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Jui-Wen Peng,1 Oswald Ndi Nfor,2 Chien-Chang Ho,3,4 Shu-Yi Hsu,2 Ming-Chih Chou,1 Yung-Po Liaw2,5 1Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan; 2Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, 40201, Taiwan; 3Department of Physical Education, Fu-Jen Catholic University, New Taipei City, 24205, Taiwan; 4Research and Development Center for Physical Education, Health, and Information Technology, Fu Jen Catholic University, New Taipei, 24205, Taiwan; 5Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, 40201, TaiwanCorrespondence: Yung-Po Liaw, No. 110 Sec. 1 Jianguo N. Road, Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, 40201, Taiwan, Tel +886436097501, Fax +886423248179, Email Liawyp@csmu.edu.tw Ming-Chih Chou, No. 110 Sec. 1 Jianguo N. Road, Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan, Tel +886424730022 ext. 11191, Fax +886423248130, Email juhan0223@yahoo.com.twPurpose: Stroke is a complex health condition caused by multiple risk factors. We investigated whether the Cytochrome P450 2C9 (CYP2C9) rs4918758 polymorphism and sex were independently and interactively associated with ischemic stroke risk among Taiwan Biobank (TWB) participants.Material and Methods: We analyzed TWB data pertaining to 9197 female and 8625 male individuals. Data collected between 2008 and 2015 were linked to medical records in the National Health Insurance Database (NHIRD). Based on multiple logistic regression analyses, we estimated odds ratios (OR) and 95% confidence intervals (CI) for ischemic stroke.Results: We found that 441 women and 468 men had ischemic stroke. There were no differences in the risk of ischemic stroke between individuals with the TC/CC genotype and those with the TT genotype [OR (95% CI) = 1.04 (0.90– 1.21)]. When compared to women, men had an OR of 1.03 (95% CI = 0.87– 1.22) for ischemic stroke. Based on further analysis, sex was found to interact with polymorphism rs4918758 (p for interaction = 0.0019). After categorizing by sex, men with TC/CC genotype showed significant ORs but not women [OR (95% CI) = 1.32 (1.07– 16.33) vs 0.83 (0.68– 1.00)]. Further stratification by genotype showed that in comparison with their female counterparts, men with the TT and TC/CC genotypes had ORs of 0.59 (95% CI = 0.44– 0.80) and 1.36 (95% CI = 1.10– 1.68), respectively.Conclusion: According to our study, the TT genotype of rs4918758 was associated with a reduced risk of ischemic stroke in Taiwanese men when compared to women, whereas the TC/CC genotype was associated with a greater risk.Keywords: stroke, genetic variant, sex, ischemic heart, gender

Jui-Wen Peng,1 Oswald Ndi Nfor,2 Chien-Chang Ho,3,4 Shu-Yi Hsu,2 Chia-Chi Lung,2 Disline Manli Tantoh,2,5 Ming-Chih Chou,1 Yung-Po Liaw2,5 1Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan; 2Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, 40201, Taiwan; 3Department of Physical Education, Fu-Jen Catholic University, New Taipei City, 24205, Taiwan; 4Research and Development Center for Physical Education, Health, and Information Technology, Fu Jen Catholic University, New Taipei, 24205, Taiwan; 5Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, 40201, TaiwanCorrespondence: Yung-Po LiawDepartment of Public Health and Institute of Public Health, Chung Shan Medical University, No. 110, Sec. 1 Jianguo N. Road, Taichung, 40201, TaiwanTel +886424730022 ext. 11838Fax +886423248179Email Liawyp@csmu.edu.twMing-Chih ChouInstitute of Medicine, Chung Shan Medical University, No. 110, Sec. 1 Jianguo N. Road, Taichung, 40201, TaiwanTel +886424730022 ext. 11191Fax +886423248130Email juhan0223@yahoo.com.twPurpose: Ischemic stroke accounts for approximately 85% of all strokes. Risk factors include atrial fibrillation, metabolic disorders, and genetic and lifestyle factors. There is limited evidence to support the association between atrial fibrillation and the risk of ischemic stroke based on genetic variants. We assessed the relationship between ischemic stroke and atrial fibrillation among participants in Taiwan Biobank (TWB) based on the rs2860905 variant of the cytochrome P450 Family 2 Subfamily C Member 9 (CYP2C9) gene.Materials and Methods: Using logistic regression analysis, we estimated the odds ratios (OR) and 95% confidence intervals (CI) for ischemic stroke among 17,726 biobank adults recruited from 2008 through 2015.Results: Of the eligible participants (n = 17,726), 906 were identified with ischemic stroke. Atrial fibrillation was positively associated with ischemic stroke (OR=3.70; 95% CI, 2.21– 6.20), whereas the rs2860905 variant was not. The OR for ischemic stroke among those with GA/AA genotype was 1.00 (95% CI, 0.82– 1.22) compared to those with the GG genotype. Based on the genotype-stratified analysis, the OR for ischemic stroke was 4.68 (95% CI, 2.70– 8.09) among individuals with GG genotype who had atrial fibrillation compared to those who did not.Conclusion: These results demonstrate that the GG genotype of the CYP2C9 rs2860905 variant appears to enhance the risk of ischemic stroke among adults in Taiwan. It could be essential to factor this genotype-specific contributor to ischemic stroke into clinical and experimental investigations of the disease in Taiwan.Keywords: genetic variation, risk prediction, stroke

Jianguo Lai,1,2 Hongli Wang,1,2 Jingwen Peng,3 Peixian Chen,4 Zihao Pan1,2 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 3Department of Rehabilitation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 4Department of Breast surgery, The First People’s Hospital of Foshan, Foshan, People’s Republic of China Background: The eighth edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for survival prediction and risk stratification in breast cancer (BC) patients after neoadjuvant chemotherapy (NCT) is of limited efficacy. This study aimed to establish a novel prognostic nomogram for predicting disease-free survival (DFS) in BC patients after NCT. Patients and methods: A total of 567 BC patients treated with NCT, from two independent centers, were included in this study. Cox proportional-hazards regression (CPHR) analysis was conducted to identify the independent prognostic factors for DFS, in order to develop a model. Subsequently, the discrimination and calibration ability of the prognostic model were assessed in terms of its concordance index (C-index), risk group stratification, and calibration curve. The performance of the nomogram was compared with that of the eighth edition of the AJCC TNM staging system via C-index. Results: Based on the CPHR model, eight prognostic predictors were screened and entered into the nomogram. The prognostic model showed better performance (p

The resistance of Gram-negative bacteria to β-lactam antibiotics is mostly due to deactivation of the antibiotics by bacterial enzymes, β-lactamases. Disclosing the factors regulating β-lactamase activity is vital for developing therapies to combat multidrug-resistant pathogens, such as Acinetobacter baumannii . Recent A. baumannii studies have revealed post-translational phosphorylation of serine β-lactamases at the active site serine. However, the functional consequences of such phosphorylation are unclear. We have taken the first steps to define these consequences through studies of OXA-24/40, a carbapenem-hydrolyzing class D β-lactamase in A. baumannii . We generated OXA-24/40 phosphorylated at its active site serine, S81, and explored its effects via NMR and MS. Phosphorylation inhibits carbapenemase activity by altering the active site conformation and impeding the carboxylation of an active site lysine, a requirement for class D β-lactamase activity. The inhibition varies with the carbapenem side chain properties. Phosphorylation-induced chemical shift perturbations extend beyond the active site, suggesting allosteric effects. Our findings offer the first atomic-level insights into the functional consequences of serine phosphorylation of class D β-lactamases.

