Simulating operational memory models using off-the-shelf program analysis tools

Memory models allow reasoning about the correctness of multithreaded programs. Constructing and using such models is facilitated by simulators that reveal which behaviours of a given program are allowed. While extensive work has been done on simulating axiomatic memory models, there has been less work on simulation of operational models. Operational models are often considered more intuitive than axiomatic models, but are challenging to simulate due to the vast number of paths through the model’s transition system. Observing that a similar path-explosion problem is tackled by program analysis tools, we investigate the idea of reducing the decision problem of “whether a given memory model allows a given behaviour” to the decision problem of “whether a given C program is safe”, which can be handled by a variety of off-the-shelf tools. We report on our experience using multiple program analysis tools for C for this purpose—a model checker (CBMC), a symbolic execution tool (KLEE), and three coverage-guided fuzzers (libFuzzer, Centipede and AFL++)—presenting two case-studies. First, we evaluate the performance and scalability of these tools in the context of the x86 memory model, showing that fuzzers offer performance competitive with that of RMEM, a state-of-the-art bespoke memory model simulator. Second, we study a more complex, recently developed memory model for hybrid CPU/FPGA devices for which no bespoke simulator is available. We highlight how different encoding strategies can aid the various tools and show how our approach allows us to simulate the CPU/FPGA model twice as deeply as in prior work, leading to us finding and fixing several infidelities in the model. We also experimented with applying three analysis tools that won the “falsification” category in the 2023 Annual Software Verification Competition (SV-COMP). We found that these tools do not scale to our use cases, motivating us to submit example C programs arising from our work for inclusion in the set of SV-COMP benchmarks, so that they can serve as challenge examples

Rescue of Pressure Overload-Induced Heart Failure by Estrogen Therapy.

BackgroundEstrogen pretreatment has been shown to attenuate the development of heart hypertrophy, but it is not known whether estrogen could also rescue heart failure (HF). Furthermore, the heart has all the machinery to locally biosynthesize estrogen via aromatase, but the role of local cardiac estrogen synthesis in HF has not yet been studied. Here we hypothesized that cardiac estrogen is reduced in HF and examined whether exogenous estrogen therapy can rescue HF.Methods and resultsHF was induced by transaortic constriction in mice, and once mice reached an ejection fraction (EF) of ≈35%, they were treated with estrogen for 10 days. Cardiac structure and function, angiogenesis, and fibrosis were assessed, and estrogen was measured in plasma and in heart. Cardiac estrogen concentrations (6.18±1.12 pg/160 mg heart in HF versus 17.79±1.28 pg/mL in control) and aromatase transcripts (0.19±0.04, normalized to control, P<0.05) were significantly reduced in HF. Estrogen therapy increased cardiac estrogen 3-fold and restored aromatase transcripts. Estrogen also rescued HF by restoring ejection fraction to 53.1±1.3% (P<0.001) and improving cardiac hemodynamics both in male and female mice. Estrogen therapy stimulated angiogenesis as capillary density increased from 0.66±0.07 in HF to 2.83±0.14 (P<0.001, normalized to control) and reversed the fibrotic scarring observed in HF (45.5±2.8% in HF versus 5.3±1.0%, P<0.001). Stimulation of angiogenesis by estrogen seems to be one of the key mechanisms, since in the presence of an angiogenesis inhibitor estrogen failed to rescue HF (ejection fraction=29.3±2.1%, P<0.001 versus E2).ConclusionsEstrogen rescues pre-existing HF by restoring cardiac estrogen and aromatase, stimulating angiogenesis, and suppressing fibrosis

