bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactome Analysis of the Influenza A Virus Transcription/Replication Machinery Identifies Protein Phosphatase 6 as a Cellular Factor Required for Efficient Virus Replication
Authors: York Ashley , Hutchinson Edward C. , Fodor Ervin 
Published: September 2014

ABSTRACT
The negative-sense RNA genome of influenza A virus is transcribed and replicated by the viral RNA-dependent RNA polymerase (RdRP). The viral RdRP is an important host range determinant, indicating that its function is affected by interactions with cellular factors. However, the identities and the roles of most of these factors remain unknown. Here, we employed affinity purification followed by mass spectrometry to identify cellular proteins that interact with the influenza A virus RdRP in infected human cells. We purified RdRPs using a recombinant influenza virus in which the PB2 subunit of the RdRP is fused to a Strep-tag. When this tagged subunit was purified from infected cells, copurifying proteins included the other RdRP subunits (PB1 and PA) and the viral nucleoprotein and neuraminidase, as well as 171 cellular proteins. Label-free quantitative mass spectrometry revealed that the most abundant of these host proteins were chaperones, cytoskeletal proteins, importins, proteins involved in ubiquitination, kinases and phosphatases, and mitochondrial and ribosomal proteins. Among the phosphatases, we identified three subunits of the cellular serine/threonine protein phosphatase 6 (PP6), including the catalytic subunit PPP6C and regulatory subunits PPP6R1 and PPP6R3. PP6 was found to interact directly with the PB1 and PB2 subunits of the viral RdRP, and small interfering RNA (siRNA)-mediated knockdown of the catalytic subunit of PP6 in infected cells resulted in the reduction of viral RNA accumulation and the attenuation of virus growth. These results suggest that PP6 interacts with and positively regulates the activity of the influenza virus RdRP.

IMPORTANCE
Influenza A viruses are serious clinical and veterinary pathogens, causing substantial health and economic impacts. In addition to annual seasonal epidemics, occasional global pandemics occur when viral strains adapt to humans from other species. To replicate efficiently and cause disease, influenza viruses must interact with a large number of host factors. The reliance of the viral RNA-dependent RNA polymerase (RdRP) on host factors makes it a major host range determinant. This study describes and quantifies host proteins that interact, directly or indirectly, with a subunit of the RdRP. It increases our understanding of the role of host proteins in viral replication and identifies a large number of potential barriers to pandemic emergence. Identifying host factors allows their importance for viral replication to be tested. Here, we demonstrate a role for the cellular phosphatase PP6 in promoting viral replication, contributing to our emerging knowledge of regulatory phosphorylation in influenza virus biology.
Mitogen-Activated Protein Kinase-Interacting Kinase Regulates mTOR/AKT Signaling and Controls the Serine/Arginine-Rich Protein Kinase-Responsive Type 1 Internal Ribosome Entry Site-Mediated Translation and Viral Oncolysis
Authors: Brown Michael C. , Dobrikov Mikhail I. , Gromeier Matthias 
Published: September 2014

ABSTRACT

Translation machinery is a major recipient of the principal mitogenic signaling networks involving Raf-ERK1/2 and phosphoinositol 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR). Picornavirus internal ribosomal entry site (IRES)-mediated translation and cytopathogenic effects are susceptible to the status of such signaling cascades in host cells. We determined that tumor-specific cytotoxicity of the poliovirus/rhinovirus chimera PVSRIPO is facilitated by Raf-ERK1/2 signals to the mitogen-activated protein kinase (MAPK)-interacting kinase (MNK) and its effects on the partitioning/activity of the Ser/Arg (SR)-rich protein kinase (SRPK) (
M. C. Brown, J. D. Bryant, E. Y. Dobrikova, M. Shveygert, S. S. Bradrick, V. Chandramohan, D. D. Bigner, and M, Gromeier
, J. Virol. 22:13135–13148, 2014, doi:http://dx.doi.org/10.1128/JVI.01883-14). Here, we show that MNK regulates SRPK via mTOR and AKT. Our investigations revealed a MNK-controlled mechanism acting on mTORC2-AKT. The resulting suppression of AKT signaling attenuates SRPK activity to enhance picornavirus type 1 IRES translation and favor PVSRIPO tumor cell toxicity and killing.

