Cellular mRNAs access second ORFs using a novel amino acid sequence-dependent coupled translation termination-reinitiation mechanism

Polycistronic transcripts are considered rare in the human genome. Initiation of translation of internal ORFs of eukaryotic genes has been shown to use either leaky scanning or highly structured IRES regions to access initiation codons. Studies on mammalian viruses identified a mechanism of coupled translation termination-reinitiation that allows translation of an additional ORF. Here, the ribosome terminating translation of ORF-1 translocates upstream to reinitiate translation of ORF-2. We have devised an algorithm to identify mRNAs in the human transcriptome in which the major ORF-1 overlaps a second ORF capable of encoding a product of at least 50 aa in length. This identified 4368 transcripts representing 2214 genes. We investigated 24 transcripts, 22 of which were shown to express a protein from ORF-2 highlighting that 3' UTRs contain protein-coding potential more frequently than previously suspected. Five transcripts accessed ORF-2 using a process of coupled translation termination-reinitiation. Analysis of one transcript, encoding the CASQ2 protein, showed that the mechanism by which the coupling process of the cellular mRNAs was achieved was novel. This process was not directed by the mRNA sequence but required an aspartate-rich repeat region at the carboxyl terminus of the terminating ORF-1 protein. Introduction of wobble mutations for the aspartate codon had no effect, whereas replacing aspartate for glutamate repeats eliminated translational coupling. This is the first description of a coordinated expression of two proteins from cellular mRNAs using a coupled translation termination-reinitiation process and is the first example of such a process being determined at the amino acid level

A Quantitative Trait Locus Analysis of Root Distribution in Perennial Ryegrass (\u3cem\u3eLolium Perenne\u3c/em\u3e L.)

Root system architecture impacts perennial ryegrass performance, with deeper roots potentially contributing to drought tolerance, nutrient interception, and anchoring of plants. Root mass in a perennial ryegrass sward is typically shallow, concentrated in the top 10 cm of soil (Troughton 1957). Phenotypic selection for deeper root systems in breeding programmes is limited by the inaccessibility of underground plant components. We aim to use quantitative trait locus (QTL) analysis to discover genetic factors influencing root architecture traits, including vertical root distribution, in perennial ryegrass. Ultimately, markers linked to root architecture QTL may be used in a marker-assisted selection strategy that would alleviate the limitations of conventional selection, and lead to ryegrass cultivars with improved production and environmental performance

Horseshoe-based Bayesian nonparametric estimation of effective population size trajectories

Phylodynamics is an area of population genetics that uses genetic sequence data to estimate past population dynamics. Modern state-of-the-art Bayesian nonparametric methods for recovering population size trajectories of unknown form use either change-point models or Gaussian process priors. Change-point models suffer from computational issues when the number of change-points is unknown and needs to be estimated. Gaussian process-based methods lack local adaptivity and cannot accurately recover trajectories that exhibit features such as abrupt changes in trend or varying levels of smoothness. We propose a novel, locally-adaptive approach to Bayesian nonparametric phylodynamic inference that has the flexibility to accommodate a large class of functional behaviors. Local adaptivity results from modeling the log-transformed effective population size a priori as a horseshoe Markov random field, a recently proposed statistical model that blends together the best properties of the change-point and Gaussian process modeling paradigms. We use simulated data to assess model performance, and find that our proposed method results in reduced bias and increased precision when compared to contemporary methods. We also use our models to reconstruct past changes in genetic diversity of human hepatitis C virus in Egypt and to estimate population size changes of ancient and modern steppe bison. These analyses show that our new method captures features of the population size trajectories that were missed by the state-of-the-art methods.Comment: 36 pages, including supplementary informatio

