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HYLS1 is a Centriolar Protein Required For Centriole Structural Integrity and Ciliogenesis
No full textAmong the largest protein-based structures found in mammalian cells, centrioles form the core of centrosomes during cell division and serve as templates for producing cilia and flagella. Defects in centriolar proteins are thus a hallmark of cancer and ciliopathies. HYLS1 has been shown to be essential for ciliogenesis, and a mutation at amino acid 211 causing a substitution of a glycine to an aspartic acid residue (D211G) is the cause of Hydrolethalus syndrome (HLS), a deadly ciliopathy. However, the molecular mechanism behind this disease and whether the lack of cilia upon HYLS1 depletion is a consequence of a centriole structural defect remains largely elusive. Here, we studied the role of HYLS1 in centriole assembly and cilia formation using HYLS1-knockout as well as HYLS1 D211G knock-in cell lines. We found that both HYLS1 knockout and HYLS1 D211G cells demonstrated an impairment of centriole distal end assembly. Specifically, HYLS1 is essential for the recruitment of the distal centriolar proteins Centrin2, TALPID3, and CEP164. Moreover, we were able to show that HYLS1 D211G impairs ciliogenesis in RPE1 cells and HYLS1 D226G, the equivalent to the HYLS1 D211G mutation in humans, impairs ciliogenesis in mouse embryonic fibroblasts. Together, these results demonstrate that HYLS1 plays essential roles in centriole distal end assembly and that the observed centriolar defects caused by HYLS1 depletion or D211G mutation are the main cause of the described defects in ciliogenesis, and thus the Hydrolethalus Syndrome
MILITARIZING THE PSYCHE: SECURITY, KINSHIP AND PSYCHIATRY IN PAKISTAN
No full textThis dissertation uses participant observation and interviews with combatants, their families, psychiatrists and local healers to understand the general category of pagalpan (madness), with acute symptoms referred to as dauras (seizures). By considering the military, households and sites of healing, the dissertation throws light on the arbitrary and fluid ways in which mental illness is diagnosed and the forms of authority that sustain the ambiguity of mental illness in contemporary Pakistan. I argue that historically mental illness has been treated from a punitive lens, suppressed or treated as signs of malingering in Pakistan. Two social features shape the way pagalpan is interpreted, experienced and treated: the presence of spiritual entities, and the intense relational experience of violence, intimacy and care in extended kin groups. Whereas is some cases pagalpan is not identified or suppressed, in other cases it is attributed to supernatural forces. The first chapter explores the experience of soldiers. In particular, it explains how soldiers in combat experience non-specific symptoms which are treated as “dodgy” by military physicians, sometimes with lethal consequences, where officers in command also use pagalpan to dismiss challenges to authority. The second chapter explores the ambivalent attitudes toward mental illness in Pakistan in general, with families treating psychosis as signs of divine inspiration, political awareness as well as abnormality (ajeeb), instead of representing someone as wholly pagal (mad) and considers aspirations to serve the state as emerging from these ambivalences as recruits seek exit from disorders in family for the stability and certainty of military service. Chapter three explores the ramifications of militarization on wider kinship networks, especially as officers and soldiers extend military behaviors into their domestic space to manage illness among kin. This in turn increases the frequency of illness including accusations of pagalpan and conversely its concealment among family members. Chapter four explores how in the context of the ongoing war on terror, people turn the external struggle against an enemy inward for the cultivation of the soul
End-to-End Simultaneous Speech Translation
No full textSpeech translation is the task of translating speech in one language to text or speech in another language, while simultaneous translation aims at lower translation latency by starting the translation before the speaker finishes a sentence. The combination of the two, simultaneous speech translation, can be applied in low latency scenarios such as live video caption translation and real-time interpretation.
