Social support networks have been shown to be related to the health status of various groups of people, when measured in different ways and under different circumstances. Yet, there have been few comparisons of this relationship across population groups. Therefore the purpose of this study was to compare the ways that social support networks relate to the health status of different population groups. The study used data that was collected in Wave I of the National Survey of Personal Health Practices and Consequences in 1979, in telephone interviews with 3025 persons aged 20-64 residing in households with telephones. Ten target groups were selected for study--those with high stress jobs, the unemployed, the aged, the widowed, the bereaved, the disabled, those who had recently experienced serious illness or injury, the poor, those with negative status inconsistency, and single parents. It was found that there was no uniform pattern in the way that social networks relate to health status, but rather different elements of social networks related to the health status of members of different target groups. These relationships were fairly consistent regardless of which of two health status measures were employed--self-rated health status and composite health status. And social networks were more strongly related to the health status of target group members than they were to the health of the general population. Existing theories regarding the ability of social networks to predict health status are explored, in an attempt to explain the findings of this study. As they prove inadequate, a new model is proposed, in which the needs of various groups are seen as determining which social network elements will be able to modify health status. That is to say, the success of social networks in maintaining health is contingent upon a proper fit between social networks, individual needs and health status. The implications of the study for social work practice and policy center around the importance of specificity in relating networks to health. In addition, avenues for future research are explored, especially in designing studies to specifically test the proposed model.

Memory T cells are critical for maintaining lifelong immunity by protecting against reinfection with previously encountered pathogens. In recent years, a subset of memory T cells termed tissue-resident memory T cells (TRM) has emerged as the primary mediator of protection at many tissue sites. Numerous studies in mice have demonstrated that TRM accelerate pathogen clearance compared with other subsets of memory T cells. The defining characteristic of TRM is that they are retained within tissues and do not circulate in the blood. The lack of TRM in blood has proved to be a barrier for investigating the role of TRM in healthy humans. As a result, there are many outstanding questions about TRM biology in humans, including which phenotypic markers identify TRM, if TRM represent a unique memory subset, as well as defining transcriptional and functional characteristics of this subset. Through a unique collaboration with the local organ procurement agency, we obtained samples from >15 tissue sites from healthy organ donors of all ages. We found that the surface marker CD69 was expressed by memory CD4+ and CD8+ T cells in multiple tissues including spleen and other lymphoid tissues, lung, and intestines, but not in blood, suggesting that this marker may identify TRM in human tissues. We identify a core transcriptional signature that distinguishes CD69+ memory T cells in tissues from CD69- memory T cells in tissues and blood with key homologies to the transcriptional profile of TRM in mice, suggesting that CD69 expression identifies TRM in humans. We show that human TRM have a distinct profile of adhesion and migration markers, and a unique dual functional capacity encompassing effector cytokine production but also the upregulation of inhibitory markers and the ability to produce IL-10 upon stimulation. These results suggest unique adaptations for TRM to maintain long-term residence within tissues and carry out pathogen clearance. We found substantial heterogeneity within human TRM in lymphoid and mucosal tissue sites, including a substantial fraction (40-60%) of TRM in various human tissues with the ability to efflux fluorescent dyes. These efflux(+) TRM had phenotypic and transcriptional characteristics associated with quiescence, including expression of immunomodulatory markers, reduced expression of exhaustion markers, and reduced turnover at steady state. Upon TCR stimulation, efflux(+) TRM produced lower levels of proinflammatory cytokines and cytotoxic molecules but had a superior ability to proliferate compared with efflux(-) TRM. However, efflux(+) also had an enhanced capacity for IL-17 production along with transcriptional features of IL-17 signaling following stimulation. Overall, these studies establish universal properties of human TRM and hint at the function of distinct TRM subsets in mediating tissue immunity.

Patient-provided data are crucial to achieving the goal of precision medicine. These data, which include family medical history, race and ethnicity, and social and behavioral determinants of health, are essential for disease risk assessment. Despite the well-established importance of patient-provided data, there are many data quality challenges that affect how this information can be used for biomedical research. To determine how to best use patient-provided data to assess disease risk, the research reflected in this dissertation was divided into three overarching aims. In Aim 1, I focused on determining the quality of race and ethnicity, family history and smoking status in clinical databases. In Aim 2, I assessed the impact of various interventions on the quality of these data, including policy changes such as the implementation of the requirements imposed by the Meaningful Use program, and patient-facing tools for collecting and sharing information with patients. In addition to these evaluations, I also developed and evaluated a method “Relationship Inference from the Electronic Health Record” (RIFTEHR), that infers familial relationships from clinical datasets. In Aim 3, I used patient-provided data to assess disease risk both at a population level, by estimating disease heritability, and at an individual level, by identifying high-risk individuals eligible for additional screening for a common disease (diabetes mellitus) and a rare disease (celiac disease). My research uncovered several data quality concerns for patient-provided data in clinical databases. When assessing the impact of interventions on the quality of these data, I found that policy interventions led to more data collection, but not necessarily to better data quality. In contrast, patient-facing tools did increase the quality of the patient-provided data. In the absence of high-quality patient-provided data for family medical history, I developed and evaluated a method for inferring this information from large clinical databases. I demonstrated that electronic health record data can be used to infer familial relationships accurately. Moreover, I showed how the use of clinical data in conjunction with the inferred familial relationships could determine disease risk in two studies. In the first study, I successfully computed disease heritability estimates for 500 conditions, some of which had not been previously studied. In the second study, I identified that screening rates among family members that are considered to be at high-risk for disease development were low for both diabetes mellitus and celiac disease. In summary, the work represented in this dissertation contributes to the understanding of the quality of patient-provided data, how interventions affect the quality of these data, and how novel methods can be applied to troves of existing clinical data to generate new knowledge to support research and clinical care.

