RA patients, 13 systemic lupus erythematosus (SLE) patients and 181 healthy controls). RA case–control association tests showed that seven metabolites exhibited significantly increased levels in RA samples compared with controls (P < 1.0 × 10−4; UTP, ethanolamine phosphate, ATP, GDP, ADP, 6-aminohexanoic acid and taurine), whereas one exhibited a decreased level (xanthine). The plasma levels of these eight metabolites were not significantly different between seropositive and seronegative RA patients (P > 0.05; n = 68 and 24, respectively). The four nucleotide levels (UTP, ATP, GDP and ADP) were significantly higher in the non-treatment patients in comparison between patients with and without treatment (P < 0.014; n = 57 and 35, respectively). Furthermore, we found that none of the four nucleotide levels showed significant differences in SLE case–control association tests (P > 0.2; 13 patients with SLE and the 181 shared controls) and psoriatic arthritis (PsA) case–control association tests (P > 0.11; 42 patients with PsA and 38 healthy controls), indicating disease specificity in RA. In conclusion, our large-scale metabolome analysis demonstrated the increased plasma nucleotide levels in RA patients, which could be used as potential clinical biomarkers of RA, especially for seronegative RA., Plasma nucleotide levels are new biomarkers for RA

To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype–phenotype associations across 52 phenotypes. Fine-mapping highlighted multiple association patterns conferring independent risks from classical HLA genes. Region-wide heritability estimates and genetic-correlation network analysis elucidated the polygenic architecture shared across the phenotypes. Sequencing of the MHC region in the Japanese population provides insight into population-specific allelic and structural variability. These data enable discovery and fine-mapping of genotype–phenotype associations across 52 phenotypes.

ObjectivesSystemic lupus erythematosus (SLE) is an autoimmune disease that is characterised by autoantibody production and widespread inflammation damaging many organs. Previous genome-wide association studies (GWASs) have revealed over 80 genetic determinants of SLE, but they collectively explain a fraction of the heritability, and only a few were proven in vivo for the involvement in SLE. We conducted a meta-analysis of SLE GWAS in the Japanese population, followed by functional analyses of a susceptibility gene with use of mutant mice.MethodsWe conducted a meta-analysis of two GWASs comprising a total of 1363 cases and 5536 controls using the 1000 Genome Project data as an imputation reference. Enrichment analyses for functional annotations were conducted. We examined Phospholipase D4 (Pld4) mutant mice to assess functional involvement of a genetic determinant.ResultsWe found a total of 14 significant loci, which included rs2582511 in AHNAK2/PLD4 recently reported in a Chinese study and a novel locus of rs143181706 in MAMLD1 (p=7.9×10−11 and 3.7×10–8, respectively). PLD4 risk allele was associated with anti-dsDNA antibody production. Enrichment analysis of genetic signals revealed involvement of a wide range of immune-related cells and pathways. Pld4 mutant mice revealed remarkably low body weight. The mice demonstrated autoimmune phenotypes compatible with SLE, including splenomegaly and lymphadenopathy, expansion of B cells and hypersecretion of BAFF and production of autoantibodies especially anti-nuclear antibody and anti-dsDNA antibody.Conclusions We found a novel susceptibility gene to SLE. Pld4 mutant mice revealed autoimmune phenotypes suggesting functional involvement of PLD4 with the basics of SLE.

