Engineering Crystal Packing in RNA-Protein Complexes II: A Historical Perspective from the Structural Studies of the Spliceosome

Cryo-electron microscopy has greatly advanced our understanding of how the spliceosome cycles through different conformational states to conduct the chemical reactions that remove introns from pre-mRNA transcripts. The Cryo-EM structures were built upon decades of crystallographic studies of various spliceosomal RNA-protein complexes. In this review we give an overview of the crystal structures solved in the Nagai group, utilizing many of the strategies to design crystal packing as described in the accompanying paper

Short- and Long-Term Results of Open Versus Laparoscopic Appendectomy

Clinical advantages of laparoscopic appendectomy have been shown in numerous trials and reviews. Most of these advantages are small and of limited clinical relevance, while laparoscopic operation costs are reported to be higher. The present study compares short- and long-term results of conventional appendectomy with or without diagnostic laparoscopy (OA), and laparoscopic appendectomy (LA). All adult patients who underwent appendectomy in our institution from 1995 to 2005 were included retrospectively. Patient data were retrieved from medical records, questionnaires sent by mail, and records of general practitioners. Primary outcome parameters were long-term complications, readmissions, and reinterventions (> 30 days postoperatively). Secondary outcome parameters were short-term complications, readmissions, and reinterventions (a parts per thousand currency sign30 days postoperatively). A total of 755 patients were included, 545 of whom underwent OA, with the remaining 210 undergoing LA. In the long term there were few complications noted, and there were no significant differences in complications between the two groups. Within 30 days postoperatively, LA was associated with a significantly higher incidence of abdominal abscesses with consequent diagnostic investigations, interventions, and readmissions. Although laparoscopic appendectomy is known to deliver clinical advantages, it is associated with a higher incidence of abdominal abscesses. Because the procedure is about to become the standard of care, future research must be directed at solving this issue. The expected lower incidence of incisional hernia and small bowel obstruction after laparoscopic appendectomy was not shown in the present stud

Optical map guided genome assembly

Background The long reads produced by third generation sequencing technologies have significantly boosted the results of genome assembly but still, genome-wide assemblies solely based on read data cannot be produced. Thus, for example, optical mapping data has been used to further improve genome assemblies but it has mostly been applied in a post-processing stage after contig assembly. Results We proposeOpticalKermitwhich directly integrates genome wide optical maps into contig assembly. We show how genome wide optical maps can be used to localize reads on the genome and then we adapt the Kermit method, which originally incorporated genetic linkage maps to the miniasm assembler, to use this information in contig assembly. Our experimental results show that incorporating genome wide optical maps to the contig assembly of miniasm increases NGA50 while the number of misassemblies decreases or stays the same. Furthermore, when compared to the Canu assembler,OpticalKermitproduces an assembly with almost three times higher NGA50 with a lower number of misassemblies on realA. thalianareads. Conclusions OpticalKermitsuccessfully incorporates optical mapping data directly to contig assembly of eukaryotic genomes. Our results show that this is a promising approach to improve the contiguity of genome assemblies.Peer reviewe

The mu - e Conversion in Nuclei, mu --> e gamma, mu --> 3e Decays and TeV Scale See-Saw Scenarios of Neutrino Mass Generation

We perform a detailed analysis of lepton flavour violation (LFV) within minimal see-saw type extensions of the Standard Model (SM), which give a viable mechanism of neutrino mass generation and provide new particle content at the electroweak scale. We focus, mainly, on predictions and constraints set on each scenario from mu --> e gamma, mu --> 3e and mu - e conversion in the nuclei. In this class of models, the flavour structure of the Yukawa couplings between the additional scalar and fermion representations and the SM leptons is highly constrained by neutrino oscillation measurements. In particular, we show that in some regions of the parameters space of type I and type II see-saw models, the Dirac and Majorana phases of the neutrino mixing matrix, the ordering and hierarchy of the active neutrino mass spectrum as well as the value of the reactor mixing angle theta_{13} may considerably affect the size of the LFV observables. The interplay of the latter clearly allows to discriminate among the different low energy see-saw possibilities.Comment: Expressions for the factors |C_{me}|^2 and |C_{mu3e}|^2 in the mu-e conversion and mu-->3e decay rates, eqs. (36) and (49), respectively, corrected; results in subsections 2.2 and 2.3 quantitatively changed, qualitatively remain the same; figures 2, 3, 4 and 5 replace

Facilitated sequence assembly using densely labeled optical DNA barcodes:A combinatorial auction approach

