A mutational analysis and molecular dynamics simulation of quinolone resistance proteins QnrA1 and QnrC from Proteus mirabilis

<p>Abstract</p> <p>Background</p> <p>The first report on the transferable, plasmid-mediated quinolone-resistance determinant <it>qnrA1 </it>was in 1998. Since then, <it>qnr </it>alleles have been discovered worldwide in clinical strains of Gram-negative bacilli. Qnr proteins confer quinolone resistance, and belong to the pentapeptide repeat protein (PRP) family. Several PRP crystal structures have been solved, but little is known about the functional significance of their structural arrangement.</p> <p>Results</p> <p>We conducted random and site-directed mutagenesis on <it>qnrA1 </it>and on <it>qnrC</it>, a newly identified quinolone-resistance gene from <it>Proteus mirabilis</it>. Many of the Qnr mutants lost their quinolone resistance function. The highly conserved hydrophobic Leu or Phe residues at the center of the pentapeptide repeats are known as <it>i </it>sites, and loss-of-function mutations included replacement of the <it>i </it>site hydrophobic residues with charged residues, replacing the <it>i</it>^-2site, N-terminal to the <it>i </it>residues, with bulky side-chain residues, introducing Pro into the β-helix coil, deletion of the N- and C-termini, and excision of a central coil. Molecular dynamics simulations and homology modeling demonstrated that QnrC overall adopts a stable β-helix fold and shares more similarities with MfpA than with other PRP structures. Based on homology modeling and molecular dynamics simulation, the dysfunctional point mutations introduced structural deformations into the quadrilateral β-helix structure of PRPs. Of the pentapeptides of QnrC, two-thirds adopted a type II β-turn, while the rest adopted type IV turns. A gap exists between coil 2 and coil 3 in the QnrC model structure, introducing a structural flexibility that is similar to that seen in MfpA.</p> <p>Conclusion</p> <p>The hydrophobic core and the β-helix backbone conformation are important for maintaining the quinolone resistance property of Qnr proteins. QnrC may share structural similarity with MfpA.</p

Association between exposure to noise and risk of hypertension: A meta-analysis of observational epidemiological studies

Background and Objective: An increasing amount of original studies suggested that exposure to noise could be associated with the risk of hypertension, but the results remain inconsistent and inconclusive. We aimed to synthesize available epidemiological evidence about the relationship between various types of noise and hypertension, and to explore the potential dose-response relationship between them in an up-to-date meta-analysis. Methods: We conducted a literature search of PubMed and Embase from these databases’ inception through December 2016 to identify observational epidemiological studies examining the association between noise and risk of hypertension. A Random-effects model was used to combine the results of included studies. Dose-response meta-analysis was conducted to examine the potential dose-response relationship. Results: Thirty-two studies (five cohort studies, one case-control study, and twenty-six cross-section Studies) involving 264,678 participants were eligible for inclusion. Pooled result showed that living or working in environment with noise exposure was significantly associated with increase risk of hypertension (OR 1.62; 95% CI: 1.40 to 1.88). We found no evidence of a curve linear association between noise and risk of hypertension. Dose-response analysis suggested that, for an increment of per 10 dB(A) of noise, the combined odds ratio of hypertension was 1.06 (95% CI: 1.04 to 1.08). Conclusions: Integrated epidemiological evidence supports the hypothesis that exposure to noise may be a risk factor of hypertension, and there is a positive dose-response association between them

Is carrot consumption associated with a decreased risk of lung cancer? A meta-analysis of observational studies