We study the existence of radially symmetric solutions of the following nonlinear scalar field equations in ℝ N {\mathbb{R}^{N}} ( N ≥ 2 {N\geq 2} ): ${(*)_{m}}$ { - Δ ⁢ u = g ⁢ ( u ) - μ ⁢ u in ⁢ ℝ N , ∥ u ∥ L 2 ⁢ ( ℝ N ) 2 = m , u ∈ H 1 ⁢ ( ℝ N ) , \displaystyle\begin{cases}-\Delta u=g(u)-\mu u\quad\text{in }\mathbb{R}^{N},% \cr\lVert u\rVert_{L^{2}(\mathbb{R}^{N})}^{2}=m,\cr u\in H^{1}(\mathbb{R}^{N})% ,\end{cases} where g ⁢ ( ξ ) ∈ C ⁢ ( ℝ , ℝ ) {g(\xi)\in C(\mathbb{R},\mathbb{R})} , m > 0 {m>0} is a given constant and μ ∈ ℝ {\mu\in\mathbb{R}} is a Lagrange multiplier. We introduce a new approach using a Lagrange formulation of problem ( * ) m {(*)_{m}} . We develop a new deformation argument under a new version of the Palais–Smale condition. For a general class of nonlinearities related to [H. Berestycki and P.-L. Lions, Nonlinear scalar field equations. I: Existence of a ground state, Arch. Ration. Mech. Anal. 82 (1983), no. 4, 313–345], [H. Berestycki and P.-L. Lions, Nonlinear scalar field equations. II. Existence of infinitely many solutions, Arch. Ration. Mech. Anal. 82 (1983), no. 4, 347–375], [J. Hirata, N. Ikoma and K. Tanaka, Nonlinear scalar field equations in ℝ N {\mathbb{R}^{N}} : Mountain pass and symmetric mountain pass approaches, Topol. Methods Nonlinear Anal. 35 (2010), no. 2, 253–276], it enables us to apply minimax argument for L 2 {L^{2}} constraint problems and we show the existence of infinitely many solutions as well as mountain pass characterization of a minimizing solution of the problem inf ⁡ { ∫ ℝ N 1 2 ⁢ | ∇ ⁡ u | 2 - G ⁢ ( u ) ⁢ d ⁢ x : ∥ u ∥ L 2 ⁢ ( ℝ N ) 2 = m } , G ⁢ ( ξ ) = ∫ 0 ξ g ⁢ ( τ ) ⁢ 𝑑 τ . \inf\Bigg{\{}\int_{\mathbb{R}^{N}}{1\over 2}|{\nabla u}|^{2}-G(u)\,dx:\lVert u% \rVert_{L^{2}(\mathbb{R}^{N})}^{2}=m\Bigg{\}},\quad G(\xi)=\int_{0}^{\xi}g(% \tau)\,d\tau.

MicroRNAs (miRNAs) modulate the post-transcriptional regulation of target genes and are related to biology of complex human traits, but genetic landscape of miRNAs remains largely unknown. Given the strikingly tissue-specific miRNA expression profiles, we here expand a previous method to quantitatively evaluate enrichment of genome-wide association study (GWAS) signals on miRNA–target gene networks (MIGWAS) to further estimate tissue-specific enrichment. Our approach integrates tissue-specific expression profiles of miRNAs (∼1800 miRNAs in 179 cells) with GWAS to test whether polygenic signals enrich in miRNA–target gene networks and whether they fall within specific tissues. We applied MIGWAS to 49 GWASs (nTotal = 3 520 246), and successfully identified biologically relevant tissues. Further, MIGWAS could point miRNAs as candidate biomarkers of the trait. As an illustrative example, we performed differentially expressed miRNA analysis between rheumatoid arthritis (RA) patients and healthy controls (n = 63). We identified novel biomarker miRNAs (e.g. hsa-miR-762) by integrating differentially expressed miRNAs with MIGWAS results for RA, as well as novel associated loci with significant genetic risk (rs56656810 at MIR762 at 16q11; n = 91 482, P = 3.6 × 10−8). Our result highlighted that miRNA–target gene network contributes to human disease genetics in a cell type-specific manner, which could yield an efficient screening of miRNAs as promising biomarkers.

The genetic background of intracranial artery stenosis (ICAS), a major cause of ischemic stroke, remains elusive. We performed the world's first genome-wide association study (GWAS) of ICAS using DNA samples from Japanese subjects, to identify the genetic factors associated with ICAS and their correlation with clinical features. We also conducted a phenome-wide association study (PheWAS) of the top variant identified via GWAS to determine its association with systemic disease. The GWAS involved 408 patients with ICAS and 349 healthy controls and utilized an Asian Screening Array of venous blood samples. The PheWAS was performed using genotypic and phenotypic data of the Biobank Japan Project, which contained information on 46 diseases and 60 quantitative trait data from 150,000 Japanese individuals. The GWAS revealed that the East Asian-specific functional variant of RNF213, rs112735431 (c.14429G A, p.Arg4810Lys), was associated with ICAS (odds ratio, 12.3; 95% CI 5.5 to 27.5; P = 7.8 × 10

