Indian Institute of Science Bangalore
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N-Heterocyclic Carbene-Catalyzed Synthesis of Oxazolones, e-Lactones and N-N Axially Chiral Molecules
No full textThe diverse reactivity of N-heterocyclic carbenes (NHCs) in organocatalysis is due to the possibility of different modes of action. Although NHC-bound enolates and dienolates were well-known, the NHC-bound cross-conjugated aza-trienolates were undisclosed. We have demonstrated the synthesis of pyrrolooxazolones via NHC-bound azatrienolate intermediates. In the same fashion, involvement of chiral alpha-carbon center (proximal reaction centre) in dynamic kinetic resolution (DKR) via NHC-bound enolates were known. However, the gamma, gamma-disubstituted chiral carbon center (remote reaction centre) involving in DKR via NHC-bound dienolates were unknown. We have recently demonstrated the DKR of gamma,gamma-disubstituted indole 2-carboxaldehydes via NHC-Lewis acid cooperative catalysis for the synthesis of tetracyclic epsilon-lactones. Additionally, NHC-catalyzed atroposelective synthesis of C-C and C-N axially chiral molecules were known, and the asymmetric synthesis of axially chiral N-N molecules remains unknown in carbene catalysis. We have demonstrated the N-heterocyclic carbene (NHC)-catalyzed selective amidation reaction leading to the atroposelective synthesis of N-N axially chiral 3-amino quinazolinones.UGC CSI
Wetting and Frictional Properties of Hexagonal Boron Nitride with Atomic-Scale Defects and Roughness
No full textTwo-dimensional (2D) materials such as graphene, hexagonal boron nitride (hBN), and molybdenum disulfide (MoS2) have become materials of choice for applications spanning optoelectronics, atomically thin coatings, and high-throughput and high-selectivity membranes. In such applications, the exposure of 2D materials (e.g., hBN) to liquids underscores the importance of understanding 2D material-liquid interactions. Wettability is one of the important interfacial properties of 2D materials such as hBN, and understanding it is vital for designing devices for seawater desalination and osmotic power harvesting. The contact angle of water is the fundamental property measured in experimental investigations on wettability; so far, however, studies have not considered the effect of defects on the water contact angle on hBN surfaces. In this thesis, we simulated the wetting behaviour of water on monolayer and bulk hBN, in their pristine and defective forms, using classical molecular dynamics simulations supported by quantum-mechanical density functional theory calculations. We considered five defect topologies – the B, N, BN, B2N, and B3N vacancy defects – and also studied the effect of the defect concentration on the water contact angle to investigate more realistically the interfacial properties of defective hBN. We found that defects at a concentration of 0.082 nm-2 no longer affect the wetting properties of hBN surfaces. While bulk hBN, modeled as a stack of four monolayers, showed hydrophilic behavior, monolayer hBN exhibited hydrophobic behaviour. Additionally, hBN surfaces containing B and B2N vacancies exhibited increased hBN-water electrostatic interactions, especially at a higher vacancy concentration of 0.328 nm-2. We found that the presence of surface roughness, but not that of vacancy defects, leads to remarkable agreement with the experimentally observed water contact angle of 66° on freshly synthesized, uncontaminated hBN. Additionally, the inclusion of surface roughness accurately predicts the experimental water slip length of ~1 nm on hBN. Our results underscore the importance of considering realistic 2D materials with surface roughness models while modeling nanomaterial-water interfaces in molecular simulations
Hybrid Physics-Data Driven Models for the Solution of Mechanics Based Inverse Problems
No full textInverse problems pose a significant challenge as they aim to estimate the causal factors that result in a measured response. However, the responses are often truncated, partially available, and corrupted by measurement noise, rendering the problems ill-posed, and may have multiple or no solutions. Solving such problems using regularization transforms them into a family of well-posed functions. While physics-based models are interpretable, they operate under approximations and assumptions. Data-driven models such as machine learning and deep learning have shown promise in solving mechanics-based inverse problems, but they lack robustness, convergence, and generalization when operating under partial information, compromising the interpretability and explainability of their predictions. To overcome these challenges, hybrid physics-data-driven models can be formulated by integrating prior knowledge of physical laws, expert knowledge, spatial invariances, empirically validated rules, etc., acting as a regularizing agent to select a more feasible solution space. This approach improves prediction accuracy, robustness, generalization, interpretability, and explainability of the data-driven models. In this dissertation, we propose various physics-data-driven models to solve inverse problems related to engineering mechanics by integrating prior knowledge and its representation into a data-driven pipeline at different stages. We have used these hybrid models to solve six different inverse problems, such as leakage estimation of a pressurized habitat, estimating dispersion relations of a waveguide, structural damage identification, filtering temperature effects in guided waves, material property prediction, and guided wave generation and material design.
