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Alport syndrome (AS) is a hereditary nephritis characterized by structural abnormalities in the glomerular basement membrane resulting from pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes. Conventional pathological evaluations reveal nonspecific light microscopic changes and diagnostic clues can be obtained through electron microscopy. Type IV collagen staining elucidates distinct patterns based on AS inheritance, aiding in subtype classification. However, limitations arise, particularly in autosomal dominant cases. Genetic testing, particularly next-generation sequencing, gains prominence due to its ability to identify diverse mutations within COL4A3, COL4A4, and COL4A5.

Tumour budding shows promise as a prognostic factor in various cancers, but its widespread application is hindered by the lack of large, validated studies and standardized criteria. This meta-analysis aims to review and examine the prognostic role of tumour budding specifically in noncolorectal gastrointestinal and pancreatobiliary tract cancers, broadening our perspective on its clinical relevance. The literature review was conducted through PubMed, Embase, and Web of Science from inception till 20 February 2023. Pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) were calculated to assess the relation between tumour budding and clinicopathologic features, as well as overall survival. Each study was evaluated using the Newcastle-Ottawa Scale and both heterogeneity and publication bias were analysed. In this meta-analysis of 57 studies across various cancer types, multivariate HR revealed worse overall survival in oesophageal squamous cell carcinoma (HR 3.34 [95% CI 2.21-5.04]), gastric adenocarcinoma (2.03 [1.38-2.99]), pancreatic ductal adenocarcinoma (2.56 [2.02-3.25]), and biliary tract adenocarcinoma (3.11 [2.46-3.93]) with high-grade tumour budding. Additionally, high-grade tumour budding consistently correlated with adverse clinicopathological features, including lymph node metastasis, lymphovascular invasion, and distant metastasis without any observed inverse association. High heterogeneity was noted. Our study suggests that tumour budding is a valuable prognostic marker in various cancers. Nonetheless, standardized criteria tailored to specific organ types are necessary to enhance its clinical utility., (© 2024 John Wiley & Sons Ltd.)

Background: We previously identified ezetimibe, an inhibitor of Niemann-Pick C1-like intracellular cholesterol transporter 1 and European Medicines Agency-approved lipid-lowering agent, as a potent autophagy activator. However, its efficacy against pulmonary fibrosis has not yet been evaluated. This study aimed to determine whether ezetimibe has therapeutic potential against idiopathic pulmonary fibrosis., Methods: Primary lung fibroblasts isolated from both humans and mice were employed for mechanistic in vitro experiments. mRNA sequencing of human lung fibroblasts and gene set enrichment analysis were performed to explore the therapeutic mechanism of ezetimibe. A bleomycin-induced pulmonary fibrosis mouse model was used to examine in vivo efficacy of the drug. Tandem fluorescent-tagged microtubule-associated protein 1 light chain 3 transgenic mice were used to measure autophagic flux. Finally, the medical records of patients with idiopathic pulmonary fibrosis from three different hospitals were reviewed retrospectively, and analyses on survival and lung function were conducted to determine the benefits of ezetimibe., Results: Ezetimibe inhibited myofibroblast differentiation by restoring the mechanistic target of rapamycin complex 1-autophagy axis with fine control of intracellular cholesterol distribution. Serum response factor, a potential autophagic substrate, was identified as a primary downstream effector in this process. Similarly, ezetimibe ameliorated bleomycin-induced pulmonary fibrosis in mice by inhibiting mechanistic target of rapamycin complex 1 activity and increasing autophagic flux, as observed in mouse lung samples. Patients with idiopathic pulmonary fibrosis who regularly used ezetimibe showed decreased rates of all-cause mortality and lung function decline., Conclusion: Our study presents ezetimibe as a potential novel therapeutic for idiopathic pulmonary fibrosis., Competing Interests: Conflict of interest: The authors have applied for a patent entitled “Pharmaceutical composition for preventing, improving, alleviating or treating pulmonary fibrosis containing ezetimibe as an active ingredient”. The authors have nothing else to disclose., (Copyright ©The authors 2024.)

Background: Despite the widespread impact of the severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019, COVID-19) and vaccination in South Korea, our understanding of kidney diseases following these events remains limited. We aimed to address this gap by investigating the characteristics of glomerular diseases following the COVID-19 infection and vaccination in South Korea., Methods: Data from multiple centers were used to identify de novo glomerulonephritis (GN) cases with suspected onset following COVID-19 infection or vaccination. Retrospective surveys were used to determine the COVID-19-related histories of patients who were initially not implicated. Bayesian structural time series and autoregressive integrated moving average models were used to determine causality., Results: Glomerular diseases occurred shortly after the infection or vaccination. The most prevalent postinfection GN was podocytopathy (42.9%), comprising primary focal segmental glomerulosclerosis and minimal change disease, whereas postvaccination GN mainly included immunoglobulin A nephropathy (IgAN; 57.9%) and Henoch-Schönlein purpura nephritis (HSP; 15.8%). No patient progressed to end-stage kidney disease. Among the patients who were initially not implicated, nine patients with IgAN/HSP were recently vaccinated against COVID-19. The proportion of glomerular diseases changed during the pandemic in South Korea, with an increase in acute interstitial nephritis and a decrease in pauci-immune crescentic GN., Conclusion: This study showed the characteristics of GNs following COVID-19 infection or vaccination in South Korea. Understanding these associations is crucial for developing effective patient management and vaccination strategies. Further investigation is required to fully comprehend COVID-19's impact on GN.

Background: This study aimed to develop a machine learning-based 2-year risk prediction model for early identification of patients with rapid progressive immunoglobulin A nephropathy (IgAN). We also assessed the model's performance to predict the long-term kidney-related outcome of patients., Methods: A retrospective cohort of 1,301 patients with biopsy-proven IgAN from two tertiary hospitals was used to derive and externally validate a random forest-based prediction model predicting primary outcome (30% decline in estimated glomerular filtration rate from baseline or end-stage kidney disease requiring renal replacement therapy) and secondary outcome (improvement of proteinuria) within 2 years after kidney biopsy., Results: For the 2-year prediction of primary outcomes, precision, recall, area-under-the-curve, precision-recall-curve, F1, and Brier score were 0.259, 0.875, 0.771, 0.242, 0.400, and 0.309, respectively. The values for the secondary outcome were 0.904, 0.971, 0.694, 0.903, 0.955, and 0.113, respectively. From Shapley Additive exPlanations analysis, the most informative feature identifying both outcomes was baseline proteinuria. When Kaplan-Meier analysis for 10-year kidney outcome risk was performed with three groups by predicting probabilities derived from the 2-year primary outcome prediction model (low, moderate, and high), high (hazard ratio [HR], 13.00; 95% confidence interval [CI], 9.52-17.77) and moderate (HR, 12.90; 95% CI, 9.92-16.76) groups showed higher risks compared with the low group. From the 2-year secondary outcome prediction model, low (HR, 1.66; 95% CI, 1.42-1.95) and moderate (HR, 1.42; 95% CI, 0.99-2.03) groups were at greater risk for 10-year prognosis than the high group., Conclusion: Our machine learning-based 2-year risk prediction models for the progression of IgAN showed reliable performance and effectively predicted long-term kidney outcome.

