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Totality and the Interwar German-Language Novel
No full textTotality and the Interwar German-Language Novel analyzes the interwar novel within the framework of the capitalism’s developmental historicity and logic. Within this context, the interwar novel appears as an index of capitalism’s historical specificity (of the early twentieth century) and its generality. This study undertakes a formal analysis of a selection of interwar novels alongside an analysis of forms of capitalist economy like money, value, abstract labor, and class, in order to demonstrate how the novel, the literary form most interested in social totality, must contend with the open-ended spatio-temporal character of capitalism. The dissertation argues that economic forms inscribe themselves in literary texts. For the novel, this means that the economic is inscribed in, for example, the systems of its characters, its use of genre, the patterning of its plots, and its narrative points of view. This inscription, however, is not direct. Rather, the text of the novel, as a fiction, can be read as providing ideological and illusory resolutions to real, political-economic antagonisms
Essential proteins in Plasmodium falciparum: a functional and metabolic study
No full textMalaria is an old-world disease that is caused by infections with Plasmodium spp. Probing the essential proteins and pathways of the parasite can uncover new drug targets for the development of next-generation antimalarials. The purpose of this study was to investigate three distinct metabolic vulnerabilities in Plasmodium falciparum, the most lethal species of human malaria parasites. First, we explored the use of lipoate to understand why this nutrient must be scavenged by malaria parasites and found a lipoate-dependent protein called the H protein, which is essential for parasite survival. Additional insight into the various features of the H protein have shed light on the dispensability of the unconserved C-terminal tail and the essentiality of the lipoylated active site lysine. A complementation study with the E. coli H protein suggests that unconserved domains or interaction motifs may be involved in H protein essentiality. Second, we analyzed the metabolic and transcriptomic consequences of multidrug-resistant P. falciparum exposed to sublethal doses of novel antimalarials belonging to the pyrazoleamide and spiroindolone family of drugs. These chemically-distinct drugs target ATP4, a P-type ATPase that is responsible for intracellular Na+ homeostasis. An A211V mutation in ATP4 results in an interesting phenomenon; decreased sensitivity to pyrazoleamides, and increased sensitivity to spiroindolones. Lastly, we determined the essentiality of the non-mevalonate isoprenoid biosynthesis pathway of the parasite apicoplast. The rate-limiting step is the conversion of glyceraldehyde-3-phosphate to 1-deoxy-D-xylulose 5-phosphate by DXP synthase (DXS). Genetic knockout of DXS followed by removal of mevalonate supplementation demonstrates that DXS is essential for parasite survival. Taken together, these three stories shed light on the roles of essential proteins in Plasmodium falciparum and inform existing and potential drug discovery efforts
AN ETHICAL CASE FOR A NEW SPECULUM
No full textIn the field of Obstetrics and Gynecology, the usage of the speculum is widespread – many procedures in gynecological health require the physician to look into the vagina. However, the creation of the speculum is steeped in unethical history and a legacy of dehumanization and pain – one that carries into present day. The usage of the speculum shows a form of complicity towards harms, both harms of the past, and current present harms. We have an ethical obligation through the principles of beneficence and nonmaleficence to ensure that healthcare providers do not continue to be complicit in this harm, and to instead move towards other options.
This thesis attempts to craft an argument as to this ethical obligation, as well as to fully describe the injustice that has been done due to the speculum. Using philosophy and bioethics, this thesis looks at the complicity of past harms and the pain and harm that continued usage of the speculum perpetuates. As we move forward in advances in medicine across the board, we should also work towards advancing the medical care of people with uteri. This thesis will also cover some alternatives to the speculum that we can use instead. Overall, the speculum needs to be made anew, and we have an ethical obligation to move towards these new alternatives and leave the speculum as it was historically created behind
OPTIMIZATION OF PULMONARY ARTERY MECHANICAL TESTING
No full textPulmonary arterial hypertension (PAH) is a rare and incurable disease with mortality within 3 years in 28-55% of high-risk patients1. The progression of PAH has been known to be associated with increased vascular stiffness and vascular remodeling. Recent studies have suggested that increased stiffness may in-fact be a driver for some of the metabolic abnormalities observed during PAH2,3. To gain more insights into this relationship, we need to quantify the differences in mechanical properties of healthy and hypertensive pulmonary arteries. The stress-strain relationship is the gold standard for the ex-vivo stiffness measurement of arteries. While the use of a tissue puller for stress-strain measurement is well-optimized for large muscular arteries, it has not been used to test pulmonary arteries as their thin walls and low basal tone make it challenging to make precise measurements (of wall thickness and lumen diameter)4. Thus, the goals of this study were to: 1) establish a reliable protocol for rat pulmonary artery tensile testing and 2) quantify the differences in stiffness between hypertensive and healthy pulmonary arteries.
First, a methodology to improve the fidelity of determining the lumen diameter and wall thickness was developed. Using this approach, we observed that the modulus was negatively correlated with the length of the vessel segment tested. This suggests that vessel length should be standardized to perform reliable comparisons between groups. Next, we performed tensile tensing on both control and hypertensive pulmonary arteries, after standardizing vessel segment lengths. For stress-strain data modeled using a one-term exponential equation, we observed that intact hypertensive arteries were ~2.7 times stiffer than control arteries at low strain (strain=0.8). Whereas at high strain (strain=2.8) intact and decellularized hypertensive arteries were 20 and 29 times stiffer than control arteries respectively. For stress-strain data modeled using a two-term exponential equation, we observed no significant difference in stiffness at the hypertensive hoop stress value, but at normal hoop stress, hypertensive vessels were 2.2 times stiffer than controls. These findings and the methods proposed in this study will help in designing experiments investigating the relationship between changes in biomechanical signals and the progression of PAH
EPIGENETIC CONTROL OF TOPOISOMERASE1 LESION REPAIR BY A MACRO-HISTONE
Get PDFSingle-stranded DNA lesions (SSLs) are among the most common types of DNA damage. One predominant example for SSLs is Topoisomerase 1 cleavage complex (TOP1cc), which forms as a result of TOP1 activity in response to torsional DNA stress during DNA transactions such as transcription and DNA replication. TOP1ccs are frequently found at transcriptional start sites (TSSs) and can cause DNA damage and chromosome aberrations if not properly resolved. TOP1 inhibitors, such as camptothecin (CPT), are used as a pharmacological tool to trap TOP1cc on DNA, causing excessive DNA damage that kills cancer cells. What promotes efficient TOP1 function at DNA supercoil-forming regions while simultaneously preventing excessive TOP1cc accumulation remains unknown. Given that chromatin plays a central role in regulating the repair of double strand DNA breaks (DSBs), we propose that epigenetic control may similarly be a driver of TOP1cc repair. In previous work, we uncovered the macro-histone variant macroH2A1.1, but not its alternatively spliced macroH2A1.2 isoform, as an interactor of several TOP1cc repair factors. Here, we apply state-of-the-art genome-wide mapping approaches to investigate the relationship between macroH2A1.1 and TOP1 activity. We further relate macroH2A1.1 alternative splicing in cancer TOP1 inhibitor sensitivity across a panel of breast cancer cells with distinct macroH2A1.1 expression levels. Together, my findings point to a role for macroH2A1.1 as an epigenetic regulator of TOP1cc turnover at the TSS and a predictor of therapy responsiveness to TOP1 inhibition
CAUSES AND CONSEQUENCES OF SECURITY FORCE TRANSITIONS DURING INSURGENCIES: CASE STUDY: SOMALIA
No full textThe Afghan army crumbled at the conclusion of the U.S combat mission in Afghanistan, returning control to the Taliban insurgents in August 2021. The troubling question has been, “Why did the United States and its allies decide to terminate security force assistance to Afghanistan while there was an active insurgency?” To respond to such a query, this study explicitly tries to addresses the causes of security transfers between foreign and local forces during insurgencies. It develops a conceptual framework that uses Somalia as a case study to examine six causal factors that determined the security transfers during an al-Shabaab insurgency between the study period of 2017-2021. It also situates elements of the current security transition from 2022-2024 to contextualize findings of the selected study period. The empirical methodology of the study makes use of process tracing and secondary data analysis to establish causality by critically examining rich data from 19 events related to the security handovers, 7 United Nations Security Council(UNSC) Resolutions, 12 key documents(Policy and strategic guidelines and conference documents), 26 published articles and journals, 15 quotes, 6 research reports published on Somalia by the Armed Conflict Location &Event Data Project (ACLED), two key video recordings, observations and books. The study identifies the six causes of security transfers between foreign and local forces as; A reduction of foreign troops, Donor fatigue, the capacity of local forces to fend off insurgents, reduction of insurgent violence, competing interests between local and external actors, and the local government's desire to assume control of its nation’s security. In order to prevent a recurrence of ceding control to insurgents at the conclusion of a foreign intervention, this study also provides potentially useful insights on the formulation of new policies for security force transfers and the challenges of fragmented security force assistance in insurgencies or armed conflict
Method Validation for Measurement of Hair Nicotine Levels in Adolescents with Congenital Heart Disease (CHD)
Get PDFThe use of e-cigarettes (i.e., vaping) among adolescents in the United States has recently doubled, as reported by SAMHSA in 2020. Adolescents who have survived congenital heart disease (CHD) are at an elevated risk to the harmful effects of e-cigarettes. When CHD survivors reach 12 years of age, they begin the process of transitioning care from a pediatric to an adult cardiologist which entails them assuming more responsibility for their health care. In the US, 1/3 of those with CHD discontinue cardiology care during the transition period, which is the time where they are exposed by peer pressure to start using e-cigarettes (Jackson et al., 2018). Therefore, there is a need to assess exposure to tobacco for adolescents with CHD in order to develop and implement prevention strategies.
