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HYPOXIA AND IRON ATTENUATE THE EFFECT OF ASCORBIC ACID ON PROSTATE CANCER CELLS
Get PDFAscorbic acid is an antioxidant at low concentrations and a pro-oxidant at higher concentrations. As a pro-oxidant, it is being examined as a potential treatment for cancer because it has greater specificity to prevent growth of cancer cells than noncancer cells. The effectiveness of ascorbic acid to decrease the growth of cancer cells depends primarily on the generation of extracellular H2O2, which requires both iron and oxygen. Both iron and oxygen vary in the tumor microenvironment, thereby influencing the effectiveness of ascorbic acid to prevent tumor cell growth. This study examines the effects of hypoxia and iron status on the effectiveness of ascorbic acid to inhibit tumor cell growth in the androgen-independent prostate cancer PC3 cell line.
To study the effects of hypoxia, cells were exposed to an atmosphere consisting of 1% O2, 5% CO2, and 94% nitrogen for 24 hours before a 4-hour treatment with ascorbic acid in normoxia, after which the cells were returned to the hypoxic environment. Controls were cultures incubated solely in normoxia. Viability was assessed with the MTT assay, reactive oxygen species were measured in a H2DCFDA assay, oxidative stress was measured using the glutathione assay, and iron levels were measured using the ferene assay. DNA damage was assessed through immunocytochemistry by staining γ-H2AX foci. Gene expression for the NF-ĸB and Nrf2 pathways was done using qRT-PCR.
The IC50 for ascorbic acid increased with both pre-incubation with iron and hypoxia compared to controls but was unaffected for hydrogen peroxide. Despite lower cell killing, hypoxia increased intracellular reactive oxygen species and oxidative stress, while iron increased markers of DNA damage with ascorbic acid treatment. The results indicate that one potential protection mechanism for both iron and hypoxia is the induction of anti-apoptotic genes through the NF-ĸB pathway. This study highlights the importance of the tumor microenvironment for the effectiveness of ascorbic acid in treating cancer
Green, Red: World Literature and Revolutions in Punjab, 1960s-70s
No full textWhat happens when the ripples of Cold War geopolitics come to disturb the backwaters of a peasant countryside? And how do subaltern writers invent new aesthetic forms to comprehend and combat these historical transformations? “Green, Red: World Literature and Revolutions in Agrarian Punjab, 1960s-70s,” answers these questions by examining the successive confrontations between Indo-Soviet diplomacy, the US-sponsored Green Revolution, and the Mao-inspired Naxalite insurgency in agrarian Punjab, the northwestern state of India. In 1968, these global churnings produced a new movement, jujharvad (lit. resistance), in Punjabi literature. Apart from featuring Punjabi translations of the leading figures of the Global 1960s – Fanon, Sartre, and Mao – the jujharvadi magazines frequently juxtaposed a range of unexpected figures: French structuralists, medieval Sufis, African poets, and Sikh gurus, among other local revolutionary poets. Part of a longer historical project, “Green, Red” scrutinizes the origins of this uncanny laboratory of world literature in Punjab. Where recent scholarship foregrounds Third World contact zones – Beirut, Cairo, Colombo, Tashkent – as sites for decolonizing world literature, I offer a counter-history from the margins of rural India. Moving between contact zones, agricultural farms, and central prisons, “Green Red” examines how the problematic of “scale” in world literature is mediated by the machinations of Cold War geopolitics and economy
BRAF V600E AND O-GLCNACYLATION DURING ACUTE ISCHEMIA REPERFUSION INJURY ON CARDIOMYOCYTES IN AN EX VIVO MURINE MODEL
No full textA common consequence of coronary artery disease is ischemic heart damage from impaired oxygen supply leading to tissue damage. O-GlcNAcylation is a form of glycosylation mediated by O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA), which catalyze the addition and removal of the signaling molecule O-linked β-N-acetylglucosamine (O-GlcNAc), respectively. O-GlcNAc has been identified as having a dynamic role in adaptation to stress by cycling on and off various intracellular proteins. Previous work in our lab suggested that ERK1/2 undergo O-GlcNAcylation in cardiomyocytes and when OGT activity is inhibited ERK1/2 phosphorylation is suppressed. BRAF activates Mek1/2 by dual phosphorylation which activates ERK1/2, through a typical MAPK pathway cascade. We sought to investigate the relationship between