Objectives: Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise at various sites throughout the body. The gastroenteropancreatic (GEP) tract is the most common site of NETs. We investigated the clinicopathologic features of patients with GEP-NETs and the utility of digital image analysis, which was compared to eyeball estimation, a conventional method used to determine the Ki-67 labeling index., Methods: The clinicopathologic data of GEP-NET patients at Gangnam Severance Hospital from January 2008 to October 2019 were retrospectively analyzed. Each case was reclassified according to the 2019 World Health Organization classification system, to which the classification of grade 3 was added. Comparisons between eyeball estimation and the digital image analysis method for Ki-67 index assessment were performed by calculating Cohen's kappa (k) coefficient., Results: In total, 345 patients with GEP-NETs were enrolled. The mean age was 49.3 (range 13-79) years, with more male (61.1%) than female patients. The primary tumor sites were the rectum (70.1%), pancreas (12.5%), stomach (6.7%), and duodenum (5.8%). Overall, 298 (86.4%), 35 (10.1%), 2 (0.6%), and 10 (2.9%) patients exhibited grade 1, 2, and 3 and neuroendocrine carcinoma, respectively. Statistical analysis revealed that age > 50 years, tumor size > 2 cm, and presence of lymphovascular invasion, nodal metastasis, and distant metastasis were significantly associated with short overall survival. Additionally, 283 patients underwent digital image analysis of the Ki-67 index, and substantial agreement was found between the two methods (κ value: 0.765)., Conclusions: Eyeball estimation revealed non-inferior results compared with digital image analysis. Further research is needed to evaluate the possibility of using digital image analysis as an alternative analysis method., Competing Interests: None., (IJCEP Copyright © 2023.)

This study investigated whether histopathological classification and histologic lesion scores could significantly and independently predict the progression to end-stage kidney disease (ESKD) in Korean patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis-glomerulonephritis (AAV-GN). This study included 113 patients with AAV-GN confirmed by kidney biopsy. The glomerular, tubulointerstitial, and vascular lesions were systematically assessed using a scoring system. The scoring system was adopted from the Banff scoring system but also the Oxford study and the revision of the ISN/RPS. For comparison, the scores were classified into two groups; the low, and the high, and the difference was investigated between ESKD and non-ESKD groups using Cox proportional analysis. At diagnosis, the median age was 59.0 years and 33.6% were males. Of 113 patients, 44.2% had ESKD progression during follow-up. There were significant differences in several kidney-, inflammation-, and AAV-pathogenesis-related variables between AAV-GN patients with ESKD and those without. The sclerotic class exhibited the worst renal prognosis among the four histopathological classes. Among histopathological features, high interstitial fibrosis, tubular atrophy and global glomerulitis scores were significantly associated with ESKD progression. Whereas multivariable Cox analysis revealed only a high global glomerulitis score which means global endocapillary hypercellularity in a larger number of glomeruli is an independent predictor of ESKD progression. Moreover, among clinical and histopathological features, a high global glomerulitis score could also predict ESKD progression in addition to serum blood urea nitrogen and creatinine. This study demonstrated the worst renal prognosis for the sclerotic class and first discovered that a high global glomerulitis score was an independent predictor of ESKD in patients with AAV-GN., (© 2023. Springer Nature Limited.)

Rationale: The World Health Organization defines a perivascular epithelioid cell tumor (PEComa) as a mesenchymal neoplasia composed of perivascular epithelioid cells with characteristic morphological and immunohistochemical features. Although PEComas have the potential to behave in a malignant fashion, malignant PEComas are extremely rare., Patient Concerns: An 83-year-old man visited our clinic presented with palpable, painless, and movable mass in the right knee area., Diagnoses: Malignant PEComa was diagnosed by incisional biopsy. No metastases was confirmed by radiologic imaging including PET/CT, magnetic resonance imaging, high resolution computed tomography., Interventions: We performed wide excision of the mass and used an anterolateral thigh free flap to reconstruct the defect on the right knee., Outcomes: The permanent histopathology showed malignant PEComa was totally resected. The flap which was performed to cover the defect was survived and the patient discharge without any complications., Lessons: PEComa can metastasize to various anatomical regions. Although there is no established standardized treatment, radical resection is still considered the cornerstone of treatment. Rapid and appropriate defect coverage is important to improve the patient's prognosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Free tissue transfer is the preferred method of reconstructing head and neck defects, with a success rate of approximately 95%. Although flap failure is uncommon, it has a major impact on patient morbidity and diminishes quality of life, making it is important to investigate the causes of flap failure., Methods: This retrospective chart review analyzed patients who underwent free tissue transfer during head and neck reconstruction at a single institution between 2016 and 2021., Results: During the study period, 58 patients underwent 60 free flap procedures. Revision surgery was needed in 14 patients. Subsequent free flap surgery was performed in one patient, and three free flaps (5%) could not be salvaged. Cardiovascular disease was significantly associated with flap failure, and venous congestion (thrombosis) was the most common reason for revision surgery., Conclusion: Cardiovascular disease clearly emerged as a factor related to the failure of free flap surgery, and this issue warrants particular attention in patients for whom free tissue transfer is planned.

