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Realizing efficient long-distance intramolecular charge transport based on a hopping mechanism is a key challenge in molecular electronics. In hopping transport, a smaller reorganization energy (λ) and energy difference between hopping sites (ΔEhs) should lead to a smaller activation energy and faster charge transfer. However, the development of π-extended molecules that meet these requirements is challenging. In this study, we successfully synthesized several nanometer-scale π-extended molecules composed of a fused π-conjugated unit as a hopping site for reducing λ. Conformational twists between fused units effectively localize π-conjugation in each unit, contributing to reducing ΔEhs. The expected electronic structures of the oligomers were confirmed using spectroscopic and electrochemical measurements. Single-molecule conductance measurements exhibited higher conductance and lower activation energy than those of nonfused oligothiophenes. First-principles calculations indicated that smaller λ and ΔEhsvalues explain the high conductance. These results highlight the efficiency of the proposed molecular design for effective intramolecular hopping transport.

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 HLAhaplotypes 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.

Graphical abstract: Photography of the microfluidic polymer chip system for the determination of anionic surfactants.

This intervention describes the installation art piece, named 107 m3Pavilion, inspired to reveal the 'difference' between the breath a human's CO2emission versus a tree's absorption. The disparity in the extent of breath creates imbalance.

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.

Herein we report the synthesis of a circularly arranged sextuple triptycene gear molecule, hexakis(10-dodecyloxy-9-triptycyl)ethynylbenzene, via the trimerization of the corresponding triyne with a cobalt catalyst. The six triptycene gears are closely engaged with each other as confirmed by single crystal X-ray structure analysis, and their motion in solution was established by NMR spectroscopy. Notably, when one bulky RuCp* complex was attached to one triptycene gear, the whole movement of the six gears was highly restricted via their mechanical engagement. Development of such a multigear molecule would provide a structural basis for molecular motion transmission systems with a switching function.

Both symmetrical and unsymmetrical cyclophanes containing disilane units, tetrasila[2.2]cyclophanes 1–9, were synthesized. The synand anticonformations and the kinetics of inversion between two anti-isomers were investigated by X-ray diffraction and variable-temperature NMR analysis, respectively. The flipping motion of two aromatic rings was affected by the bulkiness of the aromatic moiety (1vs 6), the phase (solid vs solution), and the inclusion by host molecules (1vs 1⊂[Ag2L]2+). The photophysical, electrochemical, and structural properties of the compounds were thoroughly investigated. Unsymmetrical tetrasila[2.2]cyclophanes 5–8displayed blue–green emission arising from intramolecular charge transfer. Compound 6emitted a brilliant green light in the solid state under 365 nm irradiation and showed a higher fluorescence quantum yield in the solid state (Φ = 0.49) than in solution (Φ = 0.05). We also obtained planar chiral tetrasila[2.2]cyclophane 9, which showed interesting chiroptical properties, such as a circularly polarized luminescence (CPL) with a dissymmetry factor of |glum| = ca. 2 × 10–3at 500 nm. Moreover, an organic green light-emitting diode that showed a maximum external quantum efficiency (ηext) of ca. 0.4% was fabricated by doping 4,4′-bis(2,2′-diphenylvinyl)-1,1′-biphenyl with 6.

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.

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.

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.

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.

A flow-injection analysis (FIA) method for assaying an anionic surfactant (AS) using AS optode detector was demonstrated. The optode membrane consists of 2-nitrophenyl octyl ether as a plasticizer, lactone form rhodamine B (L-RB) and poly(vinyl chloride). The linear response concentration range of the AS optode to AS was 20 - 100 μmol dm-3 in the FIA system. The sampling rate for an AS ion (40 μmol dm-3 sodium dodecylbenzenesulfonate) in the proposed FIA system was ca.5 samples h-1. The AS level in commercially available laundry detergents by the proposed FIA system was determined.

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.