The dissertation presents a detailed overview of inverse problems, definitions of the six inverse problems, and the motivation behind using hybrid models for their solution. Six different hybrid models, such as adaptive model calibration, physics-informed neural networks, inverse deep surrogate, deep latent variable, and unsupervised representation learning models, are formulated, and arranged on different levels of a pyramid, showing the trade-off between autonomy and explainability. All these new methods are designed with practical implementation in mind. The first model uses an adaptive real-time calibration framework to estimate the severity of leaks in a pressurized deep space habitat before they become a threat to the crew and habitat. The second model utilizes a physics-informed neural network to estimate the speed of wave propagation in a waveguide from limited experimental observations. The third model uses deep surrogate models to solve structural damage identification and material property prediction problems. The fourth model proposes a domain knowledge-based data augmentation scheme for ultrasonic guided waves-based damage identification. The fifth model uses unsupervised feature learning to solve guided waves-based structural anomaly detection and filtering the temperature effects on guided waves. The final model employs a deep latent variable model for structural anomaly detection, guided wave generation, and material design problems. Overall, the thesis demonstrates the effectiveness of hybrid models that combine prior knowledge with machine learning techniques to address a wide range of inverse problems. These models offer faster, more accurate, and more automated solutions to these problems than traditional methods
Studies on Bodipy-platinum(Ii/Iv) Conjugates for Cellular Imaging and Photodynamic Therapy
No full textCancer emerges from the abnormal proliferation of aberrant cells. Amidst a multitude of treatment options, chemotherapy is widely used as a viable methodology. Despite its widespread use, it is encumbered with significant limitations due to drug related side-effects. Consequently, in recent times, photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) have emerged as highly promising alternatives to traditional chemotherapy. This thesis aims to conceive and synthesize new platinum(II/IV) complexes using ligands as multifunctional agents for effective phototherapy and photochemotherapy applications. In the initial phase, a series of mono-functional platinum(II) complexes [Pt(L1-3)Cl]Cl (1-3) were synthesized having BODIPY (boron-dipyrromethene)-tagged dipicolylamine (dpa) ligands (L2 and L3) as green and red light emitting photosensitizers along with a benzyl derivative of dpa (L1). These mono-functional complexes exhibit remarkable affinity for DNA binding, as evidenced from a study employing the model nucleobase 9-EtG, while also displaying the ability to generate singlet oxygen upon photoactivation of the BODIPY photosensitizer. In subsequent investigations, we synthesized a novel platinum(IV)-BODIPY conjugate, named Oxoplatin-B (4), derived from cisplatin. The prodrug exhibited photo-induced ligand release, accompanied by the simultaneous formation of the cisplatin core through a two-electron Pt(IV)-Pt(II) reduction process. Encouraged from the results obtained with the green light Pt(IV) prodrug, we embarked on investigating the possibilities of a clinically applicable platinum(IV) prodrug with the formulation [Pt(NH3)2Cl2(OH)(L6)] (6), having a red light active BODIPY ligand (HL6). Upon red light irradiation, the complex exhibited significant PDT activity with sub-micromolar IC50 values in cancer cells such as HeLa and MCF-7. Moving forward, we introduced a novel prodrug (7) formulation that combines a platinum(IV) core with a bioactive biotin (vitamin B7) moiety, covalently linked to a PEGylated BODIPY ligand (HL7) designed to respond to red light stimulation and for enhanced bioavailability. Notably, the complex displays remarkable stability in solution in dark, but rapidly activates upon red light exposure without any need for external reducing agents. Finally, we made a comprehensive study on the synthesis and characterization of a hetero-bimetallic Ru(II)-Pt(IV) conjugate (9). This conjugate presents a dual-action Pt(IV) complex with a chemo-active unit and a BODIPY-Ru(II)-bis-terpyridine dyad complex as a photosensitizer. This prodrug induced significant photocytotoxicity with remarkably high phototherapeutic index (PI) value of >4500 in A549 cancer cells. The findings of this thesis work pave the way for innovative approaches in the design and development of new generation of platinum(II/IV) complexes having BODIPY-based photosensitizers, offering exciting prospects in PDT and cellular imaging applications
