Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare and chronic autoimmune liver disease. While genetic factors are believed to play a crucial role in the etiopathogenesis of AIH, our understanding of these genetic risk factors is still limited. In this study, we aimed to identify susceptibility loci to further understand the pathogenesis of this disease. APPROACH AND RESULTS: We conducted a case-control association study of 1,622 Chinese patients with AIH type 1 and 10,466 population controls from two independent cohorts. A meta-analysis was performed to ascertain variants associated with AIH type 1. A single-nucleotide polymorphism within the human leukocyte antigen (HLA) region showed the strongest association with AIH (rs6932730: OR = 2.32; p = 9.21 × 10-73 ). The meta-analysis also identified two non-HLA loci significantly associated with AIH: CD28/CTLA4/ICOS on 2q33.3 (rs72929257: OR = 1.31; p = 2.92 × 10-9 ) and SYNPR on 3p14.2 (rs6809477: OR = 1.25; p = 5.48 × 10-9 ). In silico annotation, reporter gene assays, and CRISPR activation experiments identified a distal enhancer at 2q33.3 that regulated expression of CTLA4. In addition, variants near STAT1/STAT4 (rs11889341: OR = 1.24; p = 1.34 × 10-7 ), LINC00392 (rs9564997: OR = 0.81; p = 2.53 × 10-7 ), IRF8 (rs11117432: OR = 0.72; p = 6.10 × 10-6 ), and LILRA4/LILRA5 (rs11084330: OR = 0.65; p = 5.19 × 10-6 ) had suggestive association signals with AIH. CONCLUSIONS: Our study identifies two novel loci (CD28/CTLA4/ICOS and SYNPR) exceeding genome-wide significance and suggests four loci as potential risk factors. These findings highlight the importance of costimulatory signaling and neuro-immune interaction in the pathogenesis of AIH.

Aryne 1,4-Disubstitution and Remote Diastereoselective 1,2,4-Trisubstitution via a Nucleophilic Annulation-[5,5]-Sigmatropic Rearrangement Process.

Both aryne 1,4-disubstitution and 1,2,4-trifunctionalization were accomplished from tertiary amines bearing a penta-2,4-dien-1-yl moiety. These transformations could directly incorporate a C-N and a C-C bond para to each other on an aryne intermediate via a sequential nucleophilic addition and [5,5]-sigmatropic rearrangement. When arynes bearing 3-tethered electrophiles were employed, a cascade regioselective nucleophilic addition, intramolecular cyclization, and remote diastereoselective [5,5]-sigmatropic rearrangement process was observed. Our density functional theory (DFT) calculations revealed that hydrogen-bonding interactions between two C-H hydrogens on the penta-2,4-dien-1-yl chain and the oxygen anion generated upon N-nucleophilic annulation reaction in the [5,5]-sigmatropic rearrangement step is responsible for the remote diastereoselective control in this reaction system.

Performance and efficiency of machine learning algorithms for analyzing rectangular biomedical data.

Most biomedical datasets, including those of 'omics, population studies, and surveys, are rectangular in shape and have few missing data. Recently, their sample sizes have grown significantly. Rigorous analyses on these large datasets demand considerably more efficient and more accurate algorithms. Machine learning (ML) algorithms have been used to classify outcomes in biomedical datasets, including random forests (RF), decision tree (DT), artificial neural networks (ANN), and support vector machine (SVM). However, their performance and efficiency in classifying multi-category outcomes of rectangular data are poorly understood. Therefore, we compared these metrics among the 4 ML algorithms. As an example, we created a large rectangular dataset using the female breast cancers in the surveillance, epidemiology, and end results-18 database, which were diagnosed in 2004 and followed up until December 2016. The outcome was the five-category cause of death, namely alive, non-breast cancer, breast cancer, cardiovascular disease, and other cause. We analyzed the 54 dichotomized features from ~45,000 patients using MatLab (version 2018a) and the tenfold cross-validation approach. The accuracy in classifying five-category cause of death with DT, RF, ANN, and SVM was 69.21%, 70.23%, 70.16%, and 69.06%, respectively, which was higher than the accuracy of 68.12% with multinomial logistic regression. Based on the features' information entropy, we optimized dimension reduction (i.e., reduce the number of features in models). We found 32 or more features were required to maintain similar accuracy, while the running time decreased from 55.57 s for 54 features to 25.99 s for 32 features in RF, from 12.92 s to 10.48 s in ANN, and from 175.50 s to 67.81 s in SVM. In summary, we here show that RF, DT, ANN, and SVM had similar accuracy for classifying multi-category outcomes in this large rectangular dataset. Dimension reduction based on information gain will increase the model's efficiency while maintaining classification accuracy.

