Profiling Alloy Models

Modeling of software-intensive systems using formal declarative modeling languages offers a means of managing software complexity through the use of abstraction and early identification of correctness issues by formal analysis. Alloy is one such language used for modeling systems early in the development process. Nevertheless, little work has been done to study the styles and techniques commonly used in Alloy models. We present the first static analysis study of Alloy models. We investigate research questions that examine a large corpus of 2,138 Alloy models. To evaluate these research questions, we create a methodology that leverages the power of ANTLR pattern matching and the query language XPath. We investigate the parse tree generated from each Alloy model and identify instances of formulated queries that are of interest to our research questions. We present the results and discuss the findings from examining these research questions. Our research questions are split into three categories depending on their purpose and implementation complexity. Characteristics of Models include ``surface-level" research questions that aim to identify what language constructs are used commonly. We also correlate certain model features using linear regression to determine the best predictors for model length and field count. Patterns of Use questions are considerably more complex and attempt to identify how modelers are using Alloy's constructs. Analysis Complexity questions explore the use of Alloy model features and constructs that may impact solving time. We draw conclusions from the results of our research questions and present findings for language and tool designers, educators and optimization developers. Findings aimed at language and tool designers present ways to improve the Alloy language by adding constructs or removing unused ones based on trends identified in our corpus of models. Findings for educators are intended to highlight underutilized language constructs and features, and help student modelers avoid discouraged practices. Lastly, we present a number of findings for optimization developers that provide suggestions for back-end improvements

Static Profiling of Alloy Models

© 2022 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works.Modeling of software-intensive systems using formal declarative modeling languages offers a means of managing software complexity through the use of abstraction and early identification of correctness issues by formal analysis. Alloy is one such language used for modeling systems early in the development process. Little work has been done to study the styles and techniques commonly used in Alloy models. We present the first static analysis study of Alloy models. We investigate research questions that examine a large corpus of 1,652 Alloy models. To evaluate these research questions, we create a methodology that leverages the power of ANTLR pattern matching and the query language XPath. Our research questions are split into two categories depending on their purpose. The Model Characteristics category aims to identify what language constructs are used commonly. Modeling Practices questions are considerably more complex and identify how modelers are using Alloy's constructs. We also evaluate our research questions on a subset of models from our corpus written by expert modelers. We compare the results of the expert corpus to the results obtained from the general corpus to gain insight into how expert modelers use the Alloy language. We draw conclusions from the findings of our research questions and present actionable items for educators, language and environment designers, and tool developers. Actionable items for educators are intended to highlight underutilized language constructs and features, and help student modelers avoid discouraged practices. Actionable items aimed at language designers present ways to improve the Alloy language by adding constructs or removing unused ones based on trends identified in our corpus of models. The actionable items aimed at environment designers address features to facilitate model creation. Actionable items for tool developers provide suggestions for back-end optimizations.Natural Sciences and Engineering Research Council of Canada

Marjoram Relaxes Rat Thoracic Aorta Via a PI3-K/eNOS/cGMP Pathway.

Despite pharmacotherapeutic advances, cardiovascular disease (CVD) remains the primary cause of global mortality. Alternative approaches, such as herbal medicine, continue to be sought to reduce this burden. is recognized for many medicinal values, yet its vasculoprotective effects remain poorly investigated. Here, we subjected rat thoracic aortae to increasing doses of an ethanolic extract of (OME). OME induced relaxation in a dose-dependent manner in endothelium-intact rings. This relaxation was significantly blunted in denuded rings. N(ω)-nitro-l-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) significantly reduced the OME-induced vasorelaxation. Cyclic guanosine monophosphate (cGMP) levels were also increased by OME. Moreover, wortmannin or LY294002 significantly reduced OME-induced vasorelaxation. Blockers of ATP-sensitive or Ca2+-activated potassium channels such as glibenclamide or tetraethylamonium (TEA), respectively, did not significantly affect OME-induced relaxation. Similarly, verapamil, a Ca channel blocker, indomethacin, a non-selective cyclooxygenase inhibitor, and pyrilamine, a H1 histamine receptor blocker, did not significantly modulate the observed relaxation. Taken together, our results show that OME induces vasorelaxation via an endothelium-dependent mechanism involving the phosphoinositide 3-kinase (PI3-K)/ endothelial nitric oxide (NO) synthase (eNOS)/cGMP pathway. Our findings further support the medicinal value of marjoram and provide a basis for its beneficial intake. Although consuming marjoram may have an antihypertensive effect, further studies are needed to better determine its effects in different vascular beds

Automatic versus manual pressure support reduction in the weaning of post-operative patients: a randomised controlled trial

Introduction Reduction of automatic pressure support based on a target respiratory frequency or mandatory rate ventilation (MRV) is available in the Taema-Horus ventilator for the weaning process in the intensive care unit (ICU) setting. We hypothesised that MRV is as effective as manual weaning in post-operative ICU patients. Methods There were 106 patients selected in the postoperative period in a prospective, randomised, controlled protocol. When the patients arrived at the ICU after surgery, they were randomly assigned to either: traditional weaning, consisting of the manual reduction of pressure support every 30 minutes, keeping the respiratory rate/tidal volume (RR/TV) below 80 L until 5 to 7 cmH(2)O of pressure support ventilation (PSV); or automatic weaning, referring to MRV set with a respiratory frequency target of 15 breaths per minute (the ventilator automatically decreased the PSV level by 1 cmH(2)O every four respiratory cycles, if the patient`s RR was less than 15 per minute). The primary endpoint of the study was the duration of the weaning process. Secondary endpoints were levels of pressure support, RR, TV (mL), RR/TV, positive end expiratory pressure levels, FiO(2) and SpO(2) required during the weaning process, the need for reintubation and the need for non-invasive ventilation in the 48 hours after extubation. Results In the intention to treat analysis there were no statistically significant differences between the 53 patients selected for each group regarding gender (p = 0.541), age (p = 0.585) and type of surgery (p = 0.172). Nineteen patients presented complications during the trial (4 in the PSV manual group and 15 in the MRV automatic group, p < 0.05). Nine patients in the automatic group did not adapt to the MRV mode. The mean +/- sd (standard deviation) duration of the weaning process was 221 +/- 192 for the manual group, and 271 +/- 369 minutes for the automatic group (p = 0.375). PSV levels were significantly higher in MRV compared with that of the PSV manual reduction (p < 0.05). Reintubation was not required in either group. Non-invasive ventilation was necessary for two patients, in the manual group after cardiac surgery (p = 0.51). Conclusions The duration of the automatic reduction of pressure support was similar to the manual one in the postoperative period in the ICU, but presented more complications, especially no adaptation to the MRV algorithm. Trial Registration Trial registration number: ISRCTN3745664

NADPH oxidase 4 inhibition is a complementary therapeutic strategy for spinal muscular atrophy

IntroductionSpinal muscular atrophy (SMA) is a fatal neurodegenerative disorder, characterized by motor neuron (MN) degeneration and severe muscular atrophy and caused by Survival of Motor Neuron (SMN) depletion. Therapies aimed at increasing SMN in patients have proven their efficiency in alleviating SMA symptoms but not for all patients. Thus, combinational therapies are warranted. Here, we investigated the involvement of NADPH oxidase 4 (NOX4) in SMA-induced spinal MN death and if the modulation of Nox4 activity could be beneficial for SMA patients.MethodsWe analysed in the spinal cord of severe type SMA-like mice before and at the disease onset, the level of oxidative stress and Nox4 expression. Then, we tested the effect of Nox4 inhibition by GKT137831/Setanaxib, a drug presently in clinical development, by intrathecal injection on MN survival and motor behaviour. Finally, we tested if GKT137831/Setanaxib could act synergistically with FDA-validated SMN-upregulating treatment (nusinersen).ResultsWe show that NOX4 is overexpressed in SMA and its inhibition by GKT137831/Setanaxib protected spinal MN from SMA-induced degeneration. These improvements were associated with a significant increase in lifespan and motor behaviour of the mice. At the molecular level, GKT137831 activated the pro-survival AKT/CREB signaling pathway, leading to an increase in SMN expression in SMA MNs. Most importantly, we found that the per os administration of GKT137831 acted synergistically with a FDA-validated SMN-upregulating treatment.ConclusionThe pharmacological inhibition of NOX4 by GKT137831/Setanaxib is neuroprotector and could represent a complementary therapeutic strategy to fight against SMA

Ziziphus nummularia attenuates the malignant phenotype of human pancreatic cancer cells: Role of ros

