bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiviral Effect, Safety, and Pharmacokinetics of Five-Day Oral Administration of Deleobuvir (BI 207127), an Investigational Hepatitis C Virus RNA Polymerase Inhibitor, in Patients with Chronic Hepatitis C
Authors: Larrey Dominique , Lohse Ansgar W. , Trepo Christian , Bronowicki Jean-Pierre , Arastéh Keikawus , Bourlière Marc , Calleja Jose Luis , Stern Jerry O. , Nehmiz Gerhard , Abdallah Nasri , Berger Kristi L. , Marquis Martin , Steffgen Jürgen , Kukolj George 
Published: July 2013

ABSTRACT

Deleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days' deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN;
n
= 15) and treatment-experienced (TE;
n
= 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (
n
= 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log
10
(with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log
10
. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistance
in vitro
were detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.
Effect of Intracellular Expression of Antimicrobial Peptide LL-37 on Growth of Escherichia coli Strain TOP10 under Aerobic and Anaerobic Conditions
Authors: Liu Wei , Dong Shi Lei , Xu Fei , Wang Xue Qin , Withers T. Ryan , Yu Hongwei D. , Wang Xin 
Published: July 2013

ABSTRACT

Antimicrobial peptides (AMPs) can cause lysis of target bacteria by directly inserting themselves into the lipid bilayer. This killing mechanism confounds the identification of the intracellular targets of AMPs. To circumvent this, we used a shuttle vector containing the inducible expression of a human cathelicidin-related AMP, LL-37, to examine its effect on
Escherichia coli
TOP10 under aerobic and anaerobic growth conditions. Induction of LL-37 caused growth inhibition and alteration in cell morphology to a filamentous phenotype. Further examination of the
E. coli
cell division protein FtsZ revealed that LL-37 did not interact with FtsZ. Moreover, intracellular expression of LL-37 results in the enhanced production of reactive oxygen species (ROS), causing lethal membrane depolarization under aerobic conditions. Additionally, the membrane permeability was increased after intracellular expression of LL37 under both aerobic and anaerobic conditions. Transcriptomic analysis revealed that intracellular LL-37 mainly affected the expression of genes related to energy production and carbohydrate metabolism. More specifically, genes related to oxidative phosphorylation under both aerobic and anaerobic growth conditions were affected. Collectively, our current study demonstrates that intracellular expression of LL-37 in
E. coli
can inhibit growth under aerobic and anaerobic conditions. While we confirmed that the generation of ROS is a bactericidal mechanism for LL-37 under aerobic growth conditions, we also found that the intracellular accumulation of cationic LL-37 influences the redox and ion status of the cells under both growth conditions. These data suggest that there is a new AMP-mediated bacterial killing mechanism that targets energy metabolism.
Republished: Emerging concepts in the management of acute retinal necrosis
Authors: Wong Robert William , Jumper J Michael , McDonald H Richard , Johnson Robert N , Fu Arthur , Lujan Brandon J , Cunningham Emmett T 
Published: July 2013

Abstract
Acute retinal necrosis (ARN), also known as Kirisawa-type uveitis, is an uncommon condition caused by infection of the retina by one of the herpes family of viruses, most typically varicella zoster virus or herpes simplex virus and less commonly cytomegalovirus. Clinical diagnosis can be challenging and is often aided by PCR-based analysis of ocular fluids. Treatment typically involves extended use of one or more antiviral agents. Long term retinal detachment risk is high. We review the literature on ARN and present an approach to the diagnosis and management of this serious condition.
An efficient computation of handle and tunnel loops via Reeb graphs
Authors: Dey Tamal K. , Fan Fengtao , Wang Yusu 
Published: July 2013

