How to Rewind with Minimal Interaction

Khurana, Dakshita ProQuest Dissertations & Theses University of Cali 2018 해외박사(DDOD)

The notion of simulation is central to cryptography: often, to demonstrate that an adversary did not recover any information about private inputs of other participants, we exhibit the existence of a simulator that generates the adversary's view. First introduced in the context of zero-knowledge proof systems and secure computation, today the rewinding technique is synonymous with protocol security and polynomial simulation. Prior to this work, all known rewinding techniques in the plain. In this thesis, we demonstrate the first rewinding techniques that require only a single message from each participant. Using these techniques, we overcome several barriers from literature to construct for the first time, based on standard sub-e. &bull. &bull.

Mitogenic signaling and cell-cycle activation mediate neurodegeneration in Drosophila

Khurana, Vikram Harvard University 2006 해외박사(DDOD)

Background. Previous studies have demonstrated re-expression of cell-cycle markers within postmitotic neurons in neurodegenerative tauopathies, including Alzheimer's disease (AD). However, the critical questions of whether cell-cycle activation is causal or epiphenomenal to tau-induced neurodegeneration and which signaling pathways mediate cell-cycle activation in tauopathy remain unresolved. Methods. Genetic analysis in Drosophila is well suited to address the issue of causality and is utilized here to address these questions. Key features of human tauopathies, including tau hyperphosphorylation and progressive neurodegeneration, are recapitulated by transgenic expression of human or mutant wild-type tau. Furthermore, fly and mammalian cell-cycle machineries are substantially conserved, as are mitogenic signaling pathways including the TOR pathway. Thus, the relationship between tau-induced neurodegeneration, cell-cycle activation and mitogenic signaling pathways in vivo can appropriately be investigated in flies. Results. Cell-cycle activation accompanies wild-type and mutant tau-induced neurodegeneration in Drosophila, and genetically interfering with cell-cycle progression substantially reduces neurodegeneration. Our data support a role for cell-cycle activation downstream of tau phosphorylation, directly preceding apoptosis. We accordingly show that ectopic cell-cycle activation leads to apoptosis of postmitotic neurons in vivo. In addition, inhibition of cell-cycle checkpoints substantially enhances tau-induced neurodegeneration in the fly brain, indicating a potential protective role for checkpoint proteins against aberrant mitogenic stress in adult postmitotic neurons. As in AD, TOR (target of rapamycin kinase) activity is increased in our model and is required for neurodegeneration. TOR activation enhances tau-induced neurodegeneration in a cell cycle-dependent manner and, when ectopically activated, drives cell-cycle activation and apoptosis in postmitotic neurons. Other signaling molecules that activate TOR also enhance tau-induced neurodegeneration. Finally, mutation of all five tyrosine residues of tau to phenylalanine does not prevent cell-cycle activation, indicating that direct interactions between tau and SH2 domain-containing proteins are not a requirement for cell-cycle activation. Conclusions. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model and cell-cycle checkpoints protect against tau-induced neurodegeneration in vivo . Our data identify TOR and the cell cycle as potential therapeutic targets in tauopathies and AD.

Computational studies of natural and synthetic ion channels

Khurana, Ekta University of Pennsylvania 2008 해외박사(DDOD)

This thesis addresses questions pertaining to three different systems-gemini surfactants, synthetic peptide ion channels and M2 proton channel from influenza A virus. The excellent surfactant properties of gemini surfactants enable their applications from consumer products to vectors for gene transfection. The results emerging from a neutron reflection study of a series of these surfactants reveal their unusual interfacial behavior, demanding a higher resolution picture for their further exploration. Synthetic cyclic peptides self-assemble to form excellent ion channels with a wide range of potential applications ranging from nanomaterials to antimicrobial agents, but the mechanism of their self-assembly is not clear. The M2 proton channel was used regularly as a target for anti-influenza drugs before the appearance of resistant viral strains with mutated forms of M2, including the avian flu strain. Although the NMR and X-ray crystal structures reported recently have significantly advanced the understanding of M2, a complete knowledge of the drug binding to the channel required to design new drugs for the mutated forms remains incomplete. The goal of the thesis is to shed light on these uncertainties at the molecular level. Molecular dynamics (MD) simulations at different levels of details have been used as a tool to complement the experiments and answer the unresolved questions. Using atomistic simulations, we observe gemini surfactant aggregation below air-water interface explaining their unusual behavior detected by experiments. Large-scale simulations of coarse-grained (CG) cyclic peptides at a liquid-liquid interface demonstrate a likely self-assembly mechanism and pave the way to the exploration of CG models to study cyclic peptides in different environments and nanomaterials at liquid-liquid interfaces. Atomistic simulations of the transmembrane domain of M2 in DMPC bilayers reveal possible structural transitions that would occur as the channel switches between its open and closed states. The drug binding site and the orientation of the drug in the open state of the channel are confirmed to be in agreement with the one proposed by crystallographic studies, and a change in the drug orientation with the closing of the channel is proposed. In conclusion, the results of MD simulations have filled some missing gaps in the existing pictures that have emerged from experiments and in principle can be used to guide further experiments.

