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Catalytic microsweepers with single-iron-atom centers were designed to search for and inhibit Helicobacter pylori using dynamically navigated reciprocating locomotion.

Genetically encoded molecular tools are crucial for live cell RNA imaging, and few are available for endogenous RNA imaging. We develop a new genetically encoded sensor using conformation switching RNA induced fluorogenic proteins that enable multicolor and signal-amplified imaging of endogenous RNAs. The sensor system is designed with an RNA sensing module and a degron-fused fluorescent protein reporter. Target RNA induces conformation switching of the RNA sensing module to form RNA aptamers that stabilize the degron-fused protein for fluorogenic imaging. This sensor is demonstrated for high-contrast imaging of survivin mRNA abundance and dynamics in live cells. Moreover, the sensor system is extended to a multicolor palette by screening fluorogenic proteins of distinct colors, and engineered into a signal amplifier using the split fluorescent protein design. The sensor is further exploited for imaging lncRNA MALAT-1 and its translocation dynamics during mitosis. Our sensor system can afford a valuable platform for RNA imaging in biomedical research and clinical theranostics.

Background Tuberculosis (TB) is one of the leading causes of morbidity and mortality in Western China. Preclinical studies have suggested the protective effect of the C-type lectin receptor of family 4 member E (CLEC4E) from TB. Herein, we investigated the association between CLEC4E gene variants and TB susceptibility in a western Chinese Han population. Methods We genotyped four single nucleotide polymorphisms (SNPs) rs10841856, rs10770847, rs10770855 and rs4480590 in the CLEC4E gene using the improved multiplex ligation detection reaction (iMLDR) assay in 900 TB cases and 1534 healthy controls. Results After stratifying the whole data by sex, it was found that males exhibited mutant allele G of rs10841856 was more strongly associated with increased TB risk after Bonferroni correction (OR = 1.334, 95% CI: 1.142–1.560; P p = 0.001 after Bonferroni correction). The genetic model analysis found that rs10841856 was associated with the increased risk of TB among males under the dominant model (OR = 1.557, 95% CI = 1.228–1.984, P P Conclusions Our study revealed that rs10841856 in the CLEC4E gene might be related to increased TB risk, especially the dominant genetic model among male Han individuals from Western China

Autophagy and endocytosis are essential in regulating cellular homeostasis and cancer immunotherapeutic responses. Existing methods for autophagy and endocytosis imaging are susceptible to cellular micro-environmental changes, and direct fluorogenic visualization of their fluxes remains challenging. We develop a novel strategy via clicking of organelle-enriched probes (COP), which comprises a pair of trans-cyclooctenol (TCO) and tetrazine probes separately enriched in lysosomes and mitochondria (in autophagy) or plasma membrane (in endocytosis). These paired probes are merged and boost a fluorogenic click reaction in response to autophagic or endocytic flux that ultimately fuses mitochondria or plasma membrane into lysosomes. We demonstrate that this strategy enables direct visualization of autophagic and endocytic fluxes, and confer insight into correlation of autophagic or endocytic flux to cell surface expression of immunotherapeutic targets such as MHC-I and PD-L1. The COP strategy provides a new paradigm for imaging autophagic and endocytic fluxes, and affords potential for improved cancer immunotherapy using autophagy or endocytosis inhibitors., A new strategy is developed for direct fluorogenic imaging of autophagic and endocytic fluxes via clicking of organelle-enriched trans-cyclooctenol and tetrazine derived probes.

