bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transfer of the Amino-Terminal Nuclear Envelope Targeting Domain of Human MX2 Converts MX1 into an HIV-1 Resistance Factor
Authors: Goujon Caroline , Moncorgé Olivier , Bauby Hélène , Doyle Tomas , Barclay Wendy S. , Malim Michael H. 
Published: June 2014

ABSTRACTThe myxovirus resistance 2 (MX2) protein of humans has been identified recently as an interferon (IFN)-inducible inhibitor of human immunodeficiency virus type 1 (HIV-1) that acts at a late postentry step of infection to prevent the nuclear accumulation of viral cDNA (C. Goujon et al., Nature 502:559–562, 2013,http://dx.doi.org/10.1038/nature12542; M. Kane et al., Nature 502:563–566, 2013,http://dx.doi.org/10.1038/nature12653; Z. Liu et al., Cell Host Microbe 14:398–410, 2013,http://dx.doi.org/10.1016/j.chom.2013.08.015). In contrast, the closely related human MX1 protein, which suppresses infection by a range of RNA and DNA viruses (such as influenza A virus [FluAV]), is ineffective against HIV-1. Using a panel of engineered chimeric MX1/2 proteins, we demonstrate that the amino-terminal 91-amino-acid domain of MX2 confers full anti-HIV-1 function when transferred to the amino terminus of MX1, and that this fusion protein retains full anti-FluAV activity. Confocal microscopy experiments further show that this MX1/2 fusion, similar to MX2 but not MX1, can localize to the nuclear envelope (NE), linking HIV-1 inhibition with MX accumulation at the NE. MX proteins are dynamin-like GTPases, and while MX1 antiviral function requires GTPase activity, neither MX2 nor MX1/2 chimeras require this attribute to inhibit HIV-1. This key discrepancy between the characteristics of MX1- and MX2-mediated viral resistance, together with previous observations showing that the L4 loop of the stalk domain of MX1 is a critical determinant of viral substrate specificity, presumably reflect fundamental differences in the mechanisms of antiviral suppression. Accordingly, we propose that further comparative studies of MX proteins will help illuminate the molecular basis and subcellular localization requirements for implementing the noted diversity of virus inhibition by MX proteins.IMPORTANCEInterferon (IFN) elicits an antiviral state in cells through the induction of hundreds of IFN-stimulated genes (ISGs). The human MX2 protein has been identified as a key effector in the suppression of HIV-1 infection by IFN. Here, we describe a molecular genetic approach, using a collection of chimeric MX proteins, to identify protein domains of MX2 that specify HIV-1 inhibition. The amino-terminal 91-amino-acid domain of human MX2 confers HIV-1 suppressor capabilities upon human and mouse MX proteins and also promotes protein accumulation at the nuclear envelope. Therefore, these studies correlate the cellular location of MX proteins with anti-HIV-1 function and help establish a framework for future mechanistic analyses of MX-mediated virus control.
Absence of Genetic Differences among G10P[11] Rotaviruses Associated with Asymptomatic and Symptomatic Neonatal Infections in Vellore, India
Authors: Libonati Margaret H. , Dennis Allison F. , Ramani Sasirekha , McDonald Sarah M. , Akopov Asmik , Kirkness Ewen F. , Kang Gagandeep , Patton John T. 
Published: June 2014

ABSTRACT
Rotaviruses (RVs) are leading causes of severe diarrhea and vomiting in infants and young children. RVs with G10P[11] genotype specificity have been associated with symptomatic and asymptomatic neonatal infections in Vellore, India. To identify possible viral genetic determinants responsible for differences in symptomology, the genome sequences of G10P[11] RVs in stool samples of 19 neonates with symptomatic infections and 20 neonates with asymptomatic infections were determined by Sanger and next-generation sequencing. The data showed that all 39 viruses had identical genotype constellations (G10-P[11]-I2-R2-C2-M2-A1-N1-T1-E2-H3), the same as those of the previously characterized symptomatic N155 Vellore isolate. The data also showed that the RNA and deduced protein sequences of all the Vellore G10P[11] viruses were nearly identical; no nucleotide or amino acid differences were found that correlated with symptomatic versus asymptomatic infection. Next-generation sequencing data revealed that some stool samples, both from neonates with symptomatic infections and from neonates with asymptomatic infections, also contained one or more positive-strand RNA viruses (Aichi virus, astrovirus, or salivirus/klassevirus) suspected of being potential causes of pediatric gastroenteritis. However, none of the positive-strand RNA viruses could be causally associated with the development of symptoms. These results indicate that the diversity of clinical symptoms in Vellore neonates does not result from genetic differences among G10P[11] RVs; instead, other undefined factors appear to influence whether neonates develop gastrointestinal disease symptoms.