Aim: The prognostic role of CD274 (programmed cell death ligand 1 (PD-L1)) overexpression has been examined in many studies. However, the results are controversial and conflicting. The present study aims to investigate the potential role of CD274 (PD-L1) immunohistochemical overexpression as a prognostic marker in malignant tumours., Methods: We searched PubMed, Embase and Web of Science from inception to December 2021 to identify potentially eligible studies. The pooled HRs with 95% CIs were calculated to identify the association between CD274 (PD-L1) overexpression and overall survival (OS), cancer-specific survival, disease-free survival, recurrence-free survival and progression-free survival in 10 lethal malignant tumours. Heterogeneity and publication bias were also analysed., Results: The study included 57 322 patients from 250 eligible studies (241 articles). The meta-analysis by tumour type using multivariate HR revealed worse OS in non-small cell lung cancer (HR 1.41, 95% CI 1.19 to 1.68), hepatocellular carcinoma (HR 1.75, 95% CI 1.11 to 2.74), pancreatic cancer (HR 1.84, 95% CI 1.12 to 3.02), renal cell carcinoma (HR 1.55, 95% CI 1.12 to 2.14) and colorectal cancer (HR 1.46, 95% CI 1.14 to 1.88). Estimated HRs showed associations between CD274 (PD-L1) overexpression and worse prognosis across different types of tumours in various survival endpoints, but no inverse correlation was identified. The heterogeneity for most of the pooled results was high., Conclusions: This large meta-analysis suggests that CD274 (PD-L1) overexpression is a potential biomarker for multiple types of cancers. However, further studies are needed to reduce high heterogeneity., Prospero Registration Number: CRD42022296801., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by autoreactive B cells and dysregulation of many other types of immune cells including myeloid cells. Lupus nephritis (LN) is a common target organ manifestations of SLE. Tonicity-responsive enhancer-binding protein (TonEBP, also known as nuclear factor of activated T-cells 5 (NFAT5)), was initially identified as a central regulator of cellular responses to hypertonic stress and is a pleiotropic stress protein involved in a variety of immunometabolic diseases. To explore the role of TonEBP, we examined kidney biopsy samples from patients with LN. Kidney TonEBP expression was found to be elevated in these patients compared to control patients - in both kidney cells and infiltrating immune cells. Kidney TonEBP mRNA was elevated in LN and correlated with mRNAs encoding inflammatory cytokines and the degree of proteinuria. In a pristane-induced SLE model in mice, myeloid TonEBP deficiency blocked the development of SLE and LN. In macrophages, engagement of various toll-like receptors (TLRs) that respond to damage-associated molecular patterns induced TonEBP expression via stimulation of its promoter. Intracellular signaling downstream of the TLRs was dependent on TonEBP. Therefore, TonEBP can act as a transcriptional cofactor for NF-κB, and activated mTOR-IRF3/7 via protein-protein interactions. Additionally, TonEBP-deficient macrophages displayed elevated efferocytosis and animals with myeloid deficiency of TonEBP showed reduced Th1 and Th17 differentiation, consistent with macrophages defective in TLR signaling. Thus, our data show that myeloid TonEBP may be an attractive therapeutic target for SLE and LN., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The National Institutes of Health (NIH) lupus nephritis activity and chronicity indices, which comprise six activity scores and four chronicity scores, have a long development history. The 2018 revised International Society of Nephrology/Renal Pathology Society classification for lupus nephritis adopted the most recent NIH indices to replace subclasses A, C, and A/C. Although an evidence-based approach should further evaluate the clinical significance of the modified NIH indices, recent validation studies demonstrated that the modified chronicity indices have a strong correlation with kidney outcome of lupus nephritis.

Current treatment strategies for autoimmune diseases may not sufficiently control aberrant metabolism in B-cells. To address this concern, we investigated a biguanide derivative, IM156, as a potential regulator for B-cell metabolism in vitro and in vivo on overactive B-cells stimulated by the pro-inflammatory receptor TLR-9 agonist CpG oligodeoxynucleotide, a mimic of viral/bacterial DNA. Using RNA sequencing, we analyzed the B-cell transcriptome expression, identifying the major molecular pathways affected by IM156 in vivo. We also evaluated the anti-inflammatory effects of IM156 in lupus-prone NZB/W F1 mice. CD19 + B-cells exhibited higher mitochondrial mass and mitochondrial membrane potential compared to T-cells and were more susceptible to IM156-mediated oxidative phosphorylation inhibition. In vivo, IM156 inhibited mitochondrial oxidative phosphorylation, cell cycle progression, plasmablast differentiation, and activation marker levels in CpG oligodeoxynucleotide-stimulated mouse spleen B-cells. Interestingly, IM156 treatment significantly increased overall survival, reduced glomerulonephritis and inhibited B-cell activation in the NZB/W F1 mice. Thus, our data indicated that IM156 suppressed the mitochondrial membrane potentials of activated B-cells in mice, contributing to the mitigation of lupus activity. Hence, IM156 may represent a therapeutic alternative for autoimmune disease mediated by B-cell hyperactivity., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Dynamic nuclear polarization (DNP) is a powerful tool to enhance the NMR signals of molecules by transferring polarization from unpaired electron spins to nuclei through microwave irradiation. The resulting signal enhancements can enable the analysis of samples that have previously been intractable by NMR spectroscopy, including proteins, nucleic acids, and metabolites in cells. To carry out DNP, the sample is doped with a polarization agent, a biradical containing two nitroxide moieties. DNP applications in cells, however, present significant challenges as nitroxides are often susceptible to the reducing cellular environment. Here, we introduce a novel polarization agent, POPAPOL, that exhibits increased lifetimes under reducing conditions. We also compare its bioresistance and DNP performance with three popular, commercially available polarization agents. Our work indicates that pyrrolidine-based nitroxides can outperform piperidine-based nitroxides in cellular environments, and that future polarization agent designs must carefully balance DNP performance and stability for cellular applications., (© 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Background: Acute lung injury (ALI) is the most serious complication of subarachnoid hemorrhage (SAH). We investigated role of autophagy and inflammatory signaling pathways in lung damage and therapeutic effects of dexmedetomidine (DEX)., Methods: Fifty male Wistar rats were randomly divided into five groups: sham, SAH, SAH+ DEX5, SAH+DEX25, and SAH+DEX50. SAH was induced using endovascular perforation technique. All rats received mechanical ventilation for 60 minutes. At 2 and 24 h of SAH induction, SAH+DEX groups were treated with 5, 25, and 50 µg/kg of DEX, respectively. Histological ALI score and pulmonary edema were assessed after 48 h. Lung expression of LC3B, ATG3, p62, TLR4, TLR9, and NFκB was assessed using western blotting and quantitative PCR. Blood levels of IL-6, IL-1β, IFN-γ, and TNFα were also assessed., Results: SAH induced ALI and pulmonary edema, which were attenuated in SAH+DEX5 (P < 0.001 for both) and SAH+DEX25 groups (P = 0.001 and P < 0.001 for ALI and edema, respectively). Lung expressions of LC3B and ATG3 were upregulated in SAH group, which was attenuated in SAH+DEX5 and SAH+DEX25 groups. Lung expressions of TLR4, TLR9, and NFκB were increased in SAH group, which was attenuated in SAH+DEX5 group. Blood IL-6 level was increased in SAH group and attenuated in SAH+DEX5 and SAH+DEX25 groups. Blood IFN-γ level was lower in SAH group than in sham group, and it was increased in SAH+DEX25 group., Conclusions: Low-dose DEX treatment after SAH may protect against ALI by disrupting pathological brain-lung crosstalk and alleviating autophagy flux and TLR-dependent inflammatory pathways.

Tubulointerstitial fibrosis is characterized by accumulation of the extracellular matrix in the interstitium. Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family, is known for promoting cancer metastasis, invasion and stromal fibrosis in various organs. Our previous study demonstrated expression of LOXL2 in kidney podocytes and tubular epithelial cells, and the association between elevated LOXL2 and tubulointerstitial fibrosis. The present study evaluated the effect of LOXL2 inhibition using an inhibitory monoclonal antibody (AB0023) on tubulointerstitial fibrosis in a folic acid-induced tubulointerstitial fibrosis mouse model. The association of LOXL2 with epithelial-mesenchymal transformation-related molecules was also evaluated in vitro using HK-2 cells. The present data demonstrated that AB0023 prevented the progression of tubulointerstitial fibrosis significantly, as determined by trichrome and picro-sirius red staining, as well as the total collagen assay. The mean expression of phosphorylated Smad2 and Smad4 was lower in the AB0023-treated group although it was not statistically significant. Following transforming growth factor-β (TGF-β) challenge, LOXL2-deficient HK-2 cells exhibited significantly lower expression of the mesenchymal markers vimentin and fibronectin than control HK-2 cells. In conclusion, LOXL2 inhibition ameliorates renal fibrosis through the TGF-β/Smad signalling pathway., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Choi et al.)

