Miracle-dz/UniFAR-FTUs huggingface dataset:
LReplay: a pending period based deterministic replay scheme

Debugging parallel program is a well-known difficult problem. A promising method to facilitate debugging parallel program is using hardware support to achieve deterministic replay. A hardware-assisted deterministic replay scheme should have a small log size, as well as low design cost, to be feasible for adopting by industrial processors. To achieve the goals, we propose a novel and succinct hardware-assisted deterministic replay scheme named LReplay. The key innovation of LReplay is that instead of recording the logical time orders between instructions or instruction blocks as previous investigations, LReplay is built upon recording the pending period information [6]. According to the experimental results on Godson-3, the overall log size of LReplay is about 0.55B/K-Inst (byte per k-instruction) for sequential consistency, and 0.85B/K-Inst for Godson-3 consistency. The log size is smaller in an order of magnitude than state-of-art deterministic replay schemes incuring no performance loss. Furthermore, LReplay only consumes about $1.3%$ area of Godson-3, since it requires only trivial modifications to the existing components of Godson-3. The above features of LReplay demonstrate the potential of integrating hardware-assisted deterministic replay into future industrial processors.
Development of a Flexible Augmented Prototyping System

In designing physical objects, tangible models play an important part. Recent advances in augmented reality displays show new directions to support this field of prototyping. This paper focuses on the combination of rapid prototyping of physical objects and luminous tangible interfaces: digital imagery is projected on physical models. This yields a number of issues, including the design of the mixed-reality dialogue and the perceived quality of the augmented prototype. A system, called WARP (Workbench for Augmented Rapid Prototyping) is under development; the first implementation employs a turntable supports movement of the object, while a variety of materials and lighting conditions can be applied. Its evaluation yields a number of future issues, including hybrid modeling and optics and location tracking.
Four-Dimensional Neuronal Signaling by Nitric Oxide: A Computational Analysis

Nitric oxide (NO) is now recognized as a transmitter of neurons that express the neuronal isoform of the enzyme nitric oxide synthase. NO, however, violates some of the key tenets of chemical transmission, which is classically regarded as occurring at points of close apposition between neurons. It is the ability of NO to diffuse isotropically in aqueous and lipid environments that has suggested a radically different form of signaling in which the transmitter acts four-dimensionally in space and time, affecting volumes of the brain containing many neurons and synapses. Although “volume signaling” clearly challenges simple connectionist models of neural processing, crucial to its understanding are the spatial and temporal dynamics of the spread of NO within the brain. Existing models of NO diffusion, however, have serious shortcomings because they represent solutions for “point-sources,” which have no physical dimensions. Methods for overcoming these difficulties are presented here, and results are described that show how NO spreads from realistic neural architectures with both simple symmetrical and irregular shapes. By highlighting the important influence of the geometry of NO sources, our results provide insights into the four-dimensional spread of a diffusing messenger. We show for example that reservoirs of NO that accumulate in volumes of the nervous system where NO is not synthesized contribute significantly to the temporal and spatial dynamics of NO spread.
Modelling the spatial heterogeneity and molecular correlates of lymphocytic infiltration in triple-negative breast cancer

Lymphocytic infiltration is associated with a favourable prognosis and predicts response to chemotherapy in many cancer types, including the aggressive triple-negative breast cancer (TNBC). However, it is not well understood owing to the high levels of spatial heterogeneity within tumours, which is difficult to analyse by traditional pathological assessment. This paper describes an unbiased methodology to statistically model the spatial distribution of lymphocytes among tumour cells based on automated analysis of haematoxylin-and-eosin-stained whole-tumour section images, which is applied to two independent TNBC cohorts of 181 patients with matched microarray gene expression data. The novelty of the proposed methodology is the fusion of image analysis and statistical modelling for an integrative understanding of intratumour heterogeneity of lymphocytic infiltration. Using this methodology, a quantitative measure of intratumour lymphocyte ratio is developed and found to be significantly associated with disease-specific survival in both TNBC cohorts independent to standard clinical parameters. The proposed image-based measure compares favourably to a number of gene expression signatures of immune infiltration. In addition, heterogeneous immune infiltration at the morphological level is reflected at the molecular scale and correlated with increased expression of CTLA4, the target of ipilimumab. Taken together, these results support the fusion of high-throughput image analysis and statistical modelling to offer reproducible and robust biomarkers for the objective identification of patients with poor prognosis and treatment options.
Zidovudine (AZT) Monotherapy Selects for the A360V Mutation in the Connection Domain of HIV-1 Reverse Transcriptase

