Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy

The histone demethylase lysine-specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitin and stability. Interestingly, we found c-Myc was a key downstream effector of the USP1-KDM4A/androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC

Screening of traditional Chinese medicines with therapeutic potential on chronic obstructive pulmonary disease through inhibiting oxidative stress and inflammatory response

NADP(H): quinone oxidoreductase (QR) inducing effects of 38 bioactive TCM extracts in hepa 1c1c7 cells. The QR inducing effect was determined after 24h treatment of the hepa 1c1c7 cells in the presence or absence of tested TCMs. The data of the untreated control group was normalized as 1, and then the QR inducing activity of tested extracts was represented by the maximum folds of QR inducing activity (MQI) compared with the untreated control group. Sulforaphane (SF, 2.0 μM) was used as a positive control. The data are reported the means ± SD from three independent experiments. Figure S2. Inhibitory effects on NO production of 55 bioactive TCM extracts in RAW 264.7 cells. The NO concentration in the RAW 264.7 cell culture media was determined through the Griess reaction 24 h after treated in the presence or absence of tested TCMs and lipopolysaccharides (LPS, 1.0 μg/mL). Didox (100 μM) was adopted as a positive control. The data are reported the means ± SD from three independent experiments. The maximum inhibition rates (MIRs) of NO production under the untoxic tested concentration were calculated by comparing the decreased NO concentration in TCM-treated group with that in LPS-stimulated group. Table S1. TCM extracts with QR inducing activity and/or NO inhibitory effect. (DOCX 4312 kb

荆州区农村人口初发糖尿病胰岛功能的现状跟踪调查*

Objective: To study the change of islet function in patients with incipient diabetic characteristics through incipient diabetic tracking observation of the islet function in patients of Jingzhou area. Methods: Selection of 1220 cases of patients with diabetes mellitus in Jingzhou area as research object at the beginning, 12 months follow-up, the clinic after 3 months, 6 months and 12 months, all patients to detect blood sugar change, c-peptide release quantity, calculate insulin secretion index (HOMA -β) and insulin resistance index (HOMA IR), summarizes the characteristic of islet function in patients with changes. Results: ① The patients restored to basic standard blood sugar in 3 months by drug treatment, and the patient's blood glucose levels not seen obvious fluctuation after 6 months and 12 months; ② During follow-up, patients with diabetes sustained c-peptide release quantity reduction, and in three months after treatment, c-peptide release decreased obviously, and see a doctor at 6 months and 12 months after the comparison, the difference was statistically significant (P < 0.05). ③ During follow-up, insulin capacity was decreasing among patients with diabetes, within three months after the doctor had the greatest reduction, the difference was statistically significant (P < 0.05); ④ During follow-up, island hormone decreasing index, insulin resistance index continued to rise among patients with diabetes, and 6 months and 12 months, the most significant variations in 3 months (P < 0.05). Conclusion: With the extension of course, the pancreatic islet function in patients with early onset diabetes decreased gradually. It could be proved that there is a significant correlation between the two and especially seen in obvious function decline of pancreatic islets among the patients within 3 months.目的  通过对荆州区初发糖尿病患者的胰岛功能进行跟踪观察，探讨发现初发糖尿病患者胰岛功能的变化特点。方法  选取荆州区1220例初发糖尿病患者作为观察对象，跟踪随访12个月，在就诊后的3个月、6个月及12个月时，全部患者检测血糖变化、Ｃ-肽释放量，计算胰岛素分泌指数（HOMA-β）及胰岛素抵抗指数（HOMA-IR），观察总结患者的胰岛功能变化特点。结果  （1）通过药物治疗，患者血糖在3个月时基本达标，6个月及12个月时，患者的血糖水平未见明显波动；（2）随访期间，糖尿病患者Ｃ-肽释放量持续降低，且在就诊后3个月内，Ｃ-肽释放量下降明显，与就诊后6个月时及12个月时比较，差异有统计学意义（P＜0.05）。（3）随访期间，糖尿病患者胰岛素放量持续降低，就诊后3个月内下降最明显，差异有统计学意义（P＜0.05）；（4）随访期间，糖尿病患者胰岛素分泌指数持续降低，胰岛素抵抗指数持续升高，且与6个月时和12个月时比较，3个月时变化幅度最为显著（P＜0.05）。结论  随着病程的延长，初发糖尿病患者胰岛功能逐渐降低，二者具有显著相关性，且3个月内患者的胰岛功能下降最为显著