Background: The International IgA Nephropathy Prediction Tool has been recently developed to estimate the progression risk of immunoglobulin A nephropathy (IgAN). This study aimed to evaluate the clinical performance of this prediction tool in a large IgAN cohort in Korea., Methods: The study cohort was comprised of 2,064 patients with biopsy-proven IgAN from four medical centers between March 2012 and September 2021. We calculated the predicted risk for each patient. The primary outcome was occurrence of a 50% decline in estimated glomerular filtration rate (eGFR) from the time of biopsy or end-stage kidney disease. The model performance was evaluated for discrimination, calibration, and reclassification. We also constructed and tested an additional model with a new coefficient for the Korean race., Results: During a median follow-up period of 3.8 years (interquartile range, 1.8-6.6 years), 363 patients developed the primary outcome. The two prediction models exhibited good discrimination power, with a C-statistic of 0.81. The two models generally underestimated the risk of the primary outcome, with lesser underestimation for the model with race. The model with race showed better performance in reclassification compared to the model without race (net reclassification index, 0.13). The updated model with the Korean coefficient showed good agreement between predicted risk and observed outcome., Conclusion: In Korean IgAN patients, International IgA Nephropathy Prediction Tool had good discrimination power but underestimated the risk of progression. The updated model with the Korean coefficient showed acceptable calibration and warrants external validation.

Nephrin is a type-1 transmembrane protein and a component of the slit diaphragm renal-filtration barrier. It has several functions in actin remodeling and cell-cell adhesion. Nephrin is principally located in the kidney glomerulus, but several studies have reported that nephrin is found in the pancreas, brain, and placenta. However, nephrin expression and its role in human skin have not yet been reported. First, using single-cell RNA sequencing, immunohistochemistry, and immuno-electron microscopy, nephrin expression was confirmed in human-skin epidermal keratinocytes. Nephrin expression colocalized with the expression of zonula occludens-1 in keratinocytes and was closely related to keratinocyte cell density, proliferation, and migration. High glucose treatment decreased nephrin expression and compromised keratinocyte cell migration without yes-associated protein nuclear entry. This reduced cell migration under high glucose conditions was improved in nephrin-overexpressing keratinocytes. Nephrin was highly expressed on the margins of re-epithelized epidermis based on in vivo mice and ex vivo human skin wound models. The results demonstrate that nephrin is expressed in human-skin keratinocytes and functions in cell adhesion, proliferation, and migration. In conclusion, this study suggests that nephrin may have a variety of physiological roles in human skin., (© 2022 Federation of American Societies for Experimental Biology.)

Background: Although the transcatheter closure of atrial septal defect was established as the treatment of choice several decades ago, the process of device neoendothelialization (NE) in humans is not well understood. We aimed to measure the extent of device NE using cardiac computed tomography angiography and analyze its risk factors., Methods: Between January 2005 and February 2021, we retrospectively reviewed 164 devices of 112 patients on cardiac computed tomography angiography. We investigated device shape, contrast opacification within the device that differentiated device NE, and device-related thrombosis or vegetation. Risk factor analysis for major adverse cardiovascular events and incomplete NE according to the postprocedural period was performed., Results: Seventy patients (62.5%) were women, with a median (range) age at the time of device closure of 44.5 (0.6-79.2) years. The mean (±SD) defect size was 16.6 (±7.8) mm, and patients were followed for 35.9±33.9 months. After 6 months of device implantation, 35% of the devices (42/120) had incomplete NE. The intensity of intradevice opacification shifted from complete to partial or nonopacification over time ( P <0.001), and a similar pattern was observed in the shunt flow ( P <0.001). The bulkiness of devices also decreased in proportion to the postprocedural period ( P <0.001). Risk analysis revealed device diameter (hazard ratio, 1.18 [95% CI, 1.04-1.27]; P <0.001) as the only significant factor of incomplete NE and major adverse events., Conclusions: Incomplete NE of atrial septal defect devices was identified on cardiac computed tomography angiography in significant numbers after 6 months of the procedure. The device diameter was related to incomplete NE and major adverse events. Further prospective and multicenter studies are warranted to validate this new assessment of device NE.

Calcimimetic agents allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. Activation of this receptor can reduce glomerular proteinuria and structural damage in proteinuric animal models. However, the precise role of the podocyte CaSR remains unclear. Here, a CaSR knockdown in cultured murine podocytes and a podocyte-specific CaSR knockout in BALB/c mice were generated to study its role in proteinuria and kidney function. Podocyte CaSR knockdown abolished the calcimimetic R-568 mediated calcium ion-influx, disrupted the actin cytoskeleton, and reduced cellular attachment and migration velocity. Adriamycin-induced proteinuria enhanced glomerular CaSR expression in wild-type mice. Albuminuria, podocyte foot process effacement, podocyte loss and glomerular sclerosis were significantly more pronounced in adriamycin-treated podocyte-specific CaSR knockout mice compared to wild-type littermates. Co-treatment of wild-type mice with adriamycin and the calcimimetic cinacalcet reduced proteinuria in wild-type, but not in podocyte-specific CaSR knockout mice. Additionally, four children with nephrotic syndrome, whose parents objected to glucocorticoid therapy, were treated with cinacalcet for one to 33 days. Proteinuria declined transiently by up to 96%, serum albumin increased, and edema resolved. Thus, activation of podocyte CaSR regulates key podocyte functions in vitro and reduced toxin-induced proteinuria and glomerular damage in mice. Hence, our findings suggest a potential novel role of CaSR signaling in control of glomerular disease., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) is receiving more attention as a biomarker for eligibility for immune checkpoint inhibitors in advanced diseases. However, due to high costs and resource limitations, MSI/dMMR testing is not widely performed. Some attempts are in progress to predict MSI/dMMR status through histomorphological features on H&E slides using artificial intelligence (AI) technology. In this study, the potential predictive role of this new methodology was reviewed through a systematic review. Studies up to September 2021 were searched through PubMed and Embase database searches. The design and results of each study were summarized, and the risk of bias for each study was evaluated. For colorectal cancer, AI-based systems showed excellent performance with the highest standard of 0.972; for gastric and endometrial cancers they showed a relatively low but satisfactory performance, with the highest standard of 0.81 and 0.82, respectively. However, analyzing the risk of bias, most studies were evaluated at high-risk. AI-based systems showed a high potential in predicting the MSI/dMMR status of different cancer types, and particularly of colorectal cancers. Therefore, a confirmation test should be required only for the results that are positive in the AI test.

