bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional programs that explain their work
Authors: Perera Roly , Acar Umut A. , Cheney James , Levy Paul Blain
Published: November 2012

We present techniques that enable higher-order functional computations to "explain" their work by answering questions about how parts of their output were calculated. As explanations, we consider the traditional notion of program slices, which we show can be inadequate, and propose a new notion: trace slices. We present techniques for specifying flexible and rich slicing criteria based on partial expressions, parts of which have been replaced by holes.

We characterise program slices in an algorithm-independent fashion and show that a least slice for a given criterion exists. We then present an algorithm, called
unevaluation
, for computing least program slices from computations reified as traces. Observing a limitation of program slices, we develop a notion of
trace slice
as another form of explanation and present an algorithm for computing them. The unevaluation algorithm can be applied to any subtrace of a trace slice to compute a program slice whose evaluation generates that subtrace. This close correspondence between programs, traces, and their slices can enable the programmer to understand a computation interactively, in terms of the programming language in which the computation is expressed. We present an implementation in the form of a tool, discuss some important practical implementation concerns and present some techniques for addressing them.
Reducing the barriers to writing verified specifications
Authors: Schiller Todd W. , Ernst Michael D.
Published: November 2012

Formally verifying a program requires significant skill not only because of complex interactions between program subcomponents, but also because of deficiencies in current verification interfaces. These skill barriers make verification economically unattractive by preventing the use of less-skilled (less-expensive) workers and distributed workflows (i.e., crowdsourcing). This paper presents VeriWeb, a web-based IDE for verification that decomposes the task of writing verifiable specifications into manageable subproblems. To overcome the information loss caused by task decomposition, and to reduce the skill required to verify a program, VeriWeb incorporates several innovative user interface features: drag and drop condition construction, concrete counterexamples, and specification inlining.

To evaluate VeriWeb, we performed three experiments. First, we show that VeriWeb lowers the time and monetary cost of verification by performing a comparative study of VeriWeb and a traditional tool using 14 paid subjects contracted hourly from Exhedra Solution's vWorker online marketplace. Second, we demonstrate the dearth and insufficiency of current ad-hoc labor marketplaces for verification by recruiting workers from Amazon's Mechanical Turk to perform verification with VeriWeb. Finally, we characterize the minimal communication overhead incurred when VeriWeb is used collaboratively by observing two pairs of developers each use the tool simultaneously to verify a single program.
GPUVerify
Authors: Betts Adam , Chong Nathan , Donaldson Alastair , Qadeer Shaz , Thomson Paul
Published: November 2012

We present a technique for verifying race- and divergence-freedom of GPU kernels that are written in mainstream kernel programming languages such as OpenCL and CUDA. Our approach is founded on a novel formal operational semantics for GPU programming termed synchronous, delayed visibility (SDV) semantics. The SDV semantics provides a precise definition of barrier divergence in GPU kernels and allows kernel verification to be reduced to analysis of a sequential program, thereby completely avoiding the need to reason about thread interleavings, and allowing existing modular techniques for program verification to be leveraged. We describe an efficient encoding for data race detection and propose a method for automatically inferring loop invariants required for verification. We have implemented these techniques as a practical verification tool, GPUVerify, which can be applied directly to OpenCL and CUDA source code. We evaluate GPUVerify with respect to a set of 163 kernels drawn from public and commercial sources. Our evaluation demonstrates that GPUVerify is capable of efficient, automatic verification of a large number of real-world kernels.
Refactoring android Java code for on-demand computation offloading
Authors: Zhang Ying , Huang Gang , Liu Xuanzhe , Zhang Wei , Mei Hong , Yang Shunxiang
Published: November 2012

Computation offloading is a promising way to improve the performance as well as reducing the battery power consumption of a smartphone application by executing some parts of the application on a remote server. Supporting such capability is not easy for smartphone application developers due to (1) correctness: some code, e.g., that for GPS, gravity, and other sensors, can run only on the smartphone so that developers have to identify which parts of the application cannot be offloaded; (2) effectiveness: the reduced execution time must be greater than the network delay caused by computation offloading so that developers need to calculate which parts are worth offloading; (3) adaptability: smartphone applications often face changes of user requirements and runtime environments so that developers need to implement the adaptation on offloading. More importantly, considering the large number of today's smartphone applications, solutions applicable for legacy applications will be much more valuable. In this paper, we present a tool, named DPartner, that automatically refactors Android applications to be the ones with computation offloading capability. For a given Android application, DPartner first analyzes its bytecode for discovering the parts worth offloading, then rewrites the bytecode to implement a special program structure supporting on-demand offloading, and finally generates two artifacts to be deployed onto an Android phone and the server, respectively. We evaluated DPartner on three real-world Android applications, demonstrating the reduction of execution time by 46%-97% and battery power consumption by 27%-83%.
Exploring multi-threaded Java application performance on multicore hardware
Authors: Sartor Jennfer B. , Eeckhout Lieven
Published: November 2012

While there have been many studies of how to schedule applications to take advantage of increasing numbers of cores in modern-day multicore processors, few have focused on multi-threaded managed language applications which are prevalent from the embedded to the server domain. Managed languages complicate performance studies because they have additional virtual machine threads that collect garbage and dynamically compile, closely interacting with application threads. Further complexity is introduced as modern multicore machines have multiple sockets and dynamic frequency scaling options, broadening opportunities to reduce both power and running time.

