bluuebunny/crossref_metadata_2025_split huggingface dataset:
The 1918 Influenza Virus PB2 Protein Enhances Virulence through the Disruption of Inflammatory and Wnt-Mediated Signaling in Mice
Authors: Forero Adriana , Tisoncik-Go Jennifer , Watanabe Tokiko , Zhong Gongxun , Hatta Masato , Tchitchek Nicolas , Selinger Christian , Chang Jean , Barker Kristi , Morrison Juliet , Berndt Jason D. , Moon Randall T. , Josset Laurence , Kawaoka Yoshihiro , Katze Michael G. 
Published: December 2015

ABSTRACT
The 1918-1919 influenza pandemic remains the single greatest infectious disease outbreak in the past century. Mouse and nonhuman primate infection models have shown that the 1918 virus induces overly aggressive innate and proinflammatory responses. To understand the response to viral infection and the role of individual 1918 genes on the host response to the 1918 virus, we examined reassortant avian viruses nearly identical to the pandemic 1918 virus (1918-like avian virus) carrying either the 1918 hemagglutinin (HA) or PB2 gene. In mice, both genes enhanced 1918-like avian virus replication, but only the mammalian host adaptation of the 1918-like avian virus through reassortment of the 1918 PB2 led to increased lethality. Through the combination of viral genetics and host transcriptional profiling, we provide a multidimensional view of the molecular mechanisms by which the 1918 PB2 gene drives viral pathogenicity. We demonstrate that 1918 PB2 enhances immune and inflammatory responses concomitant with increased cellular infiltration in the lung. We also show for the first time, that 1918 PB2 expression results in the repression of both canonical and noncanonical Wnt signaling pathways, which are crucial for inflammation-mediated lung regeneration and repair. Finally, we utilize regulatory enrichment and network analysis to define the molecular regulators of inflammation, epithelial regeneration, and lung immunopathology that are dysregulated during influenza virus infection. Taken together, our data suggest that while both HA and PB2 are important for viral replication, only 1918 PB2 exacerbates lung damage in mice infected with a reassortant 1918-like avian virus.

IMPORTANCE
As viral pathogenesis is determined in part by the host response, understanding the key host molecular driver(s) of virus-mediated disease, in relation to individual viral genes, is a promising approach to host-oriented drug efforts in preventing disease. Previous studies have demonstrated the importance of host adaptive genes, HA and PB2, in mediating disease although the mechanisms by which they do so are still poorly understood. Here, we combine viral genetics and host transcriptional profiling to show that although both 1918 HA and 1918 PB2 are important mediators of efficient viral replication, only 1918 PB2 impacts the pathogenicity of an avian influenza virus sharing high homology to the 1918 pandemic influenza virus. We demonstrate that 1918 PB2 enhances deleterious inflammatory responses and the inhibition of regeneration and repair functions coordinated by Wnt signaling in the lungs of infected mice, thereby promoting virus-associated disease.
Molecular Basis of the Divergent Immunogenicity of Two Pediatric Tick-Borne Encephalitis Virus Vaccines
Authors: Beck Yvonne , Fritz Richard , Orlinger Klaus , Kiermayr Stefan , Ilk Reinhard , Portsmouth Daniel , Pöllabauer Eva-Maria , Löw-Baselli Alexandra , Hessel Annett , Kölch Doris , Howard M. Keith , Barrett P. Noel , Kreil Thomas R. 
Published: December 2015

ABSTRACT

Studies evaluating the immunogenicity of two pediatric tick-borne encephalitis virus (TBEV) vaccines have reported contradictory results. These vaccines are based on two different strains of the European TBEV subtype: FSME-Immun Junior is based on the Neudörfl (Nd) strain, whereas Encepur Children is based on the Karlsruhe (K23) strain. The antibody (Ab) response induced by these two vaccines might be influenced by antigenic differences in the envelope (E) protein, which is the major target of neutralizing antibodies. We used an established hybrid virus assay platform to compare the levels of induction of neutralizing antibodies against the two vaccine virus strains in children aged 1 to 11 years who received two immunizations with FSME-Immun Junior or Encepur Children. The influence of amino acid differences between the E proteins of the Nd and K23 vaccine strains was investigated by mutational analyses and three-dimensional computer modeling. FSME-Immun Junior induced 100% seropositivity and similar neutralizing antibody titers against hybrid viruses containing the TBEV E protein of the two vaccine strains. Encepur Children induced 100% seropositivity only against the hybrid virus containing the E protein of the homologous K23 vaccine strain. Antibody responses induced by Encepur Children to the hybrid virus containing the E protein of the heterologous Nd strain were substantially and significantly (
P
< 0.001) lower than those to the K23 vaccine strain hybrid virus. Structure-based mutational analyses of the TBEV E protein indicated that this is due to a mutation in the DI-DII hinge region of the K23 vaccine strain E protein which may have occurred during production of the vaccine seed virus and which is not present in any wild-type TBE viruses.