miR-144/451 inhibits c-Myc to promote erythroid differentiation.

Ablation of miR-144/451 disrupts homeostasis of erythropoiesis. Myc, a protooncogenic protein, is essential for erythroblast proliferation but commits rapid downregulation during erythroid maturation. How erythroblasts orchestrate maturation processes through coding and non-coding genes is largely unknown. In this study, we use miR-144/451 knockout mice as in vivo model, G1E, MEL erythroblast lines and erythroblasts from fresh mouse fetal livers as in vitro systems to demonstrate that targeted depletion of miR-144/451 blocks erythroid nuclear condensation and enucleation. This is due, at least in part, to the continued high expression of Myc in erythroblasts when miR-144/451 is absent. Specifically, miR-144/451 directly inhibits Myc in erythroblasts. Loss of miR-144/451 locus derepresses, and thus, increases the expression of Myc. Sustained high levels of Myc in miR-144/451-depleted erythroblasts blocks erythroid differentiation. Moreover, Myc reversely regulates the expression of miR-144/451, forming a positive miR-144/451-Myc feedback to ensure the complete shutoff of Myc during erythropoiesis. Given that erythroid-specific transcription factor GATA1 activates miR-144/451 and inactivates Myc, our findings indicate that GATA1-miR-144/451-Myc network safeguards normal erythroid differentiation. Our findings also demonstrate that disruption of the miR-144/451-Myc crosstalk causes anemia, suggesting that miR-144/451 might be a potential therapeutic target in red cell diseases.

Roxadustat in treating anemia in dialysis patients (ROAD): protocol and rationale of a multicenter prospective observational cohort study.

BACKGROUND: Roxadustat has been shown effective in treating patients with anemia due to chronic kidney disease. However, its long-term effect on clinical outcomes and socioeconomic burden and safety remains unclear. METHODS/DESIGN: This is a multicenter, prospective, longitudinal observational cohort study assessing if Roxadustat improves prognosis in dialysis patients. Primary outcomes will be major adverse cardiovascular events (MACE), defined as composites of cardiovascular death, myocardial infarction, cerebral infarction, hospitalization because of heart failure; all-cause mortality, and annual economic costs in two years. The data will be collected via Research electronic data capture (REDCap) based database as well as software-based dialysis registry of Sichuan province. The primary outcomes for the ROAD study participants will be compared with those in the dialysis registry cohort. Data at baseline and study follow up will also be compared to assess the association between Roxadustat and long-term clinical outcomes. DISCUSSION: The main objective of this study is to the assess long-term association of Roxadustat on MACE, all-cause mortality, socio-economic burden, safety in dialysis patients, which will provide guidance for designing further large randomized controlled trials to investigate this clinic question. STUDY REGISTRATION: The study has been registered in Chinese Clinical Trials Registry (ROAD, ROxadustat in treating Anemia in Dialysis patients, registration number ChiCTR1900025765) and provincial observational cohort database (Renal disEAse observational CoHort database, REACH, ChiCTR1900024926), registered 07 September 2019, http://www.chictr.org.cn .

Clinical characteristics of patients with chronic cough in Guangdong, China: a multicenter descriptive study.

