bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blocking ESCRT-Mediated Envelopment Inhibits Microtubule-Dependent Trafficking of Alphaherpesviruses
In Vitro
Authors: Kharkwal Himanshu , Smith Caitlin G. , Wilson Duncan W. 
Published: October 2014

ABSTRACT

Herpes simplex virus (HSV) and, as reported here, pseudorabies virus (PRV) utilize the ESCRT apparatus to drive cytoplasmic envelopment of their capsids. Here, we demonstrate that blocking ESCRT-mediated envelopment using the dominant-negative inhibitor Vps4A-EQ (Vps4A in which glutamate [E] at position 228 in the ATPase active site is replaced by a glutamine [Q]) reduced the ability of HSV and PRV particles to subsequently traffic along microtubules
in vitro
. HSV and PRV capsid-associated particles with bound green fluorescent protein (GFP)-labeled Vps4A-EQ were readily detected by fluorescence microscopy in cytoplasmic extracts of infected cells. These Vps4A-EQ-associated capsid-containing particles bound to microtubules
in vitro
but were unable to traffic along them. Using a PRV strain expressing a fluorescent capsid and a fluorescently tagged form of the envelope protein gD, we found that similar numbers of gD-positive and gD-negative capsid-associated particles accumulated in cytoplasmic extracts under our conditions. Both classes of PRV particle bound to microtubules
in vitro
with comparable efficiency, and similar results were obtained for HSV using anti-gD immunostaining. The gD-positive and gD-negative PRV capsids were both capable of trafficking along microtubules
in vitro
; however, motile gD-positive particles were less numerous and their trafficking was more sensitive to the inhibitory effects of Vps4A-EQ. We discuss our data in the context of microtubule-mediated trafficking of naked and enveloped alphaherpesvirus capsids.

IMPORTANCE
The alphaherpesviruses include several important human pathogens. These viruses utilize microtubule-mediated transport to travel through the cell cytoplasm; however, the molecular mechanisms of trafficking are not well understood. In this study, we have used a cell-free system to examine the requirements for microtubule trafficking and have attempted to distinguish between the movement of so-called “naked” and membrane-associated cytoplasmic alphaherpesvirus capsids.
Breaking the taboo: an interpretative phenomenological analysis of healthcare professionals’ experience of caring for palliative patients with disgusting symptoms
Authors: Muggleton Joshua , Guy Helen , Howard Ruth 
Published: October 2014

ObjectivesDisgusting symptoms are common in healthcare settings. Previous research has identified that healthcare professionals systematically avoid contact with patients with disgusting symptoms, potentially compromising patient care. Furthermore, research has highlighted disgust in healthcare professionals as a possible contributory factor to dehumanisation and abuse of patients. Given that healthcare professionals often feel that disgust is unprofessional, they may also feel unable to express or process disgust in their work, potentially impacting their emotional health, and contributing to burning out. Given the ubiquity of disgust in palliative care, we investigated how palliative healthcare professionals' experience and cope with disgust in their work, and how they are supported in doing so.Methods and ResultsWe interviewed six palliative healthcare professionals and analysed their transcripts using Interpretative Phenomenological Analysis, from which four themes are discussed.ConclusionsThree key findings emerged. Firstly, participants were uncomfortable talking about disgust at work, reducing their access to support for disgust. Secondly, participants often neglected their own emotional needs, and as a result, sometimes become emotionally entangled with patients. Finally, participants were at risk of reducing vital socio-emotional support for patients with disgusting symptoms. Based on our analysis, we suggest interventions to counteract these effects.
Efficacy of CAR T-cell Therapy in Large Tumors Relies upon Stromal Targeting by IFNγ
Authors: Textor Ana , Listopad Joanna J. , Wührmann Lara Le , Perez Cynthia , Kruschinski Anna , Chmielewski Markus , Abken Hinrich , Blankenstein Thomas , Charo Jehad 
Published: October 2014

