Essentials of global health, by R. Skolnik, Sudbury, Jones and Bartlett Publishers, 2008, 322 pp., including index and supplementary materials, US$57 (paperback), ISBN 13: 978-0-7637-3421-3; ISBN 10: 0-7637-3421-7

Understanding global health, edited by W.H. Markle, M. Fisher and R. Smego, Columbus, McGraw Hill, 2007, 361 pp., including index and supplemental materials, US$35 (paperback), ISBN 13: 978-0-07-148784-9; ISBN 10: 0-07-148784-0

Global health, an introductory textbook, by A. Lindstrand, S. Bergstrom, H. Rosling, B. Rubenson, B. Stenson and T. Tylleskar, Denmark, Studentlitteratur, 2006, 310 pp., including index and supplemental materials, US$35 (paperback), ISBN 978-91-44- 02198-0

An introduction to international health, by M. Seear, Toronto, Canadian Scholars Press, 2007, 352 pp., including index and supplemental materials, US$49 (paperback), ISBN 978-1-55130-327-7

Introduction to global health, by K.H. Jacobsen, Sudbury, Jones and Bartlett Publishers, 2008, 366 pp., including index and supplemental materials, US$43 (paperback), ISBN 13: 978-0-7637-5159-3; ISBN 10: 0-7637-5159-6

• an infrastructure and methodology for understanding communication on graphs;

• identification and exploration of sub-communities;

• metrics for identifying effective communicators in dynamic graphs;

• a new definition of dynamic, reciprocal social capital and its iterative computation

• a methodology to study influence in social networks in detail, using

• a class hierarchy established by social capital

• simulations mixed with reality across time and capital classes

• various attachment strategies, e.g. via friends-of-friends or full utility optimization

• a framework for answering questions such as “are these influentials accidental”

• discovery of the “middle class” of social networks, which as shown with our new metrics and simulations is the real influential in many processes

Our methods have already lead to the discovery of “mind economies” within Twitter, where interactions are designed to increase ratings as well as promoting topics of interest and whole subgroups. Reciprocal social capital metrics identify the “middle class” of Twitter which does most of the “long-term” talking, carrying the bulk of the system-sustaining conversations. We show that this middle class wields the most of the actual influence we should care about — these are not “accidental influentials.” Our approach is of interest to computer scientists, social scientists, economists, marketers, recruiters, and social media builders who want to find and present new ways of exploring, browsing, analyzing, and sustaining online social networks.

We investigated the dynamics of cell-cell junction formation and the corresponding architecture of the underlying cytoskeleton in cultured human umbilical vein endothelial cells (HUVECs). We show that the initial interaction between cells is mediated by protruding lamellipodia. Upon their retraction, cells maintain contact through thin bridges formed by filopodia-like protrusions connected by VE-cadherin-rich junctions.

Bridges share multiple features with conventional filopodia, such as an internal actin bundle associated with fascin along the length and VASP at the tip. Strikingly, unlike conventional filopodia, transformation of actin organization from the lamellipodial network to filopodial bundle during bridge formation occurs in a proximal-to-distal direction and is accompanied by recruitment of fascin in the same direction. Subsequently, bridge bundles recruit nonmuscle myosin II and mature into stress fibers. Myosin II activity was important for bridge formation and accumulation of VE-cadherin in nascent adherens junctions. Our data reveal a mechanism of cell-cell junction formation in endothelial cells utilizing lamellipodia as the initial protrusive contact, subsequently transforming into filopodia-like bridges connected through adherens junctions. Moreover, a novel lamellipodia-to-filopodia transition is employed in this context.

Chapter 1 of this work will review the efforts by Merck and Co. that lead to the isolation and discovery of potent analogs of NsAA, as well as briefly review the history of complex indole synthesis in the Smith Research Group.

Chapter 2 will describe efforts to streamline the synthesis of the chiral, non-racemic material used to make different variants of the eastern hemisphere sub-target, the development of a new tactic for bringing the two hemispheres together, and efforts to synthesize an eastern hemisphere sub-target that contains the sidechain of NsAA.

Most of Nancy’s architects were graduates of the Ecole des Beaux-Arts in Paris, and grounded in the language of classicism and its associated professional standards. Much of Nancy’s Art Nouveau had a conservative character that garnered praise from the national architectural press. Nancy’s architects were also disciples of Emile Gallé, the founder of a regional association of artists, industrialists, and designers called the Ecole de Nancy, dedicated to the promotion of Art Nouveau. Nancy’s architects freely collaborated with other artists of the Ecole on their buildings, and a sense of pride in their province led them to study local flora, the and regional legends and politics, using the iconography of plants and narratives to make architecture legible to a wide public.