IMPORTANCE
Rotavirus (RV) strains have been identified that preferentially replicate in neonates, in some cases, without causing gastrointestinal disease. Surveillance studies have established that G10P[11] RVs are a major cause of neonatal infection in Vellore, India, with half of infected neonates exhibiting symptoms. We used Sanger and next-generation sequencing technologies to contrast G10P[11] RVs recovered from symptomatic and asymptomatic neonates. Remarkably, the data showed that the RNA genomes of the viruses were virtually indistinguishable and lacked any differences that could explain the diversity of clinical outcomes among infected Vellore neonates. The sequencing results also indicated that some symptomatic and some asymptomatic Vellore neonates were infected with other enteric viruses (Aichi virus, astrovirus, salvirus/klassevirus); however, none could be correlated with the presence of symptoms in neonates. Together, our findings suggest that other poorly defined factors, not connected to the genetic makeup of the Vellore G10P[11] viruses, influence whether neonates develop gastrointestinal disease symptoms.
To ‘Get by’ or ‘get help’? A qualitative study of physicians’ challenges and dilemmas when patients have limited English proficiency
Authors: Parsons Janet A , Baker Natalie A , Smith-Gorvie Telisha , Hudak Pamela L 
Published: June 2014

ObjectiveEncounters between patients and physicians who do not speak the same language are relatively common in Canada, particularly in urban settings; this trend is increasing worldwide. Language discordance has important effects on health outcomes, including mortality. This study sought to explore physicians’ experiences of care provision in situations of language discordance in depth.DesignQualitative study based on individual interviews. Interview guides elicited physicians’ perspectives on how they determined whether communication could proceed unaided. A descriptive qualitative approach was adopted, entailing inductive thematic analysis.Participants22 physicians experienced in treating patients in situations of language discordance were recruited from the emergency and internal medicine departments of an urban tertiary-care hospital.SettingLarge, inner-city teaching hospital in Toronto, Canada, one of the most linguistically diverse cities internationally.ResultsDetermining when to ‘get by’ or ‘get help’ in order to facilitate communication was described as a fluid and variable process.Deciding which strategy to use depended on three inter-related factors: time/time constraints, acuity of situationandease of use/availability of translation aids. Participants reported at times feeling conflicted about their decisions, portraying some of these clinical encounters as a ‘troubling space’ in which they experienced one or moredilemmasrelated torealversusideal practice, responsibilityandinformed consent.ConclusionsIn situations of language discordance, a physician's decision to ‘get by’ (vs ‘get help’) rests on a judgement of whether communication can be considered ‘good enough’ to proceed and depends on the circumstances of the specific encounter. The tension set up between what is ‘ideal’ and what is practically possible can be experienced as a dilemma by physicians.The study's findings have implications for practice and policy not only in Canada but in other multilingual settings, and indicate that physicians require greater support.
Can you refuse these discounts? An evaluation of the use and price discount impact of price-related promotions among US adult smokers by cigarette manufacturers
Authors: Caraballo Ralph S , Wang Xu , Xu Xin 
Published: June 2014

