The problem of programming language concurrency semantics

Despite decades of research, we do not have a satisfactory concurrency semantics for any general-purpose programming language that aims to support concurrent systems code. The Java Memory Model has been shown to be unsound with respect to standard compiler optimisations, while the C/C++11 model is too weak, admitting undesirable thin-air executions. Our goal in this paper is to articulate this major open problem as clearly as is currently possible, showing how it arises from the combination of multiprocessor relaxed-memory behaviour and the desire to accommodate current compiler optimisations. We make several novel contributions that each shed some light on the problem, constraining the possible solutions and identifying new difficulties. First we give a positive result, proving in HOL4 that the existing axiomatic model for C/C++11 guarantees sequentially consistent semantics for simple race-free programs that do not use low-level atomics (DRF-SC, one of the core design goals). We then describe the thin-air problem and show that it cannot be solved, without restricting current compiler optimisations, using any per-candidate-execution condition in the style of the C/C++11 model. Thin-air executions were thought to be confined to programs using relaxed atomics, but we further show that they recur when one attempts to integrate the concurrency model with more of C, mixing atomic and nonatomic accesses, and that also breaks the DRF-SC result. We then describe a semantics based on an explicit operational construction of out-of-order execution, giving the desired behaviour for thin-air examples but exposing further difficulties with accommodating existing compiler optimisations. Finally, we show that there are major difficulties integrating concurrency semantics with the C/C++ notion of undefined behaviour. We hope thereby to stimulate and enable research on this key issue

Use of particle counter system for the optimization of sampling ,identification and decontamination procedures for biological aerosols dispersion in confined environment

Abstract In a CBRNe (Chemical, Biological, Radiological, Nuclear and explosive) scenario, biological agents hardly allow efficient detection/identification because of the incubation time that provides a lag in symptoms outbreak following their dissemination. The detection of atmospheric dispersion of biological agents (i.e.: toxins, viruses, bacteria and so on) is a key issue for the safety of people and security of environment. Another fundamental aspect is related to the efficiency of the sampling method, which leads to the identification of the agent released, in fact an effective sampling method is needed either to identify the contamination and to check for the decontamination procedure. Environmental monitoring is one of the ways to improve fast detection of biological agents; for instance, particle counters with the ability of discriminating between biological and non-biological particles are used for a first warning when the amount of biological particles exceeds a particular threshold. Nevertheless, these systems are not able to distinguish between pathogen and non-pathogen organisms, thus, classical “laboratory” assays are still required to unambiguously identify the particle which triggered the warning signal. In this work, a combination of commercially available equipment for detection and identification of the atmospheric dispersion of biological agents was evaluated in partnership between the Italian Army, the Department of Industrial Engineering and the School of Medicine and Surgery of the University of Rome “Tor Vergata”. The aim of this work, whose results are presented here, was to conduce preliminary studies on the dynamics of biological aerosols fallout after its dispersion, to improve detection, sampling and identification techniques. This will help minimizing the impact of the release of biological agents, guarantee environmental, and people safety and securit

Brahma is required for cell cycle arrest and late muscle gene expression during skeletal myogenesis

Although the two catalytic subunits of the SWI/SNF chromatin-remodeling complex—Brahma (Brm) and Brg1—are almost invariably co-expressed, their mutually exclusive incorporation into distinct SWI/SNF complexes predicts that Brg1- and Brm-based SWI/SNF complexes execute specific functions. Here, we show that Brg1 and Brm have distinct functions at discrete stages of muscle differentiation. While Brg1 is required for the activation of muscle gene transcription at early stages of differentiation, Brm is required for Ccnd1 repression and cell cycle arrest prior to the activation of muscle genes. Ccnd1 knockdown rescues the ability to exit the cell cycle in Brm-deficient myoblasts, but does not recover terminal differentiation, revealing a previously unrecognized role of Brm in the activation of late muscle gene expression independent from the control of cell cycle. Consistently, Brm null mice displayed impaired muscle regeneration after injury, with aberrant proliferation of satellite cells and delayed formation of new myofibers. These data reveal stage-specific roles of Brm during skeletal myogenesis, via formation of repressive and activatory SWI/SNF complexes

Human Olfactory Bulb Neural Stem Cells (Hu-OBNSCs) Can Be Loaded with Paclitaxel and Used to Inhibit Glioblastoma Cell Growth