Background/aims: Despite controversy regarding the benefits of immunosuppressive therapy in immunoglobulin A nephropathy (IgAN), clinical outcomes may vary depending on the patient's responsiveness to this therapy. This study evaluated long-term kidney outcomes according to the extent of proteinuria reduction after immunosuppression in IgAN patients., Methods: Among 927 patients with biopsy-proven IgAN, 127 patients underwent immunosuppression. Time-averaged urine protein-creatinine ratio before and within 1 year after start of immunosuppression were calculated, and responsiveness to immunosuppression was assessed as the reduction of proteinuria between the two periods. Patients were classified into tertiles according to the extent of proteinuria reduction. We compared the slopes of estimated glomerular filtration rate (eGFR) decline using a linear mixed model, and estimated hazard ratios (HRs) for disease progression (defined as development of a ≥ 30% decline in eGFR or end-stage renal disease) using a Cox proportional hazard model., Results: Median extent of proteinuria reduction was -2.1, -0.9, and -0.2 g/gCr in the first, second, and third tertiles, respectively. There were concomitant changes in the slopes of annual eGFR decline: -2.03, -2.44, and -4.62 mL/min/1.73 m2 among the first, second, and third tertiles, respectively. In multivariable Cox analysis, the HRs (95% confidence intervals) for disease progression were 0.30 (0.12 to 0.74) in the first tertile and 0.70 (0.34 to 1.45) in the second tertile compared with the thirdtertile., Conclusion: This study showed that greater proteinuria reduction after immunosuppression was associated with a lower risk of disease progression in patients with IgAN, suggesting that responsiveness to immunosuppression may be an important determinant of kidney outcomes.

The aim of this study was to clarify the nature and clinical significance of glomerular subepithelial microparticles (SMPs), located between the basal surface of the podocytes and the glomerular basement membrane. Ultrastructural morphology of 79 renal biopsy samples (obtained from 25 native and 54 transplanted kidneys), showing SMPs in the last 3 years, was reevaluated with regard to the podocyte changes and clinical condition of the patients. One hundred and nine SMPs were identified, with 32.9% of the samples having two or more per glomerulus. Overall, they were most frequently located in the open capillary loops (55%). However, in the native kidney samples with mesangial deposits, 64.3% of SMPs were present in the mesangium-bound areas. Each vesicle ranged from 46.9 to 87.1 nm, and vesicles were admixed with curved strands in larger SMPs. Diffuse effacement of the foot processes and condensation of the actin filaments were present in 56.0% and 62.4% of the samples, respectively. SMPs were associated with hematuria, proteinuria of ≥ 1 gm, and immune complex deposition in the patients with native kidneys, whereas they were related to hyperglycemia and elevated serum creatinine levels in the patients with renal allografts. Patients with native and transplanted kidneys most commonly presented with IgA nephropathy and allograft rejection, respectively. Finding SMPs in the renal biopsy samples is not rare and they may act as a footprint of podocyte injury caused by diverse etiologies. Considering their size, podocyte exosomes could be a possible source of SMPs.

The transferrin receptor (CD71) is known as a receptor for IgA1 on mesangial cells, but the role of CD71 in IgA nephropathy (IgAN) is unknown. We studied clinical implication of mesangial CD71 in 282 patients with biopsy-proven IgAN (2005-2018). The transcript and protein expression of glomerular CD71 was determined by real-time polymerase chain reaction and immunohistochemistry. Ten subjects with microscopic hematuria only and no evidence of histologic abnormalities on kidney biopsy were considered as controls. Human mesangial cells (HMCs) were treated with sera from IgAN patients and expression levels of CD71 and inflammatory cytokine markers were compared according to disease status. Disease progression was defined as a ≥30% decline in estimated glomerular filtration rate from the baseline value. During a mean follow up of 53.5 (18.3-75.9) months, 80 (28.4%) patients developed disease progression. The mRNA expression of CD71 was significantly higher in progressors than in nonprogressors (P = 0.001). Among the Oxford classification scores, patients with M1 had significantly higher CD71 expression levels than those with M0. In a multivariable Cox model, elevated transcript levels of CD71 were significantly associated with 4.32-fold higher risk of disease progression (P = 0.009). Furthermore, CD71 expression levels independently predicted the increase in proteinuria of ≥50% from the baseline (P = 0.03). Finally, HMCs treated with sera from IgAN patients with the higher Oxford score (M1E1S1T0) more increased the mRNA expression of CD71 and inflammatory markers than those with sera from negative score (M0E0S0T0). However, silencing CD71 significantly reduced expression levels of the inflammatory cytokine genes. Our results show that mesangial CD71 is significantly associated with disease progression and may play a biologic role in IgAN., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background : Frameshift indels have emerged as a predictor of immunotherapy response but were not evaluated yet to predict anti-angiogenetic agent (AAA) response or prognosis in clear cell renal cell carcinoma (ccRCC). Methods : Here, to develop biomarkers that predict survival and response to AAA, we evaluated the immunohistochemical expression of proteins whose genes frequently harbor frameshift indels in 638 ccRCC patients and correlated the individual and integrated markers with prognosis and AAA response. The mutational landscape was evaluated using targeted next-generation sequencing in 12 patients concerning protein markers. Immune gene signatures were retrieved from TCGA RNA seq data. Results : Five proteins (APC, NOTCH1, ARID1A, EYS, and filamin A) were independent adverse prognosticators and were incorporated into the Neo-fs index. Better overall, disease-specific and recurrence-free survival were observed with high Neo-fs index in univariate and multivariate survival analyses. Better AAA responses were observed with a high Neo-fs index, which reflected increased MHC class I, CD8+ T cell, cytolytic activity, and plasmacytoid dendritic cell signatures and decreased type II-IFN response signatures, as well as greater single-nucleotide variant (SNV) and indel counts. Conclusions : Neo-fs index, reflecting antitumor immune signature and more SNVs. and indels, is a powerful predictor of survival and AAA response in ccRCC.

Interleukin-4 (IL-4) expression is implicated in the pathogenesis of nephrotic syndrome (NS). This study aimed to investigate the changes in the transcriptomes of human podocytes induced by IL-4 treatment and to analyze whether these changes could be affected by simultaneous steroid treatment. Three groups of human podocytes were treated with control, IL-4, and IL-4 plus dexamethasone (DEX), respectively. We performed whole-transcriptome sequencing to identify differentially expressed genes (DEGs) between the groups. We investigated relevant biological pathways using Gene Ontology (GO) enrichment analyses. We also attempted to compare and validate the DEGs with the genes listed in PodNet, a literature-based database on mouse podocyte genes. A total of 176 genes were differentially expressed among the three groups. GO analyses showed that pathways related to cytoskeleton organization and cell signaling were significantly enriched. Among them, 24 genes were listed in PodNet, and 12 of them were previously reported to be associated with IL-4-induced changes in human podocytes. Of the 12 genes, the expression levels of BMP4 , RARB , and PLCE1 were reversed when podocytes were simultaneously treated with DEX. In conclusion, this study explored changes in the transcriptome profiles of human podocytes treated with IL-4. Few genes were reported in previous studies and were previously validated in experiments with human podocytes. We speculate that IL-4 may exert pathogenic effects on the transcriptome of human podocytes, and a few genes may be involved in the pathogenesis.