In this paper, we explore the performance of Java applications, studying how best to map application and virtual machine (JVM) threads to a multicore, multi-socket environment. We explore both the cost of separating JVM threads from application threads, and the opportunity to speed up or slow down the clock frequency of isolated threads. We perform experiments with the multi-threaded DaCapo benchmarks and pseudojbb2005 running on the Jikes Research Virtual Machine, on a dual-socket, 8-core Intel Nehalem machine to reveal several novel, and sometimes counter-intuitive, findings. We believe these insights are a first but important step towards understanding and optimizing managed language performance on modern hardware.
IFRit
Authors: Effinger-Dean Laura , Lucia Brandon , Ceze Luis , Grossman Dan , Boehm Hans-J.
Published: November 2012

We propose a new algorithm for dynamic data-race detection. Our algorithm reports no false positives and runs on arbitrary C and C++ code. Unlike previous algorithms, we do not have to instrument every memory access or track a full happens-before relation. Our data-race detector, which we call IFRit, is based on a run-time abstraction called an interference-free region (IFR). An IFR is an interval of one thread's execution during which any write to a specific variable by a different thread is a data race. We insert instrumentation at compile time to monitor active IFRs at run-time. If the runtime observes overlapping IFRs for conflicting accesses to the same variable in two different threads, it reports a race. The static analysis aggregates information for multiple accesses to the same variable, avoiding the expense of having to instrument every memory access in the program.

We directly compare IFRit to FastTrack and ThreadSanitizer, two state-of-the-art fully-precise data-race detectors. We show that IFRit imposes a fraction of the overhead of these detectors. We show that for the PARSEC benchmarks, and several real-world applications, IFRit finds many of the races detected by a fully-precise detector. We also demonstrate that sampling can further reduce IFRit's performance overhead without completely forfeiting precision.
Taming MATLAB
Authors: Dubrau Anton Willy , Hendren Laurie Jane
Published: November 2012

MATLAB is a dynamic scientific language used by scientists, engineers and students worldwide. Although MATLAB is very suitable for rapid prototyping and development, MATLAB users often want to convert their final MATLAB programs to a static language such as FORTRAN. This paper presents an extensible object-oriented toolkit for supporting the generation of static programs from dynamic MATLAB programs. Our open source toolkit, called the MATLAB Tamer, identifies a large tame subset of MATLAB, supports the generation of a specialized Tame IR for that subset, provides a principled approach to handling the large number of builtin MATLAB functions, and supports an extensible interprocedural value analysis for estimating MATLAB types and call graphs.
Higher-order symbolic execution via contracts
Authors: Tobin-Hochstadt Sam , Van Horn David
Published: November 2012

We present a new approach to automated reasoning about higher-order programs by extending symbolic execution to use behavioral contracts as symbolic values, thus enabling symbolic approximation of higher-order behavior.

Our approach is based on the idea of an abstract reduction semantics that gives an operational semantics to programs with both concrete and symbolic components. Symbolic components are approximated by their contract and our semantics gives an operational interpretation of contracts-as-values. The result is an executable semantics that soundly predicts program behavior, including contract failures, for all possible instantiations of symbolic components. We show that our approach scales to an expressive language of contracts including arbitrary programs embedded as predicates, dependent function contracts, and recursive contracts. Supporting this rich language of specifications leads to powerful symbolic reasoning using existing program constructs.

We then apply our approach to produce a verifier for contract correctness of components, including a sound and computable approximation to our semantics that facilitates fully automated contract verification. Our implementation is capable of verifying contracts expressed in existing programs, and of justifying contract-elimination optimizations.
Dependent types for JavaScript
Authors: Chugh Ravi , Herman David , Jhala Ranjit
Published: November 2012

We present Dependent JavaScript (DJS), a statically typed dialect of the imperative, object-oriented, dynamic language. DJS supports the particularly challenging features such as run-time type-tests, higher-order functions, extensible objects, prototype inheritance, and arrays through a combination of nested refinement types, strong updates to the heap, and heap unrolling to precisely track prototype hierarchies. With our implementation of DJS, we demonstrate that the type system is expressive enough to reason about a variety of tricky idioms found in small examples drawn from several sources, including the popular book JavaScript: The Good Parts and the SunSpider benchmark suite.
k-Calling context profiling
Authors: Ausiello Giorgio , Demetrescu Camil , Finocchi Irene , Firmani Donatella
Published: November 2012

