Cross-species single-cell analysis uncovers the immunopathological mechanisms associated with IgA nephropathy progression.

IgA nephropathy (IgAN) represents the main cause of renal failure, while the precise pathogenetic mechanisms have not been fully determined. Herein, we conducted a cross-species single-cell survey on human IgAN and mouse and rat IgAN models to explore the pathogenic programs. Cross-species single-cell RNA sequencing (scRNA-Seq) revealed that the IgAN mesangial cells (MCs) expressed high levels of inflammatory signatures CXCL12, CCL2, CSF1, and IL-34 and specifically interacted with IgAN macrophages via the CXCL12/CXCR4, CSF1/IL-34/CSF1 receptor, and integrin subunit alpha X/integrin subunit alpha M/complement C3 (C3) axes. IgAN macrophages expressed high levels of CXCR4, PDGFB, triggering receptor expressed on myeloid cells 2, TNF, and C3, and the trajectory analysis suggested that these cells derived from the differentiation of infiltrating blood monocytes. Additionally, protein profiling of 21 progression and 28 nonprogression IgAN samples revealed that proteins CXCL12, C3, mannose receptor C-type 1, and CD163 were negatively correlated with estimated glomerular filtration rate (eGFR) value and poor prognosis (30% eGFR as composite end point). Last, a functional experiment revealed that specific blockade of the Cxcl12/Cxcr4 pathway substantially attenuated the glomerulus and tubule inflammatory injury, fibrosis, and renal function decline in the mouse IgAN model. This study provides insights into IgAN progression and may aid in the refinement of IgAN diagnosis and the optimization of treatment strategies.

Alterations of sleep deprivation on brain function: A coordinate-based resting-state functional magnetic resonance imaging meta-analysis.

BACKGROUND: Sleep deprivation is a prevalent issue that impacts cognitive function. Although numerous neuroimaging studies have explored the neural correlates of sleep loss, inconsistencies persist in the reported results, necessitating an investigation into the consistent brain functional changes resulting from sleep loss. AIM: To establish the consistency of brain functional alterations associated with sleep deprivation through systematic searches of neuroimaging databases. Two meta-analytic methods, signed differential mapping (SDM) and activation likelihood estimation (ALE), were employed to analyze functional magnetic resonance imaging (fMRI) data. METHODS: A systematic search performed according to PRISMA guidelines was conducted across multiple databases through July 29, 2023. Studies that met specific inclu-sion criteria, focused on healthy subjects with acute sleep deprivation and reported whole-brain functional data in English were considered. A total of 21 studies were selected for SDM and ALE meta-analyses. RESULTS: Twenty-one studies, including 23 experiments and 498 subjects, were included. Compared to pre-sleep deprivation, post-sleep deprivation brain function was associated with increased gray matter in the right corpus callosum and decreased activity in the left medial frontal gyrus and left inferior parietal lobule. SDM revealed increased brain functional activity in the left striatum and right central posterior gyrus and decreased activity in the right cerebellar gyrus, left middle frontal gyrus, corpus callosum, and right cuneus. CONCLUSION: This meta-analysis consistently identified brain regions affected by sleep deprivation, notably the left medial frontal gyrus and corpus callosum, shedding light on the neuropathology of sleep deprivation and offering insights into its neurological impact.