IMPORTANCE
Our data suggest that there are major differences in the abilities of two European subtype pediatric TBEV vaccines to induce antibodies capable of neutralizing heterologous TBEV strains. This is a result of a mutation in the DI-DII hinge region of the E protein of the K23 vaccine virus strain used to manufacture Encepur Children which is not present in the Nd strain used to manufacture FSME-Immun Junior or in any other known naturally occurring TBEVs.
The Basic Domain of Herpes Simplex Virus 1 pUS9 Recruits Kinesin-1 To Facilitate Egress from Neurons
Authors: Diefenbach Russell J. , Davis April , Miranda-Saksena Monica , Fernandez Marian A. , Kelly Barbara J. , Jones Cheryl A. , LaVail Jennifer H. , Xue Jing , Lai Joey , Cunningham Anthony L. 
Published: December 2015

ABSTRACT

The alphaherpesviral envelope protein pUS9 has been shown to play a role in the anterograde axonal transport of herpes simplex virus 1 (HSV-1), yet the molecular mechanism is unknown. To address this, we used an
in vitro
pulldown assay to define a series of five arginine residues within the conserved pUS9 basic domain that were essential for binding the molecular motor kinesin-1. The mutation of these pUS9 arginine residues to asparagine blocked the binding of both recombinant and native kinesin-1. We next generated HSV-1 with the same pUS9 arginine residues mutated to asparagine (HSV-1pUS9KBDM) and then restored them being to arginine (HSV-1pUS9KBDR). The two mutated viruses were analyzed initially in a zosteriform model of recurrent cutaneous infection. The primary skin lesion scores were identical in severity and kinetics, and there were no differences in viral load at dorsal root ganglionic (DRG) neurons at day 4 postinfection (p.i.) for both viruses. In contrast, HSV-1pUS9KBDM showed a partial reduction in secondary skin lesions at day 8 p.i. compared to the level for HSV-1pUS9KBDR. The use of rat DRG neuronal cultures in a microfluidic chamber system showed both a reduction in anterograde axonal transport and spread from axons to nonneuronal cells for HSV-1pUS9KBDM. Therefore, the basic domain of pUS9 contributes to anterograde axonal transport and spread of HSV-1 from neurons to the skin through recruitment of kinesin-1.

IMPORTANCE
Herpes simplex virus 1 and 2 cause genital herpes, blindness, encephalitis, and occasionally neonatal deaths. There is also increasing evidence that sexually transmitted genital herpes increases HIV acquisition, and the reactivation of HSV increases HIV replication and transmission. New antiviral strategies are required to control resistant viruses and to block HSV spread, thereby reducing HIV acquisition and transmission. These aims will be facilitated through understanding how HSV is transported down nerves and into skin. In this study, we have defined how a key viral protein plays a role in both axonal transport and spread of the virus from nerve cells to the skin.
Risk and protective factors for falls on stairs in young children: multicentre case–control study
Authors: Kendrick D , Zou K , Ablewhite J , Watson M , Coupland C , Kay B , Hawkins A , Reading R 
Published: December 2015

