Living with HIV after Release from Prison: An Evaluation of the Long-term Health of Formerly Incarcerated Individuals who used Michigan’s Community Reentry Service

In 2003, Michigan implemented a reentry service to assist HIV-infected people incarcerated in state prisons in linking to HIV medical care immediately upon their release. We examined whether formerly incarcerated people were linked to care successfully, remained in care, and were in good health 3 years after their date of release. In all, 190 people used the service over the 5 years following its inception. Only a minority of those who were alive and not reincarcerated at the time of the evaluation engaged consistently with medical care. Unsurprisingly given low rates of engagement in care, 3 years after their release only 27% had achieved viral suppression. Concerted efforts to support formerly incarcerated HIV-infected individuals’ engagement in care over the long term are urgently needed

Polytypism and Unique Site Preference in LiZnSb: A Superior Thermoelectric Reveals Its True Colors

The first example of polytypism in the I–II–V semiconductors has been demonstrated with the synthesis of cubic LiZnSb by a low-temperature solution-phase method. This phase exhibits a unique coloring pattern that is novel for this class of compounds. The choice of site configuration has a considerable impact on the band structure of these materials, which in turn affects the transport properties. While the hexagonal polytype has been suggested as a promising n-type and extremely poor p-type thermoelectric material, the cubic analogue is calculated to have high efficiencies for both the n- and p-type derivatives (1.64 and 1.43, respectively, at 600 K). Furthermore, the cubic phase is found to be the energetically favored polytype. This surprising result provides a rationale for the lack of success in synthesizing the hexagonal polytype in either stoichiometric or n-type compositions

Understanding and targeting network-level sheddase regulation in invasive disease

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2013.Cataloged from PDF version of thesis.Includes bibliographical references (p. 197-212).Regulated cell-surface proteolysis underpins key processes of cellular growth and motility in both physiological and pathological contexts. However, comprehending how multiple proteolytic events cohesively integrate to yield context-dependent cellular behavior remains a challenge in the fields of both protease biology and systems biology in general. This work begins to address that challenge by quantitatively investigating the integrated effect of multiple diverse proteolytic events and their interaction with cell-signaling pathways from a computational network perspective, particularly focusing on A Disintegrin and Metalloproteinases (ADAMs). ADAMs have been studied for decades as the principal cell-surface "sheddases" responsible for cleaving growth factor ligands and receptor tyrosine kinase ectodomains from the cell surface. However, activity regulation, feedback, and catalytic promiscuity impede our understanding of context-dependent sheddase function, and clinical trials targeting metalloproteinases in cancer have failed in part due to a poor understanding of the complex functions they mediate. This thesis outlines a conceptual framework for studying protease network biology (Chapter 1), describes novel experimental methods designed for such a framework (Chapters 2-3), and applies both to understand protease regulation in invasive disease (Chapter 4). Using combined measurement and computational modeling, we present a paradigm for monitoring and analyzing complex networks of protease activities that interface with signaling pathways to influence cellular migration in the invasive diseases of cancer and endometriosis. We find sheddase activity integrates with signaling pathways to direct cell migration, especially through concomitant proteolysis of both ligands and receptors. We find that indirect reduction of sheddase activity through kinase inhibition can lead to an accumulation of growth-factor receptors on the cell surface, consequently producing undesired compensatory signaling feedback. Thus, here we present a novel mechanism of rapid, protease-driven resistance to kinase inhibitors, and we subsequently demonstrate strategies for overcoming resistance through drug combinations. We develop a novel microfluidic platform to study protease activities in clinical samples, and apply the technology to study the peritoneal fluid from endometriosis patients. Results indicate joint dysregulation of sheddase activity with disease. Overall, this work provides a model for measuring, understanding, and targeting networks of proteases and the kinases with which they interact.by Miles Aaron Miller.Ph.D

The performance of Mini Wright peak flow meters after prolonged use

AbstractThe accuracy of 84 new and 35 old Mini Wright peak flow meters were tested using a servo-controlled pump system. The 95% confidence limits for flow measurement across the range of the new meters was between ± 151 min−1 at the lower end of the range and ± 281 min−1 at the top of the range. The readings for 22 (63%) of the old meters (age range 1–13 yr) were within these 95% confidence limits. For the remaining 13 old meters (age range 1–13 yr) whose readings were not within these limits, there were 11 meters with readings falling below and two meters with readings above these limits. Twelve of these old meters were washed and retested and there was no significant change in their readings. Twenty of the new meters were retested after 1 yr of continuous use and their readings were significantly higher with a median value of 51 min−1 across the range, although only two of these 20 meters had readings outside the 95% confidence limits set from the 84 new meters. It is concluded that whilst Mini Wright meters aged up to 14 yr can give readings which are as good as new meters, some meters demonstrate significant changes in readings after only 1 yr and washing did not correct this change. It is recommended that clinicians prescribing peak expiratory flow (PEF) meters should be responsible for checking the patient's meter as well as their PEF readings at clinic visits

The Receptor AXL Diversifies EGFR Signaling and Limits the Response to EGFR-Targeted Inhibitors in Triple-Negative Breast Cancer Cells

