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E Protein Regulation of the T Cell Receptor Alpha – T Cell Receptor Delta Locus
No full textThe B and T lymphocytes utilize B and T cell receptors, respectively, for the specific recognition of pathogen. Somatic recombination of the antigen receptor loci imparts the immense diversity and specificity of the adaptive immune system’s antigen recognition. The recombination activating gene (RAG) 1 and 2 mediated V(D)J recombination process is a highly developmentally regulated process, occurring at strict stages of B and T lymphocyte development. Both the expression of RAG1/2 and the accessibility of the recombination substrates come under strict developmental stage-specific regulation. E protein transcription factors and the inhibitory Id proteins mediate many of the signaling and transcriptional changes that occur during lymphocyte development. While E protein binding has been identified at antigen receptor loci, the understanding of their cis-regulatory function is lacking.Recombination of the Tcra-Tcrd locus occurs during two temporally separate stages of T lymphocyte development. Tcrd, nested with Tcra, undergoes recombination first, during the double negative (DN) stage. Cells that commit to the αβ T lymphocyte lineage will then undergo Tcra recombination during the double positive (DP) stage. These processes are highly dependent on cis-acting enhancers termed Eδ and Eα. E proteins have long been known to bind at Eα, while recent DN cell E protein ChIP-seq allowed identification of a vast number of additional targets within the Tcra-Tcrd locus. A series of mutagenesis studies were pursued to better understand E protein cis-regulatory function during Tcra-Tcrd locus recombination.Eα mutants lacking one or two of the three E protein binding sites were generated. The mutant lacking two binding sites displayed a partial block in αβ T lymphocyte development at the positive selection stage. Loss of transcription at the Jα array reflected a loss in accessibility, which was mirrored by dysregulated primary and impaired secondary Vα-Jα rearrangement. Therefore, Eα E protein binding increases Tcra locus accessibility, which is required for efficient Tcra recombination and the resulting Tcra repertoire diversity.Analysis of available E protein ChIP-seq revealed strong E protein binding downstream of Trav15-dv6 family V segments. Mutagenesis of the E protein binding region directly downstream of Trav15d-1-dv6d-1 resulted in a loss of Vγ1.1Vδ6.3 T lymphocytes, whose development relies on Tcrd recombination of Trav15d-1-dv6d-1. This has established a new method of E-Id protein axis regulation of Vγ1.1Vδ6.3 T lymphocyte development. Furthermore, analysis suggested that the Vγ1.1Vδ6.1 and Vγ1.1Vδ6.3 T lymphocyte subsets compete during development, with expansion of Vγ1.1Vδ6.1 T lymphocytes only possible in the absence of Vγ1.1Vδ6.3 T lymphocytes. Competition and affinity for ligand likely play a tremendous role in this process. Analysis of two Vγ1.1Vδ6.3 TCR transgenic lines revealed that small differences in CDR3γ and CDR3δ are sufficient to significantly modulate Vγ1.1Vδ6.3 T lymphocyte development and immune profile. These findings and the generated genetic models can form the basis of elucidating the ligand of the Vγ1.1Vδ6.3 TCR.The findings presented here have advanced the understanding of E protein regulation of the Tcra-Tcrd locus, and by extension the lineage-defining potential of the Vγ1.1Vδ6.3 TCR. This is the first report of E protein cis-regulation of the Tcra locus and of Tcrd recombination of Trav15-dv6 family V segments (specifically Trav15d-1-dv6d-1). Extensive E protein binding of the Vα/Vδ array suggests further regulatory mechanisms and action.</p
Modeling Heterogeneity With Bayesian Additive Regression Trees
No full textThis work focuses on using Bayesian Additive Regression Trees (BART), a flexible and computationally efficient regression method, to model heterogeneity in data. In particular, we focus on the closely related tasks of hierarchical modeling, latent variable modeling, and density regression. We begin by introducing BART in Chapter 2, presenting the prior, various extensions, and an in-depth case study using BART to analyze the impact of ABO-incompatible cardiac transplant on infants. Chapter 3 describes a methodological contribution, in which we use BART to model data structured within known groups by allowing for group-specific forests, each of which is only updated using units corresponding to that group. We further introduce an intercept forest common to all units and a hierarchical prior across the leaf variances in order to allow for sharing of information. We find that such an approach yields more parsimonious models than other BART-based approaches in the literature, which in turn translates to better out-of-sample accuracy, at virtually no added computational cost. In Chapter 4, we consider models involving latent variables within BART. The original motivation is to extend the known-group approach in Chapter 3 