Key Points Question Which gene in the major histocompatibility complex region is associated with cervical cancer? Findings This genetic association study of 704 women with cervical cancer and 39 829 women without gynecologic disease used fine mapping of the major histocompatibility complex region by human leukocyte antigen imputation and found that HLA-B*52:01 was associated with cervical cancer in the Japanese population. Meaning These findings suggest that immune responses against human papillomaviruses are mediated by class I human leukocyte antigen molecules, which are associated with susceptibility to cervical cancer., This genetic association study uses fine mapping of the major histocompatibility complex (MHC) region by human leukocyte antigen imputation to determine whether the HLA-B*52:01 allele is associated with cervical cancer (CC) in Japanese women., Importance Understanding the genetic contribution of the major histocompatibility complex (MHC) region to the risk of cervical cancer (CC) will help understand how immune responses to infection with human papillomaviruses are associated with CC. Objective To determine whether the HLA-B*52:01 allele is associated with CC in Japanese women. Design, Setting, and Participants This was a multicenter genetic association study. Genotype and phenotype data were obtained from BioBank Japan Project. Additional patients with CC were enrolled from the Aichi Cancer Center Research Institute. An MHC fine-mapping study was conducted on CC risk in the Japanese population by applying a human leukocyte antigen (HLA) imputation method to the large-scale CC genome-wide association study data of using the Japanese population-specific HLA reference panel. Participants included 540 women in BioBank Japan Project with CC or 39 829 women without gynecologic diseases, malignant neoplasms, and MHC-related diseases as controls. An additional 168 patients with CC were recruited from Aichi Cancer Center Research Institute. Histopathological subtypes and clinical stages were not considered. Participants with low genotype call rate, closely related participants, and outliers in the principal component analysis were excluded. Data analysis was performed from August 2018 to January 2020. Main Outcomes and Measures Loci within the MHC region associated with CC risk, and the direction and size of association. Results A total of 704 CC cases and 39 556 controls were analyzed. All participants were Japanese women with a median (range) age of 67 (18 to 100) years. One of the class I HLA alleles of HLA-B*52:01 was significantly associated with CC risk (odds ratio, 1.60; 95% CI, 1.38-1.86; P = 7.4 × 10−10). Allele frequency spectra of HLA-B*52:01 are heterogeneous among worldwide populations with high frequency in Japanese populations (0.109 in controls), suggesting its population–specific risk associated with CC. The conditional analysis suggested that HLA-B*52:01 could explain most of the MHC risk associated with CC because no other HLA alleles remained significant after conditioning on the HLA-B*52:01. The HLA amino acid residue–based analysis suggested that HLA-B p.Tyr171His located in the peptide-binding groove was associated with the most significant CC risk (odds ratio, 1.47; 95% CI, 1.30-1.66; P = 1.2 × 10−9). Conclusions and Relevance The results of this study contribute to understanding of the genetic background of CC. The results suggest that immune responses mediated by class I HLA molecules are associated with susceptibility to CC.

The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of RORγt, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of RORγt. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent RORγt inhibitory activity and a favorable pharmacokinetic profile.

Conventional HLA imputation methods drop their performance for infrequent alleles, which reduces reliability of trans-ethnic MHC fine-mapping due to inter-ethnic heterogeneity in allele frequency spectra. We developed DEEP*HLA, a deep learning method for imputing HLA genotypes. Through validation using the Japanese and European HLA reference panels (n = 1,118 and 5,112), DEEP*HLA achieved the highest accuracies in both datasets (0.987 and 0.976) especially for low-frequency and rare alleles. DEEP*HLA was less dependent of distance-dependent linkage disequilibrium decay of the target alleles and might capture the complicated region-wide information. We applied DEEP*HLA to type 1 diabetes GWAS data of BioBank Japan (n = 62,387) and UK Biobank (n = 356,855), and successfully disentangled independently associated class I and II HLA variants with shared risk between diverse populations (the top signal at HLA-DRβ1 amino acid position 71; P = 6.2 ×10−119). Our study illustrates a value of deep learning in genotype imputation and trans-ethnic MHC fine-mapping.

