bluuebunny/crossref_metadata_2025_split huggingface dataset:
Poly(A)-Binding Protein Facilitates Translation of an Uncapped/Nonpolyadenylated Viral RNA by Binding to the 3′ Untranslated Region
Authors: Iwakawa Hiro-oki , Tajima Yuri , Taniguchi Takako , Kaido Masanori , Mise Kazuyuki , Tomari Yukihide , Taniguchi Hisaaki , Okuno Tetsuro 
Published: May 2012

ABSTRACT

Viruses employ an alternative translation mechanism to exploit cellular resources at the expense of host mRNAs and to allow preferential translation. Plant RNA viruses often lack both a 5′ cap and a 3′ poly(A) tail in their genomic RNAs. Instead, cap-independent translation enhancer elements (CITEs) located in the 3′ untranslated region (UTR) mediate their translation. Although eukaryotic translation initiation factors (eIFs) or ribosomes have been shown to bind to the 3′CITEs, our knowledge is still limited for the mechanism, especially for cellular factors. Here, we searched for cellular factors that stimulate the 3′CITE-mediated translation of
Red clover necrotic mosaic virus
(RCNMV) RNA1 using RNA aptamer-based one-step affinity chromatography, followed by mass spectrometry analysis. We identified the poly(A)-binding protein (PABP) as one of the key players in the 3′CITE-mediated translation of RCNMV RNA1. We found that PABP binds to an A-rich sequence (ARS) in the viral 3′ UTR. The ARS is conserved among dianthoviruses. Mutagenesis and a tethering assay revealed that the PABP-ARS interaction stimulates 3′CITE-mediated translation of RCNMV RNA1. We also found that both the ARS and 3′CITE are important for the recruitment of the plant eIF4F and eIFiso4F factors to the 3′ UTR and of the 40S ribosomal subunit to the viral mRNA. Our results suggest that dianthoviruses have evolved the ARS and 3′CITE as substitutes for the 3′ poly(A) tail and the 5′ cap of eukaryotic mRNAs for the efficient recruitment of eIFs, PABP, and ribosomes to the uncapped/nonpolyadenylated viral mRNA.
Cryphonectria nitschkei
Virus 1 Structure Shows that the Capsid Protein of Chrysoviruses Is a Duplicated Helix-Rich Fold Conserved in Fungal Double-Stranded RNA Viruses
Authors: Gómez-Blanco Josué , Luque Daniel , González José M. , Carrascosa José L. , Alfonso Carlos , Trus Benes , Havens Wendy M. , Ghabrial Said A. , Castón José R. 
Published: May 2012

ABSTRACT

Cryoelectron microscopy reconstruction of
Cryphonectria nitschkei
virus 1, a double-stranded RNA (dsRNA) virus, shows that the capsid protein (60 copies/particle) is formed by a repeated helical core, indicative of gene duplication. This unusual organization is common to chrysoviruses. The arrangement of many of these putative α-helices is conserved in the totivirus L-A capsid protein, suggesting a shared motif. Our results indicate that a 120-subunit T=1 capsid is a conserved architecture that optimizes dsRNA replication and organization.
Ethanolamine Controls Expression of Genes Encoding Components Involved in Interkingdom Signaling and Virulence in Enterohemorrhagic Escherichia coli O157:H7
Authors: Kendall Melissa M. , Gruber Charley C. , Parker Christopher T. , Sperandio Vanessa 
Published: May 2012

ABSTRACT

Bacterial pathogens must be able to both recognize suitable niches within the host for colonization and successfully compete with commensal flora for nutrients in order to establish infection. Ethanolamine (EA) is a major component of mammalian and bacterial membranes and is used by pathogens as a carbon and/or nitrogen source in the gastrointestinal tract. The deadly human pathogen enterohemorrhagic
Escherichia coli
O157:H7 (EHEC) uses EA in the intestine as a nitrogen source as a competitive advantage for colonization over the microbial flora. Here we show that EA is not only important for nitrogen metabolism but that it is also used as a signaling molecule in cell-to-cell signaling to activate virulence gene expression in EHEC. EA in concentrations that cannot promote growth as a nitrogen source can activate expression of EHEC’s repertoire of virulence genes. The EutR transcription factor, known to be the receptor of EA, is only partially responsible for this regulation, suggesting that yet another EA receptor exists. This important link of EA with metabolism, cell-to-cell signaling, and pathogenesis, highlights the fact that a fundamental means of communication within microbial communities relies on energy production and processing of metabolites. Here we show for the first time that bacterial pathogens not only exploit EA as a metabolite but also coopt EA as a signaling molecule to recognize the gastrointestinal environment and promote virulence expression.

