Search

Objective: To assess the influence of unilateral open disc repositioning surgery (ODRS) of the temporomandibular joint (TMJ) on the internal derangement (ID) of the contralateral joint., Methods: Patients with bilateral ID of TMJ who underwent unilateral ODRS were enrolled and followed-up for one year. They were divided into two groups based on the contralateral disease: the anterior disc displacement with reduction (ADDWR) and without reduction (ADDWoR). Postoperative evaluation included clinical and MRI evaluation. Indices measured were unilateral intermaxillary distance (UID), visual analogue scale (VAS), disc length (DL), condylar height (CH), and disc-condyle angle (DCA). Paired t tests were used to compare the clinical and MRI indices between different time points., Results: Ninety-six patients were enrolled, including 47 in the ADDWR group and 49 in the ADDWoR group. One-year post-surgery, ODRS led to significant increases in MMO, DL, and CH, and decrease in VAS and DCA on the operated side (P < 0.05). In ADDWR group, UID, DL, and CH increased significantly, and VAS decreased (P < 0.05), with no significant change in DCA (P > 0.05). In ADDWoR group, clinical and MRI variables worsened slightly, except for UID, which remained unchanged (P > 0.05)., Conclusions: ODRS is a promising method for correcting TMJ ID and may improve condition of ADDWR and decrease progress of ADDWoR at the contralateral joint. Preoperative bilateral TMJ evaluation is essential for better outcomes., Clinical Relevance: ODRS can effectively treat TMJ ID and produce adaptive changes in the contralateral ID, for which continuous monitoring of the contralateral joint is essential., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Metabolic remodeling is a key feature of macrophage activation and polarization. Recent studies have demonstrated the role of tricarboxylic acid (TCA) cycle metabolites in the innate immune system. In the current review, we summarize recent advances in the metabolic reprogramming of the TCA cycle during macrophage activation and polarization and address the effects of these metabolites in modulating macrophage function. Deciphering the crosstalk between the TCA cycle and the immune response might provide novel potential targets for the intervention of immune reactions and favor the development of new strategies for the treatment of infection, inflammation, and cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In the wake of emerging antimicrobial resistance, antibacterial drug development has become more critical. At the same time, development of antibacterial drugs targeting specific pathogens or resistance phenotypes that may have low prevalence presents challenges because it is difficult to conduct large, randomized controlled trials for such drugs. Animal models have increasingly supported clinical development of antibacterials; however, more work is needed to optimize the design and application of these animal models to ensure clear and actionable translation to further human investigation. This review discusses recent case studies of animal infection models used to support antibacterial drug development in order to illuminate considerations for future development of novel antibacterial drugs., (Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy 2023.)

Recent studies have shown the relevance of gut microbiota in the occurrence and development of colorectal cancer (CRC), but the causal relationship remains unclear in the human population. The present study aims to assess the causal relationship from the gut microbiota to CRC and to identify specific causal microbe taxa via genome-wide association study (GWAS) summary statistics based two-sample Mendelian randomization (MR) analyses. Microbiome GWAS (MGWAS) in the TwinsUK 1,126 twin pairs was used as discovery exposure sample, and MGWAS in 1,812 northern German participants was used as replication exposure sample. GWAS of CRC in 387,156 participants from the UK Biobank (UKB) was used as the outcome sample. Bacteria were grouped into taxa features at both family and genus levels. In the discovery sample, a total of 30 bacteria features including 15 families and 15 genera were analyzed. Five features, including 2 families (Verrucomicrobiaceae and Enterobacteriaceae) and 3 genera (Akkermansia, Blautia, and Ruminococcus), were nominally significant. In the replication sample, the genus Blautia (discovery beta=-0.01, P = 0.04) was successfully replicated (replication beta=-0.18, P = 0.01) with consistent effect direction. Our findings identified genus Blautia that was causally associated with CRC, thus offering novel insights into the microbiota-mediated CRC development mechanism., (© 2022. The Author(s).)

Radiation-induced intestinal damage (RIID) is a serious disease with limited effective treatment. Nuclear explosion, nuclear release, nuclear application and especially radiation therapy are all highly likely to cause radioactive intestinal damage. The intestinal microecology is an organic whole with a symbiotic relationship formed by the interaction between a relatively stable microbial community living in the intestinal tract and the host. Imbalance and disorders of intestinal microecology are related to the occurrence and development of multiple systemic diseases, especially intestinal diseases. Increasing evidence indicates that the gut microbiota and its metabolites play an important role in the pathogenesis and prevention of RIID. Radiation leads to gut microbiota imbalance, including a decrease in the number of beneficial bacteria and an increase in the number of harmful bacteria that cause RIID. In this review, we describe the pathological mechanisms of RIID, the changes in intestinal microbiota, the metabolites induced by radiation, and their mechanism in RIID. Finally, the mechanisms of various methods for regulating the microbiota in the treatment of RIID are summarized., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xianpeng Zu reports financial support was provided by National Natural Science Foundation of China. Xianpeng Zu reports financial support was provided by National Key Research and Development Program of China. Xianpeng Zu reports financial support was provided by Shanghai Municipal Health Commission Project. Xianpeng Zu reports financial support was provided by Three-year Action Plan for Shanghai TCM Development and Inheritance Program. Xianpeng Zu reports was provided by Sailing Program of Naval Medical University., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Childhood obesity is associated with adult major depressive disorder (MDD), but their causality is not clear., Methods: We performed a two-sample Mendelian randomization (MR) analysis to explore the causality of childhood body mass index (BMI) and childhood obesity on MDD, followed by a multivariable MR (MVMR) analysis to investigate the potential role of adult BMI in mediating such effect. We accessed genome-wide association summary statistics of childhood BMI, childhood obesity, adult BMI and adult MDD from the Early Growth Genetics consortium (n BMI  = 47 541, n obesity  = 24 160), the Genetic Investigation of Anthropometric Traits consortium (n adult&#95;BMI  = ∼700 000) and the Psychiatric Genomics consortium (n MDD  = 500 199), respectively. The MR-PRESSO test was performed to remove SNPs with potential pleiotropic effect. The MR analysis was performed by inverse-variance weighted test. Further sensitivity analyses, including the MR-Egger intercept test and leave-one-out analysis, were performed to evaluate the reliability of the results., Results: Our study found that childhood obesity might increase the odds of developing MDD in adults (OR = 1.03, 95% CI: 1.01-1.06, p = 2.6 × 10 -3 ). Children with higher BMI were more likely to develop MDD in adulthood, with an OR of 1.12 per standard deviation score (SDS) increase in BMI (95% CI: 1.07-1.17, p = 4.4 × 10 -7 ). Sensitivity analyses verified the reliability of the causality between childhood BMI/obesity and MDD. Further MVMR results revealed that the impact of childhood BMI on MDD risk was predominantly mediated by adult BMI., Conclusion: Our findings provided evidence of a causal relationship between childhood BMI/obesity and adult MDD, thus providing new insights into the prevention of MDD., (© 2022 World Obesity Federation.)