The diversity in our genome is crucial to understanding the demographic history of worldwide populations. However, we have yet to know whether subtle genetic differences within a population can be disentangled, or whether they have an impact on complex traits. Here we apply dimensionality reduction methods (PCA, t-SNE, PCA-t-SNE, UMAP, and PCA-UMAP) to biobank-derived genomic data of a Japanese population (n = 169,719). Dimensionality reduction reveals fine-scale population structure, conspicuously differentiating adjacent insular subpopulations. We further enluciate the demographic landscape of these Japanese subpopulations using population genetics analyses. Finally, we perform phenome-wide polygenic risk score (PRS) analyses on 67 complex traits. Differences in PRS between the deconvoluted subpopulations are not always concordant with those in the observed phenotypes, suggesting that the PRS differences might reflect biases from the uncorrected structure, in a trait-dependent manner. This study suggests that such an uncorrected structure can be a potential pitfall in the clinical application of PRS., Population structure, even subtle differences within seemingly homogenous populations, can have an impact on the accuracy of polygenic prediction. Here, Sakaue et al. use dimensionality reduction methods to reveal fine-scale structure in the Biobank Japan cohort and explore the performance of polygenic risk scores.

[Image: see text] The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analogue of the known piperazine RORγt inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORγt inverse agonist. Structure–activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORγt inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.

Recent developments in human genome genotyping and sequencing technologies, such as genome-wide association studies and whole-genome sequencing analyses, have successfully identified several risk genes of rheumatic diseases. Fine-mapping studies using the HLA imputation method revealed that classical and non-classical HLA genes contribute to the risk of rheumatic diseases. Integration of human disease genomics with biological, medical, and clinical databases should contribute to the elucidation of disease pathogenicity and novel drug discovery. Disease risk genes identified by large-scale genetic studies are considered to be promising resources for novel drug discovery, including drug repositioning and biomarker microRNA screening for rheumatoid arthritis.

A layered-type W–Ti–O mixed oxide was synthesized by hydrothermal synthesis from an aqueous solution of ammonium metatungstate and titanium sulfate. To avoid the formation of titania, oxalic acid was used as a reductant. Optimized synthesis led to rod-like particles comprised of MO6 (M = W, Ti) octahedra connected in a corner-sharing fashion in the c-direction and in the form of micropore-containing {W6O21} units in the a–b plane. The surface area, acidity and acid catalytic activity (alkylation) increased with the amount of the layered-type W–Ti–O phase. Strong Bronsted acid sites formed due to the thermal release of ammonia from the uncalcined precursor. Calcination at 400 °C led to the highest acidity and alkylation activity. Alkylation of benzyl alcohol and toluene led to heavy product formation due to over-alkylation of the product. The selectivity to the mono-alkylated product was improved by the addition of water, which competes with the selectively formed products for adsorption on the acid sites. FT-IR measurements showed that the layered-type W–Ti–O possesses Bronsted acid sites and at least two different Lewis acid sites. The stronger Lewis acid sites can be converted into Bronsted acid sites in the presence of water, and the weaker Lewis acid sites functioned in the presence of water. This water tolerance of Lewis acid sites is an important characteristic of layered-type W–Ti–O, as it allows the bifunctional catalyst to convert 1,3-DHA into lactic acid in water.

A dehydrative cross-etherification reaction of two different alcohols is achieved in the presence of hydrothermally synthesized tungsten-titanium mixed metal oxide (W-Ti-O) catalyst. The reaction is environmentally benign: organic solvent is not necessary and the catalyst is readily recovered and reusable.

Better prescription assistance can be provided by applying basic pharmaceutical science concepts, and by considering evidence from clinical trials. For example, several drugs are currently used to treat ulcerative colitis (UC), a form of inflammatory bowel disease. In general, after a drug is administered, it is first absorbed into the upper part of the small intestine and then enters the bloodstream. However, 5-aminosalicylic acid (5-ASA), which is commonly used to treat UC, acts locally on the colonic mucosa; its absorption must be prevented in the upper gastrointestinal tract so that it can be delivered to the colorectal mucosa. Therefore, in this case, it is important to consider drug dissolution tests rather than pharmacokinetics. Currently, three types of 5-ASA formulations are available: a pH-dependent release formulation, a time-dependent release formulation, and a combination of the two at maximum dosages of 3600, 4000, and 4800 mg, respectively. Although it is often thought that selecting a high dose is better, the clinical effectiveness of 5-ASA is determined by the amount of drug actually delivered to the lesion. Therefore, rather than dosage, it is most important to understand differences in drug solubility. It is beneficial to provide prescription assistance for the treatment of UC by 5-ASA, because when 5-ASA fails, a steroid or expensive biological drug is administered. We will present a case study and discuss the future of prescription assistance using Academic Detailing.