Background: Complement activation has been highlighted in immunoglobulin (Ig) A nephropathy pathogenesis. However, whether the complement system can affect the downstream phenotype of IgA nephropathy remains unknown. Herein, we investigated the association of mesangial C3 deposition with the Oxford classification and their joint effects on worsening kidney function., Methods: We investigated 453 patients with biopsy-proven IgA nephropathy. C3 deposition was defined as an immunofluorescence intensity of C3 ≥2+ within the mesangium. The subjects were classified according to the combination of C3 deposition and Oxford classification lesions. The primary endpoint was a composite of ≥30% decline in the estimated glomerular filtration rate or an increase in proteinuria ≥3.5 g/g during follow-up., Results: Among the Oxford classification lesions, mesangial hypercellularity (M1), segmental glomerulosclerosis (S1) and tubulointerstitial fibrosis (T1-2) and crescentic lesion significantly correlated with C3 deposition. During a median follow-up of 33.0 months, the primary endpoint occurred more in patients with M1, S1, T1-2 and mesangial C3 deposition than in those without. In individual multivariable-adjusted Cox analyses, the presence of M1, S1, T1-2 and C3 deposition was significantly associated with higher risk of reaching primary endpoint. In the combined analyses of C3 deposition and the Oxford classification lesions, the hazard ratios for the composite outcome were significantly higher in the presence of C3/M1, C3/S1 and C3/crescent than in the presence of each lesion alone., Conclusions: Complement deposition can strengthen the significance of the Oxford classification, and the presence of both components portends a poorer prognosis in IgA nephropathy., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Extracellular adenosine 5'-triphosphate (ATP) is a well-known inflammasome-activating signal. Emerging evidence demonstrates a critical role for inflammasome activation in vitiligo pathogenesis. However, the specific molecular mechanism of inflammasome-dependent melanocyte degeneration in vitiligo is still not clear. This study presents how extracellular ATP, released from keratinocytes by oxidative stress, affects melanocyte survival in vitiligo skin. H 2 O 2 -induced oxidative injury increased ATP release from keratinocytes and skin tissues. The high concentration of extracellular ATP induced both ROS production and cell death in melanocytes. Treatment with ATP caused the activation of caspase-1 as well as the production of active forms of IL-1β and IL-18 via P2X7 receptor in keratinocytes and melanocytes. Lesional and perilesional skin of vitiligo showed higher levels of ATP as well as upregulation of active caspase-1 compared with nonlesional skin, suggesting its possible role in inflammasome activation in vitiligo. Moreover, the elevated expression of CXCL9 in keratinocytes, mediated through ATP/P2X7 receptor-dependent inflammasome activation, was responsible for CLA + CD8 + T-cell chemotaxis into the skin. These results demonstrate that extracellular ATP as a danger signal activates the inflammasome pathway and increases cutaneous chemotaxis of CD8 + T cells via CXCL9 in vitiligo. Therefore, targeting ATP-P2X7 signaling may be a potential strategy for vitiligo treatment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Backgrounds: Glomerular diseases, a set of debilitating and complex disease entities, are related to mortality and morbidity. To gain insight into pathophysiology and novel treatment targets of glomerular disease, various types of biospecimens linked to deep clinical phenotyping including clinical information, digital pathology, and well-defined outcomes are required. We provide the rationale and design of the KOrea Renal biobank NEtwoRk System TOward Next-generation analysis (KORNERSTONE)., Methods: The KORNERSTONE, which has been initiated by Korea Centres for Disease Control and Prevention, is designed as a multi-centre, prospective cohort study and biobank for glomerular diseases. Clinical data, questionnaires will be collected at the time of kidney biopsy and subsequently every 1 year after kidney biopsy. All of the clinical data will be extracted from the electrical health record and automatically uploaded to the web-based database. High-quality digital pathologies are obtained and connected in the database. Various types of biospecimens are collected at baseline and during follow-up: serum, urine, buffy coat, stool, glomerular complementary DNA (cDNA), tubulointerstitial cDNA. All data and biospecimens are processed and stored in a standardised manner. The primary outcomes are mortality and end-stage renal disease. The secondary outcomes will be deterioration renal function, remission of proteinuria, cardiovascular events and quality of life., Discussion: Ethical approval has been obtained from the institutional review board of each participating centre and ethics oversight committee. The KORNERSTONE is designed to deliver pioneer insights into glomerular diseases. The study design allows comprehensive, integrated and high-quality data collection on baseline laboratory findings, clinical outcomes including administrative data and digital pathologic images. This may provide various biospecimens and information to many researchers, establish the rationale for future more individualised treatment strategies for glomerular diseases., Trial Registration: NCT03929887 .

Background and Aims: Identifying malignant biliary strictures using endobiliary brushing cytology specimens is important for treatment decision-making and prognosis prediction. The sensitivity of brushing cytology specimens based on Papanicolaou (Pap) staining is low, which hampers accurate diagnosis of indeterminate strictures. Here, we assessed the diagnostic value of immunohistochemical (IHC) and immunofluorescence (IF) staining for methionyl-tRNA synthetase 1 (MARS1)., Methods: Endobiliary brushing cytology specimens were obtained during ERCP from 80 patients with an extrahepatic biliary stricture. Pap and MARS1 IF staining were performed on liquid-based cytology slides derived from these specimens. Sections of bile duct adenocarcinoma and normal bile duct tissue were obtained from 45 patients who underwent surgery for malignant biliary stricture, and MARS1 levels were evaluated by IHC staining., Results: MARS1 IF staining was applied to brushing cytology specimens, and the results showed strong signals in malignant biliary structures but not in the negative for malignancy specimens. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 70.4%, 96.2%, 97.4%, 56.8%, and 78.8%, respectively, for conventional Pap staining and 98.1%, 96.1%, 98.1%, 96.2%, and 97.5%, respectively, for MARS1 IF (P < .0001). When IHC staining was used, MARS1 was detected in 45 bile duct adenocarcinoma sections but not in 15 normal bile duct sections. Moreover, MARS1 mRNA and protein levels were significantly higher in bile duct adenocarcinoma sections according to polymerase chain reaction and Western blot, respectively., Conclusions: The high sensitivity and accuracy of MARS1 IF staining enabled detection of malignancy in patients with indeterminate biliary stricture. Further prospective studies are needed to validate our findings. (Clinical trial registration number: KCT 0003285.)., (Copyright © 2020 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Dynamic nuclear polarization (DNP) has shown great promise as a tool to enhance the nuclear magnetic resonance signals of proteins in the cellular environment. As sensitivity increases, the ability to select and efficiently polarize a specific macromolecule over the cellular background has become desirable. Herein, we address this need and present a tetrazine-based DNP agent that can be targeted selectively to proteins containing the unnatural amino acid (UAA) norbornene-lysine. This UAA can be introduced efficiently into the cellular milieu by genetic means. Our approach is bio-orthogonal and easily adaptable to any protein of interest. We illustrate the scope of our methodology and investigate the DNP transfer mechanisms in several biological systems. Our results shed light on the complex polarization-transfer pathways in targeted DNP and ultimately pave the way to selective DNP-enhanced NMR spectroscopy in both bacterial and mammalian cells., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new species of Diosaccus Boeck, 1873 (Arthropoda, Hexanauplia, Harpacticoida) was recently discovered in Korean waters. The species was previously recognized as D. ezoensis Itô, 1974 in Korea but, here, is described as a new species, D. koreanus sp. nov. , based on the following features: 1) second inner seta on exopod of fifth thoracopod apparently longest in female, 2) outer margin of distal endopodal segment of second thoracopod ornamented with long setules in male, 3) caudal seta VII located halfway from base of rami (vs. on anterior extremity in D. ezoensis ), and 4) sixth thoracopod with three setae in female (vs. 2 setae in D. ezoensis ). In addition, there is also a mitochondrial COI sequence difference of more than 19.93% with D. ezoensis registered in NCBI. A key to Diosaccus species of the world is also provided, and new morphological features and DNA sequences are presented for two other harpacticoid species, Parathalestris verrucosa Itô, 1970 and Peltidium quinquesetosum Song & Yun, 1999. In order to clearly identify harpacticoids at the species level, both morphological and DNA sequence characteristics should be considered., (Byung-Jin Lim, Hyun Woo Bang, Heejin Moon, Jinwook Back.)

