Dechlorination Helps Defluorination: Insights into the Defluorination Mechanism of Florfenicol by S-nZVI and DFT Calculations on the Reaction Pathways.

Defluorination is essential to eliminate the antibiotic resistance and detrimental effects of florfenicol (C12H14Cl2FNO4S, FF), which is achievable by sulfidated nanoscale zerovalent iron (S-nZVI), yet a comprehensive understanding of the mechanism is lacking. Herein, we used experimental data and density functional theory calculations to demonstrate four dechlorination-promoted defluorination pathways of FF, depending on S-nZVI or not. FF was defluorinated in a rapid and then slow but continuous manner, accompanying a consecutive dechlorination to deschloro (dFF) and dideschloro FF (ddFF). Unexpectedly, the predominant defluorination occurs by spontaneous hydrolysis of ddFF to form the hydrolyzed byproduct (HO-ddFF), i.e., independent of S-nZVI, which is initiated by intramolecular attack from carbonyl O to alkyl F and is thus limited for FF and dFF owing to the diminished nucleophilicity by electron-withdrawing Cl. The removal of Cl also makes the reductive defluorination of ddFF by S-nZVI amenable. The other two minor but more rapid defluorination pathways occur in synergy with the dechlorination of FF and dFF, which are mediated by the reactive carbanion intermediates and generate HO-dFF and HO-ddFF, respectively. The reliability of these dechlorination-facilitated defluorination pathways was verified by the consistency of theoretical calculations with experimental data, providing valuable insights into the degradation of fluorinated contaminants.

Modular and diverse synthesis of amino acids via asymmetric decarboxylative protonation of aminomalonic acids.

Stereoselective protonation is a challenge in asymmetric catalysis. The small size and high rate of transfer of protons mean that face-selective delivery to planar intermediates is hard to control, but it can unlock previously obscure asymmetric transformations. Particularly, when coupled with a preceding decarboxylation, enantioselective protonation can convert the abundant acid feedstocks into structurally diverse chiral molecules. Here an anchoring group strategy is demonstrated as a potential alternative and supplement to the conventional structural modification of catalysts by creating additional catalyst-substrate interactions. We show that a tailored benzamide group in aminomalonic acids can help build a coordinated network of non-covalent interactions, including hydrogen bonds, π-π interactions and dispersion forces, with a chiral acid catalyst. This allows enantioselective decarboxylative protonation to give α-amino acids. The malonate-based synthesis introduces side chains via a facile substitution of aminomalonic esters and thus can access structurally and functionally diverse amino acids.

Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS).

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

Comprehensive Analysis of Immune-Related Prognosis of TK1 in Hepatocellular Carcinoma.

Increased expression of TK1 is associated with the progression of a variety of tumors. However, the relationship of TK1 expression with immune cell infiltration and its prognostic value in hepatocellular carcinoma (HCC) are still unknown. In this study the TCGA database was used to evaluate TK1 expression and its impact on survival in patients with HCC. Compared with normal tissue, TK1 in the liver tissue of patients with HCC was significantly up-regulated at both the mRNA and protein levels. Furthermore, TK1 expression was significantly related to pathological stage, tumor stage and lymph node metastasis, with high TK1 expression being an unfavorable prognostic factor for HCC. TK1 expression was also significantly associated with the infiltration of B cells, T cells, and dendritic cells in HCC. Single-cell sequencing analysis revealed that TK1 was associated with relatively large changes in T cells, especially gamma-delta T cells. A prognostic risk score based on TK1-related immune genes (CD40LG and TNFRSF4) was established using COX regression analysis. By integrating the immune-related risk score model with clinical features, a nomogram was constructed to predict the survival rate of HCC patients (1 year, 3-year and 5-year AUC of 0.782, 0.783 and 0.771, respectively). Knockdown of the target gene for TK1 was found to have significant anti-apoptosis and pro-proliferation effects on HepG2 cells. The level of TK1 in the serum and liver tissue of patients with HCC was significantly increased relative to healthy controls. These findings highlight the role of TK1 in the tumor immune response of HCC patients and in the proliferation and apoptosis of HepG2 cells. TK1 could therefore be a potential immunotherapy target for HCC patients, while the two immune genes related to TK1 (CD40LG And TNFRSF4) may be promising prognostic biomarkers in HCC.

