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Exploring the Impact of HIV and Osteopontin on Hippocampal Vascular Density
Get PDFSince the advent of anti-retroviral therapy (ART), many human immunodeficiency virus (HIV)-infected individuals have been able to maintain low viral loads and high CD4+ T cell counts, thereby promoting survival. However, despite treatment, patients often suffer from cerebrovascular pathologies, including atherosclerosis, vasculitis, and aneurysms, all of which significantly elevate the risk of stroke. During HIV infection, a host cell factor named osteopontin/secreted phosphoprotein 1 (OPN/SPP1), a proinflammatory phosphoprotein, is expressed at elevated levels in the central nervous system. In the context of HIV, OPN/SPP1 has been found to be neuroprotective. In a vascular context, OPN/SPP1 is typically expressed at low levels in endothelial cells but becomes heightened during injury, where it can either promote healing or, if chronically expressed, induce vascular dysfunction. Although HIV and OPN/SPP1 have been separately investigated concerning their effects on the vascular system, their combined influence remains unexplored. In this study, we examined the dual relationship between HIV and OPN/SPP1 on blood vessel density. Our findings demonstrate that HIV/OPN+ mice exhibit increased hippocampal vascular density compared to controls. These preliminary findings together with prior reports in the literature pertaining to the angiogenic nature of OPN/SPP1 and HIV-encoded proteins, trans-activator of transcription (Tat) and negative factor (Nef), may suggest a synergistic effect between HIV and OPN/SPP1 in promoting angiogenesis and points the direction to future investigations
Identity Crisis: American Studies and the Problem of National Culture in a Transnational Age
Get PDFIn the mid-twentieth century, as the U.S. reached new heights of global power, old questions of American culture—who are Americans? What defines “Americanness,” and where does it come from?—acquired new urgency. Some of the most dedicated theorists of these questions were those in the young field of American Studies, founded at Harvard in 1937. Building upon the explosion of interest in “culture” during the interwar period, American Studies scholars set out in search of a distinctly American culture. But this interdisciplinary search begs a fundamental question: what, exactly, is American culture? There lay the real problem, and the search to solve it and to offer meaningful accounts of it determined the scholarship and curricula of the field.
This dissertation follows the history of American Studies from its founding at Harvard, through its development during the Cold War and its responses to the challenges of the sixties, to its realignment in the 1990s. I argue that scholars’ uncertainty about the definition, scope, and significance of American culture created an absent center to the field, a guiding subject that always remained just out of sight. This absent center in turn created two conflicting impulses that shaped the field throughout the twentieth century: one inward toward defining a distinctive field of American culture, and the other outward, away from it and toward experimentation in methods and subjects. Ultimately, the tension between these tendencies rendered the field flexible in such a way that allowed it to absorb the potentially destabilizing political and epistemological challenges of the twentieth century. From this perspective, American Studies’ absent center emerges not as a weakness but rather as a major strength.
In tracing its whole history, from its founding into the new millennium, this dissertation offers a new portrait of American Studies that emphasizes the intellectual and institutional continuities running through this diffuse and rapidly changing field. These continuities reveal the coherence of American Studies and the way its institutional spaces fostered the creation, through seminars and funding applications and journal symposia, of powerful and lasting images of the United States
INVOLVEMENT OF THE TEN-ELEVEN TRANSLOCATION (TET) ENZYMES AND 5- HYDROXYMETHYLCYTOSINE (5HMC) IN THE DNA DAMAGE RESPONSE AND TREATMENT SENSITIVITY OF GLIOBLASTOMA STEM CELLS
Get PDFGliomas are the most common type of primary brain cancer and glioblastomas (GBM) are the most common and lethal subtype of gliomas. GBM patients face a poor prognosis due to treatment challenges, including epigenetic dysregulation, tumor heterogeneity, and almost guaranteed tumor recurrence. Glioblastoma stem cells (GSCs) disproportionality drive tumor propagation and treatment resistance, and perturbations in the epigenetic Ten-eleven translocation (TET) enzymes and its enzymatic product, 5-hydroxymethylcytosine (5hmC) have been implicated in poor GBM prognosis.
