Successful treatment of acute tubulointerstitial nephritis probably due to Benikoji CholesteHelp®, a supplement containing red yeast rice.

Red yeast rice has been used to produce alcoholic beverages and various fermented foods especially in East Asia. Since around March 2024, there have been many cases of kidney dysfunction in people who have taken certain supplements containing red yeast rice in Japan. We experienced a case of acute kidney injuries induced after taking a supplement containing red yeast rice. A 58-year-old woman was admitted to our hospital due to renal dysfunction suspected to be caused by taking the supplement Benikoji CholesteHelp®, which contains red yeast rice. With elevations of urinary tubular injury markers such as urinary ß2-microglobulin and N-acetyl-ß-D-glucosaminidase, serum creatinine levels were elevated up to 2.75 mg/dL. A kidney biopsy revealed a diagnosis of tubulointerstitial nephritis with lymphocytic infiltration of the interstitium, tubular atrophy, and interstitial fibrotic changes. After discontinuation of the supplement and initiation of the prednisolone treatment, renal dysfunction rapidly improved. The course of this case suggests tubular damage caused by the supplements containing red yeast rice. For early diagnosis and treatment, it should be noted that even what are regarded as nutritional health supplements can cause renal dysfunction.

LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy.

Introduction: Galactose-deficient IgA1 (Gd-IgA1) plays a key role in the pathogenesis of IgA nephropathy (IgAN). Tonsillectomy has been beneficial to some patients with IgAN, possibly due to the removal of tonsillar cytokine-activated cells producing Gd-IgA1. To test this hypothesis, we used immortalized IgA1-producing cell lines derived from tonsils of patients with IgAN or obstructive sleep apnea (OSA) and assessed the effect of leukemia inhibitory factor (LIF) or oncostatin M (OSM) on Gd-IgA1 production. Methods: Gd-IgA1 production was measured by lectin enzyme-linked immunosorbent assay; JAK-STAT signaling in cultured cells was assessed by immunoblotting of cell lysates; and validated by using small interfering RNA (siRNA) knock-down and small-molecule inhibitors. Results: IgAN-derived cells produced more Gd-IgA1 than the cells from patients with OSA, and exhibited elevated Gd-IgA1 production in response to LIF, but not OSM. This effect was associated with dysregulated STAT1 phosphorylation, as confirmed by STAT1 siRNA knock-down. JAK2 inhibitor, AZD1480 exhibited a dose-dependent inhibition of the LIF-induced Gd-IgA1 overproduction. Unexpectedly, high concentrations of AZD1480, but only in the presence of LIF, reduced Gd-IgA1 production in the cells derived from patients with IgAN to that of the control cells from patients with OSA. Based on modeling LIF-LIFR-gp130-JAK2 receptor complex, we postulate that LIF binding to LIFR may sequester gp130 and/or JAK2 from other pathways; and when combined with JAK2 inhibition, enables full blockade of the aberrant O-glycosylation pathways in IgAN. Conclusion: In summary, IgAN cells exhibit LIF-mediated overproduction of Gd-IgA1 due to abnormal signaling. JAK2 inhibitors can counter these LIF-induced effects and block Gd-IgA1 synthesis in IgAN.

The nucleotide-sensing Toll-Like Receptor 9/Toll-Like Receptor 7 system is a potential therapeutic target for IgA nephropathy.

The progression determinants of IgA nephropathy (IgAN) are still not fully elucidated. We have previously demonstrated that the mucosal activation of toll-like receptor (TLR) 9, which senses microbial unmethylated CpG DNA, influences progression by producing aberrantly glycosylated IgA. However, numerous recent reports of patients with IgAN presenting with gross hematuria after the mRNA vaccination for coronavirus disease 2019 suggest that the RNA-sensing system also exacerbates IgAN. Here, we investigated whether TLR7, which recognizes microbial RNA, is also involved in IgAN progression using a murine model and tonsil tissue from 53 patients with IgAN compared to samples from 40 patients with chronic tonsillitis and 12 patients with sleep apnea syndrome as controls. We nasally administered imiquimod, the ligand of TLR7, to IgAN-prone ddY mice and found that TLR7 stimulation elevated the serum levels of aberrantly glycosylated IgA and induced glomerular IgA depositions and proteinuria. Co-administered hydroxychloroquine, which inhibits TLRs, canceled the kidney injuries. In vitro, stimulating splenocytes from ddY mice with imiquimod increased interleukin-6 and aberrantly glycosylated IgA levels. The expression of TLR7 in the tonsils was elevated in patients with IgAN and positively correlated with that of a proliferation-inducing ligand (APRIL) involved in the production of aberrantly glycosylated IgA. Mechanistically, TLR7 stimulation enhanced the synthesis of aberrantly glycosylated IgA through the modulation of enzymes involved in the glycosylation of IgA. Thus, our findings suggest that nucleotide-sensing TLR9 and TLR7 play a crucial role in the pathogenesis of IgAN. Hence, nucleotide-sensing TLRs could be reasonably strong candidates for disease-specific therapeutic targets in IgAN.

