Doctor of Philosophy

dissertationMedical imaging has evolved in leaps and bounds during the last century. Several medical imaging modalities such as X-rays, single photon emission computer tomography (SPECT), positron emission tomography (PET), computer tomography (CT), magnetic resonance imaging (MRI) have been developed. However, MRI has a distinct advantage over most of these imaging techniques. MRI does not use ionizing radiation, and hence, is considered a safer option for noninvasive imaging. However, every imaging modality comes with its set of limitations and challenges. Although quantitative myocardial perfusion MRI has been studied by researchers over a few decades, it has still not developed into a clinical tool. There is no consensus on the choice of imaging protocol to be used. The scientific community is still divided on the choice of pharmacokinetic model to be used for quantification of myocardial perfusion. In this dissertation, novel techniques were developed and implemented to address a few of the challenges faced by fully quantitative myocardial perfusion MRI. We strive to make it simpler and more accurate. It is with the development of such easy-to-use techniques that cardiac perfusion MRI will find increasing clinical use. These developments are a step in the transition of quantitative myocardial perfusion MRI from an "evolving tool" to an "evolved and matured tool.

Therapeutic AAV9-mediated Suppression of Mutant SOD1 Slows Disease Progression and Extends Survival in Models of Inherited ALS

Professional Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials.No embarg

Synthesis Of Bioactive Marine Meroterpenoids : Frondosins And Liphagal

The sea conceals a mermaid’s grotto of useful chemicals-marine natural products of therapeutic potential. Marine sponges in particular are a rich source of natural products with structural diversity and novel biological activity. In recent times, there has been a growing interest in the synthesis of marine natural products. The present thesis entitled, “Synthesis of bioactive marine meroterpenoids: frondosins and liphagal” is an endeavor along the same lines and is organized under two parts –Part A and Part B. Part A: Studies towards the total synthesis of (±) frondosins A and B Frondosins A-E are IL-8 inhibiting marine meroterpenoids, with novel bicyclo[5.4.0]undecane framework, exhibiting anti-inflammatory and anti HIV-1 activities. A relatively simple and inherently flexible ring-closing metathesis (RCM) based strategy was employed to achieve the total synthesis of frondosins A (formal) and B in only 17 linear steps (total 13 operations) and 5% overall yield. A concise route, based on RCM, to the core structure of bioactive frondosins is amenable to ready appendage diversification and enables implementation of functionalization manoeuvres on all positions in the seven-membered ring of the bicyclic framework was also developed. A Diels-Alder strategy that led to the synthesis of 8-des-methyl norfrondosin A dimethyl ether is also delineated in Part A of the thesis. Part B: A concise synthesis of (±) liphagal Liphagal is a marine meroterpenoid displaying an unprecedented “liphagane” skeleton. It is a selective inhibitor of PI3K and significantly toxic against a small panel of human tumor cell lines (LoVo, CaCo-human colon and MDA-468-human breast). A concise and straightforward biomimetic strategy towards liphagal and its 14-des-formyl analogue that awarded liphagal dimethyl ether in only eight steps from commercially available building blocks is described in Part B of the thesis

Oligodendrocytes contribute to motor neuron death in ALS via SOD1 dependent mechanism

Oligodendrocytes have recently been implicated in the pathophysiology of ALS. Here we show that, in vitro, mutant SOD1 mouse oligodendrocytes induce wild-type motor neuron hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls, sporadic and familial ALS patients using two different reprogramming methods. All ALS oligodendrocyte lines induced motor neuron death through conditioned medium and in co-culture. Conditioned medium-mediated motor neuron death was associated with decreased lactate production and release, while toxicity in co-culture was lactate independent, demonstrating that motor neuron survival is not only mediated by soluble factors. Remarkably, human SOD1 shRNA treatment resulted in motor neuron rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, while it was ineffective in differentiated oligodendrocytes. Early SOD1 knockdown, in fact, rescued lactate impairment and cell toxicity in all lines tested with exclusion of samples carrying C9orf72 repeat expansions. These did not respond to SOD1 knockdown nor showed lactate release impairment. Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type some damage might be irreversible. In addition, we demonstrate that C9ORF72 patients represent an independent patient group that might not respond to the same treatment

Missingness-resilient Video-enhanced Multimodal Disfluency Detection

Most existing speech disfluency detection techniques only rely upon acoustic data. In this work, we present a practical multimodal disfluency detection approach that leverages available video data together with audio. We curate an audiovisual dataset and propose a novel fusion technique with unified weight-sharing modality-agnostic encoders to learn the temporal and semantic context. Our resilient design accommodates real-world scenarios where the video modality may sometimes be missing during inference. We also present alternative fusion strategies when both modalities are assured to be complete. In experiments across five disfluency-detection tasks, our unified multimodal approach significantly outperforms Audio-only unimodal methods, yielding an average absolute improvement of 10% (i.e., 10 percentage point increase) when both video and audio modalities are always available, and 7% even when video modality is missing in half of the samples.Comment: Accepted to Interspeech 202

Effect of Austenitization Temperature on Wear Behavior of Carbidic Austempered Ductile Iron (CADI)

Chromium bearing Austempered Ductile Iron (ADI) has been recently in the news for its improved wear performance over the ADI. The work presented below was taken up to study the effect of different austenitisation temperatures on the microstructure and wear performance of the Carbidic Austempered Ductile Iron (CADI). In this investigation Cr bearing ductile iron was subjected to austempering treatment to obtain an ausferritic microstructure. Two different austenitisation temperatures were selected whereas, the austempering temperature and time was kept unchanged. Microstructure and wear performance of this alloy, austenitized at two different temperatures was studied

Observations on Tolyposporoum penicillaria Bref(the bajri smut fungus)

This article does not have an abstract

Effect of Austenitization Temperature on Wear Behavior of Carbidic Austempered Ductile Iron (CADI)

Chromium bearing Austempered Ductile Iron (ADI) has been recently in the news for its improved wear performance over the ADI. The work presented below was taken up to study the effect of different austenitisation temperatures on the microstructure and wear performance of the Carbidic Austempered Ductile Iron (CADI). In this investigation Cr bearing ductile iron was subjected to austempering treatment to obtain an ausferritic microstructure. Two different austenitisation temperatures were selected whereas, the austempering temperature and time was kept unchanged. Microstructure and wear performance of this alloy, austenitized at two different temperatures was studied

Parametrically Amplified Low-Power MEMS Capacitive Humidity Sensor

We present the design, fabrication, and response of a polymer-based Laterally Amplified Chemo-Mechanical (LACM) humidity sensor based on mechanical leveraging and parametric amplification. The device consists of a sense cantilever asymmetrically patterned with a polymer and flanked by two stationary electrodes on the sides. When exposed to a humidity change, the polymer swells after absorbing the analyte and causes the central cantilever to bend laterally towards one side, causing a change in the measured capacitance. The device features an intrinsic gain due to parametric amplification resulting in an enhanced signal-to-noise ratio (SNR). 11-fold magnification in sensor response was observed via voltage biasing of the side electrodes without the use of conventional electronic amplifiers. The sensor showed a repeatable and recoverable capacitance change of 11% when exposed to a change in relative humidity from 25-85%. The dynamic characterization of the device also revealed a response time ~1s and demonstrated a competitive response with respect to a commercially available reference chip