Structural and Electrochemical Investigations of Monovalent and Divalent Aqueous Rechargeable Batteries
No full textSeveral stringent laws and regulations have been enforced by various National/International agencies for the adoption of sustainable methods for energy production and usage. In recent times, electric grids based on alternative renewable sources such as solar, tidal, geothermal, and biomass have witnessed an upsurge. However, the intermittent nature of renewable resources and the sub-optimal electricity distribution/transmission calls for corrective measures leading to enhancement in the efficiency of electricity utilization. It is now widely recognized that energy storage via rechargeable batteries can be an efficient strategy in making the process(es) of electricity production and utilization from the grid to the end-user. Lithium-ion batteries are considered one of the most promising candidates with their outreach in various sectors, such as portable electronics, electric mobility, and grid storage applications. While advanced LiBs may offer good power and energy density, these are unlikely to meet the stiff scale-up targets concerning performance, cost, and safety in large-scale applications such as electric vehicles and the grid. Lithium reserves are limited and distributed heterogeneously. Additionally, conventional Li-ion uses expensive and flammable organic liquid electrolytes Aqueous rechargeable batteries (both monovalent and multivalent) are considered safer alternatives to state-of-the-art LIB technology and other non-aqueous battery chemistries owing to several advantages based on higher safety, cost-effectiveness, and higher ionic conductivity. As water is the solvent, aqueous rechargeable batteries do not require a sophisticated cell assembly line. One of the significant challenges that hinder their wide-scale application is the choice of suitable electrode materials that can work in the aqueous environment. In this thesis, various electrode materials with optimized electrolyte compositions for both aqueous monovalent and multivalent metal-ion rechargeable batteries have been explored. Chapter 3 explores the aqueous rechargeable mixed ion batteries we have developed using a NASICON anode and an olivine cathode in mixed ion electrolytes. The interesting phenomenon of selective ion insertion by the host structure in the presence of more than one cation in the electrolyte is probed in detail. In Chapters 4 to 7, we have explored various host materials (redox-active 2-D covalent organic frameworks, transition metal oxides, Prussian blue analogs) for the aqueous rechargeable divalent metal ion batteries (Zn, Ca, and Mg). The electrochemical characterizations of the materials are performed in detail to account for their redox behavior. The effect of electrolyte composition on the electrochemical performance of the cell is studied in detail. The thesis also probes the underlying mechanism of the battery operation associated with the structural/phase evolution of the electrode structure (with successive cycling) in detail with the help of various post-cycling ex-situ measurements.UGC, DS
Raman Spectroscopy Instrumentation and Its Application in Deep Tissue Imaging
No full textRaman spectroscopy is based on inelastic scattering, which gives molecular information. Due to its weak nature, for a long-time Raman spectroscopy was limited to only study of molecular interactions, but with the advancement in technology such as highly compact and stable lasers, high quantum efficiency and low noise detectors and so on, Raman spectroscopy today finds itself in wide applications ranging from study on biological cells to space applications.