The Safety and Efficacy of Dorsal Root Entry Zone Lesioning for Pain Management in Patients With Brachial Plexus Avulsion: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Persistent neuropathic pain after brachial plexus avulsion (BPA) is common and generally nonresponsive to medical management. Dorsal root entry zone (DREZ) lesioning is the last resort for pain management in patients with BPA. This study aims to investigate and compare the outcomes and complications of DREZ procedures. METHODS: A systematic literature search was conducted to identify all related studies. Comparisons were based on the number of patients with preoperative pain vs postoperative pain, with the effect size calculated using the risk ratio. Mean visual analog scale (VAS) scores were extracted and analyzed between interventions. A meta-regression analysis was performed to identify risk factors for final outcomes. The rates of complications were also assessed and analyzed between interventions. RESULTS: A total of 30 studies with 917 patients (90.0% male and 10.0% female, mean age: 42.9 ± 16.6) were included in this systematic review. Of the 917 patients who underwent surgery, 655 (71.4%) patients had significant pain reduction at the last follow-up (P < .05). The weighted mean preoperative VAS score was 8.3 ± 1.3, compared with postoperative VAS scores (1.9 ± 2.2); a significant improvement was observed (P < .05). The subgroup analysis showed that microsurgical DREZotomy (MDT) is associated with better outcomes in terms of VAS score improvements compared with radiofrequency (RF)-assisted DREZ lesioning (P < .05). Meta-analysis showed that the relative risk of motor deficits was significantly lower in the MDT group, compared with the RF-assisted group (P < .05). Meta-regression showed that older age is correlated with an elevated risk of postoperative motor deficits compared with the incidence of sensory loss. CONCLUSION: DREZ lesioning is effective for intractable pain alleviation after BPA. Compared with RF-assisted DREZ lesioning, MDT is associated with better VAS score improvements and a lower rate of postoperative motor weakness.

Urinary miR-185-5p is a biomarker of renal tubulointerstitial fibrosis in IgA nephropathy.

Background: For IgA nephropathy (IgAN), tubular atrophy/interstitial fibrosis is the most important prognostic pathological indicator in the mesangial and endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy, and presence of crescents (MEST-C) score. The identification of non-invasive biomarkers for tubular atrophy/interstitial fibrosis would aid clinical monitoring of IgAN progression and improve patient prognosis. Methods: The study included 188 patients with primary IgAN in separate confirmation and validation cohorts. The associations of miR-92a-3p, miR-425-5p, and miR-185-5p with renal histopathological lesions and prognosis were explored using Spearman correlation analysis and Kaplan-Meier survival curves. Bioinformatics analysis and dual luciferase experiments were used to identify hub genes for miR-185-5p. The fibrotic phenotypes of tubular epithelial cells were evaluated in vivo and in HK-2 cells. Results: miRNA sequencing and cohort validation revealed that the expression levels of miR-92a-3p, miR-425-5p, and miR-185-5p in urine were significantly increased among patients with IgAN; these levels could predict the extent of tubular atrophy/interstitial fibrosis in such patients. The combination of the three biomarkers resulted in an area under the receiver operating characteristic curve of 0.742. The renal prognosis was significantly worse in the miR-185-5p high expression group than in the low expression group (P=0.003). Renal tissue in situ hybridization, bioinformatics analysis, and dual luciferase experiments confirmed that miR-185-5p affects prognosis in patients with IgAN mainly by influencing expression of the target gene tight junction protein 1 (TJP1) in renal tubular epithelial cells. In vitro experiment revealed that an miR-185-5p mimic could reduce TJP1 expression in HK-2 cells, while increasing the levels of α-smooth muscle actin, fibronectin, collagen I, and collagen III; these changes promoted the transformation of renal tubular epithelial cells to a fibrotic phenotype. An miR-185-5p inhibitor can reverse the fibrotic phenotype in renal tubular epithelial cells. In a unilateral ureteral obstruction model, the inhibition of miR-185-5p expression alleviated tubular atrophy/interstitial fibrosis. Conclusion: Urinary miR-185-5p, a non-invasive biomarker of tubular atrophy/interstitial fibrosis in IgAN, may promote the transformation of renal tubular epithelial cells to a fibrotic phenotype via TJP1.

Evaluation of Different Surgical Techniques for Revision Cubital Tunnel Release: A Meta-Analysis of Patient-Reported Symptoms.