Cell cycle regulatory enzyme Pin1 both catalyzes pSer/Thr- cis/trans -Pro isomerization and binds the same motif separately in its WW domain. To better understand the function of Pin1, a way to separate these activities is needed. An unnatural peptide library, R 1 CO-pSer-Pro-NHR 2 , was designed to identify ligands specific for the Pin1 WW domain. A new solid-phase phosphorylating reagent (SPPR) containing a phosphoramidite functional group was synthesized in one step from Wang resin. The SPPR was used in the preparation of the library by parallel synthesis. The final 315-member library was screened with our WW-domain-specific, enzyme-linked enzyme-binding assay (ELEBA). Four of the best hits were resynthesized, and the competitive dissociation constants were measured by ELEBA. NMR chemical-shift perturbations (CSP) of ligands with 15 N-labeled Pin1 were used to measure K d for the best four ligands directly, demonstrating that they were specific Pin1 WW domain ligands. Models of the ligands bound to the Pin1 WW domain were used to visualize the mode of binding in the WW domain.

Objective: The immune system of the body mistakenly targets its own joints in rheumatoid arthritis (RA), a chronic autoimmune disease that causes pain, inflammation, and damage. The complexity of RA often requires the simultaneous use of several different management strategies. This study examines the potential enhancement of conventional RA treatments, specifically conventional Disease-Modifying Anti-Rheumatic Drugs (cDMARDs), by the addition of formic acid, a naturally occurring substance that may possess anti-inflammatory properties., Patients and Methods: A total of 90 children diagnosed with rheumatoid arthritis were examined at our hospital from 2020 to 2022. We segregated them into two cohorts, each consisting of 45 children. One cohort was administered conventional rheumatoid arthritis (RA) treatments, referred to as cDMARDs, which specifically included methotrexate and leflunomide. The other group was administered the standard treatments in addition to a low dosage of a specialized medication known as all-trans retinoic acid. We conducted follow-up assessments on the children at 6 months and 1-year post-treatment. We sought to evaluate the efficacy of the treatments by assessing the subjective reports of the children and their physicians, analyzing the outcomes of medical examinations, and examining diagnostic images, such as X-rays. Furthermore, we took measures to ensure the safety of the treatments., Results: Among the cohort exclusively administered cDMARDs, approximately 26.7% exhibited significant improvement, 24.4% demonstrated moderate improvement, and 6.7% displayed minor improvement after a duration of 6 months. Approximately 57.8% of the children in this group experienced positive outcomes as a result of the treatment. The group that received retinoic acid also demonstrated superior outcomes. Approximately one-third (33.3%) of the participants demonstrated significant improvement, while another one-third showed moderate improvement. Additionally, 11.1% of the participants displayed minor improvement after a period of six months. Upon comparing the two groups, it was observed that the group receiving retinoic acid demonstrated a significantly superior outcome (p<0.05)., Conclusions: Overall, the incorporation of all-trans retinoic acid alongside conventional treatments for children with RA appears to enhance their efficacy.

The persistence of farmland plastic pollution has raised significant concerns regarding its potential long-term impacts on soil health in the context of global climate change. However, there are still gaps in the understanding of the impacts of plastic residues on soil microbial communities and functions in agricultural environments under unstable and extreme climatic conditions. In this study, the effects of plastic residues (two types and three shapes) on farmland soil bacterial communities and functions across varying environmental conditions were investigated through microscopic experiments. The results revealed that plastic residues subjected to wet-dry or freeze-thaw alternations exhibited greater degradation compared to those under natural conditions. The effects of plastic residue types and shapes on soil bacterial diversity and function were regulated by environmental factors. The plastic residues significantly reduced the stability of the bacterial network under natural condition (P < 0.05), whereas the opposite phenomenon was observed under wet-dry or freeze-thaw alternating conditions. Compared to under natural condition, lower numbers of bacterial functional pathways exhibiting significant differences due to plastic residues were observed under wet-dry or freeze-thaw alternating conditions. Significant associations were observed between soil bacterial communities and functions and various soil physicochemical properties under natural conditions (P < 0.05), and most of these associations were attenuated in the wet-dry or freeze-thaw alternations. This study demonstrated the potential impacts of plastic pollution on farmland soil microbiomes, which could be modulated by both residue characteristics and climatic conditions. Specifically, extreme environments could mitigate plastic-pollution-driven influences on soil microbiomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

There is no definitive approach for assessing mesenteric ischemia and determining the optimal timing for endovascular intervention in the management of spontaneous isolated dissection of the superior mesenteric artery (SISMAD). A 56-year-old male with acute abdominal pain was diagnosed with SISMAD. After evaluating mesenteric ischemia through mesenteric fractional flow reserve (FFR), FFR was 0.72, and the patient was recommended conservative treatment for SISMAD, which involves fasting, total parenteral nutrition, and anticoagulation. The patient's syndrome was relieved after conservative treatment for 14 days without stent implantation. Over the next 5 years, no recurrence of abdominal pain or worsening of SISMAD was observed in the patient. Assessing the severity of mesenteric ischemia can be done through mesenteric FFR. Upon confirmation of the exclusion of risks related to dilatation or rupture of SISMAD aneurysm, an approach in favor of conservative management for SISMAD may indeed be considered pragmatic when the FFR exceeds 0.72., Competing Interests: Conflict of interestThe authors declare that there are no conflicts of interest., (© Indian Association of Cardiovascular-Thoracic Surgeons 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Competing Interests: Competing interests. The authors declare no competing interests.

Key features of syntheses, involving the quaternary ammonium passivation of CsPbBr 3 nanocrystals (NCs), include stable, reproducible, and large (often near-unity) emission quantum yields (QYs). The archetypical example involves didodecyl dimethyl ammonium (DDDMA + )-passivated CsPbBr 3 NCs where robust QYs stem from interactions between DDDMA + and NC surfaces. Despite widespread adoption of this synthesis, specific ligand-NC surface interactions responsible for large DDDMA + -passivated NC QYs have not been fully established. Multidimensional nuclear magnetic resonance experiments now reveal a new DDDMA + -NC surface interaction, beyond established "tightly bound" DDDMA + interactions, which strongly affects observed emission QYs. Depending upon the existence of this new DDDMA + coordination, NC QYs vary broadly between 60 and 85%. More importantly, these measurements reveal surface passivation through unexpected didodecyl ammonium (DDA + ) that works in concert with DDDMA + to produce near-unity (i.e., >90%) QYs.

Aims: Vascular peroxidase 1 (VPO1) plays an important role in mediation of vascular remodeling with pulmonary arterial hypertension (PAH). This study aims to determine whether VPO1 can promote phenotypic transformation of pulmonary artery smooth muscle cells (PASMCs) and the underlying mechanisms., Main Methods: Sprague-Dawley (SD) rats were exposed to 10 % O 2 for 21 days to establish the model of vascular remodeling in pulmonary arterial hypertension. PASMCs were incubated with 3 % O 2 for 48 h to induce phenotypic transformation. Western blot was performed to detect the expressions of target proteins. The 5-ethynyl-2'-deoxyuridine (EdU) assay was conducted to measure the proliferation of PASMCs., Key Findings: In the rats exposed to hypoxia, there were increases in right ventricular systolic pressure, pulmonary vascular remodeling and phenotypic transformation of PASMCs (the down-regulated contractile proteins of α-smooth muscle actin, smooth muscle 22α while the up-regulated synthetic proteins of osteopontin, cyclinD1), accompanied by up-regulation of VPO1, increase of hypochlorous acid (HOCl) production and elevation of the phosphorylation of ERK. In the cultured PASMCs exposed to hypoxia, similar results were achieved but they were reversed by VPO1 small interfering RNA (VPO1 siRNA) or HOCl inhibitor. Replacement of hypoxia with NaOCl could induce PASMCs phenotypic transformation and activate the ERK signaling. Furthermore, ERK inhibitor (PD98059) could also attenuate hypoxia-induced PASMCs phenotypic transformation., Significance: VPO1 play a pivotal role in promotion of phenotypic transformation of PASMCs under hypoxic condition through activation of VPO1/HOCl/ERK pathway. It might serve as a potential target for prevention of pulmonary vascular remodeling., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Osteoarthritis (OA) is a common osteoarthropathy with chronic inflammatory pain as the core symptom in middle-aged and elderly people. LncRNA MEG3 (Maternally expressed gene 3) is involved in the development of OA via regulation of angiogenesis, which causes the activation and overexpression of transient receptor potential vanilloid type-1 (TRPV1). In this study, we investigated the mechanism of MEG3-TRPV1 signaling in chronic inflammatory pain (CIP) of rat model. Chronic inflammatory pain was modeled using subcutaneous microinjection of complete Freund's adjuvant (CFA) into the left hind paw of rats. We showed that TRPV1 mRNA and protein were significantly increased, while MEG3 mRNA was significantly decreased, in the DRG and SDH of CFA-induced rats. In addition, intrathecal injection of MEG3-overexpressing lentivirus significantly downregulated TRPV1 expression and alleviated chronic inflammatory pain in CFA-induced rats. Treatment with a TRPV1 antagonist also significantly relieved chronic inflammatory pain in CFA-induced rats. In general, our results reveal that MEG3 alleviates chronic inflammatory pain by downregulating TRPV1 expression. These findings may provide new therapeutic targets in the treatment of patients with OA.

Background: Existing literature suggests a positive link between childhood maltreatment (CM) and suicide ideation (SI). Nevertheless, whether social support significantly mediates this association remains unknown ., Aim: To investigate whether social support significantly mediates the association between CM and SI., Methods: In this cross-sectional study of 4732 adolescents from southwest China, we intended to discuss the association between CM and multiple types of SI. In addition, the mediation of major types of social support in this association was also investigated. A self-administrated questionnaire was used to collect the data. A series of multivariate logistic regression models were employed to estimate the association between different types of CM, social support, and SI. The possible mediation of social support in the association between CM and SI was assessed using the path model., Results: Based on the cutoffs for subscales of Childhood Trauma Questionnaire, 928 (19.61%), 1269 (26.82%), 595 (12.57%), 2337 (49.39%), and 3067 (64.81%) respondents reported physical abuse, emotional abuse, sexual abuse, physical neglect, and emotional neglect, respectively. Among all the social sources , parental support presented as a significant mediator in the association between emotional maltreatment, both abuse and neglect, and all three types of SI: 1-wk, 1-year, and lifetime. Parental social support mediated 5.31% and 29.23%, 4.80% and 24.50%, and 7.04% and 44.42% of the overall emotional abuse-SI and emotional neglect-SI associations, respectively., Conclusion: Our findings suggest that improving parental social support might be effective in preventing suicidal risk related to childhood emotional maltreatment in adolescents., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Previous studies have shown that personality traits are associated with self-harm (SH) in adolescents. However, the role of resilience in this association remains unclear. Our research aims to explore the hypothesized mediation effect of resilience in the relationship between personality traits and SH in Chinese children and adolescents., Aim: To evaluate resilience as a mediator of the association between personality traits and SH., Methods: A population-based cross-sectional survey involving 4471 children and adolescents in Yunnan province in southwestern China was carried out. Relevant data were collected by self-reporting questionnaires. Univariate and multivariate logistic regression models were employed to identify associated factors of SH. A path model was used to assess the mediation effect of resilience with respect to personality traits and SH association., Results: Among the 4471 subjects, 1795 reported SH, with a prevalence of 40.1% (95%CI: 34.4%-46.0%). All dimensions of personality traits were significantly associated with SH prevalence. Resilience significantly mediated the associations between three dimensions of personality (extroversion, neuroticism, psychoticism) and SH, accounting for 21.5%, 4.53%, and 9.65%, respectively, of the total associations. Among all dimensions of resilience, only emotional regulation played a significant mediation role., Conclusion: The results of the study suggest that improving emotion regulation ability might be effective in preventing personality-associated SH among Chinese children and adolescents., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The prevalence of high serum uric acid is increasingly rising in recent years, and diet behavior is perceived to be associated with it. This study aimed to explore the relationship between eating away from home (EAFH) and the risk of high serum uric acid in adults in South China. Methods: The data utilized in this study were from Guangdong Nutrition and Health Survey (NHS) 2015. Serum uric acid concentration was detected. EAFH in the past week was investigated. We defined EAFH as food consumption away from home. Dietary data were collected by 24-h recalls on 3 consecutive days. A generalized linear mixed-effects model was applied to compute the odds ratio (OR) and its corresponding 95% CI. Results: A total of 3,489 individuals were included in this study. A 1.27-fold OR (95% CI: 1.05-1.52, P = 0.012) of high serum uric acid was identified in adults with EAFH in comparison with those without EAFH. With respect to men, a 1.66-fold OR (95% CI: 1.3-2.1, P < 0.001) of high serum uric acid was observed. We also observed that men with EAFH had higher intakes of red meat, poultry, vegetable, carbohydrate, protein, fat, and total energy, while a lower grain intake than those without EAFH. However, there was a lack of significant association between EAFH and the odds ratio of high serum uric acid in women. Women with EAFH did not have higher consumptions of red meat, vegetable, fish, fat, and water than those without EAFH. Conclusions: This study found that EAFH was associated with an increased odds ratio of high serum uric acid in men, but not in women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Wang, Ji, Jiang, Hong, Ma, Huang, Chen and Peng.)

Allopurinol, a xanthine oxidase (XO) inhibitor, is reported to alleviate myocardial ischemia/reperfusion (I/R) injury by reducing the production of reactive oxygen species (ROS). As an XO-derived product, H 2 O 2 can act as a substrate of vascular peroxidase 1 (VPO1) to induce the generation of hypochlorous acid (HOCl), a potent oxidant. This study aims to explore whether the XO/VPO1 pathway is involved in the anti-oxidative effects of allopurinol on the myocardial I/R injury. In a rat heart model of I/R, allopurinol alleviated I/R oxidative injury accompanied by decreased XO activity, XO-derived products (H 2 O 2 and uric acid), and VPO1 expression (mRNA and protein). In a cardiac cell model of hypoxia/reoxygenation (H/R), allopurinol or XO siRNA reduced H/R injury concomitant with decreased XO activity, VPO1 expression as well as the XO and VPO1-derived products (H 2 O 2 , uric acid, and HOCl). Although knockdown of VPO1 could also exert a beneficial effect on H/R injury, it did not affect XO activity, XO expression, and XO-derived products. Based on these observations, we conclude that the novel pathway of XO/VPO1 is responsible for, at least partly, myocardial I/R-induced oxidative injury, and allopurinol exerted the cardioprotective effects on myocardial I/R injury via inhibiting the XO/VPO1 pathway., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The resistance of Gram-negative bacteria to β-lactam antibiotics stems mainly from β-lactamase proteins that hydrolytically deactivate the β-lactams. Of particular concern are the β-lactamases that can deactivate a class of β-lactams known as carbapenems. Carbapenems are among the few anti-infectives that can treat multi-drug resistant bacterial infections. Revealing the mechanisms of their deactivation by β-lactamases is a necessary step for preserving their therapeutic value. Here, we present NMR investigations of OXA-24/40, a carbapenem-hydrolyzing Class D β-lactamase (CHDL) expressed in the gram-negative pathogen, Acinetobacter baumannii. Using rapid data acquisition methods, we were able to study the "real-time" deactivation of the carbapenem known as doripenem by OXA-24/40. Our results indicate that OXA-24/40 has two deactivation mechanisms: canonical hydrolytic cleavage, and a distinct mechanism that produces a β-lactone product that has weak affinity for the OXA-24/40 active site. The mechanisms issue from distinct active site environments poised either for hydrolysis or β-lactone formation. Mutagenesis reveals that R261, a conserved active site arginine, stabilizes the active site environment enabling β-lactone formation. Our results have implications not only for OXA-24/40, but the larger family of CHDLs now challenging clinical settings on a global scale., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