to a setting where group information is unavailable. However, this idea lends itself well to many different analyses, including those involving continuous omitted or latent variables. Another application is a generalization of a BART-based approach to sensitivity analysis, in which we allow for the unobserved confounder to flexibly influence the outcome. The latent variable framework we consider is computationally efficient, can help BART model data much more accurately than if restricting oneself to observed covariates, and is widely applicable to many different settings. In Chapter 5, we study one such application in great detail: using BART for density regression. By integrating out the latent variable in our model, we can model conditional densities in a way that outperforms a variety of other approaches on simulated tasks, and also allows us to bound its posterior concentration rate. We hope that the tools we develop in this work are useful to practitioners seeking to model heterogeneity in their data and also serve as a foundation for future methodological advances.</p
Reimagining and Reclaiming a Better Future for Black Baptist Womanist Preachers
No full textMany Black women in Black Baptist traditional churches do not have the opportunity to exercise their spiritual callings to preach in the pulpit, nor do they receive adequate training to preach in alternative settings such as public platforms or online venues. Firstly, this thesis pays critical attention to why Black Baptist womanist preachers must embrace the power of the imagination – the God-given faculty - which forms and uses images to awaken us in answering our calling and spiritual gifts, bringing us closer to Christ. A holy and prophetical imagination from the Word of God gives us proper perception and perspective for preaching biblical truth. Secondly, this thesis presents a brief overview of the historical influence of the Black Church and the Black theological movement focusing on dignity, cultural identity, and political justice against racism. The focus on Black people’s struggles, predominately advocated by Black men in the pulpit or public sphere, and then forgetting to train and prepare women as Church leaders, stifles their imaginations and voices to preach. Thirdly, this thesis examines the impact of the courageous Black womanist preachers during the nineteenth century, breaking all pulpit barriers to preach wherever the Holy Spirit led them. Fourthly, this thesis discusses the inspiration of Black scholarly womanist preachers emerging from the civil rights and Black power movements of the twentieth century. These brave women impact today’s struggling Black Baptist womanist preachers to keep studying and preaching faithfully in every non-traditional setting. Fifthly, this thesis shows how a parachurch entity in this twenty-first century can fill the gap in preparing enthusiastic Black womanist preachers for preaching opportunities, whether in the pulpit or on alternative platforms. The investment of a parachurch entity, such as D.G. McBride Ministries, Inc., offers virtual space for developing laywomen and young leaders to build on their preaching craft to serve Jesus Christ.</p
Pathways to the diagnosis of Alzheimer’s Disease and other related diseases: The perceptions of racially diverse caregivers
No full textBackground: Increasing evidence suggests that early diagnosis of Alzheimer’s disease and related diseases (ADRD) offers opportunities for access to supportive services and disease management. However, most cases of ADRD are diagnosed in the later stages of the disease limiting the benefits of supportive services and increasing challenges related to the disease. This study aimed to understand facilitators and barriers to early ADRD diagnosis among Black and White individuals seeking racial differences in this process. Methods: Our sample included 21 racially diverse caregivers (n= 21) of older adults with ADRD, including Black caregivers (n=11) and White caregivers (n= 10). Semi-structured interviews were conducted individually with participants. Duke University Health System (DUHS). Data were coded for emerging themes and analyzed through the lens of the life course framework using NVIVO analysis software. Results: Facilitators and barriers along the diagnosis process were shaped by the individual, family/caregiver, and interactions with the healthcare system. Racial differences were particularly evident regarding family/caregiver's lower knowledge about ADRD, care approach offered to the care recipient, and prevalent negative interactions with the healthcare system among Black caregivers. Conclusions: The diagnosis process pathways were lengthy, characterized by caregivers' persistence, challenges to receiving an adequate cognitive assessment, and limited access to supportive services. Black caregivers experienced a more prolonged process, lower knowledge about ADRD, and challenging interactions with the healthcare system. </p
Distressed Work: Chronic Imperatives and Distress in Covid-19 Critical Care.