Findings of epidemiological studies regarding the association between carrot consumption and lung cancer risk remain inconsistent. The present study aimed to summarise the current epidemiological evidence concerning carrot intake and lung cancer risk with a meta-analysis. We conducted a meta-analysis of case–control and prospective cohort studies, and searched PubMed and Embase databases from their inception to April 2018 without restriction by language. We also reviewed reference lists from included articles. Prospective cohort or case–control studies reporting OR or relative risk with the corresponding 95 % CI of the risk lung cancer for the highest compared with the lowest category of carrot intake. A total of eighteen eligible studies (seventeen case–control studies and one prospective cohort study) were included, involving 202 969 individuals and 5517 patients with lung cancer. The pooled OR of eighteen studies for lung cancer was 0·58 (95%CI 0·45, 0·74) by comparing the highest category with the lowest category of carrot consumption. Based on subgroup analyses for the types of lung cancer, we pooled that squamous cell carcinoma (OR 0·52, 95 % CI 0·19, 1·45), small-cell carcinoma (OR 0·43, 95 % CI 0·12, 1·59), adenocarcinoma (OR 0·34, 95 % CI 0·15, 0·79), large-cell carcinoma (OR 0·40, 95 % CI 0·10, 1·57), squamous and small-cell carcinoma (OR 0·85, 95 % CI 0·45, 1·62), adenocarcinoma and large-cell carcinoma (OR 0·20, 95 % CI 0·02, 1·70) and mixed types (OR 0·61, 95 % CI 0·46, 0·81). Exclusion of any single study did not materially alter the pooled OR. Integrated epidemiological evidence from observational studies supported the hypothesis that carrot consumption may decrease the risk of lung cancer, especially for adenocarcinoma

Prevalence and Risk Factors for Dyslipidemia Among Adults in Rural and Urban China: Findings From the China National Stroke Screening and Prevention Project (CNSSPP)

Background: Dyslipidemia is a modifiable risk factor for cardiovascular disease (CVD). We investigated the prevalence and associated risk factors of dyslipidemia- raised total cholesterol (TC), raised triglycerides (TG), raised low-density lipoprotein (LDL-C), low high-density lipoprotein (HDL-C), and raised non-high-density lipoprotein (non-HDL-C) in rural and urban China. Methods: We analyzed data from 136,945 participants aged 40-100 years of the CNSSPP project for 2014. Dyslipidemia was defined by the NCEP-ATP III and the 2016 Chinese guidelines for the management of dyslipidemia in adults. Complete data on demographic, metabolic and lifestyle characteristics were used. Chi-square tests and multivariable logistic regression were used to obtain age- and sex-adjusted prevalence and risk factors for dyslipidemia among participants. Results: A total of 53.1% participants lived in rural areas. The prevalence of dyslipidemia was similar among rural and urban participants (43.2% vs. 43.3%). Regarding the components of dyslipidemia: urban compared with rural participants had a higher prevalence of low HDL-C (20.8% vs. 19.2%), whereas the prevalence of raised LDL-C (7.8% vs. 8.3%), raised TC (10.9% vs.11.8%) and raised non-HDL-C (10.0% vs. 10.9%) were lower in urban residents, (all p \u3c 0.001). Women were more likely to have raised TC than men (adjusted OR [AOR] =1.83, 95% confidence interval [CI]:1.75-1.91), raised LDL-C (AOR = 1.55, 95% CI: 1.47-1.63) and high non-HDL-C (AOR = 1.52 95% CI: 1.45-1.59) (all p \u3c 0.001). Compared with rural, urban participants had higher odds of dyslipidemia: low HDL-C (AOR = 1.04, 95% CI: 1.01-1.07), and raised TG (AOR = 1.06, 95% CI: 1.04-1.09). Hypertension and current drinker were less likely to get low HDL-C with AOR 0.93 (95% CI: 0.90-0.96) and AOR 0.73 (95% CI: 0.70-75), respectively. Overweight, obesity, central obesity and diabetes had higher odds of all dyslipidemias (p \u3c 0.001). Conclusions: Low HDL-C was higher in urban areas, whereas the remaining dyslipidemia types were more common in rural areas. Dyslipidemia was more common in women in both areas of residence. Overweight, obesity, central obesity and diabetes were associated with dyslipidemias. The need to intensify intervention programs to manage dyslipidemia and risk factors should be prioritized

Meta-analysis on the association between the frequency of tooth brushing and diabetes mellitus risk