PURPOSE: Controversy exists regarding the best option for revision surgery in refractory cubital tunnel syndrome (CuTS). The purpose of this systematic review was to evaluate the effectiveness of revision surgery and determine the optimal surgical approach for patients requiring revision surgery for CuTS. METHODS: A literature search was conducted. Characteristics of the included studies were summarized descriptively. The risk ratio between patient-reported preoperative and postoperative outcomes relating to pain, motor, and sensory deficits was calculated. A meta-regression analysis was performed to evaluate the postoperative symptom improvements based on the type of secondary surgery. Random-effects meta-analysis and descriptive statistics were used when appropriate. RESULTS: A total of 471 patients were evaluated in 20 studies. In total, 254 (53.9%) male and 217 (46.1%) female patients, with an average age of 49.2 ± 14.1 years, were included in this study. Pain was the most common symptom (n = 346, 81.6%), followed by sensory and motor dysfunction in 342 (80.6%) and 223 (52.6%) patients, respectively. Meta-analysis comparing preoperative and postoperative symptoms between patients who had submuscular transposition (SMT), subcutaneous transposition (SCT), and neurolysis showed that a significant subgroup difference exists between the types of revision surgery in sensory and motor improvements. Meta-regression showed that SMT was associated with better outcomes compared with SCT in motor and sensory improvements. CONCLUSIONS: Revision surgery for CuTS can be useful for addressing recurrent and persistent symptoms. Compared with neurolysis and SCT, SMT seems to be the superior option for revision surgery, demonstrating substantial improvement in all symptom domains. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Utility of Regional Maxillary Nerve Blocks in Improving Cleft Palate Postoperative Outcomes.

BACKGROUND: Palatoplasty procedures used to repair cleft palates are commonly associated with limiting postoperative pain. Regional anesthetic blocks have been utilized to improve pain outcomes and decrease opioid intake, yet additional data is needed to fully explore its utility in this setting. OBJECTIVE: To explore whether ultrasound-guided suprazygomatic maxillary blocks (SMB) improve postoperative pain, postoperative opioid use, time to oral feeding, and length of stay compared with a palatal field block in cleft palate repair. METHODS: In this retrospective chart review, 47 patients aged 9 to 25 months who underwent cleft palate repair between 2013 and 2020 were allocated into 2 groups: a control group where patients received only palatal local anesthetic in a field block fashion (N=29), and Maxillary block group who received ultrasound-guided SMB (N=18). Patients were matched by age and cleft Veau type. The primary outcomes were total postoperative morphine equivalent consumption, average pain scores, length of stay, and time to first oral feed. RESULTS: Comparing field block versus SMB groups, there was not a statistical difference in the overall dose of postoperative morphine equivalent opioid administration (11.71 vs. 13.36 mg; P =0.483), average pain scores (5.78 vs. 5.27; P =0.194), time to first oral feed [17.21 vs. 14.48 h; P =0.407, 95% CI: (-3.85, 9.32)] or length of stay ( P =0.292). CONCLUSION: The use of SMBs did not demonstrate a difference in the postoperative outcomes evaluated by this study. Further study is needed to define its utility in cleft palate repair.

Progress in biological age research.

Biological age (BA) is a common model to evaluate the function of aging individuals as it may provide a more accurate measure of the extent of human aging than chronological age (CA). Biological age is influenced by the used biomarkers and standards in selected aging biomarkers and the statistical method to construct BA. Traditional used BA estimation approaches include multiple linear regression (MLR), principal component analysis (PCA), Klemera and Doubal's method (KDM), and, in recent years, deep learning methods. This review summarizes the markers for each organ/system used to construct biological age and published literature using methods in BA research. Future research needs to explore the new aging markers and the standard in select markers and new methods in building BA models.

Proteomic profiling of IgA nephropathy reveals distinct molecular prognostic subtypes.

IgA nephropathy (IgAN) is a heterogeneous disease, which poses a series of challenges to accurate diagnosis and personalized therapy. Herein, we constructed a systematic quantitative proteome atlas from 59 IgAN and 19 normal control donors. Consensus sub-clustering of proteomic profiles divided IgAN into three subtypes (IgAN-C1, C2, and C3). IgAN-C2 had similar proteome expression patterns with normal control, while IgAN-C1/C3 exhibited higher level of complement activation, more severe mitochondrial injury, and significant extracellular matrix accumulation. Interestingly, the complement mitochondrial extracellular matrix (CME) pathway enrichment score achieved a high diagnostic power to distinguish IgAN-C2 from IgAN-C1/C3 (AUC>0.9). In addition, the proteins related to mesangial cells, endothelial cells, and tubular interstitial fibrosis were highly expressed in IgAN-C1/C3. Most critically, IgAN-C1/C3 had a worse prognosis compared to IgAN-C2 (30% eGFR decline, p = 0.02). Altogether, we proposed a molecular subtyping and prognostic system which could help to understand IgAN heterogeneity and improve the treatment in the clinic.

