bluuebunny/crossref_metadata_2025_split huggingface dataset:
ISG15 Functions as an Interferon-Mediated Antiviral Effector Early in the Murine Norovirus Life Cycle
Authors: Rodriguez Marisela R. , Monte Kristen , Thackray Larissa B. , Lenschow Deborah J. 
Published: June 2014

ABSTRACTHuman noroviruses (HuNoV) are the leading cause of nonbacterial gastroenteritis worldwide. Similar to HuNoV, murine noroviruses (MNV) are enteric pathogens spread via the fecal-oral route and have been isolated from numerous mouse facilities worldwide. Type I and type II interferons (IFN) restrict MNV-1 replication; however, the antiviral effectors impacting MNV-1 downstream of IFN signaling are largely unknown. Studies using dendritic cells, macrophages, and mice deficient in free and conjugated forms of interferon-stimulated gene 15 (ISG15) revealed that ISG15 conjugation contributes to protection against MNV-1 bothin vitroandin vivo. ISG15 inhibited a step early in the viral life cycle upstream of viral genome transcription. Directly transfecting MNV-1 RNA into IFN-stimulated mouse embryonic fibroblasts (MEFs) and bone marrow-derived dendritic cells (BMDC) lacking ISG15 conjugates bypassed the antiviral activity of ISG15, further suggesting that ISG15 conjugates restrict the MNV-1 life cycle at the viral entry/uncoating step. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection bothin vitroandin vivoand for the first time implicate the ISG15 pathway in the regulation of early stages of MNV-1 replication.IMPORTANCEType I IFNs are important in controlling murine norovirus 1 (MNV-1) infections; however, the proteins induced by IFNs that restrict viral growth are largely unknown. This report reveals that interferon-stimulated gene 15 (ISG15) mitigates MNV-1 replication bothin vitroandin vivo. In addition, it shows that ISG15 inhibits MNV-1 replication by targeting an early step in the viral life cycle, MNV-1 entry and/or uncoating. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection bothin vitroandin vivoand for the first time implicate the ISG15 pathway in the regulation of viral entry/uncoating.
Western Equine Encephalitis Virus: Evolutionary Analysis of a Declining Alphavirus Based on Complete Genome Sequences
Authors: Bergren Nicholas A. , Auguste Albert J. , Forrester Naomi L. , Negi Surendra S. , Braun Werner A. , Weaver Scott C. 
Published: June 2014

ABSTRACT

Western equine encephalitis virus (WEEV) is an arbovirus from the genus
Alphavirus
, family
Togaviridae
, which circulates in North America between birds and mosquitoes, occasionally causing disease in humans and equids. In recent decades, human infection has decreased dramatically; the last documented human case in North America occurred in 1994, and the virus has not been detected in mosquito pools since 2008. Because limited information exists regarding the evolution of WEEV, we analyzed the genomic sequences of 33 low-passage-number strains with diverse geographic and temporal distributions and performed comprehensive phylogenetic analyses. Our results indicated that WEEV is a highly conserved alphavirus with only approximately 5% divergence in its most variable genes. We confirmed the presence of the previously determined group A and B lineages and further resolved group B into three sublineages. We also observed an increase in relative genetic diversity during the mid-20th century, which correlates with the emergence and cocirculation of several group B sublineages. The estimated WEEV population size dropped in the 1990s, with only the group B3 lineage being sampled in the past 20 years. Structural mapping showed that the majority of substitutions in the envelope glycoproteins occurred at the E2-E2 interface. We hypothesize that an event occurred in the mid-20th century that resulted in the increased genetic diversity of WEEV in North America, followed by genetic constriction due to either competitive displacement by the B3 sublineage or stochastic events resulting from a population decline.