BACKGROUND: The clinical characteristics of patients with chronic cough are reported only in single-center survey in China, being significantly different from that in western countries. Here, we performed a multicenter study to describe the clinical characteristics of chronic cough patients. METHODS: A cross-sectional observational survey was conducted in thirteen tertiary hospitals of Guangdong, South China. Relevant data were recorded using a standardized questionnaire and analyzed, including demographics, educational attainment, cough features, and concomitant symptoms. RESULTS: Of 933 patients in this study, the median age was 40.0 (IQR 31.0-52.0) years with a peaked age of 30-39 years. The proportion of females (487, 52.2 %) was comparable to that of males (446, 47.8 %). Up to 81.9 % of the patients were non-smokers. More than two-thirds of the subjects with chronic cough had a low educational level. The median cough duration was 6.0 (IQR 3.0-24.0) months, and 73.0 % of chronic cough patients presented with dry cough. Laryngeal paresthesia was the most common concomitant symptom (704, 75.5 %), followed by rhinitis/sinusitis-related (350, 37.5 %) and respiratory symptoms (322, 34.5 %). Rhinitis/sinusitis-related symptoms more frequently occurred in patients with productive cough than in those with dry cough (49.0 % vs. 33.0 %, P < 0.001). Moreover, female patients displayed an older age and a higher prevalence of nocturnal cough compared to male patients (both P < 0.05). CONCLUSIONS: Our results show an equal gender, young profile and laryngeal paresthesia in patients with chronic cough, and different clinical features between females and males.

A novel LncRNA transcript, RBAT1, accelerates tumorigenesis through interacting with HNRNPL and cis-activating E2F3.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been identified as important epigenetic regulators that play critical roles in human cancers. However, the regulatory functions of lncRNAs in tumorigenesis remains to be elucidated. Here, we aimed to investigate the molecular mechanisms and potential clinical application of a novel lncRNA, retinoblastoma associated transcript-1 (RBAT1), in tumorigenesis. METHODS: RBAT1 expression was determined by real-time PCR in both retinoblastoma (Rb) and bladder cancer (BCa) cell lines and clinical tissues. Chromatin isolation using RNA purification (ChIRP) assays were performed to identify RBAT1-interacting proteins. Patient-derived xenograft (PDX) retinoblastoma models were established to test the therapeutic potential of RBAT1-targeting GapmeRs. RESULTS: Here, we found that RBAT1 expression was significantly higher in Rb and BCa tissues than that in adjacent tissues. Functional assays revealed that RBAT1 accelerated tumorigenesis both in vitro and in vivo. Mechanistically, RBAT1 recruited HNRNPL protein to E2F3 promoter, thereby activating E2F3 transcription. Therapeutically, GapmeR-mediated RBAT1 silencing significantly inhibited tumorigenesis in orthotopic xenograft retinoblastoma models derived from Rb cell lines and Rb primary cells. CONCLUSIONS: RBAT1 overexpression upregulates a known oncogene, E2F3, via directly recruiting HNPNPL to its promoter and cis-activating its expression. Our finding provides a novel mechanism of lncRNA biology and provides potential targets for diagnosis and treatment of Rb and BCa.

Effects of orthostatic hypotension on cognition in type 2 diabetes mellitus.

OBJECTIVE: To evaluate the effect of a decrease in blood pressure (BP) fulfilling the diagnostic criteria for orthostatic hypotension (OH) on performance in each domain of cognitive function in patients with type 2 diabetes mellitus using a cross-sectional and within-group design. METHODS: Subjects were individuals without dementia and with type 2 diabetes mellitus, including 107 individuals without OH and 94 with OH (DMOH); 95 control participants were also included. BP was assessed in both the supine and standing positions. A detailed neuropsychological assessment was made in each posture for all subjects. RESULTS: There were statistically significant differences between the patients without OH and the DMOH group with regard to some cognitive measures while supine. Standing posture exacerbated and broadened cognitive deficits in the DMOH group for all measures in the different domains of cognition including executive functioning, memory, visuospatial skills, information processing speed, and attention. When group-specific supine scores were used as baseline anchors, both the patients without OH and the DMOH group showed cognitive changes when transitioning from a supine to a standing, upright position, with the DMOH group exhibiting a wider range of neuropsychological deficits in memory, visuospatial skills, executive function, and sustained attention, as well as significant changes in information processing speed. INTERPRETATION: These data demonstrate that type 2 diabetes mellitus patients with OH had transient, posture-mediated cognitive deficits in excess of those found in diabetes mellitus without OH. Understanding the effects of OH on cognition due to autonomic failure is important, particularly as clinical assessments and neuroimaging collect data only in the seated or supine positions. ANN NEUROL 2019;86:754-761.

