bluuebunny/crossref_metadata_2025_split huggingface dataset:
The P Protein of Spring Viremia of Carp Virus Negatively Regulates the Fish Interferon Response by Inhibiting the Kinase Activity of TANK-Binding Kinase 1
Authors: Li Shun , Lu Long-Feng , Wang Zhao-Xi , Lu Xiao-Bing , Chen Dan-Dan , Nie Pin , Zhang Yong-An 
Published: September 2016

ABSTRACT

Spring viremia of carp virus (SVCV) is an efficient pathogen causing high mortality in the common carp. Fish interferon (IFN) is a powerful cytokine enabling host cells to establish an antiviral response; therefore, the strategies that SVCV uses to avoid the cellular IFN response were investigated. Here, we report that the SVCV P protein is phosphorylated by cellular TANK-binding kinase 1 (TBK1), which decreases IFN regulatory factor 3 (IRF3) phosphorylation and suppresses IFN production. First, overexpression of P protein inhibited the IFN promoter activation induced by SVCV and the IFN activity activated by the mitochondrial antiviral signaling protein (MAVS) although TBK1 activity was not blocked by P protein. Second, P protein colocalized and interacted with TBK1. Dominant negative experiments suggested that the TBK1 N-terminal kinase domain interacted with P protein and was essential for P protein and IRF3 phosphorylation. Finally, P protein overexpression reduced the IRF3 phosphorylation activated by TBK1 and reduced host cellular
ifn
transcription. Collectively, our data demonstrated that the SVCV P protein is a decoy substrate for the host phosphokinase TBK1, preventing IFN production and facilitating SVCV replication.

IMPORTANCE
TBK1 is a pivotal phosphokinase that activates host IFN production to defend against viral infection; thus, it is a potential target for viruses to negatively regulate IFN response and facilitate viral evasion. We report that the SVCV P protein functions as a decoy substrate for cellular TBK1, leading to the reduction of IRF3 phosphorylation and suppression of IFN expression. These findings reveal a novel immune evasion mechanism of SVCV.
PrP
C
Governs Susceptibility to Prion Strains in Bank Vole, While Other Host Factors Modulate Strain Features
Authors: Espinosa J. C. , Nonno R. , Di Bari M. , Aguilar-Calvo P. , Pirisinu L. , Fernández-Borges N. , Vanni I. , Vaccari G. , Marín-Moreno A. , Frassanito P. , Lorenzo P. , Agrimi U. , Torres J. M. 
Published: September 2016

ABSTRACT

Bank vole is a rodent species that shows differential susceptibility to the experimental transmission of different prion strains. In this work, the transmission features of a panel of diverse prions with distinct origins were assayed both in bank vole expressing methionine at codon 109 (Bv109M) and in transgenic mice expressing physiological levels of bank vole PrP
C
(the BvPrP-Tg407 mouse line). This work is the first systematic comparison of the transmission features of a collection of prion isolates, representing a panel of diverse prion strains, in a transgenic-mouse model and in its natural counterpart. The results showed very similar transmission properties in both the natural species and the transgenic-mouse model, demonstrating the key role of the PrP amino acid sequence in prion transmission susceptibility. However, differences in the PrP
Sc
types propagated by Bv109M and BvPrP-Tg407 suggest that host factors other than PrP
C
modulate prion strain features.

IMPORTANCE
The differential susceptibility of bank voles to prion strains can be modeled in transgenic mice, suggesting that this selective susceptibility is controlled by the vole PrP sequence alone rather than by other species-specific factors. Differences in the phenotypes observed after prion transmissions in bank voles and in the transgenic mice suggest that host factors other than the PrP
C
sequence may affect the selection of the substrain replicating in the animal model.
One-year visual outcome of small incision lenticule extraction (SMILE) surgery in high myopic eyes: retrospective cohort study
Authors: Wu Wenjing , Wang Yan , Zhang Hui , Zhang Jiamei , Li Hua , Dou Rui 
Published: September 2016

