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Immunoglobulin A (IgA) is the most abundant isotype of antibodies, provides a first line of defense at mucosal surfaces against pathogens, and thereby contributes to mucosal homeostasis. IgA is generally considered as a non-inflammatory antibody because of its main function, neutralizing pathogenic virus or bacteria. Meanwhile, IgA can induce IgA-mediated diseases, such as IgA nephropathy (IgAN) and IgA vasculitis. IgAN is characterized by the deposition of IgA and complement C3, often with IgG and/or IgM, in the glomerular mesangial region, followed by mesangial cell proliferation and excessive synthesis of extracellular matrix in glomeruli. Almost half a century has passed since the first report of patients with IgAN; it remains debatable about the mechanism how IgA antibodies selectively bind to mesangial region—a hallmark of IgAN—and cause glomerular injuries in IgAN. Previous lectin- and mass-spectrometry-based analysis have revealed that IgAN patients showed elevated serum level of undergalactosylated IgA1 in O-linked glycans of its hinge region, called galactose-deficient IgA1 (Gd-IgA1). Thereafter, numerous studies have confirmed that the glomerular IgA from IgAN patients are enriched with Gd-IgA1; thus, the first hit of the current pathogenesis of IgAN has been considered to increase circulating levels of Gd-IgA1. Recent studies, however, demonstrated that this aberrant glycosylation alone is not sufficient to disease onset and progression, suggesting that several additional factors are required for the selective deposition of IgA in the mesangial region and induce nephritis. Herein, we discuss the current understanding of the characteristics of pathogenic IgA and its mechanism of inducing inflammation in IgAN.

Despite considerable advancements in medicine, the optimal treatment for chronic kidney disease (CKD), especially diabetic kidney disease (DKD), remains a major challenge. More patients with DKD succumb to death due to cardiovascular events than due to progression to end-stage renal disease (ESRD). Moreover, patients with DKD and ESRD have remarkably poor prognosis. Current studies have appreciated the contribution of inflammation and inflammatory mediators, such as tumor necrosis factor (TNF)-related biomarkers, on the development/progression of DKD. The present review focuses on molecular roles, serum concentrations of TNF receptors (TNFRs), and their association with increased albuminuria, eGFR decline, and all-cause mortality in diabetes. Experimental studies have suggested that DKD progression occurs through the TNFα–TNFR2 inflammatory pathway. Moreover, serum TNFR levels were positively associated with albuminuria and negatively associated with estimated glomerular filtration rate (eGFR), while circulating levels of TNFRs exhibited an independent effect on all-cause mortality and eGFR decline, including ESRD, even after adjusting for existing risk factors. However, their precise function has yet to be elucidated and requires further studies.

Knee osteoarthritis (KOA) is a leading cause of knee pain and disability due to irreversible cartilage degeneration. Previous studies have not identified modifiable risk factors for KOA. In this preliminary cross-sectional study, we aimed to test the following hypotheses: individuals with severe KOA would have a significantly lower quadriceps rate of force development (RFD) than individuals with early KOA, and the decrease in quadriceps RFD would be greater than the decrease in maximum quadriceps strength in individuals with severe KOA. The maximum isometric strength of the quadriceps was assessed in individuals with mild (Kellgren and Lawrence [K&L] grade 1–2) and severe KOA (K&L grade 3–4) using a handheld dynamometer. The RFD was analyzed at 200 ms from torque onset and normalized to the body mass and maximum voluntary isometric contraction torque. To test whether the quadriceps RFD was lowered and whether the lower in the quadriceps RFD was greater than the lower in maximum quadriceps strength in individuals with severe knee OA, the Mann–Whitney U-test and analysis of covariance were performed, respectively. The effect size (ES) based on Hedges’ g with a 95% confidence interval (CI) was calculated for the quadriceps RFD and maximum quadriceps strength. Sixty-six participants were analyzed. Individuals with severe KOA displayed significantly lower quadriceps RFD (p = 0.009), the lower being greater than the lower in maximum quadriceps strength (between-group difference, ES: 0.88, -1.07 vs. 0.06, -0.22). Our results suggest that a decreased quadriceps RFD is a modifiable risk factor for progressive KOA. Our finding could help in the early detection and prevention of severe KOA.

Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis, is one of the major causes of end-stage renal disease. Significant variances in epidemiology, clinical manifestation, timing of diagnosis, management and renal prognosis of IgAN have been reported worldwide. The incidence of IgAN is the most frequent in Asia, followed by Europe, and lower in Africa. Moreover, Asian patients show more frequent acute lesions in renal histology and present poorer renal outcomes compared with Caucasians. The comorbidities also show the difference between Asians and Caucasians. Although the frequency of gross hematuria with upper respiratory tract infection is not different, comorbidities with gastrointestinal diseases are reported to be higher in Europe. Recently, genetic studies for variant ethnic patients revealed widely ranging genetic risks in each ethnicity. A genetic risk score is most elevated in Asians, intermediate in Europeans and lowest in Africans, consistent with the disease prevalence of IgAN globally. Ethnic variance might be highly affected by the difference in genetic background. However, it is also essential to mention that the different timing of diagnosis due to variant urinary screening systems and the indication for renal biopsy in different countries may also contribute to these variances. The management of IgAN also varies internationally. Currently, several novel therapies based on the pathogenesis of IgAN are being assessed and are expected to become available soon. Further understanding the ethnic variance of IgAN might help establish individualized care for this disease. Here, we review the issues of ethnic heterogeneities of IgAN.

The Gal4/UAS system is a versatile tool to manipulate exogenous gene expression of cells spatially and temporally in many model organisms. Many variations of light-controllable Gal4/UAS system are now available, following the development of photo-activatable (PA) molecular switches and integration of these tools. However, many PA-Gal4 transcription factors have undesired background transcription activities even in dark conditions, and this severely attenuates reliable light-controlled gene expression. Therefore, it is important to develop reliable PA-Gal4 transcription factors with robust light-induced gene expression and limited background activity. By optimization of synthetic PA-Gal4 transcription factors, we have validated configurations of Gal4 DNA biding domain, transcription activation domain and blue light-dependent dimer formation molecule Vivid (VVD), and applied types of transcription activation domains to develop a new PA-Gal4 transcription factor we have named eGAV (enhanced Gal4-VVD transcription factor). Background activity of eGAV in dark conditions was significantly lower than that of hGAVPO, a commonly used PA-Gal4 transcription factor, and maximum light-induced gene expression levels were also improved. Light-controlled gene expression was verified in cultured HEK293T cells with plasmid-transient transfections, and in mouse EpH4 cells with lentivirus vector-mediated transduction. Furthermore, light-controlled eGAV-mediated transcription was confirmed in transfected neural stem cells and progenitors in developing and adult mouse brain and chick spinal cord, and in adult mouse hepatocytes, demonstrating that eGAV can be applied to a wide range of experimental systems and model organisms.Key words: optogenetics, Gal4/UAS system, transcription, gene expression, Vivid

Several studies reported various crossmodal correspondences related to tactile features. These previous studies have investigated tactile-related correspondences through explicit matching or subjective evaluation tasks, which required participants to recognize relationships between tactile and other sensory features or rate tactile materials on scales with adjective labels related to visual or auditory features. However, these tasks are prone to occur the experimenter-expectancy effects and arbitrary categorization of tactile materials by the labels, making it difficult to assess implicit and non-arbitrary aspects of crossmodal correspondences. To address this, we used a speeded classification task to examine whether the angularity/roundedness of visual and auditory stimuli correspond to tactile jaggedness/fluffiness. Participants distinguished between angularity or roundedness (Experiment 1: visual shapes; Experiment 2: speech sounds) by pressing right- or left-positioned response keys with task-irrelevant jaggedness or fluffiness without prior instruction on which key represented jaggedness/fluffiness. Results showed faster keypresses for jagged/fluffy responses to angular/rounded stimuli, suggesting an implicit correspondence between these sensory features except for the experimenter-expectancy effects and the influence of the labels. Unlike previous studies that examined the correspondence with simple tactile features (e.g., weight, size), our findings suggest that even complex tactile-quality features, such as jaggedness/fluffiness, implicitly correspond to visual and auditory angularity/roundedness.

Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NH-cell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo , by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma. Allergic airway inflammation in asthma can be treated with corticosteroids, but some patients remain unresponsive to this therapy. Here, Kabata et al . show that thymic stromal lymphopoietin contributes to the corticosteroid resistance during airway inflammation through its action on natural helper cells.

Cardiovascular diseases (CVDs) are a major cause of death in patients undergoing hemodialysis (HD). Blood pressure (BP) and uremic toxins are well-known risk factors for CVDs, which are influenced by diet. Dietary fiber supplementation in patients undergoing HD may reduce the risk of CVDs by improving lipid profiles and inflammatory status and lowering the levels of the uremic toxin indoxyl sulfate (IS). In this study, we investigated the relationship between the intestinal microbiota and risk factors for CVDs, such as BP and serum IS, in patients undergoing HD who consumed fruits granola (FGR). The study participants were selected from patients undergoing HD at the Izu Nagaoka Daiichi Clinic and consumed FGR for 2 months. Body composition and blood samples were tested at months 0, 1, 2 and fecal samples were collected at months 0 and 2 for intestinal microbiota analysis. FGR consumption decreased systolic and diastolic BP, estimated salt intake, and serum IS levels and improved the stool characteristics according to the Bristol Stool Form Scale ( N  = 24). Gut microbiota analysis showed an increase in the alpha diversity and abundance of Blautia and Neglecta . The abundance of lactic acid- and ethanol-producing bacteria also significantly increased, whereas the abundance of indole-producing bacteria significantly decreased. FGR consumption could be a useful tool for salt reduction, fiber supplementation, and improvement of the intestinal environment, thus contributing to improvement of BP and the reduction of other risk factors for CVDs in patients undergoing HD.

Early detection of knee osteoarthritis (KOA) can improve treatment outcomes and prevent its progression. The aim of this systematic review was to identify the functional changes in early KOA. Electronic journal databases and platforms, including PubMed, the Physiotherapy Evidence Database, the Cochrane Central Register of Controlled Trials, and Scopus were searched. The inclusion criteria were as follows: (1) studies comparing patients with early KOA with an age-matched control group and (2) studies with objectively measured functional changes as outcomes. Studies that included individuals with Kellgren and Lawrence (K/L) grades > 2- were excluded. A random-effects model was constructed to calculate pooled standardized mean differences (SMDs). A total of nine articles were included in this systematic review. Seven studies used classification criteria to define early KOA, including knee pain; a K/L grade of 0, 1, or 2- (osteophytes only) for the medial compartment; and the presence of two out of four MRI criteria. The remaining two studies included K/L grade 1 confirmed by radiography. Early KOA participants had a significantly longer timed up-and-go test (TUG) time (pooled SMD: 0.57; 95% confidence interval: 0.15, 0.98). The two groups had similar knee extension muscle strength at 90° knee flexion. The quality of evidence for each measured outcome was “very low.” In this review, longer TUG was identified as a functional manifestation of early KOA. Further studies involving functional assessments are needed to develop a screening method to detect early KOA. Key Points • There is a need for diagnostic criteria that include functional changes in patients with early knee osteoarthritis, since radiographic facilities are not available everywhere. • In this review, a long timed up-and-go test time was identified as a functional manifestation of early knee osteoarthritis. • If the findings of this study can be replicated, measurement of TUG may allow for earlier detection of knee osteoarthritis outside the hospital and in routine clinical practice without the use of MRI or X-rays.

A proliferation-inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) superfamily. Despite advances in clinical and genetic studies, the details of the pathological roles of APRIL in IgA nephropathy (IgAN) remain to be fully defined. The present study aimed to further assess the pathological role of APRIL using a mouse model of IgAN. Mice with IgAN designated \"grouped ddY\" (gddY) were intraperitoneally administered an anti-APRIL monoclonal antibody (anti-APRIL Ab) or control IgG (Control Ab) twice each week for 2 weeks starting during the early stage of IgAN (6-7 weeks of age). Urinary albumin, serum IgA, and glomerular IgA deposition were evaluated. We further assessed the inflammatory responses during treatment by measuring the levels of the chemokine fractalkine (FKN) and its receptor CX3CR1 as well as the level of peripheral blood monocytosis. Anti-APRIL Ab treatment significantly decreased albuminuria and tissue damage combined with decreases in serum IgA levels and deposition of glomerular IgA. In contrast, the abundance of IgA+/B220+ or CD138+/B220+ B cells in the spleen and bone marrow, respectively, was unchanged. Treating gddY mice with anti-April Ab reduced the overexpression of FKN/CX3CR1 in the kidney and the increase in the population of circulating Gr1-/CD115+ monocytes. The size of the population of Gr1-/CD115+ monocytes correlated with renal FKN and urinary albumin levels. Moreover, mice treated with anti-APRIL Ab exhibited reduced progression of IgAN, serum IgA levels, and glomerular IgA deposition as well as an attenuated inflammatory process mediated by FKN-associated activation of monocytes. To the best of our knowledge, this is the first study to implicate the APRIL signal transduction pathway in the pathogenesis of nephrogenic IgA production. Moreover, our findings identify APRIL as a potential target of therapy.