Context: Observational studies have demonstrated associations between plasma proteins and obesity, but evidence of causal relationship remains to be studied., Objective: We aimed to evaluate the causal relationship between plasma proteins and body composition., Methods: We conducted a 2-sample Mendelian randomization (MR) analysis based on the genome-wide association study (GWAS) summary statistics of 23 body composition traits and 2656 plasma proteins. We then performed hierarchical cluster analysis to evaluate the structure and pattern of the identified causal associations, and we performed gene ontology enrichment analysis to explore the functional relevance of the identified proteins., Results: We identified 430 putatively causal effects of 96 plasma proteins on 22 body composition traits (except obesity status) with strong MR evidence (P < 2.53 × 10 - 6, at a Bonferroni-corrected threshold). The top 3 causal associations are follistatin (FST) on trunk fat-free mass (Beta = -0.63, SE = 0.04, P = 2.00 × 10-63), insulin-like growth factor-binding protein 1 (IGFBP1) on trunk fat-free mass (Beta = -0.54, SE = 0.03, P = 1.79 × 10-57) and r-spondin-3 (RSPO3) on WHR (waist circumference/hip circumference) (Beta = 0.01, SE = 4.47 × 10-4, P = 5.45 × 10-60), respectively. Further clustering analysis and pathway analysis demonstrated that the pattern of causal effect to fat mass and fat-free mass may be different., Conclusion: Our findings may provide evidence for causal relationships from plasma proteins to various body composition traits and provide basis for further targeted functional studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Evidence supports the observational associations of gut microbiota with a variety of psychiatric disorders, but the causal nature of such associations remains obscure. Aiming to comprehensively investigate their causal relationship and to identify specific causal microbe taxa for psychiatric diseases, we conducted a two-sample Mendelian randomization (MR) analysis of gut microbiome with 15 psychiatric diseases. Specifically, the microbiome genome-wide association study (GWAS) in 18,473 individuals from the MiBioGen study was used as exposure sample, and the GWAS for 15 psychiatric diseases was used as outcome samples. One-hundred ninety bacterial taxa from six levels were available for analysis. At a multiple-testing corrected significance level (phylum P < 5.56 × 10 -3 , class P < 3.33 × 10 -3 , order P < 2.63 × 10 -3 , family P < 1.67 × 10 -3 , genus P < 4.90 × 10 -4 , and species P < 3.33 × 10 -3 ), the following eight causal associations from seven bacterial features (one phylum + three classes + one order + one family + one species) were identified: family Prevotellaceae with autism spectrum disorder ( P = 5.31 × 10 -4 ), class Betaproteobacteria with bipolar disorder ( P = 1.53 × 10 -3 ), class Actinobacteria with schizophrenia ( P = 1.33 × 10 -3 ), class Bacteroidia and order Bacteroidales with Tourette syndrome ( P = 2.51 × 10 -3 and 2.51 × 10 -3 ), phylum Actinobacteria and class Actinobacteria with extroversion ( P = 8.22 × 10 -4 and 1.09 × 10 -3 ), and species Clostridium innocuum with neuroticism ( P = 8.92 × 10 -4 ). Sensitivity analysis showed no evidence of reverse causality, pleiotropy, and heterogeneity. Our findings offered novel insights into the gut microbiota-mediated development mechanism of psychiatric disorders., 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 © 2022 Ni, Xu, Yan, Han, Zhang, Wei, Feng, Zhao, Pei and Zhang.)

Background: Growing evidence has shown that alterations in gut microbiota composition are associated with multiple autoimmune diseases (ADs). However, it is unclear whether these associations reflect a causal relationship., Objective: To reveal the causal association between gut microbiota and AD, we conducted a two-sample Mendelian randomization (MR) analysis., Materials and Methods: We assessed genome-wide association study (GWAS) summary statistics for gut microbiota and six common ADs, namely, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes (T1D), and celiac disease (CeD), from published GWASs. Two-sample MR analyses were first performed to identify causal bacterial taxa for ADs in discovery samples. Significant bacterial taxa were further replicated in independent replication outcome samples. A series of sensitivity analyses was performed to validate the robustness of the results. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation., Results: Combining the results from the discovery and replication stages, we identified one causal bacterial genus, Bifidobacterium . A higher relative abundance of the Bifidobacterium genus was associated with a higher risk of T1D [odds ratio (OR): 1.605; 95% CI, 1.339-1.922; P FDR = 4.19 × 10 -7 ] and CeD (OR: 1.401; 95% CI, 1.139-1.722; P FDR = 2.03 × 10 -3 ), respectively. Further sensitivity analyses validated the robustness of the above associations. The results of reverse MR analysis showed no evidence of reverse causality from T1D and CeD to the Bifidobacterium genus., Conclusion: This study implied a causal relationship between the Bifidobacterium genus and T1D and CeD, thus providing novel insights into the gut microbiota-mediated development mechanism of ADs., 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 © 2022 Xu, Ni, Han, Yan, Wei, Feng, Zhang, Zhang, Li and Pei.)

Background: Myocardial ischemia reperfusion injury (MIRI) is an important mechanism of post-myocardial infarction injury and a main cause of death in patients with ischemic heart disease. Electroacupuncture (EA) pretreatment is effective for the prevention and treatment of MIRI, but mechanisms mediating the effects of cardiovascular disease EA treatments remain unclear., Objectives: To determine whether the lateral hypothalamus (LHA) and the cerebellar fastigial nucleus (FN) are involved in the protective effects of EA stimulation on MIRI., Methods: EA pretreatment was performed for 7 days before the establishment of the MIRI model. ST-segment changes on electrocardiograms were recorded and the Curtis-Walker arrhythmia score was used to evaluate changes in reperfusion injury. Hematoxylin-eosin staining was applied to evaluate the pathological and morphological changes in myocardial tissue. c-fos expression in the LHA and FN was determined by immunofluorescence staining. Glutamic (Glu) and γ-Aminobutyric acid (GABA) levels were measured using a high-performance liquid chromatography-electrochemical method., Results: EA pretreatment reduced ST-segment elevation, arrhythmia scores, and morphological changes in MIRI myocardial cells in rats, and decreased the c-fos protein expression in LHA/FN nuclei. MIRI was associated with an imbalance between GABA and Glu levels, whereas EA pretreatment increased GABA levels and decreased Glu levels in the LHA/FN., Conclusion: FN and LHA are involved in the EA-mediated attenuation of MIRI. Pretreatment with EA plays a protective role in the myocardium by regulating Glu and GABA release in the LHA and FN.