Heteroclinic intersections between Invariant Circles of Volume-Preserving Maps

We develop a Melnikov method for volume-preserving maps with codimension one invariant manifolds. The Melnikov function is shown to be related to the flux of the perturbation through the unperturbed invariant surface. As an example, we compute the Melnikov function for a perturbation of a three-dimensional map that has a heteroclinic connection between a pair of invariant circles. The intersection curves of the manifolds are shown to undergo bifurcations in homologyComment: LaTex with 10 eps figure

Intra-session and inter-day reliability of the Myon 320 electromyography system during sub-maximal contractions

Electromyography systems are widely used within the field of scientific and clinical practices. The reliability of these systems are paramount when conducting research. The reliability of Myon 320 Surface Electromyography System is yet to be determined. This study aims to determine the intra-session and inter-day reliability of the Myon 320 Surface Electromyography System. Muscle activity from fifteen participants was measured at the anterior deltoid muscle during a bilateral front raise exercise, the vastus lateralis muscle during a squat exercise and the extensor carpi radialis brevis (ECRB) muscle during an isometric handgrip task. Intra-session and inter-day reliability was calculated by intraclass correlation coefficient, standard error of measurement and coefficient of variation (CV). The normalized root mean squared (RMS) surface electromyographic signals produced good intra-session and inter-day testing intraclass correlation coefficient values (range: 0.63-0.97) together with low standard error of measurement (range: 1.49-2.32) and CV (range: 95% Confidence Interval = 0.36-12.71) measures for the dynamic-and-isometric contractions. The findings indicate that the Myon 320 Surface Electromyography System produces good to fair reliability when examining intra-session and inter-day reliability. Findings of the study provide evidence of the reliability of electromyography between trials which is essential during clinical testing.</p

Quantitative Trait Loci for Vegetative Traits in Perennial Ryegrass (\u3cem\u3eLolium Perenne\u3c/em\u3e L.)

Physiological (EP) research in forage grasses relates traits such as leaf elongation rate (LER), leaf elongation duration (LED), and leaf appearance interval (ALf), to forage yield (Chapman & Lemaire, 1993). This paper reveals preliminary quantitative trait locus (QTL) discovery for eight EP traits in perennial ryegrass. It also investigates the potential role of multivariate analyses such as principal component analysis (PCA) in QTL analysis of EP data

Diagnostic Pathways as Social and Participatory Practices: The Case of Herpes Simplex Encephalitis

Herpes simplex virus (HSV) encephalitis is a potentially devastating disease, with significant rates of mortality and co-morbidities. Although the prognosis for people with HSV encephalitis can be improved by prompt treatment with aciclovir, there are often delays involved in the diagnosis and treatment of the disease. In response, National Clinical Guidelines have been produced for the UK which make recommendations for improving the management of suspected viral encephalitis. However, little is currently known about the everyday experiences and processes involved in the diagnosis and care of HSV encephalitis. The reported study aimed to provide an account of the diagnosis and treatment of HSV encephalitis from the perspective of people who had been affected by the condition. Thirty narrative interviews were conducted with people who had been diagnosed with HSV encephalitis and their significant others. The narrative accounts reveal problems with gaining access to a diagnosis of encephalitis and shortfalls in care for the condition once in hospital. In response, individuals and their families work hard to obtain medical recognition for the problem and shape the processes of acute care. As a consequence, we argue that the diagnosis and management of HSV encephalitis needs to be considered as a participatory process, which is co-produced by health professionals, patients, and their families. The paper concludes by making recommendations for developing the current management guidelines by formalising the critical role of patients and their significant others in the identification, and treatment of, HSV encephalitis

