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We present a selection design that couples S-adenosylmethionine–dependent methylation to growth. We demonstrate its use in improving the enzyme activities of not only N-type and O-type methyltransferases by 2-fold but also an acetyltransferase of another enzyme category when linked to a methylation pathway in Escherichia coli using adaptive laboratory evolution. We also demonstrate its application for drug discovery using a catechol O-methyltransferase and its inhibitors entacapone and tolcapone. Implementation of this design in Saccharomyces cerevisiae is also demonstrated. [ABSTRACT FROM AUTHOR]

To determine the effect of mechanical stretching load and the efficacy of postmenopausal estrogen therapy (ET) on pelvic organ prolapse (POP), vaginal fibroblasts isolated from postmenopausal women with or without POP were subjected to 0.1-Hz uniaxial cyclic mechanical stretching (CS) with 10% elongation and 10−8 M 17-β-estradiol (E2) treatment. We investigated the morphological characteristics of extracellular polymers using scanning electron microscopy (SEM) and monitored the mRNA expression of type I collagen (COL I) and type III collagen (COL III) as well as the small leucine-rich proteoglycan (SLRP) family members decorin (DCN), biglycan (BGN), fibromodulin (FMO), and lumican (LUM), using real-time quantitative polymerase chain reaction (RT-PCR). Using SEM, certain viscoelastic polymers were found to be randomly distributed among fibroblasts, which for normal fibroblasts formed clusters of plum flower-like patterns under static-culture conditions and resembled stretched strips when stretched in culture, whereas polymers among POP fibroblasts resembled stretched strips under static-cultured conditions and presented broken networks when stretched in culture. RT-PCR revealed that COL I, DCN, BGN, FMO, and LUM mRNA expression was significantly higher in POP than in normal fibroblasts under static-culture condition. Following CS, COL I and BGN mRNA expression was significantly up-regulated in normal fibroblasts, and DCN and FMO mRNA expression was down-regulated in POP fibroblasts. Following concomitant CS and E2 treatment, significantly elevated COL I and DCN mRNA expression was observed in normal fibroblasts, and significantly elevated COL I and BGN mRNA expression was observed in POP fibroblasts. COL III mRNA expression was not significantly different between the POP and normal group, and CS did not significantly affect expression in either group, though COL III was down-regulated in normal fibroblasts concomitantly treated with E2 and CS. We conclude that the morphological distribution of extracellular polymers in POP fibroblasts exhibited higher sensitivity and lower tolerance to stretching loads than do normal fibroblasts. These mechanical properties were further reflected in the transcription of COL I. Defects in the compensatory function of BGN for DCN and LUM for FMO exist in POP fibroblasts, which further affect the structure and function of COL I in response to stretching load, ultimately resulting in abnormal reconstruction of pelvic supportive connective tissues and the occurrence of POP. ET can maintain stretching-induced elevations in COL I and DCN transcription in healthy women and improve stretching-induced COL I, DCN, BGN, and FMO transcriptional changes in POP women to prevent and improve POP. Only down-regulated COL III transcription was observed upon concomitant CS and E2 treatment in normal fibroblasts, which suggests that the tensile strength, not the elasticity, of the supportive connective tissues is damaged in POP and that the higher tensile strength induced by ET in healthy fibroblasts prevents POP. These findings confirm the role of higher sensitivity and lower tolerance to mechanical stretching in the pathogenesis of POP and further provide evidence supporting the use of ET to prevent and inhibit POP in postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: Recent studies have evaluated the associations between polymorphisms of the heat-shock protein 70 (HSP70) encoding genes and noise-induced hearing loss (NIHL). However, the conclusions of these studies are conflicting. The objective of this meta-analysis was to clarify the association between all known polymorphisms of HSP70 genetic loci and susceptibility to NIHL, based on existing reports. Methods: We conducted a meta-analysis of the association between Hsp70 polymorphisms (rs1043618, rs1061581, rs2075800, rs2227956, and rs2763979) and NIHL risk in both Chinese and Caucasian males. All statistical analysis was done with was conducted using the “meta” package (version 4.6–0) of R version 3.3.2 and RStudio version 1.0.44. Online databases were searched for eligible case-control studies on February 13, 2017. The odds ratio (OR), 95% confidence interval (CI), and P value were calculated using Mantel-Haenszel statistics under a random- or fixed-effect model. Results: A total of five studies, reported via four articles from online databases, were included in our meta-analysis. For rs1061581 (from three studies), a significant association was detected in the allele model, homozygote model, and dominant model (G versus A: OR (95% CI) = 1.32(1.05–1.67), GG versus AA: OR (95% CI) = 1.93(1.1–3.36), GG + AG versus AA: OR (95% CI) = 1.45(1.05–2.02)), but not in the heterozygote model or the recessive model. For rs1043618 (from five studies), rs2075800 (from two studies), rs2227956 (from four studies), rs2763979 (from two studies), no significant association was found for any genetic model. After subgroup analyses by ethnicity, significant associations were observed for the allele model, heterozygote model, and dominant model for rs1061581 and any genetic model for rs2227956 in Caucasians. Conclusions: The rs1043618, rs2075800, and rs2763979 polymorphisms were not found to be associated with susceptibility to NIHL; however, the rs1061581 and rs2227956 polymorphisms were significantly associated with NIHL in Caucasian males. [ABSTRACT FROM AUTHOR]

