bluuebunny/crossref_metadata_2025_split huggingface dataset:
Putative E3 Ubiquitin Ligase of Human Rotavirus Inhibits NF-κB Activation by Using Molecular Mimicry To Target β-TrCP
Authors: Morelli Marco , Dennis Allison F. , Patton John T. 
Published: January 2015

ABSTRACT

NF-κB plays a critical role in the induction and maintenance of innate and adaptive immune transcriptional programs. An associated inhibitor of κB protein (IκB) regulates NF-κB activation and contains a degron motif (DSGΦxS) that undergoes phosphorylation following pathogen recognition or other proinflammatory signals. The E3 ubiquitin ligase SCF
β-TrCP
recognizes this phosphodegron through its β-transducin repeat-containing protein (β-TrCP) subunit and induces IκB degradation, allowing NF-κB to translocate to the nucleus and modulate gene expression. Rotavirus (RV), a major cause of pediatric gastroenteritis, can block NF-κB activation through the action of its nonstructural protein NSP1, a putative E3 ubiquitin ligase that mediates the degradation of β-TrCP or other immunomodulatory proteins in a virus strain-specific manner. Here, we show that NSP1 targets β-TrCP by mimicking the IκB phosphodegron. The NSP1 proteins of most human and porcine RV strains conserve a C-terminal phosphodegron-like (PDL) motif, DSGΦS. Deletion of this motif or mutation of its serine residues disrupts NSP1-mediated degradation of β-TrCP and inhibition of NF-κB activation. Additionally, a point mutation within the phosphodegron-binding pocket protects β-TrCP from NSP1-mediated turnover. Fusion of the PDL motif to an NSP1 protein known to target other immunomodulatory proteins generates a chimeric NSP1 protein that can induce β-TrCP degradation and block NF-κB activation. Other viral proteins (Epstein-Barr virus LMP1, HIV-1 Vpu, and vaccinia virus A49) also contain a PDL motif and interact with β-TrCP to inhibit NF-κB activation. Taken together, these data suggest that targeting β-TrCP by molecular mimicry may be a common strategy used by human viruses to evade the host immune response.

IMPORTANCE
The transcription factor NF-κB, a central regulator of the host response to infection, is a frequent target of viral antagonism. Pathogen detection activates NF-κB by inducing the phosphorylation of an associated inhibitor protein (IκB), which targets IκB for degradation by the E3 ubiquitin ligase β-TrCP. Rotavirus, a significant cause of childhood gastroenteritis, antagonizes NF-κB through the activity of its NSP1 protein, a putative E3 ubiquitin ligase that mediates β-TrCP turnover. Here, we show that NSP1 functions by mimicking the IκB phosphodegron recognized by β-TrCP. Nearly all human rotavirus strains conserve this motif at the NSP1 C terminus, and its removal disrupts NSP1 antagonist activity. This sequence conserves the biochemical properties of the IκB phosphodegron and can rescue antagonist activity when fused to an NSP1 protein otherwise inactive against β-TrCP. Other viral proteins also mimic IκB to disrupt NF-κB activation, indicating that this is an important immune evasion strategy.
Evidence of and recommendations for non-pharmacological interventions for common geriatric conditions: the SENATOR-ONTOP systematic review protocol
Authors: Abraha Iosief , Cruz-Jentoft Alfonso , Soiza Roy L , O'Mahony Denis , Cherubini Antonio 
Published: January 2015

IntroductionNon-pharmacological therapies for common chronic medical conditions in older patients are underused in clinical practice. We propose a protocol for the assessment of the evidence of non-pharmacological interventions to prevent or treat relevant outcomes in several prevalent geriatric conditions in order to provide recommendations.Methods and analysisThe conditions of interest for which the evidence about efficacy of non-pharmacological interventions will be searched include delirium, falls, pressure sores, urinary incontinence, dementia, heart failure, orthostatic hypotension, sarcopaenia and stroke. For each condition, the following steps will be undertaken: (A) prioritising clinical questions; (B) retrieving the evidence (MEDLINE, the Cochrane Library, CINAHL and PsychINFO will be searched to identify systematic reviews); (C) assessing the methodological quality of the evidence (risk of bias according to the Cochrane method will be applied to the primary studies retrieved from the systematic reviews); (D) developing recommendations based on the evidence (Grading of Recommendations Assessment, Development and Evaluation (GRADE) items—risk of bias, imprecision, inconsistency, indirectness and publication bias—will be used to rate the overall evidence and develop recommendations).DisseminationFor each target condition, at least one systematic overview concerning the evidence of non-pharmacological interventions will be produced and published in peer-reviewed journals.
Periprocedural safety of aneurysm embolization with the Medina Coil System: the early human experience
Authors: Turk Aquilla S , Maia Orlando , Ferreira Christian Candido , Freitas Diogo , Mocco J , Hanel Ricardo 
Published: January 2015

