Mast cells are known to play an important role in allergic events and in other inflammatory reactions through varied intracellular signaling transduction proteins. RasGRP4 is a mast cell-restricted guanine nucleotide exchange factor (GEF) and diacylglycerol (DAG)/phorbol ester receptor. Interleukin (IL) -13, a critical cytokine for allergic inflammation, exerts its effects through a complex receptor system including IL-4Rα, IL-13Rα1 and IL-13Rα2. IL-13Rα2 has been reported to be a decoy receptor for IL-13. My experiments indicate that the mast cell specific RasGRP4 protein regulates the level of IL 13Rα2 and controls IL-13/ IL 13Rα1-mediated intracellar signaling events in mast cells. Phosphorylation of STAT6 plays an important role in airway hyperresponsiveness and asthma. The development of therapeutics that can regulate RasGRP4 could be used to modulate the IL-13-induced phosphorylation of STAT-6 that may be used as therapy in patients with asthma. SLE is a complex, heterogeneous systemic autoimmune disease characterized by the presence of high levels of autoantibodies. Dysregulation of RasGRP1, a Ras active gene, in mice resulted in a SLE-like disorder. Yasuda and coworkers demonstrated that a defective isoform of RasGRP1 (Δ11) was present in a subset of patients with SLE. My experiments indicate that RasGRP1 upregulates the expression of IL2RG in T cells. In contrast the Δ11 RasGRP1 isoform expressed in a subset of SLE patients leads to defective expression of IL2RG. The IL2RG chain is a common chain which forms part of a number of different receptors eg. IL-2, 4, 7, 9, 15, 21. IL-2 as well as IL-21, which shares sequence homology with IL-2, has been reported to be involved in the generation of regulatory T cells (Tregs). In SLE patients, CD4 + CD25+ Tregs, which play an essential role in controlling immunologic tolerance to self-antigens and preventing autoimmunity, are significantly decreased when compared with healthy controls. The accumulative evidence suggests that the defective isoform of RasGRP1 (Δ11) downregulates expression of IL2RG in SLE patients?? T cells and this could effect the generation of CD4 + CD25+ Tregs. This may be another immunological mechanism in loss of tolerance observed in patient with SLE.

ITC/USA 2012 Conference Proceedings / The Forty-Eighth Annual International Telemetering Conference and Technical Exhibition / October 22-25, 2012 / Town and Country Resort & Convention Center, San Diego, California / Space Link Extension (SLE) is a set of recommended standards for mission cross support developed by the Consultative Committee for Space Data Systems (CCSDS). The SLE recommendations define protocols for extending the space link from ground terminals to other facilities deeper within a ground network, allowing distributed access to space link telecommand and telemetry services. The SLE protocols are widely used to provide cross support between sites, programs, and agencies. In traditional SLE deployments, individual service instances have been manually provisioned well in advance of the commencement of cross support for a particular mission, and hardware and software resources have been allocated to those service instances at the time of provisioning. While valid, this approach requires that dedicated resources be provided for each mission and service instance, and limits an SLE provider's ability to reallocate resources in real time based on system availability or other factors. This paper discusses an alternative approach to SLE service provisioning, in which individual service instances are assigned resources from a common resource pool at the time that each service instance is initialized. The paper addresses the key design elements and technical tradeoffs involved in this approach, and discusses the potential benefits with regard to load balancing, equipment reuse, and resiliency against system failure.

ITC/USA 2012 Conference Proceedings / The Forty-Eighth Annual International Telemetering Conference and Technical Exhibition / October 22-25, 2012 / Town and Country Resort & Convention Center, San Diego, California / Space Link Extension (SLE) is a set of recommended standards for mission cross support developed by the Consultative Committee for Space Data Systems (CCSDS). The SLE recommendations define protocols for extending the space link from ground terminals to other facilities deeper within a ground network, allowing distributed access to space link telecommand and telemetry services. The SLE protocols are widely used to provide cross support between sites, programs, and agencies. Traditional SLE protocol implementations have been limited in their ability to support high data rates and large numbers of concurrent service instances. Such limited solutions were sufficient to support the needs of spacecraft health and status or older, low-rate science data. More recent missions, however, have required significantly increased data rates on both uplink and downlink paths, necessitating a new approach to SLE implementation. This paper discusses the design principles involved in implementing the SLE protocols in support of high channel and aggregate mission data rates, with particular focus on the tradeoffs necessary to provide SLE link capability at sustained single-channel rates above 1 Gigabit per second. The paper addresses significant performance bottlenecks in the conventional SLE protocol stack and proposes potential mitigation strategies for them.