A spallation target is one of the three core parts of the accelerator driven subcritical system (ADS), which has already been investigated for decades. Recently, a gravity-driven Dense Granular-flow Target (DGT) is proposed, which consists of a cylindrical hopper and an internal coaxial cylindrical beam pipe. The research on the flow rate and free surface are important for the design of the target whether in Heavy Liquid Metal (HLM) targets or the DGT. In this paper, the relations of flow rate and the geometry of the DGT are investigated. Simulations based on the discrete element method (DEM) implementing on Graphics Processing Units (GPUs) and experiments are both performed. It is found that the existence of an internal pipe doesn’t influence the flow rate when the distance from the bottom of the pipe to orifice is large enough even in a larger system. Meanwhile, snapshots of the free surface formed just below the beam pipe are given. It is observed that the free surface is stable over time. The entire research is meaningful for the design of DGT. [ABSTRACT FROM AUTHOR]

Objective: Accumulated data suggests that cerebral microbleeds (CMBs) play an important role in the decline of cognitive function, but the results remain inconsistent. In the current study, we aimed to investigate the association between CMBs and cognitive function, as well as the various effects of CMBs on different domains of cognition. Methods: We searched through the databases of PubMed, Embase, Cochrane Library, and ScienceDirect. After a consistency test, the publication bias was evaluated and a sensitivity analysis was performed with combined odds ratios (OR) and standardized mean difference (SMD) of CMBs. Results: A meta-analysis of 25 studies with 9343 participants total was conducted. Patients with CMBs had higher incidence of cognitive impairment (OR:3.5410; 95% confidence interval [CI] [2.2979, 5.4567], p<0.05) and lower scores of cognitive functions (SMD: -0.2700 [-0.4267, -0.1133], p<0.05 in Mini-Mental State Examination [MMSE] group and -0.4869 [-0.8902, -0.0818], p<0.05 in Montreal Cognitive Assessment [MoCA] group). Our results also indicated that patients with CMBs had obvious decline in cognitive functions, for instance, orientation (SMD: -0.9565 [-1.7260, -0.1869], p<0.05), attention and calculation (SMD: -1.1518 [-1.9553, -0.3484], p<0.05) and delayed recall (SMD: -0.5527 [-1.1043, -0.0011], p = 0.05). Conclusions: Our data suggested that CMBs might be an important risk factor for cognitive dysfunction, especially in the domains of orientation, attention and calculation and delayed recall functions. Prospective cohort studies with further investigations will be needed in larger samples. [ABSTRACT FROM AUTHOR]

Background and objective: Several studies have been conducted to examine the association between aldehyde dehydrogenase 2 family (ALDH2) rs671 polymorphism and essential hypertension (EH). However, the results remain inconsistent. This study aimed to clarify the association between ALDH2 rs671 polymorphism and EH susceptibility. Methods: One thousand and ninety-four cases and 1236 controls who were ethnic Han Chinese were collected for this population-based case-control study. A meta-analysis was performed to calculate the pooled odds ratio and 95% confidence interval, using allele contrast, dominant, recessive, and co-dominant models using fixed or random-effect models. Results: Significant differences were observed between EH cases and controls at the level of both genotype (χ2 = 6.656, P<0.05) and alleles (χ2 = 6.314, P<0.05). An additional meta-analysis using 4204 cases and 5435 controls established that rs671 was significantly associated with EH (P<0.00001). Conclusion: The results of our case-control study and meta-analysis showed that there is a significant association between ALDH2 rs671 polymorphism and EH susceptibility. In addition, the results of the breakdown analysis by gender suggest a male-specific association between the ALDH2 rs671 polymorphism and EH. [ABSTRACT FROM AUTHOR]