Patterns of sexual health in patients with breast cancer in China: a latent class analysis.

PURPOSE: This study aimed to identify unobserved distinct latent classes/subgroups of breast cancer (BC) patients in China with respect to various sexual health measures and examine the association of the latent membership with individual characteristics. METHODS: In a cross-sectional study, 123 BC patients were analyzed. Their sexual health was measured using the Female Sexual Functioning Index (FSFI). Latent class analysis (LCA) was used to examine the patterns of sexual health in patients. Associations of the latent class membership with individual characteristics were examined using multinomial logistic regression. RESULTS: Three a priori unknown distinct latent classes of patients were identified with respect to the 19 FSFI sexual health measures: 50 patients (41.6%) were classified in class 1 "No Impairment Group," 49 patients (39.4%) in class 2 "Organic Sexual Dysfunction Group," and 24 patients (19.1%) in class 3 "Poor Sexual Health Group." Income and anxiety were positively, whereas disease duration was negatively associated with the likelihood of being in class 2 than in class 1, patients with recurrence of cancer were likely to be in classes 2 and 3. Patients classified in class 3 were more likely to have better prior body image and have more severe menopausal symptoms, whereas less likely to have better post body image and have better partner relationships. CONCLUSION: The findings revealed the heterogeneity of sexual health among BC patients in China and may guide to identify the high-risk patients and enable early intervention.

A new simple score of chronic cough: cough evaluation test.

BACKGROUND: Chronic cough has an important impact on physical, social and psychological aspects. A simple and effective method to assess different aspects of chronic cough severity is required. We aimed to develop a simple, self-completed test, Cough Evaluation Test (CET), to evaluate cough severity and its impact on health. METHOD: The items of preliminary CET were generated based on literature review and clinical practice. Items reduction was conducted by modified Delphi method. Patients with chronic cough were recruited to complete CET, Cough Visual Analog Scales (VAS), Mandarin Chinese version of the Leicester Cough Questionnaire (LCQ-MC), and Cough Symptom Score (CSS). Reassessments were performed at 1 week apart before treatment, and after more than 2 weeks treatments. Concurrent validation, internal consistency, repeatability, responsiveness and the minimal important difference (MID) were determined. RESULTS: CET consists of five items with a 5-point Likert scale (1-5 scaling of items, 5-25 score range). The Cronbach's alpha values for CET was 0.80. CET showed a stronger correlation with LCQ-MC (r = - 0.74) compared to that between LCQ-MC with VAS (r = - 0.61). CET also showed a stronger correlation with VAS (r = 0.70) compared to that between VAS with other measures. Intraclass correlation coefficients for CET was 0.84. In patients undergoing treatment, CET scores significantly changed (p < 0.0001). The MID of CET was 2. CONCLUSION: Cough Evaluate Test is a reliable, valid and responsive tool to simply evaluate impact of cough on physical, social and psychological aspects.

Different MicroRNA Families Involved in Regulating High Temperature Stress Response during Cotton (Gossypium hirsutum L.) Anther Development.

