Bayesian Calibration and Uncertainty Quantification of a Rate-dependent Cohesive Zone Model for Polymer Interfaces

In the present work, a rate-dependent cohesive zone model for the fracture of polymeric interfaces is presented. Inverse calibration of parameters for such complex models through trial and error is computationally tedious due to the large number of parameters and the high computational cost associated. The obtained parameter values are often non-unique and the calibration inherits higher uncertainty when the available experimental data is limited. To alleviate these difficulties, a Bayesian calibration approach is used for the proposed rate-dependent cohesive zone model in this work. The proposed cohesive zone model accounts for both reversible elastic and irreversible rate-dependent separation sliding deformation at the interface. The viscous dissipation due to the irreversible opening at the interface is modeled using elastic-viscoplastic kinematics that incorporates the effects of strain rate. To quantify the uncertainty associated with the inverse parameter estimation, a modular Bayesian approach is employed to calibrate the unknown model parameters, accounting for the parameter uncertainty of the cohesive zone model. Further, to quantify the model uncertainties, such as incorrect assumptions or missing physics, a discrepancy function is introduced and it is approximated as a Gaussian process. The improvement in the model predictions following the introduction of a discrepancy function is demonstrated justifying the need for a discrepancy term. Finally, the overall uncertainty of the model is quantified in a predictive setting and the results are provided as confidence intervals. A sensitivity analysis is also performed to understand the effect of the variability of the inputs on the nature of the output.Comment: To be submitted for peer-revie

Artificial Genetically Encoded Peptides and Proteins as Next-Generation Therapeutics: Selection of ligands for Mycobacterium tuberculosis UDP-Galactopyranose Mutase as Potential Inhibitors.

Peptides and small proteins provide a dynamic platform for drug discovery and therapeutics. They have a wide range of applications including inhibition of protein-protein interaction, inhibition of transporter and enzyme activity, imaging, and as co-crystallisation ligand for structural studies. In this study, we employed in vitro selection of ligands, using mRNA display, from an artificial genetically encoded library of peptides/proteins to identify candidates that bind the enzyme Mycobacterium tuberculosis UDPGalactopyranose mutase (MtUGM). The enzyme catalyzes the reversible conversion of UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf), which is then assembled as the galactofuran layer in Mycobacterium tuberculosis (Mtb) cell wall. Cell wall biosynthesis is essential for Mtb survival and pathogenicity, deletion in genes involved in this process have proven lethal. We successfully identified macrocyclic peptides (MCPs) and affibodies specific for MtUGM from a library with a diversity >1012 clones through random non-standard peptide integrated discovery (RaPID) system and mRNA display, respectively. Enrichment of positive binders was observed for both selection processes suggesting binding specificity. Previous studies reveal that natural product-like MCPs can inhibit enzyme activity; their small size, conformational stability and high affinity for the target makes them attractive ligands. Thus, we hypothesize that identified MCPs may show inhibition of MtUGM thereby halting cell wall biosynthesis. Discovered affibodies will be used for structural analysis of MtUGM. The World Health Organisation (WHO) reported tuberculosis (TB) caused by Mtb to be one of the leading causes of death worldwide, with increasing incidences of drug resistant strains necessitating discovery of novel therapeutics. Through our study, we present a novel approach for discovering peptide/protein-based ligands for MtUGM and hope to develop an assay for screening MCPs for potential inhibitors

MANAS (MIND) AND MANOVIKARA (MENTAL DISORDER) IN AYURVEDA: A REVIEW

Ayurveda is thought to be ‘The Science of Life’, and therefore the follow involves the care of physical and mental health of creature. Ayurveda isn’t solely restricted to body or physical symptoms however conjointly provide comprehensive data concerning mental and social health. Three factors are basically responsible for the origin of any kind of disease, these are Asatmaindriyartha Samyoga (excessive utilization or non-utilization or improper utilization of sense faculties), Prajnaparadha (Intellectual blasphemy) and Parinama (time). Balanced Doshas of mind regulates the emotion while disturbed Doshas of mind plays an important role in the pathogenesis of mental diseases. The increasing level of stress in today’s time gives a huge surge of Manovikara (mental disorder). In Ayurveda many references of Manas (mind) and treatment of Manovikara (mental disorder) are available which would be easy to understand and rewarding the field of treatment. Role of Swastavritta including Daivavyapasraya, Satwavajay, Naisthiki chikitsa and Yoga are very important in the management of Manovikara. In modern era we are at the grasp of Raja and Tama which are the root cause of mental disorder. So, it is necessary to understand the Manovikara (mental disorder), its causes, symptoms, prevention and management. Present article is a review article contains review of Manas (Mind) and Manovikara (Mental disorder) in Ayurveda