ObjectiveTo determine whether the long-term visual outcome of small incision lenticule extraction (SMILE) surgery is consistent with the short-term results in high myopic eyes.DesignRetrospective cohort study; data collected from 8 August 2011 to 31 August 2015.SettingSingle refractive surgery centre.ParticipantsA total of 156 eyes were studied: 65 eyes of 39 subjects (22 female/17 male) in the high myopic group (manifest refraction spherical equivalent (MRSE) ≥−6.0 D), and 91 eyes of 54 subjects (29 female/25 male) in the control group (MRSE <−6.0 D). The inclusion criteria were subjects who had follow-ups after 1 day, 1 week, 1 month, 3, 6 months and 1 year with the manifest refraction, uncorrected and corrected distance visual acuity (UDVA/CDVA). There were no statistically significant differences between the two groups in the subjects' gender, age, or cylindrical dioptre, preoperatively (p=0.835, p=0.055, p=0.341, respectively).Primary and secondary outcome measuresUDVA, refractive stability, safety index (postoperative CDVA/preoperative CDVA), and predictability (the percentage of eyes within ±0.50 D).ResultsIn both groups, the 1-year UDVA and safety index were significantly better than results at 1 day (high myopic group: p=0.035, p<0.001; control group: p<0.016, p<0.001); the 1-year predictability showed no significant difference with the short-term results (p=1.00 in both groups). In the high myopic eyes, the 1-year MRSE was significantly worse than the short-term result (p=0.048). To correct it, the added magnitude (D) for the high myopic eyes may equal 0.13×Attempted SE (D)−0.66 D. However, the postoperative MRSE showed no differences from 1 day to 1 year (p=0.612) in the control group.ConclusionsThe 1-year visual outcomes were better than the short-term results after the SMILE surgery on the visual acuity and safety. However, the high myopic eyes suffered a significant regression at 1 year, which may be corrected by adding additional magnitude to the SE for high myopic eyes.
A comparison of pregnancy outcomes in Ghanaian women with varying dietary diversity: a prospective cohort study protocol
Authors: Osman Shaibu Mohammed , Saaka Mahama , Siassi Fereydoun , Qorbani Mostafa , Yavari Parvaneh , Danquah Ina , Sotoudeh Gity 
Published: September 2016

IntroductionPoor dietary intake during pregnancy can have negative repercussions on the mother and fetus. This study therefore aims to explore the dietary diversity (DD) of pregnant women and its associations with pregnancy outcomes among women in Northern Ghana. The main outcome variables to be measured are gestational weight gain and birth weight.Methods and analysisA prospective cohort study design will be used and 600 pregnant women in their first trimester will be systematically recruited at health facilities and followed until delivery. In three follow-up visits after recruitment, information on sociodemographic and general characteristics, physical activity (International Physical Activity Questionnaire (IPAQ) short form, dietary intake (24-hour food recall), anthropometry and pregnancy outcomes will be collected. DD will be measured three times using the minimum DD-women (MDD-W) indicator and the mean of the three values overall will be used to determine low (<5 food groups) and high (≥5 food groups) DD. Data will be analysed using SPSS. Comparisons between groups (categorical data) will be made using the χ2test for proportions, and t-tests and ANOVA will be performed on continuous variables. Regression analysis will be used to identify independent outcome predictors while controlling for possible confounding factors. The results may help to identify differences in DD between healthy and unhealthy pregnancy outcomes.Ethics and disseminationThe study protocol has been approved by the ethics committee of Tehran University of Medical Sciences and the ethical review committee of the Tamale Teaching Hospital. Written informed consent will be obtained from all subjects. The results will be published in due course.
Ability of preoperative falls to predict postsurgical outcomes in non-selected patients undergoing elective surgery at an academic medical centre: protocol for a prospective cohort study
Authors: Kronzer Vanessa L , Ben Abdallah Arbi , McKinnon Sherry L , Wildes Troy S , Avidan Michael S 
Published: September 2016

