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Abstract Background Immunoglobulin light-chain amyloidosis is a relatively rare condition with a worldwide incidence of 5.1–12.8 cases per million person-years (Baker, 2022). It is characterized by a clonal population of immunoglobulin-secreting cells that produce a monoclonal light chain of κ or λ type as either an intact molecule or a fragment. Case presentation A 69-year-old East Asian (Chinese) male patient who presented with progressive dysphagia visited multiple hospitals repeatedly for more than 2 years and was finally diagnosed with immunoglobulin light-chain amyloidosis. Conclusions Otolaryngologists should consider immunoglobulin light-chain amyloidosis when encountering suspicious clinical manifestations and intervene early to avoid misdiagnosis.

To evaluate the risk of acquiring syphilis from a donated kidney, we evaluated kidney transplantation pairs from West China Hospital, Sichuan, China, during 2007–2022. Donor-derived syphilis was rare. Risk may be higher if donors have active syphilis and may be reduced if recipients receive ceftriaxone.

Photothermal therapy (PTT) of nanomaterials is an emerging novel therapeutic strategy for breast cancer. However, there exists an urgent need for appropriate strategies to enhance the antitumor efficacy of PTT and minimize damage to surrounding normal tissues. Piezo1 might be a promising novel photothermal therapeutic target for breast cancer. This study aims to explore the potential role of Piezo1 activation in the hyperthermia therapy of breast cancer cells and investigate the underlying mechanisms. Results showed that the specific agonist of Piezo1 ion channel (Yoda1) aggravated the cell death of breast cancer cells triggered by heat stress in vitro. Reactive oxygen species (ROS) production was significantly increased following heat stress, and Yoda1 exacerbated the rise in ROS release. GSK2795039, an inhibitor of NADPH oxidase 2 (NOX2), reversed the Yoda1-mediated aggravation of cellular injury and ROS generation after heat stress. The in vivo experiments demonstrate the well photothermal conversion efficiency of TiCN under the 1,064 nm laser irradiation, and Yoda1 increases the sensitivity of breast tumors to PTT in the presence of TiCN. Our study reveals that Piezo1 activation might serve as a photothermal sensitizer for PTT, which may develop as a promising therapeutic strategy for breast cancer.

Summary: Background: The ubiquitin regulatory X (UBX) domain-containing proteins (UBXNs) are putative adaptors for ubiquitin ligases and valosin-containing protein; however, their in vivo physiological functions remain poorly characterised. We recently showed that UBXN3B is essential for activating innate immunity to DNA viruses and controlling DNA/RNA virus infection. Herein, we investigate its role in adaptive immunity. Methods: We evaluated the antibody responses to multiple viruses and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza in tamoxifen-inducible global and constitutive B cell-specific Ubxn3b knockout mice; quantified various immune populations, B lineage progenitors/precursors, B cell receptor (BCR) signalling and apoptosis by flow cytometry, immunoblotting and immunofluorescence microscopy. We also performed bone marrow transfer, single-cell and bulk RNA sequencing. Findings: Both global and B cell-specific Ubxn3b knockout mice present a marked reduction in small precursor B-II (>60%), immature (>70%) and mature B (>95%) cell numbers. Transfer of wildtype bone marrow to irradiated global Ubxn3b knockouts restores normal B lymphopoiesis, while reverse transplantation does not. The mature B population shrinks rapidly with apoptosis and higher pro and activated caspase-3 protein levels were observed following induction of Ubxn3b knockout. Mechanistically, Ubxn3b deficiency leads to impaired pre-BCR signalling and cell cycle arrest. Ubxn3b knockout mice are highly vulnerable to respiratory viruses, with increased viral loads and prolonged immunopathology in the lung, and reduced production of virus-specific IgM/IgG. Interpretation: UBXN3B is essential for B lymphopoiesis by maintaining constitutive pre-BCR signalling and cell survival in a cell-intrinsic manner. Funding: United States National Institutes of Health grants, R01AI132526 and R21AI155820.

Abstract This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive (N) and nivolumab–chemotherapy (N/C) combinations based on PD-L1 expression. Eligible patients exhibited resectable clinical stage IIA–IIIB (AJCC 8th edition) NSCLC without EGFR/ALK alterations. Patients received either mono-nivolumab (N) or nivolumab + nab-paclitaxel+ carboplatin (N/C) for three cycles based on PD-L1 expression. The primary endpoint was the major pathological response (MPR). Key secondary endpoints included the pathologic complete response (pCR), objective response rate (ORR), and event-free survival (EFS). Baseline PD-L1 expression and perioperative circulating tumor DNA (ctDNA) status were correlated with pCR and EFS. Fifty-two patients were enrolled, with 46 undergoing surgeries. The MPR was 50.0% (26/52), with 25.0% (13/52) achieving pCR, and 16.7% and 66.7% for patients with PD-L1 ≥ 50% in N and N/C groups, respectively. Thirteen (25.0%) patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment. Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR (39.1%) compared with those remained positive (6.7%, odds ratio = 6.14, 95% CI 0.84-Inf, p = 0.077). With a median follow-up of 25.1 months, the 18-month EFS rate was 64.8% (95% CI 51.9–81.0%). For patients with ctDNA– vs. ctDNA + , the 18m-EFS rate was 93.8% vs 47.3% (HR, 0.15; 95% CI 0.04, 0.94; p = 0.005). Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression ≥ 50%. ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits, which requires further confirmation in a prospective clinical trial (NCT04015778).