IMPORTANCE
In order to successfully cause disease, a pathogen must be able to sense a host environment and modulate expression of its virulence genes as well as compete with the indigenous microbiota for nutrients. Ethanolamine (EA) is present in the large intestine due to the turnover of intestinal cells. Here, we show that the human pathogen
Escherichia coli
O157:H7, which causes bloody diarrhea and hemolytic-uremic syndrome, regulates virulence gene expression through EA metabolism and by responding to EA as a signal. These findings provide the first information directly linking EA with bacterial pathogenesis.
ZNF217 Is a Marker of Poor Prognosis in Breast Cancer That Drives Epithelial–Mesenchymal Transition and Invasion
Authors: Vendrell Julie A. , Thollet Aurélie , Nguyen Nhan T. , Ghayad Sandra E. , Vinot Stéphanie , Bièche Ivan , Grisard Evelyne , Josserand Véronique , Coll Jean-Luc , Roux Pierre , Corbo Laura , Treilleux Isabelle , Rimokh Ruth , Cohen Pascale A. 
Published: May 2012

AbstractThe Krüppel-like zinc finger protein ZNF217 is a candidate oncogene in breast cancer. In this study, we showed that high levels of expression of ZNF217 mRNA are associated with poor prognosis and the development of metastases in breast cancer. Overexpression of ZNF217 in breast cancer cells stimulated migration and invasion in vitro and promoted the development of spontaneous lung or node metastases in mice in vivo. ZNF217 also promoted epithelial–mesenchymal transition (EMT) in human mammary epithelial cells, and the TGF-β–activated Smad signaling pathway was identified as a major driver of ZNF217-induced EMT. In addition, a TGF-β autocrine loop sustained activation of the TGF-β pathway in ZNF217-overexpressing mammary epithelial cells, most likely because of ZNF217-mediated direct upregulation of TGFB2 or TGFB3. Inhibition of the TGF-β pathway led to the reversal of ZNF217-mediated EMT. Together, our findings indicate that ZNF217 mRNA expression may represent a novel prognostic biomarker in breast cancer. Therapeutic targeting of ZNF217 of the TGF-β signaling pathway may benefit the subset of patients whose tumors express high levels of ZNF217. Cancer Res; 72(14); 3593–606. ©2012 AACR.
The RASSF3 Candidate Tumor Suppressor Induces Apoptosis and G1–S Cell-Cycle Arrest via p53
Authors: Kudo Takumi , Ikeda Mitsunobu , Nishikawa Misa , Yang Zeyu , Ohno Kikuo , Nakagawa Kentaro , Hata Yutaka 
Published: May 2012

Abstract
RASSF3 is the smallest member of the RASSF family of proteins that function as tumor suppressors. Unlike other members of this important family, the mechanisms through which RASSF3 suppresses tumor formation remain unknown. Here, we show that RASSF3 expression induces p53-dependent apoptosis and its depletion attenuates DNA damage–induced apoptosis. We found that RASSF3-induced apoptosis depended upon p53 expression. Exogenous expression of RASSF3 induced G1–S arrest, which was also p53 dependent. In contrast, loss of RASSF3 promoted cell-cycle progression, abrogated UVB- and VP-16–induced G1–S arrest, decreased p53 protein and target gene expression, and prevented DNA repair. RASSF3 was shown to directly interact with and facilitate the ubiquitination of MDM2, the E3 ligase that targets p53 for degradation, thereby increasing p53 stabilization. Together, our findings show the tumor suppressor activity of RASSF3, which occurs through p53 stabilization and regulation of apoptosis and the cell cycle. Cancer Res; 72(11); 2901–11. ©2012 AACR.
Design of a Phase III Clinical Trial with Prospective Biomarker Validation: SWOG S0819
Authors: Redman Mary W. , Crowley John J. , Herbst Roy S. , Hirsch Fred R. , Gandara David R. 
Published: May 2012

