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Prevention of canine Leishmania infantum infection is critical to management of visceral leishmaniasis in people living in endemic areas of Brazil. A bill (PL 1738/11), currently under consideration, proposes to establish a national vaccination policy against canine leishmaniasis in Brazil. However, there is no solid scientific evidence supporting the idea that this could reduce transmission from infected vaccinated dogs to sand flies to a level that would significantly reduce the risk of L. infantum infection or visceral leishmaniasis in humans. Thus, we advocate that insecticide-impregnated collars should the first line protective measure for public health purposes and that vaccines are applied on a case-by-case, optional basis for individual dog protection.

Configurable systems typically use #ifdefs to denote variability. Generating and compiling all configurations may be time-consuming. An alternative consists of using variability-aware parsers, such as TypeChef. In practice, compiling complete systems may be costly. Therefore, developers use sampling strategies to compile only a subset of the configurations. In our previous work, we propose a change-aware per-file analysis to compile configurable systems with #ifdefs by analyzing only configurations impacted by a code change (transformation). We implement it in a tool called CheckConfigMX , which reports the new compilation errors introduced by the transformation. We extend our previous work by performing an empirical study to evaluate 7,891 transformations applied to 32 files of configurable systems such as Linux and OpenSSL. CheckConfigMX finds 1,699 compilation errors of 34 types introduced by 155 distinct developers in 756 commits (9.19% of the analyzed transformations). In our study, the tool reduces by at least 50% (an average of 99%) the effort of evaluating the analyzed transformations compared to the exhaustive approach and without considering a feature model. In addition, we also evaluate the effectiveness of CheckConfigMX by using mutation testing. We generate 11,229 mutants by applying eight mutant operators to some evaluated files. CheckConfigMX kills all mutants. Therefore, it may help developers to reduce compilation effort to evaluate fine-grained transformations applied to configurable systems with #ifdefs .

Context: During software development, developers can make assumptions that guide their development practices to avoid bug-introducing changes. For instance, developers may consider that code with low test coverage is more likely to introduce bugs; and thus, focus their attention on that code to avoid bugs, neglecting other factors during the software development process. However, there is no knowledge about the relevance of these assumptions for developers. Objective: This study investigates the developers’ viewpoints on the relevance of certain assumptions to avoid bug-introducing changes. In particular, we analyze which assumptions developers can make during software development; how relevant these assumptions are for developers; the common viewpoints among developers regarding these assumptions; and the main reasons for developers to put more/less relevance for some assumptions. Method: We applied the Q-methodology, a mixed-method from the psychometric spectrum, to investigate the relevance of assumptions and extract the developers’ viewpoints systematically. We involved 41 developers analyzing 41 assumptions extracted from literature and personal interviews. Results: We identified five viewpoints among developers regarding their assumptions around bug-introducing changes. Despite the differences among the viewpoints, there is also consensus, for example, regarding the importance of being aware of changes invoking high number of features. Moreover, developers rely on personal and technical reasons to put relevance on some assumptions. Conclusion: These findings are valuable knowledge for practitioners and researchers towards future research directions and development practices improvements.

The Android mining sandbox approach consists in running dynamic analysis tools on a benign version of an Android app and recording every call to sensitive APIs. Later, one can use this information to (a) prevent calls to other sensitive APIs (those not previously recorded) or (b) run the dynamic analysis tools again in a different version of the app -- in order to identify possible malicious behavior. Although the use of dynamic analysis for mining Android sandboxes has been empirically investigated before, little is known about the potential benefits of combining static analysis with the mining sandbox approach for identifying malicious behavior. As such, in this paper we present the results of two empirical studies: The first is a non-exact replication of a previous research work from Bao et al., which compares the performance of test case generation tools for mining Android sandboxes. The second is a new experiment to investigate the implications of using taint analysis algorithms to complement the mining sandbox approach in the task to identify malicious behavior. Our study brings several findings. For instance, the first study reveals that a static analysis component of DroidFax (a tool used for instrumenting Android apps in the Bao et al. study) contributes substantially to the performance of the dynamic analysis tools explored in the previous work. The results of the second study show that taint analysis is also practical to complement the mining sandboxes approach, improve the performance of the later strategy in at most 28.57%., 31 pages, 6 figures. Paper accepted for publication in The Journal of Systems & Software