Incisional hernias – results of present therapy options

Sp. Sf. Pantelimon, București, Al XI-lea Congres al Asociației Chirurgilor „Nicolae Anestiadi” din Republica Moldova și cea de-a XXXIII-a Reuniune a Chirurgilor din Moldova „Iacomi-Răzeșu” 27-30 septembrie 2011Introducere: Hernia incizională este cea mai frecventă complicație după operațiile abdominale. Este dificil de estimat exact costul acestei patologii pentru societate. Dacă adăugam la costul intervenției chirurgicale și costul spitalizării, dificultățile operațiilor de recidivă multiplă, costul protezelor, morbiditățile pacienților neoperați, afectarea capacității de muncă și a calității vieții, vom avea magnitudinea problemei dezvoltate de această complicație redutabilă a tuturor intervențiilor chirurgicale. Material și metodă: Am analizat rezultatele mai multor studii de prestigiu ale unor colective românești și internaționale în domeniul herniilor incizionale. Rezultate: Din nefericire rezultatele globale ale tratamentului în hernia incizională oscilează între 12-63% pentru procedeele tisulare și între 2-36% pentru procedeele allopalstice. Abordul chirurgical este cel mai adesea bazat pe traditie si pe liberul arbitru, decat pe evidențe statistice sau ghiduri de tratament. Nu este deloc surprinzător faptul că, în ciuda noilor cuceriri în domeniul defectelor parietale și a folosirii explozive a protezelor, rata de re-operații pentru recidiva incizională se situează la același nivel. Concluzii: Componența operatorie ca unică etiologie în hernia incizională este supraestimată. Datorită faptului că și alți factori etiologici, cunoscuți sau nu, concura la apariția herniei incizionale și la re-recidivă, și datorită faptului că acești “factori” nu sunt deocamdată influențabili de tratamentul medical nu ne rămțne decât să analizăm lucid și responsabil factorii chirurg-dependenți. Greselile de tactică/tehnică chirurgicală trebuie evidențiate, explicate, și înlăturate. Soluția nu este o abordare pur tehnică, ci una fiziologică, în termeni de elasticitate, complianța și rezistența a întregului perete abdominal, deseori modificat profund de marile defecte incizionale.Introduction: incisional hernia is the most common complication after abdominal surgery. It is difficult to estimate the exact cost to society of this pathology. If we add to the cost of surgery and hospitalization costs, the difficulties of relapse multiple operations, the cost of prostheses, unoperated patient morbidity, impaired work capacity and quality of life, the magnitude of the problem we have developed this redoubtable complication of all surgical procedures. Methods: We analyzed the results of several studies of prestigious romanian and international collectives about incisional hernias. Results: Unfortunately, the overall results of treatment in incisional hernia procedures vary between 12-63% for tissular procedures and between 2-36% for allopalstic procedures. Surgical approach is most often based on tradition and the free will, rather than obvious statistical treatment guidelines. Not surprisingly, despite the new advancements in the field of herniology and the use of new parietal prosthesis, the rate of re-operations for recurrent incisional fall at the same level. Conclusions: Surgery as the only component in etiology of incisional hernias is overestimated. Due to the fact that other etiological factors, known or not compete in the emergence and re-incision hernia recurrence, and because these “factors” are not influenced by medical treatment for now, we are just lucid and analyze the factors responsible - surgeon dependent. Mistakes tactics/surgical technique must be highlighted, explained and removed. The solution is not a purely technical approach, but a physiological, in terms of elasticity, compliance and resistance of the entire abdominal wall