Contextualized medication event extraction with striding NER and multi-turn QA.

This paper describes contextualized medication event extraction for automatically identifying medication change events with their contexts from clinical notes. The striding named entity recognition (NER) model extracts medication name spans from an input text sequence using a sliding-window approach. Specifically, the striding NER model separates the input sequence into a set of overlapping subsequences of 512 tokens with 128 tokens of stride, processing each subsequence using a large pre-trained language model and aggregating the outputs from the subsequences. The event and context classification has been done with multi-turn question-answering (QA) and span-based models. The span-based model classifies the span of each medication name using the span representation of the language model. In the QA model, event classification is augmented with questions in classifying the change events of each medication name and the context of the change events, while the model architecture is a classification style that is the same as the span-based model. We evaluated our extraction system on the n2c2 2022 Track 1 dataset, which is annotated for medication extraction (ME), event classification (EC), and context classification (CC) from clinical notes. Our system is a pipeline of the striding NER model for ME and the ensemble of the span-based and QA-based models for EC and CC. Our system achieved a combined F-score of 66.47% for the end-to-end contextualized medication event extraction (Release 1), which is the highest score among the participants of the n2c2 2022 Track 1.

Mucosal Immune System Dysregulation in the Pathogenesis of IgA Nephropathy.

The mucosal immune system, via a dynamic immune network, serves as the first line of defense against exogenous antigens. Mucosal immune system dysregulation is closely associated with the pathogenesis of immunoglobulin A nephropathy (IgAN), as illustrated by IgAN having the clinical feature of gross hematuria, often concurrent with mucosal infections. Notably, previous studies have demonstrated the efficacy of tonsillectomy and found that a targeted-release formulation of budesonide reduced proteinuria in patients with IgAN. However, it remains unclear how exogenous antigens interact with the mucosal immune system to induce or exacerbate IgAN. Thus, in this review, we focus on the dysregulation of mucosal immune response in the pathogenesis of IgAN.

A topspin rate exceeding 110 rps reduces the ball time of arrival to the opponent: a table tennis rally study.

This study experimentally investigated the factors affecting the time a table tennis ball with topspin takes to reach the opponent. Six skilled young players and one coach performed topspin forehand strokes under the observation of three high-speed cameras. As the distribution of the participants' measurements was uneven, additional data were collected using a launching machine that could control the ball speed and spin. To verify the effect of the spin rate on speed decay by drag, the translational speed was measured at 0.15 s after passing the baseline (23 m/s); the balls with topspin ≥110 rps, close to participants' average (117 ± 29 rps) were 1.4 m/s faster than those with topspin ≤80 rps. The horizontal ball speed changed in the range of -3.1 to 2.6 m/s owing to table bounce. At topspins ≥110 rps the ball reached a point 1 m past the end line (estimated receiving position) 27 ± 5 ms faster than at topspins ≤80 rps, for the same initial speed. The relationship between spin rate and travel time was non-linear with boundaries at 80 and 110 rps. Therefore, maintaining a spin rate of ≥ 110 rps along with a high initial speed is an effective strategy for reducing the opponent's preparation time.

Leukemia Inhibitory Factor Signaling Enhances Production of Galactose-Deficient IgA1 in IgA Nephropathy.

OBJECTIVES: IgA nephropathy (IgAN) is thought to involve an autoimmune process wherein galactose-deficient IgA1 (Gd-IgA1), recognized as autoantigen by autoantibodies, forms pathogenic immune complexes. Mounting evidence has implicated abnormal activation of some protein-tyrosine kinases (PTKs) in IgAN. Furthermore, genome-wide association studies (GWAS) of IgAN provided insight into disease pathobiology and genetics. A GWAS locus on chromosome 22q12 contains genes encoding leukemia inhibitory factor (LIF) and oncostatin M, interleukin (IL)-6-related cytokines implicated in mucosal immunity and inflammation. We have previously shown that IL-6 mediates overproduction of Gd-IgA1 through aberrant STAT3 activation. Here, we show that LIF enhanced production of Gd-IgA1 in IgA1-secreting cells of patients with IgAN and provide initial analyses of LIF signaling. METHODS: We characterized LIF signaling that is involved in the overproduction of Gd-IgA1, using IgA1-secreting cell lines derived from peripheral blood of patients with IgAN and healthy controls (HC). We used global PTK activity profiling, immunoblotting, lectin ELISA, and siRNA knock-down. RESULTS: LIF stimulation did not significantly affect production of total IgA1 in IgA1-secreting cells from patients with IgAN or HC. However, LIF increased production of Gd-IgA1, but only in the cells from patients with IgAN. LIF stimulation enhanced phosphorylation of STAT1 in IgA1-secreting cells from patients with IgAN to a higher degree than in the cells from HC. siRNA knock-down of STAT1 blocked LIF-mediated overproduction of Gd-IgA1. Unexpectedly, this abnormal phosphorylation of STAT1 in IgA1-secreting cells from patients with IgAN was not mediated by JAK, but rather involved activation of Src-family PTKs (SFKs). CONCLUSION: Abnormal LIF/STAT1 signaling represents another pathway potentially leading to overproduction of Gd-IgA1 in IgAN, providing possible explanation for the phenotype associated with chromosome 22q12 GWAS locus. Abnormal LIF/STAT1 signaling and the associated SFKs may represent potential diagnostic and/or therapeutic targets in IgAN.