To analysis clinical phenotype and potential genetic cause of a family affected with hereditary coagulation factor Ⅻ deficiency.The prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), D-Dimer (D-D), coagulation factor Ⅻ activity (FⅫ:C) and coagulation factor Ⅻ antigen (FⅫ:Ag) were determined for phenotype diagnosis of the proband and his family members(3 generations and 5 people). Targeted capture and whole exome sequencing were performed in peripheral blood sample of the proband. Possible disease-causing mutations of F12 gene were obtained and further confirmed by Sanger sequencing. The corresponding mutation sites of the family members were analyzed afterwards. The online bioinformatics software AutoPVS1 and Mutation Taster was used to predict the effects of mutation sites on protein function.The APTT of the proband was significantly prolonged, reaching 180.9s. FⅫ:C and FⅫ:Ag of the proband was significantly reduced to 0.8% and 4.17%, respectively. The results of whole exome sequencing displayed that there were compound heterozygous mutations in F12 gene of the proband, including the c.1261G＞T heterozygous nonsense mutation in exon 11 (causing p.Glu421*) and the c.251dupG heterozygous frameshift mutation in exon 4 (causing p.Trp85Metfs*53). Both mutations are loss of function mutations with very strong pathogenicity, leading to premature termination of the protein. AutoPVS1 and Mutation Taster software predicted both mutations as pathogenic mutations. The results of Sanger sequencing revealed that c.1261G＞T heterozygous mutation of the proband was inherited from his mother, for which his brother and his daughter were c.1261G＞T heterozygous carriers. Genotype-phenotype cosegregation was observed in this family.The c.1261G＞T heterozygous nonsense mutation in exon 11 and the c.251dupG heterozygous frameshift mutation in exon 4 of the F12 gene probably account for coagulation factor Ⅻ deficiency in this family. This study reports two novel pathogenic F12 mutations for the first time worldwide.复合杂合突变导致的遗传性凝血因子Ⅻ缺陷症家系分析.对1个遗传性凝血因子Ⅻ（FⅫ）缺陷症家系进行临床表型及基因突变分析，探讨其分子致病机制.检测先证者及其家系成员（共3代5人）血浆凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）、纤维蛋白原含量（FIB）、D-D二聚体（D-D）、凝血因子Ⅻ促凝活性（FⅫ:C）和凝血因子Ⅻ抗原（FⅫ:Ag）等凝血指标。采用高通量测序方法分析先证者F12基因所有的外显子编码区及外显子-内含子交界处的基因突变情况，对检出的可疑致病突变进行Sanger测序验证，并对家系成员的相应突变位点进行检测。采用AutoPVS1和Mutation Taster在线生物信息学软件预测突变位点对蛋白功能的影响.先证者APTT结果为180.9 s，明显延长；FⅫ:C和FⅫ:Ag分别降低至0.8%和4.17%。全外显子组测序分析发现先证者F12基因存在复合杂合突变，即第11号外显子c.1261G＞T杂合无义突变（p.Glu421*）和第4号外显子c.251dupG杂合移码突变（p.Trp85Metfs*53），均为功能缺失型突变，属于极强致病性级别。Sanger测序家系验证结果显示，先证者c.1261G＞T杂合突变遗传自其母亲，其哥哥和女儿均为c.1261G＞T杂合突变携带者。在此家系中基因检测结果与血液学检查结果相符，即基因型和表型共分离.F12基因第11号外显子c.1261G＞T杂合无义突变和第4号外显子c.251dupG杂合移码突变是本例家系遗传性凝血因子Ⅻ缺陷症的分子发病机制，这两个突变均为国际上首次报道的新突变.

Herein, we develop a novel tripartite DNA probe to transport phosphorothioated substrate hairpins and an aptamer for the intramolecular CHA circuit, which achieves detection of a low amount of specific mRNA in living cells and mice. Our study provides an improved strategy to promote in vivo fluorescence imaging applications in early-stage clinical diagnosis.

MotivationDe novo peptide sequencing based on tandem mass spectrometry data is the key technology of shotgun proteomics for identifying peptides without any database and assembling unknown proteins. However, owing to the low ion coverage in tandem mass spectra, the order of certain consecutive amino acids cannot be determined if all of their supporting fragment ions are missing, which results in the low precision of de novo sequencing.ResultsIn order to solve this problem, we developed pNovo 3, which used a learning-to-rank framework to distinguish similar peptide candidates for each spectrum. Three metrics for measuring the similarity between each experimental spectrum and its corresponding theoretical spectrum were used as important features, in which the theoretical spectra can be precisely predicted by the pDeep algorithm using deep learning. On seven benchmark datasets from six diverse species, pNovo 3 recalled 29–102% more correct spectra, and the precision was 11–89% higher than three other state-of-the-art de novo sequencing algorithms. Furthermore, compared with the newly developed DeepNovo, which also used the deep learning approach, pNovo 3 still identified 21–50% more spectra on the nine datasets used in the study of DeepNovo. In summary, the deep learning and learning-to-rank techniques implemented in pNovo 3 significantly improve the precision of de novo sequencing, and such machine learning framework is worth extending to other related research fields to distinguish the similar sequences.Availability and implementationpNovo 3 can be freely downloaded from http://pfind.ict.ac.cn/software/pNovo/index.html.Supplementary informationSupplementary data are available at Bioinformatics online.

