Ubiquitin-dependent proteasomal degradation of AMPK gamma subunit by Cereblon inhibits AMPK activity

Cereblon (CRBN), a substrate receptor for Cullin-ring E3 ubiquitin ligase (CRL), is a major target protein of immunomodulatory drugs. An earlier study demonstrated that CRBN directly interacts with the catalytic α subunit of AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis, down-regulating the enzymatic activity of AMPK. However, it is not clear how CRBN modulates AMPK activity. To investigate the mechanism of CRBN-dependent AMPK inhibition, we measured protein levels of each AMPK subunit in brains, livers, lungs, hearts, spleens, skeletal muscles, testes, kidneys, and embryonic fibroblasts from wild-type and Crbn^(−/−) mice. Protein levels and stability of the regulatory AMPKγ subunit were increased in Crbn^(−/−) mice. Increased stability of AMPKγ in Crbn^(−/−) MEFs was dramatically reduced by exogenous expression of Crbn. In wild-type MEFs, the proteasomal inhibitor MG132 blocked degradation of AMPKγ. We also found that CRL4^(CRBN) directly ubiquitinated AMPKγ. Taken together, these findings suggest that CRL4^(CRBN) regulates AMPK through ubiquitin-dependent proteasomal degradation of AMPKγ

Do depression, fatigue, and body esteem influence premenstrual symptoms in nursing students?

Purpose The purpose of this study was to investigate factors affecting premenstrual symptoms among nursing students, focusing on depression, fatigue, and body esteem. Methods The participants were 145 nursing students at a university located in Changwon, Korea. Data were collected from November 2 to November 30, 2019 using self-reported structured questionnaires, and analyzed using descriptive statistics, independent t-test, analysis of variance, Pearson correlation coefficients, and multiple regression analysis. Results The mean item score for premenstrual symptoms was 2.52±0.92, indicating a low level. The mean score for depression was 16.05±7.72, and 15.2% of participants were found to be moderately depressed and 9.7% severely depressed. The mean item score for fatigue was 4.84±0.84, indicating a moderate level, and body esteem was 2.94±0.44, indicating a moderate level. The premenstrual symptoms of nursing students showed a statistically significant correlation with depression (r=–.58, p<.001), fatigue (r=.33, p<.001), and body esteem (r=–.28, p<.001). Factors impacting premenstrual symptoms of nursing students were depression (β=.47, p<.001), dysmenorrhea (β=–.18, p=.009), menstrual cycle irregularity (β=.17, p=.013), and body esteem (β=–.14, p=.038). The total explanatory power of these variables was 41.0%. Conclusion Findings from this sample of nursing students suggest that intervention programs to relieve premenstrual symptoms should focus on depression, menstrual cycle regularity, dysmenorrhea, and body esteem

The effects of diagnostic hysteroscopy on the reproductive outcomes of infertile women without intrauterine pathologies: a systematic review and meta-analysis

Purpose Hysteroscopy can be used both to diagnose and to treat intrauterine pathologies. It is well known that hysteroscopy helps to improve reproductive outcomes by treating intrauterine pathologies. However, it is uncertain whether hysteroscopy is helpful in the absence of intrauterine pathologies. This study aimed to confirm whether hysteroscopy improves the reproductive outcomes of infertile women without intrauterine pathologies. Methods We conducted a systematic review of 11 studies retrieved from Ovid-MEDLINE, Ovid-Embase, and the Cochrane Library. Two independent investigators extracted the data and used risk-of-bias tools (RoB 2.0 and ROBINS-I) to assess their quality. Results Diagnostic hysteroscopy prior to in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) was associated with a higher clinical pregnancy rate (CPR) and live birth rate (LBR) than non-hysteroscopy in patients with recurrent implantation failure (RIF) (odds ratio, 1.79 and 1.46; 95% confidence interval, 1.40–2.30 and 1.08–1.97 for CPR and LBR, respectively) while hysteroscopy prior to first IVF was ineffective. The overall meta-analysis of LBR showed statistically significant findings for RIF, but a subgroup analysis showed effects only in prospective cohorts (odds ratio, 1.40 and 1.47; 95% confidence interval, 0.62–3.16 and 1.04–2.07 for randomized controlled trials and prospective cohorts, respectively). Therefore, the LBR should be interpreted carefully and further research is needed. Conclusion Although further research is warranted, hysteroscopy may be considered as a diagnostic and treatment option for infertile women who have experienced RIF regardless of intrauterine pathologies. This finding enables nurses to educate and support infertile women with RIF prior to IVF/ICSI

Antibiotic resistance mechanisms inform discovery: identification and characterization of a novel amycolatopsis strain producing ristocetin.

Discovering new antibiotics is a major scientific challenge, made increasingly urgent by the continued development of resistance in bacterial pathogens. A fundamental understanding of the mechanisms of bacterial antibiotic resistance will be vital for the future discovery or design of new, more effective antibiotics. We have exploited our intimate knowledge of the molecular mechanism of glycopeptide antibiotic resistance in the harmless bacterium Streptomyces coelicolor to develop a new two-step cell wall bioactivity screen, which efficiently identified a new actinomycete strain containing a previously uncharacterized glycopeptide biosynthetic gene cluster. The screen first identifies natural product extracts capable of triggering a generalized cell wall stress response and then specifically selects for glycopeptide antibacterials by assaying for the induction of glycopeptide resistance genes. In this study, we established a diverse natural product extract library from actinomycete strains isolated from locations with widely varying climates and ecologies, and we screened them using the novel two-step bioassay system. The bioassay ultimately identified a single strain harboring the previously unidentified biosynthetic gene cluster for the glycopeptide ristocetin, providing a proof of principle for the effectiveness of the screen. This is the first report of the ristocetin biosynthetic gene cluster, which is predicted to include some interesting and previously uncharacterized enzymes. By focusing on screening libraries of microbial extracts, this strategy provides the certainty that identified producer strains are competent for growth and biosynthesis of the detected glycopeptide under laboratory conditions.This work was supported by funding from the Royal Society, UK (516002.K5877/ROG), the Medical Research council, UK (G0700141) and St. John’s College, University of CambridgeThis the the author accepted manuscript. The final version is available from ASM at http://aac.asm.org/content/early/2014/07/09/AAC.03349-14.abstract