Purpose: The population of obese patients is increasing in general and also at hemodialysis initiation. For successful cannulation of arteriovenous fistula, the National Kidney Foundation-Dialysis Outcome Quality Initiative guidelines suggest that the required maturation parameters are at a depth of <6 mm. There are several reports describing two-stage superficialization of arteriovenous fistulas in obese cases. Therefore, we investigated the utility and complications of one-stage superficialization of radio-cephalic fistula.Methods: From January 2011 to March 2017, we simultaneously performed forearm radio-cephalic fistula creation and superficialization of the cephalic vein for 10 patients having obesity (body mass index > 30 kg/m2) and deep cephalic vein (>6 mm). Initially, an arteriovenous anastomosis was created at an appropriate site. Subsequently, an 8–10 cm longitudinal skin incision was made along the lateral aspect of the forearm cephalic vein. The cephalic vein was identified and exposed. The cephalic vein was repositioned superficially.Results: The mean age of the patients was 53 years (range: 40–72 years) and the mean body mass index was 40.2 kg/m2(33.1–59.7 kg/m2). The cause of renal failure in eight patients was diabetic nephropathy, and in two patients, it was unknown. After the procedure, vein depth became 3.4 mm (1.9–4.6 mm) from 8.2 mm (6.0–13.4 mm). All patients who initiated dialysis underwent successful two-needle cannulation. Primary patency rate was 71.4% at 12 months (two patients underwent percutaneous transluminal angioplasty) and secondary patency rate was 100%. There was one procedure-related complication and delayed wound healing, which was improved by observation without antibiotics.Conclusion: This small series of patients indicates that one-stage superficialization of radio-cephalic fistula is a safe and effective option to start hemodialysis in obese subjects.

To assess the use of plasma free amino acids (PFAAs) as biomarkers for metabolic disorders, it is essential to identify genetic factors that influence PFAA concentrations. PFAA concentrations were absolutely quantified by liquid chromatography–mass spectrometry using plasma samples from 1338 Japanese individuals, and genome-wide quantitative trait locus (QTL) analysis was performed for the concentrations of 21 PFAAs. We next conducted a conditional QTL analysis using the concentration of each PFAA adjusted by the other 20 PFAAs as covariates to elucidate genetic determinants that influence PFAA concentrations. We identified eight genes that showed a significant association with PFAA concentrations, of which two, SLC7A2and PKD1L2, were identified. SLC7A2was associated with the plasma levels of arginine and ornithine, and PKD1L2with the level of glycine. The significant associations of these two genes were revealed in the conditional QTL analysis, but a significant association between serine and the CPS1gene disappeared when glycine was used as a covariate. We demonstrated that conditional QTL analysis is useful for determining the metabolic pathways predominantly used for PFAA metabolism. Our findings will help elucidate the physiological roles of genetic components that control the metabolism of amino acids.

Tubular injury and interstitial fibrosis are the hallmarks of chronic kidney disease. While recent studies have verified that proximal tubular injury triggers interstitial fibrosis, the impact of fibrosis on tubular injury and regeneration remains poorly understood. We generated a novel mouse model expressing diphtheria toxin receptor on renal fibroblasts to allow for the selective disruption of renal fibroblast function. Administration of diphtheria toxin induced upregulation of the tubular injury marker Ngal and caused tubular proliferation in healthy kidneys, whereas administration of diphtheria toxin attenuated tubular regeneration in fibrotic kidneys. Microarray analysis revealed down-regulation of the retinol biosynthesis pathway in diphtheria toxin-treated kidneys. Healthy proximal tubules expressed retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in retinoic acid biosynthesis. After injury, proximal tubules lost RALDH2 expression, whereas renal fibroblasts acquired strong expression of RALDH2 during the transition to myofibroblasts in several models of kidney injury. The retinoic acid receptor (RAR) RARγ was expressed in proximal tubules both with and without injury, and αB-crystallin, the product of an RAR target gene, was strongly expressed in proximal tubules after injury. Furthermore, BMS493, an inverse agonist of RARs, significantly attenuated tubular proliferation in vitro. In human biopsy tissue from patients with IgA nephropathy, detection of RALDH2 in the interstitium correlated with older age and lower kidney function. These results suggest a role of retinoic acid signaling and cross-talk between fibroblasts and tubular epithelial cells during tubular injury and regeneration, and may suggest a beneficial effect of fibrosis in the early response to injury.

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.

Previous studies have reported genome-wide mutation profile analyses in ovarian clear cell carcinomas (OCCCs). This study aims to identify specific novel molecular alterations by combined analyses of somatic mutation and copy number variation. We performed whole exome sequencing of 39 OCCC samples with 16 matching blood tissue samples. Four hundred twenty-six genes had recurrent somatic mutations. Among the 39 samples, ARID1A(62%) and PIK3CA(51%) were frequently mutated, as were genes such as KRAS(10%), PPP2R1A(10%), and PTEN(5%), that have been reported in previous OCCC studies. We also detected mutations in MLL3(15%), ARID1B(10%), and PIK3R1(8%), which are associations not previously reported. Gene interaction analysis and functional assessment revealed that mutated genes were clustered into groups pertaining to chromatin remodeling, cell proliferation, DNA repair and cell cycle checkpointing, and cytoskeletal organization. Copy number variation analysis identified frequent amplification in chr8q (64%), chr20q (54%), and chr17q (46%) loci as well as deletion in chr19p (41%), chr13q (28%), chr9q (21%), and chr18q (21%) loci. Integration of the analyses uncovered that frequently mutated or amplified/deleted genes were involved in the KRAS/phosphatidylinositol 3-kinase (82%) and MYC/retinoblastoma (75%) pathways as well as the critical chromatin remodeling complex switch/sucrose nonfermentable (85%). The individual and integrated analyses contribute details about the OCCC genomic landscape, which could lead to enhanced diagnostics and therapeutic options.

Recent evidence suggests that a substantial portion of complex disease risk alleles modify gene expression in a cell-specific manner. To identify candidate causal genes and biological pathways of immune-related complex diseases, we conducted expression quantitative trait loci (eQTL) analysis on five subsets of immune cells (CD4+T cells, CD8+T cells, B cells, natural killer (NK) cells and monocytes) and unfractionated peripheral blood from 105 healthy Japanese volunteers. We developed a three-step analytical pipeline comprising (i) prediction of individual gene expression using our eQTL database and public epigenomic data, (ii) gene-level association analysis and (iii) prediction of cell-specific pathway activity by integrating the direction of eQTL effects. By applying this pipeline to rheumatoid arthritis data sets, we identified candidate causal genes and a cytokine pathway (upregulation of tumor necrosis factor (TNF) in CD4+T cells). Our approach is an efficient way to characterize the polygenic contributions and potential biological mechanisms of complex diseases.

An understanding of the morphology of growing dendrites in alloys is needed for an analysis of microsegregation, as well as an estimation of the permeability for macroscopic fluid dynamics. Quantitative phase-field simulations were used to study the growth process of three-dimensional (3D) equiaxed dendrites in an Al-1.0 mass%Cu alloy during continuous cooling. The dendrites were analysed using an interface shape distribution (ISD) map, which provides the probability of the local interface having a morphology with a given curvedness (C) and shape factor (S). Morphological changes in the microstructure can be measured sensitively from the change in the average value of the curvedness 〈C〉 relative to the solid volume fraction. The ISD map continued to change over time during continuous cooling, implying that it was not time-invariant. Furthermore, when microstructural changes occurred, similarities between the ISD maps were observed, independent of the cooling rates and system sizes.

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- β1 (TGF-β1). 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-β1 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.

Whole-genome and -exome resequencing using next-generation sequencers is a powerful approach for identifying genomic variations that are associated with diseases. However, systematic strategies for prioritizing causative variants from many candidates to explain the disease phenotype are still far from being established, because the population-specific frequency spectrum of genetic variation has not been characterized. Here, we have collected exomic genetic variation from 1208 Japanese individuals through a collaborative effort, and aggregated the data into a prevailing catalog. In total, we identified 156 622 previously unreported variants. The allele frequencies for the majority (88.8%) were lower than 0.5% in allele frequency and predicted to be functionally deleterious. In addition, we have constructed a Japanese-specific major allele reference genome by which the number of unique mapping of the short reads in our data has increased 0.045% on average. Our results illustrate the importance of constructing an ethnicity-specific reference genome for identifying rare variants. All the collected data were centralized to a newly developed database to serve as useful resources for exploring pathogenic variations. Public access to the database is available at http://www.genome.med.kyoto-u.ac.jp/SnpDB/.