BACKGROUND AND OBJECTIVE: Epidemiological studies suggested that the frequency of tooth brushing might be associated with the risk of diabetes mellitus (DM), but the results were inconsistent and no systematic review was conducted to focus on this topic. In this meta-analysis, we synthesized available observational epidemiological evidences to identify the association between tooth brushing and DM risk and investigate the potential dose-response relationship of them. METHODS: We searched PubMed and Embase from their inception through December 2017 to identify observational studies examining the association between tooth brushing and the risk of DM. Reference lists from retrieved articles were also reviewed. We quantitatively combined results of the included studies using a random-effects model. Dose-response meta-analysis was conducted to further examine the effect of tooth brushing frequency on DM risk. RESULTS: We identified 20 relevant studies (one cohort study, 14 case-control studies, and five cross-sectional studies) involving161,189 participants and 10,884 patients with DM. Compared with the highest tooth brushing frequency, the lowest level was significantly associated with an increased risk of DM (OR 1.32, 95% CI: 1.19 to 1.47), and there was no significant heterogeneity across the included studies (P = 0.119, I2 = 28.1%). Exclusion of any single study did not materially alter the combined risk estimate. The dose-response analysis indicated that the summary odds of DM for an increment of one time of tooth brushing per day was 1.20 (95% CI: 1.16-1.24). CONCLUSIONS: Integrated epidemiological evidence supports the hypothesis that low frequency of tooth brushing may be a risk factor of DM, and lower frequencies of tooth brushing were significantly associated with higher risk of DM

Developing RNN-T Models Surpassing High-Performance Hybrid Models with Customization Capability

Because of its streaming nature, recurrent neural network transducer (RNN-T) is a very promising end-to-end (E2E) model that may replace the popular hybrid model for automatic speech recognition. In this paper, we describe our recent development of RNN-T models with reduced GPU memory consumption during training, better initialization strategy, and advanced encoder modeling with future lookahead. When trained with Microsoft's 65 thousand hours of anonymized training data, the developed RNN-T model surpasses a very well trained hybrid model with both better recognition accuracy and lower latency. We further study how to customize RNN-T models to a new domain, which is important for deploying E2E models to practical scenarios. By comparing several methods leveraging text-only data in the new domain, we found that updating RNN-T's prediction and joint networks using text-to-speech generated from domain-specific text is the most effective.Comment: Accepted by Interspeech 202

Effects of HBsAg carriers on pregnancy complications in pregnant women: a retrospective cohort study

ObjectiveHepatitis B virus (HBV) infection is a major health threat worldwide, especially in developing countries. We aimed to investigate the impact of hepatitis B carrier on pregnancy complications in pregnant women, in China.MethodsThis retrospective cohort study was conducted by using data from the EHR system of Longhua District People’s Hospital in Shenzhen, China, from January 2018 to June 2022. Binary logistic regression was used to evaluate the relationship between HBsAg carrier status and pregnancy complications and pregnancy outcomes.ResultsThe study included 2095 HBsAg carriers (exposed group) and 23,019 normal pregnant women (unexposed group). Pregnant women in the exposed group were older than the pregnant women in the unexposed group (29 (27,32) vs. 29 (26,32), p &lt; 0.001). In addition, the incidence of some adverse pregnancy complications in the exposure group was lower than that in the unexposed group, including hypothyroidism of pregnancy (adjusted odds ratio [aOR], 0.779; 95% confidence interval [CI], 0.617–0.984; p = 0.036), hyperthyroidism of pregnancy (aOR, 0.388; 95% CI, 0.159–0.984; p = 0.038), pregnancy induced hypertension (aOR, 0.699; 95% CI, 0.551–0.887; p = 0.003), antepartum hemorrhage (aOR, 0.294; 95% CI, 0.093–0.929; p = 0.037). However, compared with the unexposed group, the exposed group had a higher risk of lower birth weight (aOR, 1.12; 95% CI, 1.02–1.23; p = 0.018) and intrahepatic cholestasis of pregnancy (aOR, 2.888, 95% CI, 2.207–3.780; p &lt; 0.001).ConclusionThe prevalence rate of HBsAg carriers in pregnant women in Longhua District of Shenzhen was 8.34%. Compared with normal pregnant women, HBsAg carriers have a higher risk of ICP, a lower risk of gestational hypothyroidism and PIH, and a lower birth weight of their infants