MicroRNAs (miRNAs) are small molecule RNAs widely involved in responses to plant abiotic stresses. We performed small RNA sequencing of cotton anthers at four developmental stages under normal and high temperature (NT and HT, respectively) conditions to investigate the stress response characteristics of miRNA to HT. A total of 77 miRNAs, including 33 known miRNAs and 44 novel miRNAs, were identified, and 41 and 28 miRNAs were differentially expressed under NT and HT stress conditions, respectively. The sporogenous cell proliferation (SCP), meiotic phase (MP), microspore release period (MRP), and pollen maturity (PM) stages had 10 (including 12 miRNAs), four (including six miRNAs), four (including five miRNAs), and seven (including 11 miRNAs) HT stress-responsive miRNA families, respectively, which were identified after removing the changes in genotype-specific miRNAs under NT condition. Seven miRNA families (miR2949, miR167, and miR160 at the SCP stage; miR156 and miR172 at the MP stage; miR156 at the MRP stage; and miR393 and miR3476 at the PM stage), which had expression abundance of more than 10% of the total expression abundance, served as the main regulators responding to HT stress with positive or negative regulation patterns. These miRNAs orchestrated the expression of the corresponding target genes and led to different responses in the HT-tolerant and the HT-sensitive lines. The results revealed that the HT stress response of miRNAs in cotton anthers were stage-specific and differed with the development of anthers. Our study may enhance the understanding of the response of miRNAs to HT stress in cotton anthers and may clarify the mechanism of plant tolerance to HT stress.

TLR4 and nucleolin influence cell injury, apoptosis and inflammatory factor expression in respiratory syncytial virus-infected N2a neuronal cells.

Respiratory syncytial virus (RSV) infection was recently reported to be associated with central nervous system (CNS) symptoms and neurological complications; however, related studies are very limited. Moreover, the molecular mechanism underlying RSV neuropathogenesis is still unclear. Our previous study revealed that toll-like receptor 4 (TLR4) and nucleolin (C23) could be modulated and that they played a role during RSV infection in mouse neuronal-2a (N2a) cells. In the present study, the effects of silencing of TLR4 and C23 on RSV propagation and N2a cellular responses were examined by using RNA interference technology. Four N2a cell treatment groups were established, namely, a normal control group, RSV control group, TLR4 siRNA + RSV group, and C23 siRNA + RSV group. Expression changes in NeuN protein and colocalization of C23 and TLR4 with RSV F protein were assessed using confocal microscopy. Changes in TLR4 and C23 mRNA expression, TLR4, C23, TLR3, TLR7, and p-NF-κB protein expression, and interleukin (IL)-8, IL-6, and tumor necrosis factor (TNF-α) cytokine secretion was measured using quantitative real-time reverse-transcription polymerase chain reaction, Western blot analysis, and enzyme-linked immunosorbent assay, respectively. RSV titers and the apoptotic status of N2a cells were monitored using plaque formation assays and flow cytometry, respectively. The results indicated that TLR4 and C23 gene knockdown decreased the amount of F protein in RSV-infected N2a cells, inhibited RSV propagation, attenuated N2a neuronal injury, diminished cell apoptosis levels, downregulated TLR3 and TLR7 protein expression, and reduced inflammatory protein expression. Therefore, TLR4 and C23 knockdown influences cell injury, apoptosis and inflammatory protein expression in RSV-infected N2a cells.

Inhibiting Hypoxia and Chemotherapy-Induced Cancer Cell Metastasis under a Valid Therapeutic Effect by an Assistance of Biomimetic Oxygen Delivery.

Tumor metastasis is the most dangerous stage in tumorigenesis and its evolution, which causes about 80% clinical death. However, common therapies including chemotherapy may increase the risk of tumor metastasis while killing cancer cells. Tumor metastasis is closely related to many factors in the tumor microenvironment, especially hypoxia. As one of the characteristics of a malignant tumor microenvironment, hypoxia plays an important role in the growth, metabolism, and metastasis of tumors. Upregulation of the hypoxia-inducible factor (HIF) would stimulate the metastasis and migration of cancer cells. In this study, we developed an artificial oxygen carrier system, a hemoglobin-loaded liposome (Hb@lipo), which was capable of effectively delivering oxygen to tumor. The way of providing oxygen not only alleviated tumor hypoxia but also downregulated the expression of HIF, which is conducive to reducing tumor malignancy. Alleviating the tumor hypoxic microenvironment alone is not enough to inhibit tumor metastasis; thus, we prepared the liposome containing a chemotherapeutic agent cabazitaxel (CBZ@lipo). Our data indicated that the combination therapy of Hb@lipo and CBZ@lipo can efficiently kill cancer cells and inhibit tumor growth. At the same time, it can effectively entrap cancer cells in tumor sites by relieving the hypoxic microenvironment of tumors and reduce the metastasis of cancer cells during and after the chemotherapy. Our research may provide a clinical cancer chemotherapy reference that reduces the risk of cancer cell metastasis while inhibiting tumor growth.