AimTo investigate risk and protective factors for stair falls in children aged <5 years.MethodsMulticentre case–control study at hospitals, minor injury units and general practices in and around four UK study centres. Cases were children with medically attended stair fall injuries. Controls were matched on age, sex, calendar time and study centre. A total of 610 cases and 2658 controls participated.ResultsCases’ most common injuries were bangs on the head (66%), cuts/grazes not requiring stitches (14%) and fractures (12%). Parents of cases were significantly more likely not to have stair gates (adjusted OR (AOR) 2.50, 95% CI 1.90 to 3.29; population attributable fraction (PAF) 21%) or to leave stair gates open (AOR 3.09, 95% CI 2.39 to 4.00; PAF 24%) both compared with having closed stair gates. They were more likely not to have carpeted stairs (AOR 1.52, 95% CI 1.09 to 2.10; PAF 5%) and not to have a landing part-way up their stairs (AOR 1.34, 95% CI 1.08 to 1.65; PAF 18%). They were more likely to consider their stairs unsafe to use (AOR 1.46, 95% CI 1.07 to 1.99; PAF 5%) or to be in need of repair (AOR 1.71, 95% CI 1.16 to 2.50; PAF 5%).ConclusionStructural factors including having landings part-way up the stairs and keeping stairs in good repair were associated with reduced stair fall injury risk. Family factors including having stair gates, not leaving gates open and having stair carpets were associated with reduced injury risk. If these associations are causal, addressing these factors in housing policy and routine child health promotion could reduce stair fall injuries.
Characteristics of admissions and variations in the use of basic investigations, treatments and outcomes in Kenyan hospitals within a new Clinical Information Network
Authors: Ayieko Philip , Ogero Morris , Makone Boniface , Julius Thomas , Mbevi George , Nyachiro Wycliffe , Nyamai Rachel , Were Fred , Githanga David , Irimu Grace , English Mike 
Published: December 2015

BackgroundLack of detailed information about hospital activities, processes and outcomes hampers planning, performance monitoring and improvement in low-income countries (LIC). Clinical networks offer one means to advance methods for data collection and use, informing wider health system development in time, but are rare in LIC. We report baseline data from a new Clinical Information Network (CIN) in Kenya seeking to promote data-informed improvement and learning.MethodsData from 13 hospitals engaged in the Kenyan CIN between April 2014 and March 2015 were captured from medical and laboratory records. We use these data to characterise clinical care and outcomes of hospital admission.ResultsData were available for a total of 30 042 children aged between 2 months and 15 years. Malaria (in five hospitals), pneumonia and diarrhoea/dehydration (all hospitals) accounted for the majority of diagnoses and comorbidity was found in 17 710 (59%) patients. Overall, 1808 deaths (6%) occurred (range per hospital 2.5%–11.1%) with 1037 deaths (57.4%) occurring by day 2 of admission (range 41%–67.8%). While malaria investigations are commonly done, clinical health workers rarely investigate for other possible causes of fever, test for blood glucose in severe illness or ascertain HIV status of admissions. Adherence to clinical guideline-recommended treatment for malaria, pneumonia, meningitis and acute severe malnutrition varied widely across hospitals.ConclusionDeveloping clinical networks is feasible with appropriate support. Early data demonstrate that hospital mortality remains high in Kenya, that resources to investigate severe illness are limited, that care provided and outcomes vary widely and that adoption of effective interventions remains slow. Findings suggest considerable scope for improving care within and across sites.
Application of an autoregressive integrated moving average model for predicting injury mortality in Xiamen, China
Authors: Lin Yilan , Chen Min , Chen Guowei , Wu Xiaoqing , Lin Tianquan 
Published: December 2015

ObjectiveInjury is currently an increasing public health problem in China. Reducing the loss due to injuries has become a main priority of public health policies. Early warning of injury mortality based on surveillance information is essential for reducing or controlling the disease burden of injuries. We conducted this study to find the possibility of applying autoregressive integrated moving average (ARIMA) models to predict mortality from injuries in Xiamen.MethodThe monthly mortality data on injuries in Xiamen (1 January 2002 to 31 December 2013) were used to fit the ARIMA model with the conditional least-squares method. The values p, q and d in the ARIMA (p, d, q) model refer to the numbers of autoregressive lags, moving average lags and differences, respectively. The Ljung–Box test was used to measure the ‘white noise’ and residuals. The mean absolute percentage error (MAPE) between observed and fitted values was used to evaluate the predicted accuracy of the constructed models.ResultsA total of 8274 injury-related deaths in Xiamen were identified during the study period; the average annual mortality rate was 40.99/100 000 persons. Three models, ARIMA (0, 1, 1), ARIMA (4, 1, 0) and ARIMA (1, 1, (2)), passed the parameter (p<0.01) and residual (p>0.05) tests, with MAPE 11.91%, 11.96% and 11.90%, respectively. We chose ARIMA (0, 1, 1) as the optimum model, the MAPE value for which was similar to that of other models but with the fewest parameters. According to the model, there would be 54 persons dying from injuries each month in Xiamen in 2014.ConclusionThe ARIMA (0, 1, 1) model could be applied to predict mortality from injuries in Xiamen.
Diagnostic accuracy of the Whooley questions for the identification of depression: a diagnostic meta-analysis
Authors: Bosanquet Katharine , Bailey Della , Gilbody Simon , Harden Melissa , Manea Laura , Nutbrown Sarah , McMillan Dean 
Published: December 2015