The goal of this study was to determine the involvement of TETs and 5hmC in treatment sensitivity of GSCs, with a focus on the role of 5hmC in the DNA Damage Response (DDR) and the potential of ascorbic acid (AA) as an anticancer epigenetic therapeutic. We used cell viability, apoptosis, immunoblotting, immunocytochemistry, bisulfite sequencing, and proximity ligation assays in stem-like primary neurosphere (GSC) GBM cell lines, GBM1A and 612 cells, treated with epigenetic modifying and DNA damaging agents to achieve the research objective. We found that enhancing TETs activity and 5hmC levels increased treatment sensitivity of GSCs to the standard of care GBM therapeutics, ionizing radiation (IR) and Temozolomide (TMZ). 5hmC was involved in regulating the DDR by directly interacting with DDR proteins and 5hmC levels corresponded with the magnitude of DDR protein levels in GSCs. Evidence suggests that 5hmC regulates the DDR through noncanonical protein interactions and these mechanisms showed specificity to Non-Homologous End Joining (NHEJ). We also showed that low-dose AA could act as an anticancer therapeutic and present the novel mechanism by which enhanced susceptibility of ascorbic acid-treated GSCs to DNA damage therapies results from a TET-mediated increase in H3K36me3-induced euchromatin states that increase genomic susceptibility to DNA damage.
We propose that TETs and 5hmC play an important role in GSC treatment sensitivity by regulating the DDR and chromatin architecture of these cells. These findings highlight the importance of understanding epigenetic dysregulation in GSCs and provide insight into potential mechanisms mediating the association between low TET and hypo-hydroxymethylation with worse GBM patient prognosis. These results also indicate that ascorbic acid could serve as an adjuvant therapy by restoring TET activity and re-sensitizing GSCs to conventional radio- and chemotherapeutics
DIAGNOSTICS AND OPTIMIZATION OF DT CHROMATOGRAPHY AND FILTRATION AUTOMATION SYSTEMS FOR NUCLEIC ACID CONCENTRATION
No full textThis study presents an innovative approach to purifying RNA samples, with a specific emphasis on mRNA possessing a poly(A) sequence. The methodology involves a systematic series of steps, including liquid addition to a sample container containing the target mRNA and a solid affinity material (such as oligo(dT) or hydroxyapatite), followed by agitation, liquid removal, and subsequent elution of the desired mRNA. Key components of the apparatus include a sample container, reservoir, collection container, pressure-generating source, valve assembly, and an agitation mechanism. This results in highly efficient RNA extraction, particularly for mRNA, with superior yield and purity. Notably, this achievement minimizes solvent usage, signifying a significant advancement in molecular biology and biotechnology applications.
