Data-Driven Inference of Representation Invariants

A representation invariant is a property that holds of all values of abstract type produced by a module. Representation invariants play important roles in software engineering and program verification. In this paper, we develop a counterexample-driven algorithm for inferring a representation invariant that is sufficient to imply a desired specification for a module. The key novelty is a type-directed notion of visible inductiveness, which ensures that the algorithm makes progress toward its goal as it alternates between weakening and strengthening candidate invariants. The algorithm is parameterized by an example-based synthesis engine and a verifier, and we prove that it is sound and complete for first-order modules over finite types, assuming that the synthesizer and verifier are as well. We implement these ideas in a tool called Hanoi, which synthesizes representation invariants for recursive data types. Hanoi not only handles invariants for first-order code, but higher-order code as well. In its back end, Hanoi uses an enumerative synthesizer called Myth and an enumerative testing tool as a verifier. Because Hanoi uses testing for verification, it is not sound, though our empirical evaluation shows that it is successful on the benchmarks we investigated.Comment: 18 Pages, Full version of PLDI 2020 pape

High-Performance Transactional Event Processing

Abstract. This paper presents a transactional framework for low-latency, high-performance, concurrent event processing in Java. At the heart of our framework lies Reflexes, a restricted programming model for highly responsive systems. A Reflex task is an event processor that can run at a higher priority and preempt any other Java thread, including the garbage collector. It runs in an obstruction-free manner with time-oblivious code. We extend Reflexes with a publish/subscribe communication system, itself based on an optimistic transactional event processing scheme, that provides efficient coordination between time-critical, low-latency tasks.We report on the comparison with a commercial JVM, and show that it is possible for tasks to achieve 50 µs response times with way less than 1% of the executions failing to meet their deadlines.

How Developers Use Data Race Detection Tools

Developers need help with multithreaded programming. We investigate how two program analysis tools are used by de-velopers at Google: THREADSAFETY, an annotation-based static data race analysis, and TSAN, a dynamic data race de-tector. The data was collected by interviewing seven veteran industry developers at Google, and provides unique insight into how four different teams use tooling in different ways to help with multithreaded programming. The result is a collec-tion of perceived pros and cons of using THREADSAFETY and TSAN, as well as general issues with multithreading

Serum Calprotectin - A novel diagnostic and prognostic marker in Inflammatory Bowel Diseases

OBJECTIVES: There is an unmet need for novel blood-based biomarkers that offer timely and accurate diagnostic and prognostic testing in inflammatory bowel diseases (IBD). We aimed to investigate the diagnostic and prognostic utility of serum calprotectin (SC) in IBD. METHODS: A total of 171 patients (n=96 IBD, n=75 non-IBD) were prospectively recruited. A multi-biomarker model was derived using multivariable logistic regression analysis. Cox proportional hazards model was derived to assess the contribution of each variable to disease outcomes. RESULTS: SC correlated strongly with current biomarkers, including fecal calprotectin (FC) (n=50, ρ=0.50, P=1.6 × 10−4). SC was the strongest individual predictor of IBD diagnosis (odds ratio (OR): 9.37 (95% confidence interval (CI): 2.82–34.68), P=4.00 × 10−4) compared with other markers (C-reactive protein (CRP): OR 8.52 (95% CI: 2.75–28.63), P=2.80 × 10−4); albumin: OR 6.12 (95% CI: 1.82–22.16), P=0.004). In a subset of 50 patients with paired SC and FC, the area under receiver operating characteristic discriminating IBD from controls was better for FC than for SC (0.99, (95% CI 0.87–1.00) and 0.87 (95% CI:0.78–0.97), respectively; P=0.01). At follow-up (median 342 days; interquartile range: 88–563), SC predicted treatment escalation and/or surgery in IBD (hazard ratio (HR) 2.7, 95% CI: 1.1–4.9), in particular Crohn’s disease (CD) (HR 4.2, 95% CI 1.2–15.3). A model incorporating SC and either CRP or albumin has a positive likelihood ratio of 24.14 for IBD. At 1 year, our prognostic model can predict treatment escalation in IBD in 65% of cases (95% CI: 43–79%) and 80% (95% CI: 31–94%) in CD if ≥2 blood marker criteria are met. CONCLUSIONS: A diagnostic and prognostic model that combines SC and other blood-based biomarkers accurately predicts the inflammatory burden in IBD and has the potential to predict disease and its outcomes. Our data warrant further detailed exploration and validation in large multicenter cohorts

Risk factors for breast cancer in postmenopausal Caucasian and Chinese-Canadian women

Abstract Introduction Striking differences exist between countries in the incidence of breast cancer. The causes of these differences are unknown, but because incidence rates change in migrants, they are thought to be due to lifestyle rather than genetic differences. The goal of this cross-sectional study was to examine breast cancer risk factors in populations with different risks for breast cancer. Methods We compared breast cancer risk factors among three groups of postmenopausal Canadian women at substantially different risk of developing breast cancer - Caucasians (N = 413), Chinese women born in the West or who migrated to the West before age 21 (N = 216), and recent Chinese migrants (N = 421). Information on risk factors and dietary acculturation were collected by telephone interviews using questionnaires, and anthropometric measurements were taken at a home visit. Results Compared to Caucasians, recent Chinese migrants weighed on average 14 kg less, were 6 cm shorter, had menarche a year later, were more often parous, less often had a family history of breast cancer or a benign breast biopsy, a higher Chinese dietary score, and a lower Western dietary score. For most of these variables, Western born Chinese and early Chinese migrants had values intermediate between those of Caucasians and recent Chinese migrants. We estimated five-year absolute risks for breast cancer using the Gail Model and found that risk estimates in Caucasians would be reduced by only 11% if they had the risk factor profile of recent Chinese migrants for the risk factors in the Gail Model. Conclusions Our results suggest that in addition to the risk factors in the Gail Model, there likely are other factors that also contribute to the large difference in breast cancer risk between Canada and China

Structural Basis of PP2A Inhibition by Small t Antigen

The SV40 small t antigen (ST) is a potent oncoprotein that perturbs the function of protein phosphatase 2A (PP2A). ST directly interacts with the PP2A scaffolding A subunit and alters PP2A activity by displacing regulatory B subunits from the A subunit. We have determined the crystal structure of full-length ST in complex with PP2A A subunit at 3.1 Å resolution. ST consists of an N-terminal J domain and a C-terminal unique domain that contains two zinc-binding motifs. Both the J domain and second zinc-binding motif interact with the intra-HEAT-repeat loops of HEAT repeats 3–7 of the A subunit, which overlaps with the binding site of the PP2A B56 subunit. Intriguingly, the first zinc-binding motif is in a position that may allow it to directly interact with and inhibit the phosphatase activity of the PP2A catalytic C subunit. These observations provide a structural basis for understanding the oncogenic functions of ST

Systemic Inflammation in Preclinical Ulcerative Colitis

Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins. Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored. Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1ß, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-¿B, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis. Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors. © 2021 The Author