CD45 alleviates airway inflammation and lung fibrosis by limiting expansion and activation of ILC2s.

Group 2 innate lymphoid cells (ILC2s) are critical for the immune response against parasite infection and tissue homeostasis and involved in the pathogenesis of allergy and inflammatory diseases. Although multiple molecules positively regulating ILC2 development and activation have been extensively investigated, the factors limiting their population size and response remain poorly studied. Here, we found that CD45, a membrane-bound tyrosine phosphatase essential for T cell development, negatively regulated ILC2s in a cell-intrinsic manner. ILC2s in CD45-deficient mice exhibited enhanced proliferation and maturation in the bone marrow and hyperactivated phenotypes in the lung with high glycolytic capacity. Furthermore, CD45 signaling suppressed the type 2 inflammatory response by lung ILC2s and alleviated airway inflammation and pulmonary fibrosis. Finally, the interaction with galectin-9 influenced CD45 signaling in ILC2s. These results demonstrate that CD45 is a cell-intrinsic negative regulator of ILC2s and prevents lung inflammation and fibrosis via ILC2s.

Visualization of the landscape of the read alignment shape of ATAC-seq data using Hellinger distance metric.

Assay for Transposase-Accessible Chromatin using high-throughput sequencing (ATAC-seq) is the popular technique using next-generation sequencing to measure chromatin accessibility and identify open chromatin regions. While read alignment shape information of next-generation sequencing data with intensity information has been used in various bioinformatics methods, few studies have focused on pure shape information alone. In this study, we investigated what types of ATAC-seq read alignment shapes are observed for the promoter region and whether the pure shape information was related or unrelated to other gene features. We introduced a novel concept and pipeline for handling the pure shape information of NGS data as probability distributions and quantifying their dissimilarities by information theory. Based on this concept, we demonstrate that the pure shape information of ATAC-seq data is correlated with chromatin openness and some gene characteristics. On the other hand, it is suggested that the pure information of ATAC-seq read alignment shape is unlikely to contain additional information to explain differences in RNA expression. Our study suggests that viewing the read alignment shape of NGS data as probability distributions enables us to capture the characteristics of the genome-wide landscape of such data in a non-parametric manner.

Data-driven identification and classification of nonlinear aging patterns reveals the landscape of associations between DNA methylation and aging.

BACKGROUND: Aging affects the incidence of diseases such as cancer and dementia, so the development of biomarkers for aging is an important research topic in medical science. While such biomarkers have been mainly identified based on the assumption of a linear relationship between phenotypic parameters, including molecular markers, and chronological age, numerous nonlinear changes between markers and aging have been identified. However, the overall landscape of the patterns in nonlinear changes that exist in aging is unknown. RESULT: We propose a novel computational method, Data-driven Identification and Classification of Nonlinear Aging Patterns (DICNAP), that is based on functional data analysis to identify biomarkers for aging and potential patterns of change during aging in a data-driven manner. We applied the proposed method to large-scale, public DNA methylation data to explore the potential patterns of age-related changes in methylation intensity. The results showed that not only linear, but also nonlinear changes in DNA methylation patterns exist. A monotonous demethylation pattern during aging, with its rate decreasing at around age 60, was identified as the candidate stable nonlinear pattern. We also analyzed the age-related changes in methylation variability. The results showed that the variability of methylation intensity tends to increase with age at age-associated sites. The representative variability pattern is a monotonically increasing pattern that accelerates after middle age. CONCLUSION: DICNAP was able to identify the potential patterns of the changes in the landscape of DNA methylation during aging. It contributes to an improvement in our theoretical understanding of the aging process.

Cell population-based framework of genetic epidemiology in the single-cell omics era.

Genetic epidemiology is a rapidly advancing field due to the recent availability of large amounts of omics data. In recent years, it has become possible to obtain omics information at the single-cell level, so genetic epidemiological models need to be updated to integrate with single-cell expression data. In this perspective paper, we propose a cell population-based framework for genetic epidemiology in the single-cell era. In this framework, genetic diversity influences phenotypic diversity through the diversity of cell population profiles, which are defined as high-dimensional probability distributions of the state spaces of biomolecules of each omics layer. We discuss how biomolecular experimental measurement data can capture the different properties of this distribution. In particular, single-cell data constitute a sample from this population distribution where only some coordinate values are observable. From a data analysis standpoint, we introduce methodology for feature extraction from cell population profiles. Finally, we discuss how this framework can be applied not only to genetic epidemiology but also to systems biology.