Abstract
Adoptive T-cell therapy using chimeric antigen receptor–modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In an HER2–dependent tumor model, tumor rejection by HER2–specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFNγ receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting. Cancer Res; 74(23); 6796–805. ©2014 AACR.
ITPR1 Protects Renal Cancer Cells against Natural Killer Cells by Inducing Autophagy
Authors: Messai Yosra , Noman Muhammad Zaeem , Hasmim Meriem , Janji Bassam , Tittarelli Andrés , Boutet Marie , Baud Véronique , Viry Elodie , Billot Katy , Nanbakhsh Arash , Ben Safta Thouraya , Richon Catherine , Ferlicot Sophie , Donnadieu Emmanuel , Couve Sophie , Gardie Betty , Orlanducci Florence , Albiges Laurence , Thiery Jerome , Olive Daniel , Escudier Bernard , Chouaib Salem 
Published: October 2014

AbstractClear cell renal cell carcinomas (RCC) frequently display inactivation of von Hippel-Lindau (VHL) gene leading to increased level of hypoxia-inducible factors (HIF). In this study, we investigated the potential role of HIF2α in regulating RCC susceptibility to natural killer (NK) cell–mediated killing. We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK-mediated lysis as compared with the VHL-corrected cell line (WT7). This resistance was found to require HIF2α stabilization. On the basis of global gene expression profiling and chromatin immunoprecipitation assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF2α and that targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Mechanistically, HIF2α in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NK-mediated killing through the activation of autophagy in target cells by NK-derived signal. Interestingly, both ITPR1 and Beclin-1 silencing in 786-0 cells inhibited NK-induced autophagy and subsequently increased granzyme B activity in target cells. Finally, in vivo ITPR1 targeting significantly enhanced the NK-mediated tumor regression. Our data provide insight into the link between HIF2α, the ITPR1-related pathway, and natural immunity and strongly suggest a role for the HIF2α/ITPR1 axis in regulating RCC cell survival. Cancer Res; 74(23); 6820–32. ©2014 AACR.
Inhibition of mTORC1/2 Overcomes Resistance to MAPK Pathway Inhibitors Mediated by PGC1α and Oxidative Phosphorylation in Melanoma
Authors: Gopal Y.N. Vashisht , Rizos Helen , Chen Guo , Deng Wanleng , Frederick Dennie T. , Cooper Zachary A. , Scolyer Richard A. , Pupo Gulietta , Komurov Kakajan , Sehgal Vasudha , Zhang Jiexin , Patel Lalit , Pereira Cristiano G. , Broom Bradley M. , Mills Gordon B. , Ram Prahlad , Smith Paul D. , Wargo Jennifer A. , Long Georgina V. , Davies Michael A. 
Published: October 2014

Abstract
Metabolic heterogeneity is a key factor in cancer pathogenesis. We found that a subset of BRAF- and NRAS-mutant human melanomas resistant to the MEK inhibitor selumetinib displayed increased oxidative phosphorylation (OxPhos) mediated by the transcriptional coactivator PGC1α. Notably, all selumetinib-resistant cells with elevated OxPhos could be resensitized by cotreatment with the mTORC1/2 inhibitor AZD8055, whereas this combination was ineffective in resistant cell lines with low OxPhos. In both BRAF- and NRAS-mutant melanoma cells, MEK inhibition increased MITF expression, which in turn elevated levels of PGC1α. In contrast, mTORC1/2 inhibition triggered cytoplasmic localization of MITF, decreasing PGC1α expression and inhibiting OxPhos. Analysis of tumor biopsies from patients with BRAF-mutant melanoma progressing on BRAF inhibitor ± MEK inhibitor revealed that PGC1α levels were elevated in approximately half of the resistant tumors. Overall, our findings highlight the significance of OxPhos in melanoma and suggest that combined targeting of the MAPK and mTORC pathways may offer an effective therapeutic strategy to treat melanomas with this metabolic phenotype. Cancer Res; 74(23); 7037–47. ©2014 AACR.
Haemorrhagic and thrombotic diatheses in mouse models with thrombocytosis
Authors: Strassel Catherine , Kubovcakova Lucia , Mangin Pierre H. , Ravanat Catherine , Freund Monique , Skoda Radek C. , Denis Cécile V. , Dupuis Arnaud , Herbrecht Raoul , Gachet Christian , Lanza François 
Published: October 2014