In the first work we aim to develop a 3D Raman imaging system that can give both chemical and morphological information of the concealed object using Universal Multiple Angle Raman spectroscopy (UMARS). Spatial offset Raman spectroscopy (SORS) is a widely used Raman technique and they can obtain Raman signals upto depth of 5 cm. Using UMARS technique we were able to demonstrate that we could obtain Raman signals of deeply buried objects (>5 cm). In the second work, we developed a 3D Raman Monte Carlo model for the UMARS experiments. The model was developed to simulate light propagation inside a chicken tissue with an ellipsoid object containing different chemicals embedded inside it. The 2D Raman intensity map obtained in this simulation was compared to the 2D Raman intensity map obtained by experiments and they were found to be in agreement. In the third work, we developed a low cost (< 4lakhs INR), portable (30×30cm), high throughput (f/3) and minimum optical aberration Raman spectrometer. In the fourth work, we developed a novel spectrometer design. Unlike current diffraction grating based spectrometer, this novel spectrometer utilizes multi diffraction orders. This design can be operated in an optical addition mode, where the different orders (+1 and -1) of the diffraction grating are focused onto the same detector plane such that the same wavelengths of both the order are optically combined to yield better signal to noise ratio. In another mode, this spectrometer records different wavelength range of the diffracted orders onto the detector, thus obtaining a long range spectrum without the need for a complex mechanism for rotating the grating. In the fifth and final work, we developed a low cost charge coupled devices (CCD) data acquisition module for spectroscopy applications. Here a CCD data acquisition system was developed based on field programmable arrays (FPGA)
ALE-based Monolithic Finite Element Strategies for Fluid Structure Interaction Problems
No full textFluid-structure interactions (FSI) represent a class of engineering problems which involve a two-way coupling between the solid motion and the fluid flow. The deformation of the solid caused by the fluid forces at the boundary of the solid generates the boundary condition for the fluid flow. Such interactions are widespread in engineering and also in nature. The fluttering of aircraft wings and compressor blades, flapping of the wings of birds and insects, floating of ships, sound produced by musical instruments like drums and trumpets, inflation of automobile airbags, dynamics of spacecraft parachutes, flowing of blood through the arteries and veins pumped by the human heart are all examples of FSI problems. The non-linearity in the equations of fluid mechanics and large deformation structural mechanics along with the requirement to satisfy the interface conditions between solid and fluid makes it almost impossible for this class of problems to be dealt with analytically. However, with the emergence of computers, there have been significant advances in this class of problems numerically.
In this thesis we present new monolithic finite element strategies for solving various classes of fluid-structure interaction problems. The term `monolithic' means that the governing equations of the solid and fluid along with the interface and boundary conditions are solved simultaneously. The developed strategies are based on the Arbitrary Lagrangian-Eulerian (ALE) formulation for the fluid domain, and the Lagrangian framework for the solid domain.
First, we develop a new monolithic FEM formulation for problems involving a compressible fluid and a hyperelastic structure fully coupled with the thermal field. We develop an `energy-momentum conserving' time-stepping strategy, i.e., in the Lagrangian limit, the time-stepping strategy that we propose conserve the total energy, and the linear and angular momenta. Detailed proofs with numerical validations are provided. We use a displacement-based Lagrangian formulation for the structure, and a velocity-based ALE mixed formulation with appropriately chosen interpolations for the various field variables to ensure stability of the resulting numerical procedure. Apart from physical variables such as displacement, velocity, etc., no new variables are introduced in the formulation.
Next, we present a two-dimensional monolithic FEM-based strategy for FSI problems involving partly immersed (floating) hyperelastic solids in an incompressible fluid. This strategy can be used for studying the dynamics of freely floating bodies as well as the accurate computation of hydrodynamic forces acting on them. Since the portion of the solid immersed in the fluid varies with time, one cannot use the same nodes for the solid and the fluid at the interface. The continuity requirements at the fluid-structure interface have been satisfied in a weak sense using the mortar method. The flexibility of the ALE technique permits us to treat the free surface of the fluid as a Lagrangian entity where the mesh velocity and material velocity are equal. This allows us to model the interface as a contact between the solid and fluid surfaces. The same strategy can be used to analyse sloshing in containers with curved or deformable walls.
Next, motivated by micro-electro-mechanical systems (MEMS), we present a monolithic FEM-based strategy for problems involving the deformation of a hyperelastic solid and an incompressible fluid in the presence of an electrostatic field. The equations of electrostatics are solved on the reference configuration over both the solid and fluid domains, with voltage and electric displacement continuity imposed at the interface. The fluid is assumed to be a non-conductor of electricity so that there is no flow of charge through the fluid. The concept of generalized permittivity is used to model the solid as a general dielectric material.