Supplemental Digital Content is available in the text

Although susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA. We performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed. Rs6904716 in LEMD2of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10−8), followed by rs6986423 in CSMD1(p = 2.4 × 10−6) and rs17727339 in FCRL3(p = 1.4 × 10−5). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations. Many of the susceptibility loci were shared between ACPA-positive and -negative RA.

Although central blood pressure (BP) is considered to be more closely associated with large arterial remodeling and cardiovascular outcomes than brachial BP, few studies have investigated these associations with changes in small arteries. As morphological changes in retinal vessels might be associated with cardiovascular outcomes, we conducted a cross-sectional study to investigate the association of central BP with retinal vessel caliber.

To examine relationships among gastroesophageal reflux disease (GERD) symptoms, dietary behaviors, and sleep duration in the general population.

An Integrative Study of the Genetic, Social and Environmental Determinants of Chronic Kidney Disease Characterized by Tubulointerstitial Damages in the North Central Region of Sri Lanka: Shanika NANAYAKKARA, et al. Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University— Previous investigations on chronic kidney disease of unknown etiology characterized by tubulointerstitial damages (CKDu) in the North Central Region (NCR) of Sri Lanka have supported the involvement of social, environmental and genetic factors in its pathogenesis. Methods: We conducted a social‐environmental‐ and‐genetic epidemiology study on a male population in NCR to investigate the genetic and environmental contributors. We recruited 311 case‐series patients and 504 control candidates. Of the 504 control candidates, 218 (43%) were eliminated because of the presence of hypertension, proteinuria, high HbA1c, high serum creatinine or high alpha‐1 microglobulin in urine. None of 18 metals measured (μg/l) in urine, including Cd, As and Pb, showed significantly higher concentrations in cases compared with controls. As speciation results showed that 75.80% of total urinary As was in the form of arsenobetaine, which is non‐toxic to humans. None of the metal concentrations in drinking water samples exceeded guideline values. A genome‐wide association study (GWAS) was conducted to determine the genetic contributors. The GWAS yielded a genome‐wide significant association with CKDu for a single nucleotide polymorphism (SNP; rs6066043; p=5.23 ~ 10.9 in quantitative trait locus analysis; p=3.73 ~ 10.8 in dichotomous analysis) in SLC13A3 (sodium‐dependent dicarboxylate transporter member 3). The population attributable fraction and odds ratio for this SNP were 50% and 2.13. Genetic susceptibility was identified as the major risk factor for CKDu. However, 43% of the apparently healthy male population suffers from non‐communicable diseases, suggesting their possible influence on CKDu progression.

Peritoneal dialysis (PD) solution contains high concentrations of glucose and glucose degradation products (GDPs). One of several GDPs—3,4-dideoxyglucosone-3-ene (3,4-DGE)—was recently identified as the most reactive and toxic GDP in PD fluids. In vitro, 3,4-DGE has been shown to induce mesothelial cell damage; however, its role in peritoneal fibrosis in vivoremains unclear. In the present study, we intraperitoneally administered chlorhexidine gluconate (CG) for mild peritoneal injury, and we then injected 3,4-DGE [38μmol/L (low concentration) or 145μmol/L (high concentration)] 5 times weekly for 4 weeks. Significant thickening of the parietal peritoneal membrane was observed only when treatment with low or high concentrations of 3,4-DGE occurred after CG administration, but not when either CG or 3,4-DGE alone was given. The combination of CG and 3,4-DGE also caused upregulation of messenger RNA expression of transforming growth factor β1, connective tissue growth factor, fibronectin, collagen type 1 α1 chain, alpha smooth muscle actin (α–SMA), vascular endothelial growth factor 164, NADPH oxidase 1 and 4, p22phox, p47phox, and gp91phox in peritoneal tissue. Treatment with CG alone was sufficient to cause significant F4/80-positive macrophage infiltration, appearance of α–SMA-positive cells, and vessel formation in the submesothelial layer. Addition of 3,4-DGE markedly enhanced those changes and induced apoptosis, mainly in leukocytes. The concentration of 3,4-DGE in the abdominal cavity declined more rapidly in CG-treated mice than in PBS-treated mice. Peritoneal membrane permeability determined by peritoneal equilibration test showed high transport conditions in peritoneum treated with both CG and 3,4-DGE. These results indicate that, when mild peritoneal damage is already present, 3,4-DGE causes peritoneal thickening and fibrosis, resulting in deterioration of peritoneal membrane function.