IntroductionFalls are increasingly recognised for their ability to herald impending health decline. Despite the likely susceptibility of postsurgical patients to falls, a detailed description of postoperative falls in an unselected surgical population has never been performed. One study suggests that preoperative falls may forecast postoperative complications. However, a larger study with non-selected surgical patients and patient-centred outcomes is needed to provide the generalisability and justification necessary to implement preoperative falls assessment into routine clinical practice. The aims of this study are therefore twofold. First, we aim to describe the main features of postoperative falls in a population of unselected surgical patients. Second, we aim to test the hypothesis that a history of falls in the 6 months prior to surgery predicts postoperative falls, poor quality of life, functional dependence, complications and readmission.Methods and analysisTo achieve these goals, we study adult patients who underwent elective surgery at our academic medical centre and were recruited to participate in a prospective, survey-based cohort study called Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) (NCT02032030). Patients who reported falling in the 6 months prior to surgery will be considered ‘exposed.’ The primary outcome of interest is postoperative falls within 30 days of surgery. Secondary outcomes include postoperative functional dependence, quality of life (both physical and mental), in-hospital complications and readmission. Regression models will permit controlling for important confounders.Ethics and disseminationThe home institution's Institutional Review Board approved this study (IRB ID number 201505035). The authors will publish the findings, regardless of the results.
Prevalence and factors associated with the occurrence of bacterial enteropathogens in suckling piglets in farrow‐to‐finish herds
Authors: Dors A. , Czyżewska‐Dors E. , Wasyl D. , Pomorska‐Mól M. 
Published: September 2016

The aim of the study was to determine both environmental and infectious factors, influencing occurrence of bacterial enteropathogens in suckling piglets. For this purpose, a cross‐sectional study in 70 Polish farrow‐to‐finish pig herds was performed. In each herd, presence of selected intestinal pathogens (Escherichia coli, Clostridium perfringens and Salmonella species) in faeces of suckling piglets were determined using bacteriological and PCR methods. Using logistic regression models, risk factors for enterotoxigenic E coli with fimbriae F4 (ETEC‐F4) and C perfringens type A were established. Prevalence of bacterial enteropathogens in investigated herds was as follows (on herd and sample level): ETEC‐F4 30.0 per cent and 9.3 per cent, respectively, C perfringens type A 91.4 per cent and 58.3 per cent, C perfringens type C 1.4 per cent and 0.3 per cent, Salmonella species 2.9 per cent and 0.5 per cent. The occurrence of ETEC‐F4 was associated with presence of diarrhoea in piglets and vulval discharge in sows. Vulval discharge in sows, not slatted floor in farrowing pen and lack of coccidiosis prevention were determined as risk factors for C perfringens type A. The results obtained in the study revealed the high prevalence of enteropathogenic bacteria in pig herds and indicate management and organisation of production as factors having the greatest impact on the incidence of bacterial enteropathogens in piglets before weaning.
Molecular Pathways: Targeting Steroid Receptor Coactivators in Cancer
Authors: Lonard David M. , O'Malley Bert W. 
Published: September 2016

Abstract
Coactivators represent a large class of proteins that partner with nuclear receptors and other transcription factors to regulate gene expression. Given their pleiotropic roles in the control of transcription, coactivators have been implicated in a broad range of human disease states, including cancer. This is best typified by the three members of the steroid receptor coactivator (SRC) family, each of which integrates steroid hormone signaling and growth factor pathways to drive oncogenic gene expression programs in breast, endometrial, ovarian, prostate, and other cancers. Because of this, coactivators represent emerging targets for cancer therapeutics, and efforts are now being made to develop SRC-targeting agents, such as the SI-2 inhibitor and the novel SRC stimulator, MCB-613, that are able to block cancer growth in cell culture and animal model systems. Here, we will discuss the mechanisms through which coactivators drive cancer progression and how targeting coactivators represent a novel conceptual approach to combat tumor growth that is distinct from the use of other targeted therapeutic agents. We also will describe efforts to develop next-generation SRC inhibitors and stimulators that can be taken into the clinic for the treatment of recurrent, drug-resistant cancers. Clin Cancer Res; 22(22); 5403–7. ©2016 AACR.
Development and Validation of a Six-Gene Recurrence Risk Score Assay for Gastric Cancer
Authors: Lee Keun-Wook , Lee Sung Sook , Hwang Jun-Eul , Jang Hee-Jin , Lee Hyun-Sung , Oh Sang Cheul , Lee Sang Ho , Sohn Bo Hwa , Kim Sang Bae , Shim Jae-Jun , Jeong Woojin , Cha Minse , Cheong Jae-Ho , Cho Jae Yong , Lim Jae Yun , Park Eun Sung , Kim Sang Cheol , Kang Yoon-Koo , Noh Sung Hoon , Ajani Jaffer A. , Lee Ju-Seog 
Published: September 2016