[Multiorgan Thromboembolism due to Thrombus in the Remnant Superior Pulmonary Vein After Left Upper Division Segmentectomy:Report of a Case].

A 67 years old male had underwent left upper division segmentectomy. On the sixth day after surgery, he had developed unconsciousness, aphasia and unilateral spatial neglect. Brain MRI revealed a cerebral infarction, and percutaneous cerebral thrombectomy was performed. Enhanced computed tomography revealed thrombus formation in the remnant superior pulmonary vein (SPV), left renal infarction and right acute limb ischemia. After starting anticoagulant therapy with apixaban the thrombus reduced and neurological symptoms improved. A thrombus in the SPV may cause serious whole body organ infarction in the same way as a left atrial thrombus. It was suggested that left upper division segmentectomy was associated with the risk of remnant pulmonary vein thrombosis.

Dual deletion of guanylyl cyclase-A and p38 mitogen-activated protein kinase in podocytes with aldosterone administration causes glomerular intra-capillary thrombi.

Natriuretic peptides exert not only blood-lowering but also kidney-protective effects through guanylyl cyclase-A (GC-A), a natriuretic peptide receptor. Signaling through GC-A has been shown to protect podocytes from aldosterone-induced glomerular injury, and a p38 mitogen-activated protein kinase (MAPK) inhibitor reduced glomerular injury in aldosterone-infused podocyte-specific GC-A knockout mice. To explore the role of p38 MAPK in podocytes, we constructed podocyte-specific p38 MAPK and GC-A double knockout mice (pod-double knockout mice). Unexpectedly, aldosterone-infused and high salt-fed (B-ALDO)-treated pod-double knockout mice resulted in elevated serum creatinine, massive albuminuria, macrophage infiltration, foot process effacement, nephrin and podocin reduction, and additionally, intra-capillary fibrin thrombi, indicating endothelial injury. Microarray analysis showed increased plasminogen activator inhibitor-1 (PAI-1) in glomeruli of B-ALDO-treated pod-double knockout mice. In B-ALDO-treated pod-double knockout mice, PAI-1 increased in podocytes, and treatment with PAI-1 neutralizing antibody ameliorated intra-capillary thrombus formation. In vitro, deletion of p38 MAPK by the CRISPR/Cas9 system and knockdown of GC-A in human cultured podocytes upregulated PAI-1 and transforming growth factor- ß1 (TGF-ß1). When p38 MAPK knockout podocytes, transfected with a small interfering RNA to suppress GC-A, were co-cultured with glomerular endothelial cells in a transwell system, the expression of TGF-ß1 was increased in glomerular endothelial cells. PAI-1 inhibition ameliorated both podocyte and endothelial injury in the transwell system signifying elevated PAI-1 in podocytes is a factor disrupting normal podocyte-endothelial crosstalk. Thus, our results indicate that genetic dual deletion of p38 MAPK and GC-A in podocytes accelerates both podocyte and endothelial injuries, suggesting these two molecules play indispensable roles in podocyte function.

Magnetoresistance originated from the Au/S interface in Au/1,6-hexanedithiol/Au single-molecule junctions at room temperature.

We report a magnetic response of Au/1,6-hexanedithiol/Au single-molecule junctions at room temperature using a mechanically controllable break junction method. The electrical resistance of the junction was found to increase up to 5.5% under a magnetic field. This phenomenon could originate from the unpaired charge at the Au/S interface.

Hitherto-Unnoticed Self-Transmissible Plasmids Widely Distributed among Different Environments in Japan.

Various conjugative plasmids were obtained by exogenous plasmid capture, biparental mating, and/or triparental mating methods from different environmental samples in Japan. Based on phylogenetic analyses of their whole-nucleotide sequences, new IncP/P-1 plasmids that could be classified into novel subgroups were obtained. Mini-replicons of the plasmids were constructed, and each of them was incompatible with at least one of the IncP/P-1 plasmids, although they showed diverse iteron sequences in their oriV regions. There were two large clades of IncP/P-1 plasmids, clade I and II. Plasmids in clade I and II included antibiotic resistance genes. Notably, nucleotide compositions of newly found plasmids exhibited different tendencies compared with those of the previously well-studied IncP/P-1 plasmids. Indeed, the host range of plasmids of clade II was different from that of clade I. Although few PromA plasmids have been reported, the number of plasmids belonging to PromAß, and -γ subgroups detected in this study was close to that of IncP/P-1 plasmids. The host ranges of PromAγ and PromAδ plasmids were broad and transferred to different and distinct classes of Proteobacteria. Interestingly, PromA plasmids and many IncP/P-1 plasmids do not carry any accessory genes. These findings indicate the presence of "hitherto-unnoticed" conjugative plasmids, including IncP/P-1 or PromA derivative ones in nature. These plasmids would have important roles in the exchange of various genes, including antibiotic resistance genes, among different bacteria in nature. IMPORTANCE Plasmids are known to spread among different bacteria. However, which plasmids spread among environmental samples and in which environments they are present is still poorly understood. This study showed that unidentified conjugative plasmids were present in various environments. Different novel IncP/P-1 plasmids were found, whose host ranges were different from those of known plasmids, showing wide diversity of IncP/P-1 plasmids. PromA plasmids, exhibiting a broad host range, were diversified into several subgroups and widely distributed in varied environments. These findings are important for understanding how bacteria naturally exchange their genes, including antibiotic resistance genes, a growing threat to human health worldwide.