Insights into the cotton anther development through association analysis of transcriptomic and small RNA sequencing.

BACKGROUND: Plant anther development is a systematic and complex process precisely controlled by genes. Regulation genes and their regulatory mechanisms for this process remain elusive. In contrast to numerous researches on anther development with respect to mRNAs or miRNAs in many crops, the association analysis combining both omics has not been reported on cotton anther. RESULTS: In this study, the molecular mechanism of cotton anther development was investigated with the employment of association analysis of transcriptome and small RNA sequencing during the predefined four stages of cotton anther development, sporogenuous cell proliferation (SCP), meiotic phase (MP), microspore release period (MRP) and pollen maturity (PM). Analysis revealed that the differentially expressed genes are increasingly recruited along with the developmental progress. Expression of functional genes differed significantly among developmental stages. The genes related with cell cycle, progesterone-mediated oocyte maturation, and meiosis are predominantly expressed at the early stage of anther development (SCP and MP), and the expression of genes involved in energy metabolism, flavonoid biosynthesis, axon guidance and phospholipase D signaling pathways is mainly enriched at the late stage of anther development (MRP and PM). Analysis of expression patterns revealed that there was the largest number of differentially expressed genes in the MP and the expression profiles of differentially expressed genes were significantly increased, which implied the importance of MP in the entire anther development cycle. In addition, prediction and analysis of miRNA targeted genes suggested that miRNAs play important roles in anther development. The miRNAs ghr-miR393, Dt_chr12_6065 and At_chr9_3080 participated in cell cycle, carbohydrate metabolism and auxin anabolism through the target genes, respectively, to achieve the regulation of anther development. CONCLUSIONS: Through the association analysis of mRNA and miRNA, our work gives a better understanding of the preferentially expressed genes and regulation in different developmental stages of cotton anther and the importance of meiotic phase, and also the involvement of miRNAs in precise regulation for this process, which would be valuable for clarifying the mechanism of plant anther development in response to internal and external environments.

Respiratory syncytial virus prolifically infects N2a neuronal cells, leading to TLR4 and nucleolin protein modulations and RSV F protein co-localization with TLR4 and nucleolin.

BACKGROUND: Respiratory syncytial virus (RSV) infects the central nervous system, resulting in neurological symptoms. However, the precise underlying pathogenic mechanisms have not been elucidated. In the present study, the infectivity of RSV on N2a neuronal cells and the possible roles of Toll-like receptor 4 (TLR4) and nucleolin (C23) during RSV infection were investigated. METHODS: We compared two experimental groups (infected and non-infected) and monitored the RSV viral titers in the culture supernatant by a viral plaque assay. We also inspected the morphology of the nucleus in infected N2a cells. We measured the level of RSV F protein and studied its co-localization with TLR4 and nucleolin using immunofluorescence assays and laser confocal microscopy. The potential interaction of RSV F protein with TLR4 and nucleolin was examined by coimmunoprecipitation. The expression changes of TLR4, nucleolin, TLR3 and TLR7 proteins in N2a cells and IL-6 and TNF-α in the culture supernatant were investigated by Western Blot analysis and ELISA assay. Changes in neuronal cell apoptosis status was examined by flow cytometry. RESULTS: The results demonstrated prolific RSV infection of N2a cells, which triggered a decrease of NeuN protein expression, coinciding with an increase of nuclear lesions, F protein expression, RSV viral titers, and late apoptotic levels of N2a cells. RSV infection induced co-localization of RSV F protein with TLR4 and nucleolin, which could potentially lead to a direct interaction. Furthermore, it was found that TLR4 and nucleolin levels increased early after infection and decreased subsequently, whereas TLR3 and TLR7 expression increased throughout RSV infection. CONCLUSION: The RSV Long strain can prolifically infect N2a neuronal cells, modulating the expression of TLR4 and nucleolin, as well as TLR3, TLR7 and their downstream inflammatory factors, and inducing the co-localization of the RSV F protein with TLR4 and nucleolin.