29 novel 20(S)-aminophosphonate derivatives of camptothecin were synthesized via a FeCl 3 - catalyzed one-pot reaction. All of these compounds displayed similar or superior cytotoxic activity in comparison with that of Irinotecan against Hep3B, MCF-7, A-549, MDA-MB-231, KB, and multidrug-resistant (MDR) KB-vin cell lines. Out of them, compound B07 exhibited significant cytotoxicity and 10-fold improvement in activity compared to Irinotecan. Mechanistically, B07 not only induced cell apoptosis and cell cycle arrest in Hep3B and MCF-7 cells, but also inhibited Topoisomerase I activity in the cell and cell-free system in a manner similar to that of Irinotecan. In both xenograft and primary HCC mouse models, B07 showed significant anti-tumor activity and was more potent than Irinotecan. Additionally, the acute toxicity assay showed that B07 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the FVB/N mice. Therefore, these findings indicate that compound B07 could be a potential Topoisomerase I poison drug candidate for further clinical trial., (Copyright © 2021. Published by Elsevier Inc.)

Plant diseases caused by phytopathogenic fungi reduce the yield and quality of crops. To develop novel antifungal agents, we designed and synthesized eight series of quinazolinone derivatives and evaluated their anti-phytopathogenic fungal activity. The bioassay results revealed that compounds KZL-15 , KZL-22 , 5b , 6b , 6c , 8e , and 8f exhibited remarkable antifungal activity in vitro . Especially, compound 6c displayed the highest bioactivity against Sclerotinia sclerotiorum , Pellicularia sasakii , Fusarium graminearum , and Fusarium oxysporum , displaying appreciable IC 50 values (50% inhibitory concentration) of 2.46, 2.94, 6.03, and 11.9 μg/mL, respectively. A further mechanism interrogation revealed abnormal mycelia, damaged organelles, and changed permeability of cell membranes in S. sclerotiorum treated with compound 6c . In addition, the in vivo bioassay indicated that compound 6c possessed comparable curative and protective effects (87.3 and 90.7%, respectively) to the positive control azoxystrobin (89.5 and 91.2%, respectively) at 100 μg/mL concentration against S. sclerotiorum . This work validated the potential of compound 6c as a new and promising fungicide candidate, contributing to the exploration of potent antifungal agents.

Importance: The prevention of chemotherapy-induced nausea and vomiting has an important role in the overall management of cancer treatment., Objective: To evaluate whether adding aprepitant to palonosetron and dexamethasone can further prevent the incidence and severity of nausea and vomiting caused by FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) chemotherapy regimens among women with gastrointestinal cancer at higher risk., Design, Setting, and Participants: This phase 3, double-blind, placebo-controlled randomized clinical trial recruited young women (age ≤50 years) who drank little or no alcohol and had gastrointestinal cancer for which they received FOLFOX or FOLFIRI chemotherapy. A total of 248 women were enrolled and assigned in the ratio 1:1 to intervention and control groups from August 4, 2015, to March 31, 2020. Intention-to-treat analysis was used to evaluate patient baseline characteristics and efficacy. The analysis was conducted on October 30, 2020., Interventions: Patients were randomly assigned to the aprepitant group (aprepitant, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 6 mg, orally 30 minutes before chemotherapy initiation on day 1) or the placebo group (placebo, 125 mg, orally 60 minutes before initiation of chemotherapy on day 1 and 80 mg orally on each morning of days 2 and 3; palonosetron, 0.25 mg, intravenously; and dexamethasone, 12 mg, orally 30 minutes before chemotherapy initiation on day 1)., Main Outcomes and Measures: The primary end point was the complete response (CR) rate, defined as the proportion of patients without emesis episodes or rescue medication use during the overall phase of the first cycle. Other efficacy indicators, such as no vomiting and no nausea, were measured as the secondary and exploratory end points., Results: A total of 248 women from 4 clinical centers in China entered this study, and 243 patients (aprepitant regimen, 125 patients [51.4%]; placebo regimen, 118 patients [48.5%]) were evaluable for efficacy and safety; mean (SD) age of the total population was 40.1 (7.3) years. The CR rate was significantly higher in the aprepitant group vs the control group overall (107 [87.0%] vs 80 [66.7%]; P < .001) and in the acute (114 [92.7%] vs 91 [75.8%]; P = .001) and delayed (109 [88.6%] vs 84 [70.0%]; P = .001) phases of the trial. The incidence of adverse events was similar between the 2 groups (100 [80.0%] vs 96 [81.3%]; P = .79), and no grade 3 or 4 aprepitant treatment-related adverse events were observed. Multivariable analysis revealed that aprepitant use was the only independent factor associated with CR during the overall phase., Conclusions and Relevance: The combination of aprepitant with palonosetron and dexamethasone provided increased antiemetic efficacy in the FOLFOX or FOLFIRI chemotherapy regimen and was well tolerated by younger women with gastrointestinal cancer who have a history of little or no alcohol consumption., Trial Registration: ClinicalTrials.gov Identifier: NCT03674294.

A 60-year-old man was hospitalized because of numbness and weakness in the right upper limb. Magnetic resonance imaging revealed a large mass in the right upper lobe invading the right eighth cervical and first thoracic nerve root. Biopsy pathology confirmed primary lung adenocarcinoma with a clinical stage of cT4N0M0 IIIA, negative for anaplastic lymphoma kinase fusion gene and epidermal growth factor receptor mutations but positive for programmed death ligand 1 (3%). Neoadjuvant tislelizumab and chemotherapy were offered to this patient with Pancoast tumor, and tumor shrinkage of 71% was achieved. After the operation, surgical pathology indicated pathologic complete response (pCR). Circulating tumor cells testing was negative after the first adjuvant treatment. In this case, we provide real-world evidence of encouraging pCR with neoadjuvant tislelizumab and chemotherapy for a patient with Pancoast tumor., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Hypoxia causes a series of responses supporting cells to survive in harsh environments. Substantial post-transcriptional and translational regulation during hypoxia has been observed. However, detailed regulatory mechanism in response to hypoxia is still far from complete. RNA m 6 A modification has been proven to govern the life cycle of RNAs. Here, we reported that total m 6 A level of mRNAs was decreased during hypoxia, which might be mediated by the induction of m 6 A eraser, ALKBH5. Meanwhile, expression levels of most YTH family members of m 6 A readers were systematically down-regulated. Transcriptome-wide analysis of m 6 A revealed a drastic reprogramming of m 6 A epitranscriptome during cellular hypoxia. Integration of m 6 A epitranscriptome with either RNA-seq based transcriptome analysis or mass spectrometry (LC-MS/MS) based proteome analysis of cells upon hypoxic stress revealed that reprogramming of m 6 A epitranscriptome reshaped the transcriptome and proteome, thereby supporting efficient generation of energy for adaption to hypoxia. Moreover, ATP production was blocked when silencing an m 6 A eraser, ALKBH5, under hypoxic condition, demonstrating that m 6 A pathway is an important regulator during hypoxic response. Collectively, our studies indicate that crosstalk between m 6 A and HIF1 pathway is essential for cellular response to hypoxia, providing insights into the underlying molecular mechanisms during hypoxia.

The functional mechanisms of multidomain proteins often exploit interdomain interactions, or "cross-talk." An example is human Pin1, an essential mitotic regulator consisting of a Trp-Trp (WW) domain flexibly tethered to a peptidyl-prolyl isomerase (PPIase) domain, resulting in interdomain interactions important for Pin1 function. Substrate binding to the WW domain alters its transient contacts with the PPIase domain via means that are only partially understood. Accordingly, we have investigated Pin1 interdomain interactions using NMR paramagnetic relaxation enhancement (PRE) and molecular dynamics (MD) simulations. The PREs show that apo-Pin1 samples interdomain contacts beyond the range suggested by previous structural studies. They further show that substrate binding to the WW domain simultaneously alters interdomain separation and the internal conformation of the WW domain. A 4.5-μs all-atom MD simulation of apo-Pin1 suggests that the fluctuations of interdomain distances are correlated with fluctuations of WW domain interresidue contacts involved in substrate binding. Thus, the interdomain/WW domain conformations sampled by apo-Pin1 may already include a range of conformations appropriate for binding Pin1's numerous substrates. The proposed coupling between intra-/interdomain conformational fluctuations is a consequence of the dynamic modular architecture of Pin1. Such modular architecture is common among cell-cycle proteins; thus, the WW-PPIase domain cross-talk mechanisms of Pin1 may be relevant for their mechanisms as well., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Zhang et al.)

Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19th century. Over the past 200 years, many compounds from this class were isolated, and most of them and their analogs possess various bioactivities. In this review, we survey the updated literature on bioactive alkaloids and highlight research achievements of this alkaloid class during the period of 2014-2018. We reviewed over 400 molecules with a broad range of bioactivities, including antitumor, antidiabetic and its complications, antibacterial, antifungal, antiviral, antiparasitic, insecticidal, anti-inflammatory, antioxidant, neuroprotective, and other activities. This review should provide new indications or directions for the discovery of new and better drugs from the original naturally occurring isoquinoline alkaloids., (© 2020 Wiley Periodicals LLC.)

In the present study, we aimed to obtain a high yield and productivity for glucosamine using a low-cost solid-state culture with Aspergillus sydowii BCRC 31742. The fermentation conditions, such as inoculum biomass, moisture content, and supplemental volume and mineral salt, were chosen to achieve high productivity of glucosamine (GlcN). When the initial supplemental volume used was 3 mL/g substrate, the yield and productivity of GlcN were 48.7 mg/gds and 0.69 mg/gds·h, respectively. This result will be helpful for the industrialization of the process.

TGFβ signaling pathway is critical for the cell division, differentiation and apoptosis, the aberrant regulation of which will result in severe diseases including cancer. N6-methyl-adenosine (m 6 A) is one of the most abundant modifications on mRNA, it is unclear yet how m 6 A epitranscriptome response to stimulation of TGFβ. Here, we found that cellular m 6 A level of RNA was elevated after TGFβ treatment, which might be regulated by upregulation of WTAP and METTL3. MeRIP-Seq of mRNAs of MCF7 with or without treated by TGFβ showed that mRNA with upregulated m 6 A modification level after TGFβ treatment were enriched in TGFβ signaling pathway. Phosphorylated level of SMAD2 or SMAD3 induced by TGFβ was impaired when WTAP was silenced. Moreover, the m 6 A modification and mRNA level of JunB, which is known as a cell cycle inhibitor, both were increased after induction of TGFβ and decreased after knockdown of WTAP. Intriguingly, growth inhibition caused by TGFβ was rescued in WTAP-knockdown cells. Collectively, these results reveal the key role that m 6 A pathway playing in the cell cycle arrest induced by TGFβ signaling, providing new mechanisms explanation for growth inhibition mediated by TGFβ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The prevention and control of plant diseases and insect pests is the most crucial issue facing crop protection. To discover novel pesticide candidates with diverse chemical structures from natural products, a series of luotonin A analogues were designed, synthesized and evaluated for their antifungal and insecticidal activities. Most of these compounds exhibited potent activity against Botrytis cinerea, Magnaporthe oryzae and Aphis craccivora. Among them, the antifungal activity of compound 10s against B. cinerea was comparable to azoxystrobin (EC 50  = 0.09 mM) and against M. oryzae (EC 50  = 0.19 mM) was slightly weaker than that of azoxystrobin (EC 50  = 0.17 mM). Compounds 10k and 10o are the most active compounds against A. craccivora having identical mortality value of 42.05% at 50 μg/mL, respectively, which were slightly lower than pymetrozine (51.14%) at the same concentration. Revealed morphological changes of the fungal cell surface by scanning electron microscopy indicated that luotonin A analogues might exert their antifungal activity by destroying fungal cell membrane and cell wall. Furthermore, the results of the in vivo protective and curative activities of the compound 10s against S. sclerotiorum and B. cinerea showed that the curative effect was stronger than its protective effect and the curative effects reached 67.17% and 73.82% at 80 μg/mL respectively. The above results further demonstrated the potential of luotonin A analogues as novel fungicides and insecticides., Competing Interests: Declaration of competing interest The authors state no conflict of interest., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A distinctive feature of mechanically interlocked molecules (MIMs) is the relative motion between the mechanically bonded components, and often it is the functional basis for artificial molecular machines and new functional materials. Optimization of machine or materials performance requires knowledge of the underlying atomic-level mechanisms that control the motion. The field of biomolecular NMR spectroscopy has developed a diverse set of pulse schemes that can characterize molecular dynamics over a broad time scale, but these techniques have not yet been used to characterize the motion within MIMs. This study reports the first observation of NMR relaxation dispersion related to MIM motion. The rotary (pirouette) motion of α-cyclodextrin (αCD) wheels was characterized in a complementary pair of rotaxanes with pirouetting switched ON or OFF. 13 C and 1 H NMR relaxation dispersion measurements reveal previously unknown exchange dynamics for the αCD wheels in the pirouette-ON rotaxane with a rate constant of 2200 s -1 at 298 K and an activation barrier of Δ F ‡ = 43 ± 3 kJ/mol. The exchange dynamics disappear in the pirouette-OFF rotaxane, demonstrating their switchable nature. The 13 C and 1 H sites exhibiting relaxation dispersion suggest that the exchange involves "macrocycle breathing", in which the αCD wheel fluctuates between a contracted or expanded state, the latter enabling diffusive rotary motion about the axle. The substantial insight from these NMR relaxation dispersion methods suggests similar dynamic NMR methods can illuminate the fast time scale (microsecond to millisecond) mechanisms of intercomponent motion in a wide range of MIMs.

It was highlighted that in the original article [1] the data on categorical variables was wrongly arranged in Table 1 and there was an incorrect statement in the fourth paragraph of the Discussion section.

A new species of the genus Megophrys from Zhejiang Province, China is described. Molecular phylogenetic analyses supported the new taxon as an independent clade nested into the Megophrys clade and sister to M. lishuiensis . The new species could be distinguished from its congeners by a combination of the following morphological characteristics: (1) small size (SVL 31.0-36.3 mm in male and 41.6 mm in female); (2) vomerine ridge present and vomerine teeth absent; (3) tongue not notched behind; (4) a small horn-like tubercle at the edge of each upper eyelid; (5) tympanum distinctly visible, rounded; (6) two metacarpal tubercles in hand; (7) relative finger lengths: II < I < IV < III; (8) toes with rudimentary webbing at bases; (9) heels overlapping when thighs are positioned at right angles to the body; (10) tibiotarsal articulation reaching tympanum to eye when leg stretched forward; (11) an internal single subgular vocal sac in male; (12) in breeding male, the nuptial pads with black nuptial spines on the dorsal bases of the first and second fingers., (Bin Wang, Yan-Qing Wu, Jun-Wei Peng, Sheng-Chao Shi, Ning-Ning Lu, Jun Wu.)

RNA binding proteins (RBPs) are a large protein family that plays important roles at almost all levels of gene regulation through interacting with RNAs, and contributes to numerous biological processes. However, the complete list of eukaryotic RBPs including human is still unavailable. Here, we systematically identified RBPs in 162 eukaryotic species based on both computational analysis of RNA binding domains (RBDs) and large-scale RNA binding proteomic data, and established a comprehensive eukaryotic RBP database, EuRBPDB (http://EuRBPDB.syshospital.org). We identified a total of 311 571 RBPs with RBDs (corresponding to 6368 ortholog groups) and 3,651 non-canonical RBPs without known RBDs. EuRBPDB provides detailed annotations for each RBP, including basic information and functional annotation. Moreover, we systematically investigated RBPs in the context of cancer biology based on published literatures, PPI-network and large-scale omics data. To facilitate the exploration of the clinical relevance of RBPs, we additionally designed a cancer web interface to systematically and interactively display the biological features of RBPs in various types of cancers. EuRBPDB has a user-friendly web interface with browse and search functions, as well as data downloading function. We expect that EuRBPDB will be a widely-used resource and platform for both the communities of RNA biology and cancer biology., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Monosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin-based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin-induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin-based chemotherapy., Methods: In total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI-CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTC QLQ-CIPN20), time to grade 2 neurotoxicity (NCI-CTCAE or the oxaliplatin-specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3-year disease-free survival (DFS) and adverse events., Results: There were no significant differences between the arms in the rate of NCI-CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTC QLQ-CIPN20 or time to grade 2 neurotoxicity using NCI-CTCAE and the oxaliplatin-specific neuropathy scale. GM1 substantially decreased participant-reported acute neurotoxicity (sensitivity to cold items [P < .01], discomfort swallowing cold liquids [P < .01], throat discomfort [P < .01], muscle cramps [P < .01]). The rates of dose reduction or withdrawal were not significantly different between the arms (P = .08). The 3-year DFS rates were 85% and 83% in the GM1 and placebo arms, respectively (P = .19). There were no differences in toxicity between the arms., Conclusion: Patients receiving GM1 were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity. (ClinicalTrials.gov number, NCT02251977)., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Higher dietary acid load (DAL) was considered to be associated with an elevated risk of hypertension, while related data from mainland China remains scarce and incomplete. We aim to evaluate the association between DAL and the risk of hypertension among adults from South China., Methods: We conducted a nutrition and health survey in Guangdong Province located in southern China from 2015 to 2017. A four-stage probability sampling method was utilized to select representative samples of citizens aged ≥18 years old. DAL was assessed by potential renal acid load (PRAL) and net endogenous acid production (NEAP). Participants were divided to 4 groups (Q1-Q4) according to the quartile points of PRAL or NEAP distributions. Generalized linear mixed effects models were applied to evaluate the association between DAL and the risk of hypertension., Results: A total of 3501 individuals were eligible for this study and 45.9% was male participants. Hypertension rate was 30.7%. A higher PRAL was associated with higher prevalence rate of hypertension among the male (P-trend = 0.03). OR for Q2 was 1.34 (95%CI, 0.94-1.91), Q3 was 1.53 (95%CI = 1.08, 2.16) and Q4 was 1.51 (95%CI, 1.08-2.16) among the male. However, as for total participants, the female, the participants with ≤55 years or participants with > 55 years, the associations were lack of significance. With respect to association between NEAP and hypertension, non-significant results were identified., Conclusions: The current study indicated male hypertension was associated with higher PRAL, while given to this study was cross-sectional design, further studies are warranted to verify the association.

In this paper, the nitrogen atom was inserted into the anthracycline system of the isocryptolepine nucleus to obtain the "Aza"-type structure benzo[4,5]imidazo[1,2-c] quinazoline. A series of "Aza"-type derivatives were designed, synthesized and evaluated for their antifungal activity against six plant fungi in vitro. Among all derivatives, compounds A-0, B-1 and B-2 showed significant antifungal activity against B. cinerea with the EC 50 values of 2.72 μg/mL, 5.90 μg/mL and 4.00 μg/mL, respectively. Compound A-2 had the highest activity against M. oryzae with the EC 50 values of 8.81 μg/mL, and compound A-1 demonstrated the most control efficacy against R. solani (EC 50 , 6.27 μg/mL). Moreover, compound A-0 was selected to investigate the in vivo tests against B. cinerea and the results indicated that the preventative efficacy of it up to 72.80% at 100 μg/mL. Preliminary mechanism studies revealed that after treatment with A-0 at 5 µg/mL, the B. cinerea mycelia appeared curved, collapsed and the cell membrane integrity may be damaged. The reactive oxygen species production, mitochondrial membrane potential and nuclear morphometry of mycelia have been changed, and the membrane function and cell proliferation of mycelia were destroyed. Compounds A-0, A-1, B-1 and B-2 presented weaker toxicities against two cells lines than isocryptolepine. This study lays the foundation for the future development of isocryptolepine derivatives as environmentally friendly and safe agricultural fungicides., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Complex RNA-RNA interactions underlie fundamental biological processes. However, a large number of RNA-RNA interactions remain unknown. Most existing methods used to map RNA-RNA interactions are based on proximity ligation, but these strategies also capture a huge amount of intramolecular RNA secondary structures, making it almost impossible to detect most RNA-RNA interactions. To overcome this limitation, we developed an efficient, genome-wide method, Capture Interacting RNA and Deep Sequencing (CIRDES) for in vivo capturing of the RNA interactome. We designed multiple 20-nt CIRDES probes tiling the whole RNA sequence of interest. This strategy obtained high selectivity and low background noise proved by qRT-PCR data. CIRDES enriched target RNA and its interacting RNAs from cells crosslinked by formaldehyde in high efficiency. After hybridization and purification, the captured RNAs were converted to the cDNA library after a highly efficient ligation to a 3' end infrared-dye-conjugated RNA adapter based on adapter ligation library construction. Using CIRDES, we detected highly abundant known interacting RNA, as well as a large number of novel targets of U6 snRNA. The enrichment of U4 snRNA, which interacts with U6, confirmed the robustness of the identification of the RNA-RNA interaction by CIRDES. These results suggest that the CIRDES is an efficient strategy for genome-wide RNA-RNA interactome analysis.

Inspired by quinine and its analogues, we designed, synthesized, and evaluated two series of quinoline small molecular compounds ( a and 2a ) and six series of quinoline derivatives ( 3a - f ) for their antifungal activities. The results showed that compounds 3e and 3f series exhibited significant fungicidal activities. Significantly, compounds 3f-4 (EC 50 = 0.41 μg/mL) and 3f-28 (EC 50 = 0.55 μg/mL) displayed the superior in vitro fungicidal activity and the potent in vivo curative effect against Sclerotinia sclerotiorum . Preliminary mechanism studies showed that compounds 3f-4 and 3f-28 could cause changes in the cell membrane permeability, accumulation of reactive oxygen species, loss of mitochondrial membrane potential, and effective inhibition of germination and formation of S. sclerotiorum sclerotia. These results indicate that compounds 3f-4 and 3f-28 are novel potential fungicidal candidates against S. sclerotiorum derived from natural products.