Background: Age at natural menopause (ANM) is an important index for women's health. Either early or late ANM is associated with a series of adverse outcomes later in life. Despite being an inheritable trait, its genetic determinant has not yet been fully understood., Methods: Aiming to better characterize the genetic architecture of ANM, we conducted genome-wide association study (GWAS) meta-analyses in European-specific as well as trans-ancestry samples by using GWAS summary statistics from the following 3 large studies: the Reproductive Genetics Consortium (ReproGen; N = 69 626), the UK Biobank cohort (UKBB; N = 111 593) and the BioBank Japan Project (BBJ; N = 43 861), followed by a series of bioinformatical assessments and functional annotations., Results: By integrating the summary statistics from the 3 GWAS of up to 225 200 participants, this largest meta-analysis identified 49 novel loci and 3 secondary signals that were associated with ANM at the genome-wide significance level (P < 5 × 10-8). No population specificity or heterogeneity was observed at most of the associated loci. Functional annotations prioritized 90 candidate genes at the newly identified loci. Among the 26 traits that were genetically correlated with ANM, hormone replacement therapy (HRT) exerted a causal relationship, implying a causal pattern by which HRT was determined by ANM., Conclusion: Our findings improved our understanding of the etiology of female menopause, as well as shed light on potential new therapies for abnormal menopause., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glioma, the most common primary brain tumor in adults, can be difficult to discern radiologically from other brain lesions, which affects surgical planning and follow-up treatment. Recent advances in MRI demonstrate that preoperative diagnosis of glioma has stepped into molecular and algorithm-assisted levels. Specifically, the histology-based glioma classification is composed of multiple different molecular subtypes with distinct behavior, prognosis, and response to therapy, and now each aspect can be assessed by corresponding emerging MR sequences like amide proton transfer-weighted MRI, inflow-based vascular-space-occupancy MRI, and radiomics algorithm. As a result of this novel progress, the clinical practice of glioma has been updated. Accurate diagnosis of glioma at the molecular level can be achieved ahead of the operation to formulate a thorough plan including surgery radical level, shortened length of stay, flexible follow-up plan, timely therapy response feedback, and eventually benefit patients individually., 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 Wei and Wei.)

Background: Although recent studies have revealed an association between the composition of the gut microbiota and obesity, whether specific gut microbiota cause obesity has not been determined., Objectives: The aim of this study is to determine the causal relationship between specific gut microbiota and abdominal obesity. Based on genome-wide association study (GWAS) summary statistics, we performed a 2-sample Mendelian randomization (MR) analysis to evaluate whether the gut microbiota affects abdominal obesity., Methods: Gut microbiota GWAS in 1126 twin pairs (age range, 18-89 years; 89% were females) from the TwinsUK study were used as exposure data. The primary outcome tested was trunk fat mass (TFM) GWAS in 492,805 participants (age range, 40-69 years; 54% were females) from the UK Biobank. The gut microbiota were classified at family, genus, and species levels. A feature was defined as a distinct family, genus, or species. MR analysis was mainly performed by an inverse variance-weighted test or Wald ratio test, depending on the number of instrumental variables (IVs) involved. A sensitivity analysis was performed on significant results by a weighted median test and a weighted genetic risk score (GRS) analysis., Results: Results of MR analyses provided evidence of a causal association between 3 microbiota features and TFM, including 1 family [Lachnosiraceae; P = 0.02; β = 0.001 (SEE, 4.28 × 10-4)], 1 genus [Bifidobacterium; P = 5.0 × 10-9; β = -0.08 (SEE, 0.14)], and 1 species [Prausnitzii; P = 0.03; β = -0.007 (SEE, 0.003)]. Both the weighted median test and GRS analysis successfully validated the association of the genetically predicted family, Lachnosiraceae (Pweighted median = 0.03; PGRS = 0.004)., Conclusions: Our findings provided evidence of a causal association between gut microbiota and TFM in UK adults and identified specific bacteria taxa that may regulate the fat metabolism, thus offering new direction for the treatment of obesity., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Osteoporosis and obesity are two severe complex diseases threatening public health worldwide. Both diseases are under strong genetic determinants as well as genetically correlated. Aiming to identify pleiotropic genes underlying obesity and osteoporosis, we performed a bivariate genome-wide association (GWA) meta-analysis of hip bone mineral density (BMD) and total body fat mass (TBFM) in 12,981 participants from seven samples, and followed by in silico replication in the UK biobank (UKB) cohort sample (N = 217,822). Combining the results from discovery meta-analysis and replication sample, we identified one novel locus, 17q21.31 (lead SNP rs12150327, NC&#95;000017.11:g.44956910G > A, discovery bivariate P = 4.83 × 10 -9 , replication P = 5.75 × 10 -5 ) at the genome-wide significance level (ɑ = 5.0 × 10 -8 ), which may have pleiotropic effects to both hip BMD and TBFM. Functional annotations highlighted several candidate genes, including KIF18B, C1QL1, and PRPF19 that may exert pleiotropic effects to the development of both body mass and bone mass. Our findings can improve our understanding of the etiology of osteoporosis and obesity, as well as shed light on potential new therapies.

Bone mineral density (BMD) and lean body mass (LBM) not only have a considerable heritability each, but also are genetically correlated. However, common genetic determinants shared by both traits are largely unknown. In the present study, we performed a bivariate genome-wide association study (GWAS) meta-analysis of hip BMD and trunk lean mass (TLM) in 11,335 subjects from 6 samples, and performed replication in estimated heel BMD and TLM in 215,234 UK Biobank (UKB) participants. We identified 2 loci that nearly attained the genome-wide significance (GWS, p < 5.0 × 10 -8 ) level in the discovery GWAS meta-analysis and that were successfully replicated in the UKB sample: 11p15.2 (lead SNP rs12800228, discovery p = 2.88 × 10 -7 , replication p = 1.95 × 10 -4 ) and 18q21.32 (rs489693, discovery p = 1.67 × 10 -7 , replication p = 1.17 × 10 -3 ). The above 2 pleiotropic loci may play a pleiotropic role for hip BMD and TLM development. So our findings provide useful insights that further enhance our understanding of genetic interplay between BMD and LBM.

Recent studies have demonstrated the important role played by gut microbiota in regulating bone development, but the evidence of such causal relationship is still sparse in human population. The aim of this study is to assess the causal relationship from gut microbiota to bone development and to identify specific causal bacteria taxa via a Mendelian randomization (MR) approach. A genome-wide association study (GWAS) summary statistic based two-sample MR analysis was performed. Summary statistics of microbiome GWAS (MGWAS) in 1126 twin pairs of the TwinsUK study was used as discovery sample, and the MGWAS in 984 Dutch participants from the LifeLines-DEEP cohort was used as replication sample. Estimated heel bone mineral density (eBMD) GWAS in 426,824 participants from the UK biobank (UKB) cohort was used as outcome. Bacteria were grouped into taxa features at both order and family levels. In the discovery sample, a total of 25 bacteria features including 9 orders and 16 families were analyzed. Fourteen features (5 orders + 9 families) were nominally significant, including 5 orders (Bacteroidales, Clostridiales, Lactobacillales, Pasteurellales and Verrucomicrobiales) and 9 families (Bacteroidaceae, Clostridiaceae, Lachnospiraceae, Mogibacteriaceae, Pasteurellaceae, Porphyromonadaceae, Streptococcaceae, Verrucomicrobiaceae and Veillonellaceae). One order Clostridiales and its child taxon, family Lachnospiraceae, were successfully replicated in the replication sample (Clostridiales P discovery  = 3.32 × 10 -3 P replication  = 7.29 × 10 -3 ; Lachnospiraceae P discovery  = 0.03 P replication  = 7.29 × 10 -3 ). Our findings provided evidence of causal relationship from microbiota to bone development, as well as identified specific bacteria taxa that regulated bone mass variation, thus providing new insights into the microbiota mediated bone development mechanism., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Secondary glioblastomas (sGBM) are derived from previously lower-grade [World Health Organization (WHO) grades II or III] gliomas. Lower-grade benign-behaving gliomas may retain their former grade following recurrence, or may become malignant higher-grade glioblastomas. Prediction of tumor behavior in lower-grade gliomas is critical for individualized glioma therapy. A total of 89 patients were included between January 2000 and January 2019 in the present study to establish a nomogram via univariate and multivariate logistic regression analyses. Nomogram predictive performance was tested in the validation group. We then analyzed 36 O-6-methylguanine-DNA methyltransferase ( MGMT ) unmethylated lower-grade gliomas from patients seen at West China Hospital of Sichuan University. Survival statistics were calculated with the Kaplan-Meier method. Two clinical factors (molecular diagnosis and WHO grade), five radiological factors (location, cortical involvement, multicentricity, uniformity, and margin enhancement), one biomarker ( 1p19q codeletion), and a combination of three biomarkers ( IDH +/ ATRX -/ TP53 -) were associated with glioma upgrading. Nomograms positive for these prognostic factors had an AUC of 0.880 in the derivation group and 0.857 in the validation group. The calibration and score-stratified survival curves for the derivation group and validation group were good. An operational nomogram was published at https://warrenwrl.shinyapps.io/DynNomapp/. The overall survival of secondary gliomas in the MGMT-unmethylated cohort were influenced independently by the use of temozolomide during the treatment of formerly low-grade gliomas ( p =0.00096). Clinical and radiological factors and biomarker-based behavior-oriented nomograms may offer a feasible identification tool for the detection of sGBM precursors. This method may further assist neurosurgeons with the stratification of lower-grade glioma cases and thus the development of better, more individualized treatment plans., 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 © 2020 Wei, Zhang, Li, Yang, Xue and Wei.)

