C-DOC: Co-State Desensitized Optimal Control

In this paper, co-states are used to develop a framework that desensitizes the optimal cost. A general formulation for an optimal control problem with fixed final time is considered. The proposed scheme involves elevating the parameters of interest into states, and further augmenting the co-state equations of the optimal control problem to the dynamical model. A running cost that penalizes the co-states of the targeted parameters is then added to the original cost function. The solution obtained by minimizing the augmented cost yields a control which reduces the dispersion of the original cost with respect to parametric variations. The relationship between co-states and the cost-to-go function, for any given control law, is established substantiating the approach. Numerical examples and Monte-Carlo simulations that demonstrate the proposed scheme are discussed

Desensitization and Deception in Differential Games with Asymmetric Information

Desensitization addresses safe optimal planning under parametric uncertainties by providing sensitivity function-based risk measures. This paper expands upon the existing work on desensitization to address safe planning for a class of two-player differential games. In the proposed game, parametric uncertainties correspond to variations in a vector of model parameters about its nominal value. The two players in the proposed formulation are assumed to have information about the nominal value of the parameter vector. However, only one of the players is assumed to have complete knowledge of parametric variation, creating a form of information asymmetry in the proposed game. The lack of knowledge regarding the parametric variations is expected to result in state constraint violations for the player with an information disadvantage. In this regard, a desensitized feedback strategy that provides safe trajectories is proposed for the player with incomplete information. The proposed feedback strategy is evaluated in instances involving one pursuer and one evader with an uncertain dynamic obstacle, where the pursuer is assumed to know only the nominal value of the obstacle's speed. At the same time, the evader knows the obstacle's true speed, and also the fact that the pursuer possesses only the nominal value. Subsequently, deceptive strategies are proposed for the evader, who has an information advantage, and these strategies are assessed against the pursuer's desensitized strategy

Growing Up Amid Ethno‐Political Conflict: Aggression and Emotional Desensitization Promote Hostility to Ethnic Outgroups

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134287/1/cdev12599.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134287/2/cdev12599_am.pd

IST Austria Thesis

Directed cell migration is a hallmark feature, present in almost all multi-cellular organisms. Despite its importance, basic questions regarding force transduction or directional sensing are still heavily investigated. Directed migration of cells guided by immobilized guidance cues - haptotaxis - occurs in key-processes, such as embryonic development and immunity (Middleton et al., 1997; Nguyen et al., 2000; Thiery, 1984; Weber et al., 2013). Immobilized guidance cues comprise adhesive ligands, such as collagen and fibronectin (Barczyk et al., 2009), or chemokines - the main guidance cues for migratory leukocytes (Middleton et al., 1997; Weber et al., 2013). While adhesive ligands serve as attachment sites guiding cell migration (Carter, 1965), chemokines instruct haptotactic migration by inducing adhesion to adhesive ligands and directional guidance (Rot and Andrian, 2004; Schumann et al., 2010). Quantitative analysis of the cellular response to immobilized guidance cues requires in vitro assays that foster cell migration, offer accurate control of the immobilized cues on a subcellular scale and in the ideal case closely reproduce in vivo conditions. The exploration of haptotactic cell migration through design and employment of such assays represents the main focus of this work. Dendritic cells (DCs) are leukocytes, which after encountering danger signals such as pathogens in peripheral organs instruct naïve T-cells and consequently the adaptive immune response in the lymph node (Mellman and Steinman, 2001). To reach the lymph node from the periphery, DCs follow haptotactic gradients of the chemokine CCL21 towards lymphatic vessels (Weber et al., 2013). Questions about how DCs interpret haptotactic CCL21 gradients have not yet been addressed. The main reason for this is the lack of an assay that offers diverse haptotactic environments, hence allowing the study of DC migration as a response to different signals of immobilized guidance cue. In this work, we developed an in vitro assay that enables us to quantitatively assess DC haptotaxis, by combining precisely controllable chemokine photo-patterning with physically confining migration conditions. With this tool at hand, we studied the influence of CCL21 gradient properties and concentration on DC haptotaxis. We found that haptotactic gradient sensing depends on the absolute CCL21 concentration in combination with the local steepness of the gradient. Our analysis suggests that the directionality of migrating DCs is governed by the signal-to-noise ratio of CCL21 binding to its receptor CCR7. Moreover, the haptotactic CCL21 gradient formed in vivo provides an optimal shape for DCs to recognize haptotactic guidance cue. By reconstitution of the CCL21 gradient in vitro we were also able to study the influence of CCR7 signal termination on DC haptotaxis. To this end, we used DCs lacking the G-protein coupled receptor kinase GRK6, which is responsible for CCL21 induced CCR7 receptor phosphorylation and desensitization (Zidar et al., 2009). We found that CCR7 desensitization by GRK6 is crucial for maintenance of haptotactic CCL21 gradient sensing in vitro and confirm those observations in vivo. In the context of the organism, immobilized haptotactic guidance cues often coincide and compete with soluble chemotactic guidance cues. During wound healing, fibroblasts are exposed and influenced by adhesive cues and soluble factors at the same time (Wu et al., 2012; Wynn, 2008). Similarly, migrating DCs are exposed to both, soluble chemokines (CCL19 and truncated CCL21) inducing chemotactic behavior as well as the immobilized CCL21. To quantitatively assess these complex coinciding immobilized and soluble guidance cues, we implemented our chemokine photo-patterning technique in a microfluidic system allowing for chemotactic gradient generation. To validate the assay, we observed DC migration in competing CCL19/CCL21 environments. Adhesiveness guided haptotaxis has been studied intensively over the last century. However, quantitative studies leading to conceptual models are largely missing, again due to the lack of a precisely controllable in vitro assay. A requirement for such an in vitro assay is that it must prevent any uncontrolled cell adhesion. This can be accomplished by stable passivation of the surface. In addition, controlled adhesion must be sustainable, quantifiable and dose dependent in order to create homogenous gradients. Therefore, we developed a novel covalent photo-patterning technique satisfying all these needs. In combination with a sustainable poly-vinyl alcohol (PVA) surface coating we were able to generate gradients of adhesive cue to direct cell migration. This approach allowed us to characterize the haptotactic migratory behavior of zebrafish keratocytes in vitro. Furthermore, defined patterns of adhesive cue allowed us to control for cell shape and growth on a subcellular scale