Calling context trees are one of the most fundamental data structures for representing the interprocedural control flow of a program, providing valuable information for program understanding and optimization. Nodes of a calling context tree associate performance metrics to whole distinct paths in the call graph starting from the root function. However, no explicit information is provided for detecting short hot sequences of activations, which may be a better optimization target in large modular programs where groups of related functions are reused in many different parts of the code. Furthermore, calling context trees can grow prohibitively large in some scenarios. Another classical approach, called edge profiling, collects performance metrics for caller-callee pairs in the call graph, allowing it to detect hot paths of fixed length one. We study a generalization of edge and context-sensitive profiles by introducing a novel data structure called k-calling context forest (k-CCF). Nodes in a k-CCF associate performance metrics to paths of length at most k that lead to each distinct routine of the program, providing edge profiles for k=1, full context-sensitive profiles for k equal to infinity, as well as any other intermediate point in the spectrum. We study the properties of the k-CCF both theoretically and experimentally on a large suite of prominent Linux applications, showing how to construct it efficiently and discussing its relationships with the calling context tree. Our experiments show that the k-CCF can provide effective space-accuracy tradeoffs for interprocedural contextual profiling, yielding useful clues to the hot spots of a program that may be hidden in a calling context tree and using less space for small values of k, which appear to be the most interesting in practice.
Reim & ReImInfer
Authors: Huang Wei , Milanova Ana , Dietl Werner , Ernst Michael D.
Published: November 2012

Reference immutability ensures that a reference is not used to modify the referenced object, and enables the safe sharing of object structures. A pure method does not cause side-effects on the objects that existed in the pre-state of the method execution. Checking and inference of reference immutability and method purity enables a variety of program analyses and optimizations. We present ReIm, a type system for reference immutability, and ReImInfer, a corresponding type inference analysis. The type system is concise and context-sensitive. The type inference analysis is precise and scalable, and requires no manual annotations. In addition, we present a novel application of the reference immutability type system: method purity inference.

To support our theoretical results, we implemented the type system and the type inference analysis for Java. We include a type checker to verify the correctness of the inference result. Empirical results on Java applications and libraries of up to 348kLOC show that our approach achieves both scalability and precision.
White box sampling in uncertain data processing enabled by program analysis
Authors: Bao Tao , Zheng Yunhui , Zhang Xiangyu
Published: November 2012

Sampling is a very important and low-cost approach to uncertain data processing, in which output variations caused by input errors are sampled. Traditional methods tend to treat a program as a blackbox. In this paper, we show that through program analysis, we can expose the internals of sample executions so that the process can become more selective and focused. In particular, we develop a sampling runtime that can selectively sample in input error bounds to expose discontinuity in output functions. It identifies all the program factors that can potentially lead to discontinuity and hash the values of such factors during execution in a cost-effective way. The hash values are used to guide the sampling process. Our results show that the technique is very effective for real-world programs. It can achieve the precision of a high sampling rate with the cost of a lower sampling rate.
Reusing debugging knowledge via trace-based bug search
Authors: Gu Zhongxian , Barr Earl T. , Schleck Drew , Su Zhendong
Published: November 2012

Some bugs, among the millions that exist, are similar to each other. One bug-fixing tactic is to search for similar bugs that have been reported and resolved in the past. A fix for a similar bug can help a developer understand a bug, or even directly fix it. Studying bugs with similar symptoms, programmers may determine how to detect or resolve them. To speed debugging, we advocate the systematic capture and reuse of debugging knowledge, much of which is currently wasted. The core challenge here is how to search for similar bugs. To tackle this problem, we exploit semantic bug information in the form of execution traces, which precisely capture bug semantics. This paper introduces novel tool and language support for semantically querying and analyzing bugs. We describe OSCILLOSCOPE, an Eclipse plugin, that uses a bug trace to exhaustively search its database for similar bugs and return their bug reports. OSCILLOSCOPE displays the traces of the bugs it returns against the trace of the target bug, so a developer can visually examine the quality of the matches. OSCILLOSCOPE rests on our bug query language (BQL), a flexible query language over traces. To realize OSCILLOSCOPE, we developed an open infrastructure that consists of a trace collection engine, BQL, a Hadoop-based query engine for BQL, a trace-indexed bug database, as well as a web-based frontend. OSCILLOSCOPE records and uploads bug traces to its infrastructure; it does so automatically when a JUnit test fails. We evaluated OSCILLOSCOPE on bugs collected from popular open-source projects. We show that OSCILLOSCOPE accurately and efficiently finds similar bugs, some of which could have been immediately used to fix open bugs.
Disruptive and Transformative Education: Designing learning in the digital age
Authors: Miller Allison
Published: November 2012

Emerging changes to the way education is being delivered means that educators need to increase their technological domain of knowledge as well as improve their information and communication technology (ICT) skills to be able to design and facilitate learning in the digital age. These disruptive and transformative learning experiences will then better equip learners for a life of learning in a rapidly changing world.
Spreading of Excellence in SARNET Network on Severe Accidents: The Education and Training Programme
Authors: Paci Sandro , Van Dorsselaere Jean-Pierre
Published: November 2012

The SARNET2 (severe accidents Research NETwork of Excellence) project started in April 2009 for 4 years in the 7th Framework Programme (FP7) of the European Commission (EC), following a similar first project in FP6. Forty-seven organisations from 24 countries network their capacities of research in the severe accident (SA) field inside SARNET to resolve the most important remaining uncertainties and safety issues on SA in water-cooled nuclear power plants (NPPs). The network includes a large majority of the European actors involved in SA research plus a few non-European relevant ones. The “Education and Training” programme in SARNET is a series of actions foreseen in this network for the “spreading of excellence.” It is focused on raising the competence level of Master and Ph.D. students and young researchers engaged in SA research and on organizing information/training courses for NPP staff or regulatory authorities (but also for researchers) interested in SA management procedures.
Usability Testing for Serious Games: Making Informed Design Decisions with User Data
Authors: Moreno-Ger Pablo , Torrente Javier , Hsieh Yichuan Grace , Lester William T.
Published: November 2012