A special family of non-trivial loops on a surface called handle and tunnel loops associates closely to geometric features of "handles" and "tunnels" respectively in a 3D model. The identification of these handle and tunnel loops can benefit a broad range of applications from topology simplification/repair, and surface parameterization, to feature and shape recognition. Many of the existing efficient algorithms for computing non-trivial loops cannot be used to compute these special type of loops. The two algorithms known for computing handle and tunnel loops provably have a serious drawback that they both require a tessellation of the interior and exterior spaces bounded by the surface. Computing such a tessellation of three dimensional space around the surface is a non-trivial task and can be quite expensive. Furthermore, such a tessellation may need to refine the surface mesh, thus causing the undesirable side-effect of outputting the loops on an altered surface mesh.
In this paper, we present an efficient algorithm to compute a basis for handle and tunnel loops without requiring any 3D tessellation. This saves time considerably for large meshes making the algorithm scalable while computing the loops on the original input mesh and not on some refined version of it. We use the concept of the Reeb graph which together with several key theoretical insights on linking number provide an initial set of loops that provably constitute a handle and a tunnel basis. We further develop a novel strategy to tighten these handle and tunnel basis loops to make them geometrically relevant. We demonstrate the efficiency and effectiveness of our algorithm as well as show its robustness against noise, and other anomalies in the input.
A hardware unit for fast SAH-optimised BVH construction
Authors: Doyle Michael J. , Fowler Colin , Manzke Michael 
Published: July 2013

Ray-tracing algorithms are known for producing highly realistic images, but at a significant computational cost. For this reason, a large body of research exists on various techniques for accelerating these costly algorithms. One approach to achieving superior performance which has received comparatively little attention is the design of specialised ray-tracing hardware. The research that does exist on this topic has consistently demonstrated that significant performance and efficiency gains can be achieved with dedicated microarchitectures. However, previous work on hardware ray-tracing has focused almost entirely on the traversal and intersection aspects of the pipeline. As a result, the critical aspect of the management and construction of acceleration data-structures remains largely absent from the hardware literature.
We propose that a specialised microarchitecture for this purpose could achieve considerable performance and efficiency improvements over programmable platforms. To this end, we have developed the first dedicated microarchitecture for the construction of binned SAH BVHs. Cycle-accurate simulations show that our design achieves significant improvements in raw performance and in the bandwidth required for construction, as well as large efficiency gains in terms of performance per clock and die area compared to manycore implementations. We conclude that such a design would be useful in the context of a heterogeneous graphics processor, and may help future graphics processor designs to reduce predicted technology-imposed utilisation limits.
ICFP 2002
Authors: Findler Robert Bruce , Felleisen Matthias 
Published: July 2013

Assertions play an important role in the construction of robust software. Their use in programming languages dates back to the 1970s. Eiffel, an object-oriented programming language, wholeheartedly adopted assertions and developed the "Design by Contract" philosophy. Indeed, the entire object-oriented community recognizes the value of assertion-based contracts on methods.
In contrast, languages with higher-order functions do not support assertion-based contracts. Because predicates on functions are, in general, undecidable, specifying such predicates appears to be meaningless. Instead, the functional languages community developed type systems that statically approximate interesting predicates.

In this paper, we show how to support higher-order function contracts in a theoretically well-founded and practically viable manner. Specifically, we introduce ?
CON
, a typed lambda calculus with assertions for higher-order functions. The calculus models the assertion monitoring system that we employ in Dr Scheme. We establish basic properties of the model (type soundness, etc.) and illustrate the usefulness of contract checking with examples from Dr Scheme's code base.

We believe that the development of an assertion system for higherorder functions serves two purposes. On one hand, the system has strong practical potential because existing type systems simply cannot express many assertions that programmers would like to state. nOn the other hand, an inspection of a large base of invariants may provide inspiration for the direction of practical future type system research.
miR-205 Targets PTEN and PHLPP2 to Augment AKT Signaling and Drive Malignant Phenotypes in Non–Small Cell Lung Cancer
Authors: Cai Junchao , Fang Lishan , Huang Yongbo , Li Rong , Yuan Jie , Yang Yi , Zhu Xun , Chen Baixue , Wu Jueheng , Li Mengfeng 
Published: July 2013

