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Background Cystoscopy plays an important role in bladder cancer (BCa) diagnosis and treatment, but its sensitivity needs improvement. Artificial intelligence has shown promise in endoscopy, but few cystoscopic applications have been reported. We report a Cystoscopy Artificial Intelligence Diagnostic System (CAIDS) for BCa diagnosis. Methods In total, 69 204 images from 10 729 consecutive patients from 6 hospitals were collected and divided into training, internal validation, and external validation sets. The CAIDS was built using a pyramid scene parsing network and transfer learning. A subset (n = 260) of the validation sets was used for a performance comparison between the CAIDS and urologists for complex lesion detection. The diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values and 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. Results The diagnostic accuracies of the CAIDS were 0.977 (95% CI = 0.974 to 0.979) in the internal validation set and 0.990 (95% CI = 0.979 to 0.996), 0.982 (95% CI = 0.974 to 0.988), 0.978 (95% CI = 0.959 to 0.989), and 0.991 (95% CI = 0.987 to 0.994) in different external validation sets. In the CAIDS vs urologists’ comparisons, the CAIDS showed high accuracy and sensitivity (accuracy = 0.939, 95% CI = 0.902 to 0.964; sensitivity = 0.954, 95% CI = 0.902 to 0.983) with a short latency of 12 seconds, much more accurate and quicker than the expert urologists. Conclusions The CAIDS achieved accurate BCa detection with a short latency. The CAIDS may provide many clinical benefits, from increasing the diagnostic accuracy for BCa, even for commonly misdiagnosed cases such as flat cancerous tissue (carcinoma in situ), to reducing the operation time for cystoscopy.

Objective The purpose of this study was to perform a systematic review and meta-analysis on the association between insomnia and the risk of developing into metabolic syndrome (including hypertension, hyperglycemia, hyperlipidemia and obesity). Method We conducted our research according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analyses). After the search term was determined, we searched Pubmed and Embase databases until December 1, 2020 for the observational studies. We used random effects models to aggregate risk estimates for individual studies and the odds ratio (OR) as well as 95% confidence intervals (CI) were calculated for pooled data. Heterogeneity in this study was assessed by using I2 statistic. Results 12 studies were eventually included in this meta-analysis which contained metabolic syndrome related symptoms (hypertension, hyperglycemia, hyperlipidemia and obesity). The combined OR value and 95% CI of the hypertension group was 1.41 (1.19–1.67). The hyperglycemia group was 1.29 (1.11–1.50). The hyperlipidemia group was 1.12 (0.92–1.37) and the obesity group was 1.31 (1.03–1.67). Conclusion The risk of insomnia patients suffering from hypertension, hyperglycemia, hyperlipidemia and obesity in metabolic syndrome was 1.41 times, 1.29 times and 1.31 times than people without insomnia respectively.

INTRODUCTION The efficacy of vitamin D for migraine remains controversial. We conduct a systematic review and meta-analysis to explore the influence of vitamin D versus placebo on treatment in migraine patients. METHODS We search PubMed, EMbase, Web of Science, EBSCO, and Cochrane library databases through April 2020 for randomized controlled trials assessing the effect of vitamin D versus placebo on treatment efficacy in migraine patients. This meta-analysis is performed using the random-effect model. RESULTS Five randomized controlled trials are included in the meta-analysis. Overall, compared with control group in migraine patients, vitamin D treatment is associated with substantially reduced number of headache days (standard mean difference [SMD], -0.53; 95% confidence interval [CI], -0.83 to -0.23; P = 0.0006), frequency of headache attacks (SMD, -1.09; 95% CI, -1.86 to -0.32; P = 0.006), headache severity (SMD, -0.55; 95% CI, -0.91 to -0.19; P = 0.0003), and Migraine Disability Assessment score (SMD, -0.76; 95% CI, -1.11 to -0.40; P < 0.0001). CONCLUSIONS Vitamin D treatment is effective to alleviate migraine.

Purpose We conducted this meta-analysis to compare postoperative outcomes between meatal-based flap (Mathieu) and tubularized incised plate (TIP) techniques for distal hypospadias. Methods A comprehensive literature search of PUBMED, Web of Science, EMBASE, and Cochrane Library was conducted. Outcomes evaluated in this review were fistula, meatal stenosis, wound dehiscence and flap necrosis. We calculated odds ratio (OR) with 95% confidential interval (CI) to compare postoperative outcomes between Mathieu and TIP after data extraction and literature identification. All data were analyzed using Review Manager 5.2. In order to find potential affective factors, meta-regression and subgroup analyses were applied. Results 16 studies, 1386 patients, including 762 patients receiving Mathieu and 624 individuals subjected to TIP met the inclusion criteria. The synthetic data suggested that Mathieu and TIP were comparable in terms of fistula (OR = 0.93; 95% CI: 0.65 to 1.33; P = 0.70, I2 = 14%), wound dehiscence (OR = 0.89; 95% CI: 0.33 to 2.39; P = 0.81, I2 = 11%), and flap necrosis (OR = 1.9; 95% CI: 0.51 to 7.09; P = 0.20, I2 = 38%) without significant heterogeneity for each comparison group. Pooled estimates showed a significantly lower rate of meatal stenosis with Mathieu than with TIP (OR = 0.41; 95% CI: 0.24 to 0.73; P = 0.002, I2 = 4%). Subgroup analyses showed that the difference between Mathieu and TIP was more obvious in the studies published before 2013 in meatal stenosis. The modified Mathieu technique and a running suture for urethroplasty might be relevant to a lower rate of meatal stenosis in the data, although no statistical significance in the present effects model overall was found. One-way sensitivity analysis showed that the results were stable. There was no publication bias detected using both funnel plot and Egger's test. Conclusion This meta-analysis suggested that Mathieu and TIP technique were equivalent for primary distal hypospadias in terms of fistula, wound dehiscence, and flap necrosis. Pooled estimates indicated that there was a lower rate of meatal stenosis with Mathieu rather than with TIP significantly. The modified Mathieu technique and a running suture for urethroplasty might be relevant to a lower rate of meatal stenosis. Type of study Meta-analysis. Level of evidence IV

The gene encoding collagen like tail subunit of asymmetric acetylcholinesterase (COLQ) is responsible for the transcription of three strands of collagen of acetylcholinesterase, which is attached to the endplate of neuromuscular junctions. Mutations in the COLQ gene are inherited in an autosomal-recessive manner and can lead to type V congenital myasthenia syndrome (CMS), which manifests as decreased muscle strength at birth or shortly after birth, respiratory failure, restricted eye movements, drooping of eyelids, and difficulty swallowing. Here we reported three variants within COLQ in two unrelated children with CMS. An intronic variant (c.393+1G>A) and a novel missense variant (p.Q381P) were identified as compound heterozygous in a 13-month-old boy, with the parents being carriers of each. An intragenic deletion including exons 14 and 15 was found in a homozygous state in a 12-year-old boy. We studied the relative expression of the COLQ and AChE gene in the probands' families, performed three-dimensional protein structural analysis, and analyzed the conservation of the missense mutation c.1142A>C (p.Q381P). The splicing mutation c.393+1G>A was found to affect the normal splicing of COLQ exon 5, resulting in a 27-bp deletion. The missense mutation c.1142A>C (p.Q381P) was located in a conserved position in different species. We found that homozygous deletion of COLQ exons 14–15 resulted in a 241-bp deletion, which decreased the number of amino acids and caused a frameshift translation. COLQ expression was significantly lower in the probands than in the probands' parents and siblings, while AChE expression was significantly higher. Moreover, the mutations were found to cause significant differences in the predicted three-dimensional structure of the protein. The splicing mutation c.393+1G>A, missense mutation c.1A>C (p.Q381P), and COLQ exon 14–15 deletion could cause CMS.

Introduction: To evaluate the potential predictive value of the Mayo Adhesive Probability (MAP) score combined with the RENAL score for intraoperative outcomes in retroperitoneal laparoscopic nephron-sparing surgery (NSS) in an Eastern Asian population. Methods: An initial of 388 patients undergoing retroperitoneal laparoscopic NSS were identified. MAP and RENAL scores were calculated according to CT and a logistic regression model was adopted as a combination of the RENAL score and the MAP score. Results: A total of 293 patients were included. The overall intraoperative complication rate was 7.5% (21 cases). The MAP score was found to correlate with operation time (OT; r = 0.169), estimated blood loss (EBL; r = 0.318), and intraoperative complications (r = 0.242). The RENAL score was correlated with warm is­chemia time (r = 0.503), OT (r = 0.334), intraoperative complications (r = 0.178), and EBL (r = 0.218). The MAP score and the RENAL score were reliable predictors of overall intraoperative complications, with areas under the curve (AUC) of 0.728 and 0.759, respectively. After combination of these 2 scores, the AUC of overall intra-operative complications was improved with statistical significance (AUC = 0.847, combination vs. RENAL score: p = 0.044 < 0.05; combination vs. MAP score: p = 0.005 < 0.05). Conclusion: The MAP score is an important predictor of EBL, OT, and intraoperative complications in retroperitoneal laparoscopic NSS and its combination with the RENAL score showed a superior predictive value compared to a single score in overall intraoperative complications. The MAP score might be considered in preoperative radiologic aspects as regularly as the RENAL score.

Objective: The aim of this meta-analysis was to evaluate the efficacy and safety of total tubeless percutaneous nephrolithotomy (PCNL) versus standard PCNL. Method: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Chinese Biomedical Literature Database were researched. Randomized controlled trials (RCTs) and clinically controlled trials (CCTs) comparing total tubeless PCNL (tubeless and stentless) versus standard PCNL were included in this review. The related studies that met the inclusion criteria were included in the meta-analysis. Two reviewers independently assessed the quality of each included studies and extracted data. RevMan 5.1. was used for meta-analysis. Outcome: Five RCTs and four CCTs were included, involving a total of 652 patients. All patients were divided into the total tubeless PCNL group and the standard PCNL group. The pooled results showed that the total tubeless PCNL group significantly reduced the hospital stay [weighted mean difference (WMD) −1....

PURPOSE To evaluate the effect of acute kidney injury (AKI) duration and severity on long-term renal functional outcomes in patients undergoing partial nephrectomy (PN). METHODS Altogether 292 consecutive patients undergoing laparoscopic PN from 2010 to 2018 were identified in two medical centers. In addition, the AKI duration {transient AK [≤ 3d] or persistent AKI [> 3d]} was combined with AKI severity (stages) to elucidate their relationships with long-term functional results. Kaplan-Meier (KM) analysis was also used to compare among patients with no AKI, transient AKI, and persistent AKI. Moreover, the Cox-proportional hazards regression model was utilized to assess the risk factors for renal function deterioration. RESULTS Altogether 67 patients (22.9%) experienced postoperative AKI. 75% eGFR preserve rate during the follow-up was compared among patients with no AKI, transient AKI and persistent AKI using KM analysis and log-rank test, which revealed significant difference. After adjusting for age and warm ischemia time by multivariate model proportional hazards analysis, AKI duration and severity were identified as the risk factors (Stage 1-transient AKI vs. non-AKI: adjusted hazard ratio (HR) 4.361, 95% confidential interval (CI) [2.062-9.233], p

Mental retardation, X-linked 21/34 (MRX21/34), is a rare intellectual disability disease caused by mutations in the IL1RAPL1 (Interleukin-1 Receptor Accessory Protein-Like 1) gene. Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from PBMCs collected from a ten-year-old boy with MRX21/34. The iPSCs showed stable amplification, expressed pluripotent genes, displayed a normal karyotype, and had characteristics of trilineage differentiation potential in an in vitro differentiation assay.

Background Long non-coding RNA (lncRNA) has been confirmed to exert a critical effect on the progression of tumors, including prostate cancer. Previous literature has demonstrated LINC01116 involves in activities of multiple cancers. However, the underlying role of LINC01116 in prostate cancer remains unclear. Methods qRT-PCR measured the expression of LINC01116 in prostate cancer cells. EdU experiment was used to detect cell proliferation. Transwell assays detected cell migration and invasion. Immunofluorescence staining and western blot assays were utilized to measure EMT progress. The binding relationship between RNAs was confirmed by a series of mechanism assays. In addition, rescue experiments were conducted to verify the relationship among RNAs. Results LINC01116 was found to be highly expressed in prostate cancer cells. Functional assays indicated that inhibition of LINC01116 could suppress cell proliferation, migration, invasion and EMT progress. Also, miR-744-5p was proven to bind with LINC01116. Moreover, UBE2L3 was verified as the target gene of miR-744-5p. In rescue assays, we discovered that inhibited miR-744-5p or overexpressed UBE2L3 could offset the suppressive influence of silencing LINC01116 on prostate cancer cells. Conclusion Our study suggested that lncRNA LINC01116 acted as an oncogene in prostate cancer and accelerated prostate cancer cell growth through regulating miR-744-5p/UBE2L3 axis.

Highlights • This is the first study of dominant-negative PD-1 armored anti-CD19 CAR t cells on refractory b cell lymphoma, demonstrated that the modified CAR t cells were safe and tolerable without extra toxicity. • This study indicated that the efficacy of this new CAR t cell was promising for the management of transformed follicular lymphoma (FL) and early-relapsed FL. • It proved the possibility that CAR T-cell function could be improved by interrupting the PD-1/PD-L1 axis which was validated preliminarily in this clinical study., Refractory/relapsed B cell lymphoma patients who received the available anti-CD19 chimeric antigen receptor (CAR) T cells may still experience a short duration of remission. Here in this study, we evaluated the safety and efficacy of a novel dominant-negative programmed cell death-1 (PD-1) armored anti-CD19 CAR T cells. A total of 9 patients (including 4 diffuse large B cell lymphomas, DLBCL, 2 transformed follicular lymphomas, TFL, and 3 follicular lymphomas, FL) received the novel CAR T cells infusion at a dose of more than 1 × 106/kg. Grade ≥ 3 cytokine release syndrome (CRS) and neurotoxicity were observed in 11.1% (n = 1/9) and 11.1% (n = 1/9) of patients, respectively. The overall response rate (ORR) was 77.8% (n = 7/9) and complete response (CR) rate was 55.6% (n = 5/9). Two patients have ongoing CR (all at 20+ months). CAR T cells expanded after infusion and continued to be detectable at 12+ months in patients with ongoing CR. This novel CD19-CAR T cell was safe and effective with durable remissions in patients with refractory/relapsed B cell lymphoma.

BackgroundThe rapid development of coronavirus disease 2019 (COVID-19) pandemic has become a great threat to global health. Its mortality is associated with inflammation-related airway mucus hypersecretion and dysfunction of expectoration, and the subsequent mucus blockage of the bronchioles at critical stage is attributed to hypoxemia, complications, and even death. Traditional Chinese medicine (TCM) has rich experience in expectorant, including treatment of COVID-19 patients with airway mucus dysfunction, yet little is known about the mechanisms. This study is aiming to explore the potential biological basis of TCM herbal expectorant for treating COVID-19.ObjectiveTo get core herbs with high used frequency applications in the actions of expectoration by using association rule algorithm and to investigate the multitarget mechanisms of core herbs in expectorant formulae for COVID-19 therapies.MethodsForty prescriptions for expectorant were retrieved from TCM Formulae. The ingredient compounds and targets of core herbs were collected from the TCMSP database, Gene-Cards, and NCBI. The protein interaction network (PPI) was constructed by SRING, and the network analysis was done by Cytoscape software. Bioconductor was applied for functional enrichment analysis of targets.ResultsThe core herbs of expectorant could regulate core pathways (MAP kinase activity, cytokine receptor binding, G-protein-coupled receptor binding, etc.) via interactions of ingredients (glycyrol, citromitin, etc.) on mucin family to eliminate phlegm.ConclusionTCM herbal expectorant could regulate MAPK and cytokine-related pathways, thereby modulating Mucin-family to affect mucus generation and clearance and eventually retarding the deterioration of COVID-19 disease.

Background Beta‐propeller protein‐associated neurodegeneration (BPAN) is a rare, X‐linked dominant neurodegenerative disease mainly characterized by developmental delay, intellectual disability, epilepsy in childhood and dystonia, parkinsonism, dementia in adulthood. BPAN is caused by variants in WD repeat domain 45(WDR45), which is characterized by iron accumulation in the basal ganglia, however, it may be atypical in early brain MRI. Methods Whole exome sequencing was performed for five parents‐offspring trios and phenotype‐driven data analyses were conducted. All candidate variants were confirmed by Sanger sequencing. Results Here, we report five independent children presented variable degree of developmental delay, intellectual disability, and/or epilepsy. Five de novo variants of WDR45 including four novel truncating variants (one splicing variant, two nonsense variants, and one frameshift variant) were identified. Although their early brain MRI showed no obvious iron accumulation, multifocal spikes, or polyspikes in electroencephalograms (EEG) were observed in four patients. Conclusion Our study reports four patients with new variants in WDR45, which expands the mutation spectrum of WDR45. In addition, our findings provide an early and precise diagnosis basis of BPAN, which is helpful for accurate genetic counseling and prenatal diagnosis., Our study reports five de novo variants with BPAN including four new variants in five independent non‐consanguineous Chinese families, which enlarges the mutation spectrum of WDR45. The application of trio exome sequencing contributes to the early detection of BPAN, which can help patients get timely genetic counseling preventing the disease from worsening and open the way for preimplantation genetic diagnosis and future prenatal check‐ups.

Allan-Herndon-Dudley syndrome (AHDS) is a rare, X-chromosome-linked inherited disorder that affects brain development and is caused by a mutation in SLC16A2. Herein, we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells of a one-year-old male infant with AHDS using Sendai-virus-mediated reprogramming. These iPSCs exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three germ layers in vitro. Additionally, this iPSC line was found to maintain a normal karyotype and retain the pathogenic mutation in SLC16A2, facilitating the study of disease mechanisms and development of new therapies of AHDS.

Objective: To compare the surgical feasibility, oncological and functional results between sutureless and suture techniques in retroperitoneal laparoscopic nephron-sparing surgery (LNSS). Materials...

Mitochondrial DNA depletion syndrome-13 (MTDPS13) is a rare autosomal recessive mitochondrial disease caused by mutations in the FBXL4 (F-box and leucine-rich repeat protein 4) gene. Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from PBMCs collected from a one-year-old female patient with MTDPS13. The iPSCs were stable during amplification, expressed pluripotent genes, maintained a normal karyotype, and showed characteristics of the three germs layers in an in vitro differentiation assay.

BACKGROUND This study aimed to clarify the diagnosis and expand the understanding of dopa-responsive dystonia (DRD). MATERIAL AND METHODS Relevant data from clinical diagnoses and genetic mutational analyses in 3 Han Chinese patients with sporadic DRD were collected and analyzed. Protein structure/function was predicted. RESULTS One novel mutation of c.679A>G (p.T227A) in GCH1 and 3 known mutations of c.457C>T (p.R153X), c.739G>A (p.G247S), and c.698G>A (p.R227H) in tyrosine hydroxylase (TH) have been found and predicted to be damaging or deleterious. All of the mutations were localized in conserved sequences. The iterative threading assembly refinement (I-TASSER) server generated three-dimensional (3D) atomic models based on protein sequences from the novel nonsense mutation of c.679A>G (p.T227A) in GCH1, which showed that residue 227 was located in the GCH1 active site. CONCLUSIONS Patients carrying different non-synonymous variants had remarkable variation in clinical phenotype. This study expands the spectrum of genotypes and phenotypes of DRD in the Han Chinese ethnicity, provides new insights into the molecular mechanism of DRD, and helps the diagnosis and treatment of DRD.

In the tyrosine kinase inhibitor (TKI) era, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the most potential approach for cure of adult patients with Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL). TKI plus chemotherapy has strikingly increased response rates and depth of response, and facilitated allo-HSCT, which decreases relapse and improves survival eventually. Meanwhile, for those with older age or comorbidities at diagnosis, TKI in combination with reduced-intensity chemotherapy or chemotherapy-free strategy reduces treatment-related mortality, deferred intensive chemotherapy increases molecular responses and reduced-intensity conditioning (RIC) allo-HSCT improves survival finally. Of note, according to minimal residual disease (MRD) and BCR/ABL1 kinase domain mutation screening, prophylactic or preemptive maintenance therapy with a sensitive TKI decreases relapse further. Regarding transplantation-related mortality and impaired quality of life related to complications of allo-HSCT, autologous-HSCT (auto-HSCT) among those with early and persistent molecular remission and the most potent TKI ponatinib plus intensive chemotherapy has exhibited non-inferior survival to allo-HSCT. Even so, risk-adapted strategy isn't available now. Lastly, outcomes of relapse after allo-HSCT are dismal due to TKIs exposure, and new therapeutic interventions combined with TKIs shed light on this thorny problem.

TRAF family member-associated NF-κB activator (TANK) is a scaffold protein that assembles into the interferon (IFN) regulator factor 3 (IRF3)-phosphorylating TANK-binding kinase 1 (TBK1)–(IκB) kinase ε (IKKε) complex, where it is involved in regulating phosphorylation of the IRF3 and IFN production. However, the functions of TANK in encephalomyocarditis virus (EMCV) infection-induced type I IFN production are not fully understood. Here, we demonstrated that, instead of stimulating type I IFN production, the EMCV-HB10 strain infection potently inhibited Sendai virus- and polyI:C-induced IRF3 phosphorylation and type I IFN production in HEK293T cells. Mechanistically, EMCV 3C protease (EMCV 3C) cleaved TANK and disrupted the TANK–TBK1–IKKε–IRF3 complex, which resulted in the reduction in IRF3 phosphorylation and type I IFN production. Taken together, our findings demonstrate that EMCV adopts a novel strategy to evade host innate immune responses through cleavage of TANK.

This study aimed to investigate the clinical characteristics and prognostic significance of monosomal karyotypes (MKs) in patients with acute myeloid leukemia (AML).We retrospectively analyzed the clinical data for 498 patients with AML, of whom 233 (46.8%) had an abnormal karyotype, including 42 with MKs (8.4%) and 70 with a complex karyotype (CK) (14.1%).Patients with MKs were older (median age 62.5 vs. 52 years, p=0.003) and had lower median hemoglobin levels (62.5 vs. 77 g/L, p=0.009) and lower white blood cell counts (7.0×10MK is an independent risk factor for poor prognosis in AML patients.Amaç: Bu çalışmada akut myeloid lösemi (AML) hastalarında monozomal karyotipe (MK) sahip olmanın klinik özellikleri ve prognostik önemini araştırmak hedeflenmiştir. Gereç ve Yöntemler: Retrospektif olarak 498 AML hastasının klinik verileri incelenmiştir. Bu hastalardan 233’ünde (%46,8) anormal karyotip saptanmış olup, bunların da 42’sinde (%8,4) MK ve 70’inde kompleks karyotip (KK) bulunmuştur. Bulgular: Hastalardan MK’ya sahip olanlar daha yaşlı olup (ortanca 62,5 vs. 52 yıl; p=0,003), daha düşük ortanca hemoglobin düzeyine (62,5 vs. 77 g/L; p=0,009) ve daha düşük beyaz küre sayısına (7,0×109/L vs. 11,7×109/L, p=0,008) sahipti. Ünivaryant analizde MK ya da KK’ya sahip olan hastaların diğer hastalara göre toplam sağkalımı daha düşük bulundu. (MK için ortanca sağkalım süresi 7,3 vs. 26,3 ay, p0,001 ve CK için 14,8 vs. 26,3 ay, p0,001). Toplam sağkalım için yapılan, multivaryant analizde ise MK ve “National Comprehesnsive Cancer Network” prognostik grubu anlamlı bulunan faktörlerdi. Sonuç: AML’li hastalarda MK kötü prognoza işaret eden bağımsız bir risk faktörüdür.

Porcine reproductive and respiratory syndrome virus (PRRSV) has caused tremendous economic losses and continues to be a serious problem to the swine industry worldwide. The structure and function of PRRSV nonstructural protein 12 (NSP12) is still unknown. In this study, we produced a monoclonal antibody, named as 1E5, against the NSP12 protein of HP (highly pathogenic) -PRRSV strain HuN4. A series of partially overlapping recombinant NSP12 truncations and synthesized peptides were used to define the epitope recognized by 1E5. We found that 130KANATSMRFH139 is the minimal linear epitope and that it is highly conserved among some HP-PRRSV isolates of type 2 PRRSV, but not the classical isolates of type 2 PRRSV or the isolates of type 1 PRRSV. Therefore, 1E5 can be used to establish a valuable tool to distinguish infections with HP-PRRSV isolates of type 2 PRRSV from the classical isolates of type 2 PRRSV and type 1 PRRSV.

Background Mitochondrial DNA depletion syndrome-13 (MTDPS13) is caused by mutations in FBXL4 (F-box and leucine-rich repeat protein 4), a nuclear gene encoding an F-box protein that plays a role in maintaining mtDNA integrity and stability. Methods We identified a novel homozygous FBXL4 gene mutation, c.993dupA (p.L332Tfs*3), in a 1-year-old girl of Han Chinese descent. We performed three-dimensional protein structural analysis and targeted mtDNA next-generation sequencing. We analysed FBXL4 expression and mitochondrial DNA level, and reviewed mutations reported in FBXL4-related literature. Results This mutation resulted in premature termination of translation and loss of 288 amino acids from C-terminus. A three-dimensional structural analysis revealed that conserved LRR domains were lost in mutant FBXL4 protein, which likely affected its ability to form protein-protein interactions. There were no differences in FBXL4 mRNA expression levels between the patient and her parents. There were no mtDNA mutations in either the patient or her parents. However, ND1/GAPDH ratio in lymphocytes and urine, which represents mtDNA/nuclear DNA ratio, showed that the number of mitochondrial genomes was significantly lower in the patient than in her parents or wild-type subjects. Conclusion Homozygous FBXL4 gene mutation, c.993dupA, can cause mitochondrial dysfunction, and LRR region is especially important for FBXL4 protein function.

This study aimed at exploring whether the time interval (TI) between prostate biopsy and surgery affect the outcomes of radical prostatectomy (RP). A comprehensive search of the PubMed, Embase, and Cochrane Library databases was conducted to identify all eligible studies. After quality assessment and date extraction, a systematic review and meta-analysis was performed. A total of 9 studies with 8579 patients were included in our meta-analysis. Pooled data showed no significant differences between groups of TI ≤ 2 weeks and > 2 weeks in operative time, estimated blood loss, transfusion rate, bilateral nerve preservation, positively surgical margin, and complications. For comparison between TI ≤ 4 and > 4 weeks, shorter TI would be associated with significantly less estimated blood loss (p = 0.045) and lower rate of bilateral nerve preservation (p = 0.002). In addition, for TI ≤ 6 versus > 6 weeks, significantly less bilateral nerve preservation (p = 0.025) and more positive surgical margin (p = 0.020) could be found in the earlier surgery group. Sensitivity analysis indicated that TI had no impact on any outcomes of robot-assisted laparoscopic radical prostatectomy (RALP). As shorter TI was associated with lower rate of bilateral nerve preservation and higher rate of positive surgical margin, it would be better to perform RP with a TI of 4 or 6 weeks after biopsy. While for RALP, shorter TI did not have any impact on outcomes of RALP, It is feasible and safe to perform RALP within 2, 4, or 6 weeks.

The traditional concept of diencephalon (thalamus plus hypothalamus) and with it the entire traditional subdivision of the developing neural tube are being challenged by novel insights obtained by mapping the expression of key developmental genes. A model in which the hypothalamus is placed in the most rostral portion of the neural tube, followed caudally by a diencephalon formed by prethalamus, thalamus and pretectum has been proposed. The adult thalamus and hypothalamus are quite unlike each other in connectivity and functions. Here we review work on the role of the secreted morphogen protein Sonic hedgehog (Shh) in the developing diencephalon and hypothalamic region to show how different these two regions are also from this point of view. Shh from the prechordal plate (PCP) induces and patterns the hypothalamus but there is no evidence that this role is fulfilled by a morphogen gradient. Later, the hypothalamic primordium itself expresses Shh and a large part of the hypothalamus belongs to the Shh lineage, including the ventral domains. Neural Shh is necessary to complete the specification (lateral hypothalamus), differentiation and growth of the hypothalamus. Although Gli2A is the major effector of Shh in this region, hypothalamic specification also depends on the suppression of Gli3R by Shh secreted by the PCP as well as the neuroepithelium. The thalamus is patterned by an Shh morphogen gradient originated in the ZLI following similar mechanisms to those in the spinal cord. The thalamus itself does not belong to the Shh lineage. Gli2A is necessary for appropriate growth and specification of the thalamic nuclei, to the exception of the medial and intralaminar groups (limbic-related), whose development depends on Gli3R. Beyond specification and patterning, the scarce data available about cell sorting and aggregation in these two regions shows key differences between them as well. In summary, not only expression patterns but also developmental mechanisms support a separation of the traditional thalamus and hypothalamus into different prosomeric domains.

Purpose This study aimed to develop a simple nomogram based on the Mayo Adhesive Probability (MAP) score combined with the RENAL nephrometry score (RNS) to predict intraoperative complications before partial nephrectomy (PN) in Asian populations. Materials and methods This study retrospectively collected patients undergoing PN at three medical centers. Each component of the MAP score and the RNS (6 variables) was evaluated to assess its association with intraoperative complications by multivariable logistic regression with backward elimination. Results A total of 46 cases (7.2%) with intraoperative complications were identified among 637 patients. After backward elimination, three variables, including tumor diameter (4-7 cm vs. ≤4 cm: odds ratio [OR], 4.339; 95% confidence interval [CI], 1.943-9,692; ≥7 cm vs. ≤4 cm: OR, 8.434; 95% CI, 1.225-58.090), nearness to the collecting system (4-7 mm vs. ≥7 mm: OR, 2.988; 95% CI, 1.293-6.907; ≤4 mm vs. ≥7 mm: OR, 21.394; 95% CI, 6.122-74.756), and perirenal fat stranding type (type 1 vs. no stranding: OR, 3.119; 95% CI, 1.079-9.017; type 2 vs. no stranding: OR, 18.722; 95% CI, 6.757-51.868), were retained. The predictive power (measured by area under the curve [AUC]) of the nomogram was observed to be superior to the RNS or MAP score alone (RNS: 0.686, MAP score: 0.729, the nomogram: 0.837), but comparable to their combination (0.813). Conclusions The simple nomogram contains fewer components than the combination of the RNS and MAP scores yet demonstrates equivalent predictive power for intraoperative complications.

Summary Type I interferon (IFN) plays an essential role in the host innate immune responses. Several ubiquitin-conjugating enzyme (E2) family members were reported to regulate type I IFN production and host antiviral immune responses. However, the molecular mechanisms are still not fully understood. Here, we report that UBE2S acts as a negative regulator in the type I IFN signaling pathway. Ectopic expression of UBE2S inhibits host antiviral immune responses and enhances viral replications, whereas deficiency of UBE2S enhances host antiviral immune responses and suppresses viral replications both in vitro and in vivo. Inhibition of type І IFN production by UBE2S is independent on its E2 and E3 enzymic activity. Mechanistically, UBE2S interacts with TBK1 and recruits ubiquitin-specific protease 15 (USP15) to remove Lys63 (K63)-linked polyubiquitin chains of TBK1. Our findings reveal a role of the UBE2S-USP15-TBK1 axis in the regulation of host antiviral innate immune responses.

Objective To compare the safety and efficacy of percutaneous nephrolithotripsy (PCNL) in supine versus prone position for patients with renal or upper ureteral calculi. Methods A systematic search of Pubmed, Embase and Cochrane Central Register of Controlled Trials was performed to identify all eligible studies. All included randomized controlled trials (RCTs) were evaluated based on the inclusion and exclusion criteria. After quality assessment and date extraction, a meta-analysis was performed using RevMan 5.3 software. Results A total of 15 RCTs with 1474 patients were included in our meta-analysis. Pooled data showed that PCNL in supine position could significantly reduce the operative time [weighted mean difference (WMD) −12.02, 95% confidence interval (CI) −20.49 to −3.54, p = 0.005] and rate of fever [risk ratio (RR) 0.67, 95% CI 0.46 to 0.97, p = 0.03] compared to prone position. In addition, no significant differences could be found between groups in stone-free rate (p = 0.31), hospital stay (p = 0.59) and rate of overall complications (p = 0.11), mainly including urinary leakage (p = 0.83), pleural effusion (p = 0.74) and blood transfusion (p = 0.58). Conclusions The current study found comparable stone-free rate and significant lower rate of postoperative fever in supine PCNL compared with prone PCNL. PCNL in supine position could be a safe and efficient choice for patients with renal or upper ureteral calculi.

Summary: DExD/H-box helicase members are key receptors for recognizing viral nucleic acids, and they regulate retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated type I interferon (IFN) production. Here, we report that the DExD/H-box helicase family member DExD/H-box RNA helicase 19 (DDX19) is a negative regulator of type I IFN production. Ectopic expression of DDX19 suppressed poly(I:C) (polyinosinic-polycytidylic acid)- and Sendai-virus-induced type I IFN production, whereas knockdown of DDX19 expression enhanced type I IFN production. Mechanistically, DDX19 inhibited TANK-binds kinase 1 (TBK1)- and inhibitor-κb kinase ε (IKKε)-mediated phosphorylation of interferon regulatory factor 3 (IRF3) by disrupting the interaction between TBK1 or IKKε and IRF3. Additionally, DDX19 recruited Lamtor2 and then formed the TBK1-IKKε-Lamtor2-DDX19-IRF3 complex to suppress IFN production by promoting TBK1 and IKKε degradation. We generated Ddx19 knockout mice using transcription activator-like effector nucleases (TALENs) and found that Ddx19 deficiency in vivo augmented type I IFN production, resulting in suppression of encephalomyocarditis virus replication. These data show that DDX19 is an important negative regulator of RLR-mediated type I IFN production. : DExD/H-box helicase members are key receptors for recognizing viral nucleic acids and participate in regulating RLR-mediated type I IFN production. Zhang et al. show that DDX19 acts as a critical negative regulator of type I IFN production by disrupting TBK1-IKKε-IRF3 complex formation and recruiting Lamtor2 to degrade TBK1 and IKKε. Keywords: DDX19, IRF3, IKKε, Lamtor2, negative regulatory, type I IFN, TBK1

Objective To establish a rat model of type 2 diabetes (T2DM) manifesting the Chinese medicine syndrome pattern of both qi and yin deficiency for evaluating the efficacy of a Chinese herbal formula (CHF), integrative medicine (IM), and pioglitazone (PIO) on T2DM indicators in the animal model. Methods The rat model was induced by a high-fat diet (HFD) and streptozotocin (STZ, 30 mg/kg). CHF (3.4 g/kg), PIO (2.7 mg/kg), and IM (3.4 g CHF + 2.7 mg PIO) were administered to rats once daily for 14 days. Related laboratory parameters were observed. Results Diabetic rats showed unsmooth fur, alopecia, reduced activity, huddling, somnolence, depression, pale or reddened tongue, damp/dark red tail, and high levels of water and food intake, urine volume, and stool weight, but weakened grip strength. Low levels of serum SOD, Na + -K + -ATPase, cAMP/cGMP, and a high level of iNOS were observed. Hyperglycemia, hyperinsulinemia, insulin resistance, high levels of serum glucagon/IDE and pancreatic amylin, and low serum and pancreatic SS levels were evident as well. Conclusions A rat model of T2DM with both qi and yin deficiency was successfully replicated. CHF appeared to be more efficacious than IM and PIO in the rat model of qi and yin deficiency pattern of T2DM, though IM and PIO were each found to have their merits and drawbacks in attenuating T2DM indicators in the rat model.