Context Refactoring is a key practice in agile methodologies used by a number of developers, and available in popular IDEs. However, it is unclear whether the refactoring mechanics have the same meaning for developers. Objective In this article, we revisit the refactoring mechanics. Method We conduct a survey with 107 developers of popular Java projects on GitHub. We asked them about the output of seven refactoring types applied to small programs. Results Developers do not expect the same outputs in all questions. The refactoring mechanics is based on developers’ experience for a number of them (71.02%). Some developers (75.70%) use IDEs to apply refactorings. However, the output yielded by the preferred IDE is different from what they want. Conclusion Developers and IDE developers use different mechanics for most refactoring types considered in our survey, and this may impact developers’ communication.

Context: It is common to consider Alloy signatures or UML classes as data types that have a canonical fixed interpretation: the elements of the type correspond to terms recursively generated by the type constructors. However, these language constructs resemble data types but, strictly, they are not. Objective: In this article, we propose an idiom to specify data types in Alloy. Method: We compare our approach to others in the context of checking data refinement using the Alloy Analyzer tool. Results: Some previous studies do not include the generation axiom and may perform unsound analysis. Other studies recommend some optimizations to overcome a limitation in the Alloy Analyzer tool. Conclusion: The problem is not related to the tool but the way data types must be represented in Alloy. This study shows the importance of using automated analyses to test translation between different language constructs.

Context: Mutation analysis is a popular but costly approach to assess the quality of test suites. One recent promising direction in reducing costs of mutation analysis is to identify redundant mutations, i.e., mutations that are subsumed by some other mutations. A previous approach found redundant mutants manually through truth tables but it cannot be applied to all mutations. Another work derives them using automatic test suite generators but it is a time consuming task to generate mutants and tests, and to execute tests. Objective: This article proposes an approach to discover redundant mutants by proving subsumption relations among method-level mutation operators using weak mutation testing. Method: We conceive and encode a theory of subsumption relations in the Z3 theorem prover for 37 mutation targets (mutations of an expression or statement). Results: We automatically identify and prove a number of subsumption relations using Z3, and reduce the number of mutations in a number of mutation targets. To evaluate our approach, we modified MuJava to include the results of 24 mutation targets and evaluate our approach in 125 classes of 5 large open source popular projects used in prior work. Our approach correctly discards mutations in 75.93% of the cases, and reduces the number of mutations by 71.38%. Conclusions: Our approach offers a good balance between the effort required to derive subsumption relations and the effectiveness for the targets considered in our evaluation in the context of strong mutation testing.