IntroductionIntracranial saccular aneurysms, if untreated, carry a high risk of morbidity and mortality from intracranial bleeding. Embolization coils are the most common treatment. We describe the periprocedural safety and performance of the initial human experience with the next generation Medina Coil System.MethodsThe Medina Coil System is a layered three-dimensional coil made from a radiopaque, shape set core wire, and shape memory alloy outer coil filaments. Nine aneurysms in five patients were selected for treatment with the Medina Coil System.ResultsNine aneurysms in five patients, ranging from 5 to 17 mm in size in various locations, were treated with the Medina Coil System. No procedural or periprocedural complications were encountered. Procedure times, number of coils used to treat the aneurysm, and use of adjunctive devices were much less than anticipated if conventional coil technology had been used.ConclusionsThe Medina Coil System is a next generation coil that combines all of the familiar and expected procedural safety and technique concepts associated with conventional coils. We found improved circumferential aneurysm filling, which may lead to improved long term outcomes, with fewer devices and faster operating times.
Creating Repeatable Computer Science and Networking Experiments on Shared, Public Testbeds
Authors: Edwards Sarah , Liu Xuan , Riga Niky 
Published: January 2015

There are many compelling reasons to use a shared, public testbed such as GENI, Emulab, or PlanetLab to conduct experiments in computer science and networking. These testbeds support creating experiments with a large and diverse set of resources. Moreover these testbeds are constructed to inherently support the repeatability of experiments as required for scientifically sound research. Finally, the artifacts needed for a researcher to repeat their own experiment can be shared so that others can readily repeat the experiment in the same environment.
However using a shared, public testbed is different from conducting experiments on resources either owned by the experimenter or someone the experimenter knows. Experiments on shared, public testbeds are more likely to use large topologies, use scarce resources, and need to be tolerant to outages and maintenances in the testbed. In addition, experimenters may not have access to low-level debugging information.
This paper describes a methodology for new experimenters to write and deploy repeatable and sharable experiments which deal with these challenges by: having a clear plan; automating the execution and analysis of an experiment by following best practices from software engineering and system administration; and building scalable experiments. In addition, the paper describes a case study run on the GENI testbed which illustrates the methodology described.
R990G Polymorphism of Calcium Sensing Receptor Gene Is Associated with High Parathyroid Hormone Levels in Subjects with Vitamin D Deficiency: A Cross-Sectional Study
Authors: Majid Hafsa , Khan Aysha Habib , Moatter Tariq 
Published: January 2015

Single nucleotide polymorphisms (SNPs), R990G and A986S of the calcium sensing receptor (CaSR) gene, are shown to influence response of parathyroid hormone (PTH) in subjects with optimal vitamin D levels. This cross-sectional study was conducted in subjects with vitamin D deficiency (VDD) to observe associations between CaSR polymorphisms, plasma iPTH, and serum calcium levels. Adult females (n=140) with known VDD, intact parathyroid hormone (iPTH), and calcium levels were recruited for genotype analysis. The frequencies of the 986 alleles GG, GT, and TT were 68%, 25%, and 7%, respectively, whereas the frequencies of the 990 alleles AA, AG, and GG were 80%, 8.9%, and 11.1%, respectively. The subjects with GG genotype of R990G polymorphism had higher iPTH levels (148.65 versus 91.47 and 86.1 pg/mL for GG versus AA, AG, resp.,P= 0.008 ) and lower calcium levels (8.4 versus 9.04 and 9.07 mg/dL for GG versus AA, AG, resp.,P= 0.002). No such association of A986S polymorphism with plasma iPTH or serum calcium levels was observed in the present study. Patients with VDD bearing the GG genotype of R990G SNPs are prone to have higher iPTH levels and lower calcium.
Modulation and Predictors of Periprosthetic Bone Mineral Density following Total Knee Arthroplasty
Authors: Mau-Moeller Anett , Behrens Martin , Felser Sabine , Bruhn Sven , Mittelmeier Wolfram , Bader Rainer , Skripitz Ralf 
Published: January 2015