Introduction: Systemic lupus erythematosus (SLE) is a disabling, chronic, multisystem autoimmune disease that occurs in women of childbearing years (15-40) and spans a lifetime. Little is known about the relevance that social support has in the context of mental health wellbeing for patients with SLE. Physicians may be an adequate source of support when it comes to SLE. Since there are arrays of triggers for depression, there is a need to understand the SLE experience to help with disease management. Objective: To examine the association of social support from a physician and the mental health wellbeing of SLE patients. Methods: We examined 652 SLE patients from the Georgians Organized Against Lupus (GOAL) cohort. Descriptive analysis was performed. Univariate analysis was performed to examine the associations of the main dependent variables (Short Form Health Survey (SF-12) and Patient Health Questionnaire (PHQ-9)) and each independent variable. Both, univariate and multivariate logistic regression analyses were conducted to determine associations between selected characteristics and main independent variables (emotional or social support and social support from a physician) with the categorized mental component score and PHQ9 depression score, individually and together. Ninety-five percent confidence intervals were used to determine statistical significance. Results: SLE patients who perceived having enough emotional/social support were found to have an overall better mental health status than the average American, and 64% less likely to be depressed compared to patients who did not have enough emotional/social support. Patients who were categorized as having social support from a physician were found to be in poorer mental health statuses, as measured by the MCS SF-12 and PHQ9 depression score. Conclusion: The findings of this study show that emotional or social support is associated with a better mental health well-being for SLE patients. SLE patients who have enough emotional or social support were found to have above normal general mental health and less depression. This study did not show any direct associations between physician social support and mental health wellbeing.

Mast cells are known to play an important role in allergic events and in other inflammatory reactions through varied intracellular signaling transduction proteins. RasGRP4 is a mast cell-restricted guanine nucleotide exchange factor (GEF) and diacylglycerol (DAG)/phorbol ester receptor. Interleukin (IL) -13, a critical cytokine for allergic inflammation, exerts its effects through a complex receptor system including IL-4Rα, IL-13Rα1 and IL-13Rα2. IL-13Rα2 has been reported to be a decoy receptor for IL-13. My experiments indicate that the mast cell specific RasGRP4 protein regulates the level of IL 13Rα2 and controls IL-13/ IL 13Rα1-mediated intracellar signaling events in mast cells. Phosphorylation of STAT6 plays an important role in airway hyperresponsiveness and asthma. The development of therapeutics that can regulate RasGRP4 could be used to modulate the IL-13-induced phosphorylation of STAT-6 that may be used as therapy in patients with asthma. SLE is a complex, heterogeneous systemic autoimmune disease characterized by the presence of high levels of autoantibodies. Dysregulation of RasGRP1, a Ras active gene, in mice resulted in a SLE-like disorder. Yasuda and coworkers demonstrated that a defective isoform of RasGRP1 (Δ11) was present in a subset of patients with SLE. My experiments indicate that RasGRP1 upregulates the expression of IL2RG in T cells. In contrast the Δ11 RasGRP1 isoform expressed in a subset of SLE patients leads to defective expression of IL2RG. The IL2RG chain is a common chain which forms part of a number of different receptors eg. IL-2, 4, 7, 9, 15, 21. IL-2 as well as IL-21, which shares sequence homology with IL-2, has been reported to be involved in the generation of regulatory T cells (Tregs). In SLE patients, CD4 + CD25+ Tregs, which play an essential role in controlling immunologic tolerance to self-antigens and preventing autoimmunity, are significantly decreased when compared with healthy controls. The accumulative evidence suggests that the defective isoform of RasGRP1 (Δ11) downregulates expression of IL2RG in SLE patients?? T cells and this could effect the generation of CD4 + CD25+ Tregs. This may be another immunological mechanism in loss of tolerance observed in patient with SLE.

No description available.

