Polarization restricts hepatitis C virus entry into HepG2 hepatoma cells

The primary reservoir for hepatitis C virus (HCV) replication is believed to be hepatocytes, which are highly polarized with tight junctions (TJ) separating their basolateral and apical domains. HepG2 cells develop polarity over time, resulting in the formation and remodeling of bile canalicular (BC) structures. HepG2 cells expressing CD81 provide a model system to study the effects of hepatic polarity on HCV infection. We found an inverse association between HepG2-CD81 polarization and HCV pseudoparticle entry. As HepG2 cells polarize, discrete pools of claudin-1 (CLDN1) at the TJ and basal/lateral membranes develop, consistent with the pattern of receptor staining observed in liver tissue. The TJ and nonjunctional pools of CLDN1 show an altered association with CD81 and localization in response to the PKA antagonist Rp-8-Br-cyclic AMPs (cAMPs). Rp-8-Br-cAMPs reduced CLDN1 expression at the basal membrane and inhibited HCV infection, supporting a model where the nonjunctional pools of CLDN1 have a role in HCV entry. Treatment of HepG2 cells with proinflammatory cytokines, tumor necrosis factor alpha and gamma interferon, perturbed TJ integrity but had minimal effect(s) on cellular polarity and HCV infection, suggesting that TJ integrity does not limit HCV entry into polarized HepG2 cells. In contrast, activation of PKC with phorbol ester reduced TJ integrity, ablated HepG2 polarity, and stimulated HCV entry. Overall, these data show that complex hepatocyte-like polarity alters CLDN1 localization and limits HCV entry, suggesting that agents which disrupt hepatocyte polarity may promote HCV infection and transmission within the liver

Divergent evolution of protein conformational dynamics in dihydrofolate reductase.

Molecular evolution is driven by mutations, which may affect the fitness of an organism and are then subject to natural selection or genetic drift. Analysis of primary protein sequences and tertiary structures has yielded valuable insights into the evolution of protein function, but little is known about the evolution of functional mechanisms, protein dynamics and conformational plasticity essential for activity. We characterized the atomic-level motions across divergent members of the dihydrofolate reductase (DHFR) family. Despite structural similarity, Escherichia coli and human DHFRs use different dynamic mechanisms to perform the same function, and human DHFR cannot complement DHFR-deficient E. coli cells. Identification of the primary-sequence determinants of flexibility in DHFRs from several species allowed us to propose a likely scenario for the evolution of functionally important DHFR dynamics following a pattern of divergent evolution that is tuned by cellular environment

The Luminosity Function of Galaxies in Compact Groups

From R-band images of 39 Hickson compact groups (HCGs), we use galaxy counts to determine a luminosity function extending to M_R=-14.0, approximately two magnitudes deeper than previous compact group luminosity functions. We find that a single Schechter function is a poor fit to the data, so we fit a composite function consisting of separate Schechter functions for the bright and faint galaxies. The bright end is best fit with M^*=-21.6 and alpha=-0.52 and the faint end with M^*=-16.1 and alpha=-1.17. The decreasing bright end slope implies a deficit of intermediate luminosity galaxies in our sample of HCGs and the faint end slope is slightly steeper than that reported for earlier HCG luminosity functions. Furthermore, luminosity functions of subsets of our sample reveal more substantial dwarf populations for groups with x-ray halos, groups with tidal dwarf candidates, and groups with a dominant elliptical or lenticular galaxy. Collectively, these results support the hypothesis that within compact groups, the initial dwarf galaxy population is replenished by "subsequent generations" formed in the tidal debris of giant galaxy interactions.Comment: 26 pages, to be published in The Astrophysical Journal, 8 greyscale plates (figures 1 and 2) can be retrieved at http://www.astro.psu.edu/users/sdh/pubs.htm

Prenatal development is linked to bronchial reactivity: epidemiological and animal model evidence

Chronic cardiorespiratory disease is associated with low birthweight suggesting the importance of the developmental environment. Prenatal factors affecting fetal growth are believed important, but the underlying mechanisms are unknown. The influence of developmental programming on bronchial hyperreactivity is investigated in an animal model and evidence for comparable associations is sought in humans. Pregnant Wistar rats were fed either control or protein-restricted diets throughout pregnancy. Bronchoconstrictor responses were recorded from offspring bronchial segments. Morphometric analysis of paraffin-embedded lung sections was conducted. In a human mother-child cohort ultrasound measurements of fetal growth were related to bronchial hyperreactivity, measured at age six years using methacholine. Protein-restricted rats' offspring demonstrated greater bronchoconstriction than controls. Airway structure was not altered. Children with lesser abdominal circumference growth during 11-19 weeks' gestation had greater bronchial hyperreactivity than those with more rapid abdominal growth. Imbalanced maternal nutrition during pregnancy results in offspring bronchial hyperreactivity. Prenatal environmental influences might play a comparable role in humans

What promotes or prevents greater use of appropriate compression in people with venous leg ulcers? A qualitative interview study with nurses in the north of England using the Theoretical Domains Framework

OBJECTIVES: To investigate factors that promote and prevent the use of compression therapy in people with venous leg ulcers. DESIGN: Qualitative interview study with nurses using the Theoretical Domains Framework (TDF). SETTING: Three National Health Service Trusts in England. PARTICIPANTS: Purposive sample of 15 nurses delivering wound care. RESULTS: Nurses described factors which made provision of compression therapy challenging. Organisational barriers (TDF domains environmental context and resources/knowledge, skills/behavioural regulation) included heavy/increasing caseloads; lack of knowledge/skills and the provision of training; and prescribing issues (variations in bandaging systems/whether nurses could prescribe). Absence of specialist leg ulcer services to refer patients into was perceived as a barrier to providing optimal care by some community-based nurses. Compression use was perceived to be facilitated by clinics for timely initial assessment; continuity of staff and good liaison between vascular/leg ulcer clinics and community teams; clear local policies and care pathways; and opportunities for training such as ‘shadowing’ in vascular/leg ulcer clinics. Patient engagement barriers (TDF domains goals/beliefs about consequences) focused on getting patients ‘on board’ with compression, and supporting them in using it. Clear explanations were seen as key in promoting compression use. CONCLUSIONS: Rising workload pressures present significant challenges to enhancing leg ulcer services. There may be opportunities to develop facilitated approaches to enable community nursing teams to make changes to practice, enhancing quality of patient care. The majority of venous leg ulcers could be managed in the community without referral to specialist community services if issues relating to workloads/skills/training are addressed. Barriers to promoting compression use could also be targeted, for example, through the development of clear patient information leaflets. While the patient engagement barriers may be easier/quicker to address than organisational barriers, unless organisational barriers are addressed it seems unlikely that all people who would benefit from compression therapy will receive it

Delivering word retrieval therapies for people with aphasia in a virtual communication environment

Background: Delivering therapy remotely, via digital technology, can enhance provision for people with aphasia. EVA Park is a multi-user virtual island that can be used for such delivery. The first EVA Park study showed that daily language stimulation delivered via the platform improved functional communication and was positively received by users (Marshall et al, 2016; Amaya et al, 2018). This paper reports two single case studies, evaluating its capacity to deliver targeted language interventions. The first employed therapy for noun retrieval, using cued picture naming and modified Sematic Feature Analysis. The second employed modified Verb Network Strengthening Treatment (VNeST). Aims: This study aimed to determine if treatment delivery was feasible in EVA Park, as assessed by participant compliance, treatment fidelity and participants’ views. It explored the impact of the therapies on treated and untreated word production, connected speech and functional communication. Methods & Procedures: Two participants with aphasia each received 20 sessions of individual therapy in EVA Park, delivered over 5 weeks. Feasibility was assessed by measuring compliance with the therapy regime, recording and checking the fidelity of 20% of treatment sessions, and using post therapy interviews to explore participant views. Treatment outcomes were evaluated via repeated measures single case designs, in which assessments were administered twice before therapy, immediately post therapy and five weeks later. Outcome measures included Object Picture Naming (study 1), Sentence Elicitation Pictures (study 2), Naming 84 items from the Object and Action Naming Battery (study 2), Narrative Production (Study 2), the Northwestern Assessment of Verb and Sentences: Argument Structure Production Test (Study 2) and Communication Activities of Daily Living – 2 (Study 1 & 2). Outcomes & Results: Feasibility results were excellent. Both participants were fully compliant with the therapy regime. There was at least 90% fidelity with the treatment protocols and participant views were positive. Outcomes varied across the studies. The noun therapy significantly improved the naming of treated words, with good maintenance. Lexical gains were less evident on the Sentence Elicitation Pictures used in the VNeST study. Neither study demonstrated generalisation to untreated words, connected speech or functional communication. Conclusions: Two treatment approaches, designed for face to face delivery, could be delivered remotely in EVA Park. Outcomes for the noun treatment were comparable to previous evaluations. Comparisons with previous research were more challenging for VNeST, owing to differences in methodology. Further evaluations of other treatment approaches are warranted

Strategies designed to help healthcare professionals to recruit participants to research studies.