In the final part of this thesis, we generalize the formulation in the previous chapter by introducing compressibility effects in the fluid flow, and analyse the effect of fluid compressibility on the response of MEMS devices of various geometries.
In all the formulations developed above, a hybrid formulation is used to prevent locking of thin structures. Also, in every formulation, we carry out a consistent linearization resulting in exact tangent stiffness matrices which ensure that the concerned algorithm converges quadratically within each time step. Detailed expressions for the stiffness matrices and load vectors are provided in each chapter so that any interested reader can easily implement any of these strategies. A number of benchmark examples have been presented to illustrate the good performance of the proposed strategies
Development of Solution Methodologies for Multi-Product, Multi-Component, Production-Inventory Planning Problem in a Component Remanufacturing Environment considering Backorders and Quantity Discounts
No full textClosed loop supply chain has been an area of research which has evolved over the years. This thesis aims to address a problem in this domain, specifically from the perspective of an Original Equipment Manufacturer (OEM) in the discrete product manufacturing industry. The OEM seeks to involve remanufacturing as part of its business process wherein its major concern is to satisfy demands for multiple products from customers. To satisfy the demands of products, the OEM needs to assemble the products using multiple components. These components can be obtained from multiple sources viz: manufacturing, remanufacturing, and purchasing from external suppliers.
Incorporating remanufacturing is beneficial for the OEM as it aids in reducing energy consumption and the overall costs. Specifically, the remanufacturing cost is observed to be generally between 40–60% of the manufacturing cost and consuming only 20% of a firm’s effort. Moreover, due to technological constraints, certain components do exist, which cannot be made in-house. Such components need to be only purchased from external suppliers who offer quantity discounts, to motivate the OEM to buy in bulk. Thus, the OEM needs to consider this aspect too while making the purchase decision. Also, at times, if the complete demand for products cannot be satisfied in a said period due to capacity restrictions, the unsatisfied portion of the demand is backordered to future periods. Furthermore, priority is given to satisfy this backordered demand before satisfying current demand of that period.
The OEM thus needs to plan the production and inventory adequately and optimally in such a way that its overall profit is maximized subject to various constraints. This thesis predominantly intends to aid the OEM in this process by addressing a Multi-Product (MP), Multi-Component (MC), Production-Inventory Planning problem (PIPP) in a Component Remanufacturing Environment (CRE) considering Backorders (BO) and Quantity Discounts (QD), [shortly referred as MP-MC-PIPP in CRE with BO and QD], with an objective of maximizing total profit for the OEM. This research problem is addressed by proposing three research objectives.
As part of the first research objective, an Integer Linear Programming (ILP) model is developed with an objective of maximize the OEM profit. The computational complexity of the developed ILP model is studied by varying values of few parameters, one at a time, and empirically observed that the research problem defined in this study is computationally intractable to obtain optimal solution for large scale problem instances. Due to this computational intractable nature of the ILP model, 20 variants of Greedy Heuristic Algorithm (GHA), are proposed as the second research objective of the study. To arrive at the multiple variants of GHA, the overall research problem is split into four integrated decision problems, namely, the, Product Assembly-Backorder (PAB) Problem, Dismantling Products – Remanufacturing Components (DisP-RMC) Problem, Manufacturing Component (MC) Problem and Purchasing Component with Quantity Discount (PCQD) Problem. Subsequently certain decision rule(s) are proposed for solving each of these decision problems. The 20 variants of the GHA are thus proposed by having a combination of the decision rules proposed for the various decision problems. Furthermore, the performance evaluation of each of the 20 variants of GHA is analyzed both empirically and statistically, by developing a suitable computational experiment [that is, by (a) defining experimental design, (b) identifying benchmark procedures, and (c) identifying suitable performance measures] and the 3 top better performing variants of GHA are identified.
