Assemblin Homolog of Herpes Simplex Virus Type 1 Retains Proteolytic Activity When Expressed as a Recombinant Two-Chain Enzyme

AbstractThe herpes simplex virus type 1 (HSV) maturational proteinase is synthesized as a precursor that undergoes two autoproteolytic cleavages; one at its (M)aturational site, which eliminates its carboxyl “tail,” and a second at its (R)elease site, which separates the amino proteolytic half of the precursor from its nonproteolytic carboxyl half. In cytomegalovirus (CMV) the proteolytic half of the precursor, called assemblin, undergoes a third cleavage at an (I)nternal site that converts it from a single-chain to a two-chain enzyme that retains activity. The HSV assemblin homolog has no I site and therefore does not form a counterpart two-chain enzyme. In the work reported here we have cloned and expressed HSV sequences that encode mimics of the Anand Acsubunits of two-chain CMV assemblin. We show that when these HSV sequences are coexpressed in eukaryotic cells, the resulting subunits associate spontaneously to form an active two-chain enzyme. We also show that the two-chain HSV enzyme, like the natural one-chain form, retains its marked preference for HSV over CMV substrates, and that intertypic recombinant two-chain assemblin (e.g., HSV An/CMV Ac) does not form because the cross-species subunits do not interact. We conclude from these results that (i) there are not intrinsic structural differences in the HSV assemblin homolog that preclude its functioning as a CMV-like two-chain enzyme, (ii) the substrate selectivity shown by the single-chain HSV enzyme was not noticeably relaxed in the HSV two-chain mimic, and (iii) the interactive domains, through which the Anand Acportions of the single-chain enzymes associate, differ between HSV and CMV

Adolescents' Understanding of Smoking and Vaping Risk Language: Cognitive Interviews to Inform Scale Development

Introduction: Perceived message effectiveness (PME) is a common metric to understand receptivity to tobacco prevention messages, yet most measures have been developed with adults. We examined adolescents' interpretation of language within candidate items for a new youth-targeted PME measure using cognitive interviewing. We sought to understand the meaning adolescents assigned to our candidate PME items to improve item wording. Aims and Methods: Participants were 20 adolescents, ages 13-17 years from the United States. Cognitive interviews used a structured guide to elicit feedback on comprehension, answer retrieval, and language regarding a set of Reasoned Action Approach-based survey items that assessed the PME of smoking and vaping prevention ads. We employed thematic analysis to synthesize findings from the interviews. Results: Interviews identified three main issues related to survey items: ambiguity of language, word choice (risk and other terminology), and survey item phrasing. Adolescents preferred direct, definitive language over more ambiguous phrasing which they saw as less serious (eg, "will"instead of "could"). For risk terminology, they preferred terms such as "harmful"and "dangerous"over "risky,"which was viewed as easy to discount. The term "negative effects"was interpreted as encompassing a broader set of tobacco harms than "health effects."Adolescents said that the term "vape"was preferable to "e-cigarette,"and identified ways to simplify item wording for greater clarity. Conclusions: Tobacco risk terms that appear similar differ in meaning to adolescents, and more direct and unambiguous language is preferred. Our findings informed changes to the PME scale items to improve clarity and reduce measurement error. Implications: This study adds to the literature on how adolescents interpret tobacco prevention language. Adolescents may interpret terminology differently than adults, which could lead to ambiguity in meaning and thus measurement error. Through cognitive interviewing, we identified and improved the language in a youth-focused PME measure for tobacco and vaping prevention

Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial

Background: Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs. Methods: We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2–T4 pN0–N3 M0 or pTany N1–3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m²) or carboplatin (area under the curve [AUC]4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m²) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants. Findings: Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30–0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0–47·5). 3-year event-free estimates were 71% (95% CI 61–78) and 46% (36–56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported. Interpretation: Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population. Funding: Cancer Research UK

Theory and simulation of quantum photovoltaic devices based on the non-equilibrium Green's function formalism