IMPORTANCE
Western equine encephalitis virus (WEEV) has caused several epidemics that resulted in the deaths of thousands of humans and hundreds of thousands of equids during the past century. During recent decades, human infection decreased drastically and the virus has not been found in mosquito pools since 2008. Because limited information exists regarding the evolution of WEEV, we analyzed 33 complete genome sequences and conducted comprehensive phylogenetic analyses. We confirmed the presence of two major lineages, one of which diverged into three sublineages. Currently, only one of those sublineages is found circulating in nature. Understanding the evolution of WEEV over the past century provides a unique opportunity to observe an arbovirus that is in decline and to better understand what factors can cause said decline.
Maturation and Vesicle-Mediated Egress of Primate Gammaherpesvirus Rhesus Monkey Rhadinovirus Require Inner Tegument Protein ORF52
Authors: Anderson Melissa S. , Loftus Matthew S. , Kedes Dean H. 
Published: June 2014

ABSTRACT
The tegument layer of herpesviruses comprises a collection of proteins that is unique to each viral species. In rhesus monkey rhadinovirus (RRV), a close relative of the human oncogenic pathogen Kaposi's sarcoma-associated herpesvirus, ORF52 is a highly abundant tegument protein tightly associated with the capsid. We now report that ORF52 knockdown during RRV infection of rhesus fibroblasts led to a greater than 300-fold reduction in the viral titer by 48 h but had little effect on the number of released particles and caused only modest reductions in the levels of intracellular viral genomic DNA and no appreciable change in viral DNA packaging into capsids. These data suggested that the lack of ORF52 resulted in the production and release of defective particles. In support of this interpretation, transmission electron microscopy (TEM) revealed that without ORF52, capsid-like particles accumulated in the cytoplasm and were unable to enter egress vesicles, where final tegumentation and envelopment normally occur. TEM also demonstrated defective particles in the medium that closely resembled the accumulating intracellular particles, having neither a full tegument nor an envelope. The disruption in tegument formation from ORF52 suppression, therefore, prevented the incorporation of ORF45, restricting its subcellular localization to the nucleus and appearing, by confocal microscopy, to inhibit particle transport toward the periphery. Ectopic expression of small interfering RNA (siRNA)-resistant ORF52 was able to partially rescue all of these phenotypic changes. In sum, our results indicate that efficient egress of maturing virions and, in agreement with studies on murine gammaherpesvirus 68 (MHV-68), complete tegumentation and secondary envelopment are dependent on intact ORF52.

IMPORTANCE
The tegument, or middle layer, of herpesviruses comprises both viral and cellular proteins that play key roles in the viral life cycle. A subset of these proteins is present only within members of one of the three subfamilies (alphaherpesviruses, betaherpesviruses, or gammaherpesviruses) of
Herpesviridae
. In this report, we show that the gammaherpesvirus-specific tegument protein ORF52 is critical for maturation of RRV, the closest relative of Kaposi's sarcoma-associated herpesvirus (KSHV) (a human cancer-causing pathogen) that has undergone this type of analysis. Without ORF52, the nascent subviral particles are essentially stuck in maturation limbo, unable to acquire the tegument or outer (envelope) layers. This greatly attenuates infectivity. Our data, together with earlier work on a murine homolog, as well as a more distantly related human homolog, provide a more complete understanding of how early protein interactions involving virus-encoded tegument proteins are critical for virus assembly and are also, therefore, potentially attractive therapeutic targets.
Parental marital status and childhood overweight and obesity in Norway: a nationally representative cross-sectional study
Authors: Biehl Anna , Hovengen Ragnhild , Grøholt Else-Karin , Hjelmesæth Jøran , Strand Bjørn Heine , Meyer Haakon E 
Published: June 2014

ObjectiveSociodemographic changes in Norway and other western industrialised countries, including family structure and an increasing proportion of cohabiting and divorced parents, might affect the prevalence of childhood overweight and obesity issues. We aimed to examine whether parental marital status was associated with general and abdominal obesity among children. We also sought to explore whether the associations differed by gender.DesignCross-sectional.Setting127 primary schools across Norway.Participant3166 third graders (mean age 8.3 years) participating in the nationally representative Norwegian Child Growth Study in 2010.MeasurementsHeight, weight and waist circumference were objectively measured. The main outcome measures were general overweight (including obesity; body mass index ≥25 kg/m2) using International Obesity Task Force (IOTF) cut-offs and abdominal obesity (waist-to-height ratio ≥0.5) by gender and parental marital status. Prevalence ratios, adjusted for possible confounders, were calculated by log-binomial regression.ResultsGeneral overweight (including obesity) was 1.54 (95% CI 1.21 to 1.95) times more prevalent among children of divorced parents compared with children of married parents, and the corresponding prevalence ratio for abdominal obesity was 1.89 (95% CI 1.35 to 2.65). Formal tests of the interaction term parental marital status by gender were not statistically significant. However, in gender-specific analyses the association between parental marital status and adiposity measures was only statistically significant in boys (p=0.04 for general overweight (including obesity) and p=0.01 for abdominal obesity). The estimates were robust against adjustment for maternal education, family country background and current area of residence.ConclusionsGeneral and abdominal obesities were more prevalent among children of divorced parents. This study provides valuable information by focusing on societal changes in order to identify vulnerable groups.
Knee moments of anterior cruciate ligament reconstructed and control participants during normal and inclined walking
Authors: Varma Raghav K , Duffell Lynsey D , Nathwani Dinesh , McGregor Alison H 
Published: June 2014