Infections caused by Pseudomonas aeruginosa biofilm significantly endanger human health worldwide. Biofilms are closely associated with antibiotic resistance because biofilms significantly undermine the efficacy of antibiotics. A novel ultrasound-launched targeted nanoparticle was developed to universally destroy biofilm, target bacteria, deliver antibiotics, and efficiently kill bacteria via ultrasonic cavitation and antibacterial sonodynamic therapy. The nanoparticle consisted of poly (lactic-co-glycolic acid) loading ciprofloxacin and perfluoropentane with a bacteria-targeted antibody installed on the nanoparticle for binding to specific bacteria. The nanoparticle exhibited a sensitive response to ultrasound and the rapid liquid-gas phase transition of perfluoropentane resulted in a cavitation effect that destroyed the extracellular polymeric substances of the biofilm and allowed deep penetration of the antibiotics. In addition, ciprofloxacin induced additional reactive oxygen species production under ultrasound stimulation, leading to an enhanced bactericidal effect and potent anti-infective activity in vivo. This study presents an effective strategy to tackle the extracellular polymeric substance barriers for overcoming antibiotic resistance and removing a biofilm.

Anaplasma capra is an emerging tickborne human pathogen initially recognized in China in 2015; it has been reported in ticks and in a wide range of domestic and wild animals worldwide. We describe whole-genome sequences of 2 A. capra strains from metagenomic sequencing of purified erythrocytes from infected goats in China. The genome of A. capra was the smallest among members of the genus Anaplasma. The genomes of the 2 A. capra strains contained comparable G+C content and numbers of pseudogenes with intraerythrocytic Anaplasma species. The 2 A. capra strains had 54 unique genes. The prevalence of A. capra was high among goats in the 2 endemic areas. Phylogenetic analyses revealed that the A. capra strains detected in this study were basically classified into 2 subclusters with those previously detected in Asia. Our findings clarify details of the genomic characteristics of A. capra and shed light on its genetic diversity.

Abstract Continuous monitoring for immunosuppressive status, infection and complications are a must for kidney transplantation (KTx) recipients. Traditional monitoring including blood sampling and kidney biopsy, which caused tremendous medical cost and trauma. Therefore, a cheaper and less invasive approach was urgently needed. We thought that a breath test has the potential to become a feasible tool for KTx monitoring. A prospective-specimen collection, retrospective-blinded assessment strategy was used in this study. Exhaled breath samples from 175 KTx recipients were collected in West China Hospital and tested by online ultraviolet photoionization time-of-flight mass spectrometry (UVP-TOF–MS). The classification models based on breath test performed well in classifying normal and abnormal values of creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN) and tacrolimus, with AUC values of 0.889, 0.850, 0.849 and 0.889, respectively. Regression analysis also demonstrated the predictive ability of breath test for clinical creatinine, eGFR, BUN, tacrolimus level, as the predicted values obtained from the regression model correlated well with the clinical true values (p

Background The study aims to explore diagnostic value of albumin/fibrinogen ratio (AFR) and C-reactive protein (CRP)/albumin (ALB)/globulin (GLO) ratio (CAGR) for periprosthetic joint infection (PJI). Methods A retrospective analysis was conducted on clinical data collected from 190 patients who had joint replacement surgery in Qilu Hospital of Shandong University (Qingdao), from January 2017 to December 2022. Based on the occurrence of PJI after surgery, patients were divided as an infection group (10 cases) and non-infection group (180 cases). Diagnostic indicators were analyzed, univariate and multivariate logistic regression analyses were further performed to identify factors related to PJI. Sensitivity and specificity of AFR and CAGR, both individually and in combination, were calculated using ROC curves, and their diagnostic performance was compared based on the area under the curve (AUC). Results Levels of CRP, ESR, FIB, GLO, and CAGR were significantly higher in the infection group than in non-infection group (P < 0.05). Levels of ALB and AFR were significantly lower in infection group (P < 0.05). Multivariate logistic regression analysis reviewed that CRP (OR = 3.324), ESR (OR = 2.118), FIB (OR = 3.142), ALB (OR = 0.449), GLO (OR = 1.985), AFR (OR = 0.587), and CAGR (OR = 2.469) were factors influencing PJI (P < 0.05). The AUC for AFR and CAGR in diagnosing PJI were 0.739 and 0.780, while AUC for their combined detection was 0.858. Conclusion Abnormal levels of AFR and CAGR are associated with PJI, and their combined use has certain diagnostic value for PJI.

Abstract. Background:. Although ABO-incompatible (ABOi) kidney transplantation (KT) has been performed successfully, a standard preconditioning regimen has not been established. Based on the initial antidonor ABO antibody titers, an individualized preconditioning regimen is developed, and this study explored the efficacy and safety of the regimen. Methods:. From September 1, 2014, to September 1, 2020, we performed 1668 consecutive living-donor KTs, including 100 ABOi and 1568 ABO-compatible (ABOc) KTs. ABOi KT recipients (KTRs) with a lower antibody titer (≤1:8) were administered oral immunosuppressive drugs (OIs) before KT, while patients with a medium titer (1:16) received OIs plus antibody-removal therapy (plasma exchange/double-filtration plasmapheresis), patients with a higher titer (≥1:32) were in addition received rituximab (Rit). Competing risk analyses were conducted to estimate the cumulative incidence of infection, acute rejection (AR), graft loss, and patient death. Results:. After propensity score analyses, 100 ABOi KTRs and 200 matched ABOc KTRs were selected. There were no significant differences in graft and patient survival between the ABOi and ABOc groups (P = 0.787, P = 0.386, respectively). After using the individualized preconditioning regimen, ABOi KTRs showed a similar cumulative incidence of AR (10.0% υs. 10.5%, P = 0.346). Among the ABOi KTRs, the Rit-free group had a similar cumulative incidence of AR (P = 0.714) compared to that of the Rit-treated group. Multivariate competing risk analyses revealed that a Rit-free regimen reduced the risk of infection (HR: 0.31; 95% CI: 0.12–0.78, P = 0.013). Notably, antibody titer rebound was more common in ABOi KTRs receiving a Rit-free preconditioning regimen (P = 0.013) than those receiving Rit. ABOi KTRs with antibody titer rebound had a 2.72-fold risk of AR (HR: 2.72, 95% CI: 1.01–7.31, P = 0.048). ABOi KTRs had similar serum creatinine and estimated glomerular filtration rate compared to those of ABOc KTRs after the first year. Conclusions:. An individualized preconditioning regimen can achieve comparable graft and patient survival rates in ABOi KT with ABOc KT. Rit-free preconditioning effectively prevented AR without increasing the risk of infectious events in those with lower initial titers; however, antibody titer rebound should be monitored.

