bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Bacteriostatic Protein Lipocalin 2 Is Induced in the Central Nervous System of Mice with West Nile Virus Encephalitis
Authors: Noçon Aline L. , Ip Jacque P. K. , Terry Rachael , Lim Sue Ling , Getts Daniel R. , Müller Marcus , Hofer Markus J. , King Nicholas J. C. , Campbell Iain L. 
Published: October 2013

ABSTRACTLipocalin 2 (Lcn2) is a bacteriostatic factor produced during the innate immune response to bacterial infection. Whether Lcn2 has a function in viral infection is unknown. We investigated the regulation and function of Lcn2 in the central nervous system (CNS) of mice during West Nile virus (WNV) encephalitis. Lcn2 mRNA and protein were induced in the brain by day 5, and this induction increased further by day 7 postinfection but was delayed compared with the induction of the toll-like receptor 3 (TLR3) gene, retinoic acid-inducible gene 1 (RIG-I), and melanoma differentiation-associated protein 5 (MDA5) gene. The Lcn2 mRNA and protein were both found at high levels in the choroid plexus, vascular endothelium, macrophage/microglia, and astrocytes. However, some neuronal subsets contained Lcn2 protein but no detectable mRNA. In Lcn2 knockout (KO) mice, with the exception of CXC motif chemokine 5 (CXCL5), which was significantly more downregulated than in wild-type (WT) mice, expression levels of a number of other host response genes were similar in the two genotypes. The brain from Lcn2 and WT mice with WNV encephalitis contained similar numbers of infiltrating macrophages, granulocytes, and T cells. Lcn2 KO and WT mice had no significant difference in tissue viral loads or survival after infection with different doses of WNV. We conclude that Lcn2 gene expression is induced to high levels in a time-dependent fashion in a variety of cells and regions of the CNS of mice with WNV encephalitis. The function of Lcn2 in the host response to WNV infection remains largely unknown, but our data indicate that it is dispensable as an antiviral or immunoregulatory factor in WNV encephalitis.
Delayed Sequelae of Neonatal Respiratory Syncytial Virus Infection Are Dependent on Cells of the Innate Immune System
Authors: Harker James A. , Yamaguchi Yuko , Culley Fiona J. , Tregoning John S. , Openshaw Peter J. M. 
Published: October 2013

ABSTRACT
Infection with respiratory syncytial virus (RSV) in neonatal mice leads to exacerbated disease if mice are reinfected with the same virus as adults. Both T cells and the host major histocompatibility complex genotype contribute to this phenomenon, but the part played by innate immunity has not been defined. Since macrophages and natural killer (NK) cells play key roles in regulating inflammation during RSV infection of adult mice, we studied the role of these cells in exacerbated inflammation following neonatal RSV sensitization/adult reinfection. Compared to mice undergoing primary infection as adults, neonatally sensitized mice showed enhanced airway fluid levels of interleukin-6 (IL-6), alpha interferon (IFN-α), CXCL1 (keratinocyte chemoattractant/KC), and tumor necrosis factor alpha (TNF-α) at 12 to 24 h after reinfection and IL-4, IL-5, IFN-γ, and CCL11 (eotaxin) at day 4 after reinfection. Weight loss during reinfection was accompanied by an initial influx of NK cells and granulocytes into the airways and lungs, followed by T cells. NK cell depletion during reinfection attenuated weight loss but did not alter T cell responses. Depletion of alveolar macrophages with inhaled clodronate liposomes reduced both NK and T cell numbers and attenuated weight loss. These findings indicate a hitherto unappreciated role for the innate immune response in governing the pathogenic recall responses to RSV infection.
Hemagglutinin Receptor Specificity and Structural Analyses of Respiratory Droplet-Transmissible H5N1 Viruses
Authors: de Vries Robert P. , Zhu Xueyong , McBride Ryan , Rigter Alan , Hanson Anthony , Zhong Gongxun , Hatta Masato , Xu Rui , Yu Wenli , Kawaoka Yoshihiro , de Haan Cornelis A. M. , Wilson Ian A. , Paulson James C. 
Published: October 2013