Data-driven comparison of multiple high-dimensional single-cell expression profiles.

Comparing multiple single-cell expression datasets such as cytometry and scRNA-seq data between case and control donors provides information to elucidate the mechanisms of disease. We propose a completely data-driven computational biological method for this task. This overcomes the challenges of conventional cellular subset-based comparisons and facilitates further analyses such as machine learning and gene set analysis of single-cell expression datasets.

Genome-wide Survival Analysis for Macular Neovascularization Development in Central Serous Chorioretinopathy Revealed Shared Genetic Susceptibility with Polypoidal Choroidal Vasculopathy.

PURPOSE: To identify susceptibility genes for macular neovascularization (MNV) development in central serous chorioretinopathy (CSC). DESIGN: Genome-wide survival analysis using a longitudinal cohort study. PARTICIPANTS: We included 402 and 137 patients with CSC but without MNV at their first visit from the Kyoto CSC Cohort and Kobe CSC dataset, respectively. All patients underwent detailed ophthalmic examinations, including multimodal imaging, such as fundus autofluorescence, spectral-domain OCT, and fluorescein angiography/indocyanine green angiography or OCT angiography. METHODS: We conducted a genome-wide survival analysis using the Kyoto CSC Cohort. We applied the Cox proportional hazard model to adjust for age, sex, and the first principal component. Single nucleotide polymorphisms (SNPs) with P values < 1.0 × 10-5 were carried forward to the replication in the Kobe CSC dataset. Moreover, we evaluated the contribution of previously reported age-related macular degeneration (AMD) susceptibility loci. We used FUMA and ToppFun for the functional enrichment analysis. MAIN OUTCOME MEASURES: The association between SNPs and MNV development in patients with CSC. RESULTS: Rs370974631 near ARMS2 displayed a genome-wide significant association in the meta-analysis of discovery and replication result (hazard ratio [HR]meta, 3.63; Pmeta = 5.76 × 10-9). Among previously reported AMD susceptibility loci, we additionally identified CFH rs800292 (HR, 0.39, P = 2.55 × 10-4), COL4A3 rs4276018 (HR, 0.26, P = 1.56 × 10-3), and B3GALTL rs9564692 (HR, 0.56, P = 8.30 × 10-3) as susceptibility loci for MNV development in CSC. The functional enrichment analysis revealed significant enrichment of 8 pathways (GO:0051561, GO:0036444, GO:0008282, GO:1990246, GO:0015272, GO:0030955, GO:0031420, and GO:0005242) related to ion transport. CONCLUSIONS: ARMS2, CFH, COL4A3, and B3GALTL were identified as susceptibility genes for MNV development in CSC. These 4 genes are known as susceptibility genes for AMD, whereas COL4A3 and B3GALTL were previously reported to be polypoidal choroidal vasculopathy (PCV)-specific susceptibility genes. Our findings revealed the shared genetic susceptibility between PCV and MNV secondary to CSC.

Improving Intramolecular Hopping Charge Transport via Periodical Segmentation of π-Conjugation in a Molecule.

The development of several-nanometer-scale π-conjugated systems for efficient intramolecular hopping charge transport remains a significant challenge. To construct localized electronic structures at the same energy in a molecule, a series of oligothiophenes, with lengths up to 10 nm and periodically twisted structures, was synthesized. Single-molecule conductance measurements of the twisted molecules revealed resistances lower than those of planar oligothiophenes. This study provides a rational molecular design to improve the intramolecular hopping charge transport in materials.

Unexpected cause of vemurafenib-induced nephrotoxicity: ferrochelatase.

Among v-raf murine sarcoma viral oncogene homolog B1 inhibitors, vemurafenib causes a higher incidence of nephrotoxicity. Bai et al. reported that vemurafenib-induced nephrotoxicity is not directly caused by viral oncogene homolog B1 inhibition but is partly caused by ferrochelatase inhibition in renal tubular epithelial cells. Because several other protein kinase inhibitors are also known to cause ferrochelatase inhibition, further studies are needed to elucidate the role of ferrochelatase in renal function and injury.

Single-Molecule Conductance of a π-Hybridized Tripodal Anchor while Maintaining Electronic Communication.

Direct hybridization between the π-orbital of a conjugated molecule and metal electrodes is recognized as a new anchoring strategy to enhance the electrical conductance of single-molecule junctions. The anchor is expected to maintain direct hybridization between the conjugated molecule and the metal electrodes, and control the orientation of the molecule against the metal electrodes. However, fulfilling both requirements is difficult because multipodal anchors aiming at a robust contact with the electrodes often break the π-conjugation, thereby resulting in an inefficient carrier transport. Herein, a new tripodal anchor framework-a 7,7-diphenyl-7H-benzo[6,7]indeno[1,2-b]thiophene (PBIT) derivative-is developed. In this framework, π-conjugation is maintained in the molecular junction, and the tripodal structure makes the molecule stand upright on the metal electrode. Molecular conductance is measured by the break junction technique. A vector-based classification and first-principles transport calculations determine the single-molecule conductance of the tripodal-anchoring structure. The conductance of the PBIT-based molecule is higher than that of the tripodal anchor having sp3 carbon atoms in the carrier transport pathway. These results demonstrate that extending the π-conjugation to the tripodal leg is an effective strategy for enhancing the conductivities of single-molecule junctions.

Interpretation of omics data analyses.

Omics studies attempt to extract meaningful messages from large-scale and high-dimensional data sets by treating the data sets as a whole. The concept of treating data sets as a whole is important in every step of the data-handling procedures: the pre-processing step of data records, the step of statistical analyses and machine learning, translation of the outputs into human natural perceptions, and acceptance of the messages with uncertainty. In the pre-processing, the method by which to control the data quality and batch effects are discussed. For the main analyses, the approaches are divided into two types and their basic concepts are discussed. The first type is the evaluation of many items individually, followed by interpretation of individual items in the context of multiple testing and combination. The second type is the extraction of fewer important aspects from the whole data records. The outputs of the main analyses are translated into natural languages with techniques, such as annotation and ontology. The other technique for making the outputs perceptible is visualization. At the end of this review, one of the most important issues in the interpretation of omics data analyses is discussed. Omics studies have a large amount of information in their data sets, and every approach reveals only a very restricted aspect of the whole data sets. The understandable messages from these studies have unavoidable uncertainty.

Genome-wide association study of individual differences of human lymphocyte profiles using large-scale cytometry data.

Human immune systems are very complex, and the basis for individual differences in immune phenotypes is largely unclear. One reason is that the phenotype of the immune system is so complex that it is very difficult to describe its features and quantify differences between samples. To identify the genetic factors that cause individual differences in whole lymphocyte profiles and their changes after vaccination without having to rely on biological assumptions, we performed a genome-wide association study (GWAS), using cytometry data. Here, we applied computational analysis to the cytometry data of 301 people before receiving an influenza vaccine, and 1, 7, and 90 days after the vaccination to extract the feature statistics of the lymphocyte profiles in a nonparametric and data-driven manner. We analyzed two types of cytometry data: measurements of six markers for B cell classification and seven markers for T cell classification. The coordinate values calculated by this method can be treated as feature statistics of the lymphocyte profile. Next, we examined the genetic basis of individual differences in human immune phenotypes with a GWAS for the feature statistics, and we newly identified seven significant and 36 suggestive single-nucleotide polymorphisms associated with the individual differences in lymphocyte profiles and their change after vaccination. This study provides a new workflow for performing combined analyses of cytometry data and other types of genomics data.

Intrinsic defect formation and the effect of transition metal doping on transport properties in a ductile thermoelectric material α-Ag2S: a first-principles study.

In this paper, the electronic structure and transport properties of a ductile thermoelectric material α-Ag2S are examined using first-principles calculations combined with the Boltzmann transport equation within a constant relaxation-time approximation. The use of the exchange-correlation functional SCAN + rVV10 successfully describes the geometric and electronic structure of α-Ag2S with a direct bandgap value of 0.99 eV, which is consistent with the previous experimental observations. Based on the calculations of the formation energy of typical intrinsic defects, it is found that intrinsic defect formation greatly affects the conductivity of the system where silver vacancy and interstitial silver act as p-type and n-type defects, respectively. Large Seebeck coefficients at room-temperature, of around -760 µV K-1 for n-type and 1400 µV K-1 for p-type, are realized. It is also suggested that the doping of fully filled d-block elements such as Cu and Au not only maintained the Seebeck coefficients at high values but also improved electrical conductivity by more than 1.4 times, leading to the improvement of the power factor by up to 40% compared to the non-doped sample at low carrier concentration.

Correction: Intrinsic defect formation and the effect of transition metal doping on transport properties in a ductile thermoelectric material α-Ag2S: a first-principles study.

Correction for 'Intrinsic defect formation and the effect of transition metal doping on transport properties in a ductile thermoelectric material α-Ag2S: a first-principles study' by Ho Ngoc Nam et al., Phys. Chem. Chem. Phys., 2021, DOI: .

Impact of heart failure severity on bone mineral density among older patients with heart failure.

The study aimed to identify factors related to bone mineral density (BMD) among older patients with heart failure (HF). A total of 70 consecutive patients with HF aged 65 years or older who were admitted to an acute hospital due to worsening condition were enrolled before discharge. BMD of the femoral neck was evaluated using the DEXA method. Physical function, as well as echocardiographic and laboratory findings including biomarker of HF severity were collected. Bivariate and multiple regression analyses were employed to determine the association between BMD and the clinical variables. Bivariate analysis determined that age, grip strength, walking speed, serum albumin, and N-terminal pro B-type natriuretic peptide (NT-proBNP) were significantly correlated with BMD (P < 0.01), whereas other clinical parameters were not. The multiple regression analysis identified NT-proBNP as an independent related factor for BMD after adjusting with confounding clinical variables. NT-proBNP was independently related to BMD among older patients with HF. Our results suggest the inclusion of bone fracture prevention strategies in disease management programs, especially for older patients with HF.

CFH and VIPR2 as susceptibility loci in choroidal thickness and pachychoroid disease central serous chorioretinopathy.

Central serous chorioretinopathy (CSC) is a common disease affecting younger people and may lead to vision loss. CSC shares phenotypic overlap with age-related macular degeneration (AMD). As recent studies have revealed a characteristic increase of choroidal thickness in CSC, we conducted a genome-wide association study on choroidal thickness in 3,418 individuals followed by TaqMan assays in 2,692 subjects, and we identified two susceptibility loci: CFH rs800292, an established AMD susceptibility polymorphism, and VIPR2 rs3793217 (P = 2.05 × 10-10 and 6.75 × 10-8, respectively). Case-control studies using patients with CSC confirmed associations between both polymorphisms and CSC (P = 5.27 × 10-5 and 5.14 × 10-5, respectively). The CFH rs800292 G allele is reportedly a risk allele for AMD, whereas the A allele conferred risk for thicker choroid and CSC development. This study not only shows that susceptibility genes for CSC could be discovered using choroidal thickness as a defining variable but also, deepens the understanding of differences between CSC and AMD pathophysiology.

Predictive impact of early mobilization on rehospitalization for elderly Japanese heart failure patients.

The aim of this study was to determine whether early mobilization was associated with rehospitalization among elderly heart failure patients. We measured the time from admission to mobilization and other clinical characteristics for 190 heart failure patients (mean age, 80.7 years). The primary outcome was heart failure rehospitalization. Kaplan-Meier survival curves were plotted and the hazard ratios for rehospitalization were determined using Cox proportional hazards regression models. During a median follow-up period of 750 days, 58 patients underwent rehospitalization. The time from admission to mobilization was significantly longer for these patients than for those who were not rehospitalized. Univariate and multivariate Cox proportional hazards analyses showed that the time from admission to mobilization was an independent predictor of rehospitalization, and receiver-operating characteristic analysis determined an optimal cutoff value of 3 days for differentiating the patients more likely to experience a subsequent cardiac event (sensitivity, 76%; specificity, 69%; area under the curve, 0.667). Kaplan-Meier survival curve analysis showed a significantly lower event rate in the ≤ 3-day group (p = 0.001, log-rank test). In conclusion, the time from admission to mobilization may be one of the strongest predictors of rehospitalization in elderly heart failure patients. Early mobilization within 3 days may be an initial target for the acute phase treatment of heart failure.