bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Acid Stability of the Hemagglutinin Protein Enhances H5N1 Influenza Virus Growth in the Upper Respiratory Tract but Is Insufficient for Transmission in Ferrets
Authors: Zaraket Hassan , Bridges Olga A. , Duan Susu , Baranovich Tatiana , Yoon Sun-Woo , Reed Mark L. , Salomon Rachelle , Webby Richard J. , Webster Robert G. , Russell Charles J. 
Published: July 2013

ABSTRACT
Influenza virus entry is mediated by the acidic-pH-induced activation of hemagglutinin (HA) protein. Here, we investigated how a decrease in the HA activation pH (an increase in acid stability) influences the properties of highly pathogenic H5N1 influenza virus in mammalian hosts. We generated isogenic A/Vietnam/1203/2004 (H5N1) (VN1203) viruses containing either wild-type HA protein (activation pH 6.0) or an HA2-K58I point mutation (K to I at position 58) (activation pH 5.5). The VN1203-HA2-K58I virus had replication kinetics similar to those of wild-type VN1203 in MDCK and normal human bronchial epithelial cells and yet had reduced growth in human alveolar A549 cells, which were found to have a higher endosomal pH than MDCK cells. Wild-type and HA2-K58I viruses promoted similar levels of morbidity and mortality in C57BL/6J mice and ferrets, and neither virus transmitted efficiently to naive contact cage-mate ferrets. The acid-stabilizing HA2-K58I mutation, which diminishes H5N1 replication and transmission in ducks, increased the virus load in the ferret nasal cavity early during infection while simultaneously reducing the virus load in the lungs. Overall, a single, acid-stabilizing mutation was found to enhance the growth of an H5N1 influenza virus in the mammalian upper respiratory tract, and yet it was insufficient to enable contact transmission in ferrets in the absence of additional mutations that confer α(2,6) receptor binding specificity and remove a critical N-linked glycosylation site. The information provided here on the contribution of HA acid stability to H5N1 influenza virus fitness and transmissibility in mammals in the background of a non-laboratory-adapted virus provides essential information for the surveillance and assessment of the pandemic potential of currently circulating H5N1 viruses.
Influences on Trimerization and Aggregation of Soluble, Cleaved HIV-1 SOSIP Envelope Glycoprotein
Authors: Klasse Per Johan , Depetris Rafael S. , Pejchal Robert , Julien Jean-Philippe , Khayat Reza , Lee Jeong Hyun , Marozsan Andre J. , Cupo Albert , Cocco Nicolette , Korzun Jacob , Yasmeen Anila , Ward Andrew B. , Wilson Ian A. , Sanders Rogier W. , Moore John P. 
Published: July 2013

ABSTRACT
We describe methods to improve the properties of soluble, cleaved gp140 trimers of the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) for use in structural studies and as immunogens. In the absence of nonionic detergents, gp140 of the KNH1144 genotype, terminating at residue 681 in gp41 (SOSIP.681), has a tendency to form higher-order complexes or aggregates, which is particularly undesirable for structure-based research. We found that this aggregation in the absence of detergent does not involve the V1, V2, or V3 variable regions of gp120. Moreover, we observed that detergent forms micelles around the membrane-proximal external region (MPER) of the SOSIP.681 gp140 trimers, whereas deletion of most of the MPER residues by terminating the gp140 at residue 664 (SOSIP.664) prevented the aggregation that otherwise occurs in SOSIP.681 in the absence of detergent. Although the MPER can contribute to trimer formation, truncation of most of it only modestly reduced trimerization and lacked global adverse effects on antigenicity. Thus, the MPER deletion minimally influenced the kinetics of the binding of soluble CD4 and a CD4-binding site antibody to immobilized trimers, as detected by surface plasmon resonance. Furthermore, the MPER deletion did not alter the overall three-dimensional structure of the trimers, as viewed by negative-stain electron microscopy. Homogeneous and aggregate-free MPER-truncated SOSIP Env trimers are therefore useful for immunogenicity and structural studies.
Endothelial Cell Stimulation Overcomes Restriction and Promotes Productive and Latent HIV-1 Infection of Resting CD4
+
T Cells
Authors: Shen Anding , Baker Jacob J. , Scott Geoffrey L. , Davis Yelena P. , Ho Yen-Yi , Siliciano Robert F. 
Published: July 2013