Background The spectrum of classical and non-classical HLA genes related to the risk of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in the Japanese population has not been studied in detail. We conducted a case-control analysis of classical and non-classical HLA genes. Methods We used next-generation sequencing (NGS)-based HLA genotyping methods for mapping risk for 45 MS patients, 31 NMOSD patients, and 429 healthy controls. We evaluated the association of the HLA variants with the risk of MS and NMOSD using logistic regression analysis and Fisher’s exact test. Results We confirmed that HLA-DRB1*15:01 showed the strongest association with MS (P = 2.1 × 10−5; odds ratio [OR] = 3.44, 95% confidence interval [95% CI] = 1.95–6.07). Stepwise conditional analysis identified HLA-DRB1*04:05, HLA-B*39:01, and HLA-B*15:01 as being associated with independent MS susceptibility (PConditional

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6–7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10−12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10−12), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10−7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production., Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.

Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA , a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10 −9 ), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1 , explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.

To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype-phenotype associations across 52 phenotypes. Fine-mapping highlighted multiple association patterns conferring independent risks from classical HLA genes. Region-wide heritability estimates and genetic-correlation network analysis elucidated the polygenic architecture shared across the phenotypes.

Psoriasis vulgaris (PsV) is an autoimmune disease of skin and joints with heterogeneity in epidemiologic and genetic landscapes of global populations. We conducted an initial genome-wide association study and a replication study of PsV in the Japanese population (606 PsV cases and 2,052 controls). We identified significant associations of the single nucleotide polymorphisms with PsV risk at TNFAIP3-interacting protein 1 and the major histocompatibility complex region ( P = 3.7 × 10 −10 and 6.6 × 10 −15 , respectively). By updating the HLA imputation reference panel of Japanese (n = 908) to expand HLA gene coverage, we fine-mapped the HLA variants associated with PsV risk. Although we confirmed the PsV risk of HLA-C*06:02 (odds ratio = 6.36, P = 0.0015), its impact was relatively small compared with those in other populations due to rare allele frequency in Japanese (0.4% in controls). Alternatively, HLA-A*02:07, which corresponds to the cysteine residue at HLA-A amino acid position 99 (HLA-A Cys99), demonstrated the most significant association with PsV (odds ratio = 4.61, P = 1.2 × 10 –10 ). In addition to HLA-A*02:07 and HLA-C*06:02, stepwise conditional analysis identified an independent PsV risk of HLA-DQβ1 Asp57 (odds ratio = 2.19, P = 1.9 × 10 –6 ). Our PsV genome-wide association study in Japanese highlighted the genetic architecture of PsV, including the identification of HLA risk variants.

Layered-structure-type niobium oxides were synthesized by the hydrothermal method by using ammonium niobium oxalate as a precursor. The X-ray diffraction pattern (Cu-Kα) of the synthesized niobium oxide showed characteristic peaks at 2θ = 22.7° and 46.2°, indicating the linear corner-sharing of NbO6 octahedra in the c-direction. From Raman measurements, the layered-structure-type niobium oxide was composed of NbO6 octahedra and {Nb6O21} pentagonal units. The presence of micropores was confirmed by N2 adsorption at low pressure (1.0 × 10−6), indicating that the arrangement of the a–b plane was an interconnection of the crystal structure motifs of {Nb6O21} units and micropore channels but without long-range order (deformed orthorhombic). Ammonium cations and water were desorbed from the deformed orthorhombic niobium oxide by calcination at 400 °C, and Bronsted acid sites were formed. The deformed orthorhombic niobium oxide showed high catalytic activity as a solid acid compared to the catalytic activities of other crystalline niobium oxides. The order of catalytic activity for the alkylation of benzyl alcohol and anisole was deformed orthorhombic Nb2O5 > TT-Nb2O5, amorphous Nb2O5 ≫ T-Nb2O5, pyrochlore Nb2O5.

In this paper we consider the following nonlinear Schrodinger equations: { − Δ u + V ( x ) u = f ( u ) in R N , u ∈ H 1 ( R N ) . Here N ≥ 2 and V ( x ) ∈ C ( R N , R ) is invariant under a group action G ⊂ O ( N ) . We deal with both finite group actions and infinite group actions. The existence of a positive solution will be shown for a wide class of nonlinearities f ( u ) .

