bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary Macrophages Rely on Histone Deacetylase 1 and 2 Expression To Induce Type I Interferon in Response to Gammaherpesvirus Infection
Authors: Mounce Bryan C. , Mboko Wadzanai P. , Kanack Adam J. , Tarakanova Vera L. 
Published: December 2013

ABSTRACT
Type I interferon is induced shortly following viral infection and represents a first line of host defense against a majority of viral pathogens. Not surprisingly, both replication and latency of gammaherpesviruses, ubiquitous cancer-associated pathogens, are attenuated by type I interferon, although the mechanism of attenuation remains poorly characterized. Gammaherpesviruses also target histone deacetylases (HDACs), a family of pleiotropic enzymes that modify gene expression and several cell signaling pathways. Specifically, we have previously shown that a conserved gammaherpesvirus protein kinase interacts with HDAC1 and -2 to promote gammaherpesvirus replication in primary macrophages. In the current study, we have used genetic approaches to show that expression of HDAC1 and -2 is critical for induction of a type I interferon response following gammaherpesvirus infection of primary macrophages. Specifically, expression of HDAC1 and -2 was required for phosphorylation of interferon regulatory factor 3 (IRF3) and accumulation of IRF3 at the beta interferon promoter in gammaherpesvirus-infected primary macrophages. To our knowledge, this is the first demonstration of a specific role for HDAC1 and -2 in the induction of type I interferon responses in primary immune cells following virus infection. Furthermore, because HDAC1 and -2 are overexpressed in several types of cancer, our findings illuminate potential side effects of HDAC1- and -2-specific inhibitors that are currently under development as cancer therapy agents.

IMPORTANCE
Gammaherpesviruses establish chronic infection in a majority of the adult population and are associated with several malignancies. Infected cells counteract gammaherpesvirus infection via innate immune signaling mediated primarily through type I interferon. The induction of type I interferon expression proceeds through several stages using molecular mechanisms that are still incompletely characterized. In this study, we show that expression of HDAC1 and -2 by macrophages is required to mount a type I interferon response to incoming gammaherpesvirus. The involvement of HDAC1 and -2 in the type I interferon response highlights the pleiotropic roles of these enzymes in cellular signaling. Interestingly, HDAC1 and -2 are deregulated in cancer and are attractive targets of new cancer therapies. Due to the ubiquitous and chronic nature of gammaherpesvirus infection, the role of HDAC1 and -2 in the induction of type I interferon responses should be considered during the clinical development of HDAC1- and -2-specific inhibitors.
Highly Divergent Integration Profile of Adeno-Associated Virus Serotype 5 Revealed by High-Throughput Sequencing
Authors: Janovitz Tyler , Oliveira Thiago , Sadelain Michel , Falck-Pedersen Erik 
Published: December 2013

ABSTRACT
Adeno-associated virus serotype 5 (AAV-5) is a human parvovirus that infects a high percentage of the population. It is the most divergent AAV, the DNA sequence cleaved by the viral endonuclease is distinct from all other described serotypes and, uniquely, AAV-5 does not cross-complement the replication of other serotypes. In contrast to the well-characterized integration of AAV-2, no published studies have investigated the genomic integration of AAV-5. In this study, we analyzed more than 660,000 AAV-5 integration junctions using high-throughput integrant capture sequencing of infected human cells. The integration activity of AAV-5 was 99.7% distinct from AAV-2 and favored intronic sequences. Genome-wide integration was highly correlated with viral replication protein binding and endonuclease sites, and a 39-bp consensus integration motif was revealed that included these features. Algorithmic scanning identified 126 AAV-5 hot spots, the largest of which encompassed 3.3% of all integration events. The unique aspects of AAV-5 integration may provide novel tools for biotechnology and gene therapy.

