α1-Syntrophin–deficient skeletal muscle exhibits hypertrophy and aberrant formation of neuromuscular junctions during regeneration

α1-Syntrophin is a member of the family of dystrophin-associated proteins; it has been shown to recruit neuronal nitric oxide synthase and the water channel aquaporin-4 to the sarcolemma by its PSD-95/SAP-90, Discs-large, ZO-1 homologous domain. To examine the role of α1-syntrophin in muscle regeneration, we injected cardiotoxin into the tibialis anterior muscles of α1-syntrophin–null (α1syn−/−) mice. After the treatment, α1syn−/− muscles displayed remarkable hypertrophy and extensive fiber splitting compared with wild-type regenerating muscles, although the untreated muscles of the mutant mice showed no gross histological change. In the hypertrophied muscles of the mutant mice, the level of insulin-like growth factor-1 transcripts was highly elevated. Interestingly, in an early stage of the regeneration process, α1syn−/− mice showed remarkably deranged neuromuscular junctions (NMJs), accompanied by impaired ability to exercise. The contractile forces were reduced in α1syn−/− regenerating muscles. Our results suggest that the lack of α1-syntrophin might be responsible in part for the muscle hypertrophy, abnormal synapse formation at NMJs, and reduced force generation during regeneration of dystrophin-deficient muscle, all of which are typically observed in the early stages of Duchenne muscular dystrophy patients

Recurrence of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin G Deposits with a Striated Ultrastructure

This is the peer-reviewed but unedited manuscript version of the following article: Nephron 2020;144(suppl 1):43–48 (DOI: 10.1159/000512330)]. The final, published version is available at http://www.karger.com/?doi=10.1159/000512330

Clinical characteristics and risk factors for septic shock in patients receiving emergency drainage for acute pyelonephritis with upper urinary tract calculi

<p>Abstract</p> <p>Background</p> <p>Acute pyelonephritis (APN) is a common complication of ureteral obstruction caused by urolithiasis, and it can be lethal if it progresses to septic shock. We investigated the clinical characteristics of patients undergoing emergency drainage and assessed risk factors for septic shock.</p> <p>Methods</p> <p>A retrospective study was performed of 98 patients (101 events) requiring emergency drainage at our urology department for obstructive APN associated with upper urinary tract calculi from January 2003 to January 2011. Clinical characteristics were summarized, and risk factors for septic shock were assessed by logistic regression analysis.</p> <p>Results</p> <p>Objective evidence of sepsis was found in 64 (63.4%) events, and 21 events (20.8%) were categorized as septic shock. Ninety-six patients recovered, but 2 patients died of septic shock. Multivariate analysis revealed that age and the presence of paralysis were independent risk factors for septic shock.</p> <p>Conclusions</p> <p>APN associated with upper urinary tract calculi is a severe disease that should be treated with caution, particularly when risk factors are present.</p

Serum phosphate levels modify the impact of parathyroid hormone levels on renal outcomes in kidney transplant recipients

Separate assessment of mineral bone disorder (MBD) parameters including calcium, phosphate, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D (1,25D) predict renal outcomes in kidney transplant recipients (KTRs), with conflicting results. To date, data simultaneously evaluating these parameters and interwoven relations on renal outcomes are scarce. We conducted a prospective long-term follow-up cohort study included 263 KTRs with grafts functioning at least 1 year after transplantation. The outcome was a composite of estimated GFR halving and graft loss. Cox regression analyses were employed to evaluate associations between a panel of six MBD parameters and renal outcomes. The outcome occurred in 98 KTRs during a median follow-up of 10.7 years. In a multivariate Cox analysis, intact PTH (iPTH), phosphate, and 1,25D levels were associated with the outcome (hazard ratio, 1.60 per log scale; 95% confidence interval, 1.19–2.14, 1.60 per mg/dL; 1.14–2.23 and 0.82 per 10 pg/mL; 0.68–0.99, respectively). Competing risk analysis with death as a competing event yielded a similar result. After stratification into four groups by iPTH and phosphate medians, high risks associated with high iPTH was not observed in KTRs with low phosphate levels (P-interaction < 0.1). Only KTRs not receiving active vitamin D, poor 1,25D status predicted the worse outcome (P-interaction < 0.1). High iPTH, phosphate, and low 1,25D, but not FGF23, levels predicted poor renal outcomes. Simultaneous evaluation of PTH and phosphate levels may provide additional information regarding renal allograft prognosis.Doi Y., Hamano T., Ichimaru N., et al. Serum phosphate levels modify the impact of parathyroid hormone levels on renal outcomes in kidney transplant recipients. Scientific Reports 10, 13766 (2020); https://doi.org/10.1038/s41598-020-70709-4

