Priming of STAT1 and STAT3 for cytokine-triggered degradation by the proteasome upon A2Aadenosine receptor (A2AAR) expression

The A2A adenosine receptor (A2AAR) functions as a key non-redundant suppressor of inflammatory responses in vivo. However, whether it regulates activation of the JAK-STAT pathway utilised by many pro-inflammatory cytokines is unknown. Using a vascular endothelial cell model system, I have demonstrated that adenovirus-mediated expression of the human A2AAR conferred an ability of IFNα, leptin and a soluble IL- 6 receptor-α/IL-6 (sIL-6Rα/IL-6) trans-signalling complex to promote a time-dependent reduction in the levels of STAT proteins that was entirely due to proteasomal degradation. In terms of functional consequences, degradation was sufficient to attenuate sIL-6Rα/IL-6-stimulated STAT3-dependent up-regulation of vascular endothelial growth factor receptor-2 (VEGFR-2) and enhance eNOS expression. Degradation required JAK activity since A) it was blocked by preincubation with JAK inhibitor. B) STAT1 but not STAT3 was resistant to both tyrosine phosphorylation and down-regulation in response to leptin and C) a Tyr705→Phe mutated STAT3 was also resistant to cytokine-triggered degradation, suggesting that JAK-mediated phosphorylation of this residue is required to produce the effect. Consistent with this hypothesis, sIL-6Rα/IL-6 treatment of A2AAR-expressing cells resulted in the accumulation of polyubiquitylated endogenous and epitope-tagged recombinant wild-type but not Tyr705→ Phe-mutated STAT3. In addition the results show that inhibition of proteasome function was sufficient to block the inhibitory effect of the A2AAR on STAT3 phosphorylation, demonstrating that priming of STATs for degradation is the only mechanism responsible for the reduced cytokine-stimulated STAT phosphorylation observed in A2AAR-expressing cells. To date there is only one E3 ligase known for mediating STAT degradation which is SLIM protein. However, our results suggest the involvement of another E3 ubiquitin ligase in HUVECs, since we have been unable to detect SLIM message or protein in HUVECs under conditions in which STAT degradation occurs. In addition, while Tyr-phosphorylation is clearly the critical step in targeting STATs for degradation in A2AAR-expressing cells, it is unclear as to whether it functions simply as a classical phosphodegron, or whether the nuclear translocation that occurs as a result of phosphorylation is also important for localising the phosphorylated STAT dimer with the relevant E3 ubiquitin ligase. Together, these observations suggest a model whereby expression of the A2AAR in endothelial cells primes JAK-phosphorylated STATs for polyubiquitylation and subsequent degradation by the proteasome following cytokine treatment, and represents a previously unappreciated mechanism by which G-protein-coupled receptors can negatively regulate responsiveness to specific JAK-STAT-mobilising adipocytokines acting on the vascular endothelium

The role of data mining techniques and tools in big data management in healthcare field

Data mining is one of the most important modern techniques used to achieve high output standards at all levels. The twenty-first century saw the advent of a new trend to improve medical services in the healthcare sector. To bridge the gap between previous studies and the practical applications of data mining, this study aimed to review the theoretical literature and previous studies related to the demonstration of data mining techniques and tools and their role in big data management. To achieve the objectives of the study, the researchers used a descriptive, analytical, documentary method. The study concluded many results including that in the era of the knowledge and technology revolution, data mining is one of the important issues, that requires everyone to take into account its achievements in our current era, as well as the existence of a correlation between big data and the provision of a separate health service in the field of healthcare, and work to address epidemics and discover vaccines for them. In the healthcare industry, data mining plays a vital role, especially in predicting various types of diseases. In detecting diseases, diagnosis is the main tool. The study recommended the need to conduct more experimental and exploratory studies dealing with healthcare data mining techniques and tools and their effect on the management of big data volumes, especially in our Arab countries and the need for the development of models and action plans and the development of processes and methods from which data in the healthcare sector can be explored