SummaryWe studied haemostasis in two mouse models with thrombocytosis caused by different pathogenic mechanisms. In one strain (Yall;Mpl-/-) thrombocytosis is driven by a misbalance between thrombopoietin and its receptor, whereas in the other strain, thrombocytosis is caused by expressing a human JAK2-V617F transgene (FF1) that depends on activation by Cre-recombinase (VavCre;FF1, MxCre;FF1). Thrombotic responses were increased following some, but not all types of challenges. In a vaso-occlusive thrombotic model following collagen-adrenaline injection we found increased mortality in both strains. Arterial thrombosis, examined after ferric chloride-induced carotid injury, was accelerated but with little impact on maximal thrombus size. In a vena cava stasis model, clots were of similar size as in wild-type controls, but exhibited a different composition with a higher platelet to fibrin ratio. Both thrombocytosis strains displayed increased haemorrhagic tendency in a tail bleeding assay. Yall;Mpl and VavCre;FF1 displayed a lower proportion of the more reactive high-molecular-weight forms of von Willebrand factor in their plasma, mimicking essential thrombocythaemia with very high platelet counts. Bleeding could not be explained by clear defects in platelet activation, which were normal or only weakly decreased. In conclusion, these models of thrombocytosis recapitulate several features of the haemorrhagic and thrombotic diatheses in ET and PV demonstrating potentials but also some limitations to study these major complications.
The optimal management of patients on oral anticoagulation undergoing coronary artery stenting
Authors: Faxon David , Airaksinen Juhani , Schlitt Axel , Marìn Francisco , Bhatt Deepak , Lip Gregory , Rubboli Andrea 
Published: October 2014

SummaryEven 10 years after the first appearance in the literature of articles reporting on the management of patients on oral anticoagulation (OAC) undergoing percutaneous coronary intervention with stent (PCI-S), this issue is still controversial. Nonetheless, some guidance for the everyday management of this patient subset, accounting for about 5–8 % of all patients referred for PCI-S, has been developed. In general, a period of triple therapy (TT) of OAC, with either vitamin K–antagonists (VKA) or non-vitamin K–antagonist oral anticoagulants (NOAC), aspirin, and clopidogrel is warranted, followed by the combination of OAC, and a single antiplatelet agent for up to 12 months, and then OAC alone. The duration of the initial period of TT is dependent on the individual risk of thromboembolism, and bleeding, as well as the clinical context in which PCI-S is performed (elective vs acute coronary syndrome), and the type of stent implanted (bare-metal vs drug-eluting). In this article, we aim to provide a comprehensive, ata- glance, overview of the management strategies, which are currently suggested for the peri-procedural, medium-term, and long-term periods following PCI-S in OAC patients. While acknowledging that most of the evidence has been obtained from patients on OAC because of atrial fibrillation, and with warfarin being the most frequently used VKA, we refer in this overview to the whole population of OAC patients undergoing PCI-S. We refer to the whole population of patients on OAC undergoing PCI-S also when OAC is carried out with NOAC rather than VKA, pointing out, when appropriate, the particular management issues.Note: The review process for this paper was fully handled by Christian Weber, Editor-in-Chief.
Variability of CONUS Lightning in 2003–12 and Associated Impacts
Authors: Koshak William J. , Cummins Kenneth L. , Buechler Dennis E. , Vant-Hull Brian , Blakeslee Richard J. , Williams Earle R. , Peterson Harold S. 
Published: October 2014

AbstractChanges in lightning characteristics over the conterminous United States (CONUS) are examined to support the National Climate Assessment (NCA) program. Details of the variability of cloud-to-ground (CG) lightning characteristics over the decade 2003–12 are provided using data from the National Lightning Detection Network (NLDN). Changes in total (CG + cloud flash) lightning across part of the CONUS during the decade are provided using satellite Lightning Imaging Sensor (LIS) data. The variations in NLDN-derived CG lightning are compared with available statistics on lightning-caused impacts to various U.S. economic sectors. Overall, a downward trend in total CG lightning count is found for the decadal period; the 5-yr mean NLDN CG count decreased by 12.8% from 25 204 345.8 (2003–07) to 21 986 578.8 (2008–12). There is a slow upward trend in the fraction and number of positive-polarity CG lightning, however. Associated lightning-caused fatalities and injuries, and the number of lightning-caused wildland fires and burn acreage also trended downward, but crop and personal-property damage costs increased. The 5-yr mean LIS total lightning changed little over the decadal period. Whereas the CONUS-averaged dry-bulb temperature trended upward during the analysis period, the CONUS-averaged wet-bulb temperature (a variable that is better correlated with lightning activity) trended downward. A simple linear model shows that climate-induced changes in CG lightning frequency would likely have a substantial and direct impact on humankind (e.g., a long-term upward trend of 1°C in wet-bulb temperature corresponds to approximately 14 fatalities and over $367 million in personal-property damage resulting from lightning).
Water Vapor–Forced Greenhouse Warming over the Sahara Desert and the Recent Recovery from the Sahelian Drought
Authors: Evan Amato T. , Flamant Cyrille , Lavaysse Christophe , Kocha Cécile , Saci Azzedine 
Published: October 2014

Abstract
The Sahel region of West Africa experiences decadal swings between periods of drought and abundant rainfall, and a large body of work asserts that these variations in the West African monsoon are a response to changes in the temperatures of the tropical Atlantic and Indian Oceans. However, here it is shown that when forced by SST alone, most state-of-the-art climate models do not reproduce a statistically significant upward trend in Sahelian precipitation over the last 30 years and that those models with a significant upward trend in rainfall seem to achieve this result for disparate reasons. Here the role of the Saharan heat low (SHL) in the recovery from the Sahelian drought of the 1980s is examined. Using observations and reanalyses, it is demonstrated that there has been an upward trend in SHL temperature that is coincident with the drought recovery. A heat and moisture budget analysis of the SHL suggests that the rise in temperature is due to greenhouse warming by water vapor, but that changes in water vapor are strongly dependent upon the temperature of the SHL: a process termed the Saharan water vapor–temperature (SWAT) feedback. It is shown that the structure of the drought recovery is consistent with a warming SHL and is evidence of a fundamental, but not exclusive, role for the SHL in the recent increase in Sahelian monsoon rainfall.
Identifying the Skeleton of the Madden–Julian Oscillation in Observational Data
Authors: Stechmann Samuel N. , Majda Andrew J. 
Published: October 2014

Abstract
The Madden–Julian oscillation (MJO) skeleton model offers a theoretical prediction of the MJO’s structure. Here, a method is described for identifying this structure in observational data. The method utilizes projections onto equatorial wave structures, and a main question is: Can this method isolate the MJO without using temporal filtering or empirical orthogonal functions? For the data projection, a wide range of data is incorporated: multiple variables (wind, geopotential height, water vapor, and, as a proxy for convective activity, outgoing longwave radiation), multiple pressure levels (850 and 200 hPa), and multiple latitudes (both equatorial and off-equatorial). Such a data variety is combined using a systematic method, and it allows for a distinction between the Kelvin and Rossby components of the MJO’s structure. Results are illustrated for some well-known cases, and statistical measures are presented to quantify the variability of the MJO skeleton signal, MJOS(x, t), and its amplitude, MJOSA(t). The robustness of the methods is demonstrated through a suite of sensitivity studies, including tests with two projection methods. When the projection is based on the skeleton model’s energy, as opposed to the standard L2 energy, water vapor is seen to be of primary importance. Finally, a simple interpretation is given for the MJO skeleton structure: it is related to the wave response to a moving heat source. From either perspective, the methods here identify signals that project onto coupled convection–circulation patterns, and the results suggest that a large portion of the MJO’s structure is consistent with such a coupled pattern.
Communication of Uncertainty in Temperature Forecasts
Authors: Marimo Pricilla , Kaplan Todd R. , Mylne Ken , Sharpe Martin 
Published: October 2014