Exploitation of the potential ability of human olfactory bulb (hOB) cells to carry, release, and deliver an effective, targeted anticancer therapy within the central nervous system (CNS) milieu remains elusive. Previous studies have demonstrated the marked ability of several types of stem cells (such as mesenchymal stem cells (MSCs) to carry and release different anti-cancer agents such as paclitaxel (PTX). Herein we investigate the ability of human olfactory bulb neural stem cells (Hu-OBNSCs) to carry and release paclitaxel, producing effective cytotoxic effects against cancer cells. We isolated Hu-OBNSCs from the hOB, uploaded them with PTX, and studied their potential cytotoxic effects against cancer cells in vitro. Interestingly, the Hu-OBNSCs displayed a five-fold increase in their resistance to the cytotoxicity of PTX, and the PTX-uploaded Hu-OBNSCs were able to inhibit proliferation and invasion, and to trigger marked cytotoxic effects on glioblastoma multiforme (GBM) cancer cells, and Human Caucasian fetal pancreatic adenocarcinoma 1 (CFPAC-1) in vitro. Despite their ability to resist the cytotoxic activity of PTX, the mechanism by which Hu-OBNSCs acquire resistance to PTX is not yet explained. Collectively our data indicate the ability of the Hu-OBNSCs to resist PTX, and to trigger effective cytotoxic effects against GBM cancer cells and CFPAC-1. This indicates their potential to be used as a carrier/vehicle for targeted anti-cancer therapy within the CNS

Lack of prophylaxis before the onset of acute venous thromboembolism among hospitalized cancer patients: the SWIss Venous ThromboEmbolism Registry (SWIVTER).

BACKGROUND: Venous thromboembolism (VTE) prophylaxis remains underutilized, particularly in cancer patients. We explored clinical predictors of prophylaxis in hospitalized cancer patients before the onset of acute VTE. METHODS: In the SWiss Venous ThromboEmbolism Registry, 257 cancer patients (61 +/- 15 years) with acute VTE and prior hospitalization for acute medical illness or surgery within 30 days (91% were at high risk with Geneva VTE risk score > or =3) were enrolled. RESULTS: Overall, 153 (60%) patients received prophylaxis (49% pharmacological and 21% mechanical) before the onset of acute VTE. Outpatient status at the time of VTE diagnosis [odds ratio (OR) 0.31, 95% confidence interval (CI) 0.18-0.53], ongoing chemotherapy (OR 0.51, 95% CI 0.31-0.85), and recent chemotherapy (OR 0.53, 95% CI 0.32-0.88) were univariately associated with the absence of VTE prophylaxis. In multivariate analysis, intensive care unit admission within 30 days (OR 7.02, 95% CI 2.38-20.64), prior deep vein thrombosis (OR 3.48, 95% CI 2.14-5.64), surgery within 30 days (OR 2.43, 95% CI 1.19-4.99), bed rest >3 days (OR 2.02, 95% CI 1.08-3.78), and outpatient status (OR 0.38, 95% CI 0.19-0.76) remained the only independent predictors of thromboprophylaxis. CONCLUSIONS: Although most hospitalized cancer patients were at high risk, 40% did not receive any prophylaxis before the onset of acute VTE. There is a need to improve thromboprophylaxis in cancer patients, particularly in the presence of recent or ongoing chemotherapy

Degradation of Cdc25A by \u3b2-TrCP during S phase and in response to DNA damage

The Cdc25A phosphatase is essential for cell-cycle progression because of its function in dephosphorylating cyclin-dependent kinases. In response to DNA damage or stalled replication, the ATM and ATR protein kinases activate the checkpoint kinases Chk1 and Chk2, which leads to hyperphosphorylation of Cdc25A1\u20133. These events stimulate the ubiquitin-mediated pro- teolysis of Cdc25A1,4,5 and contribute to delaying cell-cycle progression, thereby preventing genomic instability1\u20137. Here we report that b-TrCP is the F-box protein that targets phosphory- lated Cdc25A for degradation by the Skp1/Cul1/F-box protein complex. Downregulation of b-TrCP1 and b-TrCP2 expression by short interfering RNAs causes an accumulation of Cdc25A in cells progressing through S phase and prevents the degradation of Cdc25A induced by ionizing radiation, indicating that b-TrCP may function in the intra-S-phase checkpoint. Consistent with this hypothesis, suppression of b-TrCP expression results in radioresistant DNA synthesis in response to DNA damage\u2014a phenotype indicative of a defect in the intra-S-phase checkpoint that is associated with an inability to regulate Cdc25A properly. Our results show that b-TrCP has a crucial role in mediating the response to DNA damage through Cdc25A degradation

Preoperative bi-fractionated accelerated radiation therapy for combined treatment of locally advanced rectal cancer in a consectutive series of unselected patients