Residual stress generation in tungsten-copper brazed joint using brazing alloy

Understanding the residual stress state in brazed joints is crucial for operational design and life time performance of the part in service. High magnitudes residual stresses are expected in the joined materials following cooling from brazing temperatures (≈950°C) due to large mismatches in material properties such as coefficient of thermal expansion and Young’s modulus. This study aims at further understanding of the generation and distribution of residual stresses when brazing tungsten to copper using a eutectic gold-copper brazing alloy. This configuration is potentially useful for future divertor designs. Finite Element Analysis (FEM) has been used to predict the brazing induced stresses and residual stress measurements were carried out on the brazed joint by X-ray diffraction (XRD) to validate the prediction model. Large residual stresses are predicted and measured in the tungsten; however there is disagreement in the sign of the stress. Predicted stresses are highly tensile in nature close to the brazing interface, whereas the measured stresses are highly compressive. The disagreement is believed to be caused by the model not accurately simulating the complex brazing process. Residual stress measurements on the copper were not possible due to texturing during brazing, grain growth and significant inelastic strains and deformations. Misalignment of parent materials was also observed to significantly affect residual stresses

Residual stress generations in brazed tungsten dissimilar joints

Understanding the residual stress state in brazed joints is crucial for the operational design and lifetime performance of the part in service. High-magnitude residual stresses are expected in the joined materials following cooling from brazing temperatures (≈950 °C) due to large mismatches in the thermal and mechanical properties. This paper aims at further understanding of the residual stresses caused when brazing tungsten to copper and tungsten to 316L austenitic steel using a eutectic gold-copper brazing alloy. These configurations are potentially useful for future diverter designs. Finite element analysis has been used to predict the brazing-induced stresses and residual stress measurements were carried out on the brazed joint by X-ray diffraction to validate the prediction model. Large residual stresses are predicted and measured in the tungsten; however, there is disagreement in the nature of the stress in the tungsten-copper configuration. Predicted stresses are highly tensile in nature close to the brazing interface, whereas the measured stresses are highly compressive. The disagreement is believed to be caused by the model not accurately simulating the complex brazing process. Residual stress measurements on the copper were not possible due to texturing during brazing, grain growth, and significant inelastic strains. There is excellent correlation between the measured and predicted stresses in the tungsten-316L configuration. High-tensile stresses were predicted in the tungsten (magnitude approximately 1000 MPa close to the braze interface) and high tensile stresses were measured (magnitude approximately 800 MPa in the same region). Joint misalignment of parent materials was also observed to significantly affect the residual stresses

Hospital costs of out-of-hospital cardiac arrest patients treated in intensive care; a single centre evaluation using the national tariff-based system

OBJECTIVES: There is a scarcity of literature reporting hospital costs for treating out of hospital cardiac arrest (OOHCA) survivors, especially within the UK. This is essential for assessment of cost-effectiveness of interventions necessary to allow just allocation of resources within the National Health Service. We set out primarily to calculate costs stratified against hospital survival and neurological outcomes. Secondarily, we estimated cost effectiveness based on estimates of survival and utility from previous studies to calculate costs per quality adjusted life year (QALY). SETTING: We performed a single centre (London) retrospective review of in-hospital costs of patients admitted to the intensive care unit (ICU) following return of spontaneous circulation (ROSC) after OOHCA over 18 months from January 2011 (following widespread introduction of targeted temperature management and primary percutaneous intervention). PARTICIPANTS: Of 69 successive patients admitted over an 18-month period, survival and cerebral performance category (CPC) outcomes were obtained from review of databases and clinical notes. The Trust finance department supplied ICU and hospital costs using the Payment by Results UK system. RESULTS: Of those patients with ROSC admitted to ICU, survival to hospital discharge (any CPC) was 33/69 (48%) with 26/33 survivors in CPC 1–2 at hospital discharge. Cost per survivor to hospital discharge (including total cost of survivors and non-survivors) was £50 000, cost per CPC 1–2 survivor was £65 000. Cost and length of stay of CPC 1–2 patients was considerably lower than CPC 3–4 patients. The majority of the costs (69%) related to intensive care. Estimated cost per CPC 1–2 survivor per QALY was £16 000. CONCLUSIONS: The costs of in-hospital patient care for ICU admissions following ROSC after OOHCA are considerable but within a reasonable threshold when assessed from a QALY perspective