Hair nicotine concentration has been increasingly used as a biomarker for tobacco use and second-hand exposure due to the ease of collection and storage. Among chromatographic methods, hair analyses have been commonly performed with liquid chromatography–tandem mass spectrometry (LC–MS/MS) or GC/MS, due to their sensitivity and ability to specifically detect nicotine (Kim et al., 2008). Few studies, however, have examined an isotope dilution method for measuring hair nicotine in GC/MS. The aim of this study was to validate the isotope dilution GC/MS method for measuring nicotine in hair samples obtained from adolescents who have survived congenital heart disease.
There are several ways to assess an individual’s exposure to nicotine, including collection of saliva, urine, and hair samples. This study found that GC/MS-based isotope dilution method is a valid approach for determining nicotine in hair samples. The validation process involved assessing linearity, precision, limit of detection, and recovery. Using calibration standards, linearity was strong amongst all batches (R2 > 0.99). The average of the limit of detection was 0.144, which was comparable to previous studies. The precision and recovery values were also within the acceptable range. Additionally, the correlation between primary and duplicate hair sample analyses indicated good reproducibility and consistency. The results contribute to the growing body of evidence supporting the use of hair nicotine as a reliable and non-invasive biomarker for assessing nicotine exposure in research and clinical settings
Making the Call: Race, Poverty, and Police Utilization During Domestic Conflict
No full textDespite well-documented legal cynicism and police distrust among Black Americans, studies of 911 calls and surveys of crime victims suggest that 911 call rates are higher in Black neighborhoods and that Black victims are more likely than non-Black victims to notify police. While some researchers have discussed police utilization by Black women to address domestic conflict and violence, the literature does not sufficiently address the question of why police utilization, particularly for domestic issues, might be more likely among Black Americans. This dissertation seeks to fill this gap in the literature with a focus on race, poverty, and police utilization during domestic conflict.
I begin by analyzing National Crime Victimization Survey (NCVS) data. I find that when offenders are romantic partners or family or household members, Black victims are considerably more likely to notify police than non-Black victims. Next, I explore race and police utilization at the neighborhood level in Baltimore, Maryland. Conditioning on an index of neighborhood disadvantage and homicide rates, I find that the percentage of Black residents in a census tract is positively and significantly associated with domestic incident 911 call rates, but negatively associated with most other types of 911 calls.
Finally, I conduct and analyze interviews with 49 residents of disadvantaged Baltimore neighborhoods to better understand my quantitative findings. Even as many, particularly Black, participants conveyed legal cynicism and a disinclination to call the police to report crime, over two thirds of participants discussed calling the police during a dispute with a romantic partner or family member or reported that the police have been called on themselves during such incidents. I argue that when resources are limited and violence is a probable component of domestic disputes, the unique aspects of domestic conflict combine with criminal justice system exposure to increase the likelihood of police utilization. Pervasive criminal justice system exposure can erode the stigma of arrest and generate system expertise that engenders situationally specific police utilization. Thus, the deep penetration of the criminal justice system into the social fabric of poor Black communities results in the co-occurrence of legal cynicism and police utilization
Development of self-assembling nucleic acid nanotherapeutics for the treatment of cancer
No full textEnormous progress has been made in the understanding and treatment of cancer. Unfortunately, many of the innovative treatments discovered have run into roadblocks due to the inherent heterogeneity found within many cancer types. This suggests the need for flexible, targeted therapies that can attack multiple pathways. Self-assembling single-stranded oligonucleotide amphiphiles represent such a class of materials.