Abstract
The role of cetuximab in the treatment of advanced non–small cell lung cancer (NSCLC) is currently unclear. The molecular target of cetuximab, epidermal growth factor receptor (EGFR), as measured by FISH, has shown potential as a predictive biomarker for cetuximab efficacy in NSCLC. SWOG S0819 is a phase III trial evaluating both the value of cetuximab in this setting and EGFR FISH as a predictive biomarker. This work describes the decision process for determining the design and interim monitoring plan for S0819. Six possible designs were evaluated in terms of their properties and the hypotheses that can be addressed within the design constraints. A subgroup-focused, multiple-hypothesis design was selected for S0819 that incorporates coprimary endpoints to assess cetuximab in both the overall study population and among EGFR FISH-positive (FISH+) patients, with the sample size determined based on evaluation in the EGFR FISH+ group. The chosen interim monitoring plan specifies interim evaluations of both efficacy and futility in the EGFR FISH+ group alone. The futility-monitoring plan to determine early stopping in the EGFR FISH-nonpositive group is based on evaluation within the positive group, the entire study population, and the nonpositive group. SWOG S0819 uses a design that addresses both the biomarker-driven and general-efficacy objectives of this study. Clin Cancer Res; 18(15); 4004–12. ©2012 AACR.
FOXA1 Is Essential for Aryl Hydrocarbon Receptor–Dependent Regulation of Cyclin G2
Authors: Ahmed Shaimaa , Al-Saigh Sarra , Matthews Jason 
Published: May 2012

Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the effects of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recently, AHR has emerged as a potential therapeutic target for breast cancer by virtue of its ability to modulate estrogen receptor-α (ERα) signalling and/or its ability to block cell proliferation. Our previous studies identified cyclin G2 (CCNG2), an inhibitor of cell-cycle progression, as an AHR target gene; however, the mechanism of this regulation is unknown. Chromatin immunoprecipitation assays in T-47D human breast cancer cells revealed a TCDD-dependent recruitment of AHR, nuclear co-activator 3 (NCoA3) and the transcription factor forkhead box A1 (FOXA1), a key regulator of breast cancer cell signaling, to CCNG2 resulting in increases in CCNG2 mRNA and protein levels. Mutation of the AHR response element (AHRE) and forkhead-binding sites abolished TCDD-induced CCNG2-regulated reporter gene activity. RNA interference–mediated knockdown of FOXA1 prevented the TCDD-dependent recruitment of AHR and NCoA3 to CCNG2 and reduced CCNG2 mRNA levels. Interestingly, knockdown of FOXA1 also caused a marked decrease in ERα, but not AHR protein levels. However, RNA interference–mediated knockdown of ERα, a negative regulator of CCNG2, had no effect on TCDD-dependent AHR or NCoA3 recruitment to or expression of CCNG2. These findings show that FOXA1, but not ERα, is essential for AHR-dependent regulation of CCNG2, assigning a role for FOXA1 in AHR action. Mol Cancer Res; 10(5); 636–48. ©2012 AACR.
Prevalence of Sequence Variants in the RAS-Mitogen Activated Protein Kinase Signaling Pathway in Pre-Adolescent Children With Hypertrophic Cardiomyopathy
Authors: Pablo Kaski Juan , Syrris Petros , Shaw Adam , Alapi Krisztina Zuborne , Cordeddu Viviana , Esteban Maria Teresa Tome , Jenkins Sharon , Ashworth Michael , Hammond Peter , Tartaglia Marco , McKenna William J. , Elliott Perry M. 
Published: May 2012

Background—
Most cases of apparently idiopathic hypertrophic cardiomyopathy (HCM) in children are caused by mutations in cardiac sarcomere protein genes. HCM also commonly occurs as an associated feature in some patients with disorders caused by mutations in genes encoding components of the RAS-mitogen activated protein kinase (MAPK) signaling pathway. Although diagnosis of these disorders is based on typical phenotypic features, the dysmorphic manifestations can be subtle and therefore overlooked. The aim of this study was to determine the prevalence of mutations in RAS-MAPK genes in preadolescent children with idiopathic HCM.