Background: Letermovir, an inhibitor of unique long (UL)56-encoded cytomegalovirus (CMV)-terminase, shows prophylactic effects with low-grade adverse events in hematopoietic stem cell transplant recipients. Despite few case reports on acquired letermovir resistance, the frequency of de novo amino acid (A.A.) changes encoded by UL56 in CMV-infected tissues is unclear., Methods: We analyzed CMV UL56 sequences between the conserved region IV and variable region I in 175 formalin-fixed, paraffin-embedded tissues obtained from 147 patients showing positive CMV immunochemical staining between November 2012 and October 2016. Nucleotides 552-1330 of the open reading frame of UL56 were amplified with 5 primers and sequenced by a dideoxy fluorescence-based cycle., Results: Six (3.4%) tissues from 4 (2.7%) patients harbored A.A. substitutions. There were no known potent resistant mutations. However, we found C325Y in 2 tissues from 1 patient, along with other mutations. Four novel A.A. changes, which have not been observed in previous in vitro experiments, were identified (T244I, S301T, G312V, and M434I). Most (9 of 11, 81.8%) of the A.A. changes occurred between the codons 301 and 325 present between the conserved regions V and VI., Conclusions: The treatment difficulties associated with letermovir resistance in a clinical setting need to be verified before its widespread use., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose: To evaluate elasticity and perfusion change associated with fibrosis in a rabbit model of unilateral ureter obstruction using shear wave elastography (SWE) and contrast-enhanced ultrasonography (CEUS)., Methods: Complete unilateral ureter obstruction by ligation was performed in the left kidney of 15 rabbits. Renal elasticity on SWE and perfusion change on CEUS at the renal cortex were measured before and after the operation. Histopathological renal fibrosis was quantified by the stained area ratio with Masson trichrome and Picrosirius red using ImageJ analysis. Renal elasticity and perfusion values were compared by the Mann-Whitney U test and Proc Mixed as a function of time. Spearman's correlation was used to analyze differences between imaging values and fibrosis., Results: The duration of imaging follow-up was up to 49 days, with interval imaging performed 1-3 times. Renal elasticity values were higher in obstructed kidneys compared to contralateral kidneys (31.0 kPa vs 16.4 kPa, p < 0.001) and increased according to postoperative time (0.46 kPa/day). With respect to renal fibrosis, SWE values were positively correlated with Masson trichrome (ρ = 0.651, p < 0.001) and Picrosirius red (ρ = 0.514, p = 0.007). Among CEUS parameters, mean transit time was negatively correlated with renal fibrosis by Masson trichrome (ρ = - 0.639, p = 0.001) and Picrosirius red (ρ = - 0.625, p = 0.001). Rise time and time to peak were positively correlated with renal fibrosis., Conclusion: Obstructive uropathy resulted in changes to both renal elasticity and perfusion. Renal fibrosis was moderately associated with increased renal cortical stiffness and both delayed and decreased cortical perfusion., Key Points: • Obstructive uropathy causes changes in elasticity and perfusion in a rabbit model. • Renal fibrosis from obstructive uropathy increases renal cortical stiffness, and both delay and decrease cortical perfusion.

We aimed to determine the relative contribution of each complement (C3 and C4d) deposition to the progression of IgA nephropathy (IgAN). We enrolled a total of 380 patients with biopsy-confirmed IgAN. Mesangial deposition of C3(<2+ vs. ≥2+) and C4d(positive vs. negative) was evaluated by immunofluorescence staining and immunohistochemistry, respectively. Study endpoint was the composite of a 30% decline in eGFR or ESRD. The risk of reaching the primary outcome was significantly higher in patients having C3 ≥ 2+ and C4d(+) than in corresponding counterparts. Adding C3 deposition to clinical data acquired at kidney biopsy modestly increased the area under the receiver-operating characteristic curve, net reclassification improvement, and integrated discrimination improvement (IDI); adding C4d increased IDI only. In conclusion, mesangial C3 and C4d deposition was an independent risk factor for progression of IgAN. C3 showed better predictability than C4d, suggesting that lectin pathway alone has limited clinical prognostic value., Competing Interests: Declaration of Competing Interest All the authors declared no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The mitochondrial genome of a dogielinotid amphipod, Haustorioides koreanus , was completely sequenced for the first time. The total mitogenome length of H . koreanus was 14,839 bp with 13 protein-coding genes, two ribosomal RNA genes, and 22 transfer RNA genes. The phylogenetic tree confirmed that H. koreanus belongs to the families Hyalellidae in the same clade and to the suborder Senticaudata within Amphipoda. This is the first record of the complete mitochondrial genome sequence of the family Dogielinotidae., Competing Interests: The authors declare no conflict of interest. The authors alone are responsible for the content and writing of the paper., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The split inteins from the DnaE cyanobacterial family are efficient and versatile tools for protein engineering and chemical biology applications. Their ultrafast splicing kinetics allow for the efficient production of native proteins from two separate polypeptides both in vitro and in cells. They can also be used to generate proteins with C-terminal thioesters for downstream applications. In this chapter, we describe a method based on a genetically fused version of the DnaE intein Npu for the preparation of doubly modified proteins through recombinant expression. In particular, we provide protocols for the recombinant production of modified ubiquitin through amber suppression where fused Npu is used (1) as a traceless purification tag or (2) as a protein engineering tool to introduce C-terminal modifications for subsequent attachment to other proteins of interest. Our purification protocol allows for quick and facile separation of truncated products and eliminates the need for engineering protease cleavage sites. Our approach can be easily adapted to different proteins and applications where the simultaneous presence of internal and C-terminal modifications is desirable.

