Insights into biofilm dispersal regulation from the crystal structure of the PAS-GGDEF-EAL region of RbdA from Pseudomonas aeruginosa

© 2018 American Society for Microbiology. RbdA is a positive regulator of biofilm dispersal of Pseudomonas aeruginosa. Its cytoplasmic region (cRbdA) comprises an N-terminal Per-ARNT-Sim (PAS) domain followed by a diguanylate cyclase (GGDEF) domain and an EAL domain, whose phosphodiesterase activity is allosterically stimulated by GTP binding to the GGDEF domain. We report crystal structures of cRbdA and of two binary complexes: one with GTP/Mg 2+ bound to the GGDEF active site and one with the EAL domain bound to the c-di-GMP substrate. These structures unveil a 2-fold symmetric dimer stabilized by a closely packed N-terminal PAS domain and a noncanonical EAL dimer. The autoinhibitory switch is formed by an α-helix (S-helix) immediately N-terminal to the GGDEF domain that interacts with the EAL dimerization helix (α6-E) of the other EAL monomer and maintains the protein in a locked conformation. We propose that local conformational changes in cRbdA upon GTP binding lead to a structure with the PAS domain and S-helix shifted away from the GGDEF-EAL domains, as suggested by small-angle X-ray scattering (SAXS) experiments. Domain reorientation should be facilitated by the presence of an α-helical lever (H-helix) that tethers the GGDEF and EAL regions, allowing the EAL domain to rearrange into an active dimeric conformation

Birth Weight and the Risk of Cardiovascular Outcomes: A Report From the Large Population-Based UK Biobank Cohort Study

BackgroundBirth weight has been reported to be associated with the risk of incident cardiovascular disease (CVD); however, the relationship remains inconclusive. Here, we aimed to prospectively assess the associations between birth weight and CVD risk using the data from UK Biobank, a large-scale, prospective cohort study.MethodsWe included 270,297 participants who were free of CVD at baseline and reported their birth weight for analyses. The primary outcome was incident CVD. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were calculated using Cox proportional hazards models adjusted for potential confounding variables.ResultsDuring a median follow-up of 8.07 years (IQR: 7.4-8.7 years), 10,719 incident CVD events were recorded. The HRs for low birth weight vs. normal birth weight (2.5-4.0 kg) were 1.23 (95% CI: 1.09-1.38) for risk of incident CVD, 1.52 (95% CI: 1.18-1.95) for stroke, 1.33 (95% CI: 1.07-1.64) for myocardial infarction, and 1.15 (95% CI: 1.01-1.32) for CHD. For the ones with low birth weight, the risk of CVD is reduced by 11% for every kilogram of birth weight gain. The association of low birth weight with CVD was stronger among those younger than 55 years (p = 0.001). No association between high birth weight and risk of cardiovascular outcomes was found.ConclusionLow birth weight was associated with an increased risk of cardiovascular events. These findings highlight the longstanding consequence of low birth weight on cardiovascular system

Spectrum of Oncogenic Driver Mutations in Lung Adenocarcinomas from East Asian Never Smokers

PURPOSE:We previously showed that 90% (47 of 52; 95% CI, 0.79 to 0.96) of lung adenocarcinomas from East Asian never-smokers harbored well-known oncogenic mutations in just four genes: EGFR, HER2, ALK, and KRAS. Here, we sought to extend these findings to more samples and identify driver alterations in tumors negative for these mutations. EXPERIMENTAL DESIGN:We have collected and analyzed 202 resected lung adenocarcinomas from never smokers seen at Fudan University Shanghai Cancer Center. Since mutations were mutually exclusive in the first 52 examined, we determined the status of EGFR, KRAS, HER2, ALK, and BRAF in stepwise fashion as previously described. Samples negative for mutations in these 5 genes were subsequently examined for known ROS1 fusions by RT-PCR and direct sequencing. RESULTS:152 tumors (75.3%) harbored EGFR mutations, 12 (6%) had HER2 mutations, 10 (5%) had ALK fusions all involving EML4 as the 5' partner, 4 (2%) had KRAS mutations, and 2 (1%) harbored ROS1 fusions. No BRAF mutation were detected. CONCLUSION:The vast majority (176 of 202; 87.1%, 95% CI: 0.82 to 0.91) of lung adenocarcinomas from never smokers harbor mutant kinases sensitive to available TKIs. Interestingly, patients with EGFR mutant patients tend to be older than those without EGFR mutations (58.3 Vs 54.3, P = 0.016) and patient without any known oncogenic driver tend to be diagnosed at a younger age (52.3 Vs 57.9, P = 0.013). Collectively, these data indicate that the majority of never smokers with lung adenocarcinoma could benefit from treatment with a specific tyrosine kinase inhibitor

Artificial intelligence for dementia prevention

INTRODUCTION: A wide range of modifiable risk factors for dementia have been identified. Considerable debate remains about these risk factors, possible interactions between them or with genetic risk, and causality, and how they can help in clinical trial recruitment and drug development. Artificial intelligence (AI) and machine learning (ML) may refine understanding.// METHODS: ML approaches are being developed in dementia prevention. We discuss exemplar uses and evaluate the current applications and limitations in the dementia prevention field.// RESULTS: Risk-profiling tools may help identify high-risk populations for clinical trials; however, their performance needs improvement. New risk-profiling and trial-recruitment tools underpinned by ML models may be effective in reducing costs and improving future trials. ML can inform drug-repurposing efforts and prioritization of disease-modifying therapeutics.// DISCUSSION: ML is not yet widely used but has considerable potential to enhance precision in dementia prevention

Controllable Synthesis of Single-Crystalline CdO and Cd(OH)2Nanowires by a Simple Hydrothermal Approach