Methods and Results—

Seventy-eight patients diagnosed with apparently nonsyndromic HCM aged ≤13 years underwent clinical and genetic evaluation. The entire protein coding sequence of 9 genes implicated in Noonan syndrome and related conditions (
PTPN11
,
SOS1
,
HRAS
,
KRAS
,
NRAS
,
BRAF
,
RAF1
,
MAP2K1,
and
MAP2K2
), together with
CBL
(exons 8 and 9) and
SHOC2
(4A>G), were screened for mutations. Five probands (6.4%) carried novel sequence variants in
SOS1
(2 individuals),
BRAF
,
MAP2K1,
and
MAP2K2
. Structural and molecular data suggest that these variants may have functional significance. Nine cardiac sarcomere protein genes were screened also; 2 individuals also had mutations in
MYBPC.

Conclusions—
This study reports novel and potentially pathogenic sequence variants in genes of the RAS-MAPK pathway, suggesting that genetic lesions promoting signaling dysregulation through RAS contribute to disease pathogenesis or progression in children with HCM.
Persistent Renal Damage After Contrast-Induced Acute Kidney Injury
Authors: Maioli Mauro , Toso Anna , Leoncini Mario , Gallopin Michela , Musilli Nicola , Bellandi Francesco 
Published: May 2012

Background—
The temporal evolution of renal function in patients with acute kidney injury after contrast medium (CI-AKI) is not well known. The aim of this observational study was to evaluate the incidence, risk factors, and prognostic implications of persistent renal damage (RD) in patients with preexistent moderate-to-severe renal dysfunction.

Methods and Results—

From June 2003 to March 2008, 3986 patients underwent coronary angiography at our institution; 1490 of 3986 had an estimated creatinine clearance of <60 mL/min and were enrolled. CI-AKI was defined as an absolute increase ≥0.5 mg/dL over baseline serum creatinine within 3 days after the administration of contrast medium (iodixanol). In patients who developed CI-AKI, persistent RD was defined as a relative decrease of creatinine clearance ≥25% over baseline at 3 months. Patients whose creatinine clearance returned to baseline (or nearly) were classified as transient RD. The overall incidence of CI-AKI was 12.1%, and persistent RD occurred in 18.6% of CI-AKI patients. At Cox regression analysis, nephropathy risk score ≥17, left ventricular ejection fraction ≤30%, and increased value of serum creatinine ≥1.5-fold from baseline within 5 days were found to be significant risk factors for persistent RD. At 5 years, the incidence of death was significantly higher in patients with persistent RD than in both patients with transient RD (
P
=0.015) and those without CI-AKI (
P
=0.0001). A similar trend was observed for the combined end point of death, dialysis and cardiovascular events.

Conclusions—
These results suggest that CI-AKI is not always a transient, benign creatininopathy, but rather a direct cause of worsening renal function. The occurrence of CI-AKI can identify patients at increased risk of cardiovascular events.
Deficits in Heel-Rise Height and Achilles Tendon Elongation Occur in Patients Recovering From an Achilles Tendon Rupture
Authors: Silbernagel Karin Grävare , Steele Robert , Manal Kurt 
Published: May 2012

Background: Whether an Achilles tendon rupture is treated surgically or not, complications such as muscle weakness, decrease in heel-rise height, and gait abnormalities persist after injury. Purpose: The purpose of this study was to evaluate if side-to-side differences in maximal heel-rise height can be explained by differences in Achilles tendon length. Study Design: Case series; Level of evidence, 4. Method: Eight patients (mean [SD] age of 46 [13] years) with acute Achilles tendon rupture and 10 healthy subjects (mean [SD] age of 28 [8] years) were included in the study. Heel-rise height, Achilles tendon length, and patient-reported outcome were measured 3, 6, and 12 months after injury. Achilles tendon length was evaluated using motion analysis and ultrasound imaging. Results: The Achilles tendon length test-retest reliability (intraclass correlation coefficient = 0.97) was excellent. For the healthy subjects, there were no side-to-side differences in tendon length and heel-rise height. Patients with Achilles tendon ruptures had significant differences between the injured and uninjured side for both tendon length (mean [SD] difference, 2.6-3.1 [1.2-1.4] cm, P = .017-.028) and heel-rise height (mean [SD] difference, –4.1 to –6.1 [1.7-1.8] cm, P = .012-.028). There were significant negative correlations ( r = −0.943, P = .002, and r = −0.738, P = .037) between the side-to-side difference in heel-rise height and Achilles tendon length at the 6- and 12-month evaluations, respectively. Conclusion: The side-to-side difference found in maximal heel-rise height can be explained by a difference in Achilles tendon length in patients recovering from an Achilles tendon rupture. Minimizing tendon elongation appears to be an important treatment goal when aiming for full return of function.
Combined ω3 and ω6 Supplementation in Children With Attention-Deficit Hyperactivity Disorder (ADHD) Refractory to Methylphenidate Treatment
Authors: Perera Hemamali , Jeewandara Kamal Chandima , Seneviratne Sudarshi , Guruge Chandima 
Published: May 2012