IMPORTANCE
Viral integration into the host genome is an important aspect of virus host cell biology. Genomic integration studies of the small single-stranded AAVs have largely focused on site preferential integration of AAV-2, which depends on the viral replication protein (Rep). We have now established the first genome wide integration profile of the highly divergent AAV-5 serotype. Using integrant capture sequencing, more than 600,000 AAV-5 integration junctions in human cells were analyzed. AAV-5 integration hot spots were 99.7% distinct from AAV-2. Integration favored intronic sequences, occurred on all chromosomes, and integration hot spot distribution was correlated with human genomic GAGC repeats and transcriptional activity. These features support expansion of AAV-5 based vectors for gene transfer considerations.
Interferon-Stimulated Poly(ADP-Ribose) Polymerases Are Potent Inhibitors of Cellular Translation and Virus Replication
Authors: Atasheva Svetlana , Frolova Elena I. , Frolov Ilya 
Published: December 2013

ABSTRACT
The innate immune response is the first line of defense against most viral infections. Its activation promotes cell signaling, which reduces virus replication in infected cells and leads to induction of the antiviral state in yet-uninfected cells. This inhibition of virus replication is a result of the activation of a very broad spectrum of specific cellular genes, with each of their products usually making a small but detectable contribution to the overall antiviral state. The lack of a strong, dominant function for each gene product and the ability of many viruses to interfere with the development of the antiviral response strongly complicate identification of the antiviral activity of the activated individual cellular genes. However, we have previously developed and applied a new experimental system which allows us to define a critical function of some members of the poly(ADP-ribose) polymerase (PARP) family in clearance of Venezuelan equine encephalitis virus mutants from infected cells. In this new study, we demonstrate that PARP7, PARP10, and the long isoform of PARP12 (PARP12L) function as important and very potent regulators of cellular translation and virus replication. The translation inhibition and antiviral effect of PARP12L appear to be mediated by more than one protein function and are a result of its direct binding to polysomes, complex formation with cellular RNAs (which is determined by both putative RNA-binding and PARP domains), and catalytic activity.

IMPORTANCE
The results of this study demonstrate that interferon-stimulated gene products PARP7, PARP10, and PARP12L are potent inhibitors of the replication of Venezuelan equine encephalitis virus and other alphaviruses. The inhibitory functions are determined by more than a single mechanism, and one of them is based on the ability of these proteins to regulate cellular translation. Interference with the cellular translational machinery depends on the integrity of both the amino-terminal domain, containing a number of putative RNA-binding motifs, and the catalytic function of the carboxy-terminal PARP domain. The PARP-induced changes in translation efficiency appear to have a more potent effect on the synthesis of virus-specific proteins than on that of cellular proteins, thus making PARP-specific translational downregulation an important contributor to the overall development of the antiviral response.
Long-term trajectories of back pain: cohort study with 7-year follow-up
Authors: Dunn Kate M , Campbell Paul , Jordan Kelvin P 
Published: December 2013

ObjectiveTo describe long-term trajectories of back pain.DesignMonthly data collection for 6 months at 7-year follow-up of participants in a prospective cohort study.SettingPrimary care practices in Staffordshire, UK.Participants228 people consulting their general practitioners with back pain, on whom information on 6-month back pain trajectories had been collected during 2001–2003, and who had valid consent and contact details in 2009–2010, were contacted. 155 participants (68% of those contacted) responded and provided sufficient data for primary analyses.Outcome measuresTrajectories based on patients’ self-reports of back pain were identified using longitudinal latent class analysis. Trajectories were characterised using information on disability, psychological status and presence of other symptoms.ResultsFour clusters with different back pain trajectories at follow-up were identified: (1) no or occasional pain, (2) persistent mild pain, (3) fluctuating pain and (4) persistent severe pain. Trajectory clusters differed significantly from each other in terms of disability, psychological status and other symptoms. Most participants remained in a similar trajectory as 7 years previously (weighted κ 0.54; 95% CI 0.42 to 0.65).ConclusionsMost people with back pain appear to follow a particular pain trajectory over long time periods, and do not have frequently recurring or widely fluctuating patterns. The results are limited by lack of information about the time between data collection periods and by loss to follow-up. However, findings do raise questions about standard divisions into acute and chronic back pain. A new framework for understanding the course of back pain is proposed.
Effectiveness of continence promotion for older women via community organisations: a cluster randomised trial
Authors: Tannenbaum Cara , Agnew Rona , Benedetti Andrea , Thomas Doneal , van den Heuvel Eleanor 
Published: December 2013