Background: Glioblastoma is the most common primary malignant brain tumor. Recent studies have shown that hematological biomarkers have become a powerful tool for predicting the prognosis of patients with cancer. However, most studies have only investigated the prognostic value of unilateral hematological markers. Therefore, we aimed to establish a comprehensive prognostic scoring system containing hematological markers to improve the prognostic prediction in patients with glioblastoma., Patients and Methods: A total of 326 patients with glioblastoma were randomly divided into a training set and external validation set to develop and validate a hematological-related prognostic scoring system (HRPSS). The least absolute shrinkage and selection operator Cox proportional hazards regression analysis was used to determine the optimal covariates that constructed the scoring system. Furthermore, a quantitative survival-predicting nomogram was constructed based on the hematological risk score (HRS) derived from the HRPSS. The results of the nomogram were validated using bootstrap resampling and the external validation set. Finally, we further explored the relationship between the HRS and clinical prognostic factors., Results: The optimal cutoff value for the HRS was 0.839. The patients were successfully classified into different prognostic groups based on their HRSs (P < 0.001). The areas under the curve (AUCs) of the HRS were 0.67, 0.73, and 0.78 at 0.5, 1, and 2 years, respectively. Additionally, the 0.5-, 1-y, and 2-y AUCs of the HRS were 0.51, 0.70, and 0.79, respectively, which validated the robust prognostic performance of the HRS in the external validation set. Based on both univariate and multivariate analyses, the HRS possessed a strong ability to predict overall survival in both the training set and validation set. The nomogram based on the HRS displayed good discrimination with a C-index of 0.81 and good calibration. In the validation cohort, a high C-index value of 0.82 could still be achieved. In all the data, the HRS showed specific correlations with age, first presenting symptoms, isocitrate dehydrogenase mutation status and tumor location, and successfully stratified them into different risk subgroups., Conclusions: The HRPSS is a powerful tool for accurate prognostic prediction in patients with newly diagnosed glioblastoma., 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 © 2020 Zhao, Li, Yang, Wei, Wang, Song, Guo, Du and Wei.)

Appendicular lean mass (ALM) is a heritable trait associated with loss of lean muscle mass and strength, or sarcopenia, but its genetic determinants are largely unknown. Here we conducted a genome-wide association study (GWAS) with 450,243 UK Biobank participants to uncover its genetic architecture. A total of 1059 conditionally independent variants from 799 loci were identified at the genome-wide significance level (p < 5 × 10 -9 ), all of which were also significant at p < 5 × 10 -5 in both sexes. These variants explained ~15.5% of the phenotypic variance, accounting for more than one quarter of the total ~50% GWAS-attributable heritability. There was no difference in genetic effect between sexes or among different age strata. Heritability was enriched in certain functional categories, such as conserved and coding regions, and in tissues related to the musculoskeletal system. Polygenic risk score prediction well distinguished participants with high and low ALM. The findings are important not only for lean mass but also for other complex diseases, such as type 2 diabetes, as ALM is shown to be a protective factor for type 2 diabetes.

Background: Fat mass and lean mass are two biggest components of body mass. Both fat mass and lean mass are under strong genetic determinants and are correlated., Methods: We performed a bivariate genome-wide association meta-analysis of (lean adjusted) leg fat mass and (fat adjusted) leg lean mass in 12,517 subjects from 6 samples, and followed by in silico replication in large-scale UK biobank cohort sample (N = 370 097)., Results: We identified four loci that were significant at the genome-wide significance (GWS, α = 5.0 × 10 -8 ) level at the discovery meta-analysis, and successfully replicated in the replication sample: 2q36.3 (rs1024137, p discovery  = 3.32 × 10 -8 , p replication  = 4.07 × 10 -13 ), 5q13.1 (rs4976033, p discovery  = 1.93 × 10 -9 , p replication  = 6.35 × 10 -7 ), 12q24.31 (rs4765528, p discovery  = 7.19 × 10 -12 , p replication  = 1.88 × 10 -11 ) and 18q21.32 (rs371326986, p discovery  = 9.04 × 10 -9 , p replication  = 2.35 × 10 -95 ). The above four pleiotropic loci may play a pleiotropic role for fat mass and lean mass development., Conclusions: Our findings further enhance the understanding of the genetic association between fat mass and lean mass and provide a new theoretical basis for their understanding.

Aiming to identify pleiotropic genomic loci for bone mineral density and bone size, we performed a bivariate GWAS in five discovery samples and replicated in two large-scale samples. We identified 2 novel loci at 2q37.1 and 6q26. Our findings provide insight into common genetic architecture underlying both traits., Introduction: Bone mineral density (BMD) and bone size (BS) are two important factors that contribute to the development of osteoporosis and osteoporotic fracture. Both BMD and BS are highly heritable and they are genetically correlated. In this study, we aim to identify pleiotropic loci associated with BMD and BS., Methods: We conducted a bivariate genome-wide association (GWA) analysis of hip BMD and hip BS in 6180 participants from 5 samples, followed by in silico replication in the UK Biobank study of BMD (N = 426,824) and the deCODE study of BS (N = 28,954), respectively., Results: SNPs from 2 genomic loci were significant at the genome-wide significance (GWS) level (p lt; 5 × 10 -8 ) in the discovery samples and were successfully replicated in the replication samples (2q37.1, lead SNP rs7575512, discovery p = 1.49 × 10 -10 , replication p = 0.05; 6q26, lead SNP rs1040724, discovery p = 1.95 × 10 -8 , replication p = 0.03). Functional annotations suggested functional relevance of the identified variants to bone development., Conclusion: Our findings provide insight into the common genetic architecture underlying BMD and BS, and enhance our understanding of the potential mechanism of osteoporosis fracture.