BMP-6 promotes type 2 immune response during enhancement of rat mandibular bone defect healing.

Introduction: Bone morphogenetic proteins (BMPs) are used as key therapeutic agents for the treatment of difficult fractures. While their effects on osteoprogenitors are known, little is known about their effects on the immune system. Methods: We used permutations of BMP-6 (B), vascular endothelial growth factor (V), and Hedgehog signaling pathway activator smoothened agonist (S), to treat a rat mandibular defect and investigated healing outcomes at week 8, in correlation with the cellular landscape of the immune cells in the fracture callus at week 2. Results: Maximum recruitment of immune cells to the fracture callus is known to occur at week 2. While the control, S, V, and VS groups remained as nonunions at week 8; all BMP-6 containing groups - B, BV, BS and BVS, showed near-complete to complete healing. This healing pattern was strongly associated with significantly higher ratios of CD4 T (CD45+CD3+CD4+) to putative CD8 T cells (CD45+CD3+CD4-), in groups treated with any permutation of BMP-6. Although, the numbers of putative M1 macrophages (CD45+CD3-CD11b/c+CD38high) were significantly lower in BMP-6 containing groups in comparison with S and VS groups, percentages of putative - Th1 cells or M1 macrophages (CD45+CD4+IFN-γ+) and putative - NK, NKT or cytotoxic CD8T cells (CD45+CD4-IFN-γ+) were similar in control and all treatment groups. Further interrogation revealed that the BMP-6 treatment promoted type 2 immune response by significantly increasing the numbers of CD45+CD3-CD11b/c+CD38low putative M2 macrophages, putative - Th2 cells or M2 macrophages (CD45+CD4+IL-4+) cells and putative - mast cells, eosinophils or basophils (CD45+CD4-IL-4+ cells). CD45- non-haematopoietic fractions of cells which encompass all known osteoprogenitor stem cells populations, were similar in control and treatment groups. Discussion: This study uncovers previously unidentified regulatory functions of BMP-6 and shows that BMP-6 enhances fracture healing by not only acting on osteoprogenitor stem cells but also by promoting type 2 immune response.

Biological age models based on a healthy Han Chinese population.

BACKGROUND: Biological age (BA) may reflect the actual aging state in humans better than chronological age (CA). The study aimed to construct BA models suitable for the Chinese Han population by selecting appropriate aging markers and evaluation methods. METHODS: A total of 1207 individuals (21∼91 years) from the Han Chinese population in Beijing were examined for essential organ functions, and 156 cardiovascular, pulmonary function, and atherosclerotic indices and clinical and genetic factors were used as candidate markers of aging. BA models were constructed using multiple linear regression (MLR), principal component analysis (PCA), and the Klemera and Doubal method (KDM). Models were internally and externally validated using cross-validation and disease populations. RESULTS: Nine aging markers were selected. Two MLR, three PCA, and three KDM models were successfully constructed. External validation showed that the difference between CA and BA was most significant in the PCA3 and KDM2 models, while there was no significant difference in the MLR1 and MLR2 models; the fitted lines for BA in the disease population were higher than those in the healthy population in the MLR1, MLR2, KDM1, and KDM2 models, while the other models showed the opposite. CONCLUSIONS: Based on a healthy population in Beijing, nine markers representing multiple organ/system functions were screened from the candidate markers, eight methods were successfully used to construct BA models, and the KDM2 model was found to potentially be more appropriate for assessing BA in the Chinese Han population.

Predictive ability of obesity- and lipid-related indicators for metabolic syndrome in relatively healthy Chinese adults.