Nicotinamide phosphoribosyltransferase (NAMPT) is a critical rate-limiting enzyme involved in NAD synthesis that has been shown to contribute to the progression of liver cancer. However, the potential role and mechanism of NAMPT in hepatitis B virus (HBV)-associated liver cancer remain unclear. The present study assessed the expression of NAMPT in HBV-positive and -negative liver cancer cells, and investigated whether HBV-induced NAMPT expression is dependent on HBV X protein (HBx). In addition, the role of NAMPT in HBV replication and transcription, and in HBV-mediated liver cancer cell growth was explored. The effects of NAMPT on the glycolytic pathway were also evaluated. Reverse transcription-quantitative PCR and western blotting results revealed that NAMPT expression levels were significantly higher in HBV-positive liver cancer cells than in HBV-negative liver cancer cells, and this effect was HBx-dependent. Moreover, the activation of NAMPT was demonstrated to be required for HBV replication and transcription. The NAMPT inhibitor FK866 repressed cell survival and promoted cell death in HBV-expressing liver cancer cells, and these effects were attenuated by nicotinamide mononucleotide. Furthermore, the inhibition of NAMPT was associated with decreased glucose uptake, decreased lactate production and decreased ATP levels in HBV-expressing liver cancer cells, indicating that NAMPT may promote the aerobic glycolysis. Collectively, these findings reveal a positive feedback loop in which HBV enhances NAMPT expression and the activation of NAMPT promotes HBV replication and HBV-mediated malignant cell growth in liver cancer. The present study highlights the important role of NAMPT in the regulation of aerobic glycolysis in HBV-mediated liver cancer, and suggests that NAMPT may be a promising treatment target for patients with HBV-associated liver cancer.

OBJECTIVE: To investigate the nutritional recovery status of children with moderate or severe malnutrition during hospitalization after discharge. METHODS: The children with moderate or severe malnutrition were given nutrition support during hospitalization. They received a regular follow-up and nutrition guidance after discharge. The weight-for-age and height-for-age Z-scores reaching above -2SD were considered the nutrition criterion for ending follow-up. RESULTS: Among the 298 children with moderate or severe malnutrition, 174 (58.4%) reached the criterion for ending follow-up, 100 (33.6%) were lost to follow-up, 18 (6.0%) died, and 6 (2.0%) did not reach the criterion for ending follow-up after 18 months of follow-up. The children with malnutrition in the department of surgery had a significantly higher proportion of children reaching the criterion for ending follow-up than those in the department of internal medicine (P < 0.05). The children with severe malnutrition had a significantly higher loss to follow-up rate than those with moderate nutrition (P < 0.05). The majority of children with emaciation reached the criterion for ending follow-up at month 3 after discharge, while those with growth retardation reached such the criterion at months 3-6 after discharge. Up to 1 year after discharge, more than 80% of the children with different types of malnutrition reached the nutrition criterion for ending follow-up. CONCLUSIONS: Most of the children with malnutrition who adhere to follow-up can reach the expected nutrition criterion within 1 year after discharge. The children with growth retardation have slower nutritional recovery than those with emaciation.