ABSTRACT

Highly active antiretroviral therapy (HAART) is able to suppress human immunodeficiency virus type 1 (HIV-1) to undetectable levels in the majority of patients, but eradication has not been achieved because latent viral reservoirs persist, particularly in resting CD4
+
T lymphocytes. It is generally understood that HIV-1 does not efficiently infect resting CD4
+
T cells, and latent infection in those cells may arise when infected CD4
+
T lymphoblasts return to resting state. In this study, we found that stimulation by endothelial cells can render resting CD4
+
T cells permissible for direct HIV infection, including both productive and latent infection. These stimulated T cells remain largely phenotypically unactivated and show a lower death rate than activated T cells, which promotes the survival of infected cells. The stimulation by endothelial cells does not involve interleukin 7 (IL-7), IL-15, CCL19, or CCL21. Endothelial cells line the lymphatic vessels in the lymphoid tissues and have frequent interactions with T cells
in vivo
. Our study proposes a new mechanism for infection of resting CD4
+
T cells
in vivo
and a new mechanism for latent infection in resting CD4
+
T cells.
Rapid Generation of Replication-Deficient Monovalent and Multivalent Vaccines for Bluetongue Virus: Protection against Virulent Virus Challenge in Cattle and Sheep
Authors: Celma Cristina C. P. , Boyce Mark , van Rijn Piet A. , Eschbaumer Michael , Wernike Kerstin , Hoffmann Bernd , Beer Martin , Haegeman Andy , De Clercq Kris , Roy Polly 
Published: July 2013

ABSTRACT
Since 1998, 9 of the 26 serotypes of bluetongue virus (BTV) have spread throughout Europe, and serotype 8 has suddenly emerged in northern Europe, causing considerable economic losses, direct (mortality and morbidity) but also indirect, due to restriction in animal movements. Therefore, many new types of vaccines, particularly subunit vaccines, with improved safety and efficacy for a broad range of BTV serotypes are currently being developed by different laboratories. Here we exploited a reverse genetics-based replication-deficient BTV serotype 1 (BTV-1) (disabled infectious single cycle [DISC]) strain to generate a series of DISC vaccine strains. Cattle and sheep were vaccinated with these viruses either singly or in cocktail form as a multivalent vaccine candidate. All vaccinated animals were seroconverted and developed neutralizing antibody responses to their respective serotypes. After challenge with the virulent strains at 21 days postvaccination, vaccinated animals showed neither any clinical reaction nor viremia. Further, there was no interference with protection with a multivalent preparation of six distinct DISC viruses. These data indicate that a very-rapid-response vaccine could be developed based on which serotypes are circulating in the population at the time of an outbreak.
The 12-lead ECG in the emergency medical service setting: how electrode placement and paramedic gender are experienced by women
Authors: Wallen Rachael , Tunnage Bronwyn , Wells Susan 
Published: July 2013

AimThe aim of this study was to explore women’s attitudes to precordial electrode placement and 12-lead ECG acquisition in the emergency medical service setting.MethodFifty participants were recruited from university campuses. Demographic data were collected and two ECGs were recorded: one with precordial electrodes positioned on the breast and one with the electrodes under the breast. Participants’ attitudes to electrode placement and ECG acquisition were explored in a second questionnaire.ResultsTwenty-six participants (52%) preferred to have the electrodes placed on their breast, 19 (38%) were indifferent between the two placements and 5 (10%) preferred siting under the breast. 94% of the participants stated they would consent to a prehospital ECG irrespective of the gender of the paramedic crew, and all reported they would have the investigation if it facilitated definitive treatment, even if the paramedic was male.ConclusionsThe majority of participants preferred electrode placement on the breast and would consent to ECG acquisition irrespective of the gender of the operator. It is possible that paramedics are more concerned with the acceptability of acquiring an ECG than women are themselves.
Medical students’ experiences and perception of support following the death of a patient in the UK, and while overseas during their elective period
Authors: Jones Rachel , Finlay Fiona 
Published: July 2013

Abstract

Aims
To investigate medical students’ experiences and perception of support following a patient’s death, contrasting their experiences in the UK, and while overseas during their elective period.