No full textThis ethnographic study introduces the term "distressed work" to describe the emergence of chronic frictions between moral imperatives for health care workers to keep working and the dramatic increase in distress during the Covid-19 pandemic. Interviews and observant participation conducted in a hospital intensive care unit during the Covid-19 pandemic reveal how health care workers connected job duties with extraordinary emotional, physical, and moral burdens. We explore tensions between perceived obligations of health care professionals and the structural contexts of work. Key findings cluster around the moral imperatives of health care work and the distress that work engendered as work spaces, senses of vocation, patient and family interactions, and end-of-life care shifted. While the danger of working beyond limits has long been an ordinary feature of health care work, it has now become a chronic crisis. Assessing this problem in terms of distressed work and its structural contexts can better address effective, worker-informed responses to current health care labor dilemmas
The effectiveness of tax incentives in attracting investment: panel data evidence from the CFA Franc zone
No full textPredictors of the Best Outcomes Following Minimally Invasive Surgery for Grade 1 Degenerative Lumbar Spondylolisthesis.
No full textBackgroundThe factors driving the best outcomes following minimally invasive surgery (MIS) for grade 1 degenerative lumbar spondylolisthesis are not clearly elucidated.ObjectiveTo investigate the factors that drive the best 24-mo patient-reported outcomes (PRO) following MIS surgery for grade 1 degenerative lumbar spondylolisthesis.MethodsA total of 259 patients from the Quality Outcomes Database lumbar spondylolisthesis module underwent single-level surgery for degenerative grade 1 lumbar spondylolisthesis with MIS techniques (188 fusions, 72.6%). Twenty-four-month follow-up PROs were collected and included the Oswestry disability index (ODI) change (ie, 24-mo minus baseline value), numeric rating scale (NRS) back pain change, NRS leg pain change, EuroQoL-5D (EQ-5D) questionnaire change, and North American Spine Society (NASS) satisfaction questionnaire. Multivariable models were constructed to identify predictors of PRO change.ResultsThe mean age was 64.2 ± 11.5 yr and consisted of 148 (57.1%) women and 111 (42.9%) men. In multivariable analyses, employment was associated with superior postoperative ODI change (β-7.8; 95% CI [-12.9 to -2.6]; P = .003), NRS back pain change (β -1.2; 95% CI [-2.1 to -0.4]; P = .004), EQ-5D change (β 0.1; 95% CI [0.01-0.1]; P = .03), and NASS satisfaction (OR = 3.7; 95% CI [1.7-8.3]; P ConclusionPreoperative employment and surgeries, including a fusion, were predictors of superior outcomes across the domains of disease-specific disability, back pain, leg pain, quality of life, and patient satisfaction. Increasing age was predictive of superior outcomes for leg pain improvement and satisfaction
Spotlight on isavuconazole in the treatment of invasive aspergillosis and mucormycosis: design, development, and place in therapy.
No full textIn recent decades, important advances have been made in the diagnosis and treatment of invasive aspergillosis (IA) and mucormycosis. One of these advances has been the introduction of isavuconazole, a second-generation broad spectrum triazole with a favorable pharmacokinetic and safety profile and few drug-drug interactions. Phase III trials in patients with IA and mucormycosis demonstrated that isavuconazole has similar efficacy to voriconazole for the treatment of IA (SECURE trial) and liposomal amphotericin B for the treatment of mucormycosis (VITAL trial with subsequent case-control analysis) and a favorable safety profile with significantly fewer ocular, hepatobiliary, and skin and soft tissue adverse events compared to voriconazole. As a result, recent IA guidelines recommend isavuconazole (together with voriconazole) as gold standard treatment for IA in patients with underlying hematological malignancies. In contrast to liposomal amphotericin B, isavuconazole can be safely administered in patients with reduced renal function and is frequently used for the treatment of mucormycosis in patients with reduced renal function. Updated guidelines on mucormycosis are needed to reflect the current evidence and give guidance on the use of isavuconazole for mucormycosis. Studies are needed to evaluate the role of isavuconazole for 1) anti-mold prophylaxis in high-risk patients, 2) salvage treatment for IA and mucormycosis, and 3) treatment for other mold infections such as Scedosporium apiospermum
Primary Drivers of Adult Cervical Deformity: Prevalence, Variations in Presentation, and Effect of Surgical Treatment Strategies on Early Postoperative Alignment.