ObjectivesTo determine the diagnostic accuracy of the Whooley questions in the identification of depression; and, to examine the effect of an additional ‘help’ question.DesignSystematic review with random effects bivariate diagnostic meta-analysis. Search strategies included electronic databases, examination of reference lists, and forward citation searches.Inclusion criteriaStudies were included that provided sufficient data to calculate the diagnostic accuracy of the Whooley questions against a gold standard diagnosis of major depression.Data extractionDescriptive information, methodological quality criteria, and 2×2 contingency tables were extracted.ResultsTen studies met inclusion criteria. Pooled sensitivity was 0.95 (95% CI 0.88 to 0.97) and pooled specificity was 0.65 (95% CI 0.56 to 0.74). Heterogeneity was low (I2=24.1%). Primary care subgroup analysis gave broadly similar results. Four of the ten studies provided information on the effect of an additional help question. The addition of this question did not consistently improve specificity while retaining high sensitivity as reported in the original validation study.ConclusionsThe two-item Whooley questions have high sensitivity and modest specificity in the detection of depression. The current evidence for the use of an additional help question is not consistent and there is, as yet, insufficient data to recommend its use for screening or case finding.Trial registration numberCRD42014009695.
Does the engagement of clinicians and organisations in research improve healthcare performance: a three-stage review
Authors: Boaz Annette , Hanney Stephen , Jones Teresa , Soper Bryony 
Published: December 2015

ObjectiveThere is a widely held assumption that engagement by clinicians and healthcare organisations in research improves healthcare performance at various levels, but little direct empirical evidence has previously been collated. The objective of this study was to address the question: Does research engagement (by clinicians and organisations) improve healthcare performance?MethodsAn hourglass-shaped review was developed, consisting of three stages: (1) a planning and mapping stage; (2) a focused review concentrating on the core question of whether or not research engagement improves healthcare performance; and (3) a wider (but less systematic) review of papers identified during the two earlier stages, focusing on mechanisms.ResultsOf the 33 papers included in the focused review, 28 identified improvements in health services performance. Seven out of these papers reported some improvement in health outcomes, with others reporting improved processes of care. The wider review demonstrated that mechanisms such as collaborative and action research can encourage some progress along the pathway from research engagement towards improved healthcare performance. Organisations that have deliberately integrated the research function into organisational structures demonstrate how research engagement can, among other factors, contribute to improved healthcare performance.ConclusionsCurrent evidence suggests that there is an association between the engagement of individuals and healthcare organisations in research and improvements in healthcare performance. The mechanisms through which research engagement might improve healthcare performance overlap and rarely act in isolation, and their effectiveness often depends on the context in which they operate.
Educators’ perspectives about how older hospital patients can engage in a falls prevention education programme: a qualitative process evaluation
Authors: Hill Anne-Marie , McPhail Steven M , Francis-Coad Jacqueline , Waldron Nicholas , Etherton-Beer Christopher , Flicker Leon , Ingram Katharine , Haines Terry P 
Published: December 2015

ObjectivesFalls are the most frequent adverse event reported in hospitals. Patient and staff education delivered by trained educators significantly reduced falls and injurious falls in an older rehabilitation population. The purpose of the study was to explore the educators’ perspectives of delivering the education and to conceptualise how the programme worked to prevent falls among older patients who received the education.DesignA qualitative exploratory study.MethodsData were gathered from three sources: conducting a focus group and an interview (n=10 educators), written educator notes and reflective researcher field notes based on interactions with the educators during the primary study. The educators delivered the programme on eight rehabilitation wards for periods of between 10 and 40 weeks. They provided older patients with individualised education to engage in falls prevention and provided staff with education to support patient actions. Data were thematically analysed and presented using a conceptual framework.ResultsFalls prevention education led to mutual understanding between staff and patients which assisted patients to engage in falls prevention behaviours. Mutual understanding was derived from the following observations: the educators perceived that they could facilitate an effective three-way interaction between staff actions, patient actions and the ward environment which led to behaviour change on the wards. This included engaging with staff and patients, and assisting them to reconcile differing perspectives about falls prevention behaviours.ConclusionsIndividualised falls prevention education effectively provides patients who receive it with the capability and motivation to develop and undertake behavioural strategies that reduce their falls, if supported by staff and the ward environment.
Yang–Mills gauge theory and Higgs particle
Authors: Wu Tai Tsun , Wu Sau Lan 
Published: December 2015

Motivated by the experimental data on the Higgs particle from the ATLAS Collaboration and the CMS Collaboration at CERN, the standard model, which is a Yang–Mills non-Abelian gauge theory with the group [Formula: see text], is augmented by scalar quarks and scalar leptons without changing the gauge group and without any additional Higgs particle. Thus there is fermion–boson symmetry between these new particles and the known quarks and leptons. In a simplest scenario, the cancellation of the quadratic divergences in this augmented standard model leads to a determination of the masses of all these scalar quarks and scalar leptons. All these masses are found to be less than 100 GeV/c2, and the right-handed scalar neutrinos are especially light. Alterative procedures are given with less reliance on the experimental data, leading to the same conclusions.
Discovery of the first Yang–Mills gauge particle — The gluon
Authors: Wu Sau Lan 
Published: December 2015

This article “Discovery of the First Yang–Mills Gauge Particle — The Gluon” is dedicated to Professor Chen Ning Yang. The Gluon is the first Yang–Mills non-Abelian gauge particle discovered experimentally. The Yang–Mills non-Abelian gauge field theory was proposed by Yang and Mills in 1954, sixty years ago. The experimental discovery of the first Yang–Mills non-Abelian gauge particle — the gluon — in the spring of 1979 is summarized, together with some of the subsequent developments, including the role of the gluon in the recent discovery of the Higgs particle.
Kähler potential braneworld inflation in supergravity after Planck 2015
Authors: Ferricha-Alami M. , Safsafi A. , Bouaouda A. , Zarrouki R. , Bennai M. 
Published: December 2015

We analyze the slow-roll mechanism in Randall–Sundrum II braneworld with a supersymmetric hybrid inflation model. We are interested in studying various inflationary spectrum perturbation parameters in two cases. The first is the minimal Kähler potential where the inflationary parameters depend on the number of [Formula: see text]-foldings [Formula: see text] as well as the brane tension [Formula: see text], such that we produce the central value of the spectral index [Formula: see text]. The second case concerns the nonminimal Kähler potential, where the inflationary parameters depend only on the brane tension. Also, the [Formula: see text]-problem is solved for natural coupling parameter values which is not realized in the standard case. In addition, for a suitable choice of brane tension value [Formula: see text], the perturbation spectrum is widely consistent with Planck data.
Reactive transport modelling of compacting siliciclastic sediment diagenesis
Authors: Geloni C. , Ortenzi A. , Consonni A. 
Published: December 2015

Abstract
A reactive transport model (RTM) is used to simulate the diagenetic evolution of a siliciclastic reservoir with a known burial and thermal history. The diagenetic phenomena occurring in two temperature regimes are simulated: kaolinite/chlorite formation at low/medium temperatures by means of isothermal zero-dimensional (0D) flush models, and smectite illitization and quartz precipitation at high temperatures by means of 0D and 1D non-isothermal models.
Zero-dimensional models show that at 30°C kaolinite forms only in freshwater from K-feldspar and quartz. In river or seawater, muscovite is stable instead of kaolinite. Calcite formation depends on pH and total inorganic carbon. At 50°C, seawater promotes Mg-chlorite formation from mica alterations. At 70–110°C, evaporated seawater favours smectite–illite transformation and quartz precipitation.
The non-isothermal 1D models are used to simulate the diagenesis of a compacting clay expelling fluid into an underlying sandstone.
An sensitivity analysis of the clays’ thermodynamic and kinetic parameters is carried out to assess the possibility of modelling the transformation of smectite into illite in the clay, with the concomitant formation of a quartz cement in the adjacent sandstone. The results of the numerical simulations point out that the extent of the smectite–illite conversion and quartz precipitation is dependent primarily on the availability of potassium: temperature, however, does not seem to play a major role.