Nitrogen-Doped Carbon Materials as Metal-Free Catalyst for the Dechlorination of Trichloroethylene by Sulfide.

A new method for trichloroethylene (TCE) dechlorination is proposed using sulfide (HS- and S2-) as reductant under the mediation of nitrogen-doped carbon materials (NCMs). About 99% of the TCE was converted to acetylene after 200 h using this method. Dechlorination of TCE in the NCMs-sulfide system (NCSS) followed pseudo-first-order kinetics. Pyridinic N (N6) on surface of the NCMs appeared to play a critical role in NCSS as shown by the good linear relationship between the surface content of N6 and kobs. Nucleophilic substitution was suggested as the first step in TCE dechlorination, and the nucleophilic reagent was identified as a sulfur intermediate with C-S-S-H as the functional group. The generation of C-S-S-H could be ascribed to the interaction between positively charged carbon atoms in N6 and negative charged sulfide. This work is the first to demonstrate that sulfide combined with NCMs can produce active substances that are effective in TCE dechlorination and the findings will assist in the development of strategies that use natural sulfide as reductant for detoxicating organic chloroethene contaminants.

The Association Between the Genetic Variants of the NOTCH3 Gene and Ischemic Stroke Risk.

BACKGROUND Ischemic stroke (IS) is a leading cause of disability and death and NOTCH3 as a gene related with cardiac-cerebral vascular disease plays a vital role in IS development. However, the reports about the effect of genetic variants in NOTCH3 gene on IS are still few. MATERIAL AND METHODS In order to explore the association between NOTCH3 polymorphisms and IS, 134 patients with IS and 115 controls were enrolled in this case-control study. Polymerase chain reaction was used to do the genotyping of polymorphisms. The χ² test was performed to evaluate Hardy-Weinberg equilibrium (HWE) in the control group and calculate odds ratio (OR) with corresponding 95% confidence interval (CI) which represented the association intensity of NOTCH3 gene polymorphisms and IS risk. RESULTS The genotype frequencies in the control group all confirmed to HWE. TT genotype of 381C>T was associated significantly with IS risk (OR=2.441, 95%CI=1.021-5.837). TC, CC mutant genotypes of 1735T>C had higher frequencies in cases than controls and the difference was significant (P=0.013, 0.041); further, its C allele also increased 0.722 times risk in the case group than controls (OR=1.722, 95%CI=1.166-2.541). CONCLUSIONS NOTCH3 381C>T and 1735T>C polymorphisms were associated with IS and might be the risk factors for IS development, but not NOTCH3 605C>T polymorphism.

Switchable chemoselective aryne reactions between nucleophiles and pericyclic reaction partners using either 3-methoxybenzyne or 3-silylbenzyne.

Arynes are known to serve as highly reactive benzene-based synthons, which have gained numerous successes in preparing functionalized arenes. Due to the superb electrophilic nature of these fleeting species, however, it is challenging to modulate the designated aryne transformation chemoselectively, when substrates possess multiple competing reaction sites. Here, we showcase our effort to manipulate chemoselective control between two major types of aryne transformations using either 3-methoxybenzyne or 3-silylbenzyne, where nucleophilic addition-triggered reactions and non-polar pericyclic reactions could be differentiated. This orthogonal chemoselective protocol is found to be applicable between various nucleophiles, i.e., imidazole, N-tosylated/N-alkyl aniline, phenol, and alcohol, and an array of pericyclic reaction partners, i.e., furan, cyclopentadiene, pyrrole, cycloheptatrienone, and cyclohexene. Beyond arylation reactions, C-N bond insertion, Truce-Smiles rearrangement, and nucleophilic annulation are appropriate reaction modes as well. Moreover, this chemoselective protocol can find potential synthetic application.

Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1.

Background & Aims: Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients. Methods: We performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls. Results: A total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10-33; OR = 4.26) and rs7765379 (p = 5.08 × 10-18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels. Conclusions: Our study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH. Impact and implications: This study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.