Context: Maintaining software families is not a trivial task. Developers commonly introduce bugs when they do not consider existing dependencies among features. When such implementations share program elements, such as variables and functions, inadvertently using these elements may result in bugs. In this context, previous work focuses only on the occurrence of intraprocedural dependencies, that is, when features share program elements within a function. But at the same time, we still lack studies investigating dependencies that transcend the boundaries of a function, since these cases might cause bugs as well.Objective: This work assesses to what extent feature dependencies exist in actual software families, answering research questions regarding the occurrence of intraprocedural, global, and interprocedural dependencies and their characteristics.Method: We perform an empirical study covering 40 software families of different domains and sizes. We use a variability-aware parser to analyze families source code while retaining all variability information.Results: Intraprocedural and interprocedural feature dependencies are common in the families we analyze: more than half of functions with preprocessor directives have intraprocedural dependencies, while over a quarter of all functions have interprocedural dependencies. The median depth of interprocedural dependencies is 9.Conclusion: Given these dependencies are rather common, there is a need for tools and techniques to raise developers awareness in order to minimize or avoid problems when maintaining code in the presence of such dependencies. Problems regarding interprocedural dependencies with high depths might be harder to detect and fix.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder linked to the expression of mutant huntingtin. Bioenergetic dysfunction has been described to contribute to HD pathogenesis. Thus, treatment paradigms aimed to ameliorate energy deficits appear to be suitable candidates in HD. In previous studies, we observed protective effects of insulin growth factor-1 (IGF-1) in YAC128 and R6/2 mice, two HD mouse models, whereas IGF-1 and/or insulin halted mitochondrial-driven oxidative stress in mutant striatal cells and mitochondrial dysfunction in HD human lymphoblasts. Here, we analyzed the effect of IGF-1 versus insulin on energy metabolic parameters using striatal cells derived from HD knock-in mice and primary cortical cultures from YAC128 mice. STHdh(Q111/Q111) cells exhibited decreased ATP/ADP ratio and increased phosphocreatine levels. Moreover, pyruvate levels were increased in mutant cells, most probably in consequence of a decrease in pyruvate dehydrogenase (PDH) protein expression and increased PDH phosphorylation, reflecting its inactivation. Insulin and IGF-1 treatment significantly decreased phosphocreatine levels, whereas IGF-1 only decreased pyruvate levels in mutant cells. In a different scenario, primary cortical cultures derived from YAC128 mice also displayed energetic abnormalities. We observed a decrease in both ATP/ADP and phosphocreatine levels, which were prevented following exposure to insulin or IGF-1. Furthermore, decreased lactate levels in YAC128 cultures occurred concomitantly with a decline in lactate dehydrogenase activity, which was ameliorated with both insulin and IGF-1. These data demonstrate differential HD-associated metabolic dysfunction in striatal cell lines and primary cortical cultures, both of which being alleviated by insulin and IGF-1.

Protein 14-3-3 is a reliable marker of rapid neuronal damage, specifically increased in cerebrospinal fluid (CSF) of sporadic Creutzfeldt-Jakob disease (sCJD) patients. Its detection is usually performed by Western Blot (WB), prone to methodological issues. Our aim was to evaluate the diagnostic performance of a recently developed quantitative enzyme-linked immunosorbent (ELISA) assay for 14-3-3γ, in comparison with WB and other neurodegeneration markers. CSF samples from 145 patients with suspicion of prion disease, later classified as definite sCJD (n=72) or Non-prion diseases (Non-CJD; n=73) comprised our population. 14-3-3 protein was determined by WB and ELISA. Total Tau (t-Tau) and phosphorylated Tau (p-Tau) were also evaluated. Apolipoprotein E gene (ApoE) and prionic protein gene (PRNP) genotyping was assessed. ELISA 14-3-3γ levels were significantly increased in sCJD compared to Non-CJD patients (p

Huntington's disease (HD) is a polyglutamine-expansion neurodegenerative disorder caused by increased number of CAG repeats in the HTT gene, encoding for the huntingtin protein. The mutation is linked to several intracellular mechanisms, including oxidative stress. Flavones are compounds with a protective role in neurodegenerative pathologies. In the present study we analyzed the protective effect of luteolin (Lut, 3',4',5,7-tetrahydroxyflavone) and four luteolin derivatives bearing 3-alkyl chains of 1, 4, 6 and 10 carbons (Lut-C1, Lut-C4, Lut-C6, Lut-C10) in striatal cells derived from HD knock-in mice expressing mutant Htt (STHdh(Q111/Q111)) versus wild-type striatal cells (STHdh(Q7/Q7)). HD cells showed increased caspase-3-like activity and intracellular reactive oxygen species (ROS), which were significantly decreased following treatment with Lut-C4 and Lut-C6 under concentrations that enhanced cell viability. Interestingly, Lut-C4 and Lut-C6 rose the nuclear levels of phospho(Ser40)-nuclear factor (erythroid-derived-2)-like 2 (Nrf2) and Nrf2/ARE transcriptional activity. Concordantly with increased Nrf2/ARE transcription, Lut-C6 enhanced superoxide dismutase 1 (SOD1) mRNA and SOD activity and glutamate-cysteine ligase catalytic subunit (GCLc) mRNA and protein levels, while Lut-C4 induced mRNA levels of GCLc only in mutant striatal cells. Data suggest that Lut-C6 luteolin derivative (in particular) might be relevant for the development of antioxidant strategies in HD.