Surgical atitude in suppurative acute pancreatitis

UMF Carol Davila, București, Sp. Sf. Pantelimon, București, Al XI-lea Congres al Asociației Chirurgilor „Nicolae Anestiadi” din Republica Moldova și cea de-a XXXIII-a Reuniune a Chirurgilor din Moldova „Iacomi-Răzeșu” 27-30 septembrie 2011Introducere: Managementul chirurgical al pancreatitei acute severe(SAP) rămâne încă controversat. Stabilirea indicație chirurgicale și a momentului operator optim este în legătură directă cu morbiditatea și mortalitatea acestei afecțiuni. Decizia chirurgicală se bazează pe criterii clinice,morfologice- examenul computer-tomografic și criterii bacteriologice- necroza sterilă sau infectată. Infecția necrozei pancreatice reprezintă o indicație de necontestat pentru necrozectomia chirurgicală. Material și metodă: Din 2007 până în 2010, un total de 104 de pacienți cu diagnostic de SAP şi cu indicație de intervenție chirurgicală au fost admişi în secția de chirurgie generală. Rezultate: Valoarea medie a scorului APACHE II la internare a fost de 16,4 (în intervalul 8-35). Toți pacienții au necesitat intervenție chirurgicală. Mortalitatea generală a fost 13,4% (14 pacienți). Insuficiență multiplă de organ a fost evidențiată la 41 de pacienți (39,4%). Infarctul miocardic sau embolia pulmonară au fost cauzele de deces la 3 pacienți (2,88%). Vârsta (p <0.0002), scorul APACHE II la internare (p<0,0001) , prezența sau dezvoltarea insuficienței (unice sau multiple) de organ (p<0.002), infecțiile (p<0,02) şi gradul extensiei necrozei pancretice (p <0.04), gradul de control al necrosectomiei (p <0,0001) par a fi în directa relație cu supraviețuirea. Concluzii: Evaluarea chirurgicală, în dinamică,se bazează pe determinările de laborator proprii identificării sepsisului cât și pe o imagistică CT sau RMN care să cuprindă obligatoriu reconstrucții de calitate. Acestea vor asigura o evacuare completă a necrozelor infectate, încă de la intervenția primară.Introduction: Surgical management of severe acute pancreatitis (SAP) remains controversial. Establishing the surgical indication and the optimal timing for surgery is directly related to surgical morbidity and mortality. Surgical approach is based on clinical-morphological criterias, computer tomography criteria, bacteriological-sterile or infected necrosis of pancreas. Infected necrosis represent an unquestionable indication for surgery. Methods: From 2007 to 2010, a total of 104 patients with a diagnosis of SAP and indication for surgery were admitted in department of general surgery. Results: The mean APACHE II score on the day of admission was 16.4(range 8-35). All patients required operative therapy. The overall mortality was 13,4% (14 patients). Septic organ failure in 41 patients (39,4%) and myocardial infarction or pulmonary embolism in 3 patients (2,88%) were the causes of death. The patient’s age (p <0.0002), APACHE II scores at admission (p <0.0001), presence or development of (single or multiple) organ failure (p <0.002), infections (p <0.02) and extent (p <0.04) of pancreatic necrosis, and surgical control of local necrosis (p <0.0001) significantly determined survival. Conclusions: The surgical evaluation, in dynamics, is based on both the laboratory determinations proper to the identification of the sepsis, and also on a CT or MRI imagistics which must necessarily contain quality reconstructions. These will ensure a complete evaluation of the infected necrosis, from the primary intervention

Cyanomethylene-bis(phosphonate)-Based Lanthanide Complexes: Structural, Photophysical, and Magnetic Investigations

10 pagesInternational audienceThe syntheses, structural investigations, magnetic and photophysical properties of a series of 10 lanthanide mononuclear complexes, containing the heteroditopic ligand cyanomethylene-bis(5,5-dimethyl-2-oxo-1,3,2λ5-dioxa-phosphorinane) (L), are described. The crystallographic analyses indicate two structural types: in the first one, [LnIII(L)3(H2O)2]*H2O (Ln = La, Pr, Nd), the metal ions are eight-coordinated within a square antiprism geometry, while the second one, [LnIII(L)3(H2O)]*8H2O (Ln = Sm, Eu, Gd, Tb, Dy, Ho, Er), contains seven-coordinated LnIII ions within distorted monocapped trigonal prisms...