BACKGROUND: Identifying and approaching eligible participants for recruitment to research studies usually relies on healthcare professionals. This process is sometimes hampered by deliberate or inadvertent gatekeeping that can introduce bias into patient selection. OBJECTIVES: Our primary objective was to identify and assess the effect of strategies designed to help healthcare professionals to recruit participants to research studies. SEARCH METHODS: We performed searches on 5 January 2015 in the following electronic databases: Cochrane Methodology Register, CENTRAL, MEDLINE, EMBASE, CINAHL, British Nursing Index, PsycINFO, ASSIA and Web of Science (SSCI, SCI-EXPANDED) from 1985 onwards. We checked the reference lists of all included studies and relevant review articles and did citation tracking through Web of Science for all included studies. SELECTION CRITERIA: We selected all studies that evaluated a strategy to identify and recruit participants for research via healthcare professionals and provided pre-post comparison data on recruitment rates. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results for potential eligibility, read full papers, applied the selection criteria and extracted data. We calculated risk ratios for each study to indicate the effect of each strategy. MAIN RESULTS: Eleven studies met our eligibility criteria and all were at medium or high risk of bias. Only five studies gave the total number of participants (totalling 7372 participants). Three studies used a randomised design, with the others using pre-post comparisons. Several different strategies were investigated. Four studies examined the impact of additional visits or information for the study site, with no increases in recruitment demonstrated. Increased recruitment rates were reported in two studies that used a dedicated clinical recruiter, and five studies that introduced an automated alert system for identifying eligible participants. The studies were embedded into trials evaluating care in oncology mainly but also in emergency departments, diabetes and lower back pain. AUTHORS' CONCLUSIONS: There is no strong evidence for any single strategy to help healthcare professionals to recruit participants in research studies. Additional visits or information did not appear to increase recruitment by healthcare professionals. The most promising strategies appear to be those with a dedicated resource (e.g. a clinical recruiter or automated alert system) for identifying suitable participants that reduced the demand on healthcare professionals, but these were assessed in studies at high risk of bias.We would like to acknowledge the support of the Methodology theme of theCancer ExperiencesCollaborative (CECo), who have supported this review.This is the final published version. It first appeared at http://onlinelibrary.wiley.com/doi/10.1002/14651858.MR000036.pub2/abstract

Administering anticipatory medications in end-of-life care: A qualitative study of nursing practice in the community and in nursing homes

Background: In the United Kingdom, an approach to improving end-of-life care has been the introduction of ‘just in case’ or ‘anticipatory’ medications. Nurses are often responsible for deciding when to use anticipatory medications, but little is known about their experiences. Aim: To examine nurses’ decisions, aims and concerns when using anticipatory medications. Design: An ethnographic study in two UK regions, using observations and interviews with nurses working in community and nursing home teams (n = 8). Findings: Observations (n = 83) and interviews (n = 61) with community nurses. Nurses identified four ‘conditions’ that needed to be established before they implemented anticipatory medications: (1) irreversibility; (2) inability to take oral medication; (3) where the patient was able, they should consent and (4) decision had to be independent of demands or requests from patient’s relatives. By using anticipation medications, nurses sought to enable patients to be ‘comfortable and settled’ by provision of gradual relief of symptoms at the lowest dose possible. They aimed to respond quickly to needs, seeking to avoid hospital admission or medical call-out, while adhering to local prescribing policies. Worries included distinguishing between pain and agitation, balancing risks of under- and over-medication and the possibility of hastening death. Conclusion: Nurses take a leading role in the administration of anticipatory medications. Nurses apply consideration and caution to the administration of anticipatory medications but some experience emotional burden. Education, training and experience played a role in the nurses’ confidence and should continue to be central to efforts to improving the quality of palliative care in the community and nursing homes

Non-perturbative dynamics of hot non-Abelian gauge fields: beyond leading log approximation

Many aspects of high-temperature gauge theories, such as the electroweak baryon number violation rate, color conductivity, and the hard gluon damping rate, have previously been understood only at leading logarithmic order (that is, neglecting effects suppressed only by an inverse logarithm of the gauge coupling). We discuss how to systematically go beyond leading logarithmic order in the analysis of physical quantities. Specifically, we extend to next-to-leading-log order (NLLO) the simple leading-log effective theory due to Bodeker that describes non-perturbative color physics in hot non-Abelian plasmas. A suitable scaling analysis is used to show that no new operators enter the effective theory at next-to-leading-log order. However, a NLLO calculation of the color conductivity is required, and we report the resulting value. Our NLLO result for the color conductivity can be trivially combined with previous numerical work by G. Moore to yield a NLLO result for the hot electroweak baryon number violation rate.Comment: 20 pages, 1 figur