Identification of epistatic SNP combinations in rheumatoid arthritis using LAMPLINK and Japanese cohorts.

Genome-wide association studies have enabled the identification of important genetic factors in many trait studies. However, only a fraction of the heritability can be explained by known genetic factors, even in the most common diseases. Genetic loci combinations, or epistatic contributions expressed by combinations of single nucleotide polymorphisms (SNPs), have been argued to be one of the critical factors explaining some of the missing heritability, especially in oligogenic/polygenic diseases. Rheumatoid arthritis (RA) is a complex disease with more than 100 reported SNP associations, as well as various HLA haplotypes and amino acids; however, many associations between RA and inter-chromosomal SNP combinations are unknown. To discover novel associations of epistatic interactions with high odds ratios in RA, we applied the LAMPLINK method, a systematic enumerative procedure for identifying high-order SNP combinations, to a Japanese RA cohort (discovery cohort; 4024 patients with RA and 7731 controls). We validated the identified associations in a different Japanese cohort (validation cohort; 810 RA patients and 6303 controls). In this study, we identified 90 significant genetic associations in the discovery cohort. Among these, 74 (82.2%) associations were replicated in the validation cohort, and eight combinations were inter-chromosomal, all of which comprised rs7765379 or rs35265698 located in the HLA region. These two SNPs exhibited strong correlations with valine at amino acid position 11 in HLA-DRB1 (HLA-DRB1-11-Val). Finally, we discovered that rs9624 showed an association with RA through an epistatic interaction with HLA-DRB1-11-Val. Overall, LAMPLINK showed high reliability for identifying epistatic genetic contributions hidden in complex traits.

Comprehensive HLA Typing from a Current Allele Database Using Next-Generation Sequencing Data.

HLA allele information is essential for a variety of medical applications, such as genomic studies of multifactorial diseases, including immune system and inflammation-related disorders, and donor selection in organ transplantation and regenerative medicine. To obtain this information, an accurate HLA typing method that is applicable for any allele registered in HLA allele databases is needed. Here we describe a method-called HLA-HD-for determining alleles from a current HLA database using next-generation sequencing (NGS) results.

Optical fiber chemical sensing of anionic surfactants using a microfluidic polymer chip with embedded ion-selective fluorescence optode.

This study introduces a novel microfluidic polymer chip system that employs an embedded anionic surfactant (AS) ion-selective fluorescence optode (AS fluorescence optode) as a detector for measuring AS. The AS fluorescent optode comprises a lactone form of rhodamine B (L-RB) embedded in 2-nitrophenyl octyl ether plasticized poly (vinyl chloride) membrane. The AS fluorescence optode demonstrated a linear correlation between fluorescence intensity peak heights and AS concentrations within the range of less than 20 µM under optimal flow conditions. The limit of detection for AS was approximately 0.06 µM. The microfluidic system was utilized to measure AS levels in environmental samples, such as river water and tap water.

[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.

Material Separation from Polyester/Cotton Blended Fabrics Using Hydrothermal Treatment.

The production of textile products is increasing annually, and most of them are disposed of after use without recycling. One of the reasons for the low recycling percentage of discarded textile products is the difficulty of recycling as a single material as these products are produced from a combination of two or more materials. Therefore, a technology to separate materials is necessary to improve the recycling percentage of textile products and to build a sustainable recycling industry. The aim of this study was to separate the most common combination of materials, such as cotton/polyester, in an environmentally friendly technique using hydrothermal treatment with only water. Herein, the optimal treatment conditions for blended fabrics in a high-pressure reactor were studied. Moreover, cotton could be separated by treating the fabrics at 220 to 230 °C for 10 min while maintaining the shape of the fabrics. Additionally, polyester showed a melting point, confirming that polyester could be separated without decomposition into monomers, unlike common chemical recycling. The strength of the separated cotton and the molecular weight of the polyester were evaluated, and a kinetic analysis of the changes due to the treatment was conducted. The activation energy obtained from the Arrhenius plot was 111.8 kJ/mol for PET, which was smaller than 142.6 kJ/mol for cotton. This indicates that the decrease in the molecular weight of PET is more likely to occur than the change in the strength of cotton, suggesting the possibility of separating the materials from the kinetic analysis.

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.

Identification and verification of communicating accessory bile duct associated with a biliary circuit by modified and dynamic intraoperative cholangiography during laparoscopic cholecystectomy.

Communicating accessory bile duct (CABD) is a rare anatomical anomaly of the bile duct and forms a biliary circuit. It is difficult to identify during laparoscopic cholecystectomy (LC) without the use of intraoperative cholangiography (IOC). A modified IOC, in which tube insertion was performed through the infundibulum of the gallbladder, was evaluated dynamically. This procedure allowed us to accurately identify and verify the presence of CABD, a biliary circuit, and the short cystic duct. The short cystic duct could be separated safely without damaging the biliary circuit. Modified and dynamic IOC is recommended for identifying and verifying the presence of CABD during LC.

Delving into gene-set multiplex networks facilitated by a k-nearest neighbor-based measure of similarity.

Gene sets are functional units for living cells. Previously, limited studies investigated the complex relations among gene sets, but documents about their altering patterns across biological conditions still need to be prepared. In this study, we adopted and modified a classical k-nearest neighbor-based association function to detect inter-gene-set similarities. Based on this method, we built multiplex networks of gene sets for the first time; these networks contain layers of gene sets corresponding to different populations of cells. The context-based multiplex networks can capture meaningful biological variation and have considerable differences from knowledge-based networks of gene sets built on Jaccard similarity, as demonstrated in this study. Furthermore, at the scale of individual gene sets, the structural coefficients of gene sets (multiplex PageRank centrality, clustering coefficient, and participation coefficient) disclose the diversity of gene sets from the perspective of structural properties and make it easier to identify unique gene sets. In gene set enrichment analysis (GSEA), each gene set is treated independently, and its contextual and relational attributes are ignored. The structural coefficients of gene sets can supplement GSEA with information about the overall picture of gene sets, promoting the constructive reorganization of the enriched terms and helping researchers better prioritize and select gene sets.

Hematopoietic cell-derived IL-15 supports NK cell development in scattered and clustered localization within the bone marrow.

Natural killer (NK) cells are innate immune cells critical for protective immune responses against infection and cancer. Although NK cells differentiate in the bone marrow (BM) in an interleukin-15 (IL-15)-dependent manner, the cellular source of IL-15 remains elusive. Using NK cell reporter mice, we show that NK cells are localized in the BM in scattered and clustered manners. NK cell clusters overlap with monocyte and dendritic cell accumulations, whereas scattered NK cells require CXCR4 signaling. Using cell-specific IL-15-deficient mice, we show that hematopoietic cells, but not stromal cells, support NK cell development in the BM through IL-15. In particular, IL-15 produced by monocytes and dendritic cells appears to contribute to NK cell development. These results demonstrate that hematopoietic cells are the IL-15 niche for NK cell development in the BM and that BM NK cells are present in scattered and clustered compartments by different mechanisms, suggesting their distinct functions in the immune response.

Reservoir computing with the electrochemical formation and reduction of gold oxide in aqueous solutions with a three-electrode electrochemical setup.

Supervised classification of handwritten digits via physical reservoir computing (PRC) using electrochemistry with a three-electrode electrochemical setup was demonstrated. Short-term memory required for the PRC was realized for 3 bit pulse patterns by adjusting the formation/reduction ratio of gold oxides, showing a wide potential of electrochemistry as resources of PR devices.

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.

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.

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.

Predictors of in-hospital mortality in elderly patients with heart failure treated with tolvaptan.

Objectives: We conducted an analysis of first-time tolvaptan users (≥80 years old) to determine the factors associated with the prognosis of elderly patients with heart failure. Methods: We retrospectively analyzed 66 consecutive patients with worsening heart failure (aged ≥80 years) who were admitted to Fujita Health University Bantane Hospital from 2011 to 2016 and treated with tolvaptan. Differences between the in-hospital death and survival groups were evaluated. Multivariate logistic regression analysis was also performed to identify the risk factors for mortality. Results: Sixty-six patients were included, and 26 patients died during the index hospitalization. The patients who died had a significantly higher prevalence of ischemic heart disease; a higher heart rate; higher levels of plasma C-reactive protein, blood urea nitrogen (BUN), and creatinine; a lower serum albumin level; and a lower estimated glomerular filtration rate than surviving patients. The proportion of patients requiring early initiation of tolvaptan treatment (within 3 days of admission) was significantly higher in surviving patients. On the basis of multivariate logistic regression analysis, although a high heart rate and high BUN levels were independent factors for in-hospital prognosis, they were not significantly associated with the early use of tolvaptan (≤3 days vs. ≥4 days; odds ratio=0.39; 95% confidence interval=0.07-2.21; p=0.29). Conclusions: This study revealed that a higher heart rate and higher BUN levels were independent factors for in-hospital prognosis in elderly patients who received tolvaptan and that early tolvaptan use may not always be effective in elderly patients.

Robot-assisted total remnant gastrectomy for interposed jejunal pouch dysfunction 25 years after proximal gastrectomy for gastric cancer: A case report.