Abstract
Experimental economics is used to test whether undergraduate students presented with a temperature forecast with uncertainty information in a table and bar graph format were able to use the extra information to interpret a given forecast. Participants were asked to choose the most probable temperature-based outcome between a set of “lotteries.” Both formats with uncertainty information were found on average to significantly increase the probability of choosing the correct outcome. However, in some cases providing uncertainty information was damaging. Factors that influence understanding are statistically determined. Furthermore, participants who were shown the graph with uncertainty information took on average less response time compared to those who were shown a table with uncertainty information. Over time, participants improve in speed and initially improve in accuracy of choosing the correct outcome.
A Preliminary Assessment of Using Spatiotemporal Lightning Patterns for a Binary Classification of Thunderstorm Mode
Authors: Miller Paul , Ellis Andrew W. , Keighton Stephen 
Published: October 2014

Abstract
This study provides a preliminary, regional assessment of the viability of using spatiotemporal lightning patterns to classify storms into single- versus multi- and supercell storm modes. Total lightning flashes (intracloud and cloud-to-ground flashes) occurring during the afternoon and evening of the period May–August 2012 within an area of the central Appalachian Mountains region were grouped based on their spatial and temporal characteristics using single-linkage clustering. The resulting discrete thunderstorm clusters were characterized in terms of duration, motion, areal extent, and shape. These values were used to formulate four individual attribute scores representing the similarity to the expected values for a typical single-cell thunderstorm. The four scores were then combined into a storm index (SI) using relative weights determined through the analytic hierarchy process (AHP) performed on input from operational forecasters. Of the study days, 89 (72.4%) possessed appreciable lightning, of which 36 (40%) possessed a defined minimum amount of lightning activity required for further analysis. These 36 storm days were divided into two tiers according to the distribution of median daily SI values. The tier containing the 24 storm days (66.7%) with the largest median SI values possessed statistically significant smaller values of 0–6-km wind shear [13.8 knots (kt; 1 kt = 0.51 m s−1)] versus the 12 days in the lower tier of SI values (26.5 kt). This consistency between the total lightning-based classification scheme and increased vertical wind shear associated with lightning-defined multi- and supercells, also evident in synoptic atmospheric composites, lends credibility to the procedure.
Intergenerational and cross-cultural differences in emotional wellbeing, mental health service utilisation, treatment-seeking preferences and acceptability of psychological treatments for Arab Australians
Authors: Kayrouz Rony , Dear Blake F , Johnston Luke , Keyrouz Liliane , Nehme Edmond , Laube Roy , Titov Nickolai 
Published: October 2014

Background: Little is known about the intergenerational and cross-cultural differences in emotional wellbeing and acceptability of psychological treatments for Arab Australians. Aim: To contribute to the emerging data about the mental health status and needs of Arab Australians. Method: An Internet survey examined psychological distress and functional impairment as measured by the Kessler 10 Item scale (K-10) and the Sheehan Disability Scale (SDS) among Arab Australians. Additional questions enquired about their help-seeking behaviours, barriers to accessing psychological treatments and preferences for delivery of psychological treatments. A total of 252 participants were recruited through public talks, media and online promotions. Results: Forty-three percent of the respondents reported moderate-to-severe functional impairment ( M = 9.5; standard deviation ( SD) = 1.8), 32% reported high psychological distress ( M = 28.5; SD = 5.4) and 30% were born overseas. First-generation Arab Australians experiencing high psychological distress (i.e. K-10 ≥ 22), reported a greater preference for Internet-delivered treatment when compared to their second-generation counterparts. Only 18% of the sample reported seeking help from a mental health professional in the past year. The significant barriers reported by respondents with high psychological distress were poor mental health literacy, lack of time and stigma. Respondents preferred face-to-face (90%) over Internet-delivered treatment (55%). Finally, Arab Australians experienced higher psychological distress and underutilised mental health services when compared to the Australian population. Conclusion: Targeted public health campaigns that make culturally relevant interventions such as modifying existing Internet-delivered treatment for Arab Australians may reduce barriers and increase treatment options for this population.