ObjectivesPrior injury to the knee, particularly anterior cruciate ligament (ACL) injury, is known to predispose one to premature osteoarthritis (OA). The study sought to explore if there was a biomechanical rationale for this process by investigating changes in external knee moments between people with a history of ACL injury and uninjured participants during walking: (1) on different surface inclines and (2) at different speeds. In addition we assessed functional differences between the groups.Participants12 participants who had undergone ACL reconstruction (ACLR) and 12 volunteers with no history of knee trauma or injury were recruited into this study. Peak knee flexion and adduction moments were assessed during flat (normal and slow speed), uphill and downhill walking using an inclined walkway with an embedded Kistler Force plate, and a ten-camera Vicon motion capture system. Knee injury and Osteoarthritis Outcome Score (KOOS) was used to assess function. Multivariate analysis of variance (MANOVA) was used to examine statistical differences in gait and KOOS outcomes.ResultsNo significant difference was observed in the peak knee adduction moment between ACLR and control participants, however, in further analysis, MANOVA revealed that ACLR participants with an additional meniscal tear or collateral ligament damage (7 participants) had a significantly higher adduction moment (0.33±0.12 Nm/kg m) when compared with those with isolated ACLR (5 participants, 0.1±0.057 Nm/kg m) during gait at their normal speed (p<0.05). A similar (non-significant) trend was seen during slow, uphill and downhill gait.ConclusionsParticipants with an isolated ACLR had a reduced adductor moment rather an increased moment, thus questioning prior theories on OA development. In contrast, those participants who had sustained associated trauma to other key knee structures were observed to have an increased adduction moment. Additional injury concurrent with an ACL rupture may lead to a higher predisposition to osteoarthritis than isolated ACL deficiency alone.
START (STrAtegies for RelaTives) coping strategy for family carers of adults with dementia: qualitative study of participants’ views about the intervention
Authors: Sommerlad Andrew , Manela Monica , Cooper Claudia , Rapaport Penny , Livingston Gill 
Published: June 2014

ObjectivesTo analyse the experience of individual family carers of people with dementia who received a manual-based coping strategy programme (STrAtegies for RelaTives, START), demonstrated in a randomised-controlled trial to reduce affective symptoms.DesignA qualitative study using self-completed questionnaires exploring the experience of the START intervention. Two researchers transcribed, coded and analysed completed questionnaires thematically.SettingThree mental health and one neurology dementia clinic in South East England.ParticipantsParticipants were primary family carers of a patient diagnosed with dementia who provided support at least weekly to their relative. We invited those in the treatment group remaining in the START study at 2 years postrandomisation (n=132) to participate. 75 people, comprising a maximum variation sample, responded.Primary and secondary outcome measures(1) Important aspects of the therapy. (2) Continued use of the intervention after the end of the therapy. (3) Unhelpful aspects of the therapy and suggestions for improvement. (4) Appropriate time for intervention delivery.ResultsCarers identified several different components as important: relaxation techniques, education about dementia, strategies to help manage the behaviour of the person with dementia, contact with the therapist and changing unhelpful thoughts. Two-thirds of the participants reported that they continue to use the intervention's techniques at 2-year follow up. Few participants suggested changes to the intervention content, but some wanted more sessions and others wanted the involvement of more family members. Most were happy with receiving the intervention shortly after diagnosis, although some relatives of people with moderate dementia thought it should have been delivered at an earlier stage.ConclusionsParticipants’ varied responses about which aspects of START were helpful suggest that a multicomponent intervention is suited to the differing circumstances of dementia carers, providing a range of potentially helpful strategies. The continued use of the strategies 2 years after receiving the intervention could be a mechanism for the intervention remaining effective.
An automated minimum retest interval rejection rule reduces repeat CRP workload and expenditure, and influences clinician-requesting behaviour
Authors: Waldron Jenna L , Ford Clare , Dobie Donald , Danks Graham , Humphrey Richard , Rolli Alain , Gama Rousseau 
Published: June 2014

