Impact of a single nucleotide polymorphism in the CD40 gene and diabetes-associated stress factors on endothelial dysfunction

CD40 signaling is a key modulator of immunological responses and serves several biological functions across multiple organs. While its primary purpose is restoring homeostasis, its unregulated activation drives various immune-modulated pathological conditions. Its role in the development of insulin resistance and the progression of diabetes is well documented. A further contribution of CD40 signaling in escalating systemic inflammation in diabetes leads to the initiation of vascular complications. The functional single nucleotide polymorphism (SNP) in the Kozak region of the CD40 gene (T-1C, rs1883832) impacts CD40 translation efficiency and is associated with several immune and inflammation-modulated diseases. Given the role of CD40 signaling in the progression of diabetes and systemic inflammation, this SNP may also represent a genetic risk factor for diabetes. This hypothesis was investigated by examining the distribution of the T-1C SNP in patients with type 1 (T1D) and type 2 diabetes (T2D). There was, in fact, a strong association of the C-allele with T2D (odds ratio = 1.43; 95% confidence interval: 1.09-1.86). T2D patients also revealed higher plasma levels of the presumably protective soluble CD40 receptor (sCD40), which is known to neutralize the CD40 ligand (CD40L) and its pro-inflammatory capacity. Hence, in T2D patients, CD40 signaling seems to be switched on, leading to an upregulation of the compensatory sCD40 in the blood. The possibility that the T-1C SNP differentially affects the genome of sCD40L-stimulated CC and TT-genotype human cultured endothelial cells (HUVECs) was examined through RNA sequencing. The CC-genotype HUVECs exhibited a higher degree of gene expression in general and in particular of genes involved in escalating inflammation, insulin receptor recycling, and driving endothelial to mesenchymal transition (EndMT). The quiescent TT-genotype HUVECs seemed to be protected against such changes. The impact of a pro-diabetic microenvironment on the pro-inflammatory CC-genotype HUVECs was further studied. Under these conditions, they revealed an increased expression of mediators promoting inflammation, atherosclerosis, and EndMT. In addition, they showed morphological changes characteristic of a partial EndMT-like phenotype. Expression of the osmoadaptive transcription factor nuclear factor of activated T-cells (NFAT) 5 and its nuclear abundance was also increased under these conditions. Blocking NFAT5 DNA-binding in the CC-genotype HUVECs by using a neutralizing consensus NFAT5 decoy oligonucleotide significantly reduced the expression of the mesenchymal marker SM22α. Several nuclear factor κB (NF-κB)/NFAT5 dual binding sites are located in promotor regions of genes involved in the progression of atherosclerosis and EndMT. While NF-κB is known to drive inflammation and EndMT in HUVECs, less is known about the role of NFAT5 in modulating these processes. This work provides novel insights into the role of NFAT5 in enhancing NF-κB mediated vascular inflammation and EndMT under pro-diabetic conditions

Effects of resistin on platelet function and its receptor, adenylyl cyclase associated protein 1

Resistin is an adipokine which is found elevated in patients suffering from metabolic syndrome, affecting a large proportion of the population. It is characterised by obesity, insulin resistance (IR), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), which are the biggest contributors to morbidity and mortality in the modern world. Platelets play a major role in CVD, where their activation leads to formation of thrombi, which when uncontrolled, leads to the pathophysiological effects of CVD. The role of resistin in CVD progression and its mechanism of action on its target cells still remains debatable and surrounded by controversies. In a bid to assess this, the present study aims at illustrating the effect of resistin on platelet activation by deriving conclusions from platelet functional assays. This thesis makes novel observations that resistin blunts thrombin-mediated platelet aggregation and secretion and seemingly affects the platelet actin cytoskeleton. It also finds that resistin activates downstream effectors of phosphoinositide 3 kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways in platelets.Adenylyl cyclase associated protein 1 (CAP1), a cytoskeletal protein, was recently identified as a receptor for resistin. When CAP1 was investigated in platelets, interesting observations were made, where CAP1 temporally translocated from the membrane fraction in response to thrombin mediated activation. Furthermore, in an attempt to improve our knowledge of platelet biology and to delineate future avenues for exploration, an observational proteomics investigation of cytoskeletal proteins and the change in abundance upon thrombin activation was carried out, further highlighting their importance in platelet regulation. Additionally the subcellular localisation of specific cytoskeletal proteins (IQGAP1, Arp2/3, coronin1a, profilin, cofilin, villin, l-plastin, myosin IIa, and tropomyosin) that are either known or hypothesised to interact with CAP1 was also conducted. Further investigations with proteins IQGAP1 and Arp2/3 revealed that these proteins did not interact with CAP1