「人的資本(human capital)」とは1960年代、主に経済学者Schultz,T及びBecker,G(いずれもノーベル経済学賞受賞者)を中心に展開された概念で、現在に至るまで経済に内生的成長をもたらす原動力・不可欠な成長要因として重視されている。OECDでは、この「人的資本」を「個人に内在化された知識・技能(スキル)・能力(コンピテンシー)・諸属性で、個人的/社会的/経済的な幸福(well-being)を増進するもの」(OECD、2001)と幅広く捉えており、教育等人的資本への投資を、雇用促進・格差不平等是正のための重要な戦略として位置付けている。しかし日・米・欧州など先進諸国では、現在に至るまで、各国毎にばらつきはあるものの共通して、下記に示されるような「人的資本」の順調な成長を阻害し、鈍化停滞させ、或いは毀損破壊する様々な問題に悩まされてきている。即ち個人/家族/社会の分野に広汎に生じた諸問題=顕著な少子化の持続、育児・保育過程での諸暴力増大、教育・学力悪化問題、若年層の非労働力化(ニート・社会的ひきこもり等)、各年代層に増加したメンタルヘルス障害・危機等=である。これらは人的資本のフロー・ストックにダメージを与え、しかも「人的資本」を形成し、その拡大発展や再生修復を支え、推進していく力・ダイナミズム(『人的資本力』と仮称)を、長期的に減退させる「構造問題」となってきている。経済社会の高度化・グローバル化が進行する中で、「人的資本」投資の重要性への認識が昂進(IT・知価創造革命への対応や、教育の早期化・生涯教育の重視等)する一方で、構造問題は容易に改善せず、むしろ一部の国では、「人的資本」や『人的資本力』を示す諸指標の悪化が続き、「構造問題」が構造危機化するに至った。特に日本では、「人的資本・人的資本力」が、危機に陥りつつある兆候を示す諸事件・問題が急増してきたが、これは上記の「構造問題」が同時並行的に進行し、他の先進国比でも急速に深刻化したためと見られる。そこで平成不況を脱却した前後から、各方面の危機感が一段と高まり、実態解明と原因追求、解決・対応策の模索、効果的な政策提言などを巡って、論議が白熱してきている。教育機関として「人的資本」形成の一角を支えていく大学に身を置く者としても、こうした「人的資本・人的資本力」問題・危機は、避けて通れない重い課題と考える。昨今の日本における『人的資本力』諸問出とは、a.『人的資本力』(ダイナミズム)自体が衰えてきていることに起因するのか、或いはb.「人的資本」を取巻く外的環境の複雑化・高度化・加速する変化による、圧力増大(これに『人的資本力』が有効に適応し得ない)のためか、それともc.これまで十分に解明・解析されていなかった『人的資本力』阻害要因が、特定化・可視化されてきた結果であるのか、について、先行研究や文献を踏まえつつ極力理解を進めていきたい。本稿ではまず「序章」「第1章」「第2章」にて、『人的資本力』(仮称)概念の展開、日本を始めとする先進諸国『人的資本力』問題について3つの位相を軸とした整理、そして筆者が設定した問題意識の説明を行なうことと致したい。

Gastrointestinal symptoms, such as abdominal pain and diarrhea, are frequently observed in patients with Plasmodium falciparum malaria. However, the correlation between malaria intestinal pathology and intestinal microbiota has not been investigated. In the present study, infection of C57BL/6 mice with P. berghei ANKA (PbA) caused intestinal pathological changes, such as detachment of epithelia in the small intestines and increased intestinal permeability, which correlated with development with experimental cerebral malaria (ECM). Notably, an apparent dysbiosis occurred, characterized by a reduction of Firmicutes and an increase in Proteobacteria. Furthermore, some genera of microbiota correlated with parasite growth and/or ECM development. By contrast, BALB/c mice are resistant to ECM and exhibit milder intestinal pathology and dysbiosis. These results indicate that the severity of cerebral and intestinal pathology coincides with the degree of alteration in microbiota. This is the first report demonstrating that malaria affects intestinal microbiota and causes dysbiosis.