AbstractAKT signaling is constitutively activated in various cancers, due in large part to loss-of-function in the PTEN and PHLPP phosphatases that act as tumor suppressor genes. However, AKT signaling is activated widely in non–small cell lung cancers (NSCLC) where genetic alterations in PTEN or PHLPP genes are rare, suggesting an undefined mechanism(s) for their suppression. In this study, we report upregulation of the oncomir microRNA (miR)-205 in multiple subtypes of NSCLC, which directly represses PTEN and PHLPP2 expression and activates both the AKT/FOXO3a and AKT/mTOR signaling pathways. miR-205 overexpression in NSCLC cells accelerated tumor cell proliferation and promoted blood vessel formation in vitro and in vivo. Conversely, RNA interference–mediated silencing of endogenous miR-205 abrogated these effects. The malignant properties induced by miR-205 in NSCLC cells were reversed by AKT inhibitors, FOXO3a overexpression, rapamycin treatment, or restoring PHLPP2 or PTEN expression. Mechanistic investigations revealed that miR-205 overexpression was a result of NF-κB–mediated transactivation of the miR-205 gene. Taken together, our results define a major epigenetic mechanism for suppression of PTEN and PHLPP2 in NSCLC, identifying a pivotal role for miR-205 in development and progression of this widespread disease. Cancer Res; 73(17); 5402–15. ©2013 AACR.
Fusion-Derived Epithelial Cancer Cells Express Hematopoietic Markers and Contribute to Stem Cell and Migratory Phenotype in Ovarian Carcinoma
Authors: Ramakrishnan Mallika , Mathur Sandeep R. , Mukhopadhyay Asok 
Published: July 2013

Abstract
For a long time, the external milieu of cancer cells was considered to be of secondary importance when compared with its intrinsic properties. That has changed now as the microenvironment is considered to be a major contributing factor toward the progression of tumor. In this study, we show that in human and mouse epithelial ovarian carcinoma and mouse lung carcinoma, the interaction between tumor-infiltrating hematopoietic cells and epithelial cancer cells results in their fusion. Intriguingly, even after the fusion event, cancer cells retain the expression of the pan-hematopoietic marker (CD45) and various markers of hematopoietic lineage, including those of hematopoietic stem cells, indicating that the hematopoietic genome is not completely reprogrammed. This observation may have implications on the bone marrow contribution to the cancer stem cell population. Interestingly, it was seen that in both cancer models, the expression of chemokine receptor CXCR4 was largely contributed to by the fused compartment of cancer cells. We hypothesize that the superior migratory potential gained by the cancer cells due to the fusion helps in its dissemination to various secondary organs upon activation of the CXCR4/CXCL12 axis. We are the first to report the presence of a hemato-epithelial cancer compartment, which contributes to stem cell markers and CXCR4 in epithelial carcinoma. This finding has repercussions on CXCR4-based therapeutics and opens new avenues in discovering novel molecular targets against fusion and metastasis. Cancer Res; 73(17); 5360–70. ©2013 AACR.
Construction of an Immunotoxin, D2C7-(scdsFv)-PE38KDEL, Targeting EGFRwt and EGFRvIII for Brain Tumor Therapy
Authors: Chandramohan Vidyalakshmi , Bao Xuhui , Keir Stephen T. , Pegram Charles N. , Szafranski Scott E. , Piao Hailan , Wikstrand Carol J. , McLendon Roger E. , Kuan Chien-Tsun , Pastan Ira H. , Bigner Darell D. 
Published: July 2013