Total knee arthroplasty (TKA) leads to a loss of periprosthetic bone mineral density (BMD). Great importance is attached to the prevention of periprosthetic bone loss with a view to ensuring a long service life of the prosthesis. In order to provide appropriate recommendations for preventive movement therapy measures to combat peri-implant bone loss, it is necessary to know the predictors of periprosthetic BMD. The aim of this study was (1) to determine the change of periprosthetic BMD of the femur and tibia and (2) to analyse the effects of different predictors on periprosthetic BMD. Twenty-three patients with primary TKA were evaluated 10 days and 3 months postoperatively. The data analysis comprised (1) the change in periprosthetic BMD from pretest to posttest and (2) the correlations between BMD and the variables isometric maximum voluntary force, lean mass, physical activity (step count), and BMI using multiple linear regression and structural equation modelling (SEM). BMD of the distal femur was significantly reduced by 19.7% (P = 0.008) 3 months after surgery, while no changes were found in BMD of the tibia. The results of SEM demonstrate that 55% of the BMD variance was explained by the model (χ2=0.002;df=1;P=0.96;χ2/df=0.002;RMSEA<0.01;TLI=1.5;CFI=1.0). A significant direct effect was only evidenced by the variable lean mass (β=0.38;b=0.15;SE=0.07;C.R.=2.0;P=0.046). It can be assumed that a large muscle mass with accompanying distribution of high mechanical load in the bones can contribute to local changes of periprosthetic BMD. Concrete recommendations for preventing peri-implant bone loss therefore include exercises which have the aim of maintaining or building up muscle mass.
miR340 Suppresses the Stem-like Cell Function of Glioma-Initiating Cells by Targeting Tissue Plasminogen Activator
Authors: Yamashita Daisuke , Kondo Toru , Ohue Shiro , Takahashi Hisaaki , Ishikawa Madoka , Matoba Ryo , Suehiro Satoshi , Kohno Shohei , Harada Hironobu , Tanaka Junya , Ohnishi Takanori 
Published: January 2015

Abstract
Glioma-initiating cells (GIC) have stem-like cell properties thought to be sufficient for recurrence, progression, and drug resistance in glioblastomas. In the present study, we defined miRNA (miR)-340 as a differentially expressed miRNA in human GICs that inhibit GIC-mediated tumorigenesis. Furthermore, we defined tissue plasminogen activator (PLAT) as a critical direct target of miR340 for inhibition. Among miRNAs screened, we found that miR340 expression was decreased in all human GICs and in human glioblastoma tissues, compared with human neural stem cells and normal brain tissues. miR340 overexpression in GICs suppressed their proliferative, invasive, and migratory properties in vitro, triggering cell senescence in vitro and inhibiting GIC-induced tumorigenesis in mouse brains. shRNA-mediated silencing of PLAT in GICs phenocopied the effects of miR340 overexpression in vitro and in vivo, suggesting a potential role for tissue factor in stem-like cell function. Taken together, our results identified miR340 as a tumor suppressor that functions in GIC to enforce PLAT blockade and ablate their stem-like functions. Cancer Res; 75(6); 1123–33. ©2015 AACR.
No Association between Adherence to a Healthy Nordic Food Index and Colorectal Cancer: Results from a Swedish Cohort Study
Authors: Roswall Nina , Li Yingjun , Kyrø Cecilie , Sandin Sven , Löf Marie , Adami Hans-Olov , Weiderpass Elisabete 
Published: January 2015