Background We previously demonstrated in vitro that zidovudine (AZT) selects for A371V in the connection domain and Q509L in ribonuclease H (RNase H) domain of HIV-1 reverse transcriptase (RT) which, together with the thymidine analog mutations D67N, K70R and T215F, confer greater than 100-fold AZT resistance. The goal of the current study was to determine whether AZT monotherapy in HIV-1 infected patients also selects the A371V, Q509L or other mutations in the C-terminal domains of HIV-1 RT. Methodology/Principal Findings Full-length RT sequences in plasma obtained pre- and post-therapy were compared in 23 participants who received AZT monotherapy from the AIDS Clinical Trials Group study 175. Five of the 23 participants reached a primary study endpoint. Mutations significantly associated with AZT monotherapy included K70R (p = 0.003) and T215Y (p = 0.013) in the polymerase domain of HIV-1 RT, and A360V (p = 0.041) in the connection domain of HIV-1 RT. HIV-1 drug susceptibility assays demonstrated that A360V, either alone or in combination with thymidine analog mutations, decreased AZT susceptibility in recombinant viruses containing participant-derived full-length RT sequences or site-directed mutant RT. Biochemical studies revealed that A360V enhances the AZT-monophosphate excision activity of purified RT by significantly decreasing the frequency of secondary RNase H cleavage events that reduce the RNA/DNA duplex length and promote template/primer dissociation. Conclusions The A360V mutation in the connection domain of RT was selected in HIV-infected individuals that received AZT monotherapy and contributed to AZT resistance.
Effects of Porphyromonas gingivalis and Escherichia coli lipopolysaccharides on mononuclear phagocytes

The mononuclear phagocyte plays an important role in the regulation of microbe-induced inflammation, in part through its ability to secrete mediators, particularly cytokines, in response to microorganisms and their products. To evaluate the effects of the microbial flora associated with chronic adult periodontitis on cytokine induction, lipopolysaccharide (LPS) from the periodontopathogen Porphyromonas gingivalis was used to stimulate naive and phorbol ester-primed U937 monocytic cells, as well as elutriated human peripheral blood monocytes. We assessed the effect of this LPS, in comparison to that of LPS from Escherichia coli, on cell proliferation, cytokine induction, and surface expression of the LPS receptor CD14. P. gingivalis LPS stimulated proliferation of U937 cells at concentrations of greater than 1 ng/ml, while E. coli LPS inhibited proliferation. Phorbol myristic acid (PMA)-treated U937 cells and elutriated monocytes responded to E. coli LPS activation by producing tumor necrosis factor alpha (TNF-alpha) mRNA and protein; however, P. gingivalis LPS induced greater numbers of TNF-alpha mRNA-positive cells and higher (P < 0.05) levels of protein than did E. coli LPS. Both cell types expressed interleukin-1 beta (IL-1beta) mRNA and protein in response to either LPS treatment. Compared with E. coli LPS, P. gingivalis LPS induced significantly (P < 0.05) higher numbers of IL-1 mRNA-positive U937 cells and elutriated monocytes, as well as production of significantly more (P < 0.05) IL-1 protein by the monocytes. The PMA-treated U937 cells and the monocytes produced high levels of IL-1 receptor antagonist mRNA and protein which were only marginally affected by the LPS preparations. While E. coli LPS induced expression of CD 14 on the surface of PMA-primed U937 cells and monocytes, P. gingivalis LPS exhibited a significantly (P < 0.05) greater ability to enhance receptor levels. Our results indicate that P. gingivalis LPS can activate the mononuclear phagocyte for proliferation, cytokine production, and CD14 expression, providing evidence for the potential of this bacterial component to act as a critical regulatory factor in the chronic inflammatory response associated with periodontitis.
Ten Years of Hoare's Logic: A Survey—Part I

A survey of various results concerning Hoare's approach to proving partial and total correctness of programs is presented. Emphasis is placed on the soundness and completeness issues. Various proof systems for while programs, recursive procedures, local variable declarations, and procedures with parameters, together with the corresponding soundness, completeness, and incompleteness results, are discussed.
Direct comparisons of three alternative plasma fibrinogen assays with the von Clauss assay in prediction of cardiovascular disease and all‐causes mortality: the Scottish Heart Health Extended Cohort

There is strong evidence from meta‐analyses of prospective epidemiological studies that increasing plasma fibrinogen levels are associated with an increasing risk of cardiovascular disease (CVD) and all‐cause mortality. However, there are few published direct comparisons of the several different available fibrinogen assays in association with CVD or mortality. We therefore prospectively compared the standardized von Clauss assay of clottable fibrinogen with three other assays: prothrombin time (PT)‐derived clottable fibrinogen, immunonephelometric fibrinogen, and heat precipitable fibrinogen in the Scottish Heart Health Extended Cohort. Hazard ratios (HRs) for a standard deviation increase in fibrinogen for risk of CVD, adjusted for age and sex, were 1·17 (95% confidence interval [CI] 1·14; 1·21) for the von Clauss assay; 1·19 (1·06; 1·33) for the heat precipitation assay; 1·16 (1·01; 1·35) for the PT‐derived assay; and 1·28 (1·10; 1·51) for the immunonephelometric assay. HRs for all‐cause mortality were 1·21 (1·18; 1·24); 1·13 (1·01; 1·26), 1·17 (1·00; 1·37) and 1·17 (0·99; 1·39), respectively. No significant differences were observed between the assays in such comparisons. We therefore conclude that the choice between plasma fibrinogen assays in routine clinical haematology and biochemistry laboratories should depend on practical factors, and not on expected differences in the strength of associations.
Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes

Background—DNA variants appearing to predispose to drug-associated “acquired” long-QT syndrome (aLQTS) have been reported in congenital long-QT disease genes. However, the incidence of these genetic risk factors has not been systematically evaluated in a large set of patients with aLQTS. We have previously identified functionally important DNA variants in genes encoding K+ channel ancillary subunits in 11% of an aLQTS cohort. Methods and Results—The coding regions of the genes encoding the pore-forming channel proteins KvLQT1, HERG, and SCN5A were screened in (1) the same aLQTS cohort (n=92) and (2) controls, drawn from patients tolerating QT-prolonging drugs (n=67) and cross sections of the Middle Tennessee (n=71) and US populations (n=90). The frequency of three common nonsynonymous coding region polymorphisms was no different between aLQTS and control subjects, as follows: 24% versus 19% for H558R (SCN5A), 3% versus 3% for R34C (SCN5A), and 14% versus 14% for K897T (HERG). Missense mutations (absent in controls) were identified in 5 of 92 patients. KvLQT1 and HERG mutations (one each) reduced K+ currents in vitro, consistent with the idea that they augment risk for aLQTS. However, three SCN5A variants did not alter INa, which argues that they played no role in the aLQTS phenotype. Conclusions—DNA variants in the coding regions of congenital long-QT disease genes predisposing to aLQTS can be identified in ≈10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits.
Strategies of mapping between gesture data and synthesis model parameters using perceptual spaces

This paper is about mapping strategies between gesture data and synthesis model parameters by means of perceptual spaces. We define three layers in the mapping chain: from gesture data to gesture perceptual space, from sound perceptual space to synthesis model parameters, and between the two perceptual spaces. This approach makes the implementation highly modular. Both perceptual spaces are developed and depicted with their features. To get a simple mapping between the gesture perceptual subspace and the sound perceptual subspace, we need to focus our attention on the two other mappings. We explain the mapping types: explicit/implicit, static/dynamic. We also present the technical and aesthetical limits introduced by mapping. Some practical examples are given of the use of perceptual spaces in experiments done at LMA in a musical context. Finally, we discuss several implications of the mapping strategies: the influence of chosen mapping limits onto performers' virtuosity, and the incidence of mapping on the learning process with virtual instruments and on improvisation possibilities.
Do pathogens become more virulent as they spread? Evidence from the amphibian declines in Central America

The virulence of a pathogen can vary strongly through time. While cyclical variation in virulence is regularly observed, directional shifts in virulence are less commonly observed and are typically associated with decreasing virulence of biological control agents through coevolution. It is increasingly appreciated, however, that spatial effects can lead to evolutionary trajectories that differ from standard expectations. One such possibility is that, as a pathogen spreads through a naive host population, its virulence increases on the invasion front. In Central America, there is compelling evidence for the recent spread of pathogenic Batrachochytrium dendrobatidis (Bd) and for its strong impact on amphibian populations. Here, we re-examine data on Bd prevalence and amphibian population decline across 13 sites from southern Mexico through Central America, and show that, in the initial phases of the Bd invasion, amphibian population decline lagged approximately 9 years behind the arrival of the pathogen, but that this lag diminished markedly over time. In total, our analysis suggests an increase in Bd virulence as it spread southwards, a pattern consistent with rapid evolution of increased virulence on Bd's invading front. The impact of Bd on amphibians might therefore be driven by rapid evolution in addition to more proximate environmental drivers.
Systematizing pragmatic software reuse

Many software reuse tasks involve reusing source code that was not designed in a manner conducive to those tasks, requiring that ad hoc modifications be applied. Such pragmatic reuse tasks are a reality in disciplined industrial practice; they arise for a variety of organizational and technical reasons. To investigate a pragmatic reuse task, a developer must navigate through, and reason about, source code dependencies in order to identify program elements that are relevant to the task and to decide how those elements should be reused. The developer must then convert his mental model of the task into a set of actions that he can perform. These steps are poorly supported by modern development tools and practices. We provide a model for the process involved in performing a pragmatic reuse task, including the need to capture (mentally or otherwise) the developer's decisions about how each program element should be treated: this is a pragmatic-reuse plan. We provide partial support for this model via a tool suite, called Gilligan; other parts of the model are supported via standard IDE tools. Using a pragmatic-reuse plan, Gilligan can semiautomatically transform the selected source code from its originating system and integrate it into the developer's system. We have evaluated Gilligan through a series of case studies and experiments (each involving industrial developers) using a variety of source systems and tasks; we report in particular on a previously unpublished, formal experiment. The results show that pragmatic-reuse plans are a robust metaphor for capturing pragmatic reuse intent and that, relative to standard IDE tools, Gilligan can (1) significantly decrease the time that developers require to perform pragmatic reuse tasks, (2) increase the likelihood that developers will successfully complete pragmatic reuse tasks, (3) decrease the time required by developers to identify infeasible reuse tasks, and (4) improve developers' sense of their ability to manage the risk in such tasks.
A replicated molecular genetic basis for subtyping antisocial behavior in children with attention-deficit/hyperactivity disorder.

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder that in some cases is accompanied by antisocial behavior. OBJECTIVE To test if variations in the catechol O-methyltransferase gene (COMT) would prove useful in identifying the subset of children with ADHD who exhibit antisocial behavior. DESIGN Three independent samples composed of 1 clinical sample of ADHD cases and 2 birth cohort studies. PARTICIPANTS Participants in the clinical sample were drawn from child psychiatry and child health clinics in England and Wales. The 2 birth cohort studies included 1 sample of 2232 British children born in 1994-1995 and a second sample of 1037 New Zealander children born in 1972-1973. MAIN OUTCOME MEASURES Diagnosis of ADHD and measures of antisocial behavior. RESULTS We present replicated evidence that the COMT valine/methionine polymorphism at codon 158 (COMT Val158Met) was associated with phenotypic variation among children with ADHD. Across the 3 samples, valine/valine homozygotes had more symptoms of conduct disorder, were more aggressive, and were more likely to be convicted of criminal offenses compared with methionine carriers. CONCLUSIONS The findings confirm the presence of genetic heterogeneity in ADHD and illustrate how genetic information may provide biological evidence pointing to clinical subtypes.
SoK: Research Perspectives and Challenges for Bitcoin and Cryptocurrencies

Bit coin has emerged as the most successful cryptographic currency in history. Within two years of its quiet launch in 2009, Bit coin grew to comprise billions of dollars of economic value despite only cursory analysis of the system's design. Since then a growing literature has identified hidden-but-important properties of the system, discovered attacks, proposed promising alternatives, and singled out difficult future challenges. Meanwhile a large and vibrant open-source community has proposed and deployed numerous modifications and extensions. We provide the first systematic exposition Bit coin and the many related crypto currencies or 'altcoins. ' Drawing from a scattered body of knowledge, we identify three key components of Bit coin's design that can be decoupled. This enables a more insightful analysis of Bit coin's properties and future stability. We map the design space for numerous proposed modifications, providing comparative analyses for alternative consensus mechanisms, currency allocation mechanisms, computational puzzles, and key management tools. We survey anonymity issues in Bit coin and provide an evaluation framework for analyzing a variety of privacy-enhancing proposals. Finally we provide new insights on what we term disinter mediation protocols, which absolve the need for trusted intermediaries in an interesting set of applications. We identify three general disinter mediation strategies and provide a detailed comparison.
Dysfunctional Corin I555(P568) Allele Is Associated With Impaired Brain Natriuretic Peptide Processing and Adverse Outcomes in Blacks With Systolic Heart Failure: Results From the Genetic Risk Assessment in Heart Failure Substudy

Background—Corin, a transmembrane serine protease expressed in cardiomyocytes, cleaves pro–atrial natriuretic peptide and pro–brain natriuretic peptide (BNP) into biologically active peptide hormones. The minor corin I555(P568) allele, defined by the T555I and Q568P mutations, is common in persons of African ancestry and associated with increased risk for hypertension and cardiac concentric hypertrophy. The corin gene product containing the T555I and Q568P mutations has significantly reduced natriuretic peptide processing capacity. We hypothesized that the corin I555(P568) allele would be associated with adverse outcomes and impaired BNP processing in blacks with systolic heart failure. Methods and Results—This is a retrospective study of 354 subjects in the African American Heart Failure Trial Genetic Risk Assessment in Heart Failure substudy. In the corin variant group (n=50) compared with corin nonvariant group (n=300), BNP-32 (amino acids 77 to 108) was lower (190 pg/mL versus 340 pg/mL, P=0.007), but the ratio of unprocessed BNP1 to 108/processed BNP-32 was significantly higher (P=0.05). Stratified analyses were conducted because of evidence of significant interaction between the corin I555(P568) allele and treatment assignment. In the placebo arm, multivariable analysis demonstrated that the corin I555(P568) allele was associated with increased risk for death or heart failure hospitalization (relative risk 3.49; 95% CI, 1.45 to 8.39; P=0.005); however, in the treatment arm (fixed-dose combination isosorbide-dinitrate/hydralazine), the corin I555(P568) allele was not associated with adverse outcomes. Conclusions—We have identified a pharmacogenomic interaction in blacks with systolic heart failure. The corin I555(P568) allele is associated with an increased risk for death or heart failure hospitalization in patients receiving standard neurohormonal blockade, but the addition of fixed-dose combination isosorbide-dinitrate/hydralazine ameliorates this risk. A plausible mechanism for this pharmacogenomic interaction is the impaired processing of BNP in carriers of the corin I555(P568) allele as compared with noncarriers.