AbstractPurpose: The EGF receptor gene (EGFR) is most frequently amplified and overexpressed, along with its deletion mutant, EGFRvIII, in glioblastoma. We tested the preclinical efficacy of the recombinant immunotoxin, D2C7-(scdsFv)-PE38KDEL, which is reactive with a 55-amino acid (AA) region present in the extracellular domain of both EGFRwt (583-637 AAs) and EGFRvIII (292-346 AAs) proteins.Experimental Design: The binding affinity and specificity of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII were measured by surface-plasmon resonance and flow cytometry. In vitro cytotoxicity of D2C7-(scdsFv)-PE38KDEL was measured by inhibition of protein synthesis in human EGFRwt-transfected NR6 (NR6W), human EGFRvIII-transfected NR6 (NR6M), EGFRwt-overexpressing A431-epidermoid-carcinoma, and glioblastoma xenograft cells (43, D08-0493MG, D2159MG, and D270MG). In vivo antitumor efficacy of D2C7-(scdsFv)-PE38KDEL was evaluated using 43, NR6M, and D270MG orthotopic tumor models.Results: The KD of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII was 1.6 × 10−9 mol/L and 1.3 × 10−9 mol/L, respectively. Flow cytometry with NR6W and NR6M cells confirmed the specificity of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII. The D2C7-(scdsFv)-PE38KDEL IC50 was 0.18 to 2.5 ng/mL on cells expressing EGFRwt (NR6W, A431, 43, and D08-0493MG). The D2C7-(scdsFv)-PE38KDEL IC50 was approximately 0.25 ng/mL on EGFRvIII-expressing cells (NR6M) and on EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells (D2159MG and D270MG). Significantly, in intracranial tumor models of 43, NR6M, and D270MG, treatment with D2C7-(scdsFv)-PE38KDEL by convection-enhanced delivery prolonged survival by 310% (P = 0.006), 28% (P = 0.002), and 166% (P = 0.001), respectively.Conclusions: In preclinical studies, the D2C7-(scdsFv)-PE38KDEL immunotoxin exhibited significant potential for treating brain tumors expressing EGFRwt, EGFRvIII, or both. Clin Cancer Res; 19(17); 4717–27. ©2013 AACR.
NF1 Deletion Generates Multiple Subtypes of Soft-Tissue Sarcoma That Respond to MEK Inhibition
Authors: Dodd Rebecca D. , Mito Jeffrey K. , Eward William C. , Chitalia Rhea , Sachdeva Mohit , Ma Yan , Barretina Jordi , Dodd Leslie , Kirsch David G. 
Published: July 2013

Abstract
Soft-tissue sarcomas are a heterogeneous group of tumors arising from connective tissue. Recently, mutations in the neurofibromin 1 (NF1) tumor suppressor gene were identified in multiple subtypes of human soft-tissue sarcomas. To study the effect of NF1 inactivation in the initiation and progression of distinct sarcoma subtypes, we have developed a novel mouse model of temporally and spatially restricted NF1-deleted sarcoma. To generate primary sarcomas, we inject adenovirus containing Cre recombinase into NF1flox/flox; Ink4a/Arfflox/flox mice at two distinct orthotopic sites: intramuscularly or in the sciatic nerve. The mice develop either high-grade myogenic sarcomas or malignant peripheral nerve sheath tumor (MPNST)-like tumors, respectively. These tumors reflect the histologic properties and spectrum of sarcomas found in patients. To explore the use of this model for preclinical studies, we conducted a study of mitogen-activated protein kinase (MAPK) pathway inhibition with the MEK inhibitor PD325901. Treatment with PD325901 delays tumor growth through decreased cyclin D1 mRNA and cell proliferation. We also examined the effects of MEK inhibition on the native tumor stroma and find that PD325901 decreases VEGFα expression in tumor cells with a corresponding decrease in microvessel density. Taken together, our results use a primary tumor model to show that sarcomas can be generated by loss of NF1 and Ink4a/Arf, and that these tumors are sensitive to MEK inhibition by direct effects on tumor cells and the surrounding microenvironment. These studies suggest that MEK inhibitors should be further explored as potential sarcoma therapies in patients with tumors containing NF1 deletion. Mol Cancer Ther; 12(9); 1906–17. ©2013 AACR.
Development of Risk Taking: Contributions from Adolescent Testosterone and the Orbito-frontal Cortex
Authors: Peper Jiska S. , Koolschijn P. Cédric M. P. , Crone Eveline A. 
Published: July 2013

Abstract
The role of puberty in the development of risk taking remains poorly understood. Here, in a normative sample of 268 participants between 8 and 25 years old, we applied a psycho-endocrine neuroimaging approach to investigate the contribution of testosterone levels and OFC morphology to individual differences in risk taking. Risk taking was measured with the balloon analogue risk-taking task. We found that, corrected for age, higher endogenous testosterone level was related to increased risk taking in boys (more explosions) and girls (more money earned). In addition, a smaller medial OFC volume in boys and larger OFC surface area in girls related to more risk taking. A mediation analysis indicated that OFC morphology partly mediates the association between testosterone level and risk taking, independent of age. Mediation was found in such a way that a smaller medial OFC in boys potentiates the association between testosterone and risk taking but suppresses the association in girls. This study provides insights into endocrinological and neural underpinnings of normative development of risk taking, by indicating that OFC morphology, at least partly, mediates the association between testosterone and risk-taking behavior.
What Evidence Supports Special Processing for Faces? A Cautionary Tale for fMRI Interpretation
Authors: Cowell Rosemary A. , Cottrell Garrison W. 
Published: July 2013