The R403Q Myosin Mutation Implicated in Familial Hypertrophic Cardiomyopathy Causes Disorder at the Actomyosin Interface

Mutations in virtually all of the proteins comprising the cardiac muscle sarcomere have been implicated in causing Familial Hypertrophic Cardiomyopathy (FHC). Mutations in the beta-myosin heavy chain (MHC) remain among the most common causes of FHC, with the widely studied R403Q mutation resulting in an especially severe clinical prognosis. In vitro functional studies of cardiac myosin containing the R403Q mutation have revealed significant changes in enzymatic and mechanical properties compared to wild-type myosin. It has been proposed that these molecular changes must trigger events that ultimately lead to the clinical phenotype.Here we examine the structural consequences of the R403Q mutation in a recombinant smooth muscle myosin subfragment (S1), whose kinetic features have much in common with slow beta-MHC. We obtained three-dimensional reconstructions of wild-type and R403Q smooth muscle S1 bound to actin filaments in the presence (ADP) and absence (apo) of nucleotide by electron cryomicroscopy and image analysis. We observed that the mutant S1 was attached to actin at highly variable angles compared to wild-type reconstructions, suggesting a severe disruption of the actin-myosin interaction at the interface.These results provide structural evidence that disarray at the molecular level may be linked to the histopathological myocyte disarray characteristic of the diseased state

Identification of functional differences between recombinant human α and β cardiac myosin motors

The myosin isoform composition of the heart is dynamic in health and disease and has been shown to affect contractile velocity and force generation. While different mammalian species express different proportions of α and β myosin heavy chain, healthy human heart ventricles express these isoforms in a ratio of about 1:9 (α:β) while failing human ventricles express no detectable α-myosin. We report here fast-kinetic analysis of recombinant human α and β myosin heavy chain motor domains. This represents the first such analysis of any human muscle myosin motor and the first of α-myosin from any species. Our findings reveal substantial isoform differences in individual kinetic parameters, overall contractile character, and predicted cycle times. For these parameters, α-subfragment 1 (S1) is far more similar to adult fast skeletal muscle myosin isoforms than to the slow β isoform despite 91% sequence identity between the motor domains of α- and β-myosin. Among the features that differentiate α- from β-S1: the ATP hydrolysis step of α-S1 is ~ten-fold faster than β-S1, α-S1 exhibits ~five-fold weaker actin affinity than β-S1, and actin·α-S1 exhibits rapid ADP release, which is >ten-fold faster than ADP release for β-S1. Overall, the cycle times are ten-fold faster for α-S1 but the portion of time each myosin spends tightly bound to actin (the duty ratio) is similar. Sequence analysis points to regions that might underlie the basis for this finding

Identification of a Negative Allosteric Site on Human α4β2 and α3β4 Neuronal Nicotinic Acetylcholine Receptors

Acetylcholine-based neurotransmission is regulated by cationic, ligand-gated ion channels called nicotinic acetylcholine receptors (nAChRs). These receptors have been linked to numerous neurological diseases and disorders such as Alzheimer's disease, Parkinson's disease, and nicotine addiction. Recently, a class of compounds has been discovered that antagonize nAChR function in an allosteric fashion. Models of human α4β2 and α3β4 nicotinic acetylcholine receptor (nAChR) extracellular domains have been developed to computationally explore the binding of these compounds, including the dynamics and free energy changes associated with ligand binding. Through a blind docking study to multiple receptor conformations, the models were used to determine a putative binding mode for the negative allosteric modulators. This mode, in close proximity to the agonist binding site, is presented in addition to a hypothetical mode of antagonism that involves obstruction of C loop closure. Molecular dynamics simulations and MM-PBSA free energy of binding calculations were used as computational validation of the predicted binding mode, while functional assays on wild-type and mutated receptors provided experimental support. Based on the proposed binding mode, two residues on the β2 subunit were independently mutated to the corresponding residues found on the β4 subunit. The T58K mutation resulted in an eight-fold decrease in the potency of KAB-18, a compound that exhibits preferential antagonism for human α4β2 over α3β4 nAChRs, while the F118L mutation resulted in a loss of inhibitory activity for KAB-18 at concentrations up to 100 µM. These results demonstrate the selectivity of KAB-18 for human α4β2 nAChRs and validate the methods used for identifying the nAChR modulator binding site. Exploitation of this site may lead to the development of more potent and subtype-selective nAChR antagonists which may be used in the treatment of a number of neurological diseases and disorders