Nine antialgal active compounds, (i.e. trehalose (1), twenty-two methyl carbonate (2), (-)-dihydromenisdaurilide (3), 3,7,11,15-tetramethyl-2-hexadecen-1-ol (4), isophytol (5), 8-hexadecenol (6), 17-hydroxyheptadecanoic acid (7), trans-asarone (8) and 2-amino-3-mercaptopropanoic acid (9)) were isolated from Ulva pertusa for the first time by sephadex LH-20 column chromatography, silica gel column chromatography and repeated preparative TLC. Except for compound 4, all compounds represented novel isolated molecules from marine macroalgae. Further, antialgal activities of these compounds against Amphidinium carterae, Heterosigma akashiwo, Karenia mikimitoi, Phaeocystis globosa, Prorocentrum donghaiense and Skeletonema costatum were investigated for the first time. Results showed these nine compounds have selectivity antialgal effects on all test red tide microalgae, and antialgal activities against red tide microalgae obviously enhanced with the increase of concentration of antialgal compounds. Based on this, EC50–96 h values of these nine compounds for six red tide microalgae were obtained for the first time. By analyzing and comparing EC50–96 h values, it has been determined that seven compounds (1, 3, 4, 6, 7, 8 and 9) showed the superior application potential than potassium dichromate or gossonorol and other six compounds as a characteristic antialgal agent against Heterosigma akashiwo, Karenia mikimitoi and Prorocentrum donghaiense. Overall this study has suggested that green algae Ulva pertusa is a new source of bioactive compounds with antialgal activity.

Objectives Abundant studies have suggested that TLR2 genetic variants involve in susceptibility to TB infection. We tried to verified the hypothesis that TLR2 genetic loci effect on the susceptibility to TB in the Western Chinese population. Methods A total 1109 individuals (634 TB patients and 475 healthy controls) were genotyped for rs3804099, rs3804100 and rs76112010 by using a custom-by-design 2x48-Plex SNP scan TM Kit. The statistical analysis between candidate 3 SNPs and risk and phenotypes of TB were conducted in this study. Significant SNPs were further interrogated in relation to TB susceptibility to TB infection and clinical phenotypes. Results None of the three genetic loci (rs3804099, rs3804100 and rs76112010) showed statistically significant differences between all TB cases and healthy controls in genotype, allele frequencies and genetic models (all p > 0.05). Statistical comparisons of retreatment TB cases and healthy controls or primary cases revealed that rs3804099 was significantly associated with the increased risk of developing TB in Western Chinese population. For genotypes frequencies, the subgroups of retreatment TB group versus healthy control group analysis and retreatment TB group versus primary TB group analysis results showed the p = 0.041 and p = 0.002 respectively. For recessive model, the subgroup of retreatment TB group versus healthy control group and retreatment TB group versus primary TB group analyses showed the p = 0.028 and P = 0.002 after Bonferroni correction respectively. Furthermore, analysis of the genotypes of rs76112010 in relation to clinical phenotypes of active TB using the dominant model demonstrated that it was strongly correlated with different hematological parameters (Erythrocyte P = 0.043, Hemoglobin P = 0.047, Hematocrit P = 0.027). Conclusion Our study presented the significant associations of rs3804099 with TB susceptibility in the retreatment TB subgroup analysis. Our study proposed that common TLR2 genetic variants may influence TB development and disease phenotypes in Western Chinese population.

Tandem mass spectrometry has been the principal method in shotgun proteomics for peptide and protein identification. However, incorrect identifications reported by proteome search engines are still unknown, and further validation methods are needed. We have proposed a validation method pValid before, but its scope of application is limited because two features used in pValid are related to open database search and sub-optimal peptide candidates for tandem mass spectra, and the performance on complex datasets still has room for improvement. In this study, we developed a more comprehensive validation method, pValid 2, to break these limitations by removing the two features and bringing in a new feature related to the retention time predicted by a deep learning-based method pPredRT. pValid 2 yielded an average false positive rate of 0.03% and an average false negative rate of 1.37% on three testing datasets, better than those of pValid, and flagged 8.47% to 11.31% more incorrect identifications than pValid on two complex datasets. Moreover, pValid 2 flagged almost all decoy identifications in validating the open-search datasets. In addition, the function of validating identifications given by MaxQuant and MS-GF+ was implemented in pValid 2, and the validation results showed that pValid 2 performed dramatically better than three metabolic labeling validation methods. Further considering its cost-effectiveness as a pure computational approach, pValid 2 has the potential to be a widely used validation tool for peptide identifications of any proteome search engines in shotgun proteomics. SIGNIFICANCE: Identification results given by shotgun proteomics are vital to life science research. The correctness of identifications deeply affects the precision of the subsequent studies about protein structures and functions, protein-protein interactions, pathogenic mechanism, and targeted drugs. Thus, validating the correctness of identifications is crucial and urgent. In 2019, we developed an identification credibility validation method named pValid, whose false positive rate (FPR) is 0.03% and false negative rate (FNR) is 1.79%, comparable to those of the gold standard, i.e., the Synthetic-peptide validation method. However, pValid can only be used for validating the results from pFind, and its validation performance on a few complex datasets still has room for improvement. So, in this submission, we proposed pValid 2, a more comprehensive computational validation method that can validate identifications from any proteome search engines with increased discriminating power.