IFN-γ plays both pathological and protective roles during blood-stage malaria. One of its pathological roles is its contribution to anemia by suppressing erythropoiesis. Here, to evaluate the effects of IFN-γ-mediated alterations in erythropoiesis on the course of malaria infection, mice deficient in IFN-γ (GKO) were infected with two strains of the rodent malaria parasite Plasmodium yoelii, 17XL (PyL) and 17XNL (PyNL), whose host cell ranges differ. Regardless of genotype, all mice infected with PyL, which can invade any erythrocyte, developed high parasitemia and died quickly. Although PyNL caused a transient non-lethal infection in wild-type (WT) mice, some GKO mice were unable to control the infection and died. However, GKO mice were resistant to the early phase of infection, showing an impaired increase in parasitemia compared with WT mice. This resistance in the GKO mice was associated with having significantly fewer reticulocytes, which are the preferred host cells for PyNL parasites, than the WT mice. Compared with the amount of reticulocytes in GKO mice during the early stages of infection, there was a significant increase in the amount of these cells at later stages, which coincided with the inability of these mice to control the infection. We found that the growth of PyNL parasites correlated with the amount of reticulocytes. Thus, the reduced number of reticulocytes in mice lacking IFN-γ appears to be responsible for the limited parasite growth. Notably, these differences in GKO mice were at least partially reversed when the mice were injected with exogenous IFN-γ. Additionally, an artificial induction of hemolytic anemia and an increase in reticulocytes by phenylhydrazine treatment in GKO mice completely abolished the lower parasitemia and resistance during early phase infection. These results suggest that IFN-γ may contribute to the early growth of PyNL parasites by increasing the amount of reticulocytes, presumably by enhancing erythropoiesis.

英国では1950年代以降、主にケインズ主義による総需要管理政策(財政・金融政策)と完全雇用追求、社会保障充実を基本政策とすることが、保守党・労働党を問わず、実質的な「政策の枠組み」となっていた。(Consensus Politics)しかし70年代石油危機を契機に、既に経済供給面に多くの構造問題を抱えていた英国ではスタグフレーションが亢進し、悲惨指数(インフレ+失業率)悪化、財政収支悪化、ストの頻発等に対する保守・労働党政権の政策が有効性を欠く中で、消費者の生活へのダメージが増大(78年、the Winter of discontent)する「政策危機」が進行していった。79年に成立したサッチャー政権は、深刻な政策危機から脱却するために、これまでのConsensus Politicsに囚われない、経済構造改革を断行した。改革は政策の有効性や効果において試行錯誤を含むものであった(当初目的未達成の政策や、効果が乏しい例も多かった)が、政策の一貫性と優先順位は明確であり、強力なリーダーシップにより長期にわたり国民の支持を取り付け、インフレ抑制、国営企業民営化や海外直接投資導入策、税制改革、労働組合政策、規制緩和(金融ビッグバン等)、行政改革(エージェンシー制の採用等)、成長軌道への復帰などに成果を挙げた。諸政策の実施面で、第一期(79～83年)第二期(83～87年)では、現実経済とのミスマッチは抑制されていたが、第二期後半から第三期(87～90年)になると、通貨・金融政策の方向性に鮮明さを欠き、通貨ポンドのEMS加盟を巡る深刻な内部対立、87年以降の財政・金融緩和長期化に伴うインフレ再燃、経済のバブル化とその後の失速等、新たな問題が生じ、また改革の副作用ともいうべき、失業率の高止まりや所得格差拡大への対応は不十分な水準にとどまった。しかしながらサッチャー改革の「経済基本理念」はその後メージャー政権だけでなく、労働党ブレア政権にも「小さな効率的政府の追求の持続」、「伝統的な福祉依存からの脱却」などの理念として継承されている。

90年代には、これまで順調に経済成長を遂げてきた東アジア諸国(NIEs、ASEAN)で、通貨金融危機が生じ、経済閉塞に陥った。こうした深刻かつ長期的な危機には、(1)マクロ経済上の様々な不均衡の存在や、グローバルマネーフローの急激な変化等強い外的ショックが原因で発生した『構造危機』の側面に加えて、(2)構造危機への対応、危機管理策自体が引き起こした『政策危機』の要素が抜き難く存在していると考えられる。本稿では『政策危機』を「政府(当事国、国際機関を含める)による危機対応政策から直接・間接派生した新たな失敗や危機」と位置付けている。そして1997年アジア通貨危機に瀕したインドネシア・マレーシア・韓国を対象に、従来の視点である『構造危機』に、『政策危機』を座標軸として加えて、分析を試みた。即ちインドネシアでは、『構造危機』発生後、IMFとインドネシア政府の経済政策基本理念のミスマッチから、深刻な『政策危機』が発生し、『構造危機』との合併症が昂進したものと見る。これに対しマレーシア・韓国は、『政策危機』を防止・克服し、経済再生にも早期に成功した。もっともマレーシア・韓国両国の採用した政策・政策理念は大きく異なり、グローバル・スタンダード的なIMF政策へのスタンスにも差があるが、両者共、(1)グローバル経済下での「市場」の重要性・圧力の強さを十分踏まえて、(2)市場に委ねても即時的解決が困難な分野や、市場の失敗が生じた分野に対しては、政府の強い介入を躊躇なく実施し、(3)強力なリーダーシップにより政策を軌道修正しつつも一貫させたことが、政権のガバナンス維持と市場による信認の回復を果たし、『政策危機』の発生・拡大を防止克服し得たといえよう。