Effective bacterial infection eradication requires not only potent antibacterial agents but also proper dosing strategies. Current practices generally utilize point estimates of the effects of therapeutic agents, even though the actual kinetics of exposure are much more complex and relevant. Here, we use a full time course of the observed in vitro effects to develop a semimechanistic pharmacokinetic-pharmacodynamic model for eravacycline against multiple Gram-negative bacterial pathogens. This model incorporates components such as pharmacokinetics, bacterial life cycle, and drug effects to quantitatively describe the time course of antibacterial killing and the emergence of resistance. Model discrimination was performed by comparing goodness of fit, convergence diagnostics, and objective function values. Models were validated by assessing their abilities to describe bacterial count time courses in visual predictive checks. The final model describes 576 bacterial counts (expressed in log 10 CFU per milliliter) from 144 in vitro time-kill experiments with low residual error and high precision. We characterize antibacterial susceptibility as a function of the MIC and adaptive resistance. In doing so, we show that the MIC is proportional to initial susceptibility at 0 h and the development of resistance over the course of 16 h. Altogether, this model may be useful in supporting dose selection, since it incorporates in vitro pharmacodynamics and clinically observed individual drug susceptibilities.

Aiming to uncover a shared genetic basis of abdominal obesity and osteoporosis, we performed a bivariate GWAS meta-analysis of femoral neck BMD (FNK-BMD) and trunk fat mass adjusted by trunk lean mass (TFM adj ) in 11,496 subjects from 6 samples, followed by in silico replication in the large-scale UK Biobank (UKB) cohort. A series of functional investigations were conducted on the identified variants. Bivariate GWAS meta-analysis identified two novel pleiotropic loci 12q15 (lead SNP rs73134637, p = 3.45 × 10 -7 ) and 10p14 (lead SNP rs2892347, p = 2.63 × 10 -7 ) that were suggestively associated and that were replicated in the analyses of related traits in the UKB sample (osteoporosis p = 0.06 and 0.02, BMI p = 0.03 and 4.61 × 10 -3 , N up to 499,520). Cis-eQTL analysis demonstrated that allele C at rs73134637 was positively associated with IFNG expression in whole blood (N = 369, p = 0.04), and allele A at rs11254759 (10p14, p = 9.49 × 10 -7 ) was negatively associated with PRKCQ expression in visceral adipose tissue (N = 313, p = 0.04) and in lymphocytes (N = 117, p = 0.03). As a proof-of-principle experiment, the function of rs11254759, which is 235 kb 5'-upstream from PRKCQ gene, was investigated by the dual-luciferase reporter assay, which clearly showed that the haplotype carrying rs11254759 regulated PRKCQ expression by upregulating PRKCQ promoter activity (p = 4.60 × 10 -7 ) in an allelic specific manner. Mouse model analysis showed that heterozygous PRKCQ deficient mice presented decreased fat mass compared to wild-type control mice (p = 3.30 × 10 -3 ). Mendelian randomization analysis demonstrated that both FNK-BMD and TFM adj were causally associated with fracture risk (p = 1.26 × 10 -23 and 1.18 × 10 -11 ). Our findings may provide useful insights into the genetic association between osteoporosis and abdominal obesity.

A Gram-stain negative, non-motile, asporogenous, aerobic and rod-shaped bacterial strain, designated ZY113 T , was isolated from the surface of a marine red alga collected from the coast in Weihai, Shandong Province, China. Strain ZY113 T was found to grow at 4-37 °C (optimum at 28-30 °C), with 1.0-7.0% (w/v) NaCl (optimum 2.0-3.0%) and at pH 6.0-9.0 (optimum 7.0-8.0). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain ZY113 T is a member of the genus Polaribacter, with Polaribacter dokdonensis KCTC 12392 T as a close relative (97.4% similarity). The sole respiratory quinone was found to be menaquinone 6 (MK-6) and the major fatty acids were identified as iso-C 15:0 , iso-C 15:0 3-OH and iso-C 13:0 . The polar lipids were found to consist of phosphatidylethanolamine, two unidentified aminolipids and three unidentified lipids. The G + C content of the genomic DNA was determined to be 30.1 mol%. On the basis of phenotypic, genotypic and phylogenetic analysis, strain ZY113 T is considered to represent a novel species of the genus Polaribacter, for which the name Polaribacter aquimarinus sp. nov. is proposed. The type strain is ZY113 T (= KCTC 62374 T  = MCCC 1H00296 T ).

Background: Low lean body mass is the most important predictor of sarcopenia with strong genetic background. The aim of this study was to uncover genetic factors underlying lean mass development., Materials and Methods: We performed a genome-wide association study (GWAS) of fat-adjusted leg lean mass in the Framingham Heart Study (FHS, N = 6587), and replicated in the Women's Health Initiative-African American sub-sample (WHI-AA, N = 847) and the Kansas City Osteoporosis Study (KCOS, N = 2219). We also cross-validated significant variants in the publicly available body mass index (BMI) summary results (N ~ 700,000). We then performed a series of functional investigations on the identified variants., Results: Four correlated SNPs at 6p21.1 were identified at the genome-wide significance (GWS, α = 5.0 × 10 -8 ) level in the discovery FHS sample (rs551145, rs524533, rs571770, and rs545970, p = 3.40-9.77 × 10 -9 ), and were successfully replicated in both the WHI-AA and the KCOS samples (one-sided p = 1.61 × 10 -3 -0.04). They were further cross-validated by the large-scale BMI summary results (p = 7.0-9.8 × 10 -3 ). Cis-eQTL analyses associated these SNPs with the NFKBIE gene expression. Electrophoresis mobility shift assay (EMSA) in mouse C2C12 myoblast cells implied that rs524533 and rs571770 were bound to an unknown transcription factor in an allelic specific manner, while rs551145 and rs545970 did not. Dual-luciferase reporter assay revealed that both rs524533 and rs571770 downregulated luciferase expression by repressing promoter activity. Moreover, the regulation pattern was allelic specific, strengthening the evidence towards their differential regulatory effects., Conclusions: Through a large-scale GWAS followed by a series of functional investigations, we identified 2 correlated functional variants at 6p21.1 associated with leg lean mass. Our findings not only enhanced our understanding of molecular basis of lean mass development but also provided useful candidate genes for further functional studies.