Background Luteinizing hormone (LH) regulation of the ligand, natriuretic peptide precursor type C, and its receptor, natriuretic peptide receptor 2 (NPR2), is critical for oocyte maturation; however, the mechanism is not fully understood. Macrophage colony-stimulating factor (M-CSF) has recently been shown to be involved in oocyte maturation and ovulation. In the present study we determined whether or not M-CSF plays a role in the intermediate signal that mediates LH regulation of NPR2 in resumption of oocyte meiosis. Methods Immature female C57BL/6 mice were injected i.p. with 5 IU of equine chorionic gonadotropin (eCG) to stimulate follicle development. After 44–48 h, the eCG-stimulated mice were injected i.p. with an ovulatory dose of 5 IU of human chorionic gonadotropin (hCG). The ovaries were excised at selected times. Pre-ovulatory follicles (POFs) and cumulus-oocyte complexes were cultured in different media. Immunohistochemical and quantitative real-time PCR analyses were used to assess the expression of M-CSF, M-CSF receptor (M-CSF-R), and NPR2. The presence of germinal vesicle breakdown (GVBD) was examined under a stereomicroscope to morphologically evaluate resumption of oocyte meiosis. Results NPR2 was mainly expressed in cumulus cells of pre-ovulatory follicles, while M-CSF and M-CSF-R were expressed in both mural granulosa and cumulus cells. The levels of M-CSF/M-CSF-R and NPR2 decreased within 4 h after treatment of hCG. M-CSF not only reduced the expression of NPR2 mRNA via its receptor (M-CSF-R), but also increased the proportion of GVBD in oocytes. Conclusion M-CSF serves as an intermediate signal, thus inducing a vital decrease in the NPR2 levels in cumulus cells, and regulates the process of LH-induced resumption of meiosis.

OBJECTIVE In 2011, the International League Against Epilepsy (ILAE) proposed a consensus classification system of focal cortical dysplasia (FCD) to distinguish clinicopathological subtypes, for example, "isolated" FCD type Ia-c and IIa-b, versus "associated" FCD type IIIa-d. The histopathological differentiation of FCD type I and III variants remains, however, a challenging issue in everyday practice. We present a unique histopathological pattern in patients with difficult-to-diagnose FCD, which highlights this dilemma, but also helps to refine the current ILAE classification scheme of FCD. METHODS We present a retrospective series of 11 male and one female patient with early onset pharmacoresistant epilepsy of the posterior quadrant (mean age at seizure onset = 4.6 years). All surgical specimens were reviewed. Clinical histories were retrieved and extracted from archival patient files. RESULTS Microscopic inspection revealed abnormalities in cortical architecture with complete loss of layer 4 in all surgical samples of the occipital lobe, as confirmed by semiquantitative measurements (p < 0.01). Clinical history reported early transient hypoxic condition in nine patients (75%). Magnetic resonance imaging (MRI) revealed abnormal signals in the occipital lobe in all patients, and signal changes suggestive of subcortical encephalomalacia were found in seven patients. Surgical treatment achieved favorable seizure control (Engel class I and II) in seven patients with an available follow-up period of 6.1 years. SIGNIFICANCE Prominent disorganization of cortical layering and lack of any other microscopically visible principle lesion in the surgical specimen would result in this neuropathological pattern hitherto being classified as FCD ILAE type Ib. However, perinatal hypoxia with distinctive MRI changes suggested primarily a hypoxemic lesion and acquired pathomechanism of neuronal cell loss in the occipital lobe of our patient series. We propose, therefore, classifying this distinctive clinicopathological pattern as a separate variant of FCD ILAE type IIId.

In the past decade, tandem mass spectrometry (MS/MS)-based bottom-up proteomics has become the method of choice for analyzing post-translational modifications (PTMs) in complex mixtures. The key to the identification of the PTM-containing peptides and localization of the PTM-modified residues is to measure the similarities between the theoretical spectra and the experimental ones. An accurate prediction of the theoretical MS/MS spectra of the modified peptides will improve the similarity measurement. Here, we proposed the deep-learning-based pDeep2 model for PTMs. We used the transfer learning technique to train pDeep2, facilitating the training with a limited scale of benchmark PTM data. Using the public synthetic PTM data sets, including the synthetic phosphopeptides and 21 synthetic PTMs from ProteomeTools, we showed that the model trained by transfer learning was accurate (>80% Pearson correlation coefficients were higher than 0.9), and was significantly better than the models trained without transfer learning. We also showed that accurate prediction of the fragment ion intensities of the PTM neutral loss, for example, the phosphoric acid loss (-98 Da) of the phosphopeptide, will improve the discriminating power to distinguish the true phosphorylated residue from its adjacent candidate sites. pDeep2 is available at https://github.com/pFindStudio/pDeep/tree/master/pDeep2 .

As the de facto validation method in mass spectrometry-based proteomics, the target-decoy approach determines a threshold to estimate the false discovery rate and then filters those identifications beyond the threshold. However, the incorrect identifications within the threshold are still unknown and further validation methods are needed. In this study, we characterized a framework of validation and investigated a number of common and novel validation methods. We first defined the accuracy of a validation method by its false-positive rate (FPR) and false-negative rate (FNR) and, further, proved that a validation method with lower FPR and FNR led to identifications with higher sensitivity and precision. Then we proposed a validation method named pValid that incorporated an open database search and a theoretical spectrum prediction strategy via a machine-learning technology. pValid was compared with four common validation methods as well as a synthetic peptide validation method. Tests on three benchmark data sets indicated that pValid had an FPR of 0.03% and an FNR of 1.79% on average, both superior to the other four common validation methods. Tests on a synthetic peptide data set also indicated that the FPR and FNR of pValid were better than those of the synthetic peptide validation method. Tests on a large-scale human proteome data set indicated that pValid successfully flagged the highest number of incorrect identifications among all five methods. Further considering its cost-effectiveness, pValid has the potential to be a feasible validation tool for peptide identification.

To screen the genes with significant changes in DNA methylation level in active tuberculosis patients, we used the methylation chips and expanded the sample size to verify candidate genes.① This study enrolled 9 cases of active tuberculosis patients, 3 cases of latent tuberculosis patients and 3 cases of healthy controls whose age and gender were all matched. Genome DNA was extracted from peripheral blood mononuclear cell in blood samples collected from these candidates, and bisulfite conversion treatment was then conducted. After hybridization with the Illumina HD 450K Infinium Mehtylation BeadChip, the results were compared between patients group and control group, and GO and KEGG pathway analyses were performed to evaluate the function of differentially expressed genes. ② We further enrolled 60 cases of active tuberculosis patients and 60 cases of health controls (age-and gender-matched), DNA was extracted from their peripheral blood and also followed bisulfite conversion treatment. Pyrosequencing method was used to detect the methylation levels of candidate genesCompared with healthy controls, the fragments in the patients that showed low methylation change accounted for the vast majority. Most of the methylation differential fragments (DMRs) were located in the main body region, followed by the upstream region of transcription initiation site, and the lowest DMRs distribution area was 3´UTR area. GO and Pathway analysis showed that the functions of the differentially methylated regions related genes are mainly enriched in the biological processes of the regulation of leukocyte differentiation, apoptosis, cytokine regulation and inflammatory response which are closely related to tuberculosis. There were 32 CpG sites involved in the verified 7 tuberculosis related genes, and 16 CpG locus showed significant difference (In the course of MTB infection, the methylation status of genomic DNA is altered, and most of the differentially methylated regions (DMRs) are showed status of demethylation. The expressions of