Inhibition of STAT3 Signaling Reduces IgA1 Autoantigen Production in IgA Nephropathy.

INTRODUCTION: IgA nephropathy is a chronic renal disease characterized by mesangial immunodeposits that contain autoantigen, which is aberrantly glycosylated IgA1 with some hinge-region O-glycans deficient in galactose. Macroscopic hematuria during an upper respiratory tract infection is common among patients with IgA nephropathy, which suggests a connection between inflammation and disease activity. Interleukin-6 (IL-6) is an inflammatory cytokine involved in IgA immune response. We previously showed that IL-6 selectively increases production of galactose-deficient IgA1 in IgA1-secreting cells from patients with IgA nephropathy. METHODS: We characterized IL-6 signaling pathways involved in the overproduction of galactose-deficient IgA1. To understand molecular mechanisms, IL-6 signaling was analyzed by kinomic activity profiling and Western blotting, followed by confirmation assays using siRNA knock-down and small-molecule inhibitors. RESULTS: STAT3 was differentially activated by IL-6 in IgA1-secreting cells from patients with IgA nephropathy compared with those from healthy control subjects. Specifically, IL-6 induced enhanced and prolonged phosphorylation of STAT3 in the cells from patients with IgA nephropathy, which resulted in overproduction of galactose-deficient IgA1. This IL-6-mediated overproduction of galactose-deficient IgA1 could be blocked by small molecule inhibitors of JAK/STAT signaling. DISCUSSION: Our results revealed that IL-6-induced aberrant activation of STAT3-mediated overproduction of galactose-deficient IgA1. STAT3 signaling pathway may thus represent a new target for disease-specific therapy of IgA nephropathy.

A Shot Number Based Approach to Performance Analysis in Table Tennis.

The current study proposes a novel approach that improves the conventional performance analysis in table tennis by introducing the concept of frequency, or the number of shots, of each shot number. The improvements over the conventional method are as follows: better accuracy of the evaluation of skills and tactics of players, additional insights into scoring and returning skills and ease of understanding the results with a single criterion. The performance analysis of matches played at the 2012 Summer Olympics in London was conducted using the proposed method. The results showed some effects of the shot number and gender differences in table tennis. Furthermore, comparisons were made between Chinese players and players from other countries, what threw light on the skills and tactics of the Chinese players. The present findings demonstrate that the proposed method provides useful information and has some advantages over the conventional method.

Effect of Changing Table Tennis Ball Material from Celluloid to Plastic on the Post-Collision Ball Trajectory.

The official material used in table tennis balls was changed from celluloid to plastic, a material free of celluloid, in 2014. The purpose of this study was to understand the differences and similarities in the two types of ball materials by comparing their behavior upon collision with a table. The behavior of the balls before and after collision with a table, at various initial speeds ranging from 15 to 115 km/h, was captured using high-speed cameras. Velocities and spin rates before collision and velocities after collision were computed to calculate the coefficients of restitution and friction. Based on the computed variables, the post-collision trajectories of both balls were calculated by integrating the equation of motion of the ball for simulated service, smash and drive conditions with respect to time. The coefficients of restitution were higher for the plastic balls than the celluloid ones when the initial vertical velocities were higher. The coefficients of friction were higher for plastic balls when the initial horizontal contact point velocities were slower. Because of the differences in the material characteristics, the plastic ball trajectories of services with backspin and drives with great topspin were expected to be different from those of celluloid balls. Since the extent of differences between the two ball types varied depending on the initial conditions, testing at various initial conditions was suggested for comparing and understanding the characteristics of the balls.

N-acetylgalactosaminide α2,6-sialyltransferase II is a candidate enzyme for sialylation of galactose-deficient IgA1, the key autoantigen in IgA nephropathy.