Haematopoietic stem and progenitor cells (HSPCs) are de novo generated within in the ventral aspects of the embryonic dorsal aorta (DA). Cells of this haemogenic endothelium (HE) will eventually undergo an endothelial to haematopoietic transition (EHT) that involves cell budding out of the aortic wall. Despite the detailed description of the cellular events, the exact haemogenic lineage path and the underlying molecular mechanism that establish full haematopoietic competence are still not entirely understood. The transcription factor Runx1 is critical for the emergence of HSPCs and shows expression in the zebrafish HE as early as 24 hpf. To facilitate a detailed analysis of the transient HE population I generated a TgBAC(runx1P2:Citrine) reporter line under the control of the endogenous runx1 promoter on a bacterial artificial chromosome (BAC). Double-transgenic reporter lines for runx1 and the endothelial marker kdrl allowed us to isolate specifically cells of the DA away from the whole endothelial population, which could be further sub-divided into HE and non-haemogenic cells. Genomewide expression analysis within the respective tissues and upon Runx1 loss of function enabled the identification of HE-specific Runx1-regulated genes. Hereby, the gfi1ab gene appeared as the functional homologue of the murine Gfi1. I show that in zebrafish, EHT is orchestrated through a conserved Runx1-Gfi1-Lsd1 axis. The cellular functions of the remaining Runx1 targets imply that maturation into fully functional HSCs depends on epigenetic regulation due to the up-regulation of de novo DNAmethyltransferases, as well as on factors that allow the developing HSCs to respond to extrinsic cues from haematopoietic niches. Lastly, it became evident that the early HE expresses dll4 at similar levels to the rest of the aortic endothelium, indicating a common lineage path. In the absence of RUNX1 the HE remains essentially arterial and persists as an integrated part of the DA.

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Methylation controlled J protein (MCJ) is a negative regulator of mitochondrial metabolism that has a substantial impact on overall cell metabolism and function. MCJ is highly expressed by naïve CD8+ T cells, however its role in their immune effector functions was unknown. In this dissertation, it will be demonstrated that MCJ restricts the mitochondrial metabolism of CD8+ T cells, in part by reducing respiratory supercomplex formation. MCJ deficiency enhances the immune effector functions and memory responses of CD8+ T cells in a mitochondrial ATP dependent manner. As a consequence, protection to influenza virus infection is substantially improved. Reduced expression of MCJ therefore promotes viral immunity, however the loss of MCJ is not always beneficial. In cancer, decreased MCJ expression is correlated with ATP binding cassette (ABC) transporter mediated chemotherapy resistance and poor patient responses. This dissertation will also address the role of MCJ in chemoresistance. Increased mitochondrial ATP production due to MCJ deficiency is sufficient to fuel ABC transporter activity, thereby directly promoting chemoresistance. This can be reversed by restoration of MCJ function in chemoresistant cells. Overall, the results presented in this dissertation identify MCJ as a potential therapeutic target, as modulating MCJ expression can significantly affect the severity of viral infections and the responses to chemotherapy.

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<p>Cerebral ischemia elicits a wide range of events, including complex activation of various intracellular signaling pathways. This study aims to investigate the expression of vascular endothelial growth factor (VEGF) and the activation pattern of mitogen-activated protein kinases (MAPK) in reponse to focal cerebral ischemia. Furtermore, the functional roles of the p38 MAPK and the Src family kinases (SFKs) are investigated with specific signal transduction inhibitors in the rat <i>in vivo</i>. </p><p>VEGF was found upregulated in several cell types including neurons, glia and vascular cells after both permanent and transient cerebral ischemia. VEGF-receptor 1 (VEGFR1) was expressed in a similar manner, while VEGFR2 expression was more restricted and confined to endothelial cells and glia.The main MAPK pathways, including extracellular-regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38, were differentially activated by cerebral ischemia. ERK activation was present in blood vessels, suggesting a potential role in neovascularization. JNK was also activated in blood vessels in the infarcted hemisphere, possibly reflecting an interaction with ERK, whereas p38 activity was absent in vessels. In neurons, ERK was activated in cortical cells up to days of survival, while no substantial JNK or p38 activation was seen in ischemic neurons. Invading macrophages showed distinct activation of p38 and to some extent also JNK but not ERK. Glia showed activation of all MAPK to a variable extent.</p><p>Pretreatment with the p38-inhibitor SB203580 before transient cerebral ischemia (ischemia-reperfusion) was investigated with magnetic resonance imaging (MRI). The experiment group suffered worse infarcts and blood-brain barrier (BBB) damage than controls, which contrasts to previous studies. The results might be attributed to interference with protective effects of the vehicle or with preconditioning mechanisms. The SFK-inhibitor PP2 significantly reduced infarct size after cerebral ischemia-reperfusion, which is consistent with previously reported effects in permanent ischemia. Due to the multifunctional role of SFKs, it cannot be easily concluded in exactly what cellular context(s) SFKs are of importance to cerebral ischemia.</p><p>In conclusion, the VEGF and MAPK systems of extra- and intracellular signaling are activated in focal cerebral ischemia. Manipulation of p38 as well as SFK <i>in vivo </i>can influence the course of transient cerebral ischemia, which may be of significance to the understanding of the pathology of cerebral ischemia and to the development of therapeutic strategies. </p>

No description available.