Innovative Use of Waste Steel Scrap in Rigid Pavements

This paper work assessment on the study of the workability and mechanical strength properties of the high strength concrete reinforced with industrial waste fibers. This waste steel scrap material which is available from the lathe is used as a steel fiber for innovative construction industry and also in pavement construction. Lathe waste is generated by each lathe industries and dumping of these wastes in the barren soil contaminating the soil and ground water, which creates an unhealthy environment. In addition to get sustainable development and environmental benefits, lathe scrap as recycled fibers with concrete are likely to be used. Experimental studies are done to know about fresh and hardened concrete properties of SFRC and their mechanical properties such as compressive strength, flexural strength and split tensile strength are found to be increased due to the addition of steel scrap fiber in the concrete. When compared with conventional concrete to SFRC, steel fiber increases flexural strength by 40% and considerable increase in compressive and tensile strength. These fibers may also contribute to improve properties such as shrinkage reduction, modulus of elasticity, toughness, resistance to cracking and preventing crack propagation. The workability of fresh concrete containing lathe scraps are carried out by using slump test. This paper focuses on structural strength enhancement and improvement in fatigue life of rigid pavement by locally available scrap steel. These rigid pavements using steel scrap promises an appreciably higher design life, offer better serviceability and minimize crack growth and corrosion. The innovative idea of this paper is the use of waste lathe scrap as recycled steel fibers, which provides more economical and environmental sustainable SFRC PAVEMENTS. Key words: lathe scarps steel fibers, Fatigue endurance, Flexural strength, workability, Tensile strength

Prospective observational study to evaluate the pattern of adverse drug events in cancer patients receiving anti-cancer agents in a tertiary care hospital

Background: Adverse drug reactions (ADRs) associated with the use of anticancer drugs are a worldwide problem and cannot be overlooked. They range from nausea, vomiting or any other mild reaction to severe myelosuppression. The study was planned to evaluate the pattern of adverse drug events to anti-cancer agents in a tertiary care hospital.Methods: This observational prospective study was carried out in a tertiary care hospital from 1st January 2011 to 31st December 2011. A total of 213 patients who fulfilled the inclusion criteria were enrolled in the study. Out of them, 8 patients were withdrawn from the study as they subsequently underwent radiotherapy. The adverse events observed during the treatment were noted and analyzed by using applicable statistics.Results: Out of 205 patients, 98 were males and 107 were females. Breast cancer was the commonest type of cancer evident. A total 523 anti-cancer drugs were prescribed for the patients with alkylating agents being the most common. 635 adverse events (ADRs) were observed in patients with vomiting and nausea as the most common adverse drug reactions (ADREs). Majority of the ADRs (89%) had a latent onset (occurring 2 or more days after exposure to the drug). Few events were serious in nature (9%); fatal events were uncommon (0.31%). WHO causality was ‘possible’ for 94% of the events. ADRs were more frequently observed in females in the age group of 46-60 years; mood swings were significantly higher in women, while vomiting was found to be significantly common in men.Conclusions: The study showed that chemotherapy has a high potential to cause ADRs. Thus, there is a need for vigilant ADR monitoring to prevent morbidity and mortality due to ADRs