Children (6-12 years) with attention-deficit hyperactivity disorder (ADHD) being treated with methylphenidate and standard behavior therapy for more than 6 months, whose parents reported no improvement in behavior and academic learning, were randomly assigned to receive supplementation with a combined ω3 and ω6 preparation or a placebo. Outcome was measured at 3 and 6 months after treatment using a self-assessment checklist completed by the parents. Statistically significant improvement was found in the treatment group compared with the placebo group ( P < .01) in the following measures: restlessness, aggressiveness, completing work, and academic performance. Statistically significant improvement was not found at 3 months of treatment between groups but was evident at 6 months of treatment ( P < .05) with inattention, impulsiveness, and cooperation with parents and teachers. Distractibility failed to show improvement. Effect sizes ranged from 0.3 to 1.1 at 3 months and 0.2 to 1.4 at 6 months for individual symptom variables.
Professional training to reduce children’s exposure to second-hand smoke in the home: evidence-based considerations on targeting and content
Authors: Gordon Jacki , Friel Brenda , McGranachan Margaret 
Published: May 2012

Aims: Proponents of theory-based evaluations argue that the type of evidence needed by public health decision-makers is not simply whether interventions work or not. A more fruitful approach is to understand the contexts and circumstances associated with effectiveness. This article aims: to firstly understand factors influencing professionals’ practice following their participation in training that aimed to reduce children’s exposure to second-hand smoke (SHS) in the home via increased usage of brief interventions; and secondly to consider the implications of these factors for improving the skills of a diverse workforce. Methods: Questionnaires were issued to the 231 participants pre- and post-training and at three-month follow-up. Four focus groups and four interviews were run with 16 people who had attended the training in the previous four to eight months and who performed a wide range of professional roles, reflecting the diversity of those trained. Results: The three-month follow-up data indicated that some, but not all, participants had engaged in components of the brief intervention and changed their practice. This difference was largely explained by professional role. Those working in a health-visiting role or team were considered better placed to support families through a process of restricting SHS exposure in the home. Triangulated data also indicated that these professionals more often practised elements of the brief intervention. There was also some evidence that the training did not equip participants with the full range of information they wanted, or with the skills that they felt that they needed. Conclusions: Decisions on who to target for training need to be informed by an understanding of the contexts in which professionals work and the opportunities and constraints within these. Those working in a health-visiting team are credible message carriers, have opportunities to develop a relationship with families, and can be well placed to provide families with sustained support. To do so, they need clear messages on precisely how to reduce exposure. In addition, they need the skills to support families through a process of change.
Delayed Computed Tomography Arthrography of Human Knee Cartilage In Vivo
Authors: Kokkonen Harri T. , Aula Antti S. , Kröger Heikki , Suomalainen Juha-Sampo , Lammentausta Eveliina , Mervaala Esa , Jurvelin Jukka S. , Töyräs Juha 
Published: May 2012

Objective: We investigated the feasibility of delayed computed tomography (CT) arthrography for evaluation of human knee cartilage in vivo. Especially, the diffusion of contrast agent out of the joint space and the optimal time points for imaging were determined. Design: Two patients were imaged using delayed CT arthrography and delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) techniques. Results: Two hours after injection, the concentration of contrast agent in the joint space was still high enough (20% to 24.5% of the initial concentration at 0 minutes) to allow delayed CT arthrography. The half-life of the contrast agent in the joint space varied from 30 to 60 minutes. The contrast agent concentration in patellar and femoral cartilage reached the maximum after 30 and 60 minutes, respectively. According to dGEMRIC, there were no differences between patients. However, in delayed CT arthrography, the penetration of the contrast agent was higher in the osteoarthritic knee cartilage. Conclusions: Contrast agent remained in the joint space long enough to enable delayed CT arthrography of cartilage. After 30 minutes, the normalized contrast agent concentration was higher in the cartilage of the osteoarthritic knee in comparison with the healthy knee. To conclude, delayed CT arthrography exhibited potential for use in the clinical evaluation of cartilage integrity.