This thesis will focus on an end-to-end or direct approach for simultaneous speech translation. We first define the task of simultaneous speech translation, including the challenges of the task and its evaluation metrics. We then progressly introduce our contributions to tackle the challenges. First, we proposed a novel simultaneous translation policy, mono- tonic multihead attention, for transformer models on text-to-text translation. Second, we investigate the issues and potential solutions when adapting text-to-text simultaneous policies to end-to-end speech-to-text translation models. Third, we introduced the augmented memory transformer encoder for simultaneous speech-to-text translation models for better computation efficiency. Fourth, we explore a direct simultaneous speech translation with variational monotonic multihead attention policy, based on recent speech-to-unit models. At the end, we provide some directions for potential future research
Assessing the Effectiveness of U.S. Financial Regulations: A Comparative Analysis with E.U. Responses
Get PDFThis paper assesses the effectiveness of US financial regulation in carrying out its intended purpose, namely, to adequately protect investors from industry abuse, insider advantages, and fraud. Reviewing recent financial crises, the role of the SEC, high profile Supreme Court cases, and legislation, such findings call into question the legitimacy of the financial system as a whole and is worrying due to Americans’ sheer reliance on banks and securities markets. Furthermore, this paper then compares the U.S. regulatory response with that of the E.U. as a result of the Global Financial Crisis and found that E.U. regulations are more clear, more potent, and more effective in handling and preventing financial crises. This paper uses statistical data, legislative analysis, and testimonial evidence to conclude that there are severe ways in which the US regulatory regime is lacking. Particularly, through vague laws that do not take proper measures to adequately protect against a future crisis, along with the evaluation of the capacity of the SEC to enforce the financial laws in question, US financial regulation does not effectively carry out its intended purpose
ESTIMATING THE IMPACT OF BALTIMORE’S UCHOOSE YOUTH SEXUAL HEALTH INITIATIVE ON SCHOOL- AND STUDENT-LEVEL INDICATORS, THREE YEARS AFTER LAUNCH
No full textBackground: Adolescence is a critical period for young peoples’ sexual health, emphasizing the need for support during this period, particularly with regards to the prevention of unintended pregnancy or sexually transmitted infections (STIs). Despite widespread acknowledgement that young peoples’ sexual health is influenced by their socio-ecological contexts, there is relatively minimal evaluation research with regards to multi-component, multi-level sexual health initiatives. This study responds to this evidence gap by estimating the impact of Baltimore City’s community-wide UChoose youth sexual health initiative on school-level sexual health education practices and student-level sexual experiences and behaviors, three years after its July 2015 launch.
Methods: A quasi-experimental, difference-in-differences design was employed to estimate UChoose’s effects by comparing trends in Baltimore to concurrent trends in a nearby city, Philadelphia, that did not implement a similar initiative during the same period. Representative data on school-level sexual health education practices was drawn from the Center for Disease Control’s School Health Profiles teacher surveys, and representative high school student-level data was drawn from the CDC’s Youth Risk Behavior Surveys (YRBS).
Results: Three years after launch, UChoose had significant positive effects on teachers’ receipt of materials for sexual health education, receipt of professional development in HIV/STI prevention, and instruction on sexuality education topics in grades 6, 7, and 8. Statistically significant effects on student-level sexual health indicators were not observed overall, though effect heterogeneity was detected. UChoose appears to have more strongly impacted younger youth with regards to lifetime abstinence from sex, older youth with regards to secondary abstinence from sex, Black youth with regards to delayed initiation of sex and number of lifetime sexual partners, and heterosexual-identifying youth with regards to prevention of physical dating violence.
Conclusion: This study contributes to the small but growing evaluation research on multi-component community-wide youth sexual health initiatives by demonstrating that, three years after launch, UChoose had favorable impacts on school-level sexual health education practices and student-level sexual health indicators for sub-groups of students. Findings support future effect estimation over longer periods, and the continued need for greater emphasis on inclusivity in sexual health initiatives for historically marginalized groups of youth
SOCIAL FACTORS, WEARABLE ACTIVITY TRACKER USE AND PHYSICAL ACTIVITY PATTERNS IN OLDER ADULTS
No full textPhysical inactivity is an independent risk factor for multiple adverse health outcomes, threatening the health of the aging population. Wearable activity trackers (WATs) may be an innovative method to help improve physical activity (PA) patterns in older adults, including both moderate-to-vigorous physical activity (MVPA) and sedentary behaviors. The purpose of this study was to understand how WAT use, the COVID-19 pandemic, and social factors are associated with PA patterns among U.S. community-dwelling older adults.