Historically, researchers have proposed and applied many techniques to reduce the cost of mutation testing. It has become difficult to find all techniques and to understand the cost-benefit tradeoffs among them, which is critical to transitioning this technology to practice. This paper extends a prior workshop paper to summarize and analyze the current knowledge about reducing the cost of mutation testing through a systematic literature review. We selected 175 peer-reviewed studies, from which 153 present either original or updated contributions. Our analysis resulted in six main goals for cost reduction and 21 techniques. In the last decade, a growing number of studies explored techniques such as selective mutation, evolutionary algorithms, control-flow analysis, and higher-order mutation. Furthermore, we characterized 18 metrics, with particular interest in the number of mutants to be executed, test cases required, equivalent mutants generated and detected, and mutant execution speedup. We found that cost reduction for mutation is increasingly becoming interdisciplinary, often combining multiple techniques. Additionally, measurements vary even for studies that use the same techniques. Researchers can use our results to find more detailed information about particular techniques, and to design comparable and reproducible experiments.

Software maintenance may degrade the software quality. One of the primary ways to reduce undesired effects of maintenance is refactoring, which is a technique to improve software code quality without changing its observable behavior. To safely apply a refactoring, several issues must be considered: (i) identify the code parts that should be improved; (ii) determine the changes that must be applied to the code in order to improve its; (iii) evaluate the corrections impacts on code quality; and (iv) check that the observable behavior of the software will be preserved after applying the corrections. Given the amount of issues to consider, refactoring by hand has been assumed to be an expensive and error-prone task. Therefore, in this paper, we propose an agent-based platform that enables to implement an agent able to autonomously deal with the above mentioned refactoring issues. To evaluate our approach, we performed an empirical study on code smells detection and correction, code quality improvement and preservation of the software observable behavior. To answer our research questions, we analyze 5 releases of Java open source projects, ranging from 166 to 711 classes.

HighlightsWe present a design rule specification language for aspect-oriented systems.We explore its benefits to supporting the modular development of classes and aspects.We discuss how our language improves crosscutting modularity without breaking class modularity.We present a Compiler for LSD and AspectJ (COLA), a tool to automate design rules checking.We evaluate it using a real case study and compare it with other approaches. Aspect-oriented programming is known as a technique for modularizing crosscutting concerns. However, constructs aimed to support crosscutting modularity might actually break class modularity. As a consequence, class developers face changeability, parallel development and comprehensibility problems, because they must be aware of aspects whenever they develop or maintain a class. At the same time, aspects are vulnerable to changes in classes, since there is no contract specifying the points of interaction amongst these elements. These problems can be mitigated by using adequate design rules between classes and aspects. We present a design rule specification language and explore its benefits since the initial phases of the development process, specially with the aim of supporting modular development of classes and aspects. We discuss how our language improves crosscutting modularity without breaking class modularity. We evaluate it using a real case study and compare it with other approaches.

Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by striatal neurodegeneration, involving apoptosis. FK506, an inhibitor of calcineurin (or protein phosphatase 3, formerly known as protein phosphatase 2B), has shown neuroprotective effects in several cellular and animal models of HD. In the present study, we show the protective effects of FK506 in two striatal HD models, primary rat striatal neurons treated with 3-nitropropionic acid (3-NP) and immortalized striatal STHdh cells derived from HD knock-in mice expressing normal (STHdh(7/7)) or full-length mutant huntingtin (FL-mHtt) with 111 glutamines (STHdh(111/111)), under basal conditions and after exposure to 3-NP or staurosporine (STS). In rat striatal neurons, FK506 abolished 3-NP-induced increase in caspase-3 activation, DNA fragmentation/condensation and necrosis. Nevertheless, in STHdh(111/111) cells under basal conditions, FK506 did not prevent, in a significant manner, the release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria, or alter Bax/Bcl-2 ratio, but significantly reverted caspase-3 activation. In STHdh(111/111) cells treated with 0.3mM 3-NP or 25 nM STS, linked to high necrosis, exposure to FK506 exerted no significant effects on caspase-3 activation. However, treatment of STHdh(111/111) cells exposed to 10nM STS with FK506 effectively prevented cell death by apoptosis and moderate necrosis. The results suggest that FK506 may be neuroprotective against apoptosis and necrosis under mild cell death stimulus in the presence of FLmHtt.

We investigated the involvement of mitochondrial-dependent apoptosis in Huntington's disease (HD) vs. control (CTR) cybrids, obtained from the fusion of human platelets with mitochondrial DNA-depleted NT2 cells, and further exposed to 3-nitropropionic acid (3-NP) or staurosporine (STS). Untreated HD cybrids did not exhibit significant modifications in the activity of mitochondrial respiratory chain complexes I-IV or in mtDNA sequence variations suggestive of a primary role in mitochondrial susceptibility in the subpopulation of HD carriers studied. However, a slight decrease in mitochondrial membrane potential and increased formation of intracellular hydroperoxides was observed in HD cybrids under basal conditions. Furthermore, apoptotic nuclei morphology and a moderate increase in caspase-3 activation, as well as increased levels of superoxide ions and hydroperoxides were observed in HD cybrids upon 3-NP or STS treatment. 3-NP-evoked apoptosis in HD cybrids involved cytochrome c and AIF release from mitochondria, which was associated with mitochondrial Bax translocation. CTR cybrids subjected to 3-NP showed increased mitochondrial Bax and Bim levels and the release of AIF, but not cytochrome c, suggesting a different mode of cell death, linked to the loss of membrane integrity. Additionally, increased mitochondrial Bim and Bak levels, and a slight release of cytochrome c in untreated HD cybrids may help to explain their moderate susceptibility to mitochondrial-dependent apoptosis.

A serine protease enzyme was purified from Lachesis muta muta venom, with 40% yield, by gel filtration on Sephadex G-100 and affinity chromatography on Sepharose-agmatin. Homogeneity of the enzyme preparation was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the enzyme had a relative mol. wt of 45,000. The molar extinction coefficient at 280 nm was 62127 (M × cm)−1. The enzyme hydrolysed Bz-Arg-Nan with Ks = 0.233 + 0.08 mM and kcat = 2.80 ± 0.07 sec−1. All the amidines and guanidines tested for their inhibitory effect on thrombin-like enzyme behaved as competitive inhibitors of the enzyme with Ki values in the range 6.2 PM to 42.3 mM for amidines and 0.19 mM to 9.31 mM for guanidines. Dissociation constant values were analysed in terms of the binding of the inhibitors with the subsite S1 the specificity pocket of the enzyme. Ki values were discussed in accordance with those for trypsin inhibition. β-Naphthamidine was the strongest inhibitor, while guanidine was the weakest. The differences among the Ki values were interpreted in terms of the shape of the enzyme active site. For meta- and para-substituted benzamidinium ions a good correlation was found between log 1 K i and sigma Hammett values of the substituents. The substituent effects in the pi-electrons of the benzamidine ring were considered in the frame of Hiickel molecular orbital theory. A model for the binding of p-benzamidine derivatives with the primary specificity S1 subsite of the enzyme active site was proposed.