Methods
An anonymous online questionnaire was distributed to all final year medical students at one UK medical school in November 2009.

Results
220 students were contacted, 60% responded. 72% (94) of medical students had been involved in end-of-life care at some point during their course; students on elective experiencing patient death across all ages. Some students saw many patients dying during their elective period. Students had mixed emotions following a patient’s death. In the UK, students reported feeling shocked, upset and sad. When overseas, many students were angry or frustrated, and many reported feelings of injustice. Following a death, students found talking to people beneficial, but when overseas they turned to friends and family using email and Facebook, rather than talking to local doctors and nurses. Only 13% (16) of medical students thought their medical training had prepared them sufficiently to deal with death. Of those who did feel prepared some said they had gained this knowledge through working as a healthcare assistant.

Conclusions
Students feel ill prepared for experiencing the death of a patient. Even though they may have ‘medical knowledge’ they are still lacking in emotional support and are often inadequately supported around the time of a patient’s death. Medical schools should consider their curricula so that students are aware of the possible experiences and emotions which they may face when involved with the death of a patient, and students should be given advice on whom to turn to for support.
KEAP1-Dependent Synthetic Lethality Induced by AKT and TXNRD1 Inhibitors in Lung Cancer
Authors: Dai Bingbing , Yoo Suk-Young , Bartholomeusz Geoffrey , Graham Ryan A. , Majidi Mourad , Yan Shaoyu , Meng Jieru , Ji Lin , Coombes Kevin , Minna John D. , Fang Bingliang , Roth Jack A. 
Published: July 2013

Abstract
Intrinsic resistance to agents targeting phosphoinositide 3-kinase (PI3K)/AKT pathway is one of the major challenges in cancer treatment with such agents. The objective of this study is to identify the genes or pathways that can be targeted to overcome the resistance of non–small cell lung carcinoma (NSCLC) to the AKT inhibitor MK2206, which is currently being evaluated in phase I and II clinical trials. Using a genome-wide siRNA library screening and biologic characterization, we identified that inhibition of thioredoxin reductase-1 (TXNRD1), one of the key antioxidant enzymes, with siRNAs or its inhibitor, auranofin, sensitized NSCLC cells to MK2206 treatment in vitro and in vivo. We found that simultaneous inhibition of TXNRD1 and AKT pathways induced robust reactive oxygen species production, which was involved in c-jun-NH2-kinase (JNK; MAPK8) activation and cell apoptosis. Furthermore, we found that the synthetic lethality interaction between the TXNRD1 and AKT pathways occurred through the KEAP1/NRF2 cellular antioxidant pathway. Finally, we found that synthetic lethality induced by TXNRD1 and AKT inhibitors relied on wild-type KEAP1 function. Our study indicates that targeting the interaction between AKT and TXNRD1 antioxidant pathways with MK2206 and auranofin, a U.S. Food and Drug Administration-approved drug, is a rational strategy to treat lung cancer and that KEAP1 mutation status may offer a predicative biomarker for such combination approaches. Cancer Res; 73(17); 5532–43. ©2013 AACR.
Targeting Protein Tyrosine Phosphatase SHP2 for the Treatment ofPTPN11-Associated Malignancies
Authors: Yu Bing , Liu Wei , Yu Wen-Mei , Loh Mignon L. , Alter Shawn , Guvench Olgun , MacKerell Alexander D. , Tang Li-Da , Qu Cheng-Kui 
Published: July 2013