As an important trait at birth, infant head circumference (HC) is associated with a variety of intelligence- and mental-related conditions. Despite being dominated by genetics, the mechanism underlying the variation of HC is poorly understood. Aiming to uncover the genetic basis of HC, we performed a genome-wide joint association analysis by integrating the genome-wide association summary statistics of HC with that of its two related traits, birth length and birth weight, using a recently developed integrative method, multitrait analysis of genome-wide association (MTAG), and performed in silico replication in an independent sample of intracranial volume ( N = 26,577). We then conducted a series of bioinformatic investigations on the identified loci. Combining the evidence from both the MTAG analysis and the in silico replication, we identified three novel loci at the genome-wide significance level (α = 5.0 × 10 -8 ): 3q23 [lead single nucleotide polymorphism (SNP) rs9846396, p MTAG = 3.35 × 10 -8 , p replication = 0.01], 7p15.3 (rs12534093, p MTAG = 2.00 × 10 -8 , p replication = 0.004), and 9q33.3 (rs7048271 p MTAG = 9.23 × 10 -10 , p replication = 1.14 × 10 -4 ). Each of the three lead SNPs was associated with at least one of eight brain-related traits including intelligence and educational attainment. Credible risk variants, defined as those SNPs located within 500 kb of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in DNase I hypersensitive site region in brain. Nine candidate genes were prioritized at the three novel loci using multiple sources of information. Gene set enrichment analysis identified one associated pathway GO:0048009, which participates in the development of nervous system. Our findings provide useful insights into the genetic basis of HC and the relationship between brain growth and mental health., (Copyright © 2019 Yang, Zhang, Zhang, Wei, Feng, Pei and Zhang.)

The level of serum lipids is associated with bone mineral density (BMD), an important skeletal trait. Yet the causality has not been determined. Here we performed a Mendelian randomization (MR) analysis to test potential causal links between BMD and lipid profile, i.e., low-density lipoprotein cholesterol (LDC-c), total cholesterol (TC), triglyceride (TG) and high-density lipoprotein cholesterol (HDL-c). We observed causal effect of LDL-c, TC and TG to BMD, and reversely the effect of BMD to HDL-c. We further explored the effect of body mass index (BMI) in these causalities and found that the effect of LDL-c, TC and TG to BMD is independent of BMI. Our findings provided useful information in the clinical relevance of blood lipids on BMD variation and osteoporosis risk., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The prediction of clinical outcome for patients with infiltrative gliomas is challenging. Although preoperative hematological markers have been proposed as predictors of survival in glioma and other cancers, systematic investigations that combine these data with other relevant clinical variables are needed to improve prognostic accuracy and patient outcomes. We investigated the prognostic value of preoperative hematological markers, alone and in combination with molecular pathology, for the survival of 592 patients with Grade II-IV diffuse gliomas. On univariate analysis, increased neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), and decreased albumin-to-globulin ratio (AGR), all predicted poor prognosis in Grade II/III gliomas. Multivariate analysis incorporating tumor status based on the presence of IDH mutations, TERT promoter mutations, and 1p/19q codeletion showed that in lower-grade gliomas, high NLR predicted poorer survival for the triple-negative, IDH mutation only, TERT mutation only, and IDH and TERT mutation groups. NLR was an independent prognostic factor in Grade IV glioma. We therefore propose a prognostic model for diffuse gliomas based on the presence of IDH and TERT promoter mutations, 1p/19q codeletion, and NLR. This model classifies lower-grade gliomas into nine subgroups that can be combined into four main risk groups based on survival projections.

Aims: In this study, we examined the expression of lncRNA ENST00000413528 in glioma and determined its role in glioma development., Methods: LncRNA ENST00000413528 was detected in glioma tissues by lncRNA microarray. Then, we performed real-time PCR, CCK-8, colony formation assay, flow cytometry, caspase-3/7 assay and animal experiment to detect the function of ENST00000413528 in glioma after ENST00000413528 knockdown. Subsequent bioinformatics analysis, luciferase reporter assays and RNA immunoprecipitation (RIP) assay western blotting indicated possible downstream regulatory molecules. The expression of PLK1 in glioma tissues was also examined by immunohistochemistry staining., Results: Expression of ENST00000413528 was significantly increased in glioma tissues and LN229 and U251 cells. PLK1 protein could not be detected in peritumoral brain edema (PTBE) tissues; however, it showed an increasing number of positively cytoplasmic stained from WHO-Grade II to Grade III gliomas. Knockdown of ENST00000413528 in glioma cells inhibited cell proliferation and colony formation abilities, induced the G0/G1 arrest of the cell cycle, and promoted apoptosis. The dual reporter assay and RNA immunoprecipitation assay verified the interaction between ENST00000413528 and miR-593. We also demonstrated that polo-like kinase 1 (PLK1) was regulated by miR-593; PLK1 messenger RNA lacking 3'UTR partially reversed the effects caused by ENST00000413528 knockdown or miR-593 upregulation., Conclusion: lncRNA ENST00000413528 is closely related to the development of glioma via the miR-593-5p/PLK1 pathway., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Bone mineral density (BMD) at various skeletal sites have shared genetic determinants. In the present study, aiming to identify shared loci associated with BMD, we conducted a joint association study of a genomewide association study (GWAS) and a meta-analysis of BMD at different skeletal sites: (i) a single GWAS of heel BMD in 142,487 individuals from the UK Biobank, and (ii) a meta-analysis of 30 GWASs of total body (TB) BMD in 66,628 individuals from the Genetic Factors for Osteoporosis (GEFOS) Consortium. The genetic correlation coefficient of the two traits was estimated to be 0.57. We performed joint association analysis with a recently developed statistical method multi-trait analysis of GWAS (MTAG) to account for trait heterogeneity and sample overlap. The joint association analysis combining samples of up to 209,115 individuals identified 18 novel loci associated with BMD at the genomewide significance level (α = 5.0 × 10 -8 ), explaining an additional 0.43% and 0.60% of heel-BMD and TB-BMD heritability, respectively. The vast majority of the identified lead SNPs or their proxies exerted local expression quantitative trait loci (cis-eQTL) activity. Credible risk variants, defined as those SNPs located within 500 kilobases (kb) of the lead SNP and with p values within two orders of magnitude of the lead SNP, were enriched in transcription factor binding sites (p = 3.58 × 10 -4 ) and coding regions (p = 5.71 × 10 -4 ). Fifty-six candidate genes were prioritized at these novel loci using multiple sources of information, including several genes being previously reported to play a role in bone biology but not reported in previous GWASs (PPARG, FBN2, DEF6, TNFRSF19, and NFE2L1). One newly identified gene, SCMH1, was shown to upregulate the expression of several bone biomarkers, including alkaline phosphatase (ALP), collagen type 1 (COL-I), osteocalcin (OCN), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2), in mouse osteoblastic MC3T3-E1 cells, highlighting its regulatory role in bone formation. Our results may provide useful candidate genes for future functional investigations. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Aflatoxin B₁ (AFB₁) is a serious threat to the poultry industry. Proanthocyanidins (PCs) demonstrates a broad range of biological, pharmacological, therapeutic, and chemoprotective properties. The aim of this study was to investigate the ameliorative effects of PCs against AFB₁-induced histopathology, oxidative stress, and apoptosis via the mitochondrial pathway in the bursa of Fabricius (BF) of broilers. One hundred forty-four one-day old Cobb chicks were randomly assigned into four treatment groups of six replicates (6 birds each replicate) for 28 days. Groups were fed on the following four diets; (1) Basal diet without addition of PCs or AFB₁ (Control); (2) basal diet supplemented with 1 mg/kg AFB₁ from contaminated corn (AFB₁); (3) basal diet supplemented with 250 mg/kg PCs (PCs); and (4) basal diet supplemented with 1 mg/kg AFB₁ + 250 mg/kg PCs (AFB₁+ PCs). The present study results showed that antioxidant enzymes activities of total superoxide dismutase (T-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione S-transferase (GST) in AFB₁ treated group were ( p < 0.05) decreased, whereas malondialdehyde (MDA) contents were significantly increased in comparison with the control group. Furthermore, we found that dietary PCs treatment ameliorated AFB₁-induced oxidative stress in the BF through inhibiting the accumulation of MDA content and enhancing the antioxidant enzymes activities (T-SOD, CAT, GSH-Px, and GST). Similarly, PCs markedly enhanced messenger RNA (mRNA) expression of antioxidant genes ( SOD , CAT , GPx1 , and GST ) in comparison with AFB₁ group. Moreover, histological results showed that PCs alleviated AFB₁-induced apoptotic cells in the BF of broilers. In addition, both mRNA and protein expression results manifested that mitochondrial-apoptosis-associated genes ( Bax , caspase-9 , caspase-3 , and p53 and cytochrome c ) showed up-regulation, while ( Bcl-2 ) showed down-regulation in AFB₁ fed group. The supplementation of PCs to AFB₁ diet significantly reversed the mRNA and protein expression of these apoptosis-associated genes, as compared to the AFB₁ group. Our results demonstrated that PCs ameliorated AFB₁-induced oxidative stress by modulating the antioxidant defense system and apoptosis in the BF through mitochondrial pathway in broilers.

