DYNAMIC ROUTING WITH CROSS-LAYER ADAPTATIONS FOR MULTI-HOP WIRELESS NETWORKS

In recent years there has been a proliferation of research on a number of wireless multi-hop networks that include mobile ad-hoc networks, wireless mesh networks, and wireless sensor networks (WSNs). Routing protocols in such networks are of- ten required to meet design objectives that include a combination of factors such as throughput, delay, energy consumption, network lifetime etc. In addition, many mod- ern wireless networks are equipped with multi-channel radios, where channel selection plays an important role in achieving the same design objectives. Consequently, ad- dressing the routing problem together with cross-layer adaptations such as channel selection is an important issue in such networks. In this work, we study the joint routing and channel selection problem that spans two domains of wireless networks. The first is a cost-effective and scalable wireless-optical access networks which is a combination of high-capacity optical access and unethered wireless access. The joint routing and channel selection problem in this case is addressed under an anycasting paradigm. In addition, we address two other problems in the context of wireless- optical access networks. The first is on optimal gateway placement and network planning for serving a given set of users. And the second is the development of an analytical model to evaluate the performance of the IEEE 802.11 DCF in radio-over- fiber wireless LANs. The second domain involves resource constrained WSNs where we focus on route and channel selection for network lifetime maximization. Here, the problem is further exacerbated by distributed power control, that introduces addi- tional design considerations. Both problems involve cross-layer adaptations that must be solved together with routing. Finally, we present an analytical model for lifetime calculation in multi-channel, asynchronous WSNs under optimal power control

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Exploring Drug Bioaccumulation and Stabilization with Respect to Endolysosomal Ion Homeostasis Using a Systems-Based Mathematical Modeling Approach

Even though most of the FDA approved drugs currently out in the market and in the process of development are weakly basic drugs, the bioaccumulation and stabilization of these drugs are not well understood. For this purpose, we use a model drug, clofazimine (CFZ), which is an FDA-approved, weakly basic, and poorly soluble drug that has been used worldwide to treat patients with leprosy and tuberculosis diseases, curing over 16 million people in the last twenty years, to investigate its bioaccumulation and stabilization properties. During prolonged oral administration, CFZ accumulates in macrophages of humans and mice as Crystal Like Drug Inclusions (CLDIs), which have been chemically characterized to be composed of hydrochloride salts of CFZ (CFZ-H+Cl-) crystals. However, the mechanism by which the formation and stabilization of these insoluble complexes occur in cells is not known. Thus, to address this gap, we test the following hypothesis in this dissertation: due to the sufficient proton and chloride levels in endolysosomes, we hypothesize that the phase-transition-dependent drug accumulation and stabilization processes are occurring inside intracellular compartments of likely endolysosomal origin, in macrophages of humans as well as mice. To test our hypothesis, we adapt a systems-based mathematical lysosomal ion regulation model, which consists of lysosomal membrane proteins, such as the proton-pump known as Vacuolar ATPase (V-ATPase), Cl-/H+ antiporter known as CLC7, and membrane proton leak, in order to investigate the key lysosomal parameters that play essential role in the physiological, dose-dependent CFZ-H+Cl- crystal bioaccumulation. Furthermore, we examine the stabilization of the free base (CFZ) versus salt form (CFZ-H+Cl-) of the drug by mathematically fitting an in vitro pH-dependent solubility data of CFZ-H+Cl- crystal obtained at pH ranging between extracellular, cellular, and subcellular pH values, and determining the drug’s solubility properties, which include the apparent pKa, intrinsic free base and salt solubility, pHmax, and Ksp values. Moreover, we model the cellular and subcellular drug transportation and calculate i) the non-membrane and membrane drug accumulation by accounting for the cell-type dependent heterogeneous and asymmetric lipid bilayer of the biological membranes ii) the degree of supersaturation, which is a measure of thermodynamic propensity of precipitation, of both free base CFZ and CFZ-H+Cl- salt using the aforementioned solubility properties. Collectively, our computational results as well as the CFZ-H+Cl- physicochemical properties in relation to the ion contents and pH of the microenvironment suggest that the physiological and preferential phase-transition-dependent accumulation and stabilization mechanisms of CFZ-H+Cl- crystals in macrophages, more specifically in macrophage lysosomes, are primarily determined by the lysosomal V-ATPase. Moreover, we have shown that the alteration of lysosomal physiology due to lysosomal morphological changes induced upon the accumulation of intrinsic and extrinsic materials, such as cholesterol and biocrystal drugs, respectively can be reversed upon V-ATPase upregulation or inhibition of membrane proton permeability. In addition, in terms of characterizing the stabilization of free base CFZ and CFZ-H+Cl- salt, we have found the degree of supersaturation of CFZ-H+Cl- salt to be at least 1000-fold greater than that of free base CFZ in all of the cellular compartments, including the biological membranes; emphasizing the propensity of the formation and stabilization of massive CFZ-H+Cl- salt precipitate in the lysosomal environment even when introducing low (picomolar) total extracellular drug concentration.PHDBiophysicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/143973/1/wolte_1.pd