27 research outputs found
Automated Sample Ratio Mismatch (SRM) Detection and Analysis
No full textBackground: Sample Ratio Mismatch (SRM) checks can help detect data quality issues in online experimentation [3]. Not all experimentation platforms provide these checks as part of their solution. Users of these platforms must therefore manually check for SRM, or rely on additional processes—such as checklists [2]—or automation. Objective: To ensure reliable and early detection of SRM, we wanted to automate the detection and analysis of SRM in experiments running on third-party experimentation platforms. Method: A set of Looker dashboards were built to facilitate self-serve SRM detection and root cause analysis. In addition, we added email and chat based alerting to pro-actively inform experimenters of SRM and guide them towards these dashboards when needed. Results: Several cases of SRM have been detected and experimenters have been warned. Bad decisions based on flawed data were avoided. We provide one such example as an illustration. Conclusions: SRM checks are relatively straightforward to automate and can be useful for data quality monitoring even for companies who rely on third-party experimentation platforms. Pro-active alerting—rather than passive reporting—can reduce time to detection and help non-experts avoid making decisions based on biased data.Software Engineerin
A critical role for gp96 in lymphopoiesis, thrombopoiesis, and intestinal homeostasis
No full textgp96 is an endoplasmic reticulum chaperone for multiple Toll-like receptors and integrins. Our lab has generated a conditional gp96 knockout model allowing gp96 to be efficiently deleted from all tissues. Herein we demonstrate that gp96 is a master chaperone for 14 of 17 hematopoietic specific integrins and the critical role for gp96 in normal B cell and T cell development, but not for myeloid cell development. Additionally, we show that gp96 chaperones the GPIb-IX complex in platelets and is critical for normal platelet development and function, and results in a condition that closely resembles human Bernard-Soulier syndrome. Lastly, we report that global deletion of gp96 in mice results in spontaneous inflammatory bowel-like disease and a surprising role for gp96 in Wnt signaling, which is known to regulate intestinal homeostasis. Thus, my thesis work was aimed at understanding the roles and mechanisms of gp96 in (1) hematopoiesis, (2) platelet development and function, and (3) intestinal homeostasis.
Deciphering the Gift of Love: Reading Augustine's De Trinitate through Jean-Luc Marion
No full textDegree awarded: Ph.D. Systematic Theology. The Catholic University of AmericaThis dissertation can be viewed by CUA users only.The objective of this dissertation is to develop a new appreciation for how the gift of love traverses the distance between the intended signification of the Trinity and the impossibility--for us--of that very signification.Part I explores the promise of recent scholarship (e.g. that of L. Gioia, M. Hanby, P. Kolbet, L. Ayres) and interprets De Trinitate not as a metaphysical modeling of the Trinity in se, but as an rational study of the limits of theological signification. When read in light of Augustine's understanding of the relationship between hermeneutics and conversion, and emphasizing the missions of the Son and Spirit, De Trinitate offers an exposition of the soteriological transformation of the human person toward remembering, understanding, and loving God.Part II considers the gift of love in the phenomenology of Jean-Luc Marion. Supported by his concept of the saturated phenomenon, Marion offers a rigorous description of the gift of love as advancing according to its own reason and approaching not a conceptual abstraction, but a particular beloved. This gift divests the ego of its self-groundedness, inviting instead a understanding of the subject that is responsive to givenness and love, a subject that is gifted and devoted: the adonné. This rationality of love illuminates the key tension in Marion's work as one between the indetermination and limits of phenomenology and the particularity and excess demanded by the phenomenon of love.Part III is the site of the convergence of Marion's phenomneology with Augustine's own understanding of love's significance to trinitarian revelation. Marion's erotic reduction offers to De Trinitate an iconic description of the love by which God's self-revelation is mediated to us. The responsive love of the adonné sharpens Augustine's concept of the human being as made to the image of God and marks the revelation of the Trinity in the making possible what would otherwise be impossible for us: our advance in love. In turn, De Trinitate provides for Marion the revealed name by which God might be called upon in and through the particularity of love: the Father, Son, and Holy Spirit.Made available in DSpace on 2013-06-25T14:59:15Z (GMT). No. of bitstreams: 1
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Physiological demands of performance in Classical Ballet and their relationships with injury and aesthetic components
No full textA thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of