Abstract Climate change has caused severe impacts on ecosystems and biodiversity globally, especially to vulnerable mountain ecosystems; the summits bear the brunt of such effects. Therefore, six summits in Taiwan were monitored based on a standardized multi-summit approach. We used both statistical downscaling of climate data and vegetation cover data to calculate climate niches to assess the impacts of climate change. Two indicators, thermophilic and moist-philic, were applied to evaluate the overall response of vegetation dynamics. The results revealed that potential evapotranspiration increased significantly and led to a declining tendency in monthly water balance from 2014 to 2019. The general pattern of species richness was a decline. The difference in plant cover among the three surveys showed an inconsistent pattern, although some dominant species expanded, such as the dwarf bamboo Yushania niitakayamensis. The thermophilic indicator showed that species composition had changed so that there were more thermophilic species at the three lowest summits. The moist-philization indicator showed a decline of humid-preferred species in the latest monitoring period. Although total precipitation did not decrease, our results suggest that the variability in precipitation with increased temperature and potential evapotranspiration altered alpine vegetation composition and could endanger vulnerable species in the future.

Abstract. Background:. High-dose dual therapy (HDDT) with proton pump inhibitors (PPIs) and amoxicillin has attracted widespread attention due to its favorable efficacy in eradicating Helicobacter pylori (H. pylori). This study aimed to compare the efficacy and safety of high-dose PPI–amoxicillin dual therapy and bismuth-containing quadruple therapy for H. pylori rescue treatment. Methods:. This was a prospective, randomized, multicenter, non-inferiority trial. Patients recruited from eight centers who had failed previous treatment were randomly (1:1) allocated to two eradication groups: HDDT (esomeprazole 40 mg and amoxicillin 1000 mg three times daily; the HDDT group) and bismuth-containing quadruple therapy (esomeprazole 40 mg, bismuth potassium citrate 220 mg, and furazolidone 100 mg twice daily, combined with tetracycline 500 mg three times daily; the tetracycline, furazolidone, esomeprazole, and bismuth [TFEB] group) for 14 days. The primary endpoint was the H. pylori eradication rate. The secondary endpoints were adverse effects, symptom improvement rates, and patient compliance. Results:. A total of 658 patients who met the criteria were enrolled in this study. The HDDT group achieved eradication rates of 75.4% (248/329), 81.0% (248/306), and 81.3% (248/305) asdetermined by the intention-to-treat (ITT), modified intention-to-treat (MITT), and per-protocol (PP) analyses, respectively. The eradication rates were similar to those in the TFEB group: 78.1% (257/329), 84.2% (257/305), and 85.1% (257/302). The lower 95% confidence interval boundary (−9.19% in the ITT analysis, − 9.21% in the MITT analysis, and −9.73% in the PP analysis) was greater than the predefined non-inferiority margin of −10%, establishing a non-inferiority of the HDDT group vs. the TFEB group. The incidence of adverse events in the HDDT group was significantly lower than that in the TFEB group (11.1% vs. 26.8%, P

BackgroundCurrent guidelines do not recommend routine antiviral prophylaxis to prevent hepatitis B virus (HBV) reactivation in non-liver solid organ transplant (SOT) recipients with resolved HBV infection, even in anti-hepatitis B surface antigen (anti-HBs)-negative recipients and those receiving intense immunosuppression. This systematic review and meta-analysis aimed to determine the incidence, risk factors, and clinical outcomes of HBV reactivation in non-liver SOT recipients.Methods and findingsThree databases (PubMed, Embase, and Cochrane Library) were systematically searched up to December 31, 2022. Clinical studies reporting HBV reactivation in non-liver SOT recipients were included. Case reports, case series, and cohort studies with a sample size of less than 10 patients were excluded. Random-effects analysis was used for all meta-analyses. We included 2,913 non-liver SOT recipients with resolved HBV infection from 16 retrospective cohort studies in the analysis. The overall HBV reactivation rate was 2.5% (76/2,913; 95% confidence interval [95% CI 1.6%, 3.6%]; I2 = 55.0%). Higher rates of reactivation were observed in recipients with negative anti-HBs (34/421; 7.8%; 95% CI [5.2%, 10.9%]; I2 = 36.0%) by pooling 6 studies, experiencing acute rejection (13/266; 5.8%; 95% CI [2.3%, 14.5%]; I2 = 63.2%) by pooling 3 studies, receiving ABO blood type-incompatible transplantation (8/111; 7.0%; 95% CI [2.9%, 12.7%]; I2 = 0%) by pooling 3 studies, receiving rituximab (10/133; 7.3%; 95% CI [3.4%, 12.6%]; I2 = 0%) by pooling 3 studies, and receiving anti-thymocyte immunoglobulin (ATG, 25/504; 4.9%; 95% CI [2.5%, 8.1%]; I2 = 49.0%) by pooling 4 studies. Among recipients with post-transplant HBV reactivation, 11.0% (7/52; 95% CI [4.0%, 20.8%]; I2 = 0.3%) developed HBV-related hepatic failure, and 11.0% (7/52; 95% CI [4.0%, 20.8%]; I2 = 0.3%) had HBV-related death. Negative anti-HBs (crude odds ratio [OR] 5.05; 95% CI [2.83, 9.00]; p < 0.001; I2 = 0%), ABO blood type-incompatible transplantation (crude OR 2.62; 95% CI [1.05, 6.04]; p = 0.040; I2 = 0%), history of acute rejection (crude OR 2.37; 95% CI [1.13, 4.97]; p = 0.022; I2 = 0%), ATG use (crude OR 3.19; 95% CI [1.48, 6.87]; p = 0.003; I2 = 0%), and rituximab use (crude OR 3.16; 95% CI [1.24, 8.06]; p = 0.016; I2 = 0%) increased the risk of reactivation. Adjusted analyses reported similar results. Limitations include moderate heterogeneity in the meta-analyses and that most studies were conducted in kidney transplant recipients.ConclusionsNon-liver SOT recipients with resolved HBV infection have a high risk of HBV-related hepatic failure and HBV-related death if HBV reactivation occurs. Potential risk factors for HBV reactivation include rituximab use, anti-thymocyte immunoglobulin use, anti-HBs negative status, acute rejection history, and ABO blood type-incompatible transplantation. Further research on monitoring and routine antiviral prophylaxis of non-liver SOT recipients at higher risk of HBV reactivation is required.