The present study reports, for the first time, the complete mitochondrial genome (mitogenome) of Undinula vulgaris . The total mitogenome length of U. vulgaris was 15,303 bp with 13 protein-coding genes (PCGs), 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and 1 non-coding region. Phylogenetic analysis showed that U. vulgaris belonged to the same family. This is the second report of the complete mitogenome sequence of the family Calanidae., Competing Interests: The authors declare that they do not have any conflict of interest. The authors alone are responsible for the content and writing of the paper., (© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objective: To develop a diagnostic model for superficial soft tissue lesions to differentiate epidermal cyst (EC) from other lesions based on ultrasound (US) features., Materials and Methods: This retrospective study included 205 patients who had undergone US examinations for superficial soft tissue lesions and subsequent surgical excision. The study population was divided into the derivation set (n = 112) and validation set (n = 93) according to the imaging date. The following US features were analyzed to determine those that could discriminate EC from other lesions: more-than-half-depth involvement of the dermal layer, "submarine sign" (focal projection of the hypoechoic portion to the epidermis), posterior acoustic enhancement, posterior wall enhancement, morphology, shape, echogenicity, vascularity, and perilesional fat change. Using multivariable logistic regression, a diagnostic model was constructed and visualized as a nomogram. The performance of the diagnostic model was assessed by calculating the area under the curve (AUC) of the receiver operating characteristic curve and calibration plot in both the derivation and validation sets., Results: More-than-half-depth involvement of the dermal layer (odds ratio [OR] = 3.35; p = 0.051), "submarine sign" (OR = 12.2; p < 0.001), and morphology (OR = 5.44; p = 0.002) were features that outweighed the others when diagnosing EC. The diagnostic model based on these features showed good discrimination ability in both the derivation set (AUC = 0.888, 95% confidence interval [95% CI] = 0.825-0.950) and validation set (AUC = 0.902, 95% CI = 0.832-0.972)., Conclusion: More-than-half-depth of involvement of the dermal layer, "submarine sign," and morphology are relatively better US features than the others for diagnosing EC., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2019 The Korean Society of Radiology.)

Background: The α2 adrenergic agonist dexmedetomidine (DEX) has huge potential for protecting against cerebral vasospasm, a leading cause of death and disability after subarachnoid hemorrhage (SAH). Biomarker assays for SAH have recently emerged as tools for predicting vasospasm and outcomes. We investigated the effects of DEX on vasospasm and assessed relevant biomarkers in a rat SAH model., Methods: Male Wistar rats were randomly assigned to sham (n=10), vehicle (n=10), SAH (n=10), or SAH+ DEX (n=10) groups. The SAH and SAH+DEX groups received 0.3 mL injections of autologous blood into the cisterna magna, followed by intraperitoneal injections of normal saline or 10 μg/kg DEX. Forty-eight hours later, neurological deficits as well as the basilar artery (BA) wall thickness and cross-sectional area were measured. Cerebrospinal fluid (CSF) and blood samples were obtained to assess concentrations of interleukin (IL)-6, C-reactive protein (CRP), endothelin-1, and S100-β using enzyme-linked immunosorbent assays., Results: The SAH and SAH+DEX groups exhibited deteriorated neurological function as well as structural and morphological BA vasospasm. The SAH+DEX group showed an improved neurological function score (ie, a 52% decrease), a 10% reduction in wall thickness, and a BA cross-sectional area enlarged by 157%. Compared with the sham group, CSF levels of IL-6 and CRP in the SAH and SAH+DEX groups, as well as serum IL-6 and CRP levels in the SAH group, were significantly elevated. The SAH+DEX group showed significantly lower CSF IL-6 levels than the SAH group. Serum and CSF levels of endothelin-1 and S100-β were similar across all groups., Conclusions: DEX administration reduced the severity of cerebral vasospasm and improved neurological function in SAH rats; this may be closely linked to reduced CSF IL-6 levels.

Background: The diagnostic criteria of antibody-mediated rejection (ABMR) has been significantly changed since Banff 2013. The most important revision was adopting microvascular inflammation (MVI) as immunopathologic evidence for ABMR even in C4d-negative cases. In this study, we retrospectively reviewed previous allograft biopsy results and evaluated the impact of this change., Methods: We reviewed results of 536 renal allograft biopsies at Severance Hospital during 2011 to 2013, which were diagnosed according to the Banff 2009 criteria. All biopsy results were reassessed according to the Banff 2017 criteria., Results: According to the Banff 2009 criteria, antibody-mediated changes were observed in 48 cases out of the 536 allograft biopsies (9.0%). According to the Banff 2017 criteria, 28 additional cases (5.2%) were reclassified as antibody-mediated changes. Twenty-six of these cases were C4d-negative ABMR. The most frequent diagnostic finding in these cases was MVI comprising glomerulitis and peritubular capillaritis. Donor-specific antibodies were investigated in 14 of these cases, which revealed positive results in 12 cases., Conclusion: The incidence rate of ABMR has increased after the recent revision of the Banff criteria. The MVI in C4d-negative ABMR cases is the major cause for this increase., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Excessive bulking force during ureteral access sheath (UAS) placement may induce injury. The sliding friction between surfaces can be reduced with the application of ultrasonic vibration. We investigated the efficacy and safety of an ultrasonic vibration transducing device for reducing the maximal ureteral access sheath insertion force (UASIF)., Materials and Methods: A device was developed for transducing ultrasonic longitudinal-axis vibration onto the UAS at an adjustable amplitude and frequency while measuring the degree of UASIF. In the pilot study, six porcine models were used to investigate the optimal amplitude and frequency of vibration and to calculate sample size. Twelve porcine models were utilized in a randomized controlled trial. Resected ureters were pathologically evaluated for ureteral injury., Results: The transduction of ultrasonic vibration at an amplitude of 0.04 g and a frequency of 18,000 Hz resulted in a maximal UASIF reduction of 36.4% (interquartile range 32.7-43.1). Maximal UASIF tended to decrease with increasing vibration frequency. No significant differences in UASIF reductions were observed according to amplitude. In the randomized controlled trial, the maximal UASIF reduction was 37.0% (interquartile range 21.4-44.2). Grade II injury was pathologically diagnosed in 8.3% (1/12) of the ureters in both groups., Conclusions: The transduction of ultrasonic longitudinal-axis vibration onto the UAS reduces maximal UASIF and does not harm the ureter. Reducing the velocity of sheath insertion may further reduce maximal UASIF.