A simulation study on the measurement of D0-D0bar mixing parameter y at BES-III

We established a method on measuring the \dzdzb mixing parameter $y$ for BESIII experiment at the BEPCII $e^+e^-$ collider. In this method, the doubly tagged $\psi(3770) \to D^0 \overline{D^0}$ events, with one $D$ decays to CP-eigenstates and the other $D$ decays semileptonically, are used to reconstruct the signals. Since this analysis requires good $e/\pi$ separation, a likelihood approach, which combines the $dE/dx$, time of flight and the electromagnetic shower detectors information, is used for particle identification. We estimate the sensitivity of the measurement of $y$ to be 0.007 based on a $20fb^{-1}$ fully simulated MC sample.Comment: 6 pages, 7 figure

Coinfection with influenza virus and non-typeable Haemophilus influenzae aggregates inflammatory lung injury and alters gut microbiota in COPD mice

BackgroundAcute exacerbation of chronic obstructive pulmonary disease (AECOPD) is associated with high mortality rates. Viral and bacterial coinfection is the primary cause of AECOPD. How coinfection with these microbes influences host inflammatory response and the gut microbiota composition is not entirely understood.MethodsWe developed a mouse model of AECOPD by cigarette smoke exposure and sequential infection with influenza H1N1 virus and non-typeable Haemophilus influenzae (NTHi). Viral and bacterial titer was determined using MDCK cells and chocolate agar plates, respectively. The levels of cytokines, adhesion molecules, and inflammatory cells in the lungs were measured using Bio-Plex and flow cytometry assays. Gut microbiota was analyzed using 16S rRNA gene sequencing. Correlations between cytokines and gut microbiota were determined using Spearman’s rank correlation coefficient test.ResultsCoinfection with H1N1 and NTHi resulted in more severe lung injury, higher mortality, declined lung function in COPD mice. H1N1 enhanced NTHi growth in the lungs, but NTHi had no effect on H1N1. In addition, coinfection increased the levels of cytokines and adhesion molecules, as well as immune cells including total and M1 macrophages, neutrophils, monocytes, NK cells, and CD4 + T cells. In contrast, alveolar macrophages were depleted. Furthermore, coinfection caused a decline in the diversity of gut bacteria. Muribaculaceae, Lactobacillus, Akkermansia, Lachnospiraceae, and Rikenella were further found to be negatively correlated with cytokine levels, whereas Bacteroides was positively correlated.ConclusionCoinfection with H1N1 and NTHi causes a deterioration in COPD mice due to increased lung inflammation, which is correlated with dysbiosis of the gut microbiota

A new vesicle trafficking regulator CTL1 plays a crucial role in ion homeostasis

Ion homeostasis is essential for plant growth and environmental adaptation, and maintaining ion homeostasis requires the precise regulation of various ion transporters, as well as correct root patterning. However, the mechanisms underlying these processes remain largely elusive. Here, we reported that a choline transporter gene, CTL1, controls ionome homeostasis by regulating the secretory trafficking of proteins required for plasmodesmata (PD) development, as well as the transport of some ion transporters. Map-based cloning studies revealed that CTL1 mutations alter the ion profile of Arabidopsis thaliana. We found that the phenotypes associated with these mutations are caused by a combination of PD defects and ion transporter misregulation. We also established that CTL1 is involved in regulating vesicle trafficking and is thus required for the trafficking of proteins essential for ion transport and PD development. Characterizing choline transporter-like 1 (CTL1) as a new regulator of protein sorting may enable researchers to understand not only ion homeostasis in plants but also vesicle trafficking in general

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London