ABSTRACT
Two ferret-adapted H5N1 viruses capable of respiratory droplet transmission have been reported with mutations in the hemagglutinin receptor-binding site and stalk domains. Glycan microarray analysis reveals that both viruses exhibit a strong shift toward binding to “human-type” α2-6 sialosides but with notable differences in fine specificity. Crystal structure analysis further shows that the stalk mutation causes no obvious perturbation of the receptor-binding pocket, consistent with its impact on hemagglutinin stability without affecting receptor specificity.
Rodent Herpesvirus Peru Encodes a Secreted Chemokine Decoy Receptor
Authors: Lubman Olga Y. , Cella Marina , Wang Xinxin , Monte Kristen , Lenschow Deborah J. , Huang Yina H. , Fremont Daved H. 
Published: October 2013

ABSTRACTViruses have long been studied not only for their pathology and associated disease but also as model systems for understanding cellular and immunological processes. Rodent herpesvirus Peru (RHVP) is a recently characterized rhadinovirus related to murine gammaherpesvirus 68 (MHV68) and Kaposi's sarcoma-associated herpesvirus (KSHV) that establishes acute and latent infection in laboratory mice. RHVP encodes numerous unique proteins that we hypothesize might facilitate host immune evasion during infection. We report here that open reading frame (ORF) R17 encodes a high-affinity chemokine binding protein that broadly recognizes human and murine CC and C chemokines. The interaction of R17 with chemokines is generally characterized by rapid association kinetics, and in the case of CCL3, CCL4, CCL5, CCL24, and XCL1, extremely stable complexes are formed. Functionally, R17 potently inhibited CCL2-driven chemotaxis of the human monocytic cell line THP-1, CCL3-driven chemotaxis of peripheral blood mononuclear cells, and CCL2-mediated calcium flux. Our studies also reveal that R17 binds to glycosaminoglycans (GAGs) in a process dependent upon two BBXB motifs and that chemokine and GAG binding can occur simultaneously at distinct sites. Collectively, these studies suggest that R17 may play a role in RHVP immune evasion through the targeted sabotage of chemokine-mediated immune surveillance.
Sendai Virus C Proteins Regulate Viral Genome and Antigenome Synthesis To Dictate the Negative Genome Polarity
Authors: Irie Takashi , Okamoto Isao , Yoshida Asuka , Nagai Yoshiyuki , Sakaguchi Takemasa 
Published: October 2013

ABSTRACT

The order
Mononegavirales
comprises a large number of nonsegmented negative-strand RNA viruses (NNSVs). How the genome polarity is determined is a central issue in RNA virus biology. Using a prototypic species, vesicular stomatitis virus (VSV), it has been established that the negative polarity of the viral genome is defined solely by different strengths of the
cis
-acting replication promoters located at the 3′ ends of the genome and antigenome, resulting in the predominance of the genome over the antigenome. This VSV paradigm has long been applied for the
Mononegavirales
in general without concrete proof. We now found that another prototypic species, Sendai virus (SeV), undergoes a marked shift from the early antigenome-dominant to the late genome-dominant phase during the course of infection. This shift appeared to be governed primarily by the expression of the accessory C protein, because no such shift occurred in a recombinant SeV with the C gene deleted, and antigenomes were dominant throughout infection, generating antigenome-dominant and noninfectious progeny virions. Therefore, we proposed for the first time a
trans
-regulatory mechanism, the SeV paradigm, to dictate the genome polarity of an NNSV. A series of promoter-swapped SeV recombinants suggested the importance of the primary as well as secondary structures of the promoters in this
trans
-regulation.
The Cellular Peptidyl-Prolyl
cis
/
trans
Isomerase Pin1 Regulates Reactivation of Kaposi's Sarcoma-Associated Herpesvirus from Latency
Authors: Guito Jonathan , Gavina Aileen , Palmeri Diana , Lukac David M. 
Published: October 2013