BACKGROUND Antituberculosis drug-induced liver injury (ATDILI) is increasing globally and, hence, it is crucial to predict its risk in the clinical management of antituberculosis therapy. As a major antioxidant, superoxide dismutase (SOD) is mainly responsible for providing defence against oxidative stress, which is involved in ATDILI. The present study aimed to investigate the associations between polymorphisms in SOD genes, including Cu/ZnSOD (SOD1), mitochondrial manganese SOD (MnSOD or SOD2) and extracellular SOD (SOD3), as well as the susceptibility to ATDILI in a Chinese Han population. METHODS In total, 1060 Chinese Han subjects highly suspected to have tuberculosis (TB) were prospectively enrolled from West China Hospital of Sichuan University. Overall, 746 subjects comprising 118 ATDILI and 628 ATD-tolerant TB patients were eligible and were genotyped for seven single-nucleotide polymorphisms in three SOD genes (SOD1: rs4816407 and rs1041740; SOD2: rs4880; SOD3: rs699473, rs2536512, rs2855262 and rs8192290). RESULTS Logistic regression analysis showed that none of the seven genetic variants in the three SOD genes were significantly associated with susceptibility to ATDILI in the Chinese Han population after Bonferroni correction, except for a potential association for the SOD2 rs4880 A>G (G allele, p = 0.190, odds ratio = 1.53, 95% confidence interval = 1.05-2.23; GG genotype, p = 0.155). CONCLUSIONS The promising application of single-nucleotide polymorphisms in the SOD1, SOD2 and SOD3 genes as genetic markers for ATDILI is challenged, and further studies are needed with larger sample sizes and different ethnicities, especially for SOD2 rs4880.

Inadequate endometrial receptivity may be responsible for the low implantation rate of transferred embryos in in vitro fertilization (IVF) treatments. Patients with repeated implantation failure (RIF) impact the clinical pregnancy rate for IVF. We collected endometrial tissue during the implantation window of hysteroscopy biopsies from September 2016 to December 2019 and clinical data were collected simultaneously. Patients were divided into RIF and pregnant controls group according to pregnancy outcomes. A total of 82 differentially expressed endometrial proteins were identified, including 55 up-regulated proteins (>1.50-fold, P P

Two Zn MOFs {[Zn4(OH)(tipe)2(btc)2]·(OH)·9H2O·DMF}n (1·(OH)·9H2O·DMF) and {[Zn(tipe)1/2(bpdc)]·H2O}n (2·H2O) (tipe = 1,1,2,2-tetrakis(imidazol-1-yl)phenyl)ethylene, btc = 1,3,5-benezenetricarboxylate, bpdc = 2,2′-biphenyldicarboxylate) were obtained using the hydrothermal method and characterized. MOF 1 exhibits the (3,4,4,6)-connected 3D topology with point symbol of (83)(44·82)(4·84·12)(42·89·102·122). MOF 2 shows the (4,4)-connected 3D topology with point symbol of (84·102)2(42·82·102). MOF 1 and 2 present the strong luminescence emission at 507 nm and 492 nm, respectively. The energy gap ( E g), valence band (Ev) and conduction band (Ec) data of MOF 1 and 2 were 2.31 and 2.17 eV, 2.37 and 2.54 eV, 0.06 and 0.37 eV, respectively. MOF 1 and 2 are good photocatalytic and sonocatalytic catalysts for degradation of methylene blue under visible light and ultrasound irradiation. The catalytic mechanism was proposed.