This dissertation study used a multi-method design that involves secondary qualitative and quantitative analyses. The qualitative analysis was conducted using transcripts of 23 semi-structured interviews with older adults who participated in WAT-facilitated PA interventions. The quantitative analyses were conducted using older adults’ data from the National Health Information Trends Survey cross-sectional data 2019 and 2020 waves to understand the associations among older adults’ social factors, WAT use, and PA patterns before and during the first wave of the COVID-19 pandemic.
The qualitative analysis showed that older adults reflected positive experiences of using WATs to promote PA patterns but also reported issues related to WAT functionalities that can be improved. The quantitative analyses showed that older adults who were non-Hispanic African Americans, 65-74 years, women, with higher education, higher income, and living in the low-minority area were more likely to be frequent WAT users after adjusting for covariates. Male participants who were younger and had higher incomes had significantly longer weekly MVPA time than their counterparts. Male participants who were Non-Hispanic White, with higher education were more likely to have longer daily sedentary time. Frequent use of WATs was significantly associated with longer weekly MVPA time and shorter daily sedentary time. WAT use significantly mediated the associations between socioeconomic status (income and education) and weekly MVPA time.
This dissertation study suggested the need to improve U.S. older adults’ PA patterns to meet guideline requirements, and showed the existing disparities in older adults' WAT use and PA patterns, emphasizing the need to implement WATs for older adults who are socially disadvantaged to prevent further perpetuating health disparities among older Americans
The End of Impunity: Illicit Trade, Mercantile Power, and the Royal Navy, c.1713–1765
No full textThe archetypal image of the eighteenth-century Royal Navy centers the institution of the 1760s and later: an effective, professional force under firm political control. But the navy of the early Georgian period was a different animal, particularly during peacetime. This dissertation seeks to provide a fuller understanding of the early Georgian navy in order to displace the often-universalized image of the later institution, highlight the nature and magnitude of the transformation that it underwent during the eighteenth century, and complicate the explanation of that transformation. Examining the navy both in itself and as part of British society illuminates both its involvement in forming and maintaining the empire and the competing forces that acted to shape it.
This study examines the navy operating across the British empire at multiple levels, from an institutional and structural perspective down to an exploration of the experiences and relationships of individual officers aboard ship. The picture that emerges is of a small, tightly bound, internally cohesive officer corps that was powerfully protective of its customary practices and exerted considerable autonomy from political interference, yet struggled to legitimate their claims to gentlemanly status with insufficient pay. As a result, many resorted to illicit trading, which came to be common in the Caribbean and endemic on the African coast.
British merchants, recognized as important enablers of economic prosperity and national power, wielded considerable influence and were deeply interested in the navy’s activities and performance. They provided important services for the state generally and the navy specifically, and did not scruple to make demands in return, both for naval protection and for freedom from unfair competition. Throughout the eighteenth century, merchants continually attempted to apply their political influence to shape the navy into an institution that better served their needs—better at doing what they needed it to do, and responsive to their demands for how its officers should behave. That struggle initiated significant changes in the early Georgian navy that help to explain its transformation between the 1730s and the 1760s and eventually brought an end to the impunity of the officer corps
uSPIO-based Nanocarrier for Pretargeted, PET-MR Image-Guided Delivery
No full textUltrasmall superparamagnetic iron-oxide nanoparticles (uSPIO) are an attractive platform for development of smart contrast agents for MR imaging. A hydrophilic ligand with high affinity towards the surface of uSPIO core renders hydrophobic uSPIO water-soluble, biocompatible, and highly stable in physiological conditions. A small overall hydrodynamic diameter ensures optimal pharmacokinetics, tumor delivery profile and of particular interest, the enhanced T1 MR contrast. In this study, for the first time, we synthesized a ligand with facile approach that fulfills the as-proposed properties and provides multiple reactive groups for further modifications. Structural and molecular size analysis on the resultant uSPIO-ligand construct confirmed size uniformity and small hydrodynamic diameter of the construct. Its r1 relaxivity has been tested on a 7 Tesla MR Instrument and is comparable to clinically available T1 gadolinium-based contrast agent GