TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

The POLR2E rs3787016 polymorphism is associated with susceptibility to and prognosis of gastric cancer.

Long non-coding RNAs (lncRNAs) have been proposed as promising diagnostic and prognostic biomarkers for cancer. We investigated the associations of RNA polymerase II subunit E (POLR2E) rs3787016 polymorphism with the risk and prognosis of gastric cancer (GC). The study subjects included 368 GC patients who underwent surgical resection and 294 healthy volunteers, adjusted for age, gender, smoking status, alcohol status, and Helicobacter pylori infection status. The data was subjected to logistic regression analyses and revealed that the subjects carrying AA genotype of rs3787016 in POLR2E had a significant 1.85-1.98-fold increased risk of GC when compared with those carrying GG genotype (adjusted OR=1.979, 95% CI=1.198-3.267; p=0.008) or those carrying AG/GG genotypes (adjusted OR=1.847, 95% CI=1.222-2.793; p=0.004). For the GC patients, the AA genotype of rs3787016 was significantly correlated with poorly differentiated GC (p=0.018), advanced TNM stage (p=0.023), higher depth of invasion (p=0.022), positive lymph node metastasis (p=0.01), and worse overall survival (OS; p=0.004). Multivariate analysis confirmed that the POLR2E rs3787016 polymorphism is an independent prognostic factor for GC (HR=1.668, 95% CI=1.058-2.631; p=0.028). Our cumulative results thus suggest that the presence of POLR2E rs3787016 polymorphism could serve as a genetic factor that affects the susceptibility to and the prognosis of GC.

Siccirubricoccus phaeus sp. nov., isolated from oil reservoir water and emended description of the genus Siccirubricoccus.

A Gram-staining-negative, non-motile, aerobic bacterium, designated 1-3T, was isolated from oil reservoir water collected from Liaohe oilfield, north-east of China. Growth was observed at 15-40 °C (optimum 37 °C) and pH 6-10 (optimum 7). The strain can grow under nitrogen-limiting condition. Phylogenetic analysis based on 16S rRNA gene sequences showed that the novel isolate was most closely related to Siccirubricoccus deserti SYSU D8009T (96.7%), followed by Paracraurococcus ruber NS89T (95.7%) and Belnapia rosea CPCC 100156T (94.9%). Genome sequencing revealed a genome size of 6.43 Mbp and a G+C content of 71.3 mol%. The average nucleotide identity values and digital DNA-DNA hybridization between 1-3T and the reference strains were all below the cut-off level (95-96% and 70%, respectively) for species delineation. The strain possessed the cytochrome P450 enzyme, which has the potential to degrade oil. The respiratory quinone was Q-10 and the major fatty acids were summed feature 8 (C18:1 ω7c/C18:1 ω6c, 38.8%), C16:0 (25.6%) and C19:0 cyclo ω8c (22.5%). The polar lipids of strain 1-3T comprised diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and three unidentified aminolipids. Based on the genotypic and phenotypic characteristics, strain 1-3T represents a novel species of genus Siccirubricoccus, for which the name Siccirubricoccus phaeus sp. nov. is proposed. The type strain of Siccirubricoccus phaeus is 1-3T (= CGMCC 1.16799T = LMG 31398T).

Astaxanthin attenuates acute cerebral infarction via Nrf-2/HO-1 pathway in rats.

OBJECTIVE: Acute cerebral infarction (ACI) is susceptible to cause disability or death of people. Astaxanthin (ATX) possesses the protective effect of organ injury. Therefore, the study was to explore the potential mechanism of protective effect with ATX on ACI. METHODS: 30 SD rats were divided into Sham, ACI, and ATX groups. The rats in the ATX group were pretreated with ATX by gavage for three days before surgery, while the rats in the other two groups were pretreated with saline. The model of ACI was established by thread embolization. 24 h after the operation, the neurological function was scored, and cerebral infarct area and pathological morphology of brains were measured; the edema of the brain was detected by dry/wet method; Western blot was applied to measure the translocation of Nrf-2 and the protein expression of HO-1, Bax and BCL-2; Brain cell apoptosis was assessed through TUNEL; ELISA was used to detect the oxidative stress factors of catalase (CAT) superoxide dismutase (SOD), glutathione peroxidase (GPX) and malondialdehyde (MDA), and the inflammatory factors of TNF-α, IL-1ß, IL-6. RESULT: Compared with the ACI group, ATX pretreatment can significantly improve neurological function; reduce the edema index of the brain, cerebral infarct area, cerebral pathological damage and apoptosis of brain cells. Moreover, ATX also can increase the protein expression of nuclear Nrf-2, HO-1, BCL-2, CAT, SOD, and GPX by decreasing the content of TNF-α, IL-1ß, IL-6, MDA, Bax and cytosolic Nrf-2. CONCLUSION: ATX might have a protective effect of acute cerebral infarction, and the mechanism is probably associated with suppressing oxidative stress, inflammation, and apoptosis by activating Nrf-2/HO-1signalling.

Meta-Analysis of Shrinkage Mode After Neoadjuvant Chemotherapy for Breast Cancers: Association With Hormonal Receptor.

Background: Patients with concentric shrinkage mode after neoadjuvant chemotherapy (NAC) is considered to be ideal candidates for breast conserving treatment (BCT). While, what proportion of patients would represent CSM have not been well defined. This study was conducted to pool the rates of concentric shrinkage mode (CSM) in patients undergoing NAC, determine the impact of hormonal receptor on the shrinkage mode after NAC and estimate the rates of the CSM in various subgroups. Methods: We conducted a systematic review following the guidelines for Meta-Analyses and Systematic reviews for the PRISMA guidelines. We systematically searched the literature about shrinkage mode after NAC from PubMed, Web of Science, Embase, The Cochrane Library, CNKI, Wanfang database published from January 2002 to June 2020 on breast cancer shrinkage mode after NAC and carefully screened the literature by using eligibility criteria: (1) patients with primary breast cancer treated with NAC; (2) publications with available data of shrinkage mode measured by magnetic resonance imaging (MRI), or data of pathology and hormonal receptor. The association between shrinkage mode and hormonal receptor was estimated using Stata 15.1 software. Results: This analysis included a total of 2434 tumors from 23 papers. The included studies were heterogeneous (I2 = 89.4%, P<0.01). Random effects model was used to estimate the overall rates of CSM: 56.6% [95%CI (50.5%, 62.7%)]. According to the analysis of hormonal receptor, 10 of the paper was included for HR+ (hormone receptor positive) type analysis and the rate of CSM for HR+ type was 45.7% [95%CI (36.4%, 55.0%)]; 9 of the paper was used for HR- type (hormone receptor negative) analysis and the incidence of HR-CSM is 63.1% [95%CI (50.0%, 76.1%)]; with HR+ type as the control, the OR of the HR- CSM rate is 2.32 (1.32, 4.08) folds of HR+ type. From subgroup analyses, the CSM% of luminal A, luminal B, Her2+, and triple negative were 29.7% (16.5%, 42.8%); 47.2% (19.1%, 75.3%); 59.0% (39.7%, 78.3%); 66.2% (52.8%, 79.6%), respectively. Conclusions: Breast cancer patients undergoing NAC did not get an ideal odds ratio of CSM. The incidence of CSM in breast cancer after NAC is associated with hormonal receptor. Patients with triple-negative breast cancers have the highest rates of CSM after NAC. More care should be taken to select patients with the luminal subtypes for BCT throughout NAC.

Enoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients.

The oncogenic mechanisms of overnutrition, a confirmed independent cancer risk factor, remain poorly understood. Herein, we report that enoyl-CoA hydratase-1 (ECHS1), the enzyme involved in the oxidation of fatty acids (FAs) and branched-chain amino acids (BCAAs), senses nutrients and promotes mTOR activation and apoptotic resistance. Nutrients-promoted acetylation of lys101 of ECHS1 impedes ECHS1 activity by impairing enoyl-CoA binding, promoting ECHS1 degradation and blocking its mitochondrial translocation through inducing ubiquitination. As a result, nutrients induce the accumulation of BCAAs and FAs that activate mTOR signaling and stimulate apoptosis, respectively. The latter was overcome by selection of BCL-2 overexpressing cells under overnutrition conditions. The oncogenic effects of nutrients were reversed by SIRT3, which deacetylates lys101 acetylation. Severely decreased ECHS1, accumulation of BCAAs and FAs, activation of mTOR and overexpression of BCL-2 were observed in cancer tissues from metabolic organs. Our results identified ECHS1, a nutrients-sensing protein that transforms nutrient signals into oncogenic signals.Overnutrition has been linked to increased risk of cancer. Here, the authors show that exceeding nutrients suppress Enoyl-CoA hydratase-1 (ECHS1) activity by inducing its acetylation resulting in accumulation of fatty acids and branched-chain amino acids and oncogenic mTOR activation.

[Optimization and characterization of a novel FGF21 mutant].

Fibroblast growth factor 21 (FGF21) is a member of FGF family. It has been demonstrated that FGF21 is an independent, safe and effective regulator of blood glucose levels in vivo. In order to improve the activity of FGF21, we exchanged the beta10-beta12 domain of the human FGF21 with that of the mouse FGF21 to construct a novel FGF21 gene (named hmFGF21), and then subcloned hmFGF21 gene into the SUMO expression vector to create pSUMO-hmFGF21 and transformed it into E. coli Rosetta for expression of the fusion protein SUMO-hmFGF21. Both in vitro and in vivo glucose regulation activity of hmFGF21 was evaluated. The SDS-PAGE result showed that compared with wild-type hFGF21, the soluble expression of hmFGF21 increased about 2-fold. HmFGF21 was more potent in stimulation of glucose uptake in HepG2 cells in vitro. The results of anti-diabetic effect on db/db mice demonstrated that hmFGF21 had better efficacy on controlling the blood glucose of the db/db diabetic animals than wild-type hFGF21. These results suggest that the biological properties of FGF21 are significantly improved by optimization.