Abstract
We trained a neurocomputational model on six categories of photographic images that were used in a previous fMRI study of object and face processing. Multivariate pattern analyses of the activations elicited in the object-encoding layer of the model yielded results consistent with two previous, contradictory fMRI studies. Findings from one of the studies [Haxby, J. V., Gobbini, M. I., Furey, M. L., Ishai, A., Schouten, J. L., & Pietrini, P. Distributed and overlapping representations of faces and objects in ventral temporal cortex. Science, 293, 2425–2430, 2001] were interpreted as evidence for the object-form topography model. Findings from the other study [Spiridon, M., & Kanwisher, N. How distributed is visual category information in human occipito-temporal cortex? An fMRI study. Neuron, 35, 1157–1165, 2002] were interpreted as evidence for neural processing mechanisms in the fusiform face area that are specialized for faces. Because the model contains no special processing mechanism or specialized architecture for faces and yet it can reproduce the fMRI findings used to support the claim that there are specialized face-processing neurons, we argue that these fMRI results do not actually support that claim. Results from our neurocomputational model therefore constitute a cautionary tale for the interpretation of fMRI data.
Lagrangian Detection of Wind Shear for Landing Aircraft
Authors: Kafiabad Hossein Amini , Chan Pak Wai , Haller George 
Published: July 2013

AbstractRecent studies have shown that aerial disturbances affecting landing aircraft have a coherent signature in the Lagrangian aerial particle dynamics inferred from ground-based lidar scans. Specifically, attracting Lagrangian coherent structures (LCSs) mark the intersection of localized material upwelling within the cone of the lidar scan. This study tests the detection power of LCSs on historical landing data and corresponding pilot reports of disturbances from Hong Kong International Airport. The results show that a specific LCS indicator, the gradient of the finite-time Lyapunov exponent (FTLE) field along the landing path, is a highly efficient marker of turbulent upwellings. In particular, in the spring season, projected FTLE gradients closely approach the efficiency of the wind shear alert system currently in operation at the airport, even though the latter system relies on multiple sources of data beyond those used in this study. This shows significant potential for the operational use of FTLE gradients in the real-time detection of aerial disturbances over airports.
Four Current Meter Models Compared in Strong Currents in Drake Passage
Authors: Watts D. Randolph , Kennelly Maureen A. , Donohue Kathleen A. , Tracey Karen L. , Chereskin Teresa K. , Weller Robert A. , Victoria Ivan 
Published: July 2013

Abstract
Seven current meters representing four models on a stiffly buoyed mooring were placed for an 11-month deployment to intercompare their velocity measurements: two vector-measuring current meters (VMCMs), two Aanderaa recording current meter (RCM) 11s, two Aanderaa SEAGUARDs, and a Nortek Aquadopp. The current meters were placed 6-m apart from each other at about 4000-m depth in an area of Drake Passage expected to have strong currents, nearly independent of depth near the bottom. Two high-current events occurred in bursts of semidiurnal pulses lasting several days, one with peak speeds up to 67 cm s−1 and the other above 35 cm s−1. The current-speed measurements all agreed within 7% of the median value when vector averaged over simultaneous time intervals. The VMCMs, chosen as the reference measurements, were found to measure the median of the mean-current magnitudes. The RCM11 and SEAGUARD current speeds agreed within 2% of the median at higher speeds (35–67 cm s−1), whereas in lower speed ranges (0–35 cm s−1) the vector-averaged speeds for the RCM11 and SEAGUARD were 4%–5% lower and 3%–5% higher than the median, respectively. The shorter-record Aquadopp current speeds were about 6% higher than the VMCMs over the range (0–40 cm s−1) encountered.