The rooting of the work of Nancy’s architects in their region and the alliance they formed with local industry were successes that Parisian Art Nouveau architects were never able to match. Consequently, in Paris, Art Nouveau was quickly discarded, while in Nancy it was celebrated as an integral piece of regional identity and an important national achievement until 1914.

This thesis aims to obtain a more quantitative understanding of intravascular hyperoxic contrast in vivo, with the hope of increasing its precision and utility. Specifically, our work focuses on the following areas: (1) paramagnetic effects of molecular oxygen BOLD and arterial spin labeling (ASL) data, (2) degree and temporal characteristics of hyperoxia-induced reductions in cerebral blood flow (CBF), (3) use of oxygen in quantitative measurements of metabolism, and (4) biophysical mechanisms of hyperoxic T₁ contrast.

In Chapter 2, the artifactual influence of paramagnetic molecular oxygen on BOLD-modulated hyperoxic gas studies is characterized as a function of static field strength, and we show that optimum reduction in FiO₂ mitigates this effect while maintaining BOLD contrast. Since ASL measurements are highly sensitive to arterial blood T­₁ (T_1a), the value of T_1a in vivo is determined as a function of arterial oxygen partial pressure in Chapter 3. The effect of both the degree and duration of hyperoxic exposure on absolute CBF are quantified using simultaneous ASL and in vivo T_1a measurements, as described in Chapter 4. In Chapter 5, hyperoxic gas calibration of BOLD/ASL data is used to measure cerebral oxygen metabolism in a hypermetabolic swine model, with our results comparing favorably to ¹⁷O₂ measurements of absolute metabolism. In Chapter 6, a model to describe the relationship between CBF, oxygen consumption, and hyperoxic T₁ reduction is developed, which allows for a more rigorous physiological interpretation of these data. Taken together, this work represents several important steps towards making hyperoxia a more quantitative MRI contrast agent for research and clinical applications.

We begin by describing the inspiration, design, implementation of and experimentation with the first dynamical vertical climbing robot. We study numerically a version of the pendulous climbing template dynamically re-scaled for applicability to utilitarian payloads with conventional electronics and actuation, revealing that the incorporation of passive compliance can compensate for an artifact’s poorer power density and scale disadvantages relative to biology. However, the introduction of these dynamical elements raises new concerns about stability regarding both the power stroke and limb coordination that we allay via mathematical analysis. Combining these numerical and analytical insights into a series of design prototypes, we document the correspondence of the various models to the variously scaled platforms and report that our approximately two kilogram platform, DynoClimber, climbs dynamically at vertical speeds up to 1.5 bodylengths per second — in particular, the final 2.6 kg prototype climbs at an average steady state speed of 0.66 m/s against gravity on a carpeted vertical wall, in rough agreement with our various models’ predictions.

We establish whether the success of the robot is inherent to the morphology suggested by the F-G template or, instead, to a fortuitous set of parameter choices during the robot’s design. Thus we examine the effects of (i) actuator dynamics and (ii) lateral force generation on climber stability by investigating a sequence of reduced order variants of the F-G template. We prove analytically that a purely vertical climber is stable for a general class of actuator force functions, and use that result to further simplify our models by allowing the prescription of leg length. We use that simplification to demonstrate that a sprawled posture stabilizes vertical climbing by damping rotational motion during stride transitions. We also notably demonstrate through simulation that a climber’s stability does not depend on the actuation frequency it employs.

Finally, we explore the potential benefits of pendulous dynamical climbing in animals and in robots by examining the stability and power advantages of variously more and less sprawled limb morphologies when driven by conventional motors in contrast with animal-like muscles. For quadratic-in-velocity power output actuation models typical of commercially available electromechanical actuators, our results suggest the new hypothesis that sprawled posture may confer significant energetic advantage. In notable contrast, muscle-powered climbers do not experience an energetic benefit from sprawled posture due to their sufficiently distinct actuator characteristics and operating regimes. These results suggest that the benefits of sprawled posture climbing may be distinctly different depending upon the details of the climber’s sensorimotor endowment. This study also shows that even minimally intelligent foot placement improves stability when compared to the template-derived rigid sprawl.

Hydrogels are a common class of biomaterial used for cartilage tissue engineering and our initial work demonstrated the potential of a photo-polymerizable hyaluronic acid (HA) hydrogel to promote MSC chondrogenesis and improved construct maturation by optimizing macromer and MSC seeding density. The beneficial effects of dynamic compressive loading, high MSC density, and continuous mixing (orbital shaker) resulted in equilibrium modulus values over 1 MPa, well in range of native tissue.

While compressive properties are crucial, clinical translation also demands that constructs stably integrate within a defect. We utilized a push-out testing modality to assess the in vitro integration of HA constructs within artificial cartilage defects. We established the necessity for in vitro pre-maturation of constructs before repair to achieve greater integration strength and compressive properties in situ. Combining high MSC density and gentle mixing resulted in integration strength over 500 kPa, nearly 10-fold greater than previous reports of integration with MSC-based constructs. Furthermore, we demonstrated the durability of this repair system by applying dynamic loading and showed its functional contribution to the distribution of compressive loads across the repair space.

Overall, the studies contained within this thesis offer the first MSC-based tissue engineering strategy that successfully recapitulates native mechanical function while also demonstrating the potential for complete functional cartilage repair.

In this work, we model an economic system as a combination of many bilateral economic opportunities, such as that between a buyer and a seller. The transactions are complicated by the existence of many economic opportunities, and the influence they have on each other. For example, there may be several prospective sellers and buyers for the same item, with possibly differing costs and values. Such a system may be modeled by a network, where the nodes represent players and the edges represent opportunities. We study the effect of network structure on the outcome of bargaining among players, through theoretical modeling of rational agents as well as human subject experiments, when cost and values are public information.

The interactions get much more complex when sellers' cost and buyers' valuations are private. We design and analyze revenue maximizing strategies for a seller in the presence of many buyers, when the seller has uncertain information or no information about the buyers' valuations. We focus on developing pricing strategies, and compare their performance against truthful auctions. We also analyze trading strategies in financial markets, where a player quotes both buying and selling prices, again with uncertain or no information about future price evolution of the financial instrument.

The first step towardthis goal is to investigate potential attack strategies and the extent of damage they can incur. Given the flexibility that software-based operation provides, it is reasonable to expect that new malware will not demonstrate a fixed behavior over time. Instead, malware can dynamically change the parameters of their infective hosts in response to the dynamics of the network, in order to maximize their overall damage.

We first considerpropagation of malware in a battery-constrained mobile wirelessnetwork by an epidemic model in which the worm can dynamicallycontrol the transmission ranges and/or the media scanning rates of the infective nodes. The malware at each infective node may seek to contact more susceptible nodes by amplifying the transmission range andthe media scanning rate and thereby accelerate its spread. Thismay however lead to (a)~easier detection of the malware and thus moreeffective counter-measure by the network, and (b)~faster depletion of the battery which may in turn thwart further spread of the infection and/or exploitation of that node. We prove, using Pontryagin Maximum Principle from optimal control theory, that the maximum damage in this case can be attained using simple three-phase strategies: in the first phase, infective nodesuse maximum transmission ranges and media access rates to amass infective nodes.In the next phase, infective nodes reduce their access attempts and enter a stealth-mode to preserve their battery and hide from detection. In the last phase, they once again use maximum transmission attempts with largest rates but this time the primary effect is killing the infective nodes by draining their batteries.

In an alternative attack scenario, we consider the case in which the malware can control the rate of killing the infective nodes as an independent parameter of control. At each moment of time the worm at each node faces the following decisions: (i)~choosing the transmission ranges and media scanning rates so as to maximize the spread of infection subject to not exhausting its batteries by the end of the operation interval; and (ii)~whether to kill the node to inflict a large cost on the network, however at the expense of losing the chance of infecting more susceptible nodes at later times. We establish structural properties of the optimal strategy of theattacker over time.Specifically, we prove that it is optimal forthe attacker to defer killing of the infective nodes in the propagation phase until reaching a certain time and then start theslaughter with maximum effort. We also show that in the optimalattack policy, the battery resources are used according to a decreasing function of time, i.e., most aggressively during the initial phaseof the outbreak.

Upon detection of a malware outbreak, the network manager can counter the propagation of the malware by reducing the communication rates of the nodes and patching. We in turn investigate the optimal defense policies of rate reduction and patching.

We introduce quarantining the malware by reducing the reception gain of nodes as a defense mechanism. In applying this counter-measure we confront a trade-off: reducing the communication range suppresses the spread of the malware, however,it also deteriorates the network performance by introducing delay. Using Pontryagin's Maximum Principle, we derive structural characteristics of the optimal communication range as a function of timefor a wide class of cost functions. In both of the defense controls, our numerical computations reveal that the dynamic optimal controls significantly outperforms static choices and is also robust to errors in estimation of the network and attack parameters.

The distribution of patches consumes bandwidth which is specially scarce in wireless networks, and must therefore be judiciously controlled in order to attain desired trade-offs between security risks and bandwidth consumption. We consider both non-replicative and replicative dissemination of patches:a pre-determined set of dispatcher nodes distribute the patches in the former, whereas the dispatcher set continually grows in the latter as the nodes that receive the patch become dispatchers themselves. In each case, the desired trade-offs can be attained by activating at any given time only fractions of dispatchers and selecting their packet transmission rates. We formulate the above trade-offs as optimal control problems that seek to minimize the aggregate network costs that depend on security risks and the overall extra energy and bandwidth used in the network for dissemination of the security patches. We prove that the dynamic control strategies have simple structures: when the cost function associated with the energy/bandwidth consumed in patching is concave, the control strategies are bang-bang with at most one jump from the maximum to the minimum value, i.e., maximum patching rates until a certain threshold and then stop. When the cost function is strictly convex, the above transition is strict but continuous. We compare the efficacy of different dispatch models and also those of the optimum dynamic and static controls using numerical computations.