Proximal gastrectomy (PG) in combination with jejunal pouch interposition is a technique aimed at improving the postoperative dietary outcomes; however, some cases are reported to require surgical intervention owing to difficulty of food intake caused by pouch dysfunction. Herein, we present a case of robot-assisted surgery for interposed jejunal pouch (IJP) dysfunction in a 79-year-old male, occurring 25 years after the initial PG for gastric cancer. The patient had chronic anorexia for 2 years and was treated with medications and dietary guidance; however, 3 months prior to admission his quality of life had reduced, owing to worsening symptoms. The patient was diagnosed with pouch dysfunction due to extremely dilated IJP identified using computed tomography and underwent robot-assisted total remnant gastrectomy (RATRG) with IJP resection. After an uneventful course of intraoperative and postoperative treatment, he was discharged with sufficient food intake on postoperative day 9. RATRG can, thus, be considered in patients with IJP dysfunction after PG.

Atomistic simulation model on a diffusive timescale based on the extension of the cluster-activation method to continuous space.

Recently the phase-field crystal method has attracted considerable attention because it can simulate the atomic behavior of a system on a diffusive timescale. In this study an atomistic simulation model is proposed, which is an extension of the cluster-activation method (CAM) from discrete to continuous space. This approach, called the continuous CAM, can simulate various physical phenomena of atomistic systems on diffusive timescales and employs well-defined atomistic properties, such as interatomic interaction energies, as the main input parameters. The versatility of the continuous CAM was investigated by performing simulations of crystal growth in an undercooled melt, homogeneous nucleation during solidification, and formation of grain boundaries in pure metal.

Navigation by modified and dynamic intraoperative cholangiography during laparoscopic subtotal cholecystectomy for difficult gallbladder.

We used modified and dynamic intraoperative cholangiography (IOC) navigation during laparoscopic subtotal cholecystectomy for difficult gallbladders. We have defined an IOC that does not open the cystic duct as a modified IOC. Modified IOC methods include the percutaneous transhepatic gallbladder drainage (PTGBD) tube method, the infundibulum puncture method, and the infundibulum cannulation method. Case 1 was chronic cholecystitis after PTGBD for acute cholecystitis with pericholecystic abscess. In this case, modified IOC was performed via PTGBD, and biliary anatomy and incarcerated stone were confirmed. Case 2 was chronic cholecystitis after endoscopic sphincterotomy for cholecystocholedocholithiasis. In this case, modified IOC was performed via gallbladder puncture needle, and biliary anatomy and incision line were confirmed. The target point on the laparoscopic image was determined by moving the tip of the grasping forceps under modified IOC, which we call modified and dynamic IOC. We conclude that the navigation by the modified and dynamic IOC via PTGBD tube or puncture needle is useful to identify biliary anatomy, incarcerated gallbladder stone, and safe incision line during laparoscopic subtotal cholecystectomy .

Emergency transileocolic vein obliteration for life-threatening bleeding from gastric varices.

We report a case of life-threatening bleeding from gastric varices in a patient with alcoholic cirrhosis, which was treated by emergency transileocolic vein obliteration (TIO). A 46-year-old male with a massive hematemesis was transported to our hospital by ambulance. Contrast-enhanced computed tomography demonstrated large gastric varices. Temporary hemostasis using balloon tamponade was attempted, however, bleeding could not be controlled, and his vital signs were unstable despite massive blood transfusions. First, endoscopic treatment was attempted, but the visual field could not be secured due to massive bleeding. Therefore, emergency TIO under general anesthesia was attempted. After laparotomy, 5 Fr. sheath was inserted into the ileocolic vein. Posterior and left gastric veins, which were the blood supply routes of gastric varices, were identified and embolized using microcoils and a 50% glucose solution. Hemostasis was achieved and vital signs recovered. Three days after TIO, transjugular retrograde obliteration was attempted successfully to embolize the residual gastric varices. After the procedures, his condition improved. We conclude that emergency TIO is a useful rescue option for life-threatening bleeding from gastric varices if endoscopic treatment or balloon tamponade is ineffective.

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.

Design and implementation of a hybrid cloud system for large-scale human genomic research.

In the field of genomic medical research, the amount of large-scale information continues to increase due to advances in measurement technologies, such as high-performance sequencing and spatial omics, as well as the progress made in genomic cohort studies involving more than one million individuals. Therefore, researchers require more computational resources to analyze this information. Here, we introduce a hybrid cloud system consisting of an on-premise supercomputer, science cloud, and public cloud at the Kyoto University Center for Genomic Medicine in Japan as a solution. This system can flexibly handle various heterogeneous computational resource-demanding bioinformatics tools while scaling the computational capacity. In the hybrid cloud system, we demonstrate the way to properly perform joint genotyping of whole-genome sequencing data for a large population of 11,238, which can be a bottleneck in sequencing data analysis. This system can be one of the reference implementations when dealing with large amounts of genomic medical data in research centers and organizations.