A micromechanical fracture model for ductile-brittle interfaces

The micromechanical properties of a bimaterial interface depend on the (i) bonded slip and friction parameters (ii) release of fracture energy during crack growth and (iii) propagation, residual energy and shape formulations defining the failure envelope. A non-empirical fracture model is proposed for a ductile-brittle bimaterial interface. Such interfaces occur in Steel-Concrete (SC) composite wall modules, which are building blocks of nuclear and containment facilities. Similar bimaterial interfaces can occur in geotechnical structures, aerospace, ceramics and other composite applications. The thesis identifies the primary microstructural failure modes associated with such interfaces. A controlled volume fracture model for adhesively bonded interfaces is used in conjunction with Rice’s path independent J-Integral to correlate the strain energy release rate(SERR) to traction slip parameters. The linear elastic fracture model is modified to account for plasticity effects in the process zone and derive the crack tip opening displacement (CTOD). Numerical evaluation of fracture toughness parameters is performed to study impinging effects and determination of stress intensity factors. Depending on the nature of interface under consideration; appropriate tensio

Attenuation of Mycobacterium species through direct and macrophage mediated pathway by unsymmetrical diaryl urea

Tuberculosis is a major threat for mankind and the emergence of resistance strain of Mycobacterium tuberculosis (Mtb) against first line antibiotics makes it lethal for human civilization. In this study, we have synthesized different diaryl urea derivatives targeting the inhibition of mycolic acid biosynthesis. Among the 39 synthesized molecules, compounds 46, 57, 58 and 86 showed MIC values ≤ 10 μg/ml against H37Rv and mc26030 strains. The best molecule with a methyl at ortho position of the first aromatic ring and prenyl group at the meta position of the second aromatic ring showed the MIC value of 5.2 μg/ml and 1 μg/ml against H37Rv and mc26030 respectively, with mammalian cytotoxicity of 163.4 μg/ml. The effective compounds showed selective inhibitory effect on mycolic acid (epoxy mycolate) biosynthesis in14C-radiolabelled assay. At the same time these molecules also executed their potent immunomodulatory activity by up-regulation of IFN-γ and IL-12 and down-regulation of IL-10.Fil: Velappan, Anand Babu. Sastra University; IndiaFil: Charan Raja, Mamilla R.. Sastra University; IndiaFil: Datta, Dhrubajyoti. Indian Institute of Science Education and Research Pune; IndiaFil: Tsai, Yi Ting. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Halloum, Iman. Université de Montpellier; Francia. Centre National de la Recherche Scientifique; FranciaFil: Wan, Baojie. University of Illinois; Estados UnidosFil: Kremer, Laurent. Université de Montpellier; Francia. Inserm; Francia. Centre National de la Recherche Scientifique; FranciaFil: Gramajo, Hugo Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Franzblau, Scott G.. University of Illinois; Estados UnidosFil: Kar Mahapatra, Santanu. Sastra University; IndiaFil: Debnath, Joy. Sastra University; Indi

Targeted siRNA lipid nanoparticles for the treatment of KRAS-mutant tumors

K-RAS is a highly relevant oncogene that is mutated in approximately 90% of pancreatic cancers and 20–25% of lung adenocarcinomas. The aim of this work was to develop a new anti-KRAS siRNA therapeutic strategy through the engineering of functionalized lipid nanoparticles (LNPs). To do this, first, a potent pan anti-KRAS siRNA sequence was chosen from the literature and different chemical modifications of siRNA were tested for their transfection efficacy (KRAS knockdown) and anti-proliferative effects on various cancer cell lines. Second, a selected siRNA candidate was loaded into tLyp-1 targeted and non-targeted lipid nanoparticles (LNPs). The biodistribution and antitumoral efficacy of selected siRNA-loaded LNP-prototypes were evaluated in vivo using a pancreatic cancer murine model (subcutaneous xenograft CFPAC-1 tumors). Our results show that tLyp-1-tagged targeted LNPs have an enhanced accumulation in the tumor compared to non-targeted LNPs. Moreover, a significant reduction in the pancreatic tumor growth was observed when the anti-KRAS siRNA treatment was combined with a classical chemotherapeutic agent, gemcitabine. In conclusion, our work demonstrates the benefits of using a targeting approach to improve tumor accumulation of siRNA-LNPs and its positive impact on tumor reductionThis work was supported by the 2-INTRATARGET project (PCIN-2017-129/AEI) funded by MINECO-PCIN-2017-129/AEI, under the frame of EuroNanoMed III; by Consellería de Educación e Ordenación Universitaria, Xunta de Galicia's Grupos de referencia competitiva (grant number ED431C 2017/09). The authors thank TÜBİTAK (The Scientific and Technical Research Council of Turkey) for supporting this project (Project number : 217S068). S.A acknowledges the financial support for his postdoctoral research by the 2-INTRATARGET project (PCIN-2017-129/AEI) funded by MINECO-PCIN-2017-129/AEI, under the frame of EuroNanoMed IIIS

Micromechanical fracture model for ductile-brittle bimaterial interfaces

The micromechanical properties of a bimaterial interface depend on the (i) bonded slip and friction parameters (ii) release of fracture energy during crack growth and (iii) propagation, residual energy and shape formulations defining the failure envelope. A non-empirical fracture model is proposed for a ductile-brittle bimaterial interface. Such interfaces occur in Steel-Concrete (SC) composite wall modules, which are building blocks of nuclear and containment facilities. Similar bimaterial interfaces can occur in geotechnical structures, aerospace, ceramics and other composite applications. The thesis identifies the primary microstructural failure modes associated with such interfaces. A controlled volume fracture model for adhesively bonded interfaces is used in conjunction with Rice’s path independent J-Integral to correlate the strain energy release rate(SERR) to traction slip parameters. The linear elastic fracture model is modified to account for plasticity effects in the process zone and derive the crack tip opening displacement (CTOD). Numerical evaluation of fracture toughness parameters is performed to study impinging effects and determination of stress intensity factors. Depending on the nature of interface under consideration; appropriate tension softening/hardening laws are incorporated to capture the phase transformation of crack propagation in the expression of J for remote integral paths

Effect of Non-Linear Soil Structure Interaction on the Seismic Response of Critical Infrastructure Facilities

Soil structure interaction plays a crucial role in the behavior, analysis and design of heavy infrastructure of high importance such as power plants, processing facilities, hospitals, precision engineering facilities, hydraulic power infrastructure, etc. The change in frequency content of the ground motion as seismic waves propagate through the subsoil might result in the reduction or amplification of the response acceleration of seismically excited structures. SSI has a significant influence on the calculated in-structure response spectra (ISRS), and the calculated seismic design demand forces. The fundamental hypothesis is that nonlinearities at the soil-structure interface have the potential to influence the peak acceleration demands due to energy dissipation. The sources of the non-linearity include (i) non-linear structural behavior, (ii) non-linear soil behavior and (iii) geometric non-linearities across the interface such as gapping and sliding. The dissertation aims to establish a non-linear SSI analysis methodology in time domain to understand the response of structural basemat with respect to the free-field motion when subjected seismic excitation. The contribution of each source of nonlinearity on the basemat response is examined through an array of sensitivity studies. The numerical studies are carried out on the Fukushima Daichii nuclear power plant in Japan with ground motion history from the Tohoku earthquake

Carboxymethylsulfonylated ribopyrimidines: rational design of ribonuclease a inhibitors employing chemical logic

Hydrolysis of RNA by ribonuclease A crucially depends on the participation of the 2'-OH group as well as the positioning of the internucleotide bond at two different sites of the enzyme. Therefore, ribopyrimidines were modified with −SO2CH2CO2H, an acidic functional group, which was expected to interact with the phosphate binding site. These ribonucleosides were designed to understand the influence of the 2'-OH group of these inhibitors on ribonuclease A inhibition along with the effect of the −SO2CH2CO2H group. The "down" configuration of the 2'-OH group enhanced the inhibitory properties (Ki = 1.75 μm) and also imparted important Val43 H-bonding with the furanose oxygen atom of the inhibitors. One of the most important aspects of this work is that there was no serendipitous discovery of the inhibitors. The inhibitors reported in this manuscript were obtained by design by employing chemical logic

A metal-free, aqueous and general route to 1,5-disubstituted-1,2,3-triazoles: ‘reversed regioisomeric’ 1,3-dipolar cycloaddition of azides and vinyl sulfones

A metal-free, vinyl sulfone-based synthesis of 1,5-disubstituted-1,2,3-triazoles is reported for the first time. These triazoles are easily formed in a regioselective fashion by heating under reflux a mixture of a substituted vinyl sulfone and an organic azide ‘on water’. This powerful and practical route has the potential to be exploited for the synthesis of complex 1,5-disubstituted-1,2,3-triazoles

Ribonuclease A inhibition by carboxymethylsulfonyl-modified xylo- and arabinopyrimidines

A group of acidic nucleosides were synthesized to develop a new class of ribonuclease A (RNase A) inhibitors. Our recent study on carboxymethylsulfonyl-modified nucleosides revealed some interesting results in RNase A inhibition. This positive outcome triggered an investigation of the role played by secondary sugar hydroxy groups in inhibiting RNase A activity. Uridines and cytidines modified with -SO₂CH₂COOH groups at the 2'- and 3'-positions show good inhibitory properties with low inhibition constant (K_i) values in the range of 109–17 μM. The present work resulted in a set of inhibitors that undergo more effective interactions with the RNase A active site, as visualized by docking studies

Evaluation of polymerase chain reaction-based ribosomal DNA sequencing technique for the diagnosis of mycotic keratitis

Purpose: To evaluate the polymerase chain reaction (PCR) and sequencing-based ribosomal deoxyribonucleic acid (rDNA) typing technique for rapid and sensitive diagnosis of fungal keratitis. Design: Laboratory investigation. Methods: The present study included culture-based methods along with PCR and ITS2/5.8S rDNA sequencing to evaluate fungal infections in 32 corneal scrapings from patients with suspected mycotic keratitis. Results: Good correlation was found between the culture and PCR rDNA sequencing-based methods. We also identified fungal strains that were noncultivable in routine culture medium and fungal strains, which have been reported scarcely in previous reports from eastern Indian studies. Conclusions: The PCR and rDNA sequencing-based approaches may be useful alternatives to culture-based techniques for the rapid and sensitive diagnosis of fungal keratitis. We found that clinically significant pathogenic fungal strains can be detected and differentiated by this method in a short period. This method therefore is useful for the early treatment of fungal infection