The mutational burden and oligogenic inheritance in Klippel-Feil syndrome.

BACKGROUND: Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely unknown because of the genetic and phenotypic heterogeneity. METHODS: We consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis. RESULTS: We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identified BAZ1B as having the highest probability of association with KFS, followed by FREM2, SUFU, VANGL1 and KMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one variants in candidate genes, the frequency of which was significantly higher than that in the in-house controls. CONCLUSIONS: Our study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.

Multidrug-resistant bacterial infections in cirrhotic patients: an epidemiological study.

BACKGROUND: The purpose of this study is to describe the epidemiological features of bacterial infections caused by multidrug-resistant (MDR) bacteria in cirrhotic patients and their impact on mortality. METHODS: A retrospective study of cirrhotic patients with culture-confirmed bacterial infections was performed between 2011 and 2017. RESULTS: A total of 635 episodes in 563 patients with cirrhosis were included. Bacterial infections caused by MDR isolates accounted for 44.1% (280/635) of the episodes, nearly half of which were hospital acquired (48.4%). The most common MDR isolation site was the respiratory tract (36.4%, 102 episodes), followed by the abdominal cavity (35.4%, 99 episodes). Of the MDR isolates, carbapenem-resistant Enterobacteriaceae (CRE) (91 episodes) were the most common. Patients infected with MDR bacteria had significantly higher mortality than those not infected (25.1% vs 17.4%, p = 0.025). However, this increased mortality could be largely attributed to methicillin-resistant Staphylococcus aureus (MRSA). After adjustment for age, sex, and the model for end-stage liver disease (MELD) score, only MRSA infection was an independent risk factor for 28-day mortality in the multivariable Cox proportional hazard regression model analysis (HR, 2.964, 95% CI (1.175-7.478), p = 0.021). CONCLUSIONS: MDR bacterial infections, especially CRE, have become frequent in patients with cirrhosis in recent years, with MRSA infections significantly increasing short-term mortality.

Vitamin D deficiency in hepatitis C virus infection: what is old? what is new?

In the past few years, a growing body of clinical evidence has highlighted the risk of vitamin D deficiency in patients with chronic hepatitis C and that vitamin D levels are associated with the course of hepatitis C virus (HCV) infection, adverse effects, and treatment response to peginterferon/ribavirin. Recently, studies have found that vitamin D status is related to drug resistance and increased risk of infection in patients with liver cirrhosis. Vitamin D-related gene polymorphisms have been found to explain the interactions between vitamin D deficiency and HCV infection, offering a new perspective toward understanding the current problems such as the development of insulin resistance and racial differences in sustained virological response. Studies have been conducted to determine whether vitamin D supplementation as an adjuvant yields a better result compared with traditional HCV treatment. Here, we provide a brief review of the past and present knowledge of vitamin D in HCV infection.

[Relationship between the expression of uncoupling protein 2 and the damage by oxygen free radicals in acute liver failure rats].

To investigate the relationship between uncoupling protein 2 (UCP2) expression and the damage caused by oxygen free radicals in acute liver failure rat models. Thirty-five male Sprague-Dawley rats were randomly divided into two groups: the control group (15 rats) and liver failure group (20 rats). The rats were injected intraperitoneally with thioacetamide (TAA) to induce models of acute liver failure. The levels of endotoxin (ET) were detected by double antibody sandwich enzyme-linked immunosorbent assay. The expression of liver UCP2 mRNA was detected by reverse transcription polymerase chain reaction. The superoxide dismutase (SOD) and malonaldehyde (MDA) were detected by spectrophotometry. The expression of UCP2 protein was observed by immunohistochemistry. The data of the two groups were compared using Mann-Whitney U test or ANOVA. The expression of UCP2 mRNA in liver failure group was higher as compared to the control group (P value is less than 0.01); the level of MDA and endotoxin of liver failure group were higher than that of the control group (P value is less than 0.01). SOD of the liver failure group was lower (P value is less than 0.01). There was a certain correlation between UCP2 mRNA expression and ET, SOD and MDA (r = 0.952, -0.667, 0. 634 respectively, P value is less than 0.05 or 0.01). UCP2 is highly expressed in the livers of liver failure rats. A certain correlation perhaps existed between the expression of UCP2 mRNA and the serous SOD, MDA and ET.