移動能力として四つ這い以上の機能を獲得した脳性麻痺児102例(痙直型73例,アテトーゼ型29例)について,運動発達経過を比較検討した.最終移動能力である独歩と杖歩行について,寝返り,坐位,四つ這いの各粗大運動の獲得時期だけでは両群間の有意差は認められず,寝返りから四つ這い獲得までの期間において両群間に統計学的有意差があった.痙直型,アテトーゼ型とも,この期間が1年以内の症例の多くは独歩を獲得したが,2年を越える症例では歩行不能例が多かった.杖歩行例は1年から2年の間が最も多かった.寝返りから四つ這い獲得までの期間は抗重力姿勢の発達勾配を反映し,脳性麻痺の移動能力を予測するのに有用である.

In Japan, decentralized and deregulated education reform began after World War II. The Course of Study (the national curriculum) was issued in 1947 as a guideline for teachers. Since around 1950, however, tension between the Western bloc and the Eastern bloc in the international society grew. This conflict was compared to the relationship between the Ministry of Education and teacher unions in the Japanese context of education. Furthermore, the interregional gaps in student performance increased. Influenced by these matters, the Ministry embarked upon standardization of educational content by claiming that the Course of Study had legal binding force over teachers in 1958. In the 1990s, educational content was deregulated and contents in the Course of Study decreased to implement yutori education. This deregulation was criticized because critics thought that it brought about the decline of student performance. Since around 2004, therefore, restandardization has been implemented by introducing the National Achievement Tests, increasing contents and instructional hours in the Course of Study, and so on. Especially since the late 1990s, policies strengthening principals’ leadership have been implemented. A series of reforms increases principals’ leadership and autonomy in relation to teachers by reducing teachers’ voice in school governance. On the other hand, substantive authority is not devolved to individual schools, and therefore, principals’ autonomy from Boards of Education and the Ministry is not sufficiently realized.

The purpose of this paper is to analyze decentralized education reform in Japan in terms of School/Site-Based Management (SBM). In the literature, SBM embraces two major elements, namely, the devolution of decision-making authority to the individual school level and Shared Decision-Making (SDM). In Japan, school advisors and school management councils have been established with similar purposes with SBM since 2000. However, because the decision-making authority is not sufficiently devolved to each school and many groups of stakeholders are not significantly involved in decision-making processes, a SBM form of school governance has not been realized in Japan. Cet article a pour but d’analyser la réforme de décentralisation de l’éducation au Japon en termes de l’Administration basée sur l’école ou le site (SBM). Dans la littérature, la SBM se comprend de deux éléments: la dévolution au niveau de chaque école les droits d'exécuter des décisions et la politique des décisions partagées (SDM). Au Japon, les postes de conseillers et les conseils d’administration ont été établis depuis l’an 2000. Et pourtant, parce que les instances ne sont pas assez engagées dans le processus décisionnel, une forme de gouvernance des écoles selon la SBM n’a pas pu se réaliser au Japon.

We previously identified a regulatory element at the 3'-downstream region of the human angiotensinogen (hANG) gene. Using this element as a probe by the Southwestern screening, we isolated a cDNA clone, encoding Finb, a transcriptional activator with multiple zinc finger domains. The N-terminal zinc finger domain of Finb bound to the GGATGG sequence within the regulatory element. Unexpectedly, Finb repressed transcription dependent on the regulatory element. Inspection of the 5'-flanking region in the hANG promoter identified the GGATGG-like elements, which prompted us to examine the effect of Finb on the hANG promoter activity. We also found the two Finb binding elements in the 5'-flanking region of the hANG gene by the gel shift assay, both of which were necessary for transcriptional repression of the hANG promoter. These findings suggest that Finb functions as a sequence-specific transcriptional repressor of the hANG gene.