Abstract
Background: Recently, the Nordic diet has gained interest, and a healthy Nordic food index has been developed, which has been found inversely related to colorectal cancer among Danish women. This single finding, however, requires replication in other cohorts.
Methods: We conducted a prospective study in the Women's Lifestyle and Health cohort, including 45,222 women, recruited in 1991–92, and followed up ever since through Swedish registries. Participants were classified according to the Nordic food index (consisting of whole grain bread, oatmeal, apples/pears, cabbages, root vegetables, and fish/shellfish), and the association between adherence and colorectal cancer was assessed using the Cox proportional hazards models.
Results: In the fully adjusted models, we found no association, neither with the continuous index score [incidence rate ratio (IRR), 1.04; 95% confidence interval (CI), 0.95–1.12, per 1-point increment] nor in the categorical analyses (IRR, 1.09; 95% CI, 0.78–1.52 for highest vs. lowest adherers).
Conclusion: The present study does, thus, not support a previous finding of an inverse association between a healthy Nordic food index and colorectal cancer.
Impact: This article adds new evidence to the field of the Nordic diet in disease prevention. Cancer Epidemiol Biomarkers Prev; 24(4); 755–7. ©2015 AACR.
An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma
Authors: von Tresckow Bastian , Morschhauser Franck , Ribrag Vincent , Topp Max S. , Chien Caly , Seetharam Shobha , Aquino Regina , Kotoulek Sonja , de Boer Carla J. , Engert Andreas 
Published: January 2015

Abstract
Purpose: This phase I/II study investigated JNJ-40346527, a selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase as treatment for relapsed or refractory classical Hodgkin lymphoma (cHL).
Experimental Design: Patients ≥18 years with histopathologically confirmed initial diagnosis of cHL that had relapsed or was refractory after ≥1 appropriate therapies were assigned to sequential cohorts of oral daily doses of JNJ-40346527 (150, 300, 450, 600 mg every day, and 150 mg twice a day). For the dose-escalation phase, the primary endpoint was to establish the recommended phase II dose. Secondary endpoints included safety, pharmacokinetics, and pharmacodynamics.
Results: Twenty-one patients [(150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3) every day, and 150 mg twice a day: 7] were enrolled, 10 men, median age 40 (range, 19–75) years, median number of prior systemic therapies 6 (range, 3–14). No dose-limiting toxicities were observed; maximum-tolerated dose was not established. Best overall response was complete remission in 1 patient (duration, +352 days) and stable disease in 11 patients: (duration, 1.5–8 months). Median number of cycles: 4 (range, 1–16). Most common (≥20% patients) possibly drug-related adverse events (per investigator assessment) were nausea (n = 6), headache, and pyrexia (n = 5 each). JNJ-40346527 exposure increased in near dose-proportional manner over a dose range of 150 to 450 mg every day, but plateaued at 600 mg every day. Target engagement was confirmed (&gt;80% inhibition of CSF-1R phosphorylation, 4 hours after dosing).
Conclusions: JNJ-40346527, a selective inhibitor of CSF-1R was well tolerated, and preliminary antitumor results suggested limited activity in monotherapy for the treatment of cHL. Clin Cancer Res; 21(8); 1843–50. ©2015 AACR.
Intratumor Molecular and Phenotypic Diversity in Hepatocellular Carcinoma
Authors: Nault Jean-Charles , Villanueva Augusto 
Published: January 2015

Abstract
Hepatocellular carcinoma is a highly heterogeneous disease both at the molecular and clinical levels. Intratumor morphologic and genetic heterogeneity adds a new level of complexity in our understanding of liver carcinogenesis, and it is likely an important determinant of primary and secondary resistance to targeted therapies. Clin Cancer Res; 21(8); 1786–8. ©2015 AACR.
See related article by Friemel et al., p. 1951
STAT3 Signaling Is Required for Optimal Regression of Large Established Tumors in Mice Treated with Anti-OX40 and TGFβ Receptor Blockade
Authors: Triplett Todd A. , Tucker Christopher G. , Triplett Kendra C. , Alderman Zefora , Sun Lihong , Ling Leona E. , Akporiaye Emmanuel T. , Weinberg Andrew D. 
Published: January 2015