O-GlcNAcylation and ERK1/2 phosphorylation in a physiologically relevant model of cardiac ischemia reperfusion (IR) injury. Previous work in our lab found that during IR injury ERK1/2 phosphorylation reduced during ischemia and rebounds during reperfusion. We hypothesized that by expressing BRAF V600E in cardiomyocytes, ERK1/2 phosphorylation could be rescued and deliver ischemic protection even with O-GlcNAcylation inhibition. To assess the hypothesis, murine hearts were subjected to ex vivo acute IR injury. The experimental design evaluated four genotypes: control (non-transgenic), induced cardiomyocyte knockout of OGT (ickoOGT), BRAF V600E, and double transgenic (i.e. ickoOGT/BRAF V600E; DTG). The hearts were then stained with 2,3,5-triphenyl tetrazolium chloride (TTC) and slices were photographed to calculate infarct size and harvested for protein quantification. Upon comparison of the ischemic damage, there was a significant decrease in ickoOGT compared to control mice. There was no significant difference between the other groups compared to the control mice. BRAF V600E mice showed higher injury than ickoOGT and DTG mice. The injury in BRAF V600E mice was slightly attenuated in DTG mice by a quarter percent. With western analysis we confirmed that ERK1/2 was significantly suppressed in ickoOGT mice compared to control. Interestingly, we did not observe restoration of ERK1/2 phosphorylation in DTG. We found that ischemic damage negatively correlated with reperfusion flow suggesting some vascular cardiac adaptation to IR stress plays a role in cardiac protection
Spectacles of Surveillance in the "New" True Crime
Get PDFThis dissertation examines the transformation of the true-crime genre into a participatory enterprise in the 21st century as a lens for studying the forms of popular governance and truth-seeking practices that are emerging in the digital age with respect to matters of criminal justice and law enforcement. Across three chapters, I demonstrate how the conflicts over epistemic authority and state power unfolding in contemporary true crime have been poorly understood by scholars grappling with both the genre’s alleged “progressive” turn and the increased participation of the public in criminal investigations and crime reportage. In providing a more considered evaluation of some of the frameworks applied to these media and the activities they are giving rise to, this dissertation demonstrates how a desire for certainty and closure in matters of truth is driving a turn to investigatory practices that blur the boundaries between surveillance and spectacle, while reinforcing authoritarian criminal justice policies. Although true crime has become more critical of the police and criminal justice system over the last decade, I demonstrate how the practices of “citizen sleuths” and “amateur” true-crime producers lend epistemic authority to state surveillance practices and investigatory discourses even as they dis-embed these methods and forms of “evidence” from state institutional structures and turn them back onto the police. Through analyses of wrongful-conviction documentaries, YouTube “interrogation-analysis” videos, and the websleuthing and media practices of “citizen detectives,” this dissertation attempts to capture the unruly dimensions of popular governance in the digital age in the hopes of provoking a greater scholarly appreciation for the semi-autonomy of the cultural, commercial, and imaginative practices of the public in defining the shifting lines of power between the state and civil society in the 21st century
Characterizing the Mechanism of Mosaic VSG Formation After DNA Breaks in Transgenic Trypanosoma Brucei
No full textAll pathogens need to survive and proliferate in hostile environments within the infected host. Trypanosoma brucei, a unicellular protozoan parasite and causative agent of African trypanosomiasis, has evolved a complex version of antigenic variation to evade immune recognition. The parasite’s cell surface is covered with ~10 billion copies of a protein known as the Variant Surface Glycoprotein (VSG), which can be switched periodically to a distinct variant to escape host antibody clearance. To accomplish this, T. brucei utilizes its expansive VSG repertoire containing ~2000 VSG encoding genes. However, the majority of the VSG genes are incomplete fragments and can only be accessed through recombination, creating new “mosaic” VSGs. Our lab developed VSG-AMP Seq, a targeted sequencing approach that allows characterization of mosaic VSGs. Using VSG-AMP Seq, we observed that VSG AnTat1.1 frequently recombines with VSG-228, a highly homologous and complete VSG, to