This cranio-morphometric study emphasizes a "two-layer model" for eastern Eurasian anatomically modern human (AMH) populations, based on large datasets of 89 population samples including findings directly from ancient archaeological contexts. Results suggest that an initial "first layer" of AMH had related closely to ancestral Andaman, Australian, Papuan, and Jomon groups who likely entered this region via the Southeast Asian landmass, prior to 65-50 kya. A later "second layer" shared strong cranial affinities with Siberians, implying a Northeast Asian source, evidenced by 9 kya in central China and then followed by expansions of descendant groups into Southeast Asia after 4 kya. These two populations shared limited initial exchange, and the second layer grew at a faster rate and in greater numbers, linked with contexts of farming that may have supported increased population densities. Clear dichotomization between the two layers implies a temporally deep divergence of distinct migration routes for AMH through both southern and northern Eurasia.

Background: The pathophysiology of early brain injury (EBI) after subarachnoid hemorrhage (SAH) is poorly understood. The present study evaluates the influence of zinc transporter 3 (ZnT3) knockout and the depletion of vesicular zinc on EBI., Methodology: SAH was induced in ZnT3 KO mice by internal carotid artery perforation. The changes in behavior were recorded at 24 hours after SAH. Hematoxylin-eosin, Nissl and TUNEL staining were performed to evaluate neuronal apoptosis. Data from mice with a score of 8-12 in intracerebral bleeding (i.e. moderate SAH), were analyzed., Results: The degree of SAH-induced neuronal injury was directly correlated to the amount of blood lost, which in turn was negatively reflected in their behavior. The Wild Type (WT)-SAH group behaved poorly when compared to the knockout (KO)-SAH mice and their poor neurological score was accompanied by an increase in the number of apoptotic neurons. Conversely, the improvement of behavior in the KO-SAH group was associated with a marked reduction in apoptotic neurons., Conclusions: These results suggest that ZnT3 knockout may have played a vital role in the attenuation of neuronal injury after SAH and that ZnT3 may prove to be a potential therapeutic target for neuroprotection in EBI.

Epidermal growth factor (EGF) and EGF receptor (EGFR) play prominent roles in the metastasis of glioblastoma (GBM). However, the molecular mechanisms for the function of EGF and EGFR in GBM metastasis have not been elucidated. Herein, we demonstrate that coactivation of EGF and EGFR drives tumor metastasis in a matrix metalloproteinase-9 (MMP-9)-dependent manner. Expression levels of EGF, EGFR, and MMP-9 were substantially upregulated in the GBM and edema zones of patients, compared with those of paired unaffected participants. Secretion of EGF and MMP-9 was reduced in the cerebrospinal fluid (CSF) after removing GBM for 2 weeks by operation. To the mechanism, MMP-9 was upregulated by activating EGF and EGFR via PI3K/AKT- and ERK1/2-dependent pathways. Moreover, signal transducer and activator of transcription (STAT) 3 and STAT5 mediated the activation of NF-κB by PI3K/AKT and ERK1/2 pathways. This resulted in transactivation of MMP-9 in GBM. Finally, MMP-9 induction facilitated abnormal proliferation, migration, and invasion of cells, which contributed to GBM metastasis., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial interests.

Perfect matching of an assembled physical sequence to a specified designed sequence is crucial to verify design principles in genome synthesis. We designed and de novo synthesized 536,024-base pair chromosome synV in the "Build-A-Genome China" course. We corrected an initial isolate of synV to perfectly match the designed sequence using integrative cotransformation and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated editing in 22 steps; synV strains exhibit high fitness under a variety of culture conditions, compared with that of wild-type V strains. A ring synV derivative was constructed, which is fully functional in Saccharomyces cerevisiae under all conditions tested and exhibits lower spore viability during meiosis. Ring synV chromosome can extends Sc2.0 design principles and provides a model with which to study genomic rearrangement, ring chromosome evolution, and human ring chromosome disorders., (Copyright © 2017, American Association for the Advancement of Science.)

AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.

Background: Mast cells in the gut play an important role in the innate and adaptive immune responses that are relevant to human inflammatory bowel disease. However, the contribution of mast cells to the development of inflammatory bowel disease is not well understood. This study aimed to determine the role of mast cells in oxazolone-induced colitis and to explore whether the mast cell membrane stabiliser tranilast could ameliorate colonic inflammation., Methods: Wild-type rats and mast cell-deficient rats were sensitised and challenged with oxazolone, then treated with tranilast after challenge. Controls were treated with saline., Results: Mast cell-deficient rats presented a weak response to oxazolone, while wild-type rats showed severe ulcerative colitis after stimulation with oxazolone. The mast cell-deficient rats model had a significantly lower disease activity index score than wild-type rats model (1.8±1.64 vs. 8.3±0.58 respectively; P<0.01). Tranilast could reduce the secretion of cytokines, immunoglobulins and myeloperoxidase activity in tranilast treatment groups compared with the model group. The number of mast cells in the wild-type model was higher than in the other groups. There was no significant change in mast cell-deficient rats., Conclusion: Mast cells play an important role in oxazolone-induced colitis. The mast cell membrane stabiliser tranilast can ameliorate oxazolone-induced colitis via a mast cell-dependent pathway., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

To identify the primary precursors of trihalomethanes and haloacetic acids in the Yuqiao Reservoir in China, dissolved organic matters in the source water were isolated and fractionated into five different fractions (with XAD resin), and both trihalomethane and haloacetic acid formation potentials in each fraction were analysed by liquid-liquid extraction and GC-ECD. The primary precursors of trihalomethanes and haloacetic acids were identified using the index of disinfection by-product formation potential and specific disinfection by-product formation potential. In addition, the relationship between the specific ultraviolet absorbance and the specific disinfection by-product formation potential was studied using correlation analysis. The results indicated that during the sampling period, the hydrophobic acids and hydrophilic matter are the primary organic fractions in the Yuqiao Reservoir, accounting for 27.6-40.9% and 21.2-32.5%, respectively. Among the five fractions, the hydrophobic acids had the highest disinfection by-product formation potential and specific disinfection by-product formation potential, indicating that the hydrophobic acids were the primary precursors of the disinfection by-products in the Yuqiao Reservoir. A correlation analysis indicates that the specific ultraviolet absorbance had a moderately positive correlation with the specific disinfection by-product formation potential; therefore, the specific ultraviolet absorbance can be a reference index to analyse the ability of organic matter to generate disinfection by-products.