<div><p>The output from whole genome sequencing is a set of contigs, i.e. short non-overlapping DNA sequences (sizes 1-100 kilobasepairs). Piecing the contigs together is an especially difficult task for previously unsequenced DNA, and may not be feasible due to factors such as the lack of sufficient coverage or larger repetitive regions which generate gaps in the final sequence. Here we propose a new method for scaffolding such contigs. The proposed method uses densely labeled optical DNA barcodes from competitive binding experiments as scaffolds. On these scaffolds we position theoretical barcodes which are calculated from the contig sequences. This allows us to construct longer DNA sequences from the contig sequences. This proof-of-principle study extends previous studies which use sparsely labeled DNA barcodes for scaffolding purposes. Our method applies a probabilistic approach that allows us to discard “foreign” contigs from mixed samples with contigs from different types of DNA. We satisfy the contig non-overlap constraint by formulating the contig placement challenge as a combinatorial auction problem. Our exact algorithm for solving this problem reduces computational costs compared to previous methods in the combinatorial auction field. We demonstrate the usefulness of the proposed scaffolding method both for synthetic contigs and for contigs obtained using Illumina sequencing for a mixed sample with plasmid and chromosomal DNA.</p></div

Patient-reported GP health assessments rather than individual cardiovascular risk burden are associated with the engagement in lifestyle changes: Population-based survey in South Australia

© 2019 The Author(s). Background: Little is known about whether a more comprehensive health assessment, performed by a general practitioner (GP) during a clinical encounter, could influence patients' lifestyle. We aimed to investigate whether health assessments, performed by GPs, are more important than the presence of cardiovascular disease (CVD) or cardiometabolic risk factors (obesity, diabetes, hypertension, dyslipidaemia) for engagement in lifestyle change. Methods: Cross-sectional, population-based survey conducted in South Australia (September-December 2017) using face-To-face interviews and self-reported data of 2977 individuals aged 15+ years. The main outcome was engagement in four lifestyle changes: 1) increasing fruit/vegetable intake, 2) increasing physical activity level, 3) reducing alcohol consumption, and 4) attempts to stop smoking. Health assessments performed by a GP in the last 12 months included clinical/laboratory investigations (weight/waist circumference, blood pressure, glucose levels, lipid levels) and questions about lifestyle/wellbeing (current diet, physical activity, smoking status, alcohol intake, mental health, sleeping problems). Results were restricted to individuals aged 35+ years because of the low prevalence of CVD or their risk factors among younger participants. Logistic regression was used in all associations, adjusted for sociodemographic, lifestyle, mental health, and clinical variables. Results: Of the 2384 investigated adults (mean age 57.3 ± 13.9 years; 51.9% females), 10.2% had CVD and 49.1% at least one cardiometabolic risk factor. Clinical/laboratory assessments performed by the GP were 2-3 times more frequent than assessments of lifestyle, mental health status, or sleeping problems, especially among those with CVD. Individuals with CVD or a cardiometabolic risk factor were no more likely to be increasing their fruit/vegetable consumption (33.6%), physical activity level (40.9%), reducing alcohol consumption (31.1%), or trying to quit smoking (34.0%) than 'healthy' participants. However, lifestyle changes were between 30 and 100% more likely when GPs performed three or more health assessments (either clinical/laboratory or questions about lifestyle/wellbeing) than when individuals did not visit the GP or when GPs performed no any assessment during these clinical encounters (p < 0.05 in all cases). Conclusion: More frequent and comprehensive CVD-related assessments by GPs were more important in promoting a healthier lifestyle than the presence of CVD or cardiometabolic risk factors by themselves

'To take care of the patients': Qualitative analysis of Veterans Health Administration personnel experiences with a clinical informatics system

<p>Abstract</p> <p>Background</p> <p>The Veterans Health Administration (VA) has invested significant resources in designing and implementing a comprehensive electronic health record (EHR) that supports clinical priorities. EHRs in general have been difficult to implement, with unclear cost-effectiveness. We describe VA clinical personnel interactions with and evaluations of the EHR.</p> <p>Methods</p> <p>As part of an evaluation of a quality improvement initiative, we interviewed 72 VA clinicians and managers using a semi-structured interview format. We conducted a qualitative analysis of interview transcripts, examining themes relating to participants' interactions with and evaluations of the VA EHR.</p> <p>Results</p> <p>Participants described their perceptions of the positive and negative effects of the EHR on their clinical workflow. Although they appreciated the speed and ease of documentation that the EHR afforded, they were concerned about the time cost of using the technology and the technology's potential for detracting from interpersonal interactions.</p> <p>Conclusions</p> <p>VA personnel value EHRs' contributions to supporting communication, education, and documentation. However, participants are concerned about EHRs' potential interference with other important aspects of healthcare, such as time for clinical care and interpersonal communication with patients and colleagues. We propose that initial implementation of an EHR is one step in an iterative process of ongoing quality improvement.</p

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation