Application of Glycoconjugate-Functionalized Magnetic Nanoparticles as Potent Anti-Adhesion and Anti-Bacterial Agents

Magnetic nanoparticles (MNPs) are currently being extensively in multitude of biomedical applications on account of their exceptional biocompatibility. By attaching different targeting ligands/molecules, MNPs have been broadly used in magnetic hyperthermia, cancer therapy, targeted drug delivery, MRI imaging, pathogen detection, and biological cell-separation. In this dissertation, MNPs coated with polyethylene oxide (PEO) based polymer (PEO-MNPs) and functionalized with bacterial adhesin-specific glycoconjugate molecule Neu5Ac(α2-3)Gal(β1-4)-Glcβ-sp (GM3-MNPs), are investigated for their interactions with enterotoxigenic Escherichia coli (E. coli). It also describes the feasibility of using alternating magnetic fields (AMF) for targeted killing of E. coli K99 (EC K99) strain using MNPs. Lastly, the interactions of MNPs with normal human colon cells CCD-18Co are explored to assess their in vitro biocompatibility. To begin with, GM3-MNPs were synthesized by based on \u27click chemistry\u27 platform. Bacteria specific aggregation of EC K99 was seen due to interactions occurring between GM3-MNPs and adhesin molecules of EC K99. These interactions were observed by means of fluorescence microscopy, transmission electron microscopy (TEM), and colony forming units (CFU) assays. The preliminary cytotoxicity assay performed on normal colon cells CCD-18Co indicated excellent biocompatibility of GM3-MNPs. Thus, such glycoconjugate functionalized MNPs can be effectively utilized as anti-adhesion and anti-bacterial agents for reducing gastro-intestinal (GI) tract infections. Next, GM3-MNPs were used along with AMF for targeted killing of EC K99 cells. CFU/ml assays indicated that killing rate of EC K99 was mainly dependent on concentration of GM3-MNPs and AMF exposure time. Clinically relevant reduction in CFU/ml of EC K99 was achieved after 120 minutes of AMF exposure in presence of GM3-MNPs in both pure and mixed bacterial culture environment. Enormous cell-membrane damage was observed via fluorescence microscopy and TEM imaging of EC K99 cells after AMF exposure in presence of GM3-MNPs. AMF exposure in presence of GM3-MNPs also caused significant decrease in intracellular ATP levels of EC K99. These results suggest that bacterial specific glycoconjugate MNPs along with AMF can be efficiently employed as novel non-antibiotic platform to inactivate targeted bacterial pathogens. Finally, the overall biocompatibility of GM3-MNPs was examined in CCD-18Co cells and compared to PEO-MNPs. GM3-MNPs were found to have relatively stable hydrodynamic diameter in cell-culture media DMEM whereas PEO-MNPs drastically increased their size on account of protein-corona formation. Both cytotoxicity and ATP assays revealed that GM3-MNPs exhibited great biocompatibility in the cells. CCD-18Co cells also maintained their overall cell-membrane integrity in presence of GM3-MNPs. Interestingly, GM3-MNPs were able to substantially decrease the glutathione (GSH) levels in the cells leading to increased oxidative stress. Thus, by properly controlling surface properties of glycoconjugate functionalized MNPs and attaching different drugs, they can be potentially used as colon specific drug-delivery carriers for therapeutic applications

Analysis of Profitability in Pharmaceutical Industry

The present research work is a very modest effort from the side of researcher to add to the current knowledge base in the area of Pharmaceutical Industry and its financial performance. There are several research conducted by several researchers in and outside country for the Indian Pharmaceutical Industry as the industry is on the threshold of a paradigm shift from process patents to product patents and several such legal international issues. The Indian Pharmaceutical sector is highly fragmented with more than 20,000 registered units. The pharmaceutical industry in India meets around 70% of the country's demand for bulk drugs, pharmaceutical formulations, chemicals, tablets, capsules, orals and injectibles. There are two major things coming out, firstly, Indian Pharmaceutical Industry is growing in output, value, volume, number of units - steadily and showing resemblance to the entire growth story of Indian Economy. Secondly, there is a major change occurring to the very basic system of pharmaceutical business in India. By issuing the patent ordinance, India met a WTO commitment to recognize foreign product patents from 1st January 2005, the culmination of 10 year process. In this new scenario, the Indian Pharmaceutical manufacturers would not be able to manufacture patented drugs which they have been doing since long although by another process. This situation brought a very interesting and exciting research scope into the financial abilities of the industry. As such the crux of any growth or decline depends largely on the financial health it was imperative for the researcher to carry out a detailed profitability analysis of the leading pharma companies of India

PREDICTORS OF CLINICAL OUTCOMES IN INDIAN PATIENTS WITH ACUTE ENCEPHALOPATHY: A PROSPECTIVE OBSERVATIONAL STUDY FROM A TERTIARY CARE CENTER IN INDIA

Objective: Objective of the study was to evaluate the predictors of poor disease outcome at discharge and at 1 month in patients with acute encephalopathy. Methods: This prospective, observational, single center study included adult patients meeting the diagnostic criteria for acute confusion state and admitted in the intensive care unit of a tertiary care hospital. A modified Rankin Scale (mRS) score of <3 was considered as “good outcome,” while mRS ≥3 was considered as an indicator of “poor outcome.” Results: Among the total population of 219, 52.5% (n=115) were male, the mean age was 41.58 (±18.10) years and mean disease duration was 14.30 (±10.05) days (range: 1–30 days). Lethargy was the most common history at presentation (84.93%), while sleep abnormalities were least common (4.57%), and tuberculous meningitis was the most common etiology (21%). Diminution of vision, diplopia, dysarthria, cranial nerve symptoms, abdominal pain, difficulty in breathing, seizures, high-risk behavior, loss of appetite and the diagnosis of posterior reversible encephalopathy, retroviral disease, stroke and tuberculous meningitis were significant predictors of “poor outcome” at discharge (p<0.05). A diagnosis of tuberculous meningitis, history of headache, diminution of vision, diplopia, dysarthria, seizures, sensory deficits and loss of appetite and neuroimaging findings of atrophy, intracranial bleeding, demyelination, and space-occupying lesion were found to be significant predictors of “poor outcome” at 1 month post-discharge in this population (p<0.05). Conclusion: In patients with acute encephalopathy, tuberculous etiology, the presence of focal brainstem deficits and specific neuroimaging findings indicate poor outcomes at discharge as well as at 1 month follow-up

Adaptive Complex Contagions and Threshold Dynamical Systems

A broad range of nonlinear processes over networks are governed by threshold dynamics. So far, existing mathematical theory characterizing the behavior of such systems has largely been concerned with the case where the thresholds are static. In this paper we extend current theory of finite dynamical systems to cover dynamic thresholds. Three classes of parallel and sequential dynamic threshold systems are introduced and analyzed. Our main result, which is a complete characterization of their attractor structures, show that sequential systems may only have fixed points as limit sets whereas parallel systems may only have period orbits of size at most two as limit sets. The attractor states are characterized for general graphs and enumerated in the special case of paths and cycle graphs; a computational algorithm is outlined for determining the number of fixed points over a tree. We expect our results to be relevant for modeling a broad class of biological, behavioral and socio-technical systems where adaptive behavior is central.Comment: Submitted for publicatio

Bott--Kitaev periodic table and index theory

We consider topological insulators and superconductors with discrete symmetries and clarify the relevant index theory behind the periodic table proposed by Kitaev. An effective Hamiltonian determines the analytical index, which can be computed by a topological index. We focus on the spatial dimensions one, two and three, and only consider the bulk theory. In two dimensions, the $\mathbb{Z}$-valued invariants are given by the first Chern number. Meanwhile, $\mathbb{Z}_2$-valued invariants can be computed by the odd topological index and its variations. The Bott-Kitaev periodic table is well-known in the physics literature, we organize the topological invariants in the framework of KR-theory.Comment: 37 page