AbstractIn preclinical tumor models, αOX40 therapy is often successful at treating small tumors, but is less effective once the tumors become large. For a tumor immunotherapy to be successful to cure large tumors, it will most likely require not only an agonist to boost effector T-cell function but also inhibitors of T-cell suppression. In this study, we show that combining αOX40 antibodies with an inhibitor of the TGFβ receptor (SM16) synergizes to elicit complete regression of large established MCA205 and CT26 tumors. Evaluation of tumor-infiltrating T cells showed that SM16/αOX40 dual therapy resulted in an increase in proliferating granzyme B+ CD8 T cells, which produced higher levels of IFNγ, compared with treatment with either agent alone. We also found that the dual treatment increased pSTAT3 expression in both CD4 and CD8 T cells isolated from tumors. Because others have published that STAT3 signaling is detrimental to T-cell function within the tumor microenvironment, we explored whether deletion of STAT3 in OX40-expressing cells would affect this potent combination therapy. Surprisingly, we found that deletion of STAT3 in OX40-expressing cells decreased the efficacy of this combination therapy, showing that the full therapeutic potential of this treatment depends on STAT3 signaling, most likely in the T cells of tumor-bearing mice. Cancer Immunol Res; 3(5); 526–35. ©2015 AACR.
Adherence to a Mediterranean Diet and Prediction of Incident Stroke
Authors: Tsivgoulis Georgios , Psaltopoulou Theodora , Wadley Virginia G. , Alexandrov Andrei V. , Howard George , Unverzagt Frederick W. , Moy Claudia , Howard Virginia J. , Kissela Brett , Judd Suzanne E. 
Published: January 2015

Background and Purpose—
There are limited data on the potential association of adherence to Mediterranean diet (MeD) with incident stroke. We sought to assess the longitudinal association between greater adherence to MeD and risk of incident stroke.

Methods—
We prospectively evaluated a population-based cohort of 30 239 individuals enrolled in REasons for Geographic and Racial Differences in Stroke (REGARDS) study, after excluding participants with stroke history, missing demographic data or food frequency questionnaires, and unavailable follow-up information. Adherence to MeD was categorized using MeD score. Incident stroke was adjudicated by expert panel review of medical records during a mean follow-up period of 6.5 years.

Results—

Incident stroke was identified in 565 participants (2.8%; 497 and 68 cases of ischemic stroke [IS] and hemorrhagic stroke, respectively) of 20 197 individuals fulfilling the inclusion criteria. High adherence to MeD (MeD score, 5–9) was associated with lower risk of incident IS in unadjusted analyses (hazard ratio, 0.83; 95% confidence interval, 0.70–1.00;
P
=0.046). The former association retained its significance (hazard ratio, 0.79; 95% confidence interval, 0.65–0.96;
P
=0.016) after adjustment for demographics, vascular risk factors, blood pressure levels, and antihypertensive medications. When MeD was evaluated as a continuous variable, a 1-point increase in MeD score was independently associated with a 5% reduction in the risk of incident IS (95% confidence interval, 0–11%). We documented no association of adherence to MeD with incident hemorrhagic stroke. There was no interaction of race (
P
=0.37) on the association of adherence to MeD with incident IS.

Conclusions—
High adherence to MeD seems to be associated with a lower risk of incident IS independent of potential confounders. Adherence to MeD is not related to the risk of incident hemorrhagic stroke.
On the Local Available Energetics in a Moist Compressible Atmosphere
Authors: Peng Jun , Zhang Lifeng , Zhang Yun 
Published: January 2015

Abstract
A new derivation of local available energetics for a fully compressible, nonhydrostatic, moist atmosphere is presented. The available energetics is defined relative to an arbitrary dry reference state in hydrostatic balance with stable stratification. By introducing the modified potential temperature, a positive-definite expression of the moist available potential energy (APE) is derived. The change of the moist APE must include the role of convection to function both as a source of latent heat and as an atmosphere dehumidifier. The sum of this moist APE and the available elastic energy (AEE) is the moist available energy. In the local energy cycle, the moist available energy is partly used to generate kinetic energy (KE) and partly used to lift the water vapor to the higher level where it precipitates, resulting in the increase of gravitational energy of moist species. The moist APE is converted into vertical KE through the buoyancy term; the vertical KE is converted into the AEE through the vertical perturbation pressure gradient term; and the AEE is converted into horizontal KE through the horizontal divergence/convergence term. In addition, there exist two adiabatic nonconservative processes, which act on the AEE and APE, respectively. A suitable choice of the reference state should make these two processes much less significant than the conversions between the available energy and KE. An alternative method is presented to construct such a reference state. Application to the idealized baroclinic atmosphere shows that this reference state is much more relevant to the local available energy analysis than the isothermal one.