IMPORTANCE
Oncolytic immunotherapy with PVSRIPO, the type 1 live-attenuated poliovirus (PV) (Sabin) vaccine containing a human rhinovirus type 2 (HRV2) IRES, is demonstrating early promise in clinical trials with intratumoral infusion in recurrent glioblastoma (GBM). Our investigations demonstrate that the core mechanistic principle of PVSRIPO, tumor-selective translation and cytotoxicity, relies on constitutive ERK1/2-MNK signals that counteract the deleterious effects of runaway AKT-SRPK activity in malignancy.
Two Novel Simian Arteriviruses in Captive and Wild Baboons (Papio spp.)
Authors: Bailey Adam L. , Lauck Michael , Sibley Samuel D. , Pecotte Jerilyn , Rice Karen , Weny Geoffrey , Tumukunde Alex , Hyeroba David , Greene Justin , Correll Michael , Gleicher Michael , Friedrich Thomas C. , Jahrling Peter B. , Kuhn Jens H. , Goldberg Tony L. , Rogers Jeffrey , O'Connor David H. 
Published: September 2014

ABSTRACT

Since the 1960s, simian hemorrhagic fever virus (SHFV;
Nidovirales
,
Arteriviridae
) has caused highly fatal outbreaks of viral hemorrhagic fever in captive Asian macaque colonies. However, the source(s) of these outbreaks and the natural reservoir(s) of this virus remain obscure. Here we report the identification of two novel, highly divergent simian arteriviruses related to SHFV, Mikumi yellow baboon virus 1 (MYBV-1) and Southwest baboon virus 1 (SWBV-1), in wild and captive baboons, respectively, and demonstrate the recent transmission of SWBV-1 among captive baboons. These findings extend our knowledge of the genetic and geographic diversity of the simian arteriviruses, identify baboons as a natural host of these viruses, and provide further evidence that baboons may have played a role in previous outbreaks of simian hemorrhagic fever in macaques, as has long been suspected. This knowledge should aid in the prevention of disease outbreaks in captive macaques and supports the growing body of evidence that suggests that simian arterivirus infections are common in Old World monkeys of many different species throughout Africa.

IMPORTANCE
Historically, the emergence of primate viruses both in humans and in other primate species has caused devastating outbreaks of disease. One strategy for preventing the emergence of novel primate pathogens is to identify microbes with the potential for cross-species transmission in their natural state within reservoir species from which they might emerge. Here, we detail the discovery and characterization of two related simian members of the
Arteriviridae
family that have a history of disease emergence and host switching. Our results expand the phylogenetic and geographic range of the simian arteriviruses and define baboons as a natural host for these viruses. Our findings also identify a potential threat to captive macaque colonies by showing that simian arteriviruses are actively circulating in captive baboons.
Severity of Clinical Disease and Pathology in Ferrets Experimentally Infected with Influenza Viruses Is Influenced by Inoculum Volume
Authors: Moore Ian N. , Lamirande Elaine W. , Paskel Myeisha , Donahue Danielle , Qin Jing , Subbarao Kanta 
Published: September 2014

ABSTRACT

Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. However, the contributions of the volume of inoculum administered and the ferret's respiratory tract anatomy to disease outcome have not been explored. We noted variations in clinical disease outcomes and the volume of inoculum administered and investigated these differences by administering two influenza viruses (A/California/07/2009 [H1N1 pandemic] and A/Minnesota/11/2010 [H3N2 variant]) to ferrets intranasally at a dose of 10
6
50% tissue culture infective doses in a range of inoculum volumes (0.2, 0.5, or 1.0 ml) and followed viral replication, clinical disease, and pathology over 6 days. Clinical illness and respiratory tract pathology were the most severe and most consistent when the viruses were administered in a volume of 1.0 ml. Using a modified micro-computed tomography imaging method and examining gross specimens, we found that the right main-stem bronchus was consistently larger in diameter than the left main-stem bronchus, though the latter was longer and straighter. These anatomic features likely influence the distribution of the inoculum in the lower respiratory tract. A 1.0-ml volume of inoculum is optimal for delivery of virus to the lower respiratory tract of ferrets, particularly when evaluation of clinical disease is desired. Furthermore, we highlight important anatomical features of the ferret lung that influence the kinetics of viral replication, clinical disease severity, and lung pathology.