A Comparative Clinical Evaluation on the Efficacy of Kuberaksha & Yava with Lifestyle Modification, in The Management of Prameha with Special Reference to Prediabetes

We are living in the age of complexity, contradiction, and challenge relating to various health issues such as lifestyle disorder, ageing, mental health euthanasia, drug resistance and so on. Diabetes Mellitus is a Giant disease and major health issue that has reached alarming level in spite of terrific advance in modern medical science. Prediabetes is the precursor stage before Diabetes Mellitus, in which not all of the symptoms required to diagnose diabetes are present, but blood sugar is abnormally high. Prediabetic persons are considered to be at increased risk for the subsequent development Diabetes Mellitus. Sushruta Samhita mentioned, all varieties of Prameha if not treated at appropriate time, become changed to Madhumeha which is incurable. So, early detection, treatment and prevention of this disease in Prediabetic stage is needed. The modification of lifestyle should be the first aim and objectives to restrict or combat such problems, beside this prime objective, some medication which is safe and efficacious to be introduced. So, a clinical study with 60 patients has been conducted on Prediabetes through the management with ‘Kuberaksha’ and ‘Yava’ in such 2 groups of treatment. The two drugs are carrying such properties which acts in Samprapti vighatana (prevent pathogenesis) of the disease. In both cases statistically significant results are found (P<0.001 & <0.01). On comparison between two groups Kuberaksha powder showed better result than Yava powder

A novel high symmetry interlocking micro-architecture design for polymer composites with improved mechanical properties

Development and design of novel materials based on their micro-structural arrangements are being intensely investigated due to their wide range of real and potential applications. One of the key objectives of such design is to achieve multiple properties, which are often competing in nature (such as high stiffness-high damping, high strength-high toughness etc.), within a single composite material. In the present work we propose a novel interlocking micro-architecture design to achieve high symmetry in a plane within a composite. The present study shows that constraining a very low volume fraction of high damping polymer within this micro-architecture, together with a stiff polymer, results in a simultaneously high stiffness and high damping polymer composite. The proposed micro-architecture design possesses high symmetry that is not commonly found in fiber-reinforced polymer composites. The interlocking feature avoids use of extra adhesives for holding two adjacent building blocks. Finite element simulations are performed by considering the micro-architecture made of two widely used polymeric materials such as polymethyl methacrylate (PMMA as the stiffer building block) and polyurethane (PU as the soft viscous material). Our numerical predictions show remarkable stiffness and damping properties for the design over a wide range of frequencies. Simulations are also performed considering contact between two polymer interfaces to establish the fact that the geometric interlocking works well without any use of adhesive for holding the blocks together. Further simulations are performed under high frequency impulse pressure loading to study dynamic wave propagation through the micro-architecture that shows the near-isotropic response of the proposed micro-architecture

A NOVEL ARCHITECTURED POLYMER COMPOSITE FOR NEAR ISOTROPIC CHARACTERISTICS AND IMPROVED COMBINED STIFFNESS€”DAMPING PROPERTIES

A novel micro-architecture is proposed to design multifunctional composite with simultaneous stiffness and damping capabilities. The micro-architecture utilizes the hexagonal symmetry in order to manifest in-plane isotropy in the properties. The micro-architectured composite is made of circular gear and triangular shaped stiff material and a layer of viscoelastic material in between them. The gear and triangular shaped building blocks is designed to utilize the interlocking mechanism for them to transfer load through the interlock under tensile load. The combination of the stiff and the viscoelastic material in the composite yields to both high-stiffness and highdamping, which otherwise are competing in engineering materials. Numerical experiments are performed in order to characterize the design and quantify the performance parameters of the micro-architectured composite using PMMA as the stiff materials and PU as the viscoelastic materials. Quasi-static tensile behavior and damping performance under low frequency load is predicted using finite element analysis. The thickness of the PU layer is varied to investigate the effect of PU volume fraction. The simulation results show that with approximately 7 percent volume fraction of PU the composite retains 55 percent stiffness of PMMA. With the increase in PU volume fraction (layer thickness), the damping of the composite increases and the stiffness decreases. The composite achieves 10 and 50 percent damping of PU with only 7 and 30 volume percent of PU, at 10 Hz loading frequency. The combined performance (i.e. multiplication of stiffness and damping) is found to be close to Wang-Lakes line, which is notable for a polymer-polymer composite