Neutrophils self-limit swarming to contain bacterial growth in vivo

Neutrophils communicate with each other to form swarms in infected organs. Coordination of this population response is critical for the elimination of bacteria and fungi. Using transgenic mice, we found that neutrophils have evolved an intrinsic mechanism to self-limit swarming and avoid uncontrolled aggregation during inflammation. G protein–coupled receptor (GPCR) desensitization acts as a negative feedback control to stop migration of neutrophils when they sense high concentrations of self-secreted attractants that initially amplify swarming. Interference with this process allows neutrophils to scan larger tissue areas for microbes. Unexpectedly, this does not benefit bacterial clearance as containment of proliferating bacteria by neutrophil clusters becomes impeded. Our data reveal how autosignaling stops self-organized swarming behavior and how the finely tuned balance of neutrophil chemotaxis and arrest counteracts bacterial escape

Witnessing Community Violence and its Consequences: Changes Across Middle School

Community violence exposure is prevalent among youth residing in economically marginalized communities that have high rates of violence. Witnessing community violence has been concurrently associated with persistent adverse consequences. However, few studies have applied a developmental psychopathology framework and examined dynamic developmental processes between witnessing community violence and outcomes over time. Moreover, most prior studies have used analyses that assume that associations between witnessing violence and outcomes are the same for all adolescents, which is inconsistent with both developmental theories and theories specific to community violence exposure. The goal of this study was to apply a developmental psychopathological framework to (a) examine heterogeneity in changes in witnessing community violence across middle school, and (b) examine their associations with distress symptoms and aggression. I used three analyses that made different assumptions about the heterogeneity and functional form of change within a subgroup of adolescents residing in an economically marginalized community with high rates of violence. Participants were 1,323 youth (54.3% female, 17.5% Latine, 88.3% African American/Black) attending middle schools in neighborhoods with high percentages of residents below the federal poverty line and high rates of violence. I used latent curve models to identify trajectories of witnessing community violence, distress symptoms, and physical aggression for the overall sample. For witnessing community violence, a piecewise model fit the data best and indicated that witnessing community violence decreased across middle school with the steepest decrease during the 6th grade. Additionally, there were significant drops in witnessing violence during the summer. For distress symptoms, a quadratic model fit the data best such that symptoms decreased across middle school and the rate of change decreased (i.e., decelerated) over time. For aggression, a piecewise model fit the data best and indicated that the frequency of physical aggression was stable during each school year and decreased significantly during the summer. Results of a growth mixture model (GMM) analysis using the parameters of the witnessing violence trajectory as latent class indicators suggested that there was heterogeneity in trajectories of witnessing violence that could be modeled by three distinct subgroups. Latent profile analysis, which allowed the functional form of change in witnessing violence to vary over time by examining patterns in frequency, produced similar subgroups to the GMM. Thus, the GMM, which constrained the functional form to be the same across subgroups and allowed within-group variability in parameters, was further evaluated for subgroup differences in distress symptoms and physical aggression. Overall, frequencies of witnessing violence differed across subgroups, and subgroups with higher overall frequencies had greater decreases (i.e., slopes) in witnessing over time. The subgroups also differed in their overall levels of distress and aggression, but not in their rates of change (i.e., slopes) in these constructs. A rarely witnessing subgroup (22%) had the lowest levels of distress symptoms and frequencies of aggression across middle school. The frequent witnessing subgroup (33%) had the highest levels of distress symptoms and frequencies of physical aggression across middle school. Additionally, this subgroup had the largest decreases in witnessing violence and physical aggression frequencies during the summer. Finally, the moderate witnessing subgroup (45%) consistently reported levels of distress symptoms and frequency of physical aggression in between those reported by the other two subgroups. These findings suggest that there is heterogeneity in adolescents’ experiences of witnessing community violence exposure across time that can be modeled with the same functional form. These findings have implications for interventions and highlight the importance of early intervention

The Longitudinal Relationship between Callous-Unemotional Traits and Exposure to Community Violence: Examining Primary and Secondary Psychopathy in Serious Adolescent Offenders

in youth, psychopathy is often represented by callous-unemotional traits, characterized by a lack of guilt and empathy. While justice-involved youth can exhibit such traits, less research has been done in adolescents than has been with adults in the justice system. Still, previous research supports that callous-unemotional traits in particular can predict higher risk for adverse outcomes and violent behavior in youth. Various vulnerabilities and experiences contribute to the development of callous-unemotional traits, and while some individuals with psychopathic traits are thought to have been born with an innate inability to feel empathy (primary psychopathy), others may experience psychological distress in response to trauma and emotionally desensitize to cope (secondary psychopathy). Prior research shows exposure to community violence, a common and chronic experience for justice-involved adolescents, is one such traumatic event associated with callous-unemotional traits, but there remains a need to better understand how these variables influence one another over time in serious adolescent offenders, and how aggressive behaviors may be affected. Information provided by male adolescent offenders in the Pathways to Desistance study was used to investigate 1) whether youth displayed differing patterns of psychological distress that may indicate primary and secondary pathways to callous-unemotional traits, 2) how exposure to community violence and callous-unemotional traits influence one another over time across youth with primary versus secondary pathways, and 3) whether there were differences in the associations between exposure to community violence, callous-unemotional traits, and violent offending in later adolescence/early adulthood across the primary versus secondary groups. Results from a latent profile analysis resulted in larger groups of youth with low and medium levels of psychological distress, and one small group of youth with uniquely high distress. a subsequent multigroup cross lag panel model incorporating the low and medium distress participants revealed differences in the associations between callous-unemotional traits and exposure to community violence as a function of distress level. Lastly, callous-unemotional traits did not predict later aggressive offending in either group, but exposure to community violence negatively predicted later aggressive offending for youth with higher distress levels. Results support the use of psychological distress levels to better understand the longitudinal associations between exposure to community violence and callous-unemotional traits, but did not indicate increased callous-unemotional traits or exposure to community violence could positively predict later violent offending. Future studies related to the development of psychopathic traits in youth should continue to further explore what types of distress specifically may increase vulnerability for youth developing callous-unemotional traits as a way to cope with adverse experiences. Clinically, connections between violence exposure and emotional desensitization should be utilized in trauma-informed therapies with adolescents involved in the justice system who are at high risk for trauma and distress

Structure-function studies of TRPV1 alcohol modulation

The TRPV1 channel is a member of the Transient Receptor Potential (TRP) family of cation channels and is responsible for the perception of different noxious stimuli. It is mainly found in the peripheral terminals of primary sensory neurons where pain is produced and in various brain regions such as hypothalamus, cerebellum and cerebralcortex. It can be activated by a large number of physical and chemical stimuli and themost known ones include capsaicin (the active component of hot chili peppers), noxiousheat (greater than 42◦C), voltage and acidity. There is now evidence of how ethanol can potentiate TRPV1 activity when activatedby low pH (inflammation) and capsaicin, and how it can lower the temperature thresholdactivation when activated by heat. It is also known that different alcohol moleculescan affect many biophysical processes, including the kinetics of ion channels acting aspositive allosteric modulators, therefore, it is important to determine how the proprietiesof such receptors change when alcohol molecules interact with the system. Following this path, the aim of this project is to optimize a protocol which can later be used for a simpler TRPV1 expression on Xenopus laevis oocytes in order to perform experiments of electrophysiology (TEVC). Once this is achieved, using the TEVC method, it will bepossible to determine how alcohol modulates TRPV1 by figuring out the alcohol cut-off size (the maximum size alcohol that can bind and modulate to the channel) that couldindicate a direct alcohol binding site on the channel. Through this step and others that will follow in this direction, a new way of understanding pain can be accomplished by formulating more pain-inhibiting drugs that can act on additional specific sites