Usability testing is a key step in the successful design of new technologies and tools, ensuring that heterogeneous populations will be able to interact easily with innovative applications. While usability testing methods of productivity tools (e.g., text editors, spreadsheets, or management tools) are varied, widely available, and valuable, analyzing the usability of games, especially educational “serious” games, presents unique usability challenges. Because games are fundamentally different than general productivity tools, “traditional” usability instruments valid for productivity applications may fall short when used for serious games. In this work we present a methodology especially designed to facilitate usability testing for serious games, taking into account the specific needs of such applications and resulting in a systematically produced list of suggested improvements from large amounts of recorded gameplay data. This methodology was applied to a case study for a medical educational game, MasterMed, intended to improve patients’ medication knowledge. We present the results from this methodology applied to MasterMed and a summary of the central lessons learned that are likely useful for researchers who aim to tune and improve their own serious games before releasing them for the general public.
Long-Term Survival after Adrenalectomy for Asynchronous Metastasis of Bladder Cancer to the Bilateral Adrenal Glands
Authors: Washino S. , Hirai M. , Matsuzaki A. , Kobayashi Y.
Published: November 2012

Isolated adrenal metastasis of bladder cancer, particularly the bilateral, is quite rare. Systemic chemotherapy is the treatment of choice for metastatic urothelial carcinoma. However, despite initially promising response rates of approximately 45%–71%, most tumors eventually show progression, and the median survival time following chemotherapy regimen is approximately 14-15 months. Recently, favorable results of surgery for metastatic urothelial carcinoma have been reported. Here, we report a rare case of asynchronous metastasis of bladder cancer to the bilateral adrenal glands with long-term survival after bilateral adrenalectomy. A 69-year-old man underwent radical cystoprostatectomy and ileal conduit urinary diversion for invasive bladder cancer. Ten months later, left adrenalectomy was performed for a left adrenal tumor, revealing metastatic urothelial carcinoma. After adjuvant chemotherapy, a tumor in the right adrenal gland was detected. Right adrenalectomy was done, and the tumor was also found to be metastatic urothelial carcinoma. The patient had an uneventful recovery after starting steroid replacement therapy. Three years later, he was doing well and had no evidence of recurrence. Adrenalectomy for isolated adrenal metastasis of urothelial carcinoma may be a reasonable option, even if such metastases are bilateral.
Interaction between Bees and the Tristylous Flowers ofOxalis cytisoidesMart. & Zucc. (Oxalidaceae)
Authors: Krug Cristiane , Silva Cláudia Inês , Alves-dos-Santos Isabel
Published: November 2012

The interaction of bees with the tristylous flowers ofOxalis cytisoidesMart. & Zucc. (Oxalidaceae) was evaluated. The study was conducted in a semideciduous forest at the Fritz Plaumann State Park in Concórdia, Santa Catarina state. TwoOxalis cytisoidesaggregations were found and the flower visiting bees were observed. The 3 floral morphs were found at the following proportions: 16 long-, 37 mid-, and 34 shortstyled individuals (n=87). Anthesis lasted one day (6:30 AM to 3 PM). No fruit was formed in the autogamy test; thus, pollination was dependent on the visitors. The pollen grain size varied between the stamens and morphs and formed subsets in accordance with the stigma height (long/mid/short). We collected 165 bees from 30 species visiting the flowers.Hypanthium divaricatumwas the most abundant bee species (34%) and the males were often observed patrolling the flowers in search of females for mating. Analysis of the pollen loads from 34 females showed that 27 carriedO. cytisoidespollen. The most frequent bees that carriedO. cytisoidespollen grains on their bodies were considered pollinator agents, responsible for transferring pollen grains among the floral morphs.
Construction of Optimal Derivative‐Free Techniques without Memory
Authors: Soleymani F. , Babajee D. K. R. , Shateyi S. , Motsa S. S.
Published: November 2012

Construction of iterative processes without memory, which are both optimal according to the Kung‐Traub hypothesis and derivative‐free, is considered in this paper. For this reason, techniques with four and five function evaluations per iteration, which reach to the optimal orders eight and sixteen, respectively, are discussed theoretically. These schemes can be viewed as the generalizations of the recent optimal derivative‐free family of Zheng et al. in (2011). This procedure also provides an n‐step family using n + 1 function evaluations per full cycle to possess the optimal order 2n. The analytical proofs of the main contributions are given and numerical examples are included to confirm the outstanding convergence speed of the presented
iterative methods using only few function evaluations. The second aim of this work will be furnished when a hybrid algorithm for capturing all the zeros in an interval has been proposed. The novel algorithm could deal with nonlinear functions having finitely many zeros in an interval.
Sodium-Glucose Cotransporter Inhibition Prevents Oxidative Stress in the Kidney of Diabetic Rats
Authors: Osorio Horacio , Coronel Israel , Arellano Abraham , Pacheco Ursino , Bautista Rocío , Franco Martha , Escalante Bruno
Published: November 2012