AimsRepeat serum C-reactive protein (CRP) measurements on the same day or on consecutive days are of limited clinical value. Minimum retesting intervals are recommended for managing unnecessary repeat testing. As not previously reported, we studied the effect of minimum retesting interval test rejection on laboratory workload and expenditure and on clinician-requesting behaviour.MethodsIn a prospective study, we evaluated the effect of an automated 48 h CRP minimum retesting interval rule on inpatient and outpatient CRP workload and costs. Control data on inpatient and outpatient serum urea and electrolytes (UE) workload were collected during the study.ResultsOver 1 year, there was a 7.0% and 12.3% decrease in CRP requests and CRP tests analysed, respectively, following the introduction of the minimum retesting interval rule when compared to the 1 year baseline period. This equated to an estimated annual reduction in revenue costs of £10 500, but cash savings in consumable costs of £3000. There was no significant change in UE requests.ConclusionsWe report, for the first time, that automated minimum retesting interval rejection rules as a stand-alone strategy are a cheap and sustainable method for reducing unnecessary repeat CRP tests, resulting in small laboratory cash savings, more efficient use of laboratory resources and standardisation of patient care pathways. The minimum retesting interval rejection rule also altered clinician test-requesting behaviour towards more appropriate requesting.
An update to the Raymond–Roy Occlusion Classification of intracranial aneurysms treated with coil embolization
Authors: Mascitelli Justin R , Moyle Henry , Oermann Eric K , Polykarpou Maritsa F , Patel Aanand A , Doshi Amish H , Gologorsky Yakov , Bederson Joshua B , Patel Aman B 
Published: June 2014

BackgroundThe Raymond–Roy Occlusion Classification (RROC) is the standard for evaluating coiled aneurysms (Class I: complete obliteration; Class II: residual neck; Class III: residual aneurysm), but not all Class III aneurysms behave the same over time.MethodsThis is a retrospective review of 370 patients with 390 intracranial aneurysms treated with coil embolization. A Modified Raymond–Roy Classification (MRRC), in which Class IIIa designates contrast within the coil interstices and Class IIIb contrast along the aneurysm wall, was applied retrospectively.ResultsClass IIIa aneurysms were more likely to improve to Class I or II than Class IIIb aneurysms (83.34% vs 14.89%, p<0.001) and were also more likely than Class II to improve to Class I (52.78% vs 16.90%, p<0.001). Class IIIb aneurysms were more likely to remain incompletely occluded than Class IIIa aneurysms (85.11% vs 16.67%, p<0.001). Class IIIb aneurysms were larger with wider necks while Class IIIa aneurysms had higher packing density. Class IIIb aneurysms had a higher retreatment rate (33.87% vs 6.54%, p<0.001) and a trend toward higher subsequent rupture rate (3.23% vs 0.00%, p=0.068).ConclusionsWe propose the MRRC to further differentiate Class III aneurysms into those likely to progress to complete occlusion and those likely to remain incompletely occluded or to worsen. The MRRC has the potential to expand the definition of adequate coil embolization, possibly decrease procedural risk, and help endovascular neurosurgeons predict which patients need closer angiographic follow-up. These findings need to be validated in a prospective study with independent blinded angiographic grading.
Imaged-based multiscale network modelling of microporosity in carbonates
Authors: Prodanović Maša , Mehmani Ayaz , Sheppard Adrian P. 
Published: June 2014