In addition to RNA purification, this study explores the transformative impact of ultrafiltration (UF) automation systems on nucleic acid concentration, offering automation and efficiency. However, the complex nature of UF systems often leads to operational challenges, especially in terms of pressurization and filtration. The research delves into the role of diagnostics in identifying and rectifying issues inherent to UF automated systems, with a specific focus on processes involved in nucleic acid concentration. Integrating diagnostics and optimization strategies aims to provide a comprehensive understanding of the physical and chemical processes underlying UF automation systems, ensuring efficient and reliable nucleic acid concentration. This approach contributes to the broader goal of advancing automation in molecular biology and biotechnology, streamlining nucleic acid concentration processes for improved scientific methodologies and applications
PREDICTNG THE EFFICACY OF VLA15 BY EXAMINING THE GENETIC DIVERSITY OF THE CORRESPONDING OSPA VACCINE TARGET IN BORRELIA BURGDORFERI S.S. ISOLATES FROM FIELD-COLLECTED TICKS IN MARYLAND
Get PDFLyme disease, caused by the spirochetes from the Borrelia burgdorferi s.l. species complex, is the most prevalent vector-borne disease in the USA. In light of the ongoing clinical trials for the transmission blocking Lyme disease vaccine VLA15, this presents an interesting opportunity to re-examine the genetic diversity of the vaccine’s target protein OspA. This need is enhanced, considering that the last studies conducted on this topic were in the early 2000s. To that end, this study aimed to examine the diversity of ospA sequences recovered from field collected, Borrelia burgdorferi s.s. positive ticks in Baltimore County, Maryland and compare them with the existing sequences on NCBI’s GenBank to examine genetic variability and correlate with geographical location. From March 2023 to December 2023, 114 Ixodes scapularis, 4 Dermacentor variabilis and 18 Haemaphysalis longicornis ticks were collected from two collection sites. 41 Ix. scapularis ticks were found to be B. burgdorferi positive and 3 were found to be positive for Anaplasma phagocytophilum. Phylogenetic analysis of the sequence overlap between ospA sequences isolated from field samples and ospA sequences from country-wide GenBank queries focussed on sequences showed that the ospA sequences from Borrelia-positive ticks and selected GenBank sequences clustered into three separate clades. The majority of sequences from field samples clustered in clade 1 (with one in closely related clade 2) with minor point mutations (mostly silent mutations). The outliers in clade 3 were determined to be due to possibly poor sequencing results, needing further analysis. Overall ospA diversity was observed to be minimal, with strong identity with the vaccine sequence, setting up for a successful eventual release
ACUTE GRAFT VERSUS HOST DISEASE, MOUSE MODEL, AND MEDICATION
Get PDFAllogeneic hematopoietic stem cell transplantation (HSCT) is a life-saving treatment for a variety of diseases, either hematological or non-hematological. While it saves patients from previously life-threatening diseases, patients might develop a major complication after allotransplantation, called graft-versus-host-disease (GVHD), including acute GVHD and chronic GVHD. Acute GVHD usually happens within 100 days of a patient who received allogeneic HSCT, and currently, the steroid is used as the standard treatment for acute GVHD. However, many patients experience resistance to the steroid and there is no highly effective medication for them. To develop better treatment for acute GVHD patients, several mouse models have been established and several drugs have been tested to be able to reduce the severity of acute GVHD. These drugs targeted different biomolecules that are involved in the acute GVHD pathology and some of them have better performance towards specific organ damage caused by acute GVHD. However, none of them perform well in the long-term survival of patients, optimization of both the therapy itself and the process of developing it needs to be done
PARENTAL PERSPECTIVES ON SCHOOL CHOICE IN ARIZONA: PRIORITIZING SAFETY AND SECURITY TO PROMOTE EQUITABLE LEARNING ENVIRONMENTS
Get PDFSchool choice, a system that allows parents to choose which schools to enroll their children regardless of proximity, has been a contentious topic for many U.S. school districts. Although proponents of school choice suggest that it can promote competition and encourage higher-quality education using a free market framework, prior research suggests that school choice can contribute to inequity in schooling along socioeconomic and racial lines. Based on the recent discussions around school choice, the current dissertation reviewed the literature on educational inequity (through ecological systems theory) and how school choice could interact with student school-level factors to promote inequity. Next, a needs assessment of Arizona parents showed that the most significant factor parents identified regarding school choice was safety and security outcomes in their children’s schools. Given this insight, Chapter 3 reviewed the literature on safety and security, highlighting the literature’s focus on proactive approaches to school violence (e.g., school climate) to work in concert with more reactive approaches (e.g., threat response teams, surveillance). Finally, based on prior research and a review of better practices in the field, a multifaceted intervention program for Tempe Union High School District schools was presented to enhance school safety outcomes. An assessment and evaluation plan was introduced to allow schools to update their safety and security climate continuously. The current work offers critical insights into the importance of proactive school safety programs. The study provides a proof of concept that pending evaluation could be used in other school districts to promote safety and security