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma and primary effusion lymphoma. KSHV-infected cells are predominantly latent, with a subset undergoing lytic reactivation. Rta is the essential lytic switch protein that reactivates virus by forming transactivation-competent complexes with the Notch effector protein RBP-Jk and promoter DNA. Strikingly, Rta homolog analysis reveals that prolines constitute 17% of conserved residues. Rta is also highly phosphorylated
in vivo
. We previously demonstrated that proline content determines Rta homotetramerization and function. We hypothesize that proline-directed modifications regulate Rta function by controlling binding to peptidyl-prolyl
cis
/
trans
isomerases (PPIases). Cellular PPIase Pin1 binds specifically to phosphoserine- or phosphothreonine-proline (pS/T-P) motifs in target proteins. Pin1 dysregulation is implicated in myriad human cancers and can be subverted by viruses. Our data show that KSHV Rta protein contains potential pS/T-P motifs and binds directly to Pin1. Rta transactivation is enhanced by Pin1 at two delayed early viral promoters in uninfected cells. Pin1's effect, however, suggests a rheostat-like influence on Rta function. We show that in infected cells, endogenous Pin1 is active during reactivation and enhances Rta-dependent early protein expression induced by multiple signals, as well as DNA replication. Surprisingly, ablation of Pin1 activity by the chemical juglone or dominant-negative Pin1 enhanced late gene expression and production of infectious virus, while ectopic Pin1 showed inhibitory effects. Our data thus suggest that Pin1 is a unique, dose-dependent molecular timer that enhances Rta protein function, but inhibits late gene synthesis and virion production, during KSHV lytic reactivation.
Enterobius vermicularisinfection of the ovary
Authors: Powell George , Sarmah Piyush , Sethi Bhawana , Ganesan Raji 
Published: October 2013

SummaryEnterobius vermicularisis an intestinal parasite, which may occasionally involve extraintestinal sites including the female genital tract. We report a rare case of ovarian involvement, which presented with chronic right iliac fossa pain in a 31-year-old woman. A transvaginal ultrasound scan was suggestive of a right adnexal dermoid cyst; however, histological examination of the subsequent salpingo-oophorectomy specimen showed an abscess containing viableE. vermicularisova.E. vermicularisis the most prevalent human nematode worldwide. Its ova are ingested, larvae hatch and mature female worms journey to the perianal region where they lay eggs. Female worms may also migrate from the anus along the female genital tract. Although of low pathogenicity, complications such as infertility or peritonitis may arise.
Treating lateral epicondylitis with corticosteroid injections or non-electrotherapeutical physiotherapy: a systematic review
Authors: Olaussen Morten , Holmedal Oeystein , Lindbaek Morten , Brage Soeren , Solvang Hiroko 
Published: October 2013

ObjectivesTo evaluate the current evidence for the efficacy of corticosteroid injection and non-electrotherapeutic physiotherapy compared with control for treating lateral epicondylitis.DesignSystematic review.ParticipantsWe searched five databases in September 2012 for randomised controlled studies with a minimum quality rating. Of the 640 studies retrieved, 11 were included, representing 1161 patients of both sexes and all ages.InterventionsCorticosteroid injection and non-electrotherapeutic physiotherapy.Outcome measuresRelative risk (RR) or standardised mean difference (SMD) for overall improvement, pain and grip strength at 4–12, 26 and 52 weeks of follow-up.ResultsCorticosteroid injection gave a short-term reduction in pain versus no intervention or non-steroidal anti-inflammatory drugs (SMD −1.43, 95% CI −1.64 to −1.23). At intermediate follow-up, we found an increase in pain (SMD 0.32, 95% CI 0.13 to 0.51), reduction in grip strength (SMD −0.48, 95% CI −0.73 to −0.24) and negative effect on the overall improvement effect (RR 0.66 (0.53 to 0.81)). For corticosteroid injection versus lidocaine injection, the evidence was conflicting. At long-term follow-up, there was no difference on overall improvement and grip strength, with conflicting evidence for pain. Manipulation and exercise versus no intervention showed beneficial effect at short-term follow-up (overall improvement RR 2.75, 95% CI 1.30 to 5.82), but no significant difference at intermediate or long-term follow-up. We found moderate evidence for short-term and long-term effects of eccentric exercise and stretching versus no intervention. For exercise versus no intervention and eccentric or concentric exercise and stretching versus stretching alone, we found moderate evidence of no short-term effect.ConclusionsCorticosteroid injections have a short-term beneficial effect on lateral epicondylitis, but a negative effect in the intermediate term. Evidence on the long-term effect is conflicting. Manipulation and exercise and exercise and stretching have a short-term effect, with the latter also having a long-term effect.
Timing of access to secondary healthcare services for diabetes management and lower extremity amputation in people with diabetes: a protocol of a case–control study
Authors: Buckley Claire M , Ali Fauzi , Roberts Graham , Kearney Patricia M , Perry Ivan J , Bradley Colin P 
Published: October 2013