A REVIEW ON THE SIGNIFICANCE OF NITYA VIRECHANA IN THE MANAGEMENT OF JALODARA (ASCITES)

Jalodara is a type of Udara roga. It is such type of a disease which is difficult to cure. Its occurrence is increasing day by day in our society. In Jalodara, there is accumulation of fluid in between Tvak and Mamsa of Udara pradesha (abdomen). As a result, there is distension of abdomen. Its main causes are Mandagni, Srota avarodha and Apa dosha etc. Here vitiated Kapha and Vata are mainly involved. In this disease accumulated Doshas are mainly obstruct the Swedavaha and Ambuvaha srotas. It has three stages which are Ajatodakavastha, Picchavastha and Jatodakavastha. Jalodara in its Jatodakavastha is incurable. It can be correlated with Ascites based on its clinical features. Ascites is the abnormal accumulation of free fluid in the peritoneal cavity. Its most common cause is portal hypertension related to hepatic cirrhosis. Ascites is asymptomatic when there is small accumulation of fluid in peritoneal cavity. But when there is larger accumulation of fluid (> 1 lit), it shows symptoms. In this article, Ayurvedic treatment principles for Jalodara have been discussed in details. These include Nidan parivarjana, Nitya virechana, therapies which remove the defects of liquid elements (Apam doshaharanam), Dipana and Shastra karma (abdominal tapping). This article is mainly based on the review of the significance of Nitya virechana in the management of Jalodara (Ascites)

Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists

Toll-like receptor 7 (TLR7) is activated in response to the binding of single-stranded RNA. Its over-activation has been implicated in several autoimmune disorders, and thus, it is an established therapeutic target in such circumstances. TLR7 small-molecule antagonists are not yet available for therapeutic use. We conducted a ligand-based drug design of new TLR7 antagonists through a concerted effort encompassing 2D-QSAR, 3D-QSAR, and pharmacophore modelling of 54 reported TLR7 antagonists. The developed 2D-QSAR model depicted an excellent correlation coefficient (R2training: 0.86 and R2test: 0.78) between the experimental and estimated activities. The ligand-based drug design approach utilizing the 3D-QSAR model (R2training: 0.95 and R2test: 0.84) demonstrated a significant contribution of electrostatic potential and steric fields towards the TLR7 antagonism. This consolidated approach, along with a pharmacophore model with high correlation (Rtraining: 0.94 and Rtest: 0.92), was used to design quinazoline-core-based hTLR7 antagonists. Subsequently, the newly designed molecules were subjected to molecular docking onto the previously proposed binding model and a molecular dynamics study for a better understanding of their binding pattern. The toxicity profiles and drug-likeness characteristics of the designed compounds were evaluated with in silico ADMET predictions. This ligand-based study contributes towards a better understanding of lead optimization and the future development of potent TLR7 antagonists

Real World Study of Effectiveness of Gemigliptin Add-On Therapy in Type 2 Diabetes Mellitus

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral antidiabetic agents that increaseendogenous levels of incretin hormones and lead to an increased insulin level and a reduced glucagon level in a glucose-dependent way. Gemigliptin, is a potent, selective, competitive, and long-acting DPP-4 inhibitor. The objective of our study was to evaluate the realworld efficacy and safety of gemigliptin.Materials and methods: A real-world prospective, observational, single-center study conducted in the Endocrinology Department, of a tertiary care hospital. 60 patients were included with 22 (36.7%) female patients. The treatment options consisted of uncontrolled metformin monotherapy, dual combination therapy, triple oral anti-hyperglycemic agents, metformin, and basal insulin combination. Weight, body mass index (BMI), fasting plasma glucose (FPG), 2 hours post postprandial glucose (PPG), HbA1c% were documented at baseline and followed up at 3 months.Results: The baseline HbA1c, FPG and PPG were 9.50 ± 2.24 %, 176.71 ± 67.076 mg/dL, 243.37 ± 93.97 mg/dlrespectively. After 3 months of additional gemigliptin therapy, HbA1c, FPG, and PPG were significantly reduced to 8.24 ± 1.83%, 144.32 ± 50.664, 184.93 ± 69.66 respectively.Conclusions: In real world settings, gemigliptin, a new DPP-4 inhibitor was found to be effective, safe and well tolerated as add-on therapy in adult type 2 diabetes mellitus (T2DM) subjects