L-2-hydroxyglutaric aciduria is a genetic metabolic disorder. Its clinical features include elevated levels of hydroxyglutaric acid in body fluids and abnormal magnetic resonance imaging (MRI) in the subcortical white matter, which are affected by the accumulation of L-2-hydroxyglutaric acid. A boy with psychomotor retardation and progressive ataxia accompanied by abnormal brain MRI findings was tested using whole-exome sequencing. Next-generation sequencing (NGS) revealed two novel compound heterozygous frameshift mutations, c.407 del A (p.K136SfsTer3) and c.699_c700 ins A (p.D234RfsTer42), in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene, leading to premature termination codons and truncated FAD/NAD(P)-binding domain of L2HGDH protein. Further laboratory testing revealed an increase in the 2-hydroxyglutaric acid level in the urine. The results suggested that NGS could provide clues for identifying patients with abnormal neuroradiological findings in the subcortical white matter.

Oligodendrocyte precursor cells (OPC), neurons and astrocytes share a neural progenitor cell (NPC) in the early ventricular zone (VZ) of the embryonic neuroepithelium. Both switch to produce either of the three cell types and the generation of the right number of them undergo complex genetic regulation. The components of these regulatory cascades vary between brain regions giving rise to the unique morphological and functional heterogeneity of this organ. Forkhead b1 (Foxb1) is a transcription factor gene expressed by NPCs in specific regions of the embryonic neuroepithelium. We used the mutant mouse line Foxb1-Cre to analyze the cell types derived from Fobx1-expressing NPCs (the Foxb1 cell lineage) from two restricted regions, the medulla oblongata (MO; hindbrain) and the thalamus (forebrain), of normal and Foxb1-deficient mice. Foxb1 cell lineage derivatives appear as clusters in restricted regions, including the MO (hindbrain) and the thalamus (forebrain). Foxb1-expressing NPCs produce mostly oligodendrocytes (OL), some neurons and few astrocytes. Foxb1-deficient NPCs generate mostly OPC and immature OL to the detriment of neurons, astrocytes and mature OL. The axonal G-ratio however is not changed. We reveal Foxb1 as a novel modulator of neuronal and OL generation in certain restricted CNS regions. Foxb1 biases NPCs towards neuronal generation and inhibits OPC proliferation while promoting their differentiation.

Objective Mutations in polymerase gamma gene (POLG) are believed to be an important cause of early and juvenile onset of non-syndromic intractable epilepsy. The aim of this study is to investigate the incidence/prevalence of POLG pathogenic variants in epilespy patients of Han population through sequencing it.Methods Han Chinese patients with seizures prior valproic acid (VPA) exposure at Shanghai Children's Hospital were collected from 2015 to 2019. The clinical diagnosis was based on the 2014 Consensus Statement of Epilepsy by the International League against Epilepsy (ILAE). Blood sampling were performed before VPA treatment. The POLG gene DNA was sequenced by either the first or the next generation sequencing (NGS). The POLG variant burden was illustrated. Liver functions were tested to describe whether they experienced VPA toxicity.Results Totally 216 Han Chinese patients were included, aged from 1 month to 15 years old, 102 were male and 114 were female. The onset age was 1 month old to 13 years old, and the epilepsy course ranged from 2 weeks to about 3 years. VPA treatment was delivered for the generalized or intractable partial seizures at standard dosage. No patient experienced hepatic toxicity following VPA exposure. DNA sequencing data showed no patient had either a homozygous mutation or compound heterozygous mutation of POLG. Single heterozygous mutations of c.1150G>T and p.D384Y were found in 2 patients, and single heterozygous mutation of c.156_158dupGCA was found in 1 patient. None of these variants showed clinical significance.Conclusions Functional modifying POLG homozygous mutations and compound heterozygous mutations were not detected and VPA toxicity was not seen in the current study. POLG mutation frequency might be rare in Han Chinese, and standard VPA therapeutic dosage might be safe for Han Chinese patients.

We demonstrated here that the phosphorylcholine-modified polyplexes can be explored as effective gene vector for selective uptake and high transfection of cancer cells. 12-acryloyloxy dodecyl phosphorylcholine modified polyethyleneimine (PEI–ADPC) with grafting level about 13%, 8.3% and 4.5% was successfully synthesized. Gel retardation assay indicated that ADPC modification did not affect the DNA condensation ability. The PEI–ADPC 13% /DNA and PEI–ADPC 8.3% /DNA polyplexes were under 100 nm with a beneficial neutral surface at N/P ratio of 30. Sufficient ADPC shell endowed the polyplexes with high colloidal stability and low cytotoxicity. Compared to PEGylated polyplexes, it was interesting to find out that the PEI–ADPC/DNA polyplexes were selectively uptaked by liver cancer HepG2 cells. At the presence of chloroquine to exclude the limitation of lysosome escape, the ADPC-modified polyplexes showed more effective gene transfection in cancer cells than in normal cells because of the selective cell uptake. In conclusion, the convenient PC-modification modality was found to have both the function of biostability in the physiological environment and targetability toward cancer cells uniquely, which might have great potential use in cancer gene therapy.