BackgroundLower extremity amputation (LEA) is a complication of diabetes and a marker of the quality of diabetes care. Clinical and sociodemographic determinants of LEA in people with diabetes are well known. However, the role of service-related factors has been less well explored. Early referral to secondary healthcare is assumed to prevent the occurrence of LEA. The objective of this study is to investigate a possible association between the timing of patient access to secondary healthcare services for diabetes management, as a key marker of service-related factors, and LEA in patients with diabetes.Methods/designThis is a case–control study. The source population is people with diabetes. Cases will be people with diabetes who have undergone a first major LEA, identified from the hospital discharge data at each of three regional centres for diabetes care. Controls will be patients with diabetes without LEA admitted to the same centre either electively or as an emergency. Frequency-matching will be applied for gender, type of diabetes, year and centre of LEA. Three controls per case will be selected from the same population as the cases. With a power of 90% to detect OR of 0.4 for an association between ‘good quality care’ and LEA in people with diabetes, 107 cases and 321 controls are required. Services involved in diabetes management are endocrinology, ophthalmology, renal, cardiology, vascular surgery and podiatry; timing of first contact with any of these services is the main exploratory variable. Using unconditional logistic regression, an association between this exposure and the outcome of major LEA in people with diabetes will be explored, while adjusting for confounders.Ethics and disseminationEthical approval was granted by the Clinical Research Ethics Committee of the Cork Teaching Hospitals, Ireland. Results will be presented at conferences and published in peer-reviewed journals.
Respiratory infections in preterm infants and subsequent asthma: a cohort study
Authors: Montgomery Scott , Bahmanyar Shahram , Brus Ole , Hussein Oula , Kosma Paraskevi , Palme-Kilander Charlotte 
Published: October 2013

ObjectivesTo investigate whether gestational age modifies the association of airway infections that result in hospital admission during the first year after birth, with subsequent asthma risk after age 5 years.SettingHospital inpatients and a general population comparison group in Sweden followed for subsequent diagnoses in primary and secondary care.ParticipantsNational registers identified 42 334 children admitted to hospital for respiratory infection in their first year after birth during 1981–1995, individually matched with 211 594 children not admitted to hospital for infection during their first year.Primary outcomeAsthma diagnoses and prescribed asthma treatments after the age of 5 years identified through registers.ResultsCox regression was used to identify a HR (and 95% CI) of 1.51 (1.47 to 1.51) for the association of respiratory infection before 1 year of age with asthma after age 5 years, after adjustment for sex, gestational age, chronic lung disease, maternal asthma and maternal smoking. When stratified by gestational age (and with additional adjustment for birth weight), there is statistically significant effect modification by gestational age, with the highest magnitude asthma risk among those born with a gestational age of less than 28 weeks, producing an adjusted HR of 2.22 (1.59 to 3.09). This higher magnitude asthma risk persisted until after age 10 years, but differences in risk by gestational age were less pronounced for asthma after age 16 years.ConclusionsExtremely preterm infants are most likely to have chronic respiratory sequelae following respiratory infections in early life.
Positive imagery cognitive bias modification (CBM) and internet-based cognitive behavioural therapy (iCBT) versus control CBM and iCBT for depression: study protocol for a parallel-group randomised controlled trial
Authors: Williams Alishia D , Blackwell Simon E , Holmes Emily A , Andrews Gavin 
Published: October 2013

IntroductionThe current randomised controlled trial will evaluate the efficacy of an internet-delivered positive imagery cognitive bias modification (CBM) intervention for depression when compared with an active control condition and help establish the additive benefit of positive imagery CBM when delivered in combination with internet cognitive behavioural therapy for depression.Methods and analysisPatients meeting diagnostic criteria for a current major depressive episode will be recruited through the research arm of a not-for-profit clinical and research unit in Australia. The minimum sample size for each group (α set at 0.05, power at 0.80) was identified as 29, but at least 10% more will be recruited to hedge against expected attrition. We will measure the impact of CBM on primary measures of depressive symptoms (Beck Depression Inventory—second edition (BDI-II), Patient Health Questionnaire (PHQ9)) and interpretive bias (ambiguous scenarios test-depression), and on a secondary measure of psychological distress (Kessler-10 (K10)) following the 1-week CBM intervention. Secondary outcome measures of psychological distress (K10), as well as disability (WHO disability assessment schedule-II), repetitive negative thinking (repetitive thinking questionnaire), and anxiety (state trait anxiety inventory-trait version) will be evaluated following completion of the 11-week combined intervention, in addition to the BDI-II and PHQ9. Intent-to-treat marginal and mixed effect models using restricted maximum likelihood estimation will be used to evaluate the primary hypotheses. Clinically significant change will be defined as high-end state functioning (a BDI-II score <14) combined with a total score reduction greater than the reliable change index score. Maintenance of gains will be assessed at 3-month follow-up.Ethics and disseminationThe current trial protocol has been approved by the Human Research Ethics Committee of St Vincent's Hospital and the University of New South Wales, Sydney.Trial registrationAustralian New Zealand Clinical Trials Registry: ACTRN12613000139774 and Clinicaltrials.gov:NCT01787513. This trial protocol is written in compliance with the Standard Protocol Items: recommendations for Interventional Trials (SPIRIT) guidelines.
PKCι Maintains a Tumor-initiating Cell Phenotype That Is Required for Ovarian Tumorigenesis
Authors: Wang Yin , Hill Kristen S. , Fields Alan P. 
Published: October 2013

Abstract
Protein kinase Cι (PKCι) has oncogenic potential and is an attractive therapeutic target for treatment of lung cancer, particularly those tumors that express elevated PKCι. However, whether PKCι is a viable target in ovarian cancer is unknown, and virtually nothing is known about the mechanism by which PKCι drives ovarian tumorigenesis. Here, it is demonstrated that PKCι maintains a tumor-initiating cell (TIC) phenotype that drives ovarian tumorigenesis. A highly tumorigenic population of cells from human ovarian cancer cell lines exhibit cancer stem-like TIC properties, including self-renewal, clonal expansion, expression of stem-related genes, enhanced transformed growth in vitro, and aggressive tumor-initiating activity in vivo. Genetic disruption of PKCι inhibits the proliferation, clonal expansion, anchorage-independent growth, and enhanced tumorigenic properties of ovarian TICs. Biochemical analysis demonstrates that PKCι acts through its oncogenic partner Ect2 to activate a MEK/ERK signaling axis that drives the ovarian TIC phenotype. Genomic analysis reveals that PKCι and Ect2 are coordinately amplified and overexpressed in the majority of primary ovarian serous tumors, and these tumors exhibit evidence of an active PKCι-Ect2 signaling axis in vivo. Finally, this study reveals that auranofin, a potent and selective inhibitor of oncogenic PKCι signaling, inhibits the tumorigenic properties of ovarian TIC cells in vitro and in vivo. These data demonstrate that PKCι is required for a TIC phenotype in ovarian cancer, and that auranofin is an attractive therapeutic option to target deadly ovarian TICs in ovarian cancer patients.
Implications: PKCι drives a tumor-initiating cell phenotype in ovarian cancer cells that can be therapeutically targeted with auranofin, a small molecule inhibitor of PKCι signaling. Mol Cancer Res; 11(12); 1624–35. ©2013 AACR.
Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays
Authors: Flaujac Claire , Delavenne Xavier , Quenet Sara , Horellou Marie-Hélenè , Laporte Silvy , Siguret Virginie , Lecompte Thomas , Gouin-Thibault Isabelle 
Published: October 2013

SummaryWhile laboratory monitoring is not required in patients treated with apixaban, a direct factor-Xa inhibitor, assessment of its concentration is useful in some critical situations. However, few data are available on its effect on coagulation tests and on the suitability of anti-Xa assays for its quantification. It was the objective of this study to identify laboratory tests suitable for apixaban concentration assessment. Coagulation tests – PT and aPTT- and anti-Xa assays were performed in apixaban-spiked plasma samples. To evaluate the sensitivity of PT and aPTT to apixaban, we conducted a first monocenter part, with a wide range of concentrations (50–1,000 ng/ml), a large panel of reagents (20 reagents), and two coagulometers (STAR®, Stago and ACL TOP®, IL), and a second multicenter part involving 13 laboratories using either a common PT reagent (RecombiPlastin2G®) or the local PT and aPTT reagents. In the multicentre part, five blinded apixaban-spiked plasma samples (0/100/200/400/800 ng/ml – checked by HPLC-MS/MS) were used; apixaban concentrations were measured with three anti-Xa assays, apixaban calibrators and controls (Stago). PT and aPTT tests using a large panel of reagents displayed a low sensitivity to a wide range of apixaban concentrations. The concentrations to double PT ranged from 400 to >1,000 ng/ml with the 10 reagents. With the three anti-Xa assays, interlaboratory precision and accuracy were below 11% and 12%, respectively. In conclusion, whereas PT and aPTT tests were not sensitive enough to detect apixaban, the three anti-Xa assays tested using lyophilised apixaban calibrators and controls allowed to reliably quantify a wide range of apixaban concentrations.