The hyperglycemia triggers several chronic diabetic complications mediated by increased oxidative stress that eventually causes diabetic nephropathy. The aim of this study was to examine if the sodium-glucose cotransporter (SGLT2) inhibition prevents the oxidative stress in the kidney of diabetic rats.Methods. The diabetic rat model was established by intraperitoneal injection of streptozotocin (50 mg/kg). The inhibition of SGLT2 was induced by daily subcutaneous administration of phlorizin (0.4 g/kg). Oxidative stress was assessed by catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities and by immunohistochemical analysis of 3-nitrotyrosine (3-NT).Results. Streptozotocin-induced diabetes caused hyperglycemia and lower body weight. The CAT activity decreased in cortex and medulla from diabetic rats; in contrast, the GPx activity increased. Furthermore the 3-NT staining of kidney from diabetic rats increased compared to control rats. The inhibition of SGLT2 decreased hyperglycemia. However, significant diuresis and glucosuria remain in diabetic rats. The phlorizin treatment restores the CAT and GPX activities and decreases 3-NT staining.Conclusion. The inhibition of SGLT2 by phlorizin prevents the hyperglycemia and oxidative stress in kidney of diabetic rats, suggesting a prooxidative mechanism related to SGLT2 activity.
Assessment of Learners’ Motivation during Interactions with Serious Games: A Study of Some Motivational Strategies in Food-Force
Authors: Derbali Lotfi , Frasson Claude
Published: November 2012

This study investigated motivational strategies and the assessment of learners’ motivation during serious gameplay. Identifying and intelligently assessing the effects that these strategies may have on learners are particularly relevant for educational computer-based systems. We proposed, therefore, the use of physiological sensors, namely, heart rate, skin conductance, and electroencephalogram (EEG), as well as a theoretical model of motivation (Keller’s ARCS model) to evaluate six motivational strategies selected from a serious game called Food-Force. Results from nonparametric tests and logistic regressions supported the hypothesis that physiological patterns and their evolution are suitable tools to directly and reliably assess the effects of selected strategies on learners’ motivation. They showed that specific EEG “attention ratio” was a significant predictor of learners’ motivation and could relevantly evaluate motivational strategies, especially those associated with theAttentionandConfidencecategories of the ARCS model of motivation. Serious games and intelligent systems can greatly benefit from using these results to enhance and adapt their interventions.
Increased Toll-Like Receptor 2 Expression in Peptidoglycan-Treated Blood Monocytes Is Associated with Insulin Resistance in Patients with Nondiabetic Rheumatoid Arthritis
Authors: Wang Shih-Wei , Lin Tsun-Mei , Wang Chiou-Huey , Liu Hsiao-Han , Houng Jer-Yiing
Published: November 2012

The close relationship between increased TLR-2 expression in blood monocytes and insulin resistance in RA patients is shown in this study. Traditional risk factors for metabolic disorders, including the waist circumstance, body mass index (BMI), triglyceride (TG), and ratio of TG to high density lipoprotein (HDL) cholesterol, were closely correlated with HOMA (homoeostasis model assessment) index in patients with nondiabetic RA. Expressions of TLR2 in peripheral blood monocytes, following stimulation with peptidoglycan which is known as a TLR2 agonist, were closely correlated with the HOMA index, TNF-α, and IL-6 concentrations. Accordingly, TLR-2 receptor and its related inflammatory cytokines could be potential therapeutic targets in managing insulin resistance in RA patients.
Epithelial-to-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma and Pancreatic Tumor Cell Lines: The Role of Neutrophils and Neutrophil-Derived Elastase
Authors: Große-Steffen Thomas , Giese Thomas , Giese Nathalia , Longerich Thomas , Schirmacher Peter , Hänsch G. Maria , Gaida Matthias M.
Published: November 2012

Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with fibrosis and a prominent inflammatory infiltrate in the desmoplastic stroma. Moreover, in PDAC, an epithelial-to-mesenchymal transition (EMT) is observed. To explore a possible connection between the infiltrating cells, particularly the polymorphonuclear neutrophils (PMN) and the tumor cell transition, biopsies of patients with PDAC (n=115) were analysed with regard to PMN infiltration and nuclear expression ofβ-catenin and of ZEB1, well-established indicators of EMT. In biopsies with a dense PMN infiltrate, a nuclear accumulation ofβ-catenin and of ZEB1 was observed. To address the question whether PMN could induce EMT, they were isolated from healthy donors and were cocultivated with pancreatic tumor cells grown as monolayers. Rapid dyshesion of the tumor cells was seen, most likely due to an elastase-mediated degradation of E-cadherin. In parallel, the transcription factor TWIST was upregulated,β-catenin translocated into the nucleus, ZEB1 appeared in the nucleus, and keratins were downregulated. EMT was also induced when the tumor cells were grown under conditions preventing attachment to the culture plates. Here, also in the absence of elastase, E-cadherin was downmodulated. PMN as well as prevention of adhesion induced EMT also in liver cancer cell line. In conclusion, PMN via elastase induce EMTin vitro, most likely due to the loss of cell-to-cell contact. Because in pancreatic cancers the transition to a mesenchymal phenotype coincides with the PMN infiltrate, a contribution of the inflammatory response to the induction of EMT and—by implication—to tumor progression is possible.
Convergence Theorems for a Common Point of Solutions of Equilibrium and Fixed Point of Relatively Nonexpansive Multivalued Mapping Problems
Authors: Zegeye H. , Shahzad N.
Published: November 2012