Background & Aims: The association between dietary acid load and hypertension risk is inconclusive. We conducted a systematic review and meta-analysis to summarize effect of dietary acid load on blood pressure., Methods: A comprehensively search was performed in electronic databases including EMBASE, PubMed, Web of Science and Chinese National Knowledge Infrastructure. Summary ORs and their corresponding 95% CIs were computed assuming a randomized model or fixed model., Results: Ten publications comprising 4 cohort and 6 cross-sectional studies were eligible for meta-analysis. There were 8 studies about potential renal acid load (PRAL) and 4 about net endogenous acid production (NEAP). Essential hypertension was statistically associated with higher PRAL (OR = 1.14, 95% CI = 1.02-1.17). Our findings also demonstrated a positive impact of higher PRAL on elevating both diastolic pressure (WMD = 0.96, 95% CI = 0.67-1.26) and systolic pressure (WMD = 1.57, 95% CI = 1.12-2.03). A 35% increased risk of hypertension associated with higher NEAP was identified (OR = 1.35, 95% CI = 1.03-1.78)., Conclusions: The current study suggests that dietary acid load might be potential risk factor of hypertension., (Copyright © 2019 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Even though a growing number of reports indicated favorable health effects with fish consumption, kinds of hazardous substances in fish were detected in fish and to be exceeded advisory limitation. Benefit-risk assessment of commonly consumed fish is urgently needed. We conducted fish consumption survey and fish sampling in the coast of South China Sea to assess benefit-risk effect of commonly consumed fish species. For local residents, weekly methyl mercury (MeHg) exposures from commonly consumed fish species ranged from 0.12 to 2.11 μg/kg bw. Apart from Muraenesox cinereus and Acanthopagrus latus, the rest of 92% (23/25) fish species were at low risk of MeHg exposure. Daily docosahexaenoic acid intakes via consuming specific fish were between 42.18 and 1687.04 mg/day. A total of 72% (18/25) fish species could provide 200 mg/day of DNA for local residents. Benefit-risk assessment assuming intelligence quotient (IQ) score model showed net IQ point gains between 1.53 and 5.65 points with consuming various fish species, indicative of large distinction of health benefit from various fish species. This study suggests commonly consumed fish species from China South Sea could bring much more positive effect than negative effect. Species-specific fish should be considered when providing recommendations of fish consumption. Muraenesox cinereus and Acanthopagrus latus should be minded with risk of MeHg exposure in taking large amounts.

The photocatalytic performance of layered double hydroxides (LDH) is usually confined to the slow interface mobility and high recombination rate of photogenerated electron-hole pairs in material. To overcome the low photocatalytic efficiency, novel Ag 2 O/Ag decorated LDH (LDH-Ag 2 O/Ag) was successfully synthesized by depositing Ag 2 O on the surface of LDH and then converted to Ag° nanoparticles in the right position after heat treatment. The as-synthesized LDH-Ag 2 O/Ag composites were characterized by Powder X-ray diffraction (XRD), Scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), UV-visible diffuse reflectance spectra (UV-vis DRS), photoluminescence spectra (PL) and transient photocurrent (TPC) analysis. Compared with virgin LDH, the photocatalytic activities of LDH-Ag 2 O/Ag composites were enhanced significantly. The optimum photocatalytic efficiency of LDH-Ag 10 (0.0184 min -1 ) was nearly 46 times higher than that of virgin LDH (0.0004 min -1 ). The result of active species trapping experiments indicated that •OH, h + , and •O 2 - have an effect on the TC degradation, where •OH played the predominant role during the photocatalytic process. The possible photocatalytic mechanisms involving the charge transfer pathway and reactive species generation during the process of TC degradation were also discussed. The improved photocatalytic activity of LDH-Ag 2 O/Ag could be attributed to the synergetic effect between LDH and Ag 2 O/Ag that extended visible light range and reduced photogenerated charge carriers recombination., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Pin1 is a human peptidyl-prolyl cis-trans isomerase important for the regulation of phosphoproteins that are implicated in many diseases including cancer and Alzheimer's. Further biophysical study of Pin1 will elucidate the importance of the two-domain system to regulate its own activity. Here, we report near-complete backbone and side-chain 1 H, 13 C and 15 N NMR chemical shift assignments of full-length, apo Pin1 for the purpose of studying interdomain allostery and dynamics.

Inter-residue interactions stabilize protein folds and facilitate allosteric communication. Predicting which interactions are crucial and understanding why remain challenging. We highlight this through studies of a single peripheral mutation (Q33E) on the surface of the Pin1 WW domain that causes an unexpected loss of thermostability. Nuclear magnetic resonance studies attribute the loss to reorganizations of electrostatic and hydrophobic interactions, resulting in propagated conformational perturbations. The propagation demonstrates the cooperative response of Pin1 WW to external perturbations, consistent with its allosteric behavior within Pin1. Microsecond molecular dynamics simulations suggest the wild-type fold relies on couplings between a surface electrostatic network and a highly conserved hydrophobic core; Q33E directly perturbs the former, thereby disrupting the latter. These couplings suggest that predictions of mutation consequences that assume dominance of a single interaction type can be limiting, and highlight challenges in predicting protein mutational landscapes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Nitrogen (N) leaching is a major pathway of N losses in paddy fields. Here, an experiment was conducted to assess the effects of the reduction of controlled-release urea application on grain yield and N leaching in a double-cropping paddy field. Fertilization treatments included zero-N (CK, control, 0 kg N·hm -2 ), conventional urea (CU, 180 kg N·hm -2 ), and four polymer-coated urea fertilization levels, i.e., 1.0CRU, 0.9CRU, 0.8CRU, 0.7CRU, which represented 0, 10%, 20% and 30% reduction of fertilizer inputs relative to CU, respectively. Leachate was collected at the soil depth of 60 cm using field leakage pool method. Nitrogen leaching peaked shortly after fertilization, implying that measures should be taken to prevent N leaching in the early period. Nitrogen losses from leaching were 42.3 kg N·hm -2 for 0.8CRU, and by 37.7 kg N·hm -2 for 0.7CRU, significantly lower than the leaching in CU (53.9 kg N·hm -2 ). Nitrogen leaching in 0.7CRU was significantly lower than that in 1.0CRU (51.3 kg N·hm -2 ). 11.9%-13.5% of the fertilizer N was lost via leaching across the six treatments with comparable N loss rates. Rice yields, N utilization efficiency and N harvest index were significantly higher in 0.8CRU and 0.7CRU relative to CU. Our findings suggested that the use of CRU would permit a reduction in N application by 20%-30%, which could maintain the rice yield and obtain a reduction in N leaching.