MondoA and AKI and AKI-to-CKD Transition

Maeda S., Sakai S., Takabatake Y., et al. MondoA and AKI and AKI-to-CKD Transition. Journal of the American Society of Nephrology , (2024); https://doi.org/10.1681/ASN.0000000000000414.Key PointsThe expression of MondoA was decreased in the renal tubules of patients with CKD.Genetic ablation of MondoA in proximal tubules inhibited autophagy and increased vulnerability to AKI through increased expression of Rubicon.MondoA ablation during the recovery phase after ischemia-reperfusion aggravated kidney injury through downregulation of the transcription factor EB-peroxisome proliferator-activated receptor-γ coactivator-1α axis.BackgroundElderly individuals and patients with CKD are at a higher risk of AKI. The transcription factor MondoA is downregulated in the kidneys of aged individuals or patients with AKI; however, its roles in AKI development and the AKI-to-CKD transition remain unknown.MethodsWe investigated the expression of MondoA in human kidney biopsy samples, ischemia-reperfusion-injured (IRI) mouse kidneys, and cultured proximal tubular epithelial cells under hypoxia/reoxygenation. The role of MondoA during the initial and recovery phases after IRI was evaluated using proximal tubule-specific MondoA knockout mice and MondoA-deficient proximal tubular epithelial cells. Furthermore, we explored the involvement of Rubicon and transcription factor EB (TFEB), both of which are downstream factors of MondoA.ResultsMONDOA expression was decreased in the renal tubules of patients with CKD. In mouse kidneys, MondoA expression was decreased under ischemia, whereas its expression was increased during reperfusion. Genetic ablation of MondoA in proximal tubular epithelial cells inhibited autophagy and increased vulnerability to AKI through increased expression of Rubicon. Ablation of Rubicon in MondoA-deficient IRI kidneys activated autophagy and protected mitochondrial function. MondoA ablation during the recovery phase after ischemia-reperfusion aggravated kidney injury through downregulation of the TFEB-peroxisome proliferator-activated receptor-γ coactivator-1α axis. Pharmacological upregulation of TFEB contributed to maintaining mitochondrial biogenesis and increased peroxisome proliferator-activated receptor-γ coactivator-1α transcription.ConclusionsOur findings demonstrate that MondoA protected against vulnerability to AKI by maintaining autophagy and subsequently supporting mitochondrial function to prevent progression to CKD

Evaluation of Antigen-Specific IgM and IgG Production during an In Vitro Peripheral Blood Mononuclear Cell Culture Assay

The recent attention given to diseases associated with memory B-cell (mBC)-produced antibodies (Abs) suggests the need for a similar in vitro assay to evaluate the functions of mBCs. Here, we cultured peripheral blood mononuclear cells (PBMCs) with the intent to collect mBC-derived Abs in vitro and maintain their cell–cell contact-dependent interactions with helper T-cells. PBMCs were cultured with interleukin (IL)-21, CpG-oligodeoxynucleotides (ODN), phorbol myristate acetate (PMA), and phytohemagglutinin/leucoagglutinin (PHA-L) in 24-well flat-bottom plates (5 × 105 cells/well). A culture supernatant analysis of PBMCs from healthy donors (n = 10) indicated that antigen-specific IgM Ab levels in a PBMC culture supernatant might be better able to demonstrate the antigen sensitization status in a smaller peripheral blood sample, compared to IgG because Epstein–Barr virus-specific IgM mBCs circulate peripherally at a significantly higher frequency once antiviral humoral immunity has stabilized. Thus, our in vitro assay demonstrated the potential significance of antigen-specific IgM Ab production in the culture supernatants. Furthermore, an analysis of cultured PBMCs from allograft kidney recipients (n = 16) sensitized with de novo donor-specific human leukocyte antigen (HLA)-specific Abs (DSAs) showed that IgM-type HLA-specific Abs were detected mainly from the culture supernatants from PBMCs of patients with stable graft function, whereas IgG isotype HLA Abs were detectable only from patients with biopsy-proven antibody-mediated rejection. In other words, these IgG isotype Abs also represented an activated humoral immune response in vivo. Additionally, IgM- and IgG-expressing mBCs from healthy donors (n = 5) were cultured with IL-21, CpG-ODN, and a supernatant produced by stimulating CD19+ B-cell-depleted PBMCs with PHA-L and PMA in 24-well flat-bottom plates (1 × 105 cells/well), and the resulting in vitro analysis provided some information regarding the biological processes of IgG and IgM mBCs in peripheral blood. Taken together, our findings suggest that antigen-specific Ab subtype analyses of supernatants from cultured PBMCs might more effectively and accurately reflect a patient’s Ab-associated pathological condition vs. than serum IgG and IgM levels

Collective Motion of Quincke Rollers with Fully Resolved Hydrodynamics

Hydrodynamic effects are known to significantly affect the collective behavior of wet active matter systems. However, the non-linear many-body nature of these interactions makes them very challenging to analyze, particularly in dense suspensions. Quincke rollers are one of the canonical examples of artificial microswimmers. These are active particles that move freely above a plate due to the torque generated by a uniform DC electric field. A system involving many such particles exhibits a variety of collective dynamics, such as the disordered gas, polar liquid, and active crystal states. This work accomplishes numerical simulations of a 3D system containing many rollers in order to explicitly resolve the hydrodynamic interactions and understand the role these play in the resulting active dynamics. It reveals that the far-field hydrodynamic effects tend to drive ordered collective motion, while the near-field effects tend to drive disordered collective behavior, and reproduce diverse collective behavior while capturing the role of hydrodynamic effects between rollers without resorting to the approximations previously employed