Pancreatic cancer (PC) is the fourth leading cause of all cancer-related deaths. Despite major improvements in treating PC, low survival rate remains a major challenge, indicating the need for alternative approaches, including herbal medicine. Among medicinal plants is Ziziphus nummu-laria (family Rhamnaceae), which is a thorny shrub rich in bioactive molecules. Leaves of Ziziphus nummularia have been used to treat many pathological conditions, including cancer. However, their effects on human PC are still unknown. Here, we show that the treatment of human pancreatic ductal adenocarcinoma cells (Capan-2) with Ziziphus nummularia ethanolic extract (ZNE) (100–300 µg/mL) attenuated cell proliferation in a time-and concentration-dependent manner. Pretreatment with N-acetylcysteine, an ROS scavenger, attenuated the anti-proliferative effect of ZNE. In addition, ZNE significantly decreased the migratory and invasive capacity of Capan-2 with a concomitant downregulation of integrin α2 and increased cell–cell aggregation. In addition, ZNE inhibited in ovo angiogenesis as well as reduced VEGF and nitric oxide levels. Furthermore, ZNE downregulated the ERK1/2 and NF-κB signaling pathways, which are known to drive tumorigenic and metastatic events. Taken together, our results suggest that ZNE can attenuate the malignant phenotype of Capan-2 by inhibiting hallmarks of PC. Our data also provide evidence for the potential anticancer effect of Ziziphus nummularia, which may represent a new resource of novel anticancer compounds, especially ones that can be utilized for the management of PC

Origanum syriacum L. Attenuates the Malignant Phenotype of MDA-MB231 Breast Cancer Cells

Breast cancer is the leading cause of cancer-related deaths among women. Among breast cancer types, triple negative breast cancer (TNBC) is the most aggressive, and is resistant to hormonal and chemotherapeutic treatments. As such, alternative approaches that may provide some benefit in fighting this debilitating pathology are critically needed; hence the utilization of herbal medicine. Origanum syriacum L., one of the most regularly consumed plants in the Mediterranean region, exhibits antiproliferative effect on several cancer cell lines. However, whether this herb modulates the malignant phenotype of TNBC remains poorly investigated. Here, we show that in MDA-MB-231, a TNBC cell line, Origanum syriacum L. aqueous extract (OSE) inhibited cellular viability, induced autophagy determined by the accumulation of lipidized LC3 II, and triggered apoptosis. We also show that OSE significantly promoted homotypic cell-cell adhesion while it decreased cellular migration, adhesion to fibronectin, and invasion of MDA-MB-231 cells. This was supported by decreased activity of focal adhesion kinase (FAK), reduced α2 integrin expression, and downregulation of secreted PgE2, MMP2 and MMP-9, in OSE-treated cells. Finally, we also show that OSE significantly inhibited angiogenesis and downregulated the level of nitric oxide (NO) production. Our findings demonstrate the ability of OSE to attenuate the malignant phenotype of the MDA-MB-231 cells, thus presenting Origanum syriacum L. as a promising potential source for therapeutic compounds for TNBC

Validated stability indicating liquid chromatographic determination of ebastine in pharmaceuticals after pre column derivatization: Application to tablets and content uniformity testing

An accurate, simple, sensitive and selective reversed phase liquid chromatographic method has been developed for the determination of ebastine in its pharmaceutical preparations. The proposed method depends on the complexation ability of the studied drug with Zn2+ ions. Reversed phase chromatography was conducted using an ODS C18 (150 × 4.6 mm id) stainless steel column at ambient temperature with UV-detection at 260 nm. A mobile phase containing 0.025%w/v Zn2+ in a mixture of (acetonitril/methanol; 1/4) and Britton Robinson buffer (65:35, v/v) adjusted to pH 4.2, has been used for the determination of ebastine at a flow rate of 1 ml/min. The calibration curve was rectilinear over the concentration range of 0.3 - 6.0 μg/ml with a detection limit (LOD) of 0.13 μg/ml, and quantification limit (LOQ) of 0.26 μg/ml. The proposed method was successfully applied for the analysis of ebastine in its dosage forms, the obtained results were favorably compared with those obtained by a comparison method. Furthermore, content uniformity testing of the studied pharmaceutical formulations was also conducted. The composition of the complex as well as its stability constant was also investigated. Moreover, the proposed method was found to be a stability indicating one and was utilized to investigate the kinetics of alkaline and ultraviolet induced degradation of the drug. The first-order rate constant and half life of the degradation products were calculated