Hypoperfusion following acute stroke is common in the infarct core and periphery tissues. The present study evaluated the efficacy of salvianolic acid (SA) on the cerebral perfusion of patients who had suffered from acute stroke using perfusion-weighted magnetic resonance imaging (PWI) to examine the blood perfusion of the affected brain tissue prior to and following treatment. Patients who were admitted to PLA 153 Central Hospital within 72 h of acute stroke symptom onset and had a Glasgow coma scale ≥5 were randomized into two groups: SA and control groups. Patients in the SA group were administered SA 0.13 g/day for 14 days. PWI was performed for all patients at admission and post-treatment. The National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were applied to assess neurological function at admission and 3 months post treatment. A total of 159 patients were enrolled (85 patients in the SA group and 74 patients in the control group). A total of 62 patients in the SA group and 51 patients in the control group exhibited hypoperfusion in the ipsihemisphere of the diffusion-weighted magnetic resonance imaging (DWI) lesion. In addition, relative cerebral blood volume (rCBV), a ratio of the signal value of the region of interest in the same hemisphere of the DWI lesion to that of its mirror in the PWI CBV map, decreased significantly following treatment with SA compared with the control group in patients with hypoperfusion (P=0.02), which were indicated by PWI images at admission, in the DWI lesions or the surrounding areas. Additionally, there was no significant difference in patients with normal perfusion at admission in rCBV in DWI lesions or its surrounding area between the two groups at day 15. However, a significant improvement in NIHSS (P=0.001) and mRS (P=0.005) was indicated in the SA group compared with the control at day 90. The present study indicated that SA may improve the neurological dysfunction of patients with acute stroke, which may be explained by the increased perfusion of hypoperfused brain tissues.

The offshore area of the South China Sea is an important fishing ground in China. We used a food frequency questionnaire to determine marine fish consumption by local residents, and we detected mercury concentrations in commonly consumed marine fish species. In total, 127.9 g/day of the marine fish consumed was identified in 178 local residents. THg and MeHg concentrations in 209 samples of 22 fish species ranged from 11.3 to 215.0 µg/kg wt and 2.0 to 160.0 µg/kg wt, respectively. The mean MeHg exposure from marine fish to local residents was 0.099 µg/kg bw, accounting for 43.0% of the provisional tolerated weekly intake (PTWI) (1.6 µg/kg bw/week), suggesting a low health risk. However, a potentially high health risk (202.2% of PTWI) was identified in those with 97.5% MeHg exposure.

Background: Prospective real-life data on the safety and effectiveness of rituximab in Chinese patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) are limited. This real-world study aimed to evaluate long-term safety and effectiveness outcomes of rituximab plus chemotherapy (R-chemo) as first-line treatment in Chinese patients with DLBCL or FL. Hepatitis B virus (HBV) reactivation management was also investigated., Methods: A prospective, multicenter, single-arm, noninterventional study of previously untreated CD20-positive DLBCL or FL patients receiving first-line R-chemo treatment at 24 centers in China was conducted between January 17, 2011 and October 31, 2016. Enrolled patients underwent safety and effectiveness assessments after the last rituximab dose and were followed up for 3 years. Effectiveness endpoints included progression-free survival (PFS) and overall survival (OS). Safety endpoints were adverse events (AEs), serious AEs, drug-related AEs, and AEs of special interest. We also reported data on the incidence of HBV reactivation., Results: In total, 283 previously untreated CD20-positive DLBCL and 31 FL patients from 24 centers were enrolled. Three-year PFS was 59% (95% confidence interval [CI]: 50-67%) for DLBCL patients and 46% (95% CI: 20-69%) for FL patients. For DLBCL patients, multivariate analyses showed that PFS was not associated with international prognostic index, tumor maximum diameter, HBV infection status, or number of rituximab treatment cycles, and OS was only associated with age >60 years (P < 0.05). R-chemo was well tolerated. The incidence of HBV reactivation in hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative/hepatitis B core antibody-positive patients was 13% (3/24) and 4% (3/69), respectively., Conclusions: R-chemo is effective and safe in real-world clinical practice as first-line treatment for DLBCL and FL in China, and that HBV reactivation during R-chemo is manageable with preventive measures and treatment., Trial Registration: ClinicalTrials.gov, NCT01340443; https://clinicaltrials.gov/ct2/show/NCT01340443., Competing Interests: There are no conflicts of interest

Many signaling proteins consist of globular domains connected by flexible linkers that allow for substantial domain motion. Because these domains often serve as complementary functional modules, the possibility of functionally important domain motions arises. To explore this possibility, we require knowledge of the ensemble of protein conformations sampled by interdomain motion. Measurements of NMR residual dipolar couplings (RDCs) of backbone HN bonds offer a per-residue characterization of interdomain dynamics, as the couplings are sensitive to domain orientation. A challenge in reaching this potential is the need to interpret the RDCs as averages over dynamic ensembles of domain conformations. Here, we address this challenge by introducing an efficient protocol for generating conformational ensembles appropriate for flexible, multi-domain proteins. The protocol uses map-restrained self-guided Langevin dynamics simulations to promote collective, interdomain motion while restraining the internal domain motion to near rigidity. Critically, the simulations retain an all-atom description for facile inclusion of site-specific NMR RDC restraints. The result is the rapid generation of conformational ensembles consistent with the RDC data. We illustrate this protocol on human Pin1, a two-domain peptidyl-prolyl isomerase relevant for cancer and Alzheimer's disease. The results include the ensemble of domain orientations sampled by Pin1, as well as those of a dysfunctional variant, I28A-Pin1. The differences between the ensembles corroborate our previous spin relaxation results that showed weakened interdomain contact in the I28A variant relative to wild type. Our protocol extends our abilities to explore the functional significance of protein domain motions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Stachyose is a functional oligosaccharide, acting as a potential prebiotic for colonic fermentation. To understand the mechanism of how stachyose promotes the growth of probiotic bacterium, we analyzed the differences of the proteome of Lactobacillus acidophilus grown on stachyose or glucose. By a combination of two-dimensional electrophoresis and mass spectrometry analysis, we observed 16 proteins differentially abundant under these two conditions and identified 9 protein spots. Six of these proteins were highly abundant when stachyose was used as the sole carbon source. They included the phosphotransferase system, the energy coupling factor (ECF) transporter and the mannose-6-phosphate isomerase, involved in the uptake and catabolism of stachyose in Lactobacillus acidophilus CICC22162. Supportively, these observations were validated by quantitative RT-PCR analysis and enzymatic activity determination. Positive correlation was found between the content of the proteins and their mRNA levels. Additionally, we explored the recognition mechanism for stachyose binding to the newly identified ECF transporter by MD simulations and free energy analysis. Taken together, these results provide new insights into the mechanism of stachyose in promoting the growth of probiotic bacterium.

Increasing evidence shows that active sites of proteins have non-trivial conformational dynamics. These dynamics include active site residues sampling different local conformations that allow for multiple, and possibly novel, inhibitor binding poses. Yet, active site dynamics garner only marginal attention in most inhibitor design efforts and exert little influence on synthesis strategies. This is partly because synthesis requires a level of atomic structural detail that is frequently missing in current characterizations of conformational dynamics. In particular, while the identity of the mobile protein residues may be clear, the specific conformations they sample remain obscure. Here, we show how an appropriate choice of ligand can significantly sharpen our abilities to describe the interconverting binding poses (conformations) of protein active sites. Specifically, we show how 2-(2'-carboxyphenyl)-benzoyl-6-aminopenicillanic acid (CBAP) exposes otherwise hidden dynamics of a protein active site that binds β-lactam antibiotics. When CBAP acylates (binds) the active site serine of the β-lactam sensor domain of BlaR1 (BlaRS), it shifts the time scale of the active site dynamics to the slow exchange regime. Slow exchange enables direct characterization of inter-converting protein and bound ligand conformations using NMR methods. These methods include chemical shift analysis, 2-d exchange spectroscopy, off-resonance ROESY of the bound ligand, and reduced spectral density mapping. The active site architecture of BlaRS is shared by many β-lactamases of therapeutic interest, suggesting CBAP could expose functional motions in other β-lactam binding proteins. More broadly, CBAP highlights the utility of identifying chemical probes common to structurally homologous proteins to better expose functional motions of active sites., Competing Interests: The authors have declared that no competing interests exist.