Pomegranate juice attenuates acetaminophen induced hepatotoxicity in rat model of experiment

Background: Pomegranate fruit has high contents of various polyphenols and antioxidants due to which it possesses variety of therapeutic properties. In particular, pomegranate fruit peel and flowers have exhibited high antioxidant activity in different studies. Acetaminophen (APAP) overdose is the most common cause of drug induced liver toxicity including both accidental and intentional types. In our study, we investigated the protecting mechanism of pomegranate fruit juice (PJ) against toxicity caused by APAP in Wistar rats.Methods: Rats were fed with 0.2% (w/v) pomegranate fruit extract as prophylaxis to counter single dose of APAP (2 g/kg, p.o). After that variation in levels of glutathione, glutathione peroxidase (GPx), and glutathione reductase (GR) were marked.Results: A single dose of APAP elevated serum toxicity markers including lipid peroxidation. A simultaneous sharp depletion of glutathione and its metabolizing enzymes glutathione peroxidase (GPx), glutathione reductase (GR) was observed. Oral doses of PJ at (0.1% & 0.2% w/v) caused a significant (P<0.001) reduction in toxicity marker enzymes. A striking elevation in antioxidant armory was seen as in response to PJ.Conclusion: The results provide a clear picture of the defensive effect of PJ against APAP induced hepatic toxicity

Major Security Issue That Facing Social Networks with Its Main Defense Strategies

The Social Network Service "SNS" has enabled significant advancements in a wide variety of scientific fields, and as a result, it has become an extremely popular subject in both academia and business. SNSs can be extremely beneficial to users because they eliminate economic and geographical barriers and can be used for job searching, entertainment and education. Regardless of the economic and social benefits, protecting businesses and users\u27 security and privacy remains a critical issue that must be addressed. It is critical to address and evaluate social network service challenges, as they vary according to the variety of SNS sites. Thus, by discussing SNS challenges alongside available and potential solutions, users, developers, and businesses can identify relevant and timely responses to specific threats, resulting in the best SNS-based services possible. The objective of this article is to discuss the inherent challenges of social networking sites and some critical solutions for resolving them. We extracted and analyzed seminal papers to add to the corpus of literature by focusing on several critical challenges in the social network service domain and shedding light on how these challenges affect a variety of domains, including users, sites, and business. The most frequently mentioned difficulties concerned privacy risks, anonymity risks, malware, spam, identity theft, phishing, business data, social content, technical issues, and psychological difficulties. By incorporating previously discovered solutions, this paper addressed these issues. The implications for both researchers and practitioners have been discussed

Prediction of Self-Consolidating Concrete Properties using XGBoost Machine Learning Algorithm: Part 1–Workability

The Interest in Implementing Self-Consolidating Concrete (SCC) in Major Construction Projects Has Increased Significantly in Recent Years. This Paper Reports the Results of an Extensive Survey of Experimental Data of More Than 1700 SCC Mixtures from over 100 Studies Published in the Last Decade. the Survey Included the SCC Mixture Proportioning, Key Fresh Properties Including Flowability, Passing Ability, and Segregation Resistance, as Well as Some of the Derived Properties (E.g., Paste Volume). the Statistical Analysis of the Reported Parameters Showed Wide Variations in Values. the Outcome of the Survey Indicates that SCC Mixture Design and Workability Properties Do Not Systematically Lie within the Recommendations Reported in Various Guidelines. a Wide Range of Workability Tests is Used; However, only 22 % of the Studies Reported Values for Segregation Resistance. the Slump Flow Test Was the Most Tested Fresh Property and the Most Reported Values Are in Range of 591–760 Mm (X¯ = 679 Mm). the V-Funnel Time Was the Second Most Reported Test, and the Most of Reported Values Are in Range of 4.0–20 S (X¯ = 11 S). the Study Devised and Evaluated the Efficacy of using Machine Learning (ML) Models, Namely Extreme Gradient Boosting (XGBoost), to Predict the Two Most Reported Workability Characteristics of SCC, Namely Slump Flow and V-Funnel Flow Time. the Model Was Formulated to Predict Slump Flow and V-Funnel Time using a Refined Sub-Database of 852 Tests (The Extreme Data I.e., 5 % from Each Side, for the Both Properties and the Empty Data Was Deleted). the Findings Revealed that the XGBoost Model Can Provide an Accurate Prediction for the Slump Flow and V-Funnel Values, Thus Indicating its Potential as a Powerful Tool for SCC Optimization. the Findings Provide Valuable Insights into the Application of ML in SCC Research and Contribute to the Development of More Efficient and Sustainable Construction Practices