ObjectivesThe primary objective of this cluster randomised controlled trial was to compare the effectiveness of the three experimental continence promotion interventions against a control intervention on urinary symptom improvement in older women with untreated incontinence recruited from community organisations. A second objective was to determine whether changes in incontinence-related knowledge and new uptake of risk-modifying behaviours explain these improvements.Setting71 community organisations across the UK.Participants259 women aged 60 years and older with untreated incontinence entered the trial; 88% completed the 3-month follow-up.InterventionsThe three active interventions consisted of a single 60 min group workshop on (1) continence education (20 clusters, 64 women); (2) evidence-based self-management (17 clusters, 70 women); or (3) combined continence education and self-management (17 clusters, 61 women). The control intervention was a single 60 min educational group workshop on memory loss, polypharmacy and osteoporosis (17 clusters, 64 women).Primary and secondary outcome measuresThe primary outcome was self-reported improvement in incontinence 3 months postintervention at the level of the individual. The secondary outcome was change in the International Consultation on Incontinence Questionnaire (ICIQ) from baseline to 3-month follow-up. Changes in incontinence-related knowledge and behaviours were also assessed.ResultsThe highest rate of urinary symptom improvement occurred in the combined intervention group (66% vs 11% of the control group, prevalence difference 55%, 95% CI 43% to 67%, intracluster correlation 0). 30% versus 6% of participants reported significant improvement respectively (prevalence difference 23%, 95% CI 10% to 36%, intracluster correlation 0). The number-needed-to-treat was 2 to achieve any improvement in incontinence symptoms, and 5 to attain significant improvement. Compared to controls, participants in the combined intervention reported an adjusted mean 2.05 point (95% CI 0.87 to 3.24) greater improvement on the ICIQ from baseline to 3-month follow-up. Changes in knowledge and self-reported risk-reduction behaviours paralleled rates of improvement in all intervention arms.ConclusionsContinence education combined with evidence-based self-management improves symptoms of incontinence among untreated older women. Community organisations represent an untapped vector for delivering effective continence promotion interventions.Trial registrationClinicalTrials.gov ID numberNCT01239836.
Strain rate dependent micromechanical modeling of reinforced polymers with carbon nanotubes
Authors: Shokrieh Mahmood M , Mosalmani Reza , Omidi Majid Jamal 
Published: December 2013

Nano-phased polymers show strain rate dependent mechanical behaviors owing to the nature of polymers. Therefore, in this study a strain rate dependent constitutive equation is developed based on a micromechanics method, to predict the mechanical behavior of nanocomposites under various loading rates. The Goldberg et al. model, as a constitutive equation of polymers, has been used to predict the strain rate dependent mechanical behavior of pure polymers. Then, this model is combined with a micromechanics method (Halpin–Tsai model) to develop a constitutive equation for nano-phased polymers which predicts the stress–strain behavior of carbon nanotube (CNT) reinforced polymers at arbitrary strain rates. Also, contrary to the strain rate dependent behavior of the polymeric matrix, it is assumed that mechanical properties of carbon nanotube particles are not sensitive to loading rates. To verify the proposed model, predicted results are compared with the experimental data of multi-walled carbon nanotube/epoxy (tested in this study) and multi-walled carbon nanotube/polypropylene composites (available experimental data) under various tensile loading rates.
A comparative study of candesartan versus propranolol for migraine prophylaxis: A randomised, triple-blind, placebo-controlled, double cross-over study
Authors: Stovner Lars J , Linde Mattias , Gravdahl Gøril B , Tronvik Erling , Aamodt Anne H , Sand Trond , Hagen Knut 
Published: December 2013