IMPORTANCE
Ferrets are a valuable model for influenza virus pathogenesis, virus transmission, and antiviral therapy studies. Clinical disease in ferrets is an important parameter in evaluating the virulence of novel influenza viruses, and findings are extrapolated to virulence in humans. Therefore, it is highly desirable that the data from different laboratories be accurate and reproducible. We have found that, even when the same virus was administered at similar doses, different investigators reported a range of clinical disease outcomes, from asymptomatic infection to severe weight loss, ocular and nasal discharge, sneezing, and lethargy. We found that a wide range of inoculum volumes was used to experimentally infect ferrets, and we sought to determine whether the variations in disease outcome were the result of the volume of inoculum administered. These data highlight some less explored features of the model, methods of experimental infection, and clinical disease outcomes in a research setting.
Stand up for health—avoiding sedentary behaviour might lengthen your telomeres: secondary outcomes from a physical activity RCT in older people
Authors: Sjögren Per , Fisher Rachel , Kallings Lena , Svenson Ulrika , Roos Göran , Hellénius Mai-Lis 
Published: September 2014

BackgroundTelomere length has been associated with a healthy lifestyle and longevity. However, the effect of increased physical activity on telomere length is still unknown. Therefore, the aim was to study the relationship between changes in physical activity level and sedentary behaviour and changes in telomere length.MethodsTelomere length was measured in blood cells 6 months apart in 49, 68-year-old, sedentary, overweight individuals taking part in a randomised controlled physical activity intervention trial. The intervention group received individualised physical activity on prescription. Physical activity was measured with a 7-day diary, questionnaires and a pedometer. Sitting time was measured with the short version of The International Physical Activity Questionnaire.ResultsTime spent exercising as well as steps per day increased significantly in the intervention group. Reported sitting time decreased in both groups. No significant associations between changes in steps per day and changes in telomere length were noted. In the intervention group, there was a negative correlation between changes in time spent exercising and changes in telomere length (rho=−0.39, p=0.07). On the other hand, in the intervention group, telomere lengthening was significantly associated with reduced sitting time (rho=−0.68, p=0.02).ConclusionsReduced sitting time was associated with telomere lengthening in blood cells in sedentary, overweight 68-year-old individuals participating in a 6-month physical activity intervention trial.
Predictors of healthcare professionals’ attitudes towards family involvement in safety-relevant behaviours: a cross-sectional factorial survey study
Authors: Davis Rachel , Savvopoulou M , Shergill R , Shergill S , Schwappach D 
Published: September 2014

ObjectivesTo investigate predictors of healthcare professionals’ (HCPs) attitudes towards family involvement in safety-relevant behaviours.DesignA cross-sectional fractional factorial survey that assessed HCPs’ attitudes towards family involvement in two error scenarios relating to hand hygiene and medication safety. Each survey comprised two randomised vignettes that described the potential error, how the family member communicated with the HCP about the error and how the HCP responded to the family member’s question.Setting5 teaching hospitals in London, the Midlands and York. HCPs were approached on a range of medical and surgical wards.Participants160 HCPs (73 doctors; 87 nurses) aged between 21 and 65 years (mean 37) 102 were female.Outcome measuresHCP approval of family member’s behaviour; HCP reaction to the family member; anticipated effects on the family member–HCP relationship; HCP support for being questioned about hand hygiene/medication; affective rating responses.ResultsHCPs supported family member's intervening (88%) but only 41% agreed this would have positive effects on the family member/HCP relationship. Across vignettes and error scenarios the strongest predictors of attitudes were how the HCP (in the scenario) responded to the family member and whether an error actually occurred. Doctors (vs nurses) provided systematically more positive affective ratings to the vignettes.ConclusionsImportant predictors of HCPs’ attitudes towards family members’ involvement in patient safety have been highlighted. In particular, a discouraging response from HCP’s decreased support for family members being involved and had strong perceived negative effects on the family member/HCP relationship.
The Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE): study protocol for a cluster randomised controlled trial
Authors: White David , Waugh Norman , Elliott Jackie , Lawton Julia , Barnard Katharine , Campbell Michael J , Dixon Simon , Heller Simon 
Published: September 2014