We have observed and analyzed a universal temperature crossover behavior of electrical conductance in a single oligothiophene molecular wire. The crossover between the Arrhenius-type temperature dependence at high temperature and the temperature-invariant behavior at low temperature is found at a critical molecular wire length of 5.6 nm, where we found a change from the exponential length dependence to the length-invariant behavior. We have derived a scaling function analysis for the origin of the crossover behavior. After assuring that the analysis fits the explanation of the Keldysh Green’s function calculation for the temperature dependence, we have applied it to our experimental results and found successfully that our scaling function gives a universal description of the temperature dependence for all over the temperature range.

Background: Accidental needlestick injury rate among healthcare workers in Hawassa is extremely high. Epidemiological findings proved the infectious potential of this injury contaminated with a Human Immunodeficiency Virus (HIV)-infected patient's blood.Objective: This study aimed at estimating the risk of HIV transmission from patients to healthcare workers in Hawassa City, Ethiopia.Method: A probabilistic risk model was employed. Scenario-based assumptions were made for the values of parameters following a review of published reports between 2007 and 2010.Parameters: HIV prevalence, needlestick injury rate, exposure rate, sero-conversion rate, risk of HIV transmission and cumulative risk of HIV transmission.Finding: Generally, healthcare workers in Hawassa are considered to be at a relatively low (0.0035%) occupational risk of contracting HIV – less than 4 in 100,000 of healthcare workers in the town (1 in 28,751 workers a year). The 30 years' maximum cumulative risk estimate is approximately five healthcare workers per 1000 workers in the study area. Still, this small number should be considered a serious matter requiring post-exposure prophylaxis following exposure to unsafe medical practice leading to HIV infection.

Proper shielding: Encapsulated oligothiophenes for the investigation of single‐molecule conductance are described. UV/Vis/NIR measurements of the oxidized species show the absence of intermolecular interactions between the conjugated backbones. The conductance of a single‐molecule junction was measured by modified STM techniques (see picture), and the decay constant βwas determined to be 1.9 nm−1. SMU=source meter unit.

Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are generally considered multifactorial—that is, they involve both genetic and environmental factors. Technical advances in human genetics over the past 5 years have enabled the survey of the entire human genome for disease susceptibility genes and have contributed to a greater understanding of the molecular mechanisms underlying autoimmunity. Among the genetic predisposition factors identified to date, some variants have been found to be restricted to specific ethnic groups, which might reflect migration history and the natural selection that shaped genetic variation in these populations. Other genetic factors could also have exerted different magnitudes of risk for the disease among the different populations, which might be explained by their interactions with other genetic and environmental factors. These pieces of evidence suggest that substantial heterogeneity exists in the genetics underlying autoimmunity among different ethnic populations. This Review discusses the genetic heterogeneity in autoimmunity, with a focus on rheumatoid arthritis, between Asian and European populations. In addition to the most-studied and well-characterized gene HLA-DRB1, we will also describe examples of the gene–environment interactions between PADI4 and smoking, and the gene–gene interactions between PTPN22 and FCRL3.