Abstract
Diagenetic changes such as cementation or dissolution have a strong control on carbonate pore structure, and often disconnect the original intergranular pore space. Spatial distribution of submicron porosity (microporosity) that develops in the process, as well as its influence on flow properties, is difficult to image and characterize. Yet, a petrophysically rigorous pore-scale model that accounts for submicron porosity interconnectivity would help in the understanding and development of carbonate reservoirs dominated by microporosity. We present algorithms to geometrically match pore–throat networks from two separate length scales that can be extracted directly from three-dimensional (3D) rock images, or be constructed to match the relevant measured properties. We evaluate the combined influence of cementation and dissolution using a Bentheimer Sandstone sample, as well as image-identified microporosity on flow transport properties in an Estaillades Limestone sample.
FAK Inhibition Disrupts a β5 Integrin Signaling Axis Controlling Anchorage-Independent Ovarian Carcinoma Growth
Authors: Tancioni Isabelle , Uryu Sean , Sulzmaier Florian J. , Shah Nina R. , Lawson Christine , Miller Nichol L.G. , Jean Christine , Chen Xiao Lei , Ward Kristy K. , Schlaepfer David D. 
Published: June 2014

Abstract
Ovarian cancer ascites fluid contains matrix proteins that can impact tumor growth via integrin receptor binding. In human ovarian tumor tissue arrays, we find that activation of the cytoplasmic focal adhesion (FAK) tyrosine kinase parallels increased tumor stage, β5 integrin, and osteopontin matrix staining. Elevated osteopontin, β5 integrin, and FAK mRNA levels are associated with decreased serous ovarian cancer patient survival. FAK remains active within ovarian cancer cells grown as spheroids, and anchorage-independent growth analyses of seven ovarian carcinoma cell lines identified sensitive (HEY, OVCAR8) and resistant (SKOV3-IP, OVCAR10) cells to 0.1 μmol/L FAK inhibitor (VS-4718, formerly PND-1186) treatment. VS-4718 promoted HEY and OVCAR8 G0–G1 cell-cycle arrest followed by cell death, whereas growth of SKOV3-IP and OVCAR10 cells was resistant to 1.0 μmol/L VS-4718. In HEY cells, genetic or pharmacological FAK inhibition prevented tumor growth in mice with corresponding reductions in β5 integrin and osteopontin expression. β5 knockdown reduced HEY cell growth in soft agar, tumor growth in mice, and both FAK Y397 phosphorylation and osteopontin expression in spheroids. FAK inhibitor–resistant (SKOV3-IP, OVCAR10) cells exhibited anchorage-independent Akt S473 phosphorylation, and expression of membrane-targeted and active Akt in sensitive cells (HEY, OVCAR8) increased growth but did not create a FAK inhibitor–resistant phenotype. These results link osteopontin, β5 integrin, and FAK in promoting ovarian tumor progression. β5 integrin expression may serve as a biomarker for serous ovarian carcinoma cells that possess active FAK signaling. Mol Cancer Ther; 13(8); 2050–61. ©2014 AACR.
Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism
Authors: Guérin Laurent , Couturaud Francis , Parent Florence , Revel Marie-Pierre , Gillaizeau Florence , Planquette Benjamin , Pontal Daniel , Guégan Marie , Simonneau Gérald , Meyer Guy , Sanchez Olivier 
Published: June 2014

SummaryChronic thromboembolic pulmonary hypertension (CTEPH) has been estimated to occur in 0.1–0.5% of patients who survive a pulmonary embolism (PE), but more recent prospective studies suggest that its incidence may be much higher. The absence of initial haemodynamic evaluation at the time of PE should explain this discrepancy. We performed a prospective multicentre study including patients with PE in order to assess the prevalence and to describe risk factors of CTEPH. Follow-up every year included an evaluation of dyspnea and echocardiography using a predefined algorithm. In case of suspected CTEPH, the diagnosis was confirmed using right heart catheterisation (RHC). Signs of CTEPH were searched on the multidetector computed tomography (CT) and echocardiography performed at the time of PE. Of the 146 patients analysed, eight patients (5.4%) had suspected CTEPH during a median follow-up of 26 months. CTEPH was confirmed using RHC in seven cases (4.8%; 95%CI, 2.3 – 9.6) and ruled-out in one. Patients with CTEPH were older, had more frequently previous venous thromboembolic events and more proximal PE than those without CTEPH. At the time of PE diagnosis, patients with CTEPH had a higher systolic pulmonary artery pressure and at least two signs of CTEPH on the initial CT. After acute PE, the prevalence of CTEPH appears high. However, initial echocardiography and CT data at the time of the index PE suggest that a majority of patients with CTEPH had previously unknown pulmonary hypertension, indicating that a first clinical presentation of CTEPH may mimic acute PE.