No full textBackgroundPrimary drivers (PDs) of adult cervical deformity (ACD) have not been described in relation to pre- and early postoperative alignment or degree of correction.ObjectiveTo define the PDs of ACD to understand the impact of driver region on global postoperative compensatory mechanisms.MethodsPrimary cervical deformity driver/vertebral apex level were determined: CS = cervical; CTJ = cervicothoracic junction; TH = thoracic; SP = spinopelvic. Patients were evaluated if surgery included PD apex, based on the lowest instrumented vertebra (LIV): CS: LIV ≤ C7, CTJ: LIV ≤ T3, TH: LIV ≤ T12. Cervical and thoracolumbar alignment was measured preoperatively and 3 mo (3M) postoperatively. PD groups were compared with analysis of variance/Pearson χ2, paired t-tests.ResultsEighty-four ACD patients met inclusion criteria. Thoracic drivers (n = 26) showed greatest preoperative cervical and global malalignment against other PD: higher thoracic kyphosis, pelvic incidence-lumbar lordosis (PI-LL), T1 slope C2-T3 sagittal vertical axis (SVA), and C0-2 angle (P ConclusionCharacterizing ACD patients by PD type reveals differences in pre- and postoperative alignment. Evaluating surgical alignment outcomes based on PD inclusion is important in understanding alignment goals for ACD correction
Revolution and the City: Marxist Anthropologies in the Interwar Realist Novel
No full textThe German Revolution of 1918-1919 failed to topple the capitalist system that interwar Marxists held responsible for World War I. For those Marxists, the interwar era’s unprecedented urbanization reinstated capital’s dominance, representing a counterpart to the wartime destruction. Theorists including Georg Lukacs and writers such as Siegfried Kracauer, Arnold Zweig and Alfred Doblin held that the capitalist city, like the battlefield before it, distorted and diminished human nature, foreclosing the possibility of revolutionary social transformation. This dissertation argues that interwar Marxist philosophers and authors consequently turned to the realist novel; they imagined it as a poetic form of architecture that literarily reconstructed urban space to expose its capitalist foundations. The realist novel thereby empowered readers to imagine alternative spaces and emboldened them to resist by reactivating their capacities for collective action and creative transformation.
The dissertation first demonstrates that Lukacs’s interwar writings intervene into architectural and urban planning discourses to present the realist novel as a shelter from and a weapon against the capitalist city. Three exemplary literary works then reveal how this literary challenge to the capitalist city was imagined and reimagined as Germany’s political situation deteriorated. Written during the Weimar Republic’s Golden Age, Kracauer’s Ginster (1928) depicts a destructive wartime homogenization of space that transforms both battlefield and home front. The novel resists this homogenization by mapping alternative spatial organizations intent on fostering human potentialities. Penned during fascism’s rise, Zweig’s Erziehung vor Verdun (1935) shows how urban technological progress under capitalism unleashes the very destruction that flattens the city during the war. Zweig’s novel unfurls an ideal of construction capable of breaking this self-destructive cycle by reconnecting humanity’s innovations with human need. Commenced as war loomed again, Doblin’s November 1918 (1939, 1948, 1950) shows how the 1918-1919 revolution was misdirected by the urban spaces it sought to conquer. Drawing lessons from this historic failure, Doblin’s roman-fleuve sketches a limitless and dialectical progression as a critical corrective to existing conceptions of revolution.
Ultimately, this dissertation uncovers a hitherto overlooked literary tradition that presents the realist novel as a critical tool for reckoning with capitalism’s domination of our built environments