This article reviews the application of the non-equilibrium Green's function formalism to the simulation of novel photovoltaic devices utilizing quantum confinement effects in low dimensional absorber structures. It covers well-known aspects of the fundamental NEGF theory for a system of interacting electrons, photons and phonons with relevance for the simulation of optoelectronic devices and introduces at the same time new approaches to the theoretical description of the elementary processes of photovoltaic device operation, such as photogeneration via coherent excitonic absorption, phonon-mediated indirect optical transitions or non-radiative recombination via defect states. While the description of the theoretical framework is kept as general as possible, two specific prototypical quantum photovoltaic devices, a single quantum well photodiode and a silicon-oxide based superlattice absorber, are used to illustrated the kind of unique insight that numerical simulations based on the theory are able to provide.Comment: 20 pages, 10 figures; invited review pape

Empirical Phi-Discrepancies and Quasi-Empirical Likelihood: Exponential Bounds

We review some recent extensions of the so-called generalized empirical likelihood method, when the Kullback distance is replaced by some general convex divergence. We propose to use, instead of empirical likelihood, some regularized form or quasi-empirical likelihood method, corresponding to a convex combination of Kullback and χ2 discrepancies. We show that for some adequate choice of the weight in this combination, the corresponding quasi-empirical likelihood is Bartlett-correctable. We also establish some non-asymptotic exponential bounds for the confidence regions obtained by using this method. These bounds are derived via bounds for self-normalized sums in the multivariate case obtained in a previous work by the authors. We also show that this kind of results may be extended to process valued infinite dimensional parameters. In this case some known results about self-normalized processes may be used to control the behavior of generalized empirical likelihood

Low Complexity Regularization of Linear Inverse Problems

Inverse problems and regularization theory is a central theme in contemporary signal processing, where the goal is to reconstruct an unknown signal from partial indirect, and possibly noisy, measurements of it. A now standard method for recovering the unknown signal is to solve a convex optimization problem that enforces some prior knowledge about its structure. This has proved efficient in many problems routinely encountered in imaging sciences, statistics and machine learning. This chapter delivers a review of recent advances in the field where the regularization prior promotes solutions conforming to some notion of simplicity/low-complexity. These priors encompass as popular examples sparsity and group sparsity (to capture the compressibility of natural signals and images), total variation and analysis sparsity (to promote piecewise regularity), and low-rank (as natural extension of sparsity to matrix-valued data). Our aim is to provide a unified treatment of all these regularizations under a single umbrella, namely the theory of partial smoothness. This framework is very general and accommodates all low-complexity regularizers just mentioned, as well as many others. Partial smoothness turns out to be the canonical way to encode low-dimensional models that can be linear spaces or more general smooth manifolds. This review is intended to serve as a one stop shop toward the understanding of the theoretical properties of the so-regularized solutions. It covers a large spectrum including: (i) recovery guarantees and stability to noise, both in terms of $\ell^2$-stability and model (manifold) identification; (ii) sensitivity analysis to perturbations of the parameters involved (in particular the observations), with applications to unbiased risk estimation ; (iii) convergence properties of the forward-backward proximal splitting scheme, that is particularly well suited to solve the corresponding large-scale regularized optimization problem

Emotional intelligence and British expatriates’ cross-cultural adjustment in international construction projects