Abstract
Purpose: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery.
Experimental Design: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n = 267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P &lt; 0.001). We developed the recurrence risk score (RRS) by using quantitative RT-PCR to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort.
Results: We based the RRS assay on 6 genes, IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B, whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort. The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence [HR, 1.6; 95% confidence interval (CI), 1.02–2.4; P = 0.03]. In patients with stage II disease, the RRS had an HR of 2.9 (95% CI, 1.1–7.9; P = 0.03) and was the only significant independent predictor of recurrence.
Conclusions: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted. Clin Cancer Res; 22(24); 6228–35. ©2016 AACR.
MEK and TAK1 Regulate Apoptosis in Colon Cancer Cells with KRAS-Dependent Activation of Proinflammatory Signaling
Authors: McNew Kelsey L. , Whipple William J. , Mehta Anita K. , Grant Trevor J. , Ray Leah , Kenny Connor , Singh Anurag 
Published: September 2016

Abstract
MEK inhibitors have limited efficacy in treating RAS–RAF–MEK pathway–dependent cancers due to feedback pathway compensation and dose-limiting toxicities. Combining MEK inhibitors with other targeted agents may enhance efficacy. Here, codependencies of MEK, TAK1, and KRAS in colon cancer were investigated. Combined inhibition of MEK and TAK1 potentiates apoptosis in KRAS-dependent cells. Pharmacologic studies and cell-cycle analyses on a large panel of colon cancer cell lines demonstrate that MEK/TAK1 inhibition induces cell death, as assessed by sub-G1 accumulation, in a distinct subset of cell lines. Furthermore, TAK1 inhibition causes G2–M cell-cycle blockade and polyploidy in many of the cell lines. MEK plus TAK1 inhibition causes reduced G2–M/polyploid cell numbers and additive cytotoxic effects in KRAS/TAK1-dependent cell lines as well as a subset of BRAF-mutant cells. Mechanistically, sensitivity to MEK/TAK1 inhibition can be conferred by KRAS and BMP receptor activation, which promote expression of NF-κB-dependent proinflammatory cytokines, driving tumor cell survival and proliferation. MEK/TAK1 inhibition causes reduced mTOR, Wnt, and NF-κB signaling in TAK1/MEK-dependent cell lines concomitant with apoptosis. A Wnt/NF-κB transcriptional signature was derived that stratifies primary tumors into three major subtypes: Wnt-high/NF-κB-low, Wnt-low/NF-κB-high and Wnt-high/NF-κB-high, designated W, N, and WN, respectively. These subtypes have distinct characteristics, including enrichment for BRAF mutations with serrated carcinoma histology in the N subtype. Both N and WN subtypes bear molecular hallmarks of MEK and TAK1 dependency seen in cell lines. Therefore, N and WN subtype signatures could be utilized to identify tumors that are most sensitive to anti-MEK/TAK1 therapeutics.
Implications: This study describes a potential therapeutic strategy for a subset of colon cancers that are dependent on oncogenic KRAS signaling pathways, which are currently difficult to block with selective agents. Mol Cancer Res; 14(12); 1204–16. ©2016 AACR.
The Cytoskeletal Adapter Protein Spinophilin Regulates Invadopodia Dynamics and Tumor Cell Invasion in Glioblastoma
Authors: Cheerathodi Mujeeburahiman , Avci Naze G. , Guerrero Paola A. , Tang Leung K. , Popp Julia , Morales John E. , Chen Zhihua , Carnero Amancio , Lang Frederick F. , Ballif Bryan A. , Rivera Gonzalo M. , McCarty Joseph H. 
Published: September 2016