Stability Testing of Beclomethasone Dipropionate Nanoemulsion

Purpose: To perform stability studies on a nanoemulsion formulation containing beclomethasone dipropionate (BD) and prepared by spontaneous emulsification method.Method: A nanoemulsion (o/w) containing BD was prepared using eucalyptus oil, Tween-40, ethanol and distilled water. The nanoemulsions were characterized by droplet size, pH, viscosity, conductivity and refractive index. Stability studies were performed according to International Council on Harmonization (ICH) guidelines over a period of 3 months. Droplet size, pH, viscosity, conductivity and refractive index were determined monthly for 3 months. The shelf-life of the nanoemulsion formulation was determined by accelerated stability testing.Results: The droplet size, conductivity, viscosity, pH and refractive index of the optimized formulations did not change significantly (p ≥ 0.05) after 3 months of storage at room temperature (25 ºC). The shelf life was 1.83 years at room temperature.Conclusion: The study demonstrates that the physical and chemical stability of BD is enhanced when it is formulated as a nanoemulsion.Keywords: Nanoemulsion, Beclomethasone dipropionate, Shelf-life, Accelerated stability, Viscosity, Conductivity, Refractive inde

Recycling of dredged sediments in self-consolidating concrete: mix design optimization and durability study

La demande en matériaux de construction a considérablement augmenté, dont la grande majorité est d’origine naturelle. Étant donné que ces matériaux ne sont pas renouvelables, il est essentiel de trouver des matériaux alternatifs. Les études récentes menées à l’IMT Lille Douai ont montré que les matériaux issus de dragage possèdent des propriétés pouzzolaniques intéressantes et peuvent être utilisées comme ajouts cimentaires alternatifs ou comme filler. Vu le volume important dragué annuellement, cette valorisation aura des impacts environnementaux et économiques très positifs. Les objectifs visés dans cette recherche portent sur : la valorisation des sédiments du Grand Port Maritime de Dunkerque (France) dans des bétons autoplaçants (BAPs) comme ajouts cimentaires ; la valorisation des sédiments fluviaux du Château de l’Abbaye (France) dans des mortiers comme ajouts cimentaires afin d’évaluer la mobilité et la stabilité des éléments traces métalliques ; la solidification des sables dragués des Iles-de-la-Madeleine (Québec) par liant hydraulique afin de produire des roches artificielles. Dans l'ensemble, les résultats de ce travail sur les sédiments mettent en exergue la contribution substantielle de ces matériaux à l’amélioration des performances des bétons et supportent leur emploi comme ajouts cimentaires. Ces résultats contribuent à réduire l’empreinte du CO2 dans le béton, ainsi que les exploitations minières. Ils permettent également de mieux comprendre le comportement des sédiments dans les bétons à partir de certaines analyses et traitements, et d’identifier les milieux agressifs convenables à l’utilisation des sédiments.Abstract: The demand for building materials has increased enormously, and the vast majority are of natural origin. Since these materials are not renewable, it is essential to find alternatives. Recent studies at the IMT Lille Douai have shown that dredged materials have interesting pozzolanic properties and can be used as alternative cement additions or as filler. Given the large volume dredged annually, this recovery will have very positive environmental and economic impacts. The objectives of this research relate to: (1) The recycling of sediments from Grand Port Maritime de Dunkerque (France) in self-consolidating concrete (SCCs) as Supplementary cementitious materials (SCMs); (2) The recycling of fluvial sediments of Château l’Abbaye (France) in mortars as SCMs in order to assess the mobility and stability of heavy metal elements; (3) The solidification of the dredged sands of Iles-de-la-Madeline (Quebec) by hydraulic binder in order to produce artificial rocks. Overall, the results of this work on sediments highlight the substantial contribution of these materials to improving the performance of concrete and support their use as SCMs. These results contribute to reducing the footprint of CO2 in concrete, as well as mining. Also, contributes to understanding the behavior of sediments in concrete from certain analyzes and treatment. Thus, identify aggressive environments suitable for the use of sediments