form templated insertions throughout the gene. The formation of mosaic VSGs seem to utilize short stretches of shared homology to create insertions that are in frame, but the mechanism remains poorly understood. In this study, we examined the relative accessibility of VSG-228 in different locations within the genome by analyzing mosaic VSG formation. We created multiple transgenic Lister 427 parasite lines expressing AnTat1.1 with the VSG-228 coding sequence integrated into minichromosomes, a silent expression site, the rDNA spacers, or the tubulin arrays. We observed that a significant number of mosaic VSGs were formed between VSG-228 and AnTat1.1 from all tested locations. Surprisingly, VSGs integrated into the rDNA spacers and the tubulin arrays were accessible, even though VSGs are not conventionally found in those locations. In addition, VSG-228 was the most prevalent VSG that recombined with AnTat1.1, overtaking other homologous VSGs found in the genome. These results reveal that there is no specific location requirement for VSGs to recombine and form mosaics, and that shared sequences of homology between VSGs play an important role in the process. Collectively, this study builds upon our methods and strategies used to investigate the mechanisms of mosaic VSG formation
A Large Neighborhood Search Heuristic for Naval Re-Supply
Get PDFThe U.S. Military faces a myriad of optimization problems when planning re-supply of their forces. Re-supply planning must keep pace with technological advancements to other aspects of military operations so that the U.S. can remain competitive with potential adversaries.
The Logistics Aid for Sustainment and Expeditionary Readiness (LASER) employs a large neighborhood search (LNS) algorithm to modernize naval re-supply planning in the military. Preliminary results indicate that the LNS algorithm provides dramatic performance benefits compared to a more traditional, mixed integer programming approach
Towards Interpretable Scene Understanding through Parsing and Attention
Get PDFThe field of scene understanding in computer vision has witnessed remarkable advancements during the Deep Learning era, driven by the proliferation of large-scale datasets, novel architectures, and sophisticated training techniques. However, despite these strides, the challenge of developing models that not only achieve high performance but also offer interpretable insights into their decision-making processes remains a significant and pressing concern in the community.
This dissertation addresses this challenge by advancing the methodologies of semantic object parsing and interpretable attention mechanisms. The first part concentrates on leveraging parts in both unsupervised and supervised manners to enhance various downstream tasks, including few-shot learning, object segmentation, and object parsing itself. The second section investigates the potent self-attention mechanism employed within Transformer architectures, aiming to provide an interpretable extension to these models. This not only enhances their interpretability but also improves performance in fine-grained recognition and video panoptic segmentation
Resilience of Systems: Technocracy and Information Society in Japan, 1960s–1980s
No full textThis dissertation examines how the “systems approach” shaped engineers’ and technocrats’ understanding of human society and social governance in Japan. It argues that Japanese technocrats adopted a systems approach to address social problems and to establish a resilient and market-oriented “neoliberal technocracy.” The systems approach underpinning the system concept claims to employ multidisciplinary expertise to resolve research problems by analyzing, controlling, managing, and optimizing systems. Initially adopted by a technocratic coalition of engineers, economists, bureaucrats, and executives in the late 1960s, the systems approach served as a methodology for them to understand social issues and realize a utopian vision of an “information society.” This interdisciplinary collaboration gave rise to a new technocratic culture characterized by self-reflexive optimism, a holistic vision, and an interdisciplinary approach. Unlike their prewar counterparts, these technocrats acknowledged the limitations of their methodology, welcomed interdisciplinary input from social sciences, and aimed to include diverse perspectives. Despite this self-reflexivity, the holistic worldview and interdisciplinary methodologies offered by the systems approach made them optimistic that problems, uncertainties, and risks in socio-technological systems could be resolved through system building and optimization.
