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297 result(s) for "Bamford, D."
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Derivation and internal validation of a multi-biomarker-based cardiovascular disease risk prediction score for rheumatoid arthritis patients
Background Rheumatoid arthritis (RA) patients have increased risk for cardiovascular disease (CVD). Accurate CVD risk prediction could improve care for RA patients. Our goal is to develop and validate a biomarker-based model for predicting CVD risk in RA patients. Methods Medicare claims data were linked to multi-biomarker disease activity (MBDA) test results to create an RA patient cohort with age ≥ 40 years that was split 2:1 for training and internal validation. Clinical and RA-related variables, MBDA score, and its 12 biomarkers were evaluated as predictors of a composite CVD outcome: myocardial infarction (MI), stroke, or fatal CVD within 3 years. Model building used Cox proportional hazard regression with backward elimination. The final MBDA-based CVD risk score was internally validated and compared to four clinical CVD risk prediction models. Results 30,751 RA patients (904 CVD events) were analyzed. Covariates in the final MBDA-based CVD risk score were age, diabetes, hypertension, tobacco use, history of CVD (excluding MI/stroke), MBDA score, leptin, MMP-3 and TNF-R1. In internal validation, the MBDA-based CVD risk score was a strong predictor of 3-year risk for a CVD event, with hazard ratio (95% CI) of 2.89 (2.46–3.41). The predicted 3-year CVD risk was low for 9.4% of patients, borderline for 10.2%, intermediate for 52.2%, and high for 28.2%. Model fit was good, with mean predicted versus observed 3-year CVD risks of 4.5% versus 4.4%. The MBDA-based CVD risk score significantly improved risk discrimination by the likelihood ratio test, compared to four clinical models. The risk score also improved prediction, reclassifying 42% of patients versus the simplest clinical model (age + sex), with a net reclassification index (NRI) (95% CI) of 0.19 (0.10–0.27); and 28% of patients versus the most comprehensive clinical model (age + sex + diabetes + hypertension + tobacco use + history of CVD + CRP), with an NRI of 0.07 (0.001–0.13). C-index was 0.715 versus 0.661 to 0.696 for the four clinical models. Conclusion A prognostic score has been developed to predict 3-year CVD risk for RA patients by using clinical data, three serum biomarkers and the MBDA score. In internal validation, it had good accuracy and outperformed clinical models with and without CRP. The MBDA-based CVD risk prediction score may improve RA patient care by offering a risk stratification tool that incorporates the effect of RA inflammation.
A mechanism for initiating RNA-dependent RNA polymerization
In most RNA viruses, genome replication and transcription are catalysed by a viral RNA-dependent RNA polymerase. Double-stranded RNA viruses perform these operations in a capsid (the polymerase complex), using an enzyme that can read both single- and double-stranded RNA. Structures have been solved for such viral capsids, but they do not resolve the polymerase subunits in any detail 1 , 2 . Here we show that the 2 Å resolution X-ray structure of the active polymerase subunit from the double-stranded RNA bacteriophage φ6 (refs 3 , 4 ) is highly similar to that of the polymerase of hepatitis C virus, providing an evolutionary link between double-stranded RNA viruses and flaviviruses. By crystal soaking and co-crystallization, we determined a number of other structures, including complexes with oligonucleotide and/or nucleoside triphosphates (NTPs), that suggest a mechanism by which the incoming double-stranded RNA is opened up to feed the template through to the active site, while the substrates enter by another route. The template strand initially overshoots, locking into a specificity pocket, and then, in the presence of cognate NTPs, reverses to form the initiation complex; this process engages two NTPs, one of which acts with the carboxy-terminal domain of the protein to prime the reaction. Our results provide a working model for the initiation of replication and transcription.
Temperature and pH dependence of DNA ejection from archaeal lemon-shaped virus His1
The archaeal virus His1 isolated from a hypersaline environment infects an extremely halophilic archaeon Haloarcula hispanica . His1 features a lemon-shaped capsid, which is so far found only in archaeal viruses. This unique capsid can withstand high salt concentrations, and can transform into a helical tube, which in turn is resistant to extremely harsh conditions. Hypersaline environments exhibit a wide range of temperatures and pH conditions, which present an extra challenge to their inhabitants. We investigated the influence of pH and temperature on DNA ejection from His1 virus using single-molecule fluorescence experiments. The observed number of ejecting viruses is constant in pH 5 to 9, while the ejection process is suppressed at pH below 5. Similarly, the number of ejections within 15–42 °C shows only a minor increase around 25–37 °C. The maximum velocity of single ejected DNA increases with temperature, in qualitative agreement with the continuum model of dsDNA ejection.
Minor proteins, mobile arms and membrane–capsid interactions in the bacteriophage PRD1 capsid
Bacteriophage PRD1 shares many structural and functional similarities with adenovirus. A major difference is the PRD1 internal membrane, which acts in concert with vertex proteins to translocate the phage genome into the host. Multiresolution models of the PRD1 capsid, together with genetic analyses, provide fine details of the molecular interactions associated with particle stability and membrane dynamics. The N- and C-termini of the major coat protein (P3), which are required for capsid assembly, act as conformational switches bridging capsid to membrane and linking P3 trimers. Electrostatic P3–membrane interactions increase virion stability upon DNA packaging. Newly revealed proteins suggest how the metastable vertex works and how the capsid edges are stabilized.
