Lost in Abstraction: Monotonicity in Multi-Threaded Programs (Extended Technical Report)

Monotonicity in concurrent systems stipulates that, in any global state, extant system actions remain executable when new processes are added to the state. This concept is not only natural and common in multi-threaded software, but also useful: if every thread's memory is finite, monotonicity often guarantees the decidability of safety property verification even when the number of running threads is unknown. In this paper, we show that the act of obtaining finite-data thread abstractions for model checking can be at odds with monotonicity: Predicate-abstracting certain widely used monotone software results in non-monotone multi-threaded Boolean programs - the monotonicity is lost in the abstraction. As a result, well-established sound and complete safety checking algorithms become inapplicable; in fact, safety checking turns out to be undecidable for the obtained class of unbounded-thread Boolean programs. We demonstrate how the abstract programs can be modified into monotone ones, without affecting safety properties of the non-monotone abstraction. This significantly improves earlier approaches of enforcing monotonicity via overapproximations

Reactive Chlorine Species Reversibly Inhibit DnaB Protein Splicing in Mycobacteria

Intervening proteins, or inteins, are mobile genetic elements translated within host polypeptides and removed at the protein level by splicing. In protein splicing, a selfmediated reaction removes the intein, leaving only a peptide bond in place. While protein splicing can proceed in the absence of external co-factors, several natural examples of conditional protein splicing (CPS) have emerged. In CPS, the rate and accuracy of splicing is highly-dependent on environmental conditions. As activity of the intein-containing host protein is compromised prior to splicing, and inteins are highly abundant in the microbial world, CPS represents an emerging form of post-translational regulation that is potentially widespread in microbes. Reactive chlorine species (RCS) are highly-potent oxidants encountered by bacteria in a variety of natural environments, including within cells of the mammalian innate immune system. Here, we demonstrate that two naturally occurring RCS, the active compound in bleach, hypocholorous acid, and N-Chlorotaurine, can reversibly block splicing of DnaB inteins from Mycobacterium leprae and Mycobacterium smegmatis in vitro. Further, using a reporter that monitors DnaB intein activity within M. smegmatis, we show that DnaB protein splicing is inhibited by RCS in the native host. DnaB, an essential replicative helicase, is the most common intein-housing protein in bacteria. These results add to the growing list of environmental conditions relevant to the survival of the intein-containing host that influence protein splicing, as well as suggest a novel mycobacterial response to RCS. We propose a model whereby DnaB splicing, and therefore replication, can be reversibly paused when these mycobacteria encounter RCS in nature

Repeatability of brown adipose tissue measurements on FDG PET/CT following a simple cooling procedure for BAT activation

Brown Adipose Tissue (BAT) is present in a significant number of adult humans and can be activated by exposure to cold. Measurement of active BAT presence, activity, and volume are desirable for determining the efficacy of potential treatments intended to activate BAT. The repeatability of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of BAT presence, activity, and volume under controlled conditions has not been extensively studied. Eleven female volunteers underwent double baseline FDG PET imaging performed following a simple, regional cold intervention intended to activate brown fat. The cold intervention involved the lightly-clothed participants intermittently placing their feet on a block of ice while sitting in a cooled room. A repeat study was performed under the same conditions within a target of two weeks. FDG scans were obtained and maximum standardized uptake value adjusted for lean body mass (SULmax), CT Hounsfield units (HU), BAT metabolic volume (BMV), and total BAT glycolysis (TBG) were determined according to the Brown Adipose Reporting Criteria in Imaging STudies (BARCIST) 1.0. A Lin's concordance correlation (CCC) of 0.80 was found for BMV between test and retest imaging. Intersession BAT SULmax was significantly correlated (r = 0.54; p < 0.05). The session #1 mean SULmax of 4.92 ± 4.49 g/mL was not significantly different from that of session #2 with a mean SULmax of 7.19 ± 7.34 g/mL (p = 0.16). BAT SULmax was highly correlated with BMV in test and retest studies (r ≥ 0.96, p < 0.001). Using a simplified ice-block cooling method, BAT was activated in the majority (9/11) of a group of young, lean female participants. Quantitative assessments of BAT SUL and BMV were not substantially different between test and retest imaging, but individual BMV could vary considerably. Intrasession BMV and SULmax were strongly correlated. The variability in estimates of BAT activity and volume on test-retest with FDG should inform sample size choice in studies quantifying BAT physiology and support the dynamic metabolic characteristics of this tissue. A more sophisticated cooling method potentially may reduce variations in test-retest BAT studies