IntroductionPeople with type 1 diabetes (T1DM) require insulin therapy to sustain life, and need optimal glycaemic control to prevent diabetic ketoacidosis and serious long-term complications. Insulin is generally administered using multiple daily injections but can also be delivered using an infusion pump (continuous subcutaneous insulin infusion), a more costly option with benefits for some patients. The UK National Institute for Health and Care Excellence (NICE) recommend the use of pumps for patients with the greatest need, citing insufficient evidence to approve extension to a wider population. Far fewer UK adults use pumps than in comparable countries. Previous trials of pump therapy have been small and of short duration and failed to control for training in insulin adjustment. This paper describes the protocol for a large randomised controlled trial comparing pump therapy with multiple daily injections, where both groups are provided with high-quality structured education.Methods and analysisA multicentre, parallel group, cluster randomised controlled trial among 280 adults with T1DM. All participants attended the week-long dose adjustment for normal eating (DAFNE) structured education course, and receive either multiple daily injections or pump therapy for 2 years. The trial incorporates a detailed mixed-methods psychosocial evaluation and cost-effectiveness analysis. The primary outcome will be the change in glycosylated haemoglobin (HbA1c) at 24 months in those participants whose baseline HbA1c is at or above 7.5% (58 mmol/mol). The key secondary outcome will be the proportion of participants reaching the NICE target of an HbA1c of 7.5% (58 mmol/mol) or less at 24 months.Ethics and disseminationThe protocol was approved by the Research Ethics Committee North West, Liverpool East and received Medicines and Healthcare products Regulatory Agency (MHRA) clinical trials authorisation. Each participating centre gave National Health Service R&D approval. We shall disseminate study findings to study participants and through peer reviewed publications and conference presentations, including lay user groups.Trial registration numberISRCTN 61215213.
Making it thick: a volcanic plateau origin of Palaeoarchean continental lithosphere of the Pilbara and Kaapvaal cratons
Authors: Van Kranendonk Martin J. , Smithies R. Hugh , Griffin William L. , Huston David L. , Hickman Arthur H. , Champion David C. , Anhaeusser Carl R. , Pirajno Franco 
Published: September 2014

Abstract
How and when continents grew and plate tectonics started on Earth remain poorly constrained. Most researchers apply the modern plate tectonic paradigm to problems of ancient crustal formation, but these are unsatisfactory because diagnostic criteria and actualistic plate configurations are lacking. Here, we show that 3.5–3.2 Ga continental nuclei in the Pilbara Craton, Australia, and the eastern Kaapvaal Craton, southern Africa, formed as thick volcanic plateaux built on a substrate of older continental lithosphere and did not accrete through horizontal tectonic processes. These nuclei survived because of the contemporaneous development of buoyant, non-subductable mantle roots. This plateau-type of Archean continental crust is distinct from, but complementary to, Archean gneiss terranes formed over shallowly dipping zones of intraoceanic underplating (proto-subduction) on a vigorously convecting early Earth with smaller plates and primitive plate tectonics.
Pietra Serena: the stone of the Renaissance
Authors: Fratini F. , Pecchioni E. , Cantisani E. , Rescic S. , Vettori S. 
Published: September 2014

Abstract

The most frequently used material in Florentine Renaissance architecture was Pietra Serena, a sandstone that nowadays is found in a quite satisfactory state of conservation. The reason for this is that architects and stone cutters in the past made careful selections of the materials they employed. This conscientious picking out was very important because most sandstone layers have a composition that is not always suitable for assuring an acceptable durability. This paper deals with the mineralogical, chemical, petrographical and physical characteristics of the Pietra Serena sandstone quarried in the hills near Florence in order to verify what was affirmed by
Vasari (1568)
, Tuscan painter, architect and historian of art of the 16th century, and other Tuscan naturalists regarding the quality of this sandstone.