Background: Over the past several decades, hundreds of genetic studies have been conducted to investigate associations between variants and risk of tuberculosis. But results have been inconclusive and no comprehensive quantitative synopsis has been available. We aimed to provide a summary of the current understanding of the genetic architecture of tuberculosis susceptibility. Methods: We systematically searched PubMed, Embase and Web of Science to identify genetic association studies of tuberculosis published through October 16, 2018. We did a meta-analysis for genetic variants with at least three independent datasets. We graded levels of cumulative epidemiological evidence of significant associations with risk of tuberculosis using the guidelines proposed by the Human Genome Epidemiology Network and false-positive report probability tests. We performed functional annotations for these variants using data from the Encyclopedia of DNA Elements (ENCODE) Project and other databases. Findings: We identified 592 eligible articles comprising 250431 cases with tuberculosis and 698635 controls without this disease through screening a total of 21330 citations. Meta-analysis-analyses were done for 580 variants in 314 genes or loci. We found that 37 variants were nominally significantly associated with risk of tuberculosis. Cumulative epidemiological evidence for a significant association with risk of tuberculosis was graded strong for 12 variants in or near 12 genes. Data from the ENCODE and other databases suggested that 10 of the 12 variants with strong evidence and those correlated with them might fall within putative functional regions. These variants together explained approximately 15.82% of familial relative risk of tuberculosis. Interpretation: Our study summarizes current literature on the genetic architecture of tuberculosis susceptibility and provides useful data for designing future studies to investigate new genetic factors for risk of tuberculosis. Funding Statement: This research is supported by grants from National Natural Science Foundation of China 81472026, 81672095, 81702288, 81673255, 81874283, the Projects of the Health and family planning commission in Sichuan Province 16ZD004, China Postdoctoral Science Foundation Project 2018M643495, the Recruitment Program for Young Professionals of China, Army Medical University WX2015-013, Army Medical University First Affiliated Hospital SWH2015LC03, SWH2016ZDCX1012, SWH2016JQFY-02, and SWH2015QN11, Chongqing Special Postdoctoral Science Foundation XmT2018068. Declaration of Interests: The authors declared no conflicts of interest. Ethics Approval Statement: We conducted this study in accordance with the guidelines of the Human Genome Epidemiology Network (HuGENet) for systematic review of genetic association studies and the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) Statement.

AIM Although peripheral low-grade inflammation and brain-derived neurotrophic factor (BDNF) levels have been implicated in schizophrenia (SCZ), the interactions between them remain to be fully revealed. We aimed to compare BDNF and cytokines in patients with SCZ and healthy controls (HC). Additionally, we aimed to investigate the association between peripheral levels of cytokines and BDNF in patients with SCZ. METHODS Plasma levels of BDNF, interferon gamma, interleukin (IL)-10, IL-12, IL-1, IL-6, IL-8, tumor necrosis factor alpha, macrophage migration inhibitory factor, IL-1 receptor antagonist (IL-1Ra), and CD40 Ligand were compared in 45 SCZ patients and 38 HC using Luminex technology. RESULTS Compared to HC, patients had significantly higher IL-1Ra levels (P = 0.031). We found a strong positive association between BDNF and CD40 Ligand in the patient group (rho = 0.858, P < 0.001) as well as in the HC group (rho = 0.822, P < 0.001), respectively. Furthermore, there was a negative association between BDNF and tumor necrosis factor alpha in patients (rho = -0.429, P = 0.030) as well as in HC (rho = -0.649, P < 0.001). CONCLUSION These results suggest that the cytokine IL-1Ra may play a role in SCZ pathophysiology. Additionally, the interaction between cytokines and BDNF levels further indicated the diverse actions of these cytokines.

Lipase (EC 3.1.1.3) stands amongst the most important and promising biocatalysts for industrial applications. In this study, in order to realize a high-level expression of the Yarrowia lipolytica lipase gene in Pichia pastoris, we optimized the codon of LIP2 by de novo gene design and synthesis, which significantly improved the lipase expression when compared to the native lip2 gene. We also comparatively analyzed the effects of the promoter types (PAOX1 and PFLD1) and the Pichia expression systems, including the newly developed PichiaPink system, on lipase production and obtained the optimal recombinants. Bench-top scale fermentation studies indicated that the recombinant carrying the codon-optimized lipase gene syn-lip under the control of promoter PAOX1 has a significantly higher lipase production capacity in the fermenter than other types of recombinants. After undergoing methanol inducible expression for 96h, the wet cell weight of Pichia, the lipase activity and the protein content in the fermentation broth reached their highest values of 262g/L, 38,500U/mL and 2.82g/L, respectively. This study has not only greatly facilitated the bioapplication of lipase in industrial fields but the strategies utilized, such as de novo gene design and synthesis, the comparative analysis among promoters and different generations of Pichia expression systems will also be useful as references for future work in this field.