Abstract Eight new generation amide insecticide residues analysis by multiwalled carbon nanotubes (MWCNs) cleanup, combined with QuEChERS and ultrahigh performance liquid chromatography tandem mass spectrometry has been developed and successfully applied in complex matrix such as orange, celery, onion, litchi, mango, shallot, chives, avocado, garlic. The matric effect of MWCNs is optimized and compared with ordinary cleanup materials. The results show that the performance of MWCNs is fine and effectively reduce matrix interference. Through chemical structure skeletons analyzed, chlorantraniliprole, bromoantraniliprole, and cyantraniliprole can cause same product ions of m/z 286.0 or 177.1 in the ESI+ mode, then tetrachlorantraniliprole and cyclaniliprole can produce collective ions of m/z 146.9 in the ESI− mode. The coefficients (R 2) were greater than 0.9990, the limit of quantification ranges from 0.03 to 0.80 μg/kg, the recovery rate ranges from 71.2 to 120%, and the relative standard deviation (RSD) ranges from 3.8 to 9.4%. The method is fast, simple, sensitive, and suitable for the rapid determination of amide pesticides in complex matrix agricultural food.

Abstract Background Acute kidney injury (AKI) is a life-threatening complication characterized by rapid decline in renal function, which frequently occurs after transplantation surgery. However, the molecular mechanism underlying the development of post-transplant (post-Tx) AKI still remains unknown. An increasing number of studies have demonstrated that certain microRNAs (miRNAs) exert crucial functions in AKI. The present study sought to elucidate the molecular mechanisms in post-Tx AKI by constructing a regulatory miRNA–mRNA network. Results Based on two datasets (GSE53771 and GSE53769), three key modules, which contained 55 mRNAs, 76 mRNAs, and 151 miRNAs, were identified by performing weighted gene co-expression network analysis (WGCNA). The miRDIP v4.1 was applied to predict the interactions of key module mRNAs and miRNAs, and the miRNA–mRNA pairs with confidence of more than 0.2 were selected to construct a regulatory miRNA–mRNA network by Cytoscape. The miRNA–mRNA network consisted of 82 nodes (48 mRNAs and 34 miRNAs) and 125 edges. Two miRNAs (miR-203a-3p and miR-205-5p) and ERBB4 with higher node degrees compared with other nodes might play a central role in post-Tx AKI. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that this network was mainly involved in kidney-/renal-related functions and PI3K–Akt/HIF-1/Ras/MAPK signaling pathways. Conclusion We constructed a regulatory miRNA–mRNA network to provide novel insights into post-Tx AKI development, which might help discover new biomarkers or therapeutic drugs for enhancing the ability for early prediction and intervention and decreasing mortality rate of AKI after transplantation.

Introduction Essential hypertension is a major preventable risk factor for early cardiovascular disease, premature death and disability. It has been reported that telemedicine interventions can provide an innovative solution to essential hypertension to overcome the barriers that exist in traditional treatment or control. Nevertheless, this subject has not been thoroughly investigated. The goal of this study is to systematically evaluate and describe the impact of telemedicine interventions on essential hypertension.Methods and analysis To find relevant research, we will conduct a systematic literature search of three databases (PubMed, Embase and Cochrane Library), with no language limitations, in addition to researching grey literature. Two reviewers will extract the data individually, and any disagreements will be resolved by discussion or by a third reviewer. The randomised controlled trials will be chosen based on predetermined inclusion criteria. Primary outcomes will include systolic blood pressure and diastolic blood pressure after the telemedicine intervention. Secondary outcomes will include medication adherence (eg, the Morisky Medication Adherence Questionnaire), quality of life (eg, the MOS item scale of the Health Survey Short Form 36 questionnaire), blood pressure control rate and adverse events (eg, stroke, chronic renal failure, aortic dissection, myocardial infarction and heart failure). The quality of the included studies will be assessed using the Cochrane risk-of-bias method. The data will be analysed using RevMan V.5.3.5 software and STATA V.16.0 software. If heterogeneity testing reveals little or no statistical heterogeneity, a fixed effect model will be used for data synthesis; otherwise, a random effect model would be employed. We will synthesise the available evidence to perform a high-quality meta-analysis.Ethics and dissemination This project does not require ethical approval because it will be conducted using publicly available documents. The review’s findings will be published in peer-reviewed journals and publications.PROSPERO registration number CRD42021293539.