AbstractActivating mutations in PTPN11 (encoding SHP2), a protein tyrosine phosphatase (PTP) that plays an overall positive role in growth factor and cytokine signaling, are directly associated with the pathogenesis of Noonan syndrome and childhood leukemias. Identification of SHP2-selective inhibitors could lead to the development of new drugs that ultimately serve as treatments for PTPN11-associated diseases. As the catalytic core of SHP2 shares extremely high homology to those of SHP1 and other PTPs that play negative roles in cell signaling, to identify selective inhibitors of SHP2 using computer-aided drug design, we targeted a protein surface pocket that is adjacent to the catalytic site, is predicted to be important for binding to phosphopeptide substrates, and has structural features unique to SHP2. From computationally selected candidate compounds, #220–324 effectively inhibited SHP2 activity with an IC50 of 14 μmol/L. Fluorescence titration experiments confirmed its direct binding to SHP2. This active compound was further verified for its ability to inhibit SHP2-mediated cell signaling and cellular function with minimal off-target effects. Furthermore, mouse myeloid progenitors with the activating mutation (E76K) in PTPN11 and patient leukemic cells with the same mutation were more sensitive to this inhibitor than wild-type cells. This study provides evidence that SHP2 is a “druggable” target for the treatment of PTPN11-associated diseases. As the small-molecule SHP2 inhibitor identified has a simple chemical structure, it represents an ideal lead compound for the development of novel anti-SHP2 drugs. Mol Cancer Ther; 12(9); 1738–48. ©2013 AACR.
Utilisation of entomopathogenic nematodes, Heterorhabditis spp. and Steinernema spp., for the control of Agrotis ipsilon (Lepidoptera, Noctuidae) in China
Authors: Yan Xun , Wang Xiandong , Han Richou , Qiu Xuehong 
Published: July 2013

Entomopathogenic nematodes (EPN) have good application prospects for the control of the black cutworm, Agrotis ipsilon. In the present study, the effects of isolate, exposure rate, temperature and larval stage on EPN infectivity to A. ipsilon were evaluated. Results of in vitro tests showed that Steinernema carpocapsae Mex and Heterorhabditis indica LN2 were the most virulent and promising species, causing 80.0 and 83.3% mortality, respectively, to the third instar larvae at 25°C and 72 h after infection. Mortality of A. ipsilon caused by the nematodes was significantly affected by EPN exposure rate, temperature and the larval stage. Both S. carpocapsae and H. indica caused greater mortality to the third instar of A. ipsilon at 25°C than at 15, 20 and 30°C. Both EPN isolates also caused higher mortality to the second instar than to the third and fourth instar larvae of A. ipsilon. The field trials of EPN for the control of A. ipsilon also showed that S. carpocapsae Mex and H. indica LN2 reduced the damage caused by A. ipsilon and increased the cabbage yield when compared with the control. Both EPN isolates showed better control effects than cyfluthrin and Bacillus thuringiensis, indicating that these two EPN isolates could be used for sustainable control of A. ipsilon in vegetable fields in China.
Radiative Impacts of Free-Tropospheric Clouds on the Properties of Marine Stratocumulus
Authors: Christensen Matthew W. , Carrió Gustavo G. , Stephens Graeme L. , Cotton William R. 
Published: July 2013

Abstract
Observations from multiple satellites and large-eddy simulations (LESs) from the Regional Atmospheric Modeling System (RAMS) are used to determine the extent to which free-tropospheric clouds (FTCs) affect the properties of stratocumulus. Overlying FTCs decrease the cloud-top radiative cooling in stratocumulus by an amount that depends on the upper-cloud base altitude, cloud optical thickness, and abundance of moisture between the cloud layers. On average, FTCs increase the downward longwave radiative flux above stratocumulus clouds (at 3.5 km) by approximately 30 W m−2. As a consequence, this forcing translates to a relative decrease in stratocumulus cooling rates by about 20%. Overall, the reduced cloud-top radiative cooling decreases the turbulent mixing, vertical development, and precipitation rate in stratocumulus clouds at night. During the day these effects are greatly reduced because the overlying clouds shade the stratocumulus from strong solar radiation, thus reducing the net radiative effect by the upper cloud. Differences in liquid water path are also observed in stratocumulus; however, the response is tied to the diurnal cycle and the time scale of interaction between the FTCs and the stratocumulus. Radiative effects by FTCs tend to be largest in the midlatitudes where the clouds overlying stratocumulus tend to be more frequent, lower, and thicker on average. In conclusion, changes in net radiation and moisture brought about by FTCs can significantly affect the dynamics of marine stratocumulus and these processes should be considered when evaluating cloud feedbacks in the climate system.
Sensitivity of Convective Initiation Prediction to Near-Surface Moisture When Assimilating Radar Refractivity: Impact Tests Using OSSEs
Authors: Gasperoni Nicholas A. , Xue Ming , Palmer Robert D. , Gao Jidong 
Published: July 2013