In the last objective of the study, 12 variants of simulated annealing (SA) algorithm are implemented considering the solution obtained from each of the top 3 variants of the proposed GHA as initial solution to the SA algorithm. Before implementing the SA algorithm, the values of the SA parameters are set by following the Taguchi approach. Subsequently, the performance of the proposed 12 variants of SA is evaluated both, empirically and statistically and it is observed that applying the SA algorithm considering the solution obtained from the top performing proposed GHA is improving the loss of optimality considerably.
The practical implication of this study could be to devise, develop, and provide solution approaches to the OEM for the MP-MC-PIPP in CRE with BO and QD to maximize their optimal profits. Additionally, this will aid the OEM to efficiently (i) plan their inventories, (ii) deal with the aspect of backorders and (iii) choose their component purchase plan including the component suppliers in a wise manner.
However, there are certain limitations to this study, such as (a) the problem is addressed from a deterministic problem setting, (b) capacity restrictions for inventory and scrapping are not considered and (c) the input data is generated based on an experimental design and not the real data collected from OEM. In addition to overcoming the limitations mentioned in this thesis, there are many immediate future research directions for interested future researchers such as (a) developing alternate heuristic approaches and/or applying other metaheuristic algorithms for the research problem defined in this study, (b) developing an appropriate lower bound which can act as a better benchmark solution procedure instead of the estimated optimal solution and (c) considering environmental and social objectives along with the economic objectives
Development of patient-derived tumor models toward understanding disease biology and drug screening
No full textCancer is a complex disease of uncontrolled cell proliferation, which cripples the normal functioning of tissues. According to GLOBOCAN 2020, an estimated 19.3 million new cancer cases and around 10 million cancer deaths have been reported globally, indicative of the increasing cancer burden worldwide. Decades of research have gone into establishing various model systems that can serve as a platform not only for understanding the fundamental molecular basis of cancer but also for translational aspects. Selecting an ideal model system that faithfully reflects the given tumor system is one of the critical challenges faced by researchers. In this regard, model systems derived from patient biopsies serve as a powerful and robust tool for understanding the disease mechanism, preclinical drug testing, and predicting patient response. Moreover, they can be used to study the existing variations in terms of etiology, molecular aspects, and biological responses of cancers in different populations. However, there is a dearth of such tumor models, particularly derived from Indian patients. Therefore, this thesis aimed to develop two different culture-based model systems using liquid (blood) and surgical biopsies (tumor tissue) from advanced-stage breast and oral cancer patients of Indian origin, respectively. In the first part of the thesis, we present a biodegradable polymer—polycaprolactone (PCL)-based novel ex vivo 3D culture system for the expansion of circulating tumor cells (CTCs) derived from breast cancer patients. The second part of the study has dealt with the establishment and detailed characterization of a novel oral cancer cell line derived from the tissue biopsy of an advanced-stage Indian patient with a long-term tobacco chewing habit.
Development of ex-vivo 3D culture system for breast cancer patient-derived circulating tumor cells (CTCs) exhibiting differential epithelial-mesenchymal (EM) phenotypes
Breast cancer is the most prevalent cancer in women, with 2.3 million new cases and ~6.85 lakh deaths in 2020 worldwide. It is reported that 90% of cancer-associated deaths are related to metastasis —a multi-step process facilitating the spread of tumor cells from the primary site to secondary vital organs. Circulating tumor cells (CTCs) that are shed from the primary tumor into the circulation are the precursors of the metastatic cascade. In this regard, liquid biopsy,
which contains CTCs and other tumor-derived markers, has gained much attention in the recent past as a promising clinical tool (both for prognostic and diagnostic purposes). However, the pathophysiological role of CTCs in cancer metastasis is poorly explored due to their rarity in blood, thus making it challenging to establish suitable model systems. Ex vivo culture of CTCs allows the expansion of these rare populations, thus enabling detailed characterization, drug screening, and real-time monitoring during personalized treatment. Nevertheless, the current methods to isolate CTCs are majorly based on pre-enrichment for specific markers (majorly epithelial markers), thereby causing the loss of detection of heterogeneous CTCs (epithelial, mesenchymal, and other types). Furthermore, several of these techniques demand cell fixation, which essentially destroys the scope for further biological/functional characterization of CTCs. Prior studies from our laboratory have established a polymer-based 3D scaffold system in which breast cancer cells form tumoroids and show enhanced metastatic potential mimicking breast cancer progression in vivo. This in-house engineered 3D scaffold system was exploited to develop a newer 3D ex vivo model system to culture CTCs and subsequently to understand their biology, including their heterogeneity and dynamicity.
As opposed to the available CTC culturing methods that rely on pre-enrichment for EpCAM+ cells, in this work, we isolated RBC-depleted nucleated cells from the blood of advanced-stage breast cancer patients without any prior enrichment. After that, we cultured them in 3D PCL scaffolds for 14 days. We first confirmed the presence of cells in 3D culture by F-actin and nucleus staining, followed by the identification of CTCs as CK+ and CD45– cells. Using scanning electron microscopy (SEM) and immunophenotyping of pan-laminin, we demonstrated the deposition of extracellular matrix (ECM) on the scaffolds, which potentially aids the attachment of cells to the scaffolds. Detection of Ki67 and 5-bromo-2'-deoxyuridine (BrdU) positive cells revealed active cell proliferation in the 3D scaffolds. Furthermore, we demonstrated that CTCs exhibit intra- and inter-patient heterogeneity in epithelial (E) and mesenchymal (M) phenotypes that are otherwise missed out on marker-based prior enrichment approaches. Thus, the strategy of culturing whole-blood derived CTCs in PCL scaffolds offers a pathophysiologically relevant model for studying CTC biology, the interaction of CTCs with other immune cells, and individualized drug screening. Moreover, this system can be explored further to culture CTCs obtained from other carcinomas.
Establishment and characterization of a novel oral cancer cell line of Indian origin exhibiting cancer stem cell-like properties
Over the last decade, oral squamous cell carcinoma of the gingivobuccal complex (OSCC-GB) has been the leading cause of mortality in the Indian population amongst all other types of head and neck carcinomas. Interestingly, Indian oral cancer cases show dramatic etiological differences compared to that of the Western countries, primarily due to tobacco chewing habits, tobacco-associated inflammation, and fibrosis. However, given the dearth of available oral cancer cell lines, particularly of Indian origin, there is a dire need for well-characterized oral cancer cell lines to understand the disease mechanism and identify novel drug targets. Thus, we aimed to establish a novel oral cancer cell line from Indian patient origin.
In this study, we have established a cell line derived from an Indian patient with a long-term tobacco chewing habit. The cell line is named as IIOC019 after the ethnic origin, institute, cancer site, and sample number —Indian Institute of Science Oral Cancer (IIOC019). It is a spontaneously immortalized novel cell line that has been sub-cultured for over 60 passages. IIOC019 cells exhibit polygonal, cobblestone morphology along with cytokeratin 8 (CK8) expression indicating their squamous epithelial origin. The short tandem repeat (STR) profiling of IIOC019 did not match with any previously reported cell lines, thereby confirming the novelty of this cell line. Karyotype and DNA ploidy analysis revealed aneuploidy with complex chromosomal aberrations. Notably, this cell line formed aggressive tumors when injected into immunocompromised nude mice recapitulating the original patient tumor histopathology. Given that a small subpopulation of cancer stem cells (CSCs) in tumors contributes to cancer maintenance, drug resistance, and disease relapse/recurrence, we next sought to explore the cancer stemness properties exhibited by the newly derived IIOC019 cell line. Using orosphere, side-population, and Aldefluor assays, we identified the presence of a CSC subpopulation within the established cell line. Further, this cell line could be passaged in vivo in serial xenotransplantation assays, suggesting the presence of long-term repopulating stem-like cells within the cell line. These traits collectively make it a suitable model system to study the role of cancer stemness in oral cancer pathology relevant to the Indian cohort.
Taken together, the present study has focused on developing two novel solid tumor model systems that can be utilized for understanding the molecular mechanisms of disease progression and preclinical cancer therapeutics
Experimental and Theoretical Insights into Impact Phenomena of Small Scale Liquid Interfacial Systems
No full textThis work explores impact phenomena experimentally and theoretically for various
interfacial systems ranging from medical diagnostics to drop impacts on solids and
immiscible liquids. We study a hitherto unexplored impact phenomenon during
an ophthalmology procedure called Non-Contact Tonometry. Using high fidelity
experiments and theoretical modeling, we show that noninvasive ocular diagnostics
demonstrate a propensity for droplet generation and present a potential pathway for
pathogen transmission. The air puff-induced corneal deformation and subsequent
capillary waves lead to flow instabilities (Rayleigh–Taylor, Rayleigh–Plateau) that
lead to tear film ejection, expansion, stretching, and subsequent droplet formation.
Effective cooling is one of the significant application areas of impact systems. In
the context of cooling problems, we provide new insights using ab initio scaling and
boundary layer analysis of the integral and differential forms of the conservation
equations. We have probed the limiting scaling regimes by incorporating the evap-
orative effects at the liquid-vapor interface. The dependence of liquid film thickness
and Nusselt number on various non-dimensional numbers has been explored. We
then investigate the class of drop impact problems where we study impacts on solids,
bio-inspired substrates, and immiscible liquid pools at low to moderate impact en-
ergies. We explore impacts on glass, PDMS, and soft lithographically fabricated
replicas of the lotus leaf and rose petals. Surprisingly, the rose petal and lotus leaf
replicas manifest similar impact dynamics. The observation is extremely intriguing
and counter-intuitive, as rose petals and their replicas are sticky in contrast to lotus
leaves. Air entrapment in the micrometer features of bio-inspired surfaces prevents
frictional dissipation of droplet kinetic energy, leading to contact edge recession and
subsequent break-up modes of the droplet. We explore the air entrapment dynamics
beneath an impacting droplet on an immiscible viscous liquid pool using high-speed
reflection interferometry imaging and linear stability analysis. We have detected
unique hydrodynamic topology in thin air film surrounding the central air dimple
(peripheral disc). The pattern resembles spinodal and finger-like structures typi-
cally found in various thin condensed matter systems. We attribute the formation
of multi-scale thickness perturbations, associated ruptures, and finger-like protru-
sions in the draining air film as a combined artifact of thin-film and Saffman–Taylor
instabilities. We also investigate the air craters formed on the surface of the impact-
ing droplet and attribute its formation to the rapid deceleration of the droplet due to
viscous drag force. The droplet response to the external impulsive decelerating force
induces oscillatory modes on the surface exposed to the air forming capillary waves
that superimpose to form air craters of various shapes and sizes. We introduce a
non-dimensional parameter, the ratio of the drag force to the capillary force acting
on the droplet to characterize the air craters. Further, we generalize the local droplet
response with a global response model for low-impact energies based on an eigenvalue problem. We represent the penetrating drop as a constrained Rayleigh drop
problem with a dynamic contact line. The air-water interface dynamics are analyzed
using an in-viscid droplet deformation model for small deformation amplitudes. The
local and global droplet response theories conform and depict that the deformation
profiles could be represented as a linear superposition of eigenmodes in a Legendre
polynomial basis. We further study air layer dynamics beneath an impacting droplet
on a heated surface at various surface temperatures at low impact energy. The air
layer thickness profile consisting of the dimple and the peripheral disc has been
measured using high-speed reflection interferometric imaging. We decipher that a
Gaussian profile can approximate the dimple height profile characteristics. The dim-
ple thickness profile has a weak dependence on the substrate temperature and is a
function of impact energy in general. The air layer rupture time scale and rupture
radius increase with an increase in the substrate temperature. We characterize the
air layer profile as a Knudsen field and show that a unified treatment, including
continuum and non-continuum mechanics, is required to understand the air layer
dynamics. The asymmetric wetting of the substrate by the impacting droplet initi-
ates in the peripheral disc region. In the non-continuum regimes in the peripheral air
disc, we discover intriguing asymmetric interface perturbations. These perturbative
structures cause asymmetric wetting/contact between the droplet and the substrate.
The sub-micron length scales of the structures exist due to the asymptotic effects of
capillary and Van-der Waals interaction in the disc region