Objective The objective of this article is to see whether the effect of candesartan for migraine prevention, shown in one previous study, could be confirmed in a new study, and if so, whether the effect was comparable to that of propranolol (non-inferiority analysis), and whether adverse events were different. Methods In a randomised, triple-blind, double cross-over study, 72 adult patients with episodic or chronic migraine went through three 12-week treatment periods on either candesartan 16 mg, propranolol slow-release 160 mg, or placebo. The main outcome measures were days with migraine headache per four weeks (primary outcome), days with headache, hours with headache, proportion of responders (>50% reduction of migraine days from baseline), and adverse events. Results In the modified intention-to treat-analysis, candesartan and propranolol were both superior to placebo: 2.95 (95% confidence interval: 2.35–3.55%) and 2.91 (2.36–3.45%), versus 3.53 (2.98–4.08%) for migraine days per month ( p = 0.02 for both comparisons, Wilcoxon's paired signed rank test, blinded statistical analysis). Candesartan was non-inferior to propranolol (and vice versa). The proportion of responders was significantly higher on candesartan (43%) and propranolol (40%) than on placebo (23%) ( p = 0.025 and <0.050, respectively). There were more adverse events on candesartan ( n = 133%) and propranolol ( n = 143%) than on placebo ( n = 90%), and the adverse event profiles of the active substances differed somewhat. Conclusion It is confirmed that candesartan 16 mg is effective for migraine prevention, with an effect size similar to propranolol 160 mg, and with somewhat different adverse events. Trial registration: EUDRACT (2008-002312-7), ClinicalTrials.gov (NCT00884663).
Psychometric Properties of a Korean Measure of Person-Directed Care in Nursing Homes
Authors: Choi Jae-Sung , Lee Minhong 
Published: December 2013

Objective: This study examined the validity and reliability of a person-directed care (PDC) measure for nursing homes in Korea. Method: Managerial personnel from 223 nursing homes in 2010 and 239 in 2012 were surveyed. Results: Item analysis and exploratory factor analysis for the first sample generated a 33-item PDC measure with eight factors. Item analysis for the second sample resulted in 32 items. Confirmatory factor analysis verified the acceptability of the revised instrument with seven factors of 30 items (χ2 = 650.96, root mean square error of approximation = .059, nonnormed fit index = .88, comparative fit index = .90, and incremental fit index = .90). The overall scale had high internal consistency and reliability (α = .925). Conclusion: Findings from this study confirm the validity of the revised Korean PDC scale.
Prevalence of the Factor V E666D Mutation and Its Correlation With Activated Protein C Resistance in the Chinese Population
Authors: Xin-guang Chen , Yong-qiang Zhao , Shu-jie Wang , Lian-kai Fan , Hua-cong Cai 
Published: December 2013

Background: Factor V (FV) Leiden mutation-related activated protein C resistance (APCR) is one of the common inherited risk factors for venous thromboembolism (VTE) in caucasian population. Although APCR could be identified in some of the Chinese healthy people and patients with VTE, it was not related to FV Leiden mutation. In 2008, we have identified a novel FV mutation (FV E666D) in exon 13 in a hereditary APCR family. And we presumed that the novel mutation might be a genetic defect of APCR in the Chinese population. The aim of our study was to evaluate the prevalence of FV E666D mutation and its correlation with APCR in the Chinese population in a larger series. Methods: From June 2009 to January 2011, 163 consecutive patients who underwent thrombophilia tests in our hospital were recruited. The clinical data were retrospectively reviewed. Thrombophilia tests included APCR, anticoagulant proteins, and antiphospholipid antibodies. Factor V E666D mutation was detected. Result: Of the 163 patients, 6 (3.7%) were identified as APCR positive, 2.9% for patients without thrombosis and 5.1% for patients with thrombosis or thrombosis history. Factor V E666D mutation was not detectable in all the 163 patients including 6 APCR-positive patients. Conclusions: The prevalence of APCR either in the nonthrombotic patients or in the patients with thrombosis was lower than that reported in other Chinese studies. Our study couldn’t provide illustration whether FV E666D mutation is correlated with APCR in the Chinese population.
Comparison of outcomes following stereotactic body radiotherapy for non-small cell lung cancer in patients with and without pathological confirmation
Authors: Haidar Yarah M. , Rahn Douglas A. , Nath Sameer , Song William , Bazhenova Lyudmila , Makani Samir , Fuster Mark M. , Sandhu Ajay P. 
Published: December 2013

Purpose/objective: Treatment of presumed early-stage lung cancer with definitive radiation therapy in the absence of a pathologically confirmed specimen frequently occurs. However, it is not well described in the literature, and there are few North American series reporting on this patient population. We report outcomes in patients treated with stereotactic body radiotherapy (SBRT) for presumed lung cancer and compare them to outcomes in patients treated with SBRT with pathologically confirmed non-small cell lung cancer (NSCLC). Materials/methods: This study is based on a retrospective review of 55 patients with presumed or confirmed lung cancer: 23 patients had nondiagnostic or absent pathologic specimens while 32 patients had pathologically confirmed NSCLC. All patients had hypermetabolic primary lesions on a positron emission tomography (PET) or PET/computed tomography (CT) scan. SBRT was delivered as 48–56 Gy in four to five fractions via a four-dimensional CT treatment plan. Results: Of the patients without pathological confirmation, the mean age was 78 (range 63–89 years) and 17 (74%) were men. The mean tumor size was 2.5 cm (range 1.0–5.1). Reasons for not having confirmed pathologic diagnosis included indeterminate biopsy specimen or an inability to tolerate a biopsy procedure due to poor respiratory status. SBRT was chosen due to noncandidacy for surgery in 17 patients (74%) or patient refusal of surgery in six (26%). Median follow up was 24.2 months (range 1.9–64.6): 2 of the 23 patients (8.7%) had local failure at the site of SBRT and 3 (13%) had regional failure. The actuarial 12-month overall survival was 83%. The median overall survival was 30.2 months. At last follow up, 12 patients (52%) were alive up to 64.6 months after treatment. SBRT was tolerated well in this series. Acute toxicity was noted in two patients (8.7%) and chronic toxicity in three (13%). These patient characteristics and results were shown to be similar to the 32 patients with pathologically confirmed NSCLC. On Kaplan–Meier analysis, there was no significant difference ( p = 0.27) in overall survival between patients with pathologically confirmed NSCLC and those with presumed lung cancer (which was deemed most likely NSCLC). Conclusion: While biopsy confirmation remains a goal in the workup of suspected NSCLC, SBRT without pathologic confirmation may represent a safe and effective option for the treatment of presumed NSCLC among patients who cannot tolerate or refuse surgery.
Molecular and serological evidence for the circulation of the tick symbiont Midichloria (Rickettsiales: Midichloriaceae) in different mammalian species
Authors: Bazzocchi Chiara , Mariconti Mara , Sassera Davide , Rinaldi Laura , Martin Elena , Cringoli Giuseppe , Urbanelli Sandra , Genchi Claudio , Bandi Claudio , Epis Sara 
Published: December 2013

Abstract

Background
The Midichloriaceae is a novel family of the order Rickettsiales, that encompasses intracellular bacteria associated with hard ticks (Ixodidae) and other arthropods. The most intensively investigated member of this family is Midichloria mitochondrii, a symbiotic bacterium of the sheep tick Ixodes ricinus, characterized by the capacity of multiplying inside the mitochondria. A recent study suggested that these bacteria might be inoculated into the human host during the tick bite. The purpose of this study was to determine the potential infectivity of Midichloria bacteria for non-human animals exposed to the risk of tick bite.

Methods
Blood from horses, cattle, sheep and dogs exposed to the risk of tick bite was included in this study. DNAs were extracted, and amplified using 16S ribosomal RNA primers conserved in the Midichloria genus. Furthermore, sera from dogs exposed to the risk of tick bite were analyzed in order to evaluate the presence of antibodies against the recombinant flagellar protein (rFliD) from M. mitochondrii using an ELISA test.

Results
Here we present two lines of evidence that support the possibility that bacteria from the genus Midichloria are inoculated into vertebrate hosts during a tick bite: (i) a direct evidence, i.e. the detection of circulating DNA from bacteria related with M. mitochondrii, in the blood of vertebrates exposed to tick parasitism; (ii) a further indirect evidence, i.e. the presence of antibodies against an antigen from M. mitochondrii in dogs exposed to the risk of tick bite. It is interesting to note that variability was detected in the Midichloria gene sequences recovered from positive animals, and that some of these sequences were identical to those generated from tick-associated Midichloria.

Conclusions
Based on the results, and on the overall information so far published on the genus Midichloria, we suggest that these bacteria are likely to represent a novel group of vector-borne agents, with the potential of infecting mammalian hosts. Whether inoculation of Midichloria bacteria could cause a true infection and pathological alteration in mammalian hosts is still to be determined. Surely, results emphasize the relevance of Midichloria bacteria in investigations on tick immunology and tick-bite markers.