Dynamic analysis for concurrent modern C/C++ applications

Concurrent programs are executed by multiple threads that run simultaneously. While this allows programs to run more efficiently by utilising multiple processors, it brings with it numerous complications. For example, a program may behave unpredictably or erroneously when multiple threads modify the same memory location in an uncoordinated manner. Issues such as this are difficult to avoid, and when introduced, can break the program in unpredictable ways. Programmers will therefore often turn towards automated tools to aide in the detection of concurrency bugs. The work presented in this thesis aims to provide methods to aid in the creation of tools for the purpose of finding and explaining concurrency bugs. In particular, the following studies have been conducted: Dynamic Race Detection for C/C++11 With the introduction of a weak memory model in C++, many tools that provide dynamic race detection have become outdated, and are unable to adequately identify data races. This work updates an existing data race detection algorithm such that it can identify data races according to this new definition. A method for allowing programs to explore many of the weak behaviours that this new memory model permits is also provided. Record and Replay Much work has gone into record and replay, however, most of this work is focussed on whole system replay, whereby a tool will aim to record as much of the program execution as possible. Contrasting this, the work presented here aims to record as little as possible. This sparse approach has many interesting implications: some programs that were previously out of reach for record and reply become tractable, and vice versa. To back this up, controlled scheduling is introduced that is capable of applying different scheduling strategies, which combined with the record and replay is beneficial for helping to root out bugs. Tool Support Both of the above techniques have been implemented in a tool, tsan11rec, that builds on the tsan dynamic race detection tool. A large experimental evaluation is presented investigating the effectiveness of the enhanced data race detection algorithm when applied to the Firefox and Chromium web browsers, and of the novel approach to record and replay when applied to a diverse set of concurrent applications.Open Acces

Liveness-Driven Random Program Generation

Randomly generated programs are popular for testing compilers and program analysis tools, with hundreds of bugs in real-world C compilers found by random testing. However, existing random program generators may generate large amounts of dead code (computations whose result is never used). This leaves relatively little code to exercise a target compiler's more complex optimizations. To address this shortcoming, we introduce liveness-driven random program generation. In this approach the random program is constructed bottom-up, guided by a simultaneous structural data-flow analysis to ensure that the generator never generates dead code. The algorithm is implemented as a plugin for the Frama-C framework. We evaluate it in comparison to Csmith, the standard random C program generator. Our tool generates programs that compile to more machine code with a more complex instruction mix.Comment: Pre-proceedings paper presented at the 27th International Symposium on Logic-Based Program Synthesis and Transformation (LOPSTR 2017), Namur, Belgium, 10-12 October 2017 (arXiv:1708.07854

Lessons from Toxicology: Developing a 21st‑Century Paradigm for Medical Research

Biomedical developments in the 21st century provide an unprecedented opportunity to gain a dynamic systems-level and human-specific understanding of the causes and pathophysiologies of disease. This understanding is a vital need, in view of continuing failures in health research, drug discovery, and clinical translation. The full potential of advanced approaches may not be achieved within a 20th-century conceptual framework dominated by animal models. Novel technologies are being integrated into environmental health research and are also applicable to disease research, but these advances need a new medical research and drug discovery paradigm to gain maximal benefits. We suggest a new conceptual framework that repurposes the 21st-century transition underway in toxicology. Human disease should be conceived as resulting from integrated extrinsic and intrinsic causes, with research focused on modern human-specific models to understand disease pathways at multiple biological levels that are analogous to adverse outcome pathways in toxicology. Systems biology tools should be used to integrate and interpret data about disease causation and pathophysiology. Such an approach promises progress in overcoming the current roadblocks to understanding human disease and successful drug discovery and translation. A discourse should begin now to identify and consider the many challenges and questions that need to be solved

Metamorphic testing: a review of challenges and opportunities

Metamorphic testing is an approach to both test case generation and test result verification. A central element is a set of metamorphic relations, which are necessary properties of the target function or algorithm in relation to multiple inputs and their expected outputs. Since its first publication, we have witnessed a rapidly increasing body of work examining metamorphic testing from various perspectives, including metamorphic relation identification, test case generation, integration with other software engineering techniques, and the validation and evaluation of software systems. In this paper, we review the current research of metamorphic testing and discuss the challenges yet to be addressed. We also present visions for further improvement of metamorphic testing and highlight opportunities for new research