Aptamers are 3D structures made from single-stranded DNA (ssDNA) that can bind to a range of targets with high specificity and affinity. Mucin-1 (MUC1) aptamer amphiphile nanofibers were made by conjugating a fluorescent naphthalimide tail to the MUC1 aptamer. The nanofibers successfully delivered the chemotherapeutic doxorubicin (DOX) to triple negative breast cancer (TNBC) cells, and showed a favorable pharmacokinetic profile in vivo compared to analogous spherical micelles, demonstrating the benefit of high aspect ratio nanostructures for targeted delivery.
ssDNA amphiphiles with a di-alkyl tail and C12 spacer have been demonstrated to self-assemble into nanotubes. To improve the flexibility and translatability of this system, processes were developed to expand the capabilities of the system. One such process, the “excess tail” technique, offered the ability to dramatically shift the distribution of nanoparticles from spherical micelles to nanotubes. This ensured that any sequence, including those with modified nucleobases, could produce high yields of nanotubes. It additionally allowed for the encapsulation of hydrophobic drugs in the amphiphile bilayer at higher yields, thus expanding delivery capabilities.
The excess tail technique enabled the synthesis of LNA (locked nucleic acid)/DNA hybrid anti-microRNA-21 nanotubes, targeting the highly oncogenic microRNA-21 (miR-21). A layer-by-layer (LBL) design was then developed to enhance the endosomal escape of these nanotubes. The LBL nanotubes were able to effectively knockdown miR-21 in human pancreatic cancer, glioblastoma, and TNBC cell lines. As a result of this knockdown, they strongly limited cancer cell migration and invasion, suggesting a strong ability to inhibit metastasis. It was also critical to target the primary tumor. Thus, paclitaxel and DOX encapsulating nanotubes were synthesized and showed strong cytotoxicity to different cancer cell lines. By targeting both metastasis and the primary tumor, a combination treatment could be highly effective across a wide range of cancer types
INVESTIGATING HIV-1 LATENCY REVERSAL UPON COGNATE ANTIGEN RECOGNITION IN CD4+ T CELLS FROM PEOPLE ON ANTIRETROVIRAL THERAPY
No full textDespite the advancement in antiretroviral therapy (ART) which effectively prevents viral replication and transmission, there is no cure for Human Immunodeficiency Virus type 1 (HIV-1) infection. Treatment for most persons with HIV-1 (PWH) requires lifelong adherence to ART, as its cessation results in viral rebound within weeks. Viral rebound is due to the persistence of HIV-1 in long-lived resting memory CD4+ T cells. This small pool of resting CD4+ T cells denoted as the latent reservoir is a major barrier to curing HIV-1. The HIV-1 epidemic is currently affecting over 38.4 million PWH worldwide, with 1.5 million new yearly infections. In the absence of new therapeutic interventions, the goal of ending the HIV-1 epidemic will be unattainable.
One of the widely discussed strategies developed to achieve a sterilizing cure for HIV-1 infection is the so called ‘‘shock and kill’’, in which latency reversing agents (LRAs) are used to induce the expression of viral genes and expose the infected cells to elimination through viral cytopathic effects or immune-mediated clearance. Clinical trials with LRAs have demonstrated limited or no significant reduction in the reservoir size. In this thesis, we will review novel immunotherapies that could overcome the challenges of ‘’shock and kill’’ approach, with a particular focus on the engagement of dendritic cells (DC) and natural killer cells in HIV-1 cure efforts.
Important earlier work suggested that the encounter with cognate antigens (Ag) is a major cause of proliferation and persistence of HIV-1 infected CD4+ T cells. However, it remains unknown to which degree exposure to Ag leads to HIV-1 expression. In this dissertation we will investigate the intersection between encounter with Ag presented by DCs and reversal of HIV-1 latency. Understanding to which extent physiological T cell activation leads to latency reversal is key for cure efforts. However, due to the low frequency of HIV-1 infected Ag-responding cells, previous studies failed to compare HIV-1 reactivation mediated by Ag recognition versus global T cell activators. We developed a novel method that helped us enrich and expand Ag-responding cells to effectively demonstrate latency reversal upon encounter of cognate Ag. Our work offers new insights into immunological factors involved in Ag-mediated latency reversal and their impact on HIV-1 reservoir persistence