We introduce an iterative process which converges strongly to a common point of set of solutions of equilibrium problem and set of fixed points of finite family of relatively nonexpansive multi‐valued mappings in Banach spaces.
Fractures of the Scapula
Authors: Voleti Pramod B. , Namdari Surena , Mehta Samir
Published: November 2012

The scapula plays a critical role in the association between the upper extremity and the axial skeleton. Fractures of the scapula account for 0.4% to 1% of all fractures and have an annual incidence of approximately 10 per 100,000 inhabitants. Scapular fractures typically result from a high-energy blunt-force mechanism and are often associated with other traumatic injuries. The present review focuses on the presentation, diagnosis, and treatment of fractures of the scapula. Indications for surgical treatment of glenoid fossa, scapular neck, and scapular body fractures are presented in detail. Finally, the authors’ preferred surgical technique, including positioning, approach, reduction, fixation, and post-operative management, is described.
Incidental Findings in Neuroimaging: Ethical and Medicolegal Considerations
Authors: Leung Lawrence
Published: November 2012

With the rapid advances in neurosciences in the last three decades, there has been an exponential increase in the use of neuroimaging both in basic sciences and clinical research involving human subjects. During routine neuroimaging, incidental findings that are not part of the protocol or scope of research agenda can occur and they often pose a challenge as to how they should be handled to abide by the medicolegal principles of research ethics. This paper reviews the issue from various ethical (do no harm, general duty to rescue, and mutual benefits and owing) and medicolegal perspectives (legal liability, fiduciary duties, Law of Tort, and Law of Contract) with a suggested protocol of approach.
Biochemical Characterization of Coriander Cakes Obtained by Extrusion
Authors: Sriti Jazia , Neffati Manel , Msaada Kamel , Talou Thierry , Marzouk Brahim
Published: November 2012

This study was designed to examine the effect of operating conditions such as nozzle diameter on fatty acid, sterol, and tocol composition of coriander cakes. Eight fatty acids were identified, with petroselinic acid accounting for 75–77% of the total fatty acids, followed by linoleic, oleic, and palmitic acids, accounting for 12‐13%, 5%, and 3%, respectively, of the total fatty acids. β‐Sitosterol was the major sterol in all oils with 33–35% of total sterols. The next major sterols in all oils were stigmasterol (24% of total sterols) and Δ7‐stigmasterol (15% of total sterols). Coriander cake contained higher amounts of total tocotrienol where γ‐tocotrienol was the main compound.
Resistance to Irreversible EGF Receptor Tyrosine Kinase Inhibitors through a Multistep Mechanism Involving the IGF1R Pathway
Authors: Cortot Alexis B. , Repellin Claire E. , Shimamura Takeshi , Capelletti Marzia , Zejnullahu Kreshnik , Ercan Dalia , Christensen James G. , Wong Kwok-Kin , Gray Nathanael S. , Jänne Pasi A.
Published: November 2012

The clinical efficacy of EGF receptor (EGFR) kinase inhibitors gefitinib and erlotinib is limited by the development of drug resistance. The most common mechanism of drug resistance is the secondary EGFR T790M mutation. Strategies to overcome EGFR T790M-mediated drug resistance include the use of mutant selective EGFR inhibitors, including WZ4002, or the use of high concentrations of irreversible quinazoline EGFR inhibitors such as PF299804. In the current study, we develop drug-resistant versions of the EGFR-mutant PC9 cell line, which reproducibly develops EGFR T790M as a mechanism of drug resistance to gefitinib. Neither PF299804-resistant nor WZ4002-resistant clones of PC9 harbor EGFR T790M. Instead, they have shown activated insulin-like growth factor receptor (IGF1R) signaling as a result of loss of expression of IGFBP3 with the IGF1R inhibitor, BMS 536924, restoring EGFR inhibitor sensitivity. Intriguingly, prolonged exposure to either PF299804 or WZ4002 results in the emergence of a more drug-resistant subclone that exhibits ERK activation. A MEK inhibitor, CI-1040, partially restores sensitivity to the EGFR/IGF1R inhibitor combination. Moreover, an IGF1R or MEK inhibitor used in combination with either PF299804 or WZ4002 completely prevents the emergence of drug-resistant clones in this model system. Our studies suggest that more effective means of inhibiting EGFR T790M will prevent the emergence of this common drug resistance mechanism in EGFR-mutant non–small cell lung cancer. However, multiple drug resistance mechanisms can still emerge. Preventing the emergence of drug resistance, by targeting pathways that become activated in resistant cancers, may be a more effective clinical strategy. Cancer Res; 73(2); 834–43. ©2012 AACR.
Dissociating the Cognitive Effects of Levodopa versus Dopamine Agonists in a Neurocomputational Model of Learning in Parkinson’s Disease
Authors: Moustafa Ahmed A. , Herzallah Mohammad M. , Gluck Mark A.
Published: November 2012