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Use of an <i>In Vivo</i> FTA Assay to Assess the Magnitude, Functional Avidity and Epitope Variant Cross-Reactivity of T Cell Responses Following HIV-1 Recombinant Poxvirus Vaccination

<div><p>Qualitative characteristics of cytotoxic CD8⁺ T cells (CTLs) are important in measuring the effectiveness of CTLs in controlling HIV-1 infections. Indeed, in recent studies patients who are naturally resistant to HIV-1 infections have been shown to possess CTLs that are of high functional avidity and have a high capacity to recognize HIV epitope variants, when compared to HIV-1 infection progressors. When developing efficacious vaccines, assays that can effectively measure CTL quality specifically <i>in vivo</i> are becoming increasingly important. Here we report the use of a recently developed high-throughput multi-parameter technique, known as the fluorescent target array (FTA) assay, to simultaneously measure CTL killing magnitude, functional avidity and epitope variant cross-reactivity in real time <i>in vivo</i>. In the current study we have applied the FTA assay as a screening tool to assess a large cohort of over 20 different HIV-1 poxvirus vaccination strategies in mice. This screen revealed that heterologous poxvirus prime-boost vaccination regimes (i.e., recombinant fowlpox (FPV)-HIV prime followed by a recombinant vaccinia virus (VV)-HIV booster) were the most effective in generating high quality CTL responses <i>in vivo</i>. In conclusion, we have demonstrated how the FTA assay can be utilized as a cost effective screening tool (by reducing the required number of animals by >100 fold), to evaluate a large range of HIV-1 vaccination strategies in terms of CTL avidity and variant cross-reactivity in an <i>in vivo</i> setting.</p></div

i.n.FPV-HIV/i.m.VV-HIV prime-boost vaccination improves the magnitude, functional avidity and epitope variant cross-reactivity of T-cell responses compared to prime or boost vaccinations alone.

<p>Mice were vaccinated i.n. with FPV-HIV and/or i.m. VV-HIV. Mice were vaccinated with 5×10⁶ PFU of each pox virus vaccine. Booster vaccinations were given 2 weeks post the previous vaccination. T-cell responses were assessed using 252-parameter FTAs as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0105366#pone-0105366-g003" target="_blank">Figure 3</a>. a) % specific killing of FTA cells <i>in vivo</i> by CTL and b) T_H cell activity induced by prime, boost, and prime-boost vaccination regimes, showing all 6 intra-animal replicate responses (upper panels) and means and standard error of means (lower panels) to the various CTL epitopes. b) Mean and standard error of means from a). AUC and EC₅₀ values of: c) CTL responses and: d) T_H cell responses. Values are only shown where EC₅₀ values were calculable as described in the Methods. AUC and EC₅₀ values are depicted as means from 5 intra-animal replicates. The results are representative of seven independent experiments.</p

High throughput screening of HIV-1 poxvirus vaccination regimes for high magnitude, high functional avidity and high epitope variant cross-reactive T cell responses <i>in vivo</i>.

<p>Mice were vaccinated with 24 different vaccine regimes based on all combinations of FPV-HIV and VV-HIV administered either i.n. or i.m. in a prime-boost strategy as outlined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0105366#pone-0105366-t001" target="_blank">Table 1</a>. Mice were vaccinated with 5×10⁶ PFU of each vaccine and booster vaccinations were given 2 weeks after the priming vaccination. T cell responses were assessed using a 252-parameter FTA comprised of fluorescent target cells pulsed with 6 concentrations of the MHC-I binding peptides F2L, F2L mut, HIV Gag, HIV Gag mut, HIV Pol and HIV Env, and the MHC-II binding peptide Gag T_H. FTA target cells were injected i.v. into vaccinated mice 6 days post vaccination and responses assessed after 18 hr <i>in vivo</i> using harvested spleens. % specific killing and T_H cell activity was calculated as described in the Materials and Methods. a) Cumulative magnitude of T cell responses as AUC was plotted as a heat map depicting the range of highest (darkest colour) to lowest (lightest colour) T_H cell (upper panel) or CTL (lower panels) responses. b) AUC heat maps of responses to the three HIV Gag epitopes. c) EC₅₀ values of responses to the three HIV Gag epitopes. Values are only shown where EC₅₀ values were calculable as described in the Materials and Methods. AUC and EC₅₀ values are depicted as means from 6 intra-animal replicates. The results are representative of three independent experiments</p