Toxicity of Vernonia anthelmintica Linn. (Asteracea) seeds against mosquitoes vectors

The Toxicological activity (larvicidal, adulticidal and repellent toxicity) of Vernonia anthelmintica seeds fraction was tested against different species of mosquito vectors viz, malaria (Anopheles culicifacies and Anopheles stephensi), filaria (Culex quinquefasciatus) and dengue (Aedes aegypti). The larvicidal toxicity of Vernonia anthelmintica seeds fraction was evaluated against the early 4th instars larvae of different mosquitoes species. Mean LC50 value of the column fraction KAL-4 from seeds of V. anthelmintica against the larvae of An. culicifacies, An. stephensi, Culex quinquifaciatus and Aedes aegpyti were found to be 64 ppm, 70 ppm, 143 ppm and 166 ppm respectively. The larvicidal toxicity was more against An. culicifacies, An. stephensi than Culex quinquifaciatus and Aedes aegypti. The seed extracts did not show any adulticidal toxicity and repellent toxicity even at 10% concentrated impregnated paper and 5% on human hand, respectively

Antidiabetic potential of Moringa oleifera Lam. leaf extract in type 2 diabetic rats, and its mechanism of action

Purpose: To explore the antidiabetic potential of Moringa oleifera leaf extract in type 2 diabetic rats, and the underlying mechanisms.Methods: Streptozotocin (STZ) at a dose of 40 mg/kg was given to high fat diet (HFD)- fed rats to induce type 2 diabetes. M. oleifera leaf extract at doses 100, 200 and 400 mg/kg were given to 3 groups of type 2 diabetic rats. The area under curve (AUC) of glucose and homeostasis model assessment of insulin resistance (HOMA-R) were calculated using appropriate formulas, whereas levels of glucose,insulin, peroxisome proliferator activated receptor-γ (PPARγ, dipeptidyl peptidase-IV (DPP-IV) and inflammatory cytokines (IL-6, IL-1β and TNFα) were assayed using ELISA kits.Results: The leaf extract of M. oleifera significantly reduced the levels of glucose, insulin and cytokines in treated type 2 diabetic groups (p &lt; 0.05). DC group had significantly increased AUC for glucose, whereas the extract-treated groups showed significant&nbsp; decrease in glucose AUC. There was significant decrease in insulin sensitivity parameters, as indicated by increase in HOMA-R and decrease in PPARγ levels in the DC group (p &lt; 0.05). However, treatment with the M. oleifera extract reversed this trend via marked decrease in HOMA-R level and significant rise in PPARγ level. In contrast, the extract had no effect on DPP-IV concentration in diabetic treated groups (p &lt; 0.05).Conclusion: These results indicate that M. oleifera leaf extract mitigates hyperglycemia in type 2 DM by modulating hyperinsulinemia, PPARγ and inflammatory cytokines. Thus, the extract is a potential source of drug for the management of type 2 DM. Keywords: Moringa oleifera, Diabetes mellitus, Streptozotocin, Peroxisome proliferator activated receptor-γ, Dipeptidyl peptidase I