ObjectivesThe raising unit price of cigarette has been shown to be one of the most effective ways of reducing cigarette consumption and increasing rates of successful quitting. However, researchers have shown that price-sensitive smokers have used a variety of strategies to mitigate the effect of the rising price of cigarettes on their smoking habits. In particular, 23–34% of adult smokers in the US use cheaper brands, and 18–55% use coupons or promotions. Little is known about the discount use by type of brands. As such, the main purpose of this analysis is to evaluate the uses and price discount effects of these price-related discounts by manufacturers and major brands.SettingAn analysis based on the cross-sectional 2009–2010 National Adult Tobacco Survey (NATS).Participants11 766 current smokers aged 18 or above in the USA.Primary outcome measuresPrice-related discount was defined as smokers who used coupons, rebates, buy-one-get-one-free, two-for-one or any other special promotions for their last cigarettes purchase.ResultsThe use of price-related discounts and associated price impact vary widely by cigarette manufacturer and brand. Approximately one of three Camel, one of four Marlboro and one of eight Newport smokers used price-related discounts on their latest cigarette purchases. The average price reductions of discounts offered by Philip Morris (PM) or R.J. Reynolds (RJR) were around 29 cents per pack while that of Lorillard (Newport only) was 24 cents per pack. Cigarette brands that provided significant per pack price reductions include: PM Marlboro (28 cents), RJR brand Camel (41 cents), Doral (50 cents), Kool (73 cents) and Salem (80 cents), and Lorillard Newport (24 cents).ConclusionsPolicies that decrease price-minimisation strategies will benefit public health.
Failure to address potential bias in non-randomised controlled clinical trials may cause lack of evidence on patient-reported outcomes: a method study
Authors: Peinemann Frank , Labeit Alexander Michael , Thielscher Christian , Pinkawa Michael 
Published: June 2014

ObjectivesWe conducted a workup of a previously published systematic review and aimed to analyse why most of the identified non-randomised controlled clinical trials with patient-reported outcomes did not match a set of basic quality criteria.SettingThere were no limits on the level of care and the geographical location.ParticipantsThe review evaluated permanent interstitial low-dose rate brachytherapy in patients with localised prostate cancer and compared that intervention with alternative procedures such as external beam radiotherapy, radical prostatectomy and no primary therapy.Primary outcome measureFulfilment of basic inclusion criteria according to a Participants, Interventions, Comparisons, Outcomes (PICO) framework and accomplishment of requirements to contain superimposed risk of bias.ResultsWe found that 21 of 50 excluded non-randomised controlled trials did not meet the PICO inclusion criteria. The remaining 29 studies showed a lack in the quality of reporting. The resulting flaws included attrition bias due to loss of follow-up, lack of reporting baseline data, potential confounding due to unadjusted data and lack of statistical comparison between groups.ConclusionsWith respect to the reporting of patient-reported outcomes, active efforts are required to improve the quality of reporting in non-randomised controlled trials concerning permanent interstitial low-dose rate brachytherapy in patients with localised prostate cancer.
Non-pharmacological treatments for adult patients with functional constipation: a systematic review protocol
Authors: Chen Min , Zheng Hui , Li Juan , Huang Dequan , Chen Qin , Fang Jianqiao 
Published: June 2014

IntroductionThe aim of this review is to assess the effectiveness, efficacy and safety of non-pharmacological therapies for patients with functional constipation.Methods and analysisWe will electronically search OVID MEDLINE, EMBASE, Cochrane library, CINAHL, AMED and ISI web of knowledge without any language restrictions. We will also try to obtain literatures from other sources, such as a hand search of library journals or conference abstracts. After searching and screening of the studies, we will run a meta-analysis of the included randomised-controlled trials. We will summarise the results as risk ratio for dichotomous data and standardised or weighted mean difference for continuous data.DisseminationThis systematic review will summarise current evidence for using non-pharmacological therapies to treat functional constipation, and will be disseminated through peer-review publications or conference presentations.Trial registration numberPROSPERO 2014: CRD42014006686.
Rationale and study design of the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): a non-randomised, open label, adaptive dose finding trial
Authors: Waldron-Lynch Frank , Kareclas Paula , Irons Kathryn , Walker Neil M , Mander Adrian , Wicker Linda S , Todd John A , Bond Simon 
Published: June 2014