PhilosophyAt performance level, classical ballet is a form of high-intensity, intermittent exercise, requiring a strong aerobic foundation. Existing training methods have remained largely unchanged over the past century, resulting in poorly conditioned dancers who are prone to injury. The purpose of the thesis was to examine, through several inter-related studies, the demands of training and performance at professional level, and whether fitness levels of classical ballet dancers affect both aesthetic components of performance, and injury. All participants were either in the final year of elite vocational training or were professional dancers. Initial, observational, investigations indicated that both rehearsal and performance posed a variety of demands on different ranks of dancer within a company’s structure, and depicted daily workloads which supported previous complaints of fatigue. Before examination of fitness or performance could begin, novel tools to assess both aerobic fitness, and performance proficiency in ballet dancers were designed and tested for reliability and validity. Both tests met with test-retest reliability standards, with 95% limits of agreement of ±6.2 ml.kg.-1min-1 for the aerobic test, and ±1.5 points (out of 10) for the performance rating scale. High overall performance scores were then best predicted by high jumps of both legs and good active flexibility of the left leg (F=4.142, df=3, P=0.042). Following this, an intervention study investigated the effects of a period of supplemental fitness training, designed to enhance aerobic fitness, jump height and local muscular endurance, on the performance scores of a randomly assigned group of dancers. A control group continued with regular training. Performance scores at the outset of the study were compared to those following the intervention period. Overall scores for the intervention group increased by significantly more than those of the control group, (p=0.03), with greatest gains seen for control and skill, indicating that supplemental fitness training, specifically targeting aerobic and local muscular endurance, can help improve performance, particularly elements such as control and skill. Finally, two separate studies confirmed that low aerobic fitness and low body fat percentage were related to injury in ballet dancers. Further research needs to focus on fully ascertaining the physical demands of ballet, and whether better training dancers to meet these demands results in enhanced performance and reduction in injury
Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes
No full textIL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity
No full textSummaryMemory T cells are critical for long-term immunity against reinfection and require interleukin-7 (IL-7), but the mechanisms by which IL-7 controls memory T cell survival, particularly metabolic fitness, remain elusive. We discover that IL-7 induces expression of the glycerol channel aquaporin 9 (AQP9) in virus-specific memory CD8+ T cells, but not naive cells, and that AQP9 is vitally required for their long-term survival. AQP9 deficiency impairs glycerol import into memory CD8+ T cells for fatty acid esterification and triglyceride (TAG) synthesis and storage. These defects can be rescued by ectopic expression of TAG synthases, which restores lipid stores and memory T cell survival. Finally, we find that TAG synthesis is a central component of IL-7-mediated survival of human and mouse memory CD8+T cells. This study uncovers the metabolic mechanisms by which IL-7 tailors the metabolism of memory T cells to promote their longevity and fast response to rechallenge.Video Abstrac
Transcription Factor STAT3 and Type I Interferons Are Corepressive Insulators for Differentiation of Follicular Helper and T Helper 1 Cells
No full textSummaryFollicular helper T (Tfh) cells are required for the establishment of T-dependent B cell memory and high affinity antibody-secreting cells. We have revealed herein opposing roles for signal transducer and activator of transcription 3 (STAT3) and type I interferon (IFN) signaling in the differentiation of Tfh cells following viral infection. STAT3-deficient CD4+ T cells had a profound defect in Tfh cell differentiation, accompanied by decreased germinal center (GC) B cells and antigen-specific antibody production during acute infection with lymphocytic choriomeningitis virus. STAT3-deficient Tfh cells had strikingly increased expression of a number of IFN-inducible genes, in addition to enhanced T-bet synthesis, thus adopting a T helper 1 (Th1) cell-like effector phenotype. Conversely, IFN-αβ receptor blockade restored Tfh and GC B cell phenotypes in mice containing STAT3-deficient CD4+ T cells. These data suggest mutually repressive roles for STAT3 and type I IFN signaling pathways in the differentiation of Tfh cells following viral infection
The Transcription Factor FoxO1 Sustains Expression of the Inhibitory Receptor PD-1 and Survival of Antiviral CD8+ T Cells during Chronic Infection
No full textSummaryProtein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of T cell differentiation, proliferation, metabolism, and survival. Here, we show that during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) in vivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhibitor rapamycin. FoxO1 functioned as a transcriptional activator of PD-1 that promoted the differentiation of terminally exhausted CTLs. Importantly, FoxO1-null CTLs failed to persist and control chronic viral infection. Collectively, this study shows that CTLs adapt to persistent infection through a positive feedback pathway (PD-1→FoxO1→PD-1) that functions to both desensitize virus-specific CTLs to antigen and support their survival during chronic viral infection
Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection
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