Prediction of Machining Conditions Using Machine Learning

The new blast of Machine Learning (ML) and Artificial Intelligence (AI) shows extraordinary expectations in the forward leap of additive manufacturing (AM) process displaying, which is an important step toward determining the cycle structure-property relationship. The advancement of standard AI apparatuses in information science was primarily attributed to the extraordinarily huge amount of named informational collections, that may be obtained throughout the trials or first-rate reenactments. To completely take advantage of the force of AI in AM metal while lightening the reliance on "enormous information", everybody set an Improved Neural Network (INN) structure if the wires the two information and first actual standards include the preservation laws of energy, mass, and energies, towards the NN to illuminate the growing experiences. We suggest compressed-type strategies in the Dirichlet limit regulation in light of a Heaviside capability, that may precisely uphold the BCs and speed up the growing experience. The hotel structure was applied to two agent metal assembling issues, that includes the NIST AM-Benchmark series test. The examinations show that the Motel, owing to the extra actual information, may precisely foresee the temperature and also liquefy pool elements throughout the AM processes in metal along a moderate measure of named informational collections

High Deductible Health Plans and Outcomes for Patients with Diabetes: A Realist Review

Objective: This study summarizes current literature on the association between high deductible health plans (HDHPs) and outcomes for patients with diabetes, as well as elucidates factors that may be influencing the association between the two variables.Methods: A rapid realist review was conducted to synthesize empirical studies on the implementation of HDHPs among populations with diabetes. Study outcomes varied but included emergency department visits, outpatient visits, and medication adherence.Results: Sixteen articles were selected for inclusion in the review. Eleven found an association between HDHP enrollment and adverse health outcomes. Across studies, three factors influenced the effects of HDHPs on diabetes patients: income, health literacy, and intentionality of plan choice. Policy solutions to address each of these factors were distilled from the suggestions in each study.Conclusions: These findings elucidate certain factors that should be at the forefront of any discussion on reforming HDHP structure in the United States. This review will inform the scope of future work conducted by the Center for the Business of Health at UNC on the effects of HDHPs. Future research is needed with more specific outcomes measures to confirm that adverse health outcomes are being experienced by vulnerable populations.Bachelor of Science in Public Healt

Effects of resistin on platelet function and its receptor, adenylyl cyclase associated protein 1

Resistin is an adipokine which is found elevated in patients suffering from metabolic syndrome, affecting a large proportion of the population. It is characterised by obesity, insulin resistance (IR), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), which are the biggest contributors to morbidity and mortality in the modern world. Platelets play a major role in CVD, where their activation leads to formation of thrombi, which when uncontrolled, leads to the pathophysiological effects of CVD. The role of resistin in CVD progression and its mechanism of action on its target cells still remains debatable and surrounded by controversies. In a bid to assess this, the present study aims at illustrating the effect of resistin on platelet activation by deriving conclusions from platelet functional assays. This thesis makes novel observations that resistin blunts thrombin-mediated platelet aggregation and secretion and seemingly affects the platelet actin cytoskeleton. It also finds that resistin activates downstream effectors of phosphoinositide 3 kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways in platelets. Adenylyl cyclase associated protein 1 (CAP1), a cytoskeletal protein, was recently identified as a receptor for resistin. When CAP1 was investigated in platelets, interesting observations were made, where CAP1 temporally translocated from the membrane fraction in response to thrombin mediated activation. Furthermore, in an attempt to improve our knowledge of platelet biology and to delineate future avenues for exploration, an observational proteomics investigation of cytoskeletal proteins and the change in abundance upon thrombin activation was carried out, further highlighting their importance in platelet regulation. Additionally the subcellular localisation of specific cytoskeletal proteins (IQGAP1, Arp2/3, coronin1a, profilin, cofilin, villin, l-plastin, myosin IIa, and tropomyosin) that are either known or hypothesised to interact with CAP1 was also conducted. Further investigations with proteins IQGAP1 and Arp2/3 revealed that these proteins did not interact with CAP1

Automotive Movie Recommendation System based on Natural Language Processing

People are puzzled about which movie to watch these days because there are so many movies available on various OTT platforms. A recommender system would solve this problem by recommending the best movie to the user based on his genre, actor, director, and rating preferences. The cosine similarity principle would be used to guide the recommendation system. Apart from that, we will use the Tfidftransformer and count vectorizer from the sci-kit-learn library in Python in this work. In this study work, all of the approaches' constraints have been described. All of this work was done using datasets from several OTT platforms that were available on Kaggle