BACKGROUND: Galactose-deficient O-glycans in the hinge region (HR) of immunoglobulin A1 (IgA1) play a key role in the pathogenesis of IgA nephropathy (IgAN). O-Glycans of circulatory IgA1 consist of N-acetylgalactosamine (GalNAc) with a ß1,3-linked galactose; both sugars may be sialylated. In patients with IgAN, α2,6-sialylated GalNAc is a frequent form of the galactose-deficient O-glycans. Prior analyses of IgA1-producing cells had indicated that α2,6-sialyltransferase II (ST6GalNAc-II) is likely responsible for sialylation of GalNAc of galactose-deficient IgA1, but direct evidence is missing. METHODS: We produced a secreted variant of recombinant human ST6GalNAc-II and an IgA1 fragment comprised of Cα1-HR-Cα2. This IgA1 fragment and a synthetic HR peptide with enzymatically attached GalNAc residues served as acceptors. ST6GalNAc-II activity was assessed in vitro and the attachment of sialic acid to these acceptors was detected by lectin blot and mass spectrometry. RESULTS: ST6GalNAc-II was active with both acceptors. High-resolution mass spectrometry analysis revealed that up to three sialic acid residues were added to the GalNAc residues of the HR glycopeptide. CONCLUSIONS: Our data provide direct evidence that ST6GalNAc-II can sialylate GalNAc of galactose-deficient IgA1. As serum levels of galactose-deficient IgA1 with sialylated glycoforms are increased in IgAN patients, our data explain the corresponding part of the biosynthetic pathway.

Cytokines alter IgA1 O-glycosylation by dysregulating C1GalT1 and ST6GalNAc-II enzymes.

IgA nephropathy (IgAN), the most common primary glomerulonephritis, is characterized by renal immunodeposits containing IgA1 with galactose-deficient O-glycans (Gd-IgA1). These immunodeposits originate from circulating immune complexes consisting of anti-glycan antibodies bound to Gd-IgA1. As clinical disease onset and activity of IgAN often coincide with mucosal infections and dysregulation of cytokines, we hypothesized that cytokines may affect IgA1 O-glycosylation. We used IgA1-secreting cells derived from the circulation of IgAN patients and healthy controls and assessed whether IgA1 O-glycosylation is altered by cytokines. Of the eight cytokines tested, only IL-6 and, to a lesser degree, IL-4 significantly increased galactose deficiency of IgA1; changes in IgA1 O-glycosylation were robust for the cells from IgAN patients. These cytokines reduced galactosylation of the O-glycan substrate directly via decreased expression of the galactosyltransferase C1GalT1 and, indirectly, via increased expression of the sialyltransferase ST6GalNAc-II, which prevents galactosylation by C1GalT1. These findings were confirmed by siRNA knockdown of the corresponding genes and by in vitro enzyme reactions. In summary, IL-6 and IL-4 accentuated galactose deficiency of IgA1 via coordinated modulation of key glycosyltransferases. These data provide a mechanism explaining increased immune-complex formation and disease exacerbation during mucosal infections in IgAN patients.

Down-regulation of core 1 beta1,3-galactosyltransferase and Cosmc by Th2 cytokine alters O-glycosylation of IgA1.

BACKGROUND: Patients with IgA nephropathy (IgAN) have an increased amount of abnormally O-glycosylated IgA1 in circulation, in glomerular deposits and produced by tissue cells in vitro. Although increased production of Th2 cytokines by peripheral blood lymphocytes and a functional abnormality of core 1 ß1,3-galactosyltransferase (C1ß3Gal-T) have been proposed as mechanisms underlying pathogenesis of IgAN, they are still obscure and are not connected. METHODS: To clarify the effect of T-cell cytokines, we analysed the mRNA levels of C1ß3Gal-T and its molecular chaperone Cosmc, C1ß3Gal-T activity and subsequent O-glycosylation of IgA1 in a human B-cell line stimulated with these cytokines. The surface IgA1-positive human B-cell line was cultured with recombinant human IFN-γ, IL-2, IL-4 or IL-5. The production and glycosylation of IgA1 were determined by sandwich ELISA and enzyme-linked lectin binding assay, respectively. The mRNA levels of C1ß3Gal-T and Cosmc were quantitatively measured by real-time PCR. C1ß3Gal-T activity was analysed using high-performance liquid chromatography. RESULTS: IgA1 production by IL-4-stimulated cells was significantly higher than controls or after IFN-γ or IL-5. The terminal glycosylation of secreted IgA1 was altered in response to IL-4. IL-4 stimulation significantly decreased the mRNA levels of both C1ß3Gal-T and Cosmc and of C1ß3Gal-T activity. IL-4 stimulation was clearly blocked by recombinant human IL-4 soluble receptor. CONCLUSIONS: It appears that Th2 cytokine IL-4 may play a key role in controlling glycosylation of the IgA1 hinge region.