Negotiation and management of coalition resources

Khurana, Himanshu University of Maryland College Park 2002 해외박사(DDOD)

In collaborative environments ranging from commercial research and development to military joint task forces, autonomous domains form coalitions to share resources. Coalitions are peer-to-peer networks where resource sharing is achieved by the distribution of permissions for coalition resources to coalition members based on resource-sharing agreements or common access states, which are negotiated between the member domains. An important characteristic of coalitions is that they are dynamic in that member domains may leave or new domains may join during the life of the coalition. This dissertation addresses the negotiation and management of resources in dynamic coalitions. We define the problems of (1)  joint administration of access policies for jointly owned coalition resources, (2) dependency enforcement between identity and attribute certificates in coalitions, and (3) negotiation of common access states for dynamic coalitions, and provide solutions for these problems. We show that joint administration of access policies requires that the member domains set up a coalition authority that distributes attribute certificates yet retain control over the issuance of such certificates. Also, we show that shared public keys enable joint administration of access policies in a way that minimizes trust liability when compared to solutions using conventional public keys. We develop an authorization protocol to reason about the joint administration of access policies. We show that if dependencies between identity and attribute certificates in coalition networks are not enforced, registered users may be able to retain unauthorized privileges. We present a <italic> selective revocation</italic> method to enforce the certificate dependencies. We show that negotiating a common access state means obtaining the agreement of each domain to share privately owned resources and to jointly own and administer resources with the other domains of the coalition while satisfying both the negotiation constraints placed by the domains and the local access constraints of each domain. We also show that in the presence of coalition dynamics, member domains must re-negotiate the common access state multiple times. We develop a state transition model of the negotiation process and a negotiation language for the specification of a wide variety of negotiation constraints.

Delineating the Immunometabolism of Human Invariant Natural Killer T Cells

Khurana, Priya ProQuest Dissertations & Theses University of Penn 2021 해외박사(DDOD)

On-chip isotachophoresis assays for high sensitivity electrophoretic preconcentration, separation, and indirect detection

Khurana, Tarun K Stanford University 2009 해외박사(DDOD)

The origins of microfluidics field lie in microanalytical methods such as gas chromatography, high pressure liquid chromatography and capillary electrophoresis that are revolutionizing the field of chemical analysis. Microfluidic devices have been particularly attractive for separation based chemical and biological analysis since the small length scales bring fundamental improvements in reagent volume use, analysis time, resolution, and separation efficiency. However, smaller length scales and volumes are also associated with lower detection sensitivity and therefore, this limits many applications to fluorescent analytes. This dissertation focuses on electrokinetic preconcentration and separation methods to improve the detection sensitivity on microchip platform and to extend the scope of microfluidic analysis to non-fluorescent analytes. Isotachophoresis (ITP) is a robust sample preconcentration technique that leverages spatial mobility gradients to focus analytes into zones that are ∼10 mum wide. Such extreme focusing of analytes results in drastic improvement in the detection sensitivity and resolution of electrophoretic separation system. We present a theoretical and experimental study of dynamics of ITP preconcentration that helps to identify optimum operating parameters to achieve high sample preconcentration. The theoretical study involves development of analytical models to identify the fundamental parameters governing the focusing dynamics and development of perturbation model and dispersion model to reduce the complexity of this numerically stiff problem. We performed controlled experiments to isolate the effect of each parameter influencing the preconcentration dynamics from others. These experimental results are used for validation of theoretical models and also serve as guidelines for ITP preconcentration assay design. We have also developed an indirect detection technique to detect non fluorescent analytes on standard microfluidic setup equipped with fluorescence detection platforms. We leverage ITP to preconcentrate and separate analytes into distinct analyte zones arranged in order of reducing electrophoretic mobility. Using a ladder of fluorescent species with different electrophoretic mobilities (termed as fluorescent mobility markers) to demarcate the boundaries of these analyte zones, we indirectly detect the non-fluorescent analytes present. We obtain ∼1 muM detection sensitivity with this assay with high repeatability and have demonstrated indirect detection of a variety of analytes such as amino acids, organic acids and environmental toxins such as phenols and cresol. Lastly, we demonstrate simultaneous electrophoretic preconcentration and separation of analytes in a single step injection process in off-the-shelf, standard microfluidic chips using isotachophoresis (ITP). Our technique leverages an electric field gradient between the leading and trailing electrolytes to concentrate analytes into distinct non-dispersing bands. This is the first experimental study to identify that the gradient results from slow reaction kinetics of hydration and carbamation of dissolved atmospheric carbon dioxide. We use a fluorescent counterion tracer technique to study the evolution of carbonate and carbamate zones and the electric field gradient region between them. Using this assay, we have demonstrated one step focusing and separation of 25 bp DNA ladder, and the fractionation of DNA and proteins. The technique has potential to simplify and improve the detection sensitivity of many microchip electrophoresis assays.