Abstract
The Advanced Regional Prediction System (ARPS) three-dimensional variational (3DVAR) system is enhanced to include the analysis of radar-derived refractivity measurements. These refractivity data are most sensitive to atmospheric moisture content and provide high-resolution information on near-surface moisture that is important to convective initiation (CI) and precipitation forecasting. Observing system simulation experiments (OSSEs) are performed using simulated refractivity data. The impacts of refractivity on CI and subsequent forecasts are investigated in the presence of varying observation error, radar location, data coverage, and different uncertainties in the background field. Cycled refractivity assimilation and forecasts are performed and the results compared to the truth. In addition to the perfect model experiments, imperfect model experiments are performed where the forecasts use the Weather Research and Forecasting (WRF) model instead of the ARPS. A simulation for the 19 May 2010 central plain convection case is used for the OSSEs. It involves a large storm system, large convective available potential energy, and little convective inhibition, allowing for CI along a warm front in northern Oklahoma and ahead of a dryline later to the southwest. Emphasis is placed on the quality of moisture analyses and the subsequent forecasts of CI. Results show the ability of refractivity assimilation to correct low-level moisture errors, leading to improved CI forecasts. Equitable threat scores for reflectivity are generally higher when refractivity data are assimilated. Tests show small sensitivity to increased observational error or ground clutter coverage, and greater sensitivity to the limited data coverage of a single radar.
Income and child mortality in developing countries: a systematic review and meta-analysis
Authors: O'Hare Bernadette , Makuta Innocent , Chiwaula Levison , Bar-Zeev Naor 
Published: July 2013

Objective We aimed to quantify the relationship between national income and infant and under-five mortality in developing countries. Design We conducted a systematic literature search of studies that examined the relationship between income and child mortality (infant and/or under-five mortality) and meta-analysed their results. Setting Developing countries. Main outcome measures Child mortality (infant and /or under-five mortality). Results The systematic literature search identified 24 studies, which produced 38 estimates that examined the impact of income on the mortality rates. Using meta-analysis, we produced pooled estimates of the relationship between income and mortality. The pooled estimate of the relationship between income and infant mortality before adjusting for covariates is −0.95 (95% CI −1.34 to −0.57) and that for under-five mortality is −0.45 (95% CI −0.79 to −0.11). After adjusting for covariates, pooled estimate of the relationship between income and infant mortality is −0.33 (−0.39 to −0.26) while the estimate for under-five mortality is −0.28 (−0.37 to −0.19). If a country has an infant mortality of 50 per 1000 live births and the gross domestic product per capita purchasing power parity increases by 10%, the infant mortality will decrease to 45 per 1000 live births. Conclusion Income is an important determinant of child survival and this work provides a pooled estimate for the relationship.
An evaluation of the psychological impact of operational rest and recuperation in United Kingdom Armed Forces personnel: a post-intervention survey
Authors: Jones Norman , Fertout Mohammed , Parsloe Laura , Greenberg Neil 
Published: July 2013

Objective Rest and Recuperation (R&R) is a period of home leave taken during an operational deployment; we sought to examine the relationship between taking R&R and mental health. Design A survey-based post-intervention evaluation. Setting UK Participants 232 members of the UK Armed Forces; 42 of which completed pre and post R&R surveys. Main Outcome Measures Alcohol use, Post Traumatic Stress Disorder, Common Mental Disorder Symptoms and R&R experiences. Results 12.1% of respondents (n=27) reported symptoms of common mental disorder and 3.7% (n=8) reported probable PTSD. 50.0% (n=110) reported hazardous use of alcohol during R&R. In the pre- and post-assessed sample, mental health status and alcohol use levels were similar at both survey points. Using principal component analysis, five components of R&R were identified; mentally switching off from deployment, travel experience, physical recovery, relaxation, rest and social support. R&R was extremely popular and although it did not improve mental health overall, the ability to engage with or derive satisfaction from aspects of the five components was significantly associated with better mental health and less alcohol use at the end of R&R. Conclusion Operational commanders should advise personnel about the best way to actively engage with R&R before they leave theatre and be aware of the significant detrimental impact of disrupted travel arrangements upon the ability to benefit from R&R.