Background: Lenalidomide could effectively induce red blood cell (RBC) transfusion independence (TI) in patients with lower-risk (Low/Intermediate-1) myelodysplastic syndrome (MDS) with or without 5q deletion. However whether lenalidomide ultimately improves the overall survival (OS) of lower-risk MDS patients and reduces the progression to AML remains controversial. Method: A meta-analysis was conducted to examine the efficacy and safety of lenalidomide in the treatment of lower-risk MDS. Efficacy was assessed according to erythroid hematologic response (HI-E), cytogenetic response (CyR), OS and AML progression. Safety was evaluated based on the occurrence rates of grades 3–4 adverse events (AEs). Results: Seventeen studies were included consisting of a total of 2160 patients. The analysis indicated that the overall rate of HI-E was 58% with 95% confidence interval (CI) of 43–74%. The pooled estimates for the rates of CyR, complete CyR, and partial CyR were 44% (95% CI 19–68%), 21% (95% CI 13–30%) and 23% (95% CI 15–32%), respectively. The patients with 5q deletion had significantly higher rate of HI-E and CyR than those without 5q deletion (P = 0.002 and 0.001, respectively). The incidences of grades 3–4 neutropenia, thrombocytopenia, leukopenia, anemia, deep vein thrombosis, diarrhea, fatigue and rash were 51% (95% CI 30–73%), 31% (95% CI 20–42%), 9% (95% CI 5–13%), 7% (95% CI 2–12%), 3% (95% CI 2–5%), 3% (95% CI 1–5%), 2% (95% CI 1–4%) and 2% (95% CI 1–3%), respectively. Lenalidomide significantly improved OS (HR: 0.62, 95% CI 0.47–0.83, P = 0.001) and lowered the risk of AML progression in del(5q) patients (RR: 0.61, 95% CI 0.41–0.91, P = 0.014). Conclusions: In spite of the AEs, lenalidomide could be effectively and safely used for the treatment of lower-risk MDS patients with or without 5q deletion. [ABSTRACT FROM AUTHOR]

Background: The ability to perform a cognitive task while walking simultaneously (dual-tasking) is important in real life. However, the psychometric properties of dual-task walking tests have not been well established in stroke. Objective: To assess the test-retest reliability, concurrent and known-groups validity of various dual-task walking tests in people with chronic stroke. Design: Observational measurement study with a test-retest design. Methods: Eighty-eight individuals with chronic stroke participated. The testing protocol involved four walking tasks (walking forward at self-selected and maximal speed, walking backward at self-selected speed, and crossing over obstacles) performed simultaneously with each of the three attention-demanding tasks (verbal fluency, serial 3 subtractions or carrying a cup of water). For each dual-task condition, the time taken to complete the walking task, the correct response rate (CRR) of the cognitive task, and the dual-task effect (DTE) for the walking time and CRR were calculated. Forty-six of the participants were tested twice within 3–4 days to establish test-retest reliability. Results: The walking time in various dual-task assessments demonstrated good to excellent reliability [Intraclass correlation coefficient (ICC2,1) = 0.70–0.93; relative minimal detectable change at 95% confidence level (MDC95%) = 29%-45%]. The reliability of the CRR (ICC2,1 = 0.58–0.81) and the DTE in walking time (ICC2,1 = 0.11–0.80) was more varied. The reliability of the DTE in CRR (ICC2,1 = -0.31–0.40) was poor to fair. The walking time and CRR obtained in various dual-task walking tests were moderately to strongly correlated with those of the dual-task Timed-up-and-Go test, thus demonstrating good concurrent validity. None of the tests could discriminate fallers (those who had sustained at least one fall in the past year) from non-fallers. Limitation: The results are generalizable to community-dwelling individuals with chronic stroke only. Conclusions: The walking time derived from the various dual-task assessments generally demonstrated good to excellent reliability, making them potentially useful in clinical practice and future research endeavors. However, the usefulness of these measurements in predicting falls needs to be further explored. Relatively low reliability was shown in the cognitive outcomes and DTE, which may not be preferred measurements for assessing dual-task performance. [ABSTRACT FROM AUTHOR]