Abstract Picea mongolica, a native species with excellent industrial wood quality and strong sand-fixing capacity, may be utilized in construction of urban green spaces in arid areas in China. However, now the sustainability of the ecosystems where this species grows is at serious risk due to a lack of natural regeneration. In this study, we developed an efficient regeneration system and comprehensively analyzed various factors affecting somatic embryogenesis (SE) using zygotic embryos as explants. We identified the optimal plant growth regulators (PGRs) performance and the best donor trees (k81) for the generation of somatic embryos (SEMs). Additionally, we confirmed that the positive developmental window of SEMs initiation was at the end of July to early August, which is when zygotic embryos was at the late embryogeny. In this time period, specific transcripts associated with the regulation of epigenetic modifications, plant hormone-related genes, and embryonic development-related transcription factors play important roles for early SEMs initiation. These results may provide a valuable resource for vegetative propagation of Picea mongolica. Our results may help to establish a reliable protocol for plantlet regeneration, which may facilitate urban greening applications and industrialization in arid areas.

Abstract. Background. Estrogen is involved in the pathophysiological process of benign prostatic hyperplasia (BPH), in which epithelial-mesenchymal transition (EMT) plays an important role. Upregulation of aquaporin (AQP) 5, which is directly activated by estrogen, has been reported to promote EMT in multiple cells. This study aimed to examine the effects of AQP5 on estrogen-induced EMT in the prostate. Methods. Normal prostate (NP) tissue samples without any histopathological changes and BPH tissue samples with pathologically confirmed hyperplasia were obtained. An EMT cell model was subsequently established by adding estradiol (E2) to RWPE-1 cells, after which AQP5 knockdown was performed. Tissue morphological and immunohistochemical features were examined using hematoxylin-eosin and immunohistochemical staining. Western blot analysis was performed to determine the expression of AQPs, estrogen receptors, and EMT-related proteins. Cell proliferation was assessed and supernatants were collected for enzyme-linked immunosorbent assay to determine transforming growth factor-β1 (TGF-β1) concentrations. Immunofluorescence staining was performed to assess protein expressions in RWPE-1 cells. Results. BPH tissues exhibited greater EMT (TGF-β1: 1.362 ± 0.196 vs. 0.107 ± 0.067, P = 0.003; vimentin: 1.581 ± 0.508 vs. 0.221 ± 0.047, P

Abstract Routine monitoring of kidney transplant function is required for the standard care in post-transplantation management, including frequent measurements of serum creatinine with or without kidney biopsy. However, the invasiveness of these methods with potential for clinically significant complications makes them less than ideal. The objective of this study was to develop a non-invasive tool to monitor the kidney transplant function by using Surface-Enhanced Raman Spectroscopy (SERS). Urine and blood samples were collected from kidney transplant recipients after surgery. Silver nanoparticle-based SERS spectra of the urine were measured and evaluated using partial least squires (PLS) analysis. The SERS spectra were compared with conventional chemical markers of kidney transplant function to assess its predictive ability. A total of 110 kidney transplant recipients were included in this study. PLS results showed significant correlation with urine protein (R 2 = 0.4660, p

Many neurodegenerative disorders are caused by abnormal accumulation of misfolded proteins. In spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded (polyQ-expanded) ataxin-1 (ATXN1) causes neuronal toxicity. Lowering total ATXN1, especially the polyQ-expanded form, alleviates disease phenotypes in mice, but the molecular mechanism by which the mutant ATXN1 is specifically modulated is not understood. Here, we identified 22 mutant ATXN1 regulators by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes, respectively. Among them, transglutaminase 5 (TG5) preferentially regulated mutant ATXN1 over the WT protein. TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length–dependent manner, thereby preferentially modulating mutant ATXN1 stability and oligomerization. Perturbing Tg in Drosophila SCA1 models modulated mutant ATXN1 toxicity. Moreover, TG5 was enriched in the nuclei of SCA1-affected neurons and colocalized with nuclear ATXN1 inclusions in brain tissue from patients with SCA1. Our work provides a molecular insight into SCA1 pathogenesis and an opportunity for allele-specific targeting for neurodegenerative disorders.

Background: CIP2A has been proved to play a role as an oncogene in various types of malignancies while its functionality in renal clear cell carcinoma has not been investigated. Our study aimed to investigate the role of CIP2A in renal clear cell carcinoma and to explore the possible mechanisms. Methods: A total of 80 patients with renal clear cell carcinoma and 32 healthy people were included in the study. Expression of CIP2A was detected by qRT-PCR. CIP2A silencing renal clear cell carcinoma cell line was established. Its effects on cell proliferation and migration were verified by CCK-8 assay and Transwell cell assay, respectively. The effects of CIP2A overexpression on AKT and VEGF were investigated. Results: CIP2A expression level was increased in tumor tissues compared to adjacent healthy tissues. Serum levels of CIP2A protein were higher in cancer patients than in healthy controls, and serum levels of CIP2A protein were increased with increased stage of primary tumor. Serum CIP2A protein can be used to accurately predict renal clear cell carcinoma and its prognosis. CIP2A siRNA silencing inhibited tumor cell proliferation, and treatment with Akt activator reduced this inhibitory effect. CIP2A siRNA silencing decreased the expression level of VEGF and phosphorylation levels of AKT in renal clear cell carcinoma cells, while AKT activator treatment showed no significant effects on CIP2A expression. Conclusion: Downregulation of CIP2A can inhibit cancer cell proliferation and vascularization in renal clear cell carcinoma through inactivation of the Akt pathway and its downstream VEGF.