The first known virus isolates from Antarctic sea ice have complex infection patterns
Abstract Viruses are recognized as important actors in ocean ecology and biogeochemical cycles, but many details are not yet understood. We participated in a winter expedition to the Weddell Sea, Antarctica, to isolate viruses and to measure virus-like particle abundance (flow cytometry) in sea ice. We isolated 59 bacterial strains and the first four Antarctic sea-ice viruses known (PANV1, PANV2, OANV1 and OANV2), which grow in bacterial hosts belonging to the typical sea-ice genera Paraglaciecola and Octadecabacter. The viruses were specific for bacteria at the strain level, although OANV1 was able to infect strains from two different classes. Both PANV1 and PANV2 infected 11/15 isolated Paraglaciecola strains that had almost identical 16S rRNA gene sequences, but the plating efficiencies differed among the strains, whereas OANV1 infected 3/7 Octadecabacter and 1/15 Paraglaciecola strains and OANV2 1/7 Octadecabacter strains. All the phages were cold-active and able to infect their original host at 0°C and 4°C, but not at higher temperatures. The results showed that virus–host interactions can be very complex and that the viral community can also be dynamic in the winter-sea ice. Isolation, characterisation, host range and temperature adaptation of the first known Antarctic sea-ice virus isolates.
COMMON PRINCIPLES IN VIRAL ENTRY
Viruses occur throughout the biosphere. Cells of Eukarya, Bacteria, and Archaea are infected by a variety of viruses that considerably outnumber the host cells. Although viruses have adapted to different host systems during evolution and many different viral strategies have developed, certain similarities can be found. Viruses encounter common problems during their entry process into the host cells, and similar strategies seem to ensure, for example, that the movement toward the site of replication and the translocation through the host membrane occur. The penetration of the host cell's external envelope involves, across the viral world, either fusion between two membranes, channel formation through the host envelope, disruption of the membrane vesicle, or a combination of these events. Endocytic-type events may occur during the entry of a bacterial virus as well as during the entry of an animal virus; the same applies for membrane fusion.
Measurement report: Introduction to the HyICE-2018 campaign for measurements of ice-nucleating particles and instrument inter-comparison in the Hyytiälä boreal forest
The formation of ice particles in Earth's atmosphere strongly influences the dynamics and optical properties of clouds and their impacts on the climate system. Ice formation in clouds is often triggered heterogeneously by ice-nucleating particles (INPs) that represent a very low number of particles in the atmosphere. To date, many sources of INPs, such as mineral and soil dust, have been investigated and identified in the low and mid latitudes. Although less is known about the sources of ice nucleation at high latitudes, efforts have been made to identify the sources of INPs in the Arctic and boreal environments. In this study, we investigate the INP emission potential from high-latitude boreal forests in the mixed-phase cloud regime. We introduce the HyICE-2018 measurement campaign conducted in the boreal forest of Hyytiälä, Finland, between February and June 2018. The campaign utilized the infrastructure of the Station for Measuring Ecosystem-Atmosphere Relations (SMEAR) II, with additional INP instruments, including the Portable Ice Nucleation Chamber I and II (PINC and PINCii), the SPectrometer for Ice Nuclei (SPIN), the Portable Ice Nucleation Experiment (PINE), the Ice Nucleation SpEctrometer of the Karlsruhe Institute of Technology (INSEKT) and the Microlitre Nucleation by Immersed Particle Instrument (µL-NIPI), used to quantify the INP concentrations and sources in the boreal environment. In this contribution, we describe the measurement infrastructure and operating procedures during HyICE-2018, and we report results from specific time periods where INP instruments were run in parallel for inter-comparison purposes. Our results show that the suite of instruments deployed during HyICE-2018 reports consistent results and therefore lays the foundation for forthcoming results to be considered holistically. In addition, we compare measured INP concentrations to INP parameterizations, and we observe good agreement with the Tobo et al. (2013) parameterization developed from measurements conducted in a ponderosa pine forest ecosystem in Colorado, USA.
The Evolutionary History of Archaeal MCM Helicases: A Case Study of Vertical Evolution Combined with Hitchhiking of Mobile Genetic Elements
Genes encoding DNA replication proteins have been frequently exchanged between cells and mobile elements, such as viruses or plasmids. This raises potential problems to reconstruct their history. Here, we combine phylogenetic and genomic context analyses to study the evolution of the replicative minichromosome maintenance (MCM) helicases in Archaea. Several archaeal genomes encode more than one copy of the mcm gene. Genome context analysis reveals that most of these additional copies are encoded within mobile elements. Exhaustive analysis of these elements reveals diverse groups of integrated archaeal plasmids or viruses, including several head-and-tail proviruses. Some MCMs encoded by mobile elements are structurally distinct from their cellular counterparts, with one case of novel domain organization. Both genome context and phylogenetic analysis indicate that MCM encoded by mobile elements were recruited from cellular genomes. An accelerated evolution and a dramatic expansion of methanococcal MCMs suggest a host-to-virus-to-host transfer loop, possibly triggered by the loss of the archaeal initiator protein Cdc6 in Methanococcales. Surprisingly, despite extensive transfer of mcm genes between viruses, plasmids, and cells, the topology of the MCM tree is strikingly congruent with the consensus archaeal phylogeny, indicating that mobile elements encoding mcm have coevolved with their hosts and that DNA replication proteins can be also useful to reconstruct the history of the archaeal domain.