Background and objective: Metabolic syndrome (MetS) is an important risk factor for cardiovascular complications and kidney damage. Obesity- and lipid-related indices are closely related to MetS, and different indices have different predictive abilities for MetS. This study aimed to evaluate the predictive value of eight obesity- and lipid-related indicators, namely, body mass index (BMI), lipid accumulation product (LAP), body roundness index (BRI), Chinese visceral adiposity index (CVAI), body adiposity index (BAI), abdominal volume index (AVI), triglyceride glucose index (TYG), and visceral adiposity index (VAI), for MetS. Methods: A total of 1,452 relatively healthy people in Beijing were enrolled in 2016, and the correlation between the eight indicators and MetS was analyzed by multivariate logistic regression. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to analyze the predictive ability of the eight indicators for MetS. The Delong test was used to compare the AUC values of the eight indicators. MetS was defined according to the Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes (2020 edition), the revised National Cholesterol Education Program Adult Treatment Group (NCEP-ATPIII), and the International Diabetes Federation (IDF). Results: Using these three sets of criteria, LAP, TYG, CVAI, and VAI, which are based on blood lipids, had higher AUC values for MetS prediction than BMI, BRI, AVI, and BAI, which are based on anthropometry. LAP had the highest AUC values of 0.893 (0.874-0.912), 0.886 (0.869-0.903), and 0.882 (0.864-0.899), separately, based on the three sets of criteria. Conclusion: The eight obesity- and lipid-related indicators had screening value for MetS in relatively healthy people, and of the eight indicators, LAP performed the best.

Comparative Study of Preparation, Evaluation, and Pharmacokinetics in Beagle Dogs of Curcumin ß-Cyclodextrin Inclusion Complex, Curcumin Solid Dispersion, and Curcumin Phospholipid Complex.

Curcumin is a natural acidic polyphenol extracted from turmeric with a wide range of biological and pharmacological effects. However, the application of curcumin for animal production and human life is limited by a low oral bioavailability. In this study, natural curcumin was prepared for the curcumin ß-cyclodextrin inclusion complex (CUR-ß-CD), curcumin solid dispersion (CUR-PEG-6000), and curcumin phospholipid complex (CUR-HSPC) using co-precipitation, melting, and solvent methods, respectively. Curcumin complex formations were monitored using scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared (FT-IR) techniques via the shifts in the microscopic structure, molecular structure, and crystalline state. Subsequently, twenty-four female beagle dogs were randomly divided into four groups to receive unmodified curcumin and three other curcumin preparations. The validated UPLC-MS assay was successfully applied to pharmacokinetic and bioavailability studies of curcumin in beagle dog plasma, which were collected after dosing at 0 min (predose), 5 min, 15 min, 30 min, 40 min, 50 min, 1.5 h, 3 h, 4.5 h, 5.5 h, 6 h, 6.5 h, 9 h, and 24 h. The relative bioavailabilities of CUR-ß-CD, CUR-PEG-6000, and CUR-HSPC were 231.94%, 272.37%, and 196.42%, respectively. This confirmed that CUR-ß-CD, CUR-HSPC, and especially CUR-PEG-6000 could effectively improve the bioavailability of curcumin.

Defining and Studying Errors in Surgical Care: A Systematic Review.

OBJECTIVE: Our objective was to determine the extent surgical disciplines categorize, define, and study errors, then use this information to provide recommendations for both current practice and future study. SUMMARY OF BACKGROUND DATA: The report "To Err is Human" brought the ubiquity of medical errors to public attention. Variability in subsequent literature suggests the true prevalence of error remains unknown. METHODS: In January 2020, PubMed, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched. Only studies with Oxford Level of Evidence Level 3 or higher were included. RESULTS: Of 3064 studies, 92 met inclusion criteria: 6 randomized controlled trials, 4 systematic reviews, 24 cohort, 10 before-after, 35 outcome/audit, 5 cross sectional and 8 case-control studies. Over 15,933,430 patients and 162,113 errors were represented. There were 6 broad error categories, 13 different definitions of error, and 14 study methods. CONCLUSIONS: Reported prevalence of error varied widely due to a lack of standardized categorization, definitions, and study methods. Future research should focus on immediately recognizing errors to minimize harm.

Rapid de Novo Preparation of 2,6-Dideoxy Sugar Libraries through Gold-Catalyzed Homopropargyl Orthoester Cyclization.

A flexible de novo route capable of producing libraries of 2,6-dideoxy sugars is described. We have found that Au(JackiePhos)SbF6MeCN promotes the conversion of homopropargyl orthoesters into functionalized 2,3-dihydro-4H-pyran-4-ones in good to excellent yields (71-90%). These latter compounds can be easily converted into a number of otherwise difficult to access 2,6-dideoxy sugars.

Lethal Encephalitis in Seals with Japanese Encephalitis Virus Infection, China, 2017.

We isolated Japanese encephalitis virus (JEV) from brain samples of 2 seals with lethal encephalitis at Weihai Aquarium, Weihai, China, in 2017. We confirmed our findings by immunohistochemical staining and electron microscopy. Phylogenetic analysis showed this virus was genotype I. Our findings suggest that JEV might disseminate though infected zoo animals.

Long-Term Safety and Efficacy of Clomiphene Citrate for the Treatment of Hypogonadism.

PURPOSE: Clomiphene citrate may be used as an off label treatment of hypogonadism. There are few long-term data on clomiphene citrate efficacy and safety when administered for more than 3 years. We assessed improvements in testosterone and hypogonadal symptoms while on clomiphene citrate for extended periods. MATERIALS AND METHODS: We performed a retrospective review to identify patients treated with clomiphene citrate for hypogonadism (baseline testosterone less than 300 ng/dl) at a total of 2 institutions from 2010 to 2018. We assessed the duration of clomiphene citrate therapy, serum testosterone levels, symptom improvement and clomiphene citrate side effects. RESULTS: A total of 400 patients underwent clomiphene citrate treatment for a mean ± SD of 25.5 ± 20.48 months (range 0 to 84). Of the patients 280 received clomiphene citrate for 3 years or less (mean 12.75 ± 9.52 months) and 120 received it for more than 3 years (mean 51.93 ± 10.52 months). Of men on clomiphene citrate for more than 3 years 88% achieved eugonadism, 77% reported improved symptoms and 8% reported side effects. Estradiol was significantly increased following clomiphene citrate treatment. Results did not significantly differ between patients treated for more than 3, or 3 or fewer years. The most common side effects reported by patients treated more than 3 years included changes in mood in 5, blurred vision in 3 and breast tenderness in 2. There was no significant adverse event in any patient treated with clomiphene citrate. CONCLUSIONS: Clomiphene citrate is not typically offered as primary treatment of hypogonadism in men who do not desire fertility preservation. These data demonstrate that clomiphene citrate is safe and effective with few side effects when used as long-term treatment of hypogonadism.

Comprehensive Analysis of Individual Variation in the Urinary Proteome Revealed Significant Gender Differences.

Disease biomarkers are the measurable changes associated with a pathophysiological process. Without homeostatic control, urine accumulates systematic changes in the body. Thus, urine is an attractive biological material for the discovery of disease biomarkers. One of the major bottlenecks in urinary biomarker discovery is that the concentration and composition of urinary proteins are influenced by many physiological factors. To elucidate the individual variation and related factors influencing the urinary proteome, we comprehensively analyzed the urine samples from healthy adult donors (aged 20-69 years). Co-expression network analysis revealed protein clusters representing the metabolic status, gender-related differences and age-related differences in urinary proteins. In particular, we demonstrated that gender is a crucial factor contributing to individual variation. Proteins that were increased in the male urine samples include prostate-secreted proteins and TIMP1, a protein whose abundance alters under various cancers and renal diseases; however, the proteins that were increased in the female urine samples have known functions in the immune system. Nine gender-related proteins were validated on 85 independent samples by multiple reaction monitoring. Five of these proteins were further used to build a model that could accurately distinguish male and female urine samples with an area under curve value of 0.94. Based on the above results, we strongly suggest that future biomarker investigations should consider gender as a crucial factor in experimental design and data analysis. Finally, reference intervals of each urinary protein were estimated, providing a baseline for the discovery of abnormalities.