Background/Aims: Levodopa and dopamine agonists have different effects on the motor, cognitive, and psychiatric aspects of Parkinson’s disease (PD). Methods: Using a computational model of basal ganglia (BG) and prefrontal cortex (PFC) dopamine, we provide a theoretical synthesis of the dissociable effects of these dopaminergic medications on brain and cognition. Our model incorporates the findings that levodopa is converted by dopamine cells into dopamine, and thus activates prefrontal and striatal D1 and D2 dopamine receptors, whereas antiparkinsonian dopamine agonists directly stimulate D2 receptors in the BG and PFC (although some have weak affinity to D1 receptors). Results: In agreement with prior neuropsychological studies, our model explains how levodopa enhances, but dopamine agonists impair or have no effect on, stimulus-response learning and working memory. Conclusion: Our model explains how levodopa and dopamine agonists have differential effects on motor and cognitive processes in PD.
Performance Comparison of Affymetrix SNP6.0 and Cytogenetic 2.7M Whole-Genome Microarrays in Complex Cancer Samples
Authors: Bødker J.S. , Gyrup C. , Johansen P. , Schmitz A. , Madsen J. , Johnsen H.E. , Bøgsted M. , Dybkær K. , Nyegaard M.
Published: November 2012

The Affymetrix cytogenetic 2.7M whole-genome microarray (Cyto2.7M) detects genomic aberrations. The Cyto2.7M array has increased coverage in regions with cancer-related genes, ∼4-fold reduced processing time, and 5-fold reduced input requirements (100 ng) compared to the commonly used Affymetrix SNP6.0 genome-wide microarray (SNP6.0). We set out to compare the performance of these microarrays on cancer samples containing complex genomic changes. We analyzed genomic DNA from 8 lymphoma samples and 1 blood sample using both SNP6.0 and Cyto2.7M microarrays. We compared the arrays with respect to 4 parameters, including detection of copy number variations (CNV), CNV boundaries, the actual copy number (CN) assigned to the aberrations, and loss of heterozygosity. The CN state of selected regions was validated by quantitative PCR. Very high consistency between arrays on all parameters tested was observed, hence only 30 of 224 aberrations disagreed on the CN state, corresponding to a total of ∼12 Mb or 0.06% of the analyzed base pairs. Thus, the SNP6.0 and Cyto2.7M arrays are equally well suited to detect genomic aberrations in complex samples such as cancer samples. With reduced processing time and lower input requirements, the Cyto2.7M array enables genomic analysis of samples where only limited DNA is available.
Segmental Maternal UPD6 with Prenatal Growth Restriction
Authors: Poke G. , Doody M. , Prado J. , Gattas M.
Published: November 2012

We report a child with segmental maternal uniparental isodisomy of chromosome 6, involving most of the long arm distal to 6q16, detected by SNP microarray. Clinical features include prenatal growth restriction, global developmental delay, and severe gastro-esophageal reflux disease. Maternal uniparental disomy (UPD) of chromosome 6 has previously been reported to cause intrauterine growth restriction. Paternal UPD of this chromosome is well known to cause transient neonatal diabetes mellitus. We discuss reported cases of maternal UPD of chromosome 6 and consider whether our patient’s features may be due to disordered imprinting or unmasking of an autosomal recessive condition.
Bilateral Internal Mammary Artery Grafting Enhances Survival in Diabetic Patients
Authors: Dorman Malcolm J. , Kurlansky Paul A. , Traad Ernest A. , Galbut David L. , Zucker Melinda , Ebra George
Published: November 2012

Background—

The prevalence of diabetes mellitus is increasing at an unprecedented rate, affecting nearly 8% of the population. Previous studies have demonstrated a potential benefit for surgical over interventional revascularization in this group of patients. Similarly, studies have shown the superiority of bilateral internal mammary artery (BIMA) grafting over single internal mammary artery (SIMA) grafting in select populations. However, concerns about sternal wound infection have discouraged the use of BIMA grafting in diabetics. Therefore, we studied the long-term results of BIMA versus SIMA grafting in a large population of diabetic patients in whom BIMA grafting was broadly applied.

Methods and Results—

Between February 1972 and May 1994, 1107 consecutive diabetic patients underwent coronary artery bypass grafting with either SIMA (n=646) or BIMA (n=461) grafting. Optimal matching with the propensity score was used to create matched SIMA (n=414) and BIMA (n=414) cohorts. Cross-sectional follow-up (6 weeks to 30.1 years; mean, 8.9 years) determined long-term survival. There was no difference in operative mortality, sternal wound infection, or total complications between matched SIMA and BIMA groups (operative mortality, 10 of 414 [2.4%] versus 13 of 414 [3.1%];
P
=0.279; sternal wound infection, 7 of 414 [1.7%] versus 13 of 414 [3.1%];
P
=0.179); total complications, 71 of 414 [17.1%] versus 71 of 414 [17.1%];
P
=1.000). Late survival was significantly enhanced with the use of BIMA grafting (median survival: SIMA, 9.8 years versus BIMA, 13.1 years;
P
=0.001). Use of BIMA was found to be associated with late survival on Cox regression (
P
=0.003).

