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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

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....

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.

A key step of decision making is to determine the value associated with each option. The evaluation process often depends on the accumulation of evidence from multiple sources, which may arrive at different times. How evidence is accumulated for value computation in the brain during decision making has not been well studied. To address this problem, we trained rhesus monkeys to perform a decision-making task in which they had to make eye movement choices between two targets, whose reward probabilities had to be determined with the combined evidence from four sequentially presented visual stimuli. We studied the encoding of the reward probabilities associated with the stimuli and the eye movements in the orbitofrontal (OFC) and the dorsolateral prefrontal (DLPFC) cortices during the decision process. We found that the OFC neurons encoded the reward probability associated with individual pieces of evidence in the stimulus domain. Importantly, the representation of the reward probability in the OFC was transient, and the OFC did not encode the reward probability associated with the combined evidence from multiple stimuli. The computation of the combined reward probabilities was observed only in the DLPFC and only in the action domain. Furthermore, the reward probability encoding in the DLPFC exhibited an asymmetric pattern of mixed selectivity that supported the computation of the stimulus-to-action transition of reward information. Our results reveal that the OFC and the DLPFC play distinct roles in the value computation during evidence accumulation.

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.

The RNA polymerase II transcription subunit 12 homolog (MED12) is a member of the mediator complex, which plays a critical role in RNA transcription. Mutations in MED12 cause X-linked intellectual disability and other anomalies collectively grouped as MED12-related disorders. While MED12 mutations have been most commonly reported in male patients, we present the case of a 1-year-old girl with clinical characteristics similar to MED12-related disorders. To explore the clinical characteristics of the condition and its possible pathogenesis, we analyzed the patient’s clinical data; genetic testing by whole-exome sequencing revealed a de novo heterozygous mutation (c.1249-1G > C) in MED12. Further cDNA experiments revealed that the patient had an abnormal splicing at the skipping of exon9, which may have produced a truncated protein. qPCR showed decreased MED12 gene expression level in the patient, and an X-chromosome inactivation test confirmed a skewed inactivation of the X-chromosome. The lymphoblast transcription levels of the genes involved in the Gli3-dependent sonic hedgehog (SHH) signaling pathway, namely, CREB5, BMP4, and NEUROG2, were found to be significantly elevated compared with those of her parents and sex- and age-matched controls. Our results support the view that MED12 mutations may dysregulate the SHH signaling pathway, which may have accounted for the aberrant craniofacial morphology of our patient.

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.

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.

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.

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.

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.

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

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.

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.