Single-crystalline Cd(OH)2 or CdO nanowires can be selectively synthesized at 150 °C by a simple hydrothermal method using aqueous Cd(NO3)2 as precursor. The method is biosafe, and compared to the conventional oil-water surfactant approach, more environmental-benign. As revealed by the XRD results, CdO or Cd(OH)2 nanowires can be generated in high purity by varying the time of synthesis. The results of FESEM and HRTEM analysis show that the CdO nanowires are formed in bundles. Over the CdO-nanowire bundles, photoluminescence at ~517 nm attributable to near band-edge emission of CdO was recorded. Based on the experimental results, a possible growth mechanism of the products is proposed

Transcription Profile Analysis Reveals That Zygotic Division Results in Uneven Distribution of Specific Transcripts in Apical/Basal Cells of Tobacco

BACKGROUND: Asymmetric zygotic division in higher plants results in the formation of an apical cell and a basal cell. These two embryonic cells possess distinct morphologies and cell developmental fates. It has been proposed that unevenly distributed cell fate determinants and/or distinct cell transcript profiles may be the underlying reason for their distinct fates. However, neither of these hypotheses has convincing support due to technical limitations. METHODOLOGY/PRINCIPAL FINDINGS: Using laser-controlled microdissection, we isolated apical and basal cells and constructed cell type-specific cDNA libraries. Transcript profile analysis revealed difference in transcript composition. PCR and qPCR analysis confirmed that transcripts of selected embryogenesis-related genes were cell-type preferentially distributed. Some of the transcripts that existed in zygotes were found distinctly existed in apical or basal cells. The cell type specific de novo transcription was also found after zygotic cell division. CONCLUSIONS/SIGNIFICANCE: Thus, we found that the transcript diversity occurs between apical and basal cells. Asymmetric zygotic division results in the uneven distribution of some embryogenesis related transcripts in the two-celled proembryos, suggesting that a differential distribution of some specific transcripts in the apical or basal cells may involve in guiding the two cell types to different developmental destinies

Ontogeny-Driven rDNA Rearrangement, Methylation, and Transcription, and Paternal Influence

Gene rearrangement occurs during development in some cell types and this genome dynamics is modulated by intrinsic and extrinsic factors, including growth stimulants and nutrients. This raises a possibility that such structural change in the genome and its subsequent epigenetic modifications may also take place during mammalian ontogeny, a process undergoing finely orchestrated cell division and differentiation. We tested this hypothesis by comparing single nucleotide polymorphism-defined haplotype frequencies and DNA methylation of the rDNA multicopy gene between two mouse ontogenic stages and among three adult tissues of individual mice. Possible influences to the genetic and epigenetic dynamics by paternal exposures were also examined for Cr(III) and acid saline extrinsic factors. Variables derived from litters, individuals, and duplicate assays in large mouse populations were examined using linear mixed-effects model. We report here that active rDNA rearrangement, represented by changes of haplotype frequencies, arises during ontogenic progression from day 8 embryos to 6-week adult mice as well as in different tissue lineages and is modifiable by paternal exposures. The rDNA methylation levels were also altered in concordance with this ontogenic progression and were associated with rDNA haplotypes. Sperm showed highest level of methylation, followed by lungs and livers, and preferentially selected haplotypes that are positively associated with methylation. Livers, maintaining lower levels of rDNA methylation compared with lungs, expressed more rRNA transcript. In vitro transcription demonstrated haplotype-dependent rRNA expression. Thus, the genome is also dynamic during mammalian ontogeny and its rearrangement may trigger epigenetic changes and subsequent transcriptional controls, that are further influenced by paternal exposures

Asymptomatic Atrial Fibrillation among Hospitalized Patients:clinical correlates and in-hospital outcomes in Improving Care for Cardiovascular Disease in China-Atrial Fibrillation

AIMS: The clinical correlates and outcomes of asymptomatic atrial fibrillation (AF) in hospitalized patients are largely unknown. We aimed to investigate the clinical correlates and in-hospital outcomes of asymptomatic AF in hospitalized Chinese patients.METHODS AND RESULTS: We conducted a cross-sectional registry study of inpatients with AF enrolled in the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation Project between February 2015 and December 2019. We investigated the clinical characteristics of asymptomatic AF and the association between the clinical correlates and the in-hospital outcomes of asymptomatic AF. Asymptomatic and symptomatic AF were defined according to the European Heart Rhythm Association score. Asymptomatic patients were more commonly males (56.3%) and had more comorbidities such as hypertension (57.4%), diabetes mellitus (18.6%), peripheral artery disease (PAD; 2.3%), coronary artery disease (55.5%), previous history of stroke/transient ischaemic attack (TIA; 17.9%), and myocardial infarction (MI; 5.4%); however, they had less prevalent heart failure (9.6%) or left ventricular ejection fractions ≤40% (7.3%). Asymptomatic patients were more often hospitalized with a non-AF diagnosis as the main diagnosis and were more commonly first diagnosed with AF (23.9%) and long-standing persistent/permanent AF (17.0%). The independent determinants of asymptomatic presentation were male sex, long-standing persistent AF/permanent AF, previous history of stroke/TIA, MI, PAD, and previous treatment with anti-platelet drugs. The incidence of in-hospital clinical events such as all-cause death, ischaemic stroke/TIA, and acute coronary syndrome (ACS) was higher in asymptomatic patients than in symptomatic patients, and asymptomatic clinical status was an independent risk factor for in-hospital all-cause death, ischaemic stroke/TIA, and ACS.CONCLUSION: Asymptomatic AF is common among hospitalized patients with AF. Asymptomatic clinical status is associated with male sex, comorbidities, and a higher risk of in-hospital outcomes. The adoption of effective management strategies for patients with AF should not be solely based on clinical symptoms.</p