Glutathione S-transferase pi (GST-pi) inhibition and anti-inflammation activity of the ethyl acetate extract of Streptomyces sp. strain MJM 8637

AbstractTo investigate the anti-cancer properties of soil-borne actinobacteria, MJM 8637, the glutathione S-transferase pi (GST-pi) assay, anti-tumor necrosis factor (TNF)-α assay, the level of antioxidant potential by DPPH radical scavenging activity, NO scavenging activity, and ABTS radical scavenging activity in ethyl acetate extract were determined. The 16S rDNA sequencing analysis revealed that Streptomyces sp. strain MJM 8637, which was isolated from Hambak Mountain, Korea, has 99.5% similarity to Streptomyces atratus strain NBRC 3897. The physiological and the morphological characteristics of the strain MJM 8637 were also identified. The ethyl acetate extract of MJM 8637 inhibited TNF-α production approximately 61.8% at concentration 100μg/ml. The IC50 value of the strain MJM 8637 extract on GST-pi was identified to be 120.2±1.6μg/ml. In DPPH, NO, and ABTS radical scavenging assays, the IC50 values of the strain MJM 8637 extract were found to be 977.2μg/ml, 1143.7μg/ml, and 454.4μg/ml, respectively. The ethyl acetate extract of the strain MJM 8637 showed 97.2±1.3% of cell viability at 100μg/ml in RAW 264.7 cell viability assay. The results obtained from this study suggest that the ethyl acetate extract of Streptomyces sp. strain MJM 8637 could be considered as a potential source of drug for the cancers that have multidrug resistance with its GST-pi inhibition and anti-inflammation activities, and low cytotoxicity

Incorporating a real-time automatic alerting system based on electronic medical records could improve rapid response systems: a retrospective cohort study

Background Rapid response systems (RRSs) are essential components of patient safety systems; however, limited evidence exists regarding their effectiveness and optimal structures. We aimed to assess the activation patterns and outcomes of RRS implementation with/without a real-time automatic alerting system (AAS) based on electronic medical records (EMRs). Methods We retrospectively analyzed clinical data of patients for whom the RRS was activated in the surgical wards of a tertiary university hospital. We compared the code rate, in-hospital mortality, unplanned intensive care unit (ICU) admission, and other clinical outcomes before and after applying RRS and AAS as follows: pre-RRS (January 2013–July 2015), RRS without AAS (August 2015–November 2016), and RRS with AAS (December 2016–December 2017). Results In-hospital mortality per 1000 admissions decreased from 15.1 to 12.9 after RRS implementation (p < 0.001). RRS activation per 1000 admissions increased from 14.4 to 26.3 after AAS implementation. The severity of patients condition calculated using the modified early warning score increased from 2.5 (± 2.1) in the RRS without AAS to 3.6 (± 2.1) (p < 0.001) in the RRS with AAS. The total and preventable code rates and in-hospital mortality rates were comparable between the RRS implementation periods without/with AAS. ICU duration and mortality results improved in patients with RRS activation and unplanned ICU admission. The data of RRS non-activated group remained unaltered during the study. Conclusions Real-time AAS based on EMRs might help identify unstable patients. Early detection and intervention with RRS may improve patient outcomes.The author(s) received no fnancial support for the research, authorship, and/or publication of this article

Effects of low-dose topiramate on language function in children with migraine

PurposeThis study aimed to verify the safety of low-dose topiramate on language development in pediatric patients with migraine.MethodsThirty newly diagnosed pediatric patients with migraine who needed topiramate were enrolled and assessed twice with standard language tests, including the Test of Language Problem Solving Abilities (TOPs), Receptive and Expressive Vocabulary Test, Urimal Test of Articulation and Phonology, and computerized speech laboratory analysis. Data were collected before treatment, and topiramate as monotherapy was sustained for at least 3 months. The mean follow-up period was 4.3±2.7 months. The mean topiramate dosage was 0.9 mg/kg/day.ResultsThe patient's mean age was 144.1±42.3 months (male-to-female ratio, 9:21). The values of all the language parameters of the TOPs were not changed significantly after the topiramate treatment as follows: Determine cause, from 15.0±4.4 to 15.4±4.8 (P>0.05); making inference, from 17.6±5.6 to 17.5±6.6 (P>0.05); predicting, from 11.5±4.5 to 12.3±4.0 (P>0.05); and total TOPs score, from 44.1± 13.4 to 45.3±13.6 (P>0.05). The total mean length of utterance in words during the test decreased from 44.1±13.4 to 45.3±13.6 (P0.05). In the articulation and phonology validation in both groups, speech pitch and energy were not significant, and all the vowel test results showed no other significant values.ConclusionNo significant difference was found in the language-speaking ability between the patients; however, the number of vocabularies used decreased. Therefore, topiramate should be used cautiously for children with migraine