Background/aim: Multiple sclerosis (MS) is a chronic and debilitating inflammatory autoimmune disease of the central nervous system (CNS) that affects the myelinated axons in the CNS. Incomplete remissions occur more commonly with increasing duration of disease. Intravenous immunoglobulin (IVIg) has various functions as an immune modulator via macrophage activation. Clinical trials of immunoglobulin demonstrated remarkable clinical effects in several types of MS, especially in relapsing-remitting type. It is an approved method for the treatment of relapsing-remitting MS that can be used as a supportive therapy. Our study involves the case of a ten year old female patient with relapsing-remitting MS. This study was undertaken to examine the effects of IVIg used almost every 6 months in a patient with relapsing-remitting MS. Results: This case study demonstrated that treatments of IVIg used almost every 6 months in a patient with relapsing-remitting MS have potent therapeutic actions with early beneficial responses. Conclusion: IVIg used almost every 6 months shows a potential positive therapeutic treatment for relapsing-remitting MS and more large-scale clinical studies are required.

The effects of vasectomy on the reproductive organs in various species are controversial. This study investigated the morphological change and apoptosis of the testis, epididymis, and vas deferens in beagle dogs 12 months after vasectomy. The male beagles were divided into two groups: vasectomized and sham-operated groups (n=5 in each). Histopathological, ultrastructural, and TUNEL evaluation of the changes in the testis, epididymis, and ductus deferens of each animal were conducted 12 months after surgery. The mean lumen diameter, cellular thickness, mean interstitial distance, and lumen area fraction of each seminiferous tubule and ductus epididymis were measured by stereological analysis. The results showed that, compared with the sham-operated group, the seminiferous tubular epithelial cells of the testes in the vasectomized group were disorderly arranged and scattered. Significant atrophy and apoptosis were found in the endothelial cells, and a range of ultrastructural variations were observed in the cells of testes, epididymis, and vas deferens in vasectomized group. It was concluded that complete obstruction of the vas deferens as a traditional contraception method is not absolutely safe in terms of the reversal of fertility in the long run. Techniques of relieving the inner pressure in the vas deferens while maintaining the efficacy of male contraception need to be explored.

Objective - The effects of vasectomy on testes and related structures are disputable. The aim of this study was to determine whether the reproductive organs of rabbits were influenced after 12 months vasectomy. Study design – Bilateral vasectomy was performed on 10 male adult New Zealand Big Eared White Rabbits (another 10 rabbits set as sham operated group) and tissue samples were examined by light microscopy after 12 months treatment. The histologic alterations were observed and analyzed by stereology method. Cell apoptosis by Terminal Deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL) assay were employed. Result - Bilateral vasectomy for 12 months affected the morphology of testis, epididymis and vas deferens tissues. Significant changes were noted in the histological stereology analysis. The apoptosis of the cells on the testis, epididymis and vas deferens increased compared with the sham operated group. Conclusion - Our findings suggest that the reproductive tissues of rabbits were influenced in a relatively longer term vasectomy.

In the present study, we tested the efficacy and safety of Huperzine A in treatment of mild to moderate vascular dementia (VaD). This was a randomized, double-blinded, placebo-controlled study with 78 patients with mild to moderate VaD. The participants were randomized to receive either vitamin C (100-mg bid) as placebo (n = 39) or Huperzine A (0.1-mg bid) (n = 39) for 12 consecutive weeks. The mini-mental state examination (MMSE), clinical dementia rating (CDR), and activities of daily living (ADL) scores were used for the assessment of cognition. The assessments were made prior to treatment, and 4, 8, and 12 weeks of the treatment. The adverse effects of the treatment were also recorded. After 12 weeks of treatment, the MMSE, CDR, and ADL scores significantly improved in the Huperzine A group (P0.01 for all comparisons), whereas the placebo group did not show any such improvement (P0.05 for all comparisons). No serious adverse events were recorded during the treatment.Huperzine A can significantly improve the cognitive function in patients with mild to moderate vascular dementia. Further, the medicament is safe.

To evaluate the safety and efficacy of transrectal high-intensity focused ultrasound (HIFU) in the treatment of benign prostatic hyperplasia (BPH), serial studies were conducted in 150 BPH patients before and 30 min, 1, 2, 6 and 12 month(s) after Sonablate-500™ HIFU treatment. A silicon-coated indwelling 16F latex catheter was placed during the determination of the therapy zone. Preoperative and postoperative evaluations were made by using the international prostate symptom score (IPSS), quality of life (QOL), uroflowmetric findings and transrectal ultrasound, and incidence of complications. The cystourethrography was done in 23 patients within 1 year postoperatively. The results showed that after HIFU treatment, IPSS and QOL scores were significantly decreased at 1, 2, 6 and 12 month(s) (P

Cyclodextrin-modified polycations have been studied widely due to their low cytotoxicity, low immunogenicity and the ability to form inclusion complexes. However, the influence of CD modification on cellular uptake and transfection efficiency of polyplexes is still unclear. In this research, cyclodextrin-modified polyethylenimines (PEI-CD) with different CD-grafting levels were synthesized, which were named PEI-CD(15) and PEI-CD(41), respectively, according to the CD number per PEI chain. CD modification showed great influence on the DNA condensation ability of the polycation. PEI-CD(15) could protect DNA completely above N/P ratio of 2. The particle sizes of these polyplexes were about 120 nm. However, PEI-CD(41) could not protect DNA below N/P of 6, and PEI-CD(41)/DNA polyplexes were larger than 1 μm, even at N/P ratio of 10. Therefore, this research was mainly focused on PEI-CD(15). It was interesting that the PEI-CD(15)/DNA polyplexes at N/P ratio of 8 and 10 displayed excellent stability in physiological salt conditions, probably due to the hydration shell of CDs. The influence of CD modification on the cellular uptake and transfection efficiency of polyplexes depended on the type of the cells. Uptake inhibition experiments indicated that PEI/DNA polyplexes were internalized by HEK293T cells by both clathrin-mediated endocytosis and caveolae-mediated endocytosis. The route of caveolae-mediated endocytosis was significantly promoted after CD modification. So the cell uptake and transfection efficiency of PEI-CD(15)/DNA polyplexes were significantly improved for HEK293T cells. However, the uptake and transfection efficiency of PEI-CD(15)/DNA polyplexes in HepG2 cells was similar to that of PEI/DNA polyplexes, probably due to the lack of endogenous caveolins.