Background: Malignant gliomas represent the most common primary brain tumors. The prognosis of patients with malignant gliomas is poor in spite of current intensive therapy and novel therapeutic modalities are needed. Here we report that norcantharidin is effective in growth inhibition of glioma cell lines in vitro., Methods: Glioma cell lines (U87 and C6) were treated with norcantharidin. The effects of norcantharidin on the proliferation and apoptosis of glioma cells were measured by 3-[4,5-dimethylthiazol-2-thiazolyl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and flow cytometry. Western blotting was employed to determine the signaling pathway changes., Results: The results showed that norcantharidin effectively inhibited cell growth and induced apoptosis in glioma cells, which was concurrent with inhibition of the expression of phospho-MEK and phospho-ERK. Furthermore, the expression anti-apoptotic proteins Bcl-2 and Mcl-1 significantly reduced, but no changes in Bcl-xL and Bax., Conclusions: Our findings demonstrate that norcantharidin is effective for growth inhibition of glioma cell lines and suggest that norcantharidin may be a new therapeutic option for patients with glioma.

NaYF4:Eu3+ core and NaYF4:Eu3+/NaYF4 core/shell nanocrystals (NCs) were synthesized via a wet chemical method. The transmission electron microscope photographs show that the core and core/shell nanoparticles are monodisperse and uniform NCs with average diameters of 22 and 26 nm respectively. The photoluminescence (PL) properties of the samples, including the PL excitation and emission spectra, and luminescent decay curves, are investigated in detail. The results show that the intensity of 5D2 emission relative to that of 5D0 is stronger in NaYF4:Eu3+/NaYF4 core/shell NCs than that in NaYF4:Eu3+ core NCs, and a longer decay lifetime of 5D2 is observed in core/shell samples. In addition, from the corrected emission spectra of 5D0, the 5D0 radiative lifetimes were calculated. These together with the measured decay lifetime of 5D0 emission give the intrinsic quantum yields of 5D0. The results were well interpreted by considering the surface effects.

Background: The c-Jun N-terminal kinase (JNK) proteins are encoded by three genes (JNK1, JNK2, and JNK3), giving rise to multiple isoforms via alternative splicing. JNK inhibition using a chemical inhibitor SP600125 confers neuroprotection in an animal model of subarachnoid hemorrhage (SAH). The aim of this study is to investigate whether the protective effects of SP600125 were associated with modulation of tight junction proteins including claudin-5 and ZO-1 and to define which JNK isoforms were involved in the early brain injury after SAH., Methods: Seventy-five male Sprague Dawley rats (weighing 300-350 g) were randomly assigned to five groups (n = 15): (1) sham, (2) SAH, (3) SAH + DMSO (dimethyl sulfoxide), (4) SAH + 10 mg/kg SP600125, and (5) SAH + 30 mg/kg SP600125. SP600125 or DMSO was injected intraperitoneally 1 h before and 6 h after the induction of SAH. Animals from all the groups were killed 24 h after SAH, and brain tissues were dissected and subjected to electron microscopic examination, Western blot analysis, and histological evaluation., Results: SP600125 pretreatment restored tight junctions and attenuated blood-brain barrier (BBB) disruption and cerebral edema after SAH, coupled with reduced apoptosis in the cerebral cortex. SP600125 exposure restored the reduced expression of both claudin-5 and ZO-1 following SAH and normalized the levels of JNK1 and JNK3., Conclusion: Our data demonstrate that the JNK signaling plays an important role in the regulation of tight junction proteins and BBB integrity, and thus represents a promising target against brain injuries after SAH.

Gd2Si2O7:Eu3+ nanoparticles were prepared by the sol-gel method with citric acid as an additive in the precursor solutions. The crystal structure was analyzed by means of X-ray diffraction (XRD). The results indicate that the alpha-Gd2Si2O7 powders in size 35 nm are obtained at a synthesis temperature of 1,100 degrees C, and the doping ion contents do not influence the crystal structure. The excitation and emission spectra of samples were measured. The dependence of photoluminescence intensity and lifetime of level on Eu3+ concentration and synthesis temperature of samples are also discussed.

In the title compound, {[Cu(C(6)H(5)N(2)O(2))(2)]·2H(2)O}(n), the Cu(II) ion (site symmetry ) is coordinated by two N,O-bidentate ligands and two N-monodentate ligands in a distorted CuO(2)N(4) octa-hedral geometry. Each anion acts as a bridge between two cations, thus forming a two-dimensional polymeric network parallel to the ab plane. The packing is consolidated by O-H⋯O hydrogen bonds. One of the O atoms of the ligand and both water mol-ecules are disordered.

In the cabbage butterfly, Pieris melete, summer and winter diapause are induced principally by long and short daylengths, respectively; the intermediate daylengths (12-13 h) permit pupae to develop without diapause. In this study, photoperiodic control of summer and winter diapause was systematically investigated in this butterfly by examining the photoperiodic response, the number of days required to induce 50% summer and winter diapause and the duration of diapausing pupae induced under different photoperiods. Photoperiodic response curves at 18 and 20 degrees C showed that all pupae entered winter diapause at short daylengths (8-11 h), the incidence of diapause dropped to 82.3-85.5% at 22 degrees C without showing a significant difference between short daylengths, whereas the incidence of summer diapause induced by different long daylengths (14-18 h) was varied and was obviously affected by temperature. By transferring from various short daylengths (LD 8:16, LD 9:15, LD 10:14 and LD 11:13) to an intermediate daylength (LD 12.5:11.5) at different times after hatching, the number of cycles required to induce 50% winter diapause (7.28 at LD 8:16, 7.16 at LD 9:15, 7.60 at LD 10:14 and 6.94 at LD 11:13) showed no significant difference, whereas by transferring from various long daylengths (LD 14:10, LD 15:9, LD 16:8 and LD 17:7) to an intermediate daylength (LD 12.5:11.5) at different times, the number of cycles required to induce 50% summer diapause (5.95 at LD 14:10, 8.02 at LD 15:9, 6.80 at LD 16:8, 7.64 at LD 17:7) were significantly different. The intensity of winter diapause induced under different short daylengths (LD 8:16, LD 9:15, LD 10:14 and LD 11:13) was not significantly different with an average diapause duration of 87 days at a constant temperature of 20 degrees C and 92 days at a mean daily temperature of 19.0 degrees C, whereas the intensity of summer diapause induced under different long daylengths (LD 14:10, LD 15:9, LD 16:8 and LD 17:7) was significantly different (the diapause duration ranged from 75 to 86 days at a constant temperature of 20 degrees C and from 76 to 88 days at a mean daily temperature of 19.0 degrees C). All results suggested that photoperiodic control of diapause induction and termination is significantly different between aestivation and hibernation.