Systemic Lupus Erythematosus (SLE) stands as a multifaceted autoimmune disorder, characterized by a spectrum of clinical manifestations and the generation of autoantibodies against self-antigens. Our focus was on the pivotal role of B cells in the development of SLE. The study also underscored the significant contribution of regulatory B (Breg) cells in the context of SLE, suggesting their potential as key regulators of the disease process. Our results provided a deeper understanding of the intricate interplay between B cells and SLE, offering insights that were valuable for both scientific research and future designs of therapeutic approaches. Cutting-edge single-cell RNA sequencing was employed to analyze the differences in splenic Breg subsets and their molecular profiles across different stages of lupus development in mice. Transcriptome-based changes in Bregs during active disease were confirmed through phenotypic analysis. These findings provided crucial insights into the dynamic role of B cells in the pathogenesis of SLE. In addition, we delved into the intricate connection between SLE and the gut microbiota. A literature review offered a comprehensive analysis of current research, with a particular emphasis on potential interactions between bacterial flagellin and Toll-Like Receptor 5 (TLR5) on immune cells. These interactions garnered substantial attention due to their potential implications in the pathogenesis of SLE. We synthesized existing research, providing valuable insights into the complex interplay between SLE and the microbiota and suggesting promising avenues for further investigation and potential therapeutic interventions. In the final study, we explored lupus-like disease in mice with global Tlr5 deletion, initially expecting disease attenuation. Surprisingly, the results revealed an exacerbation of lupus-like symptoms, particularly in female mice lacking Tlr5. Future research will seek to uncover the mechanisms by which Tlr5 deletion modulates interactions between the host and the gut microbiota, ultimately contributing to the exacerbation of lupus-like disease. / Doctor of Philosophy / Systemic Lupus Erythematosus (SLE) is characterized by a range of health issues and the body attacking itself. In this exploration, we journey through the intricate landscape of SLE, uncovering key players and unexpected twists. In this dissertation, we journeyed through the intricate landscape of SLE, uncovering key players and unexpected twists. In this dissertation, we closely examined these immune cells, revealing how different types of B cells contributed to SLE's development. We also introduced the enigmatic regulatory B (Breg) cells, which acted as potential peacekeepers in this autoimmune reaction. Our results illuminated the complex relationship between B cells and SLE, offering insights that benefited both researchers and those seeking new treatments. We employed cutting-edge technology, single-cell RNA sequencing, to scrutinize the genetic fingerprints of B cells in mice with SLE. The results unveiled changes in Breg cells during active disease, providing critical clues about how B cells impacted SLE progression. In addition, this dissertation took us into the microscopic world of our gut inhabitants, the microbiota. We dived into a treasure trove of research, focusing on how interactions between bacterial flagellin and various microbiota elements affected immune cells through a special receptor called Toll-Like Receptor 5 (TLR5). These interactions, like hidden clues, had piqued scientists' interest for their potential role in SLE development. We synthesized existing research, offering valuable insights into the complex interplay between SLE and our microbiota. The discussion also suggested promising paths for future research and potential therapies. In the final study, we encountered a plot twist. We anticipated that deleting the Tlr5 gene would improve lupus-like disease in mice. To our surprise, the opposite happened. Lupus-like symptoms worsened, especially in female mice lacking Tlr5. Clinical signs included enlarged spleens and lymph nodes, increased immune cell activity, and kidney inflammation. But Tlr5 deletion didn't change the mice's metabolism or the leaky gut. Instead, it reshaped their gut's microbial residents. Future research aimed to uncover how Tlr5 deletion altered the interactions between the host and gut microbes, ultimately making lupus-like disease more severe. In a nutshell, this journey through SLE's complex world provided a deeper understanding of its intricacies. We met the B cells, explored the microbiota, and encountered surprises along the way. These discoveries were vital pieces of the puzzle, bringing us closer to unlocking the secrets of SLE and, perhaps, finding new ways to manage and treat this challenging autoimmune disorder.

No description available.

No description available.

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies directed against ubiquitous self-antigens, many of which are nuclear autoantigens like dsDNA and chromatin (Pisetsky, 2016), and by elevated type I interferons (IFN) (Hooks et al., 1979; Weckerle et al., 2011), a family of pro-inflammatory cytokines that have antiviral activity (Pestka et al., 2004). Microarray analysis of peripheral blood mononuclear cells (PBMC) from SLE patients discovered the increased expression of IFN-responsive genes that was named the IFN Signature (Baechler et al., 2003a; Bennett et al., 2003b; Crow et al., 2003). Genome wide association studies indicate a clear genetic component in lupus pathogenesis (Chung et al., 2011; SLEGEN et al., 2008) and murine models of SLE confirm genetic drivers of the disease (Morel, 2010; Morel et al., 2000). However, the concordance of SLE in monozygotic twins is only 30-40% (Connolly and Hakonarson, 2012), while the inc / Microbiology and Immunology