UNRAVELING THE THREAT: INTERPRETING TERRORIST GROUPS VIA NETWORK ANALYSIS AND DECISION THEORY
Get PDFIn an era defined by ever-increasing flows of data and evolving threat landscapes,
understanding the structure, behavior, nuances, and decision-making
criteria that go into understanding terrorist organizations is pivotal for effective
national security strategies. This paper employs advanced mathematical
modeling and computational techniques to uncover underlying structures
within synthetic terrorist networks. These structures are then measured, clustered,
and finally analyzed using decision theory frameworks to illuminate
potential courses of action. Commencing with a literature review, we establish
a nuanced foundation for theoretical modeling and decision criteria. A
graph theory-based approach generates synthetic terrorist networks utilizing
graphons, which are compared using Gromov-Wassersteing distances and
clustered using K-Means clustering. These clusters are then analyzed through
decision theory to measure the quality of the model and to potentially inform
strategic decisions. This research offers a comprehensive approach to interpreting
potential terrorist groups, enhancing understanding and decision-making
ability. It provides a pivotal tool for policymakers, security practitioners, and
researchers in counterterrorism efforts, bolstering preventive measures and
response strategies in an uncertain global security landscape
PUBLIC HEALTH INFORMATION SYSTEMS MODERNIZATION: A SYNTHESIS OF NEEDS FROM THE NATIONAL AND STATE PERSPECTIVE
No full textProblem Statement: The nation’s public health information systems (PHIS) infrastructure is in a crisis state. As the nation develops its long-term response to and recovery from the pandemic, public health communities face choices about how to address the PHIS crisis.
Methods: The primary objectives of this study are to: 1) Synthesize literature on socio-technical health information system evaluation frameworks; 2) Apply a socio-technical evaluation framework to identify PHIS opportunities at one state-level health department; and 3) through a national focus group, identify characteristics of an optimal future national PHIS infrastructure.
Results: Across the three chapters of this dissertation, a combination of socio and technical constructs provided the unifying context, whereby the interrelatedness of social (i.e., human, and organizational) and technical aspects of the information systems are considered in tandem. Perspectives were obtained from front-line public health professionals at the national and state-level on how to enhance the current PHIS infrastructure to better support public health goals.
Conclusions: Public health can apply sophisticated, socio-technical evaluation approaches to PHIS for an in-depth understanding of the nation’s current state, from the local level to the national level. This synthesis is intended to summarize the current issues at hand for critical strategic planning input that will help address PHIS infrastructure challenges
Oral History Interview with James F. Childress
No full textThis interview with James F. “Jim” Childress, Ph.D., was conducted remotely by Amy C. Sullivan on June 11 and 12, 2024 as part of Moral Histories: Voices and Stories from the Founding Figures of Bioethics, an oral history project of the Johns Hopkins Berman Institute of Bioethics. Prof. Childress is Professor Emeritus at the University of Virginia, University Professor Emeritus and John Allen Hollingsworth Professor of Ethics Emeritus. He is the coauthor with Tom Beauchamp of the classic, field defining bioethics text, Principles of Biomedical Ethics, currently in its 8th edition. Prof. Childress’ areas of expertise include the foundational and principles approach to bioethics, Christian social ethics, organ donation and transplantation, end-of-life decision-making, and public bioethics.
Professor Childress describes childhood experiences growing up near Mt. Airy, North Carolina in the 1940s and 50s. He discusses his Quaker upbringing, the Civil Rights Movement, and his work as a youth director in New Haven, CT, while he was a graduate student at Yale in the 1960s. Childress shares his experience and perspective on the intersection of religion and social justice, ethical considerations with organ allocation, and the role of bioethics in society. Other topics discussed include various ethical challenges in public policy and healthcare, pacifism, violence prevention, bioethics, and religion. He describes his decades-long collaboration with Tom Beauchamp writing and updating eight editions of Principles of Biomedical Ethics, a book that aimed to provide a systematic statement of ethical principles for research involving human subjects. The entire scope of his career—scholarship, service, and teaching—is also covered. The interview concludes with a discussion of the importance of public bioethics, public health decision-making in the context of individual autonomy, structural injustices, and social determinants of health