These characteristics bolstered the technocrats’ resilience against critiques and failures, as these issues were not only anticipated but could also be integrated into the framework of systems. In the 1970s, technocrats faced challenges and critiques while constructing state-funded, centralized “social systems” to address pressing issues such as pollution, waste, shortages of medical services, and traffic congestion. Rather than acknowledging the failure of the systems approach, the setbacks—coupled with the rise of personal computers and commercial information systems—prompted a shift toward interconnected yet decentralized social and technological systems. These systems were perceived as both practical and profitable, making them better suited to the idea of a liberalized market economy. This shift marked the maturation of a resilient and market-oriented neoliberal technocracy, which facilitated neoliberal reforms through the technocrats’ active political participation in the 1980s
You Won't Believe This Story! Narratology and Corporate Learning
No full textAcross the globe, companies spend more than 350 billion annually on training for their employees. Employees welcome such an investment, and list learning opportunities and professional development as key desired benefits in the workplace. Despite this investment in training and its perceived value, both employers and employees have often been left disappointed by the results of such efforts. Employers continue to remark that employees are not properly skilled for their current and future roles and employees frequently rate their provided training as ineffective and forgettable. While there are many variables at play in training effectiveness, this research focuses on one potential avenue to address this long-standing issue: the use of narrative and story within training materials for the corporate employee. Given prior research on how story can be encoded in our long-term memory and how story can be successfully utilized for behavior change, this option is explored as an avenue to increase retention and training transfer in corporate settings. In order to fully explore this potential option, the researcher is embarking on cross-disciplinary discovery with narrative experts in the fields of law, medicine, and psychology to understand how narrative and story are utilized in learning and people development. These insights will be utilized to form a prototype storytelling framework as an instructional methodology for corporate training initiatives
TOOLS FOR MESO-SCALE CHARACTERIZATION AND PROCESSING IN BIOLOGICAL TISSUES
Get PDFThe burgeoning focus on engineering transplantable tissues for therapeutic purposes engenders an urgent need for developing a comprehensive framework consisting of diverse tools for both creation and validation of such tissues. The first two pertain to methods for generating physiological mimicking tissues: the fabrication of large-scale aligned collagen matrices with myoblasts and the 3D bioprinting of skin and airway tissues. The final component focuses on the validation of ECM structure and the organization of cells within the tissues. Although there are limitations associated with fabricating larger and complex organ, this paper proposed a novel method to develop large-scale aligned collagen matrices using viscous long-chain polymers to mimic the highly aligned ECM pattern in the body. After mixed with the viscous long-chain polymers, the collagen flowed into the self-made channels. The matrices emulate the highly ordered matrices in humans. C2C12 cells retained a high viability and could align with the collagen fibrils. Additionally, the application of 3D bioprinting in creating intricate tissue architectures holds significant promise in emulating biological tissues. The fibroblasts and epithelial cells showed about 50% viability in 3D bioprinted tissues cultured in the special medium. Moreover, the clear distribution of epithelial cells in the matrix demonstrates possibilities in disease modeling and novel therapy development.
This study extends to the evaluation of tissues obtained from live animals by comparing the collagen remodeling and organization of cells in metastatic and normal lung. By applying the fiber analytic tools, we found that the length of collagen fibers is different between the metastatic lung and normal lung. Additionally, we investigated the potential effects of YAP in the alternation of E-cad and fibronectin due to the acute colitis triggered by colonization with ETBF in mice. Although no difference in the signal of E- cad between YAP and YAP-KO conditions was observed, the method can be used in validating the ECM structure and the organization of cells in artificial tissues. Through these methodologies, this study provides a comprehensive framework for studying both healthy and pathological 3D tissues, thus advancing tissue engineering and its biomedical applications