Abstract
Glioblastoma is a primary brain cancer that is resistant to all treatment modalities. This resistance is due, in large part, to invasive cancer cells that disperse from the main tumor site, escape surgical resection, and contribute to recurrent secondary lesions. The adhesion and signaling mechanisms that drive glioblastoma cell invasion remain enigmatic, and as a result there are no effective anti-invasive clinical therapies. Here we have characterized a novel adhesion and signaling pathway comprised of the integrin αvβ8 and its intracellular binding partner, Spinophilin (Spn), which regulates glioblastoma cell invasion in the brain microenvironment. We show for the first time that Spn binds directly to the cytoplasmic domain of β8 integrin in glioblastoma cells. Genetically targeting Spn leads to enhanced invasive cell growth in preclinical models of glioblastoma. Spn regulates glioblastoma cell invasion by modulating the formation and dissolution of invadopodia. Spn-regulated invadopodia dynamics are dependent, in part, on proper spatiotemporal activation of the Rac1 GTPase. Glioblastoma cells that lack Spn showed diminished Rac1 activities, increased numbers of invadopodia, and enhanced extracellular matrix degradation. Collectively, these data identify Spn as a critical adhesion and signaling protein that is essential for modulating glioblastoma cell invasion in the brain microenvironment.
Implications: Tumor cell invasion is a major clinical obstacle in glioblastoma and this study identifies a new signaling pathway regulated by Spinophilin in invasive glioblastoma. Mol Cancer Res; 14(12); 1277–87. ©2016 AACR.
Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels
Authors: Jernerén Fredrik , Lehne Benjamin C. , Chen Ming-Huei , Luben Robert N. , Johnston Carole , Elshorbagy Amany , Eppinga Ruben N. , Scott William R. , Adeyeye Elizabeth , Scott James , Böger Rainer H. , Khaw Kay-Tee , van der Harst Pim , Wareham Nicholas J. , Vasan Ramachandran S. , Zhang Weihua , Chambers John C. , Refsum Helga , Kooner Jaspal S. 
Published: September 2016

SummaryL-arginine is the essential precursor of nitric oxide, and is involved in multiple key physiological processes, including vascular and immune function. The genetic regulation of blood L-arginine levels is largely unknown. We performed a genome-wide association study (GWAS) to identify genetic factors determining serum L-arginine levels, amongst 901 Europeans and 1,394 Indian Asians. We show that common genetic variations at the KLKB1 and F12 loci are strongly associated with serum L-arginine levels. The G allele of single nucleotide polymorphism (SNP) rs71640036 (T/G) in KLKB1 is associated with lower serum L-arginine concentrations (10 µmol/l per allele copy, p=1×10−24), while allele T of rs2545801 (T/C) near the F12 gene is associated with lower serum L-arginine levels (7 µmol/l per allele copy, p=7×10−12). Together these two loci explain 7% of the total variance in serum L-arginine concentrations. The associations at both loci were replicated in independent cohorts with plasma L-arginine measurements (p<0.004). The two sentinel SNPs are in nearly complete LD with the nonsynonymous SNP rs3733402 at KLKB1 and the 5’-UTR SNP rs1801020 at F12, respectively. SNPs at both loci are associated with blood pressure. Our findings provide new insight into the genetic regulation of L-arginine and its potential relationship with cardiovascular risk.Supplementary Material to this article is available online at www.thrombosis-online.com.
Biophysical tools to assess the interaction of PF4 with polyanions
Authors: Delcea Mihaela , Greinacher Andreas 
Published: September 2016

SummaryThe antigen in heparin-induced thrombocytopenia (HIT) is expressed on platelet factor 4 (PF4) when PF4 complexes with polyanions. In recent years, biophysical tools (e. g. circular dichroism spectroscopy, atomic force microscopy, isothermal titration calorimetry, x-ray crystallography, electron microscopy) have gained an important role to complement immunological and functional assays for better understanding the interaction of heparin with PF4. This allowed identification of those features that make PF4 immunogenic (e. g. a certain conformational change induced by the polyanion, a threshold energy of the complexes, the existence of multimeric complexes, a certain number of bonds formed by PF4 with the polyanion) and to characterize the morphology and thermal stability of complexes formed by the protein with polyanions. These findings and methods can now be applied to test new drugs for their potential to induce the HIT-like adverse drug effect by preclinical in vitro testing. The methods and techniques applied to characterize the antigen in HIT may also be helpful to better understand the mechanisms underlying other antibody-mediated disorders in thrombosis and hemostasis (e. g. acquired hemophilia, thrombotic thrombocytopenic purpura). Furthermore, understanding the mechanisms making the endogenous protein PF4 immunogenic may help to understand the mechanisms underlying other autoimmune disorders.