Preterm infants that suffer cerebellar insults often develop motor disorders and cognitive difficulty. Excitatory granule cells, the most numerous neuron type in the brain, are especially vulnerable and likely instigate disease by impairing the function of their targets, the Purkinje cells. Here, we use regional genetic manipulations and in vivo electrophysiology to test whether excitatory neurons establish the firing properties of Purkinje cells during postnatal mouse development. We generated mutant mice that lack the majority of excitatory cerebellar neurons and tracked the structural and functional consequences on Purkinje cells. We reveal that Purkinje cells fail to acquire their typical morphology and connectivity, and that the concomitant transformation of Purkinje cell firing activity does not occur either. We also show that our mutant pups have impaired motor behaviors and vocal skills. These data argue that excitatory cerebellar neurons define the maturation time-window for postnatal Purkinje cell functions and refine cerebellar-dependent behaviors.

Introduction Accumulating evidence has shown the potential of bergamottin as an anticancer agent. The present study was undertaken to evaluate the anticancer affects of bergamottin (µM) against colon cancer cells. Material and methods Antiproliferative effects were evaluated by WST-1 cell viability assay. Apoptotic effects were studied by DAPI and Annexin V/PI staining. Cell cycle analysis was carried out by flow cytometry. Transwell assay was used to study the effects on cell invasion. Protein expression was estimated by the western blot method. Results The results showed that bergamottin suppresses the proliferation of all the human colon cancer cell lines. Nonetheless, the growth inhibitory effects of bergamottin on the HT-29 and RKO cells were more significant (IC50, 12.5 µM). The anticancer effects of bergamottin on the HT-29 and RKO cells were mainly due to apoptosis. Bergamottin could considerably increase the expression of Bax and reduce the expression Bcl-2. The cleavage of caspase-3, 8 and 9 was also enhanced upon bergamottin treatment of the colon cancer cells. Flow cytometric analysis showed that bergamottin also induced G2/M cell cycle arrest of the HT-29 and RKO cells. Additionally, bergamottin could also suppress the invasion of HT-29 and RKO cells. The Raf/MEK/ERK pathway is regarded as one of the essential pathways involved in the development and progression of cancers. Herein, it was observed that bergamottin could concentration dependently block this pathway in colon cancer cells. In vivo study revealed that bergamottin could also suppress the growth of tumours in xenografted mice models. Conclusions Taken together, bergamottin suppresses the proliferation of colon cancer cells and may be utilised in the development of chemotherapy for colon cancer.

Globally, non-small cell lung cancer (NSCLC) is the most common malignancy and its prognosis remains poor because of the lack of reliable early diagnostic biomarkers. The competitive endogenous RNA (ceRNA) network plays an important role in the tumorigenesis and prognosis of NSCLC. Tumor immune microenvironment (TIME) is valuable for predicting the response to immunotherapy and determining the prognosis of NSCLC patients. To understand the TIME-related ceRNA network, the RNA profiling datasets from the Genotype-Tissue Expression and The Cancer Genome Atlas databases were analyzed to identify the mRNAs, microRNAs, and lncRNAs associated with the differentially expressed genes. Weighted gene co-expression network analysis revealed that the brown module of mRNAs and the turquoise module of lncRNAs were the most important. Interactions among microRNAs, lncRNAs, and mRNAs were prognosticated using miRcode, miRDB, TargetScan, miRTarBase, and starBase databases. A prognostic model consisting of 13 mRNAs was established using univariate and multivariate Cox regression analyses and validated by the receiver operating characteristic (ROC) curve. The 22 immune infiltrating cell types were analyzed using the CIBERSORT algorithm, and results showed that the high-risk score of this model was related to poor prognosis and an immunosuppressive TIME. A lncRNA-miRNA-mRNA ceRNA network that included 69 differentially expressed lncRNAs (DElncRNAs) was constructed based on the five mRNAs obtained from the prognostic model. ROC survival analysis further showed that the seven DElncRNAs had a substantial prognostic value for the overall survival (OS) in NSCLC patients; the area under the curve was 0.65. In addition, the high-risk group showed drug resistance to several chemotherapeutic and targeted drugs including cisplatin, paclitaxel, docetaxel, gemcitabine, and gefitinib. The differential expression of five mRNAs and seven lncRNAs in the ceRNA network was supported by the results of the HPA database and RT-qPCR analyses. This comprehensive analysis of a ceRNA network identified a set of biomarkers for prognosis and TIME prediction in NSCLC.

Recently, studies on competing endogenous RNA (ceRNA) networks have become prevalent, and circular RNAs (circRNAs) have crucial implications for the development and progression of carcinoma. However, studies relevant to metastatic prostate cancer (mPCa) are scant. This study aims to discover potential ceRNAs that may be related to the prognosis of mPCa. RNA-Seq data were obtained from the MiOncoCirc database and Gene Expression Omnibus (GEO). Differential expression patterns of RNAs were examined using R packages. Circular RNA Interactome, miRTarBase, miRDB and TargetScan were applied to predict the corresponding relation between circRNAs, miRNAs and mRNAs. The Gene Ontology (GO) annotations were performed to present related GO terms, and Gene Set Enrichment Analysis (GSEA) tools were applied for pathway annotations. Moreover, survival analysis was conducted for the hub genes. We found 820 circRNAs, 81 miRNAs and 179 mRNAs that were distinguishingly expressed between primary prostate cancer (PCa) and mPCa samples. A ceRNA network including 45 circRNAs, 24 miRNAs and 56 mRNAs was constructed. In addition, the protein-protein interaction (PPI) network was built, and 10 hub genes were selected by using the CytoHubba application. Among the 10 hub genes, survival analysis showed that ITGA1, LMOD1, MYH11, MYLK, SORBS1 and TGFBR3 were significantly connected with disease-free survival (DFS). The circRNA-mediated ceRNA network provides potential prognostic biomarkers for metastatic prostate cancer.