OBJECTIVE: The SLC22A4 polymorphisms slc2F1 (rs2073838) and slc2F2 (rs3792876) are reported to be associated with rheumatoid arthritis (RA) in Japanese, but the associations have not been replicated. We assessed the RA susceptibility of slc2F1/F2 polymorphisms. METHODS: We conducted a metaanalysis for slc2F1/F2 polymorphisms to RA susceptibility, which included the replication study of an independent Japanese population consisting of 924 cases and 940 controls. A total of 9 studies (4 Japanese studies, 5 Caucasian studies) consisting of 8076 cases and 6837 controls were included in the metaanalysis. RESULTS: The replication study demonstrated significant associations in a Japanese population (OR 1.20, 95% CI 1.04–1.37, p = 0.0099, in the allelic mode; OR 1.29, 95% CI 1.08–1.55, p = 0.006, in the dominant mode; p = 0.011 in the trend mode). Significant ethnic diversities of allele frequencies of slc2F1/F2 polymorphisms were found (p = 8.6*10-8) between Caucasian and Japanese populations (0.07–0.08 and 0.30–0.32, respectively). The metaanalysis demonstrated significant associations for all studies (fixed-effect OR 1.11, 95% CI 1.05–1.18, p = 0.00084; random-effect OR 1.10, 95% CI 1.02–1.19, p = 0.017 in the allelic mode). Although subgroup analysis did not detect a significant association within Caucasian studies, significant associations were found within Japanese studies (fixed-effect and random-effect OR 1.16, 95% CI 1.07–1.25, p = 0.00012 in the allelic mode). CONCLUSION: The associations in Caucasian studies were not significant. Since the significantly low frequency of the risk allele made statistical power lower in Caucasians than in Japanese, whether significant relative risks existed in Caucasian populations was inconclusive. The significant relative risks in Japanese populations were confirmed.

Single-nucleotide polymorphisms (SNPs) are single base-pair alterations in the DNA sequence that represent a major source of genetic heterogeneity. Well-developed and sophisticated technologies exist to measure and analyze the presence of SNPs, and SNP genotyping is an important tool with which to investigate other genetic variants. SNP-based, large-scale, genome-wide association studies are detecting many polymorphisms that can be used to evaluate the risk of various common traits, including rheumatic diseases. This increased knowledge of genetic risk could potentially be used to refine medical care in rheumatology clinics in the near future.

Large studies on the genetics of common rheumatic diseases, such as rheumatoid arthritis and systemic lupus erythematosus, have identified multiple polymorphisms related to disease susceptibility, including peptidylarginine deiminase 4 (PADI4) and protein tyrosine phosphatase N22 (PTPN22). Some of the identified genes are associated with multiple autoimmune disorders, and some seem to have unique associations with particular disease entities. Although the molecules encoded by these genes have a primary role in the molecular pathways of autoimmunity, genetic variations and contribution to disease susceptibility seem to vary between ethnic groups. In this Review, we report the findings on genes associated with rheumatoid arthritis and focus on the differences in the frequency of polymorphisms between various ethnic groups.

Thrombin is a key factor in the stimulation of fibrin deposition, angiogenesis, proinflammatory processes, and proliferation of fibroblast-like cells. Abnormalities in these processes are primary features of rheumatoid arthritis (RA) in synovial tissues. Tissue destruction in joints causes the accumulation of large quantities of free hyaluronic acid (HA) in RA synovial fluid. The present study was conducted to investigate the effects of HA and several other glycosaminoglycans on antithrombin, a plasma inhibitor of thrombin. Various glycosaminoglycans, including HA, chondroitin sulfate, keratan sulfate, heparin, and heparan, were incubated with human antithrombin III in vitro. The residual activity of antithrombin was determined using a thrombin-specific chromogenic assay. HA concentrations ranging from 250 to 1000 μg/ml significantly blocked the ability of antithrombin to inhibit thrombin in the presence of Ca2+ or Fe3+, and chondroitin A, B and C also reduced this ability under the same conditions but to a lesser extent. Our study suggests that the high concentration of free HA in RA synovium may block antithrombin locally, thereby deregulating thrombin activity to drive the pathogenic process of RA under physiological conditions. The study also helps to explain why RA occurs and develops in joint tissue, because the inflamed RA synovium is uniquely rich in free HA along with extracellular matrix degeneration. Our findings are consistent with those of others regarding increased coagulation activity in RA synovium.

Inflammatory diseases encompass a variety of medical conditions. In this chapter, autoimmune diseases and allergic disorders will be our focus. The autoimmune diseases include organ-specific autoimmunities, such as type I diabetes mellitus and autoimmune thyroiditis (AITD), and organ non-specific disorders such as systemic lupus erythematosus (SLE). All of them seem to share aspects of aberrant immunologic tolerance toward self-antigens. Asthma and atopic diathesis are among the allergies. Crohn disease and SLE are relatively rare with a prevalence of 10–50 per 100,000, and rheumatoid arthritis (RA), psoriasis, AITD and asthma are commoner with a prevalence of 500 per 100,000 or much higher. The difference among ethnic groups is not prominent for rheumatoid arthritis, psoriasis, AITD or asthma, but Crohn disease and SLE affect some ethnic populations more than others. Although all of these disorders have some environmental component, asthma and atopy seem most affected by environmental factors, as is suggested by the significant increase in their incidence over the last several decades with changes in various environmental factors, especially in developed countries. Over the last 10 years, multiple linkage studies revealed many disease-linked loci throughout the genome with various consistencies. As implicated by some pathophysiological studies of inflammatory immune system related disorders, certain loci are involved in multiple disorders. In the following sections, reports on the identification of disease-associated genes or markers will be summarized for individual diseases (cytotoxic T lymphocyte-associated 4 (CTLA4), CARD15, DLG5, SLC22A4/A5, programmed cell death 1 (PDCD1), RUNX1, SLC9A3R1/NAT9, PADI4, ADAM33, DPP10, PHF11 and GPRA), followed by a discussion of the genes that have been implicated in multiple disorders.

Osteoarthritis (OA) is one of the most common diseases in the elderly. Although its pathophysiology is complex and its molecular basis remains to be determined, much evidence suggests that OA has strong genetic determinants. To search for susceptibility loci of OA, we selected seven candidate genes encoding cartilage‐specific collagens (type II, IX, X, and XI collagens) and performed association analysis for OA using single nucleotide polymorphisms (SNPs) in the coding region of these genes. Four hundred seventeen OA samples and 280 control samples were collected from the Japanese population, and 12 SNPs were genotyped. Our studies have identified two susceptibility loci of OA: COL2A1and COL9A3. An SNP in COL9A3showed significant association with knee OA (p= 0.002, odds ratio [OR] = 1.48). Haplotype analysis showed significant association between a specific haplotype of COL2A1and hip OA (p= 0.024; OR = 1.30). Further analysis of these two genes will shed light on the molecular mechanisms of OA.

A Correction to this paper has been published: https://doi.org/10.1038/s10038-020-00890-x

Renal dipeptidase (EC 3.4.13.19) activity in serum and urine from healthy volunteers (n= 20), patients with diabetes (n= 18) and patients with chronic renal failure (n= 5) was measured using glycyl-d-alanine as substrate. The assay was highly specific for the enzyme and was not affected by the various aminopeptidases present in serum and urine. No difference in serum renal dipeptidase activity was observed between the groups. The enzyme activity (U/L) in urine was higher than that in serum, irrespective of the group, suggesting the urine concentration was not affected by the serum concentration. The mean renal dipeptidase activities in urine were 2·56, 2·46 and 0·78 U/mol creatinine for healthy subjects, patients with diabetes and patients with chronic renal failure, respectively. The renal dipeptidase activity was significantly lower in the chronic renal failure group. The urinary excretion of dipeptidase (U/mmol creatinine) showed significant inverse correlations with that of β2-microglobulin, albumin and α1-microglobulin, and with serum concentrations of creatinine, β2-microglobulin and α1-microglobulin. We suggest that urine dipeptidase may be a useful marker of renal diseases.

Summary Lipocortin is a phospholipase inhibitory protein whose synthesis is induced in various cells by glucocorticoids. At least three species with molecular weights of 40,000, 30,000, and 15,000 are presently known. This protein mimics the anti-inflammatory action of glucocorticoidsin vitro as well asin vivo. The synthesis of the protein appears to be associated with the MHC genes.

Fluorescent-labeled phosphorothiolate DNA-RNA chimeric hammerhead ribozyme (thio-Rz) was synthesized. The ribozyme recognizes relatively conserved sequences in the functionally important region (V3 loop) of envelope protein of HIV-1. The thio-Rz as well as wild-type ribozyme cleaved RNA transcripts (414 base) of V3 region in a dose-dependent manner. After delivery into the cells, both wild-type and thio-Rz were able to be readily detected. The positive signals faded within 12 h in the former case, while they lasted 24 h in the latter case. The inhibitory effect by thio-Rz on cell fusion between envelope-expressing CHO cells and CD4+cells appeared to be time-dependent, and about 70% of inhibition was seen at 72 h. Possible applications of the ribozyme against HIV-1 infection were discussed.

In this communication, we demonstrate that d‐aspartate (d‐Asp) is synthesized in pheochromocytoma cells (PC12). To our knowledge this is the first report of biosynthesis of d‐Asp in mammalian cells. Synthesis of d‐Asp was demonstrated by its time‐dependent accumulation in the cell culture, and by the fact that this accumulation was proportional to the number of inoculated cells. d‐Asp in PC12 cells was identified by (i) co‐elution with authentic d‐Asp on two different HPLC columns, an octadesyl silica column and a Pirkle‐type chiral column, (ii) reversed elution order of d‐Asp and l‐Asp on another Pirkle‐type chiral column with an opposite configuration, and (iii) sensitivity to d‐Asp oxidase. In the cells the amount of d‐Asp was approx. 12–14% of total Asp and no other investigated d‐amino acid was detected. The amount of d‐Asp did not increase during the culture of mouse 3T3 fibroblasts and human neuroblastoma NB‐1 cells. Immunocytochemical staining with anti‐d‐Asp antiserum demonstrated that d‐Asp synthesized is present in the cytoplasm of the cells.

We describe the occurrence of d-aspartate oxidase activity and free d-aspartate and d-glutamate in several tissues of five fish species, carp (Cyprinus carpio), crucian carp (Carassius auratus langsdorfii), rainbow trout (Oncorhynchus mykiss), yellowtail (Seriola quinqueradiata) and sea bream (Pagrus major). N-methyl-d-aspartate was the best enzyme substrate, followed by d-aspartate and d-glutamate. The highest specific activity was observed in the liver, followed by the kidney and brain in the crucian carp and rainbow trout. In the other fishes, enzyme activities were similar in the liver and kidney and lower in the brain except the yellowtail. d-Aspartate (% of total) and d-glutamate (%) were detected with HPLC analysis in the tissues. With the exception of spleen of some species, d-glutamate concentration tended to be higher than those for d-aspartate, but d/(d+ l) ratios were higher for aspartate.

We investigated the usefulness of ribozymes in inhibiting the expression of human T-cell leukemia virus type I (HTLV-I) gene. Two hammerhead ribozymes that were against HTLV-Irex(RR) and tax(TR) mRNA were synthesized. Both ribozymes were sequence-specific in the in vitrocleavage analysis of run-off transcripts fromtax/rexcDNA. Intracellular activities of the ribozymes were studied in HTLV-I taxcDNA-transfected rat embryonic fibroblasts (Rat/Tax cells), which expressed the Tax but not Rex. Ribozymes were delivered into cells using anionic or cationic liposomes fused with hemagglutinating virus of Japan (HVJ). Cellular uptake of ribozymes complexed with HVJ-cationic liposomes was 15–20 times higher cellular uptake than naked ribozymes, and 4–5 times higher than that of ribozymes complexed with HVJ-anionic liposomes. HVJ-cationic liposomes promoted accumulation of ribozymes in cytoplasm and accelerated transport to the nucleus. Tax protein levels were decreased about 957 and were five times lower when the same amount of TR was introduced into the cells using HVJ-cationic, rather than HVJ-anionic liposomes. Inactive ribozyme and taxantisense oligodeoxynucleotides reduced Tax expression by about 207, whereas RR and taxsense oligodeoxynucleotides had no effect. These results suggest that the ribozymes' effect against taxmRNA was sequence-specific, and HVJ-cationic liposomes can be useful for intracellular introduction of ribozymes.