Conclusion—

Compared with SIMA grafting, BIMA grafting in propensity score–matched patients provides diabetics with enhanced survival without any increase in perioperative morbidity or mortality.
Targeted Neuronal Nitric Oxide Synthase Transgene Delivery Into Stellate Neurons Reverses Impaired Intracellular Calcium Transients in Prehypertensive Rats
Authors: Li Dan , Nikiforova Natalia , Lu Chieh-Ju , Wannop Kate , McMenamin Mary , Lee Chee-wan , Buckler Keith J. , Paterson David J.
Published: November 2012

Hypertension is associated with the early onset of cardiac sympathetic hyperresponsiveness and enhanced intracellular Ca
2+
concentration [Ca
2+
]
i
in sympathetic neurons from both prehypertensive and hypertensive, spontaneously hypertensive rats (SHRs). Oxidative stress is a hallmark of hypertension, therefore, we tested the hypothesis that the inhibitory action of the nitric oxide-cGMP pathway on [Ca
2+
]
i
transients is impaired in cardiac sympathetic neurons from the SHR. Stellate ganglia were isolated from young prehypertensive SHRs and age-matched normotensive Wistar-Kyoto rats. [Ca
2+
]
i
was measured by ratiometric fluorescence imaging. Neurons from the prehypertensive SHR ganglia had a significantly higher depolarization evoked [Ca
2+
]
i
transient that was also associated with decreased expression of neuronal nitric oxide synthase (nNOS), β1 subunit of soluble guanylate cyclase and cGMP when compared with the Wistar-Kyoto rat ganglia. Soluble guanylate cyclase inhibition or nNOS inhibition increased [Ca
2+
]
i
in the Wistar-Kyoto rats but had no effect in SHR neurons. A nitric oxide donor decreased [Ca
2+
]
i
in both sets of neurons, although this was markedly less in the SHR. A novel noradrenergic cell specific vector (Ad.PRSx8-nNOS/Cherry) or its control vector (Ad.PRSx8-Cherry) was expressed in sympathetic neurons. In the SHR, Ad.PRSx8-nNOS/Cherry-treated neurons had a significantly reduced peak [Ca
2+
]
i
transient that was associated with increased tissue levels of nNOS protein and cGMP concentration compared with gene transfer of Ad.PRSx8-Cherry alone. nNOS inhibition significantly increased [Ca
2+
]
i
after Ad.PRSx8-nNOS/Cherry expression. We conclude that artificial upregulation of stellate sympathetic nNOS via targeted gene transfer can directly attenuate intracellular Ca
2+
and may provide a novel method for decreasing enhanced cardiac sympathetic neurotransmission.
Aortic Pulse Wave Velocity Predicts Focal White Matter Hyperintensities in a Biracial Cohort of Older Adults
Authors: Rosano Caterina , Watson Nora , Chang YueFang , Newman Anne B. , Aizenstein Howard J. , Du Yan , Venkatraman Vijay , Harris Tamara B. , Barinas-Mitchell Emma , Sutton-Tyrrell Kim
Published: November 2012

Although the cross-sectional relationship of arterial stiffness with cerebral small vessel disease is consistently shown in middle-aged and young-old adults, it is less clear whether these associations remain significant over time in very old adults. We hypothesize that arterial stiffness is longitudinally associated with white matter characteristics, and associations are stronger within watershed areas. Neuroimaging was obtained in 2006–2008 from 303 elderly (mean age 82.9 years, 59% women, 41% black) with pulse wave velocity (PWV) measures in 1997–1998. Multivariable regression models estimated the coefficients for PWV (cm/sec) in relationship to presence, severity, and spatial distribution of white matter hyperintensities (WMH), gray matter volume, and fractional anisotropy from diffusion tensor, adjusting for demographic, cardiovascular risk factors, and diseases from 1997–1998 to 2006–2008. Higher PWV in 1997–1998 was associated with greater WMH volume in 2006–2008 within the left superior longitudinal fasciculus (age and total brain WMH adjusted,
P
=0.023), but not with WMH in other tracts or with fractional anisotropy or gray matter volume from total brain (
P
>0.2). Associations were stronger in blacks than in whites, remaining significant in fully adjusted models. Elderly with WMH in tracts related to processing speed and memory are more likely to have had higher PWV values 10 years prior, before neuroimaging data being available. Future studies should address whether arterial stiffness can serve as an early biomarker of covert brain structural abnormalities and whether early arterial stiffness control can promote successful brain aging, especially in black elderly.
A Contested Asylum System: The European Union between Refugee Protection and Border Control in the Mediterranean Sea
Authors: Klepp Silja
Published: November 2012

During the past few years the border waters between Europe and Africa have become an EU-policy crucible. In the midst of the tightening of EU border controls and refugee protection claims, supranational, national and local actors find themselves in a phase of legal insecurity and negotiation. This article is based on ethnographical research carried out in Libya, Italy and Malta. It sheds light on the different actors’ practices at sea and in the surrounding border region. It also explores how new parameters for refugee protection are emerging in the border regions of the European Union. The article argues that the policy practices of the co-operation between Italy and Libya as well as the informal operational methods carried out in the Mediterranean Sea function as a trailblazer of the overall EU refugee policy. In the long term, some of these practices will affect and change the legal basis and the formal regulations of the European refugee regime. The principle of non-refoulement could first be undermined and then abolished in this process. Using an approach that combines the empirical study of border regions with a legal anthropological perspective, the article analyses the Union’s processes of change and decision-making on local, national and supranational levels and their interconnections.