Rett syndrome is a devastating childhood neurological disorder caused by mutations in MECP2. Of the many symptoms, motor deterioration is a significant problem for patients. In mice, deleting Mecp2 from the cortex or basal ganglia causes motor dysfunction, hypoactivity, and tremor, which are abnormalities observed in patients. Little is known about the function of Mecp2 in the cerebellum, a brain region critical for motor function. Here we show that deleting Mecp2 from the cerebellum, but not from its neuronal subtypes, causes a delay in motor learning that is overcome by additional training. We observed irregular firing rates of Purkinje cells and altered heterochromatin architecture within the cerebellum of knockout mice. These findings demonstrate that the motor deficits present in Rett syndrome arise, in part, from cerebellar dysfunction. For Rett syndrome and other neurodevelopmental disorders, our results highlight the importance of understanding which brain regions contribute to disease phenotypes.

Ramón y Cajal proclaimed the neuron doctrine based on circuit features he exemplified using cerebellar basket cell projections. Basket cells form dense inhibitory plexuses that wrap Purkinje cell somata and terminate as pinceaux at the initial segment of axons. Here, we demonstrate that HCN1, Kv1.1, PSD95 and GAD67 unexpectedly mark patterns of basket cell pinceaux that map onto Purkinje cell functional zones. Using cell-specific genetic tracing with an Ascl1CreERT2 mouse conditional allele, we reveal that basket cell zones comprise different sizes of pinceaux. We tested whether Purkinje cells instruct the assembly of inhibitory projections into zones, as they do for excitatory afferents. Genetically silencing Purkinje cell neurotransmission blocks the formation of sharp Purkinje cell zones and disrupts excitatory axon patterning. The distribution of pinceaux into size-specific zones is eliminated without Purkinje cell GABAergic output. Our data uncover the cellular and molecular diversity of a foundational synapse that revolutionized neuroscience.

Added risk portended by diabetes in addition to hypertension has been related to an amplification of endothelial dysfunction. β-blockers are widely used for cardiovascular diseases and improve the endothelial function compared with a placebo. However, the effect of β-blockers on the endothelial progenitor cells (EPCs) function in diabetes is still unknown. Five β-blockers (metoprolol, atenolol, propranolol, bisoprolol, and nebivolol) were tested in EPC functional screening. Metoprolol improved EPC function significantly among the five β-blockers and was chosen for the in vivo tests in STZ induced diabetic mice. Reactive hyperemia peripheral arterial tonometry (RH-PAT) measurements were performed using the Endo-PAT2000 device in diabetic patients. Metoprolol, but not other β-blockers, improved EPC function in both tube formation and migration assay. EPC function was significantly decreased in diabetic mice, and metoprolol treatment restored damaged EPC migration capabilities and circulation EPC number. Metoprolol treatment promoted wound healing and stimulated angiogenesis in diabetic mice. Furthermore, metoprolol significantly enhanced eNOS phosphorylation and decreased O2− levels in EPCs of diabetic mice. In clinical trials, the RH-PAT index was significantly higher in metoprolol-treated versus bisoprolol-treated diabetics. Metoprolol could accelerate wound healing in diabetic mice and improve endothelial function in diabetic subjects, which may be mediated in part by improving impaired EPC function.

Tremor is currently ranked as the most common movement disorder. The brain regions and neural signals that initiate the debilitating shakiness of different body parts remain unclear. Here, we found that genetically silencing cerebellar Purkinje cell output blocked tremor in mice that were given the tremorgenic drug harmaline. We show in awake behaving mice that the onset of tremor is coincident with rhythmic Purkinje cell firing, which alters the activity of their target cerebellar nuclei cells. We mimic the tremorgenic action of the drug with optogenetics and present evidence that highly patterned Purkinje cell activity drives a powerful tremor in otherwise normal mice. Modulating the altered activity with deep brain stimulation directed to the Purkinje cell output in the cerebellar nuclei reduced tremor in freely moving mice. Together, the data implicate Purkinje cell connectivity as a neural substrate for tremor and a gateway for signals that mediate the disease.

Duchenne muscular dystrophy (DMD) is a debilitating and ultimately lethal disease involving progressive muscle degeneration and neurological dysfunction. DMD is caused by mutations in the dystrophin gene, which result in extremely low or total loss of dystrophin protein expression. In the brain, dystrophin is heavily localized to cerebellar Purkinje cells, which control motor and non-motor functions. In vitro experiments in mouse Purkinje cells revealed that loss of dystrophin leads to low firing rates and high spiking variability. However, it is still unclear how the loss of dystrophin affects cerebellar function in the intact brain. Here, we used in vivo electrophysiology to record Purkinje cells and cerebellar nuclear neurons in awake and anesthetized female mdx (also known as Dmd) mice. Purkinje cell simple spike firing rate is significantly lower in mdx mice compared to controls. Although simple spike firing regularity is not affected, complex spike regularity is increased in mdx mutants. Mean firing rate in cerebellar nuclear neurons is not altered in mdx mice, but their local firing pattern is irregular. Based on the relatively well-preserved cytoarchitecture in the mdx cerebellum, our data suggest that faulty signals across the circuit between Purkinje cells and cerebellar nuclei drive the abnormal firing activity. The in vivo requirements of dystrophin during cerebellar circuit communication could help explain the motor and cognitive anomalies seen in individuals with DMD. This article has an associated First Person interview with the first author of the paper.