Background: although preoperative RT (Radiation Therapy) is becoming the preferred approach for combined treatment of locally advanced rectal adenocarcinoma, no regimen can be now considered as a standard. Since the toxicity of preoperative RT isn't yet completely known, and the advantages of preoperative RT could be counterbalanced by increased postoperative morbidity and mortality, a monocentre series of preoperative bifractionated accelerated RT was retrospectively reviewed to clarify toxicity and outcomes after a prolonged follow up. Methods: patients were screened following these eligibility criteria: histology-proven adenocarcinoma of the rectum; distal tumour extent at 12 cm or less from the anal verge; clinical stage T3-4/anyN, or anyT/ N1-2; ECOG Performance Status 0-2. A total dose of 41.6 Gy (26 twice daily fractions of 1.6 Gy) was delivered. Surgery was carried out 17 \ub1 2 days after RT completion, adopting the total mesorectal excision technique. Results: 24 men and 23 women were enrolled; median age was 55 years (r.: 39-77). Twenty-eight patients were stage II and 19 stage III. 9 patients suffered from a recurrent tumour. 2 patients experienced a severe grade 4 gastrointestinal toxicity (a colo-vaginal fistula and an intestinal obstruction, both successfully treated). Operative mortality was nil; postoperative early complications occurred in 13 cases; mean length of hospital stay was 15 days. After a mean follow up of 44 months (r.: 18-84) 8 patients had deceased for recurrent disease, 15 were alive with a disease progression (2 pelvic recurrences and 13 pure distant deposits) and 24 were alive, without disease. The 5-year actuarial overall survival was 74.2%, the disease-free survival 62.9% and the regional control rate 84.7%. Long-term complications included 1 case of radiation enteritis requiring surgery, 2 cases of anastomotic stricture and 3 cases of bladder incontinence. Conclusion: bifractionated accelerated RT administered in the preoperative setting to patients bearing locally advanced rectal cancer is reliable and safe, as its immediate and late toxicity (mainly infectious) is acceptably low and long-term survivals are achievable. These findings support the increasing use of preoperative RT for treatment of this malignancy in experienced centres. Ongoing multicentric trials are expected to address still unsolved issues, including the benefit of CT adjunct to preoperative RT

Implication of the F-Box Protein FBXL21 in Circadian Pacemaker Function in Mammals

In mammals, the circadian clock relies on interlocked feedback loops involving clock genes and their protein products. Post-translational modifications control intracellular trafficking, functionality and degradation of clock proteins and are keys to the functioning of the clock as recently exemplified for the F-Box protein Fbxl3. The SCFFbxl3 complex directs degradation of CRY1/2 proteins and Fbxl3 murine mutants have a slower clock. To assess whether the role of Fbxl3 is phylogenetically conserved, we investigated its function in the sheep, a diurnal ungulate. Our data show that Fbxl3 function is conserved and further reveal that its closest homologue, the F-Box protein Fbxl21, also binds to CRY1 which impairs its repressive action towards the transcriptional activators CLOCK/BMAL1. However, while Fbxl3 appears to be ubiquitously expressed, Fbxl21 expression is tissue-specific. Furthermore, and in sharp contrast with Fbxl3, Fbxl21 is highly expressed within the suprachiasmatic nuclei, site of the master clock, where it displays marked circadian oscillations apparently driven by members of the PAR-bZIP family. Finally, for both Fbxl3 and Fbxl21 we identified and functionally characterized novel splice-variants, which might reduce CRY1 proteasomal degradation dependent on cell context. Altogether, these data establish Fbxl21 as a novel circadian clock-controlled gene that plays a specific role within the mammalian circadian pacemaker

Combining computational effects: commutativity and sum

We begin to develop a unified account of modularity for computational effects. We use the notion of enriched Lawvere theory, together with its relationship with strong monads, to reformulate Moggi’s paradigm for modelling computational effects; we emphasise the importance here of the operations that induce computational effects. Effects qua theories are then combined by appropriate bifunctors (on the category of theories). We give a theory of the commutative combination of effects, which in particular yields Moggi’s side-effects monad transformer (an application is the combination of side-effects with nondeterminism). And we give a theory for the sum of computational effects, which in particular yields Moggi’s exceptions monad transformer (an application is the combination of exceptions with other effects)

Down-Regulation of Myogenin Can Reverse Terminal Muscle Cell Differentiation

Certain higher vertebrates developed the ability to reverse muscle cell differentiation (dedifferentiation) as an additional mechanism to regenerate muscle. Mammals, on the other hand, show limited ability to reverse muscle cell differentiation. Myogenic Regulatory Factors (MRFs), MyoD, myogenin, Myf5 and Myf6 are basic-helix-loop-helix (bHLH) transcription factors essential towards the regulation of myogenesis