Next, we consider the case in which both malware and network can dynamically vary their parameters over time in response to the changes of the state of the system and also to each other's controls.The infinite dimension of freedom introduced by variation over time and antagonistic and strategic optimization of malware and network against each other demand new attempts for modeling and analysis. We develop a zero-sum dynamic game model and investigate the structural properties of the saddle-point strategies. We specifically show that saddle-point strategies are still simple threshold-based policies and hence, a robust dynamic defense is practicable. Finally, we develop a unified mathematical framework for calculating optimal controls of systems governed by epidemic evolution using Pontryagin’s Maximum Principle, and we demonstrate how it can be applied to contexts beyond network security. Specifically, we show how our framework can be specialized for marketing, dissemination of messages in DTN or p2p networks, health-care, etc. This dissertation in part demonstrates how using simple real analysis arguments, one can extract substantial information about the structure of optimal policies for nonlinear systems in the absence a closed-form solution.

Patterns of Weight Change in Infants with Congenital Heart Disease Following Neonatal Surgery: Potential predictors of growth failure

Sharon Y Irving

DISSERTATION SUPERVISOR: BARBARA MEDOFF-COOPER, RN, PhD

Congenital heart disease (CHD) is reported to have an incidence of 9 to 14 per 1000 live births with a prevalence estimated between 650,000 and 1.3 million persons in the United States (US). It is a structural malformation(s) of one or more heart chamber(s) and/or deformity of one or more of the major intrathoracic blood vessel(s) and the ensuing malady occurring during embryonic development. Up to one-third of infants with CHD, require surgical intervention. Improved surgical technique over the last several decades has seen an increased survival of neonates with CHD. Concomitantly there has been an emergence of co-morbidities. Growth failure is a common co-morbidity following neonatal surgery for CHD. More than 30% of these infants fall below the third percentile for weight early in their lives. Postsurgical physiology, disease severity, feeding dysfunction, and a hypermetabolic state may all contribute to growth failure, which has been associated with deficits in cognitive development, intellectual ability and neurodevelopment, effecting maturation and school performance. Early recognition and intervention of growth failure can improve health outcomes. The objective of this work is to identify patterns of growth and growth failure in infants with CHD and explore potential predictors that may be modifiable to mitigate growth failure and prevent the associated untoward consequences.

We also uncover a role for the bowl pathway in influencing niche cell specification, where bowl promotes niche cell fate, while its antagonist, lines, promotes cyst cell fate. Additionally, we present data suggesting that bowl functions as a transcriptional repressor to restrict cyst cell gene expression in precursor cells, thereby inducing niche cell specification. Ultimately since niche cells influence stem cell behavior, understanding how niche cells develop and dissecting the interactions between niches and their resident stem cells is paramount if we seek to use stem cells as tools in regenerative medicine.

Sara Elizabeth Hayik

Supervisor: Professor Bradford B. Wayland

Living radical polymerization techniques are powerful tools for prepared specialty polymer products used in applications from biotechnology to electronics. Development of catalysts for the different methods is important for increased versatility. The goals of this research were to develop new radical addition-fragmentation chain transfer (RAFT) and cobalt mediated radical polymerization (CMRP) catalysts and utilize polymers produced through controlled radical polymerization techniques for the synthesis of metal nanoparticles. Vanadium complexes were designed to mimic conventional RAFT chain transfer agents and tested in the polymerization of methylacrylate (MA) and styrene. These complexes proved unsuitable for use as RAFT catalysts. Several cobalt complexes, using salen and salen derivative ligands, were prepared and tested as CMRP catalysts for the polymerization of MA and vinyl acetate (VAc). (R,R)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino Cobalt (II) proved to be the most promising candidate for both polymers. MA was prepared with PDIs 1.32 and under while the VAc PDIs were under 1.50. In both cases, observations suggesting a controlled polymerization were reported. PDMAEMA synthesized using a RAFT polymerization was used to stabilize and control the formation of platinum, gold, and palladium nanoparticles. Protonation of the polymer chains using succinic acid or acidic metal complexes allowed for ionic cross-linking by the metal anions, which is observed through DLS analysis. Reduction of the metal complexes was then performed within the nanogel and the rapid stabilization by the polymer results in small well defined particles. Well defined particles were produced for each metal with different size ranges for each. Nanogel formation is critical mechanism for control in each system and was seen only in systems containing dianionic species