The role of transcriptional factor D-site-binding protein in circadian CCL2 gene expression in anti-Thy1 nephritis.

Mesangial proliferative glomerulonephritis (MsPGN) is an inflammatory disease, but both the nature of disease progression and its regulation remain unclear. In the present study, we monitored the course of anti-Thy1 nephritis from days 1 to 5 and established gene expression profiles at each time point using microarrays to explore the development of inflammation. According to the gene expression profiles, macrophage infiltration (triggered by CCL2 activation) was evident on day 1 and enhanced inflammation over the next few days. We screened for genes with expression levels similar to CCL2 and found that the upregulation of the circadian gene albumin D-site-binding protein (DBP) was involved in CCL2 activation in mesangial cells. More importantly, CCL2 expression showed oscillatory changes similar to DBP, and DBP induced peak CCL2 expression at 16:00 a clock on day 1 in the anti-Thy1 nephritis model. We knocked down DBP through transfection with a small interfering RNA (siRNA) and used RNA sequencing to identify the DBP-regulated TNF-α-CCL2 pathway. We performed chromatin immunoprecipitation sequencing (ChIP-Seq) and the dual luciferase assay to show that DBP bound to the TRIM55 promoter, regulating gene expression and in turn controlling the TNF-α-CCL2 pathway. In conclusion, DBP-regulated circadian CCL2 expression by the TRIM55-TNF pathway in injured mesangial cells at an early stage, which promoted macrophage recruitment and in turn triggered infiltration and inflammation in a model of anti-Thy1 nephritis.

Topical timolol for treatment of persistent granulation tissue in the setting of severe hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a potentially debilitating dermatological disease that negatively impacts patients' quality of life. Severe cases can be further complicated by persistent granulation tissue at the ostia of sinus tracts, which may prove recalcitrant to standard interventions. Herein we report such a case in which a patient experienced significant improvement from severe HS but was left with persistent granulation tissue that complicated his course of recovery. When standard interventions failed, we elected to begin treatment with topical timolol. After three months, the majority of the granulation tissue had regressed and has remained quiescent after 12 months of follow up. The patient has tolerated the treatment well and continues to use topical timolol daily as needed for flares. We believe that topical timolol can provide a practical and painless alternative to current invasive and expensive therapies for persistent granulation tissue associated with severe HS.

Whole genome characterization of a novel porcine reproductive and respiratory syndrome virus 1 isolate: Genetic evidence for recombination between Amervac vaccine and circulating strains in mainland China.

Genotype 1 porcine reproductive and respiratory syndrome virus (PRRSV 1) have been continuously isolated in China in recent years. Complete genome sequences of these isolates are important to investigate the prevalence and evolution of Chinese PRRSV 1. Herein, we describe the isolation of a novel PRRSV 1 isolate, denominated HLJB1, in the Heilongjiang province of China. Complete genome sequencing of HLJB1 showed that it shares 90.66% and 58.21% nucleotide identities with PRRSV 1 and 2 prototypic strains Lelystad virus and ATCC VR-2332, respectively. HLJB1 has a unique 5-amino-acid insertion in nsp2, which has never been described in other PRRSV 1 isolates. Whole genome-based phylogenetic analysis revealed that all Chinese PRRSV 1 isolates are clustered in pan-European subtype 1 and can be divided into four subgroups. HLJB1 resides in the subgroup of BJEU06-1-like isolates but is also closely related to the Amervac-like isolates. Additionally, recombination analyses suggested that HLJB1 is a recombinant from the Amervac vaccine and the BJEU06-1 isolate. To our best knowledge, our results provide the first genetic evidence for recombination between Amervac vaccine and circulating strains. These findings are also beneficial for studying the origin and evolution of PRRSV 1 in China.