Context-aware counter abstraction

The trend towards multi-core computing has made concurrent software an important target of computer-aided verification. Unfortunately, Model Checkers for such software suffer tremendously from combinatorial state space explosion. We show how to apply counter abstraction to real-world concurrent programs to factor out redundancy due to thread replication. The traditional global state representation as a vector of local states is replaced by a vector of thread counters, one per local state. In practice, straightforward implementations of this idea are unfavorably sensitive to the number of local states. We present a novel symbolic exploration algorithm that avoids this problem by carefully scheduling which counters to track at any moment during the search. We have carried out experiments on Boolean programs, an abstraction promoted by the success of the Slam project. The experiments give evidence of the applicability of our method to realistic programs, and of the often huge savings obtained in comparison to plain symbolic state space exploration, and to exploration optimized by partial-order methods. To our knowledge, our tool marks the first implementation of counter abstraction to programs with non-trivial local state spaces, resulting in a Model Checker for concurrent Boolean programs that promises true scalabilit

Symmetry-Aware Predicate Abstraction for Shared-Variable Concurrent Programs (Extended Technical Report)

Predicate abstraction is a key enabling technology for applying finite-state model checkers to programs written in mainstream languages. It has been used very successfully for debugging sequential system-level C code. Although model checking was originally designed for analyzing concurrent systems, there is little evidence of fruitful applications of predicate abstraction to shared-variable concurrent software. The goal of this paper is to close this gap. We have developed a symmetry-aware predicate abstraction strategy: it takes into account the replicated structure of C programs that consist of many threads executing the same procedure, and generates a Boolean program template whose multi-threaded execution soundly overapproximates the concurrent C program. State explosion during model checking parallel instantiations of this template can now be absorbed by exploiting symmetry. We have implemented our method in the SATABS predicate abstraction framework, and demonstrate its superior performance over alternative approaches on a large range of synchronization programs

Is the emergence of functional ability decline in early old age related to change in speed of cognitive processing and also to change in personality?

To test whether the onset of functional ability decline in early old age is related to change in speed of cognitive processing and personality characteristics. Among 500 randomly sampled participants, the 230 cases that did not show impairment in functional ability were selected. Mean age at Time I was 62.4 years. For this subsample, the emergence of functional ability decline was tracked across a 12-year observation period. The emergence of functional ability decline was related to change in speed of cognitive processing. Decline in functional ability was also related to increased neuroticism and external control, whereas this was not the case regarding extraversión and internal control. Cognitive processing speed was shown to be a predictor of functional disability decline; in addition, the results provided initial evidence that functional ability decline in the early aging phase could be accompanied by changes in personality, particularly neuroticism and external control. (author's abstract

Cross-case knowledge transfer in transformative research: enabling learning in and across sustainability-oriented labs through case reporting

The field of transdisciplinary sustainability research has brought forward a number of approaches aimed at fostering sustainability transformations and generating knowledge through collaborative experimentation in real-world settings. These cases are strongly embedded in their local context and thus the transfer of knowledge remains a key challenge. In this paper, we propose a case reporting approach that supports the structured and coherent reporting of such cases. This scheme is aimed at sustainability-oriented labs, where sustainability solutions are collaboratively developed through experimentation. The scheme focuses the reporting on local contexts, lab processes, and experiments. It is accompanied by a logic model and a set of four principles guiding the reporting procedure. The approach is designed to be general, in that it is applicable to diverse contexts and project designs, while its modularity allows the scheme to be adapted to the needs and specifics of each cases. The scheme was jointly developed and tested by a group of seven Urban Living Labs, each in their own unique context. With our approach we aim to contribute to knowledge transfer from and across cases of sustainability-oriented labs as emerging approaches in action-oriented research bridging the divide of case-based research and (meta) comparison

Androgen receptor as a mediator and biomarker of radioresistance in triple-negative breast cancer.

Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for radiosensitization in triple-negative breast cancer are critically needed. We characterized the radiation therapy response of 21 breast cancer cell lines and paired this radiation response data with high-throughput drug screen data to identify androgen receptor as a top target for radiosensitization. Our radiosensitizer screen nominated bicalutamide as the drug most effective in treating radiation therapy-resistant breast cancer cell lines. We subsequently evaluated the expression of androgen receptor in &gt;2100 human breast tumor samples and 51 breast cancer cell lines and found significant heterogeneity in androgen receptor expression with enrichment at the protein and RNA level in triple-negative breast cancer. There was a strong correlation between androgen receptor RNA and protein expression across all breast cancer subtypes (R2 = 0.72, p &lt; 0.01). In patients with triple-negative breast cancer, expression of androgen receptor above the median was associated with increased risk of locoregional recurrence after radiation therapy (hazard ratio for locoregional recurrence 2.9-3.2)) in two independent data sets, but there was no difference in locoregional recurrence in triple-negative breast cancer patients not treated with radiation therapy when stratified by androgen receptor expression. In multivariable analysis, androgen receptor expression was most significantly associated with worse local recurrence-free survival after radiation therapy (hazard ratio of 3.58) suggesting that androgen receptor expression may be a biomarker of radiation response in triple-negative breast cancer. Inhibition of androgen receptor with MDV3100 (enzalutamide) induced radiation sensitivity (enhancement ratios of 1.22-1.60) in androgen receptor-positive triple-negative breast cancer lines, but did not affect androgen receptor-negative triple-negative breast cancer or estrogen-receptor-positive, androgen receptor-negative breast cancer cell lines. androgen receptor inhibition with MDV3100 significantly radiosensitized triple-negative breast cancer xenografts in mouse models and markedly delayed tumor doubling/tripling time and tumor weight. Radiosensitization was at least partially dependent on impaired dsDNA break repair mediated by DNA protein kinase catalytic subunit. Our results implicate androgen receptor as a mediator of radioresistance in breast cancer and identify androgen receptor inhibition as a potentially effective strategy for the treatment of androgen receptor-positive radioresistant tumors

Reactive Chlorine Species Reversibly Inhibit DnaB Protein Splicing in Mycobacteria

Intervening proteins, or inteins, are mobile genetic elements that are translated within host polypeptides and removed at the protein level by splicing. In protein splicing, a self-mediated reaction removes the intein, leaving a peptide bond in place. While protein splicing can proceed in the absence of external cofactors, several examples of conditional protein splicing (CPS) have emerged. In CPS, the rate and accuracy of splicing are highly dependent on environmental conditions. Because the activity of the intein-containing host protein is compromised prior to splicing and inteins are highly abundant in the microbial world, CPS represents an emerging form of posttranslational regulation that is potentially widespread in microbes. Reactive chlorine species (RCS) are highly potent oxidants encountered by bacteria in a variety of natural environments, including within cells of the mammalian innate immune system. Here, we demonstrate that two naturally occurring RCS, namely, hypochlorous acid (the active compound in bleach) and N-chlorotaurine, can reversibly block splicing of DnaB inteins from Mycobacterium leprae and Mycobacterium smegmatis in vitro. Further, using a reporter that monitors DnaB intein activity within M. smegmatis, we show that DnaB protein splicing is inhibited by RCS in the native host. DnaB, an essential replicative helicase, is the most common intein-housing protein in bacteria. These results add to the growing list of environmental conditions that are relevant to the survival of the intein-containing host and influence protein splicing, as well as suggesting a novel mycobacterial response to RCS. We propose a model in which DnaB splicing, and therefore replication, is paused when these mycobacteria encounter RCS