The relationship between drug resistance, changes in signaling, and emergence of an invasive phenotype is well appreciated, but the underlying mechanisms are not well understood. Using machine learning analysis applied to the Cancer Cell Line Encyclopedia database, we identified expression of AXL, the gene that encodes the epithelial-to-mesenchymal transition (EMT)–associated receptor tyrosine kinase (RTK) AXL, as exceptionally predictive of lack of response to ErbB family receptor–targeted inhibitors. Activation of EGFR (epidermal growth factor receptor) transactivated AXL, and this ligand-independent AXL activity diversified EGFR-induced signaling into additional downstream pathways beyond those triggered by EGFR alone. AXL-mediated signaling diversification was required for EGF (epidermal growth factor)–elicited motility responses in AXL-positive TNBC (triple-negative breast cancer) cells. Using cross-linking coimmunoprecipitation assays, we determined that AXL associated with EGFR, other ErbB receptor family members, MET (hepatocyte growth factor receptor), and PDGFR (platelet-derived growth factor receptor) but not IGF1R (insulin-like growth factor 1 receptor) or INSR (insulin receptor). From these AXL interaction data, we predicted AXL-mediated signaling synergy for additional RTKs and validated these predictions in cells. This alternative mechanism of receptor activation limits the use of ligand-blocking therapies and indicates against therapy withdrawal after acquired resistance. Further, subadditive interaction between EGFR- and AXL-targeted inhibitors across all AXL-positive TNBC cell lines may indicate that increased abundance of EGFR is principally a means to transactivation-mediated signaling.United States. Dept. of Defense (Congressionally Directed Medical Research Programs, Breast Cancer Research Program (W81XWH-11-1-0088))National Science Foundation (U.S.) (Graduate Research Fellowship)Repligen Corporation (Fellowship in Cancer Research)National Cancer Institute (U.S.). Integrative Cancer Biology Program (1-U54-CA112967)David H. Koch Institute for Integrative Cancer Research at MIT (Frontier Research Program Initiator Award)National Institutes of Health (U.S.) (NIH R01-CA96504

Evaluating evolution as a learning algorithm

We interpret the Moran model of natural selection and drift as an algorithm for learning features of a simplified fitness landscape, specifically genotype superiority. This algorithm's efficiency in extracting these characteristics is evaluated by comparing it to a novel Bayesian learning algorithm developed using information-theoretic tools. This algorithm makes use of a communication channel analogy between an environment and an evolving population. We use the associated channel-rate to determine an informative population-sampling procedure. We find that the algorithm can identify genotype superiority faster than the Moran model but at the cost of larger fluctuations in uncertainty

Effects of Art Intervention on Pediatric Anxiety and Pain in the Medical Setting

Introduction: Hospitalization and illness can be a painful and stressful time for a child. There may be anxiety over procedures and inpatient stays disrupt normal routines. Previous research found that for pre-school aged children, having parents around, having the help of the hospital staff, and playing an active role in alleviating their fears were the most helpful in reducing anxiety. Another study found that visual creative expressions can be meaningful experiences for young adult cancer survivors. Additionally, there is abundant literature on formal art therapy and its favorable effects on children in the hospital, however, there are fewer studies investigating less standardized “art intervention” in the same population. The purpose of our project was to assess whether art intervention reduces anxiety and pain in inpatient and outpatient pediatric patients.https://scholarworks.uvm.edu/comphp_gallery/1224/thumbnail.jp

Single cell imaging of Bruton's Tyrosine Kinase using an irreversible inhibitor

A number of Bruton's tyrosine kinase (BTK) inhibitors are currently in development, yet it has been difficult to visualize BTK expression and pharmacological inhibition in vivo in real time. We synthesized a fluorescent, irreversible BTK binder based on the drug Ibrutinib and characterized its behavior in cells and in vivo. We show a 200 nM affinity of the imaging agent, high selectivity, and irreversible binding to its target following initial washout, resulting in surprisingly high target-to-background ratios. In vivo, the imaging agent rapidly distributed to BTK expressing tumor cells, but also to BTK-positive tumor-associated host cells

An Agent-Based Model of Signal Transduction in Bacterial Chemotaxis

We report the application of agent-based modeling to examine the signal transduction network and receptor arrays for chemotaxis in Escherichia coli, which are responsible for regulating swimming behavior in response to environmental stimuli. Agent-based modeling is a stochastic and bottom-up approach, where individual components of the modeled system are explicitly represented, and bulk properties emerge from their movement and interactions. We present the Chemoscape model: a collection of agents representing both fixed membrane-embedded and mobile cytoplasmic proteins, each governed by a set of rules representing knowledge or hypotheses about their function. When the agents were placed in a simulated cellular space and then allowed to move and interact stochastically, the model exhibited many properties similar to the biological system including adaptation, high signal gain, and wide dynamic range. We found the agent based modeling approach to be both powerful and intuitive for testing hypotheses about biological properties such as self-assembly, the non-linear dynamics that occur through cooperative protein interactions, and non-uniform distributions of proteins in the cell. We applied the model to explore the role of receptor type, geometry and cooperativity in the signal gain and dynamic range of the chemotactic response to environmental stimuli. The model provided substantial qualitative evidence that the dynamic range of chemotactic response can be traced to both the heterogeneity of receptor types present, and the modulation of their cooperativity by their methylation state