As a matter of fact, analyses demonstrate that the Pietra Serena sandstones quarried in the hills of Settignano (to the northeast of Florence) and in the Gonfolina area (Lastra a Signa, to the west of Florence), are composed of layers particularly rich in calcite present mainly as sparitic cement. This calcitic cement gives great durability to the stone as is demonstrated by the good state of conservation of some Florentine monuments realized with Pietra Serena.
Fluid-mediated alteration of eclogite lenses in subduction complexes: a case from the Leaota Massif (South Carpathians)
Authors: Negulescu Elena , Săbău Gavril 
Published: September 2014

Abstract

Large ion lithophile element enrichment is a feature of the lithologies affected by mass transfer owing to fluids from the subduction zones (Sorensen
et al.
1997), well documented, for example, in mélanges of two subduction complexes: the Franciscan Complex (California) and Samana Metamorphic Complex (Dominican Republic). Here we illustrate a similar style of K–Ba–Rb alteration of various types of eclogites and their host rocks acquired during subduction zone metamorphism and subsequent inclusion in a metamorphosed subduction–accretion mélange complex in the Leaota Massif (South Carpathians). Textural evidence at different scales (knockers-with-rinds structures, phengite and atoll garnet overprints, open cavities) and thermobaric calculations document protracted fluid–rock interaction from near-peak conditions to the retrograde stages during detachment and ascension along the subduction channel. Fluids reverting to the surface along the subduction channel play an important part in the fluid budget of subduction zones.
Whole-Genome Sequencing of Asian Lung Cancers: Second-Hand Smoke Unlikely to Be Responsible for Higher Incidence of Lung Cancer among Asian Never-Smokers
Authors: Krishnan Vidhya G. , Ebert Philip J. , Ting Jason C. , Lim Elaine , Wong Swee-Seong , Teo Audrey S.M. , Yue Yong G. , Chua Hui-Hoon , Ma Xiwen , Loh Gary S.L. , Lin Yuhao , Tan Joanna H.J. , Yu Kun , Zhang Shenli , Reinhard Christoph , Tan Daniel S.W. , Peters Brock A. , Lincoln Stephen E. , Ballinger Dennis G. , Laramie Jason M. , Nilsen Geoffrey B. , Barber Thomas D. , Tan Patrick , Hillmer Axel M. , Ng Pauline C. 
Published: September 2014

Abstract
Asian nonsmoking populations have a higher incidence of lung cancer compared with their European counterparts. There is a long-standing hypothesis that the increase of lung cancer in Asian never-smokers is due to environmental factors such as second-hand smoke. We analyzed whole-genome sequencing of 30 Asian lung cancers. Unsupervised clustering of mutational signatures separated the patients into two categories of either all the never-smokers or all the smokers or ex-smokers. In addition, nearly one third of the ex-smokers and smokers classified with the never-smoker–like cluster. The somatic variant profiles of Asian lung cancers were similar to that of European origin with G.C&gt;T.A being predominant in smokers. We found EGFR and TP53 to be the most frequently mutated genes with mutations in 50% and 27% of individuals, respectively. Among the 16 never-smokers, 69% had an EGFR mutation compared with 29% of 14 smokers/ex-smokers. Asian never-smokers had lung cancer signatures distinct from the smoker signature and their mutation profiles were similar to European never-smokers. The profiles of Asian and European smokers are also similar. Taken together, these results suggested that the same mutational mechanisms underlie the etiology for both ethnic groups. Thus, the high incidence of lung cancer in Asian never-smokers seems unlikely to be due to second-hand smoke or other carcinogens that cause oxidative DNA damage, implying that routine EGFR testing is warranted in the Asian population regardless of smoking status. Cancer Res; 74(21); 6071–81. ©2014 AACR.