Background: There is considerable discordance in the curve progression of adolescent idiopathic scoliosis (AIS) patients between monozygotic (MZ) twins, indicating that nongenetic factors must be involved in the curve progression of AIS patients. Epigenetic processes may constitute one of these factors and have not yet been investigated in relation to curve progression in AIS patients. Methods: The genome and methylome of peripheral monocytes were compared between MZ twins discordant for curve progression. Sets of differentially methylated sites were validated using the MassARRAY platform of Sequenome on additional samples. Results: In the discovery study, we found evidence suggesting a lack of differences at the genome sequence level and the presence of epigenetic differences related to the curve progression of AIS patients. The top 4 differentially methylated CpG sites associated with curve severity were tested, and only site cg01374129 (CpG site located at chr8:122583383, Hg19) was confirmed in two replication cohorts. The methylation levels of site cg01374129 were significantly lower in the progression group than in the nonprogression group. Cox regression analysis demonstrated that hypo-methylation of site cg01374129 was an independent prognostic factor for curve severity. Site cg01374129 methylation as a marker achieved a sensitivity of 76.4% and a specificity of 85.6% in differentiating between samples from patients with and without curve progression (AUC = 0.827; 95% CI: 0.780 to 0.876). Conclusion: Increased curvature is associated with decreased methylation at site cg01374129. Our results indicate that methylation of site cg01374129 may therefore serve as a promising biomarker in differing between patients with and without curve progression. Keywords: Adolescent idiopathic scoliosis, Progression, Whole genome sequencing, Methylation, Predictor

Molecular tests revealed influenza D viruses of D/OK lineage widely circulating in farmed animal species in Guangdong Province, southern China. In particular, we found high levels of influenza D virus infection in goats and pigs. We also detected viral RNA in serum specimens and feces of animals with certain severe diseases.

Neurexophilins are secreted neuropeptide-like glycoproteins, and neurexophilin1 and neurexophilin3 are ligands for the presynaptic cell adhesion molecule α-neurexin. Neurexophilins are more selectively expressed in the brain than α-neurexins, however, which led us to ask whether neurexophilins modulate the function of α-neurexin in a context-specific manner. We characterized the expression and function of neurexophilin4 in mice and found it to be expressed in subsets of neurons responsible for feeding, emotion, balance, and movement. Deletion of Neurexophilin4 caused corresponding impairments, most notably in motor learning and coordination. We demonstrated that neurexophilin4 interacts with α-neurexin and GABAARs in the cerebellum. Loss of Neurexophilin4 impaired cerebellar Golgi-granule inhibitory neurotransmission and synapse number, providing a partial explanation for the motor learning and coordination deficits observed in the Neurexophilin4 null mice. Our data illustrate how selectively expressed Neurexophilin4, an α-neurexin ligand, regulates specific synapse function and modulates cerebellar motor control.

Sex pheromones are important for agricultural pest control. The main sex pheromone components of Spodoptera litura are (Z,E)-9,11- and (Z,E)-9,12-tetradecadienyl acetate (Z9,E11-14:Ac; Z9,E12-14:Ac). In this study, we investigated the optimal conditions for encapsulation of S. litura sex pheromonesin micelles via the self-assembly method using monomethoxy poly (ethylene glycol)-poly (ε-caprolactone) (MPEG-PCL) as a biodegradable wall-forming material with low toxicity. In the L9(3(4) orthogonal experiment, 3 amphiphilic block copolymers, with different hydrophilicity to hydrophobicity ratios, were examined. Optimal encapsulation conditions included stirring of MPEG5000-PCL2000 at 1000 rpm at 30°C with 2.5:1 wall-forming: core material mass ratio. S. litura sex pheromone-loaded MPEG5000-PCL2000 micelles presented a homogeneous spherical morphology with apparent core-shell structure. The release kinetics of optimized MPEG5000-PCL2000 micelles was best explained by a first-order model. Encapsulated Z9,E11-14:Ac and Z9,E12-14:Ac were released slowly, not suddenly. Methyl oleate (MO) was used as an agent to control micellar release performance. When MO content equalled block content, micelle half-life could be prolonged, thereby controlling the release speed. Overall, our results showed MPEG-PCL as a promising controlled-release substrate for sex pheromones.

SETD2 (SET domain containing protein 2) acts as a histone H3 lysine 36 (H3K36)-specific methyltransferase and may play important roles in active gene transcription in human cells. However, its expression and role in porcine oocytes and preimplantation embryos are not well understood. Here, we used immunofluorescence and laser scanning confocal microscopy to examine SETD2 expression in porcine fetal fibroblasts, oocytes, and preimplantation embryos derived from in vitro fertilization (IVF), parthenogenetic activation (PA), and somatic cell nuclear transfer (SCNT). In porcine fetal fibroblasts, SETD2 expression was detected in interphase cells, but not in M (mitotic)-phase cells. The SETD2 signal was observed in non-surrounded nucleolus (NSN)-stage oocytes, but not in surrounded nucleolus (SN)-, metaphase I (MI)-, or metaphase II (MII)-stage oocytes. The SETD2 signal was detectable in sperm, and undetectable immediately after fertilization, detectable at the 2-cell stage, and peaked at the 4-cell stage of IVF embryos in which porcine embryonic genome is activated. Similar to the pattern found in IVF embryos, the SETD2 signal was absent from PA embryos at the 1-cell stage, but it was detected at the 2-cell stage and thereafter maintained to the blastocyst stage. Interestingly, unlike the IVF and PA embryos, the SETD2 signal was detected throughout the development of SCNT embryos, including at the 1-cell stage. These data suggest that SETD2 may be functional for embryonic gene transcription in porcine preimplantation embryos. It is further speculated that the aberrant expression of SETD2 at the 1-cell stage of porcine SCNT embryos may be a factor in the low efficiency of cloning in pig.