© 2016 Informa UK Limited, trading as Taylor & Francis Group. Today’s internationalized business demands global mindset, intercultural sensitivity and the ability to skilfully negotiate through cross-cultural interactions. Therefore, the overall aim was to investigate the influence of emotional intelligence (EI) on cross-cultural adjustment (CCA) of British expatriates working on International Architectural, Engineering and Construction assignments in Sub-Saharan Africa, China, Middle East and Indian Sub-Continent. Specifically, the causal relationship between EI and three facets of CCA i.e. work, general and interaction adjustment was explored. A sequential exploratory mixed methods design was adopted. These include extensive review of existing literature, eighteen unstructured interviews, and questionnaire survey of 191 British expatriates operating in 29 different countries from the four regions under investigation. Structural equation modelling was used to assess the causal relationship between EI and CCA. Results show that EI accounted for 91, 64 and 24% of the variance in work, interaction and general adjustment respectively. Overall, the model was able to explain 60% variance in CCA, suggesting that EI competencies play a huge role in facilitating an expatriate understand and adapt to host country culture. The findings would help decision-makers (HR managers) during expatriate selection process, in understanding that along with technical skills, it is the emotional competencies that are crucial in assisting expatriates adjust to foreign way of life

Search for Single Top Production at LEP

Single top production in e+e- annihilations is searched for in data collected by the L3 detector at centre-of-mass energies from 189 to 209 GeV, corresponding to a total integrated luminosity of 634 pb-1. Investigating hadronic and semileptonic top decays, no evidence of single top production at LEP is obtained and upper limits on the single top cross section as a function of the centre-of-mass energy are derived. Limits on possible anomalous couplings, as well as on the scale of contact interactions responsible for single top production are determined

Search for R-parity Violating Decays of Supersymmetric Particles in e+e- Collisions at LEP

A search, in e^+e^- collisions, for chargino, neutralino, scalar lepton and scalar quark pair-production is performed, without assuming R-parity conservation in decays, in the case that only one of the coupling constants lambda_ijk or lambda''_ijk is non-negligible. No signal is found in data up to a centre-of-mass energy of 208GeV. Limits on the production cross sections and on the masses of supersymmetric particles are derived

Stream and slope weathering effects on organic-rich mudstone geochemistry and implications for hydrocarbon source rock assessment: a Bowland Shale case study

This study contributes to the exploration and quantification of the weathering of organic-rich mudstones under temperate climatic conditions. Bowland Shales, exposed by a stream and slope, were sampled in order to develop a model for the effects of weathering on the mudstone geochemistry, including major and trace element geochemistry, Rock-Eval pyrolysis and δ13Corg. Four weathering grades (I – IV) are defined using a visual classification scheme; visually fresh and unaltered (I), chemically altered (II, III) and ‘paper shale’ that typifies weathered mudstone on slopes (IV). Bedload abrasion in the stream exposes of visually fresh and geochemically unaltered mudstone. Natural fractures are conduits for oxidising meteoric waters that promote leaching at the millimetre scale and/or precipitation of iron oxide coatings along fracture surfaces. On the slope, bedding-parallel fractures formed (and may continue to form) in response to chemical and/or physical weathering processes. These fractures develop along planes of weakness, typically along laminae comprising detrital grains, and exhibit millimetre- and centimetre-scale leached layers and iron oxide coatings. Fracture surfaces are progressively exposed to physical weathering processes towards the outcrop surface, and results in disintegration of the altered material along fracture surfaces. Grade IV, ‘paper shale’ mudstone is chemically unaltered but represents a biased record driven by initial heterogeneity in the sedimentary fabric. Chemically weathered outcrop samples exhibit lower concentrations of both ‘free’ (S1) (up to 0.6 mgHC/g rock) and ‘bound’ (S2) (up to 3.2 mgHC/g rock) hydrocarbon, reduced total organic carbon content (up to 0.34 wt%), reduced hydrogen index (up to 58 mgHC/gTOC), increased oxygen index (up to 19 mgCO + CO2/gTOC) and increased Tmax (up to 11 °C) compared with unaltered samples. If analysis of chemically weathered samples is unavoidable, back-extrapolation of Rock-Eval parameters can assist in the estimation of pre-weathering organic compositions. Combining Cs/Cu with oxygen index is a proxy for identifying the weathering progression from fresh material (I) to ‘paper shale’ (IV). This study demonstrates that outcrop samples in temperate climates can provide information for assessing hydrocarbon potential of organic-rich mudstones