IntroductionCD4 T regulatory cells (Tregs) are crucial for the maintenance of self-tolerance and are deficient in many common autoimmune diseases such as type 1 diabetes (T1D). Interleukin 2 (IL-2) plays a major role in the activation and function of Tregs and treatment with ultra-low dose (ULD) IL-2 could increase Treg function to potentially halt disease progression in T1D. However, prior to embarking on large phase II/III clinical trials it is critical to develop new strategies for determining the mechanism of action of ULD IL-2 in participants with T1D. In this mechanistic study we will combine a novel trial design with a clinical grade Treg assay to identify the best doses of ULD IL-2 to induce targeted increases in Tregs.Method and analysisAdaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D) is a single centre non-randomised, single dose, open label, adaptive dose-finding trial. The primary objective of DILT1D is to identify the best doses of IL-2 to achieve a minimal or maximal Treg increase in participants with T1D (N=40). The design has an initial learning phase where pairs of participants are assigned to five preassigned doses followed by an interim analysis to determine the two Treg targets for the reminder of the trial. This will then be followed by an adaptive phase which is fully sequential with an interim analysis after each participant is observed to determine the choice of dose based on the optimality criterion to minimise the determinant of covariance of the estimated target doses. A dose determining committee will review all data available at the interim(s) and then provide decisions regarding the choice of dose to administer to subsequent participants.Ethics and disseminationEthical approval for the study was granted on 18 February 2013.ResultsThe results of this study will be reported through peer-reviewed journals, conference presentations and an internal organisational report.Trial registration numbersNCT01827735,ISRCTN27852285, DRN767.
Axl receptor tyrosine kinase expression in breast cancer
Authors: D'Alfonso Timothy M , Hannah Jeffrey , Chen Zhengming , Liu Yifang , Zhou Pengbo , Shin Sandra J 
Published: June 2014

AimsTriple-negative breast cancer comprises a clinically aggressive group of invasive carcinomas. We examined a published gene expression screen of a panel of breast cancer cell lines to identify a potential triple-negative breast cancer-specific gene signature, and attempted to verify our findings by performing immunohistochemical analysis on tissue microarrays containing a large cohort of invasive breast carcinomas.MethodsThe microarray dataset for a panel of human breast cancer cell lines was interrogated for triple-negative breast cancer-specific genes. Membranous immunohistochemical expression of the protein product of theAXLgene was assessed semiquantitatively in 569 invasive breast carcinomas grouped according to molecular subgroup by immunohistochemistry.ResultsAXLwas significantly upregulated in triple-negative/basal B cell lines compared with luminal or basal A cell lines. No significant difference was observed in the level of immunohistochemical expression of Axl protein between triple-negative breast cancers and other molecular subgroups (p=0.257). Axl expression was significantly associated with lymphovascular invasion (LVI) in all subgroups combined (p=0.033), and within the luminal A (p=0.002) and triple-negative breast cancer subgroups (p=0.026).ConclusionsDespite preferential upregulation ofAXLin triple-negative/basal B cell lines, analysis of Axl protein expression in a large series of patients’ breast tumours revealed no association between Axl expression and triple-negative breast cancer or other subtype. The association of Axl expression with LVI supports previous work that implicates Axl as a promoter of invasiveness in breast cancer cell lines. Further studies are necessary to explore whether Axl expression of individual breast cancer tumours can be clinically useful.
Stochastic quantization and holographic Wilsonian renormalization group of massless fermions in AdS
Authors: Oh Jae-Hyuk 
Published: June 2014

We have studied holographic Wilsonian renormalization group (HWRG) of free massless fermionic fields in AdS space and its stochastic quantization (SQ) by identifying the Euclidean action with its boundary on-shell action. The natural extension of the relation between stochastic two-point correlation function and double trace coupling obtained from HWRG computation conjectured in [J.-H. Oh and D. P. Jatkar, J. High Energy Phys. 1211, 144 (2012) arXiv:1209.2242] to fermionic fields is established. We have confirmed that the stochastic two-point function precisely captures the radial flow of the double trace coupling via this relation.
Lateral ramps and strike-slip kinematics on Mercury
Authors: Massironi M. , Di Achille G. , Rothery D. A. , Galluzzi V. , Giacomini L. , Ferrari S. , Zusi M. , Cremonese G. , Palumbo P. 
Published: June 2014

Abstract
At a global scale, Mercury is dominated by contractional features manifested as lobate scarps, wrinkle ridges and high-relief ridges. Here, we show that some of these features are associated with strike-slip kinematic indicators, which we identified using flyby and orbital Mercury Dual Imaging System (MDIS) data and digital terrain models. We recognize oblique-shear kinematics along lobate scarps and high-relief ridges by means of (1) map geometries of fault patterns (frontal thrusts bordered by lateral ramps, strike-slip duplexes, restraining bends); (2) structural morphologies indicating lateral shearing (en echelon folding, pop-ups, pull-aparts); and (3) estimates of offsets based on displaced crater rims and differences in elevation between pop-up structures and pull-apart basins and their surroundings. Transpressional faults, documented across a wide range of latitudes, are found associated with reactivated rims of ancient buried basins and, in most cases, linked to frontal thrusts as lateral ramps hundreds of kilometres long. This latter observation suggests stable directions of tectonic transport over wide regions of Mercury's surface. In contrast, global cooling would imply an overall isotropic contraction with limited processes of lateral shearing induced by pre-existent lithospheric heterogeneities. Mantle convection therefore may have played an important role during the tectonic evolution of Mercury.
Hypoxia Promotes Nuclear Translocation and Transcriptional Function in the Oncogenic Tyrosine Kinase RON
Authors: Chang Hong-Yi , Liu Hsiao-Sheng , Lai Ming-Derg , Tsai Yuh-Shyan , Tzai Tzong-Shin , Cheng Hong-Ling , Chow Nan-Haw 
Published: June 2014

Abstract
Tumor hypoxia drives metastatic progression, drug resistance, and posttreatment relapses, but how cancer cells adapt and evolve in response to hypoxic stress is not well understood. In this study, we address this question with the discovery that the receptor tyrosine kinase RON translocates into the nucleus of hypoxic cancer cells. In response to hypoxia, nuclear RON interacts with the hypoxia-inducible factor HIF-1α in a manner that relies on RON tyrosine kinase activity, binding to the c-JUN promoter and activating it. Mechanistic investigations revealed unexpectedly that nuclear RON played a more important role in activation of the c-JUN promoter than HIF-1α, leading to increased cell proliferation, survival adaptation, in vitro migration, and tumorigenicity under hypoxic conditions. Taken together, our results pointed to a novel function for RON as a transcriptional regulator that promotes the survival of cancer cells subjected to hypoxia. These results suggest novel implications for the use of small-molecule inhibitors or monoclonal antibodies targeting the RON kinase in the prevention or treatment of advanced cancer. Cancer Res; 74(16); 4549–62. ©2014 AACR.
B cells facilitate platelet production mediated by cytokines in patients with essential thrombocythaemia
Authors: Liu Chuan-Chuan , Wang Shu-Ching , Kao Chen-Wei , Hsieh Ruey-Kuen , Chang Ming-Chih , Chang Yi-Fang , Lim Ken-Hong , Chen Caleb Gonshen 
Published: June 2014

SummaryWe investigated the role of activated B cells in thrombopoiesis through the production of interleukin (IL)-1beta and IL-6 in patients with essential thrombocythaemia. The number of B cells did not differ between essential thrombocythaemia patients, irrespective of the presence of Janus activated kinase-2 V617F mutation or wild type, and age-matched healthy adults. However, the number of IL-1beta/IL- 6-producing B cells was significantly higher in essential thrombocythaemia patients than that in healthy controls. The relatively high level of IL-1beta/IL-6 production by B cells was associated with serum B cell-activating factor and expression of Toll-like receptor 4 on B cells. A high level of B cell-activating factor was present in essential thrombocythaemia patients with both Janus activated kinase-2 genotypes. Incubation with B cell-activating factor enhanced the expression of Toll-like receptor 4 on B cells. IL-1beta and IL-6 production was not stimulated by B cell-activating factor alone; Toll-like receptor 4 was activated by lipopolysaccharide or patients’ sera to produce IL-1beta and IL-6 in B cells. Moreover, essential thrombocythaemia patient B cells facilitated megakaryocyte differentiation when co-cultured with CD34+ haematopoietic stem cells. Antibody neutralisation of IL-1beta and IL-6 attenuated megakaryocyte differentiation. These data suggest that B cells play a crucial role in thrombopoiesis in essential thrombocythaemia patients.
Gastrointestinal angiodysplasia and bleeding in von Willebrand disease
Authors: Franchini Massimo , Mannucci Pier Mannuccio 
Published: June 2014

SummaryVon Willebrand disease (VWD), the most common genetic bleeding disorder, is characterised by a quantitative or qualitative defect of von Willebrand factor (VWF). Patients with VWD suffer from mucocutaneous bleeding, of severity usually proportional to the degree of VWF defect. In particular, gastrointestinal bleeding associated with angiodysplasia is often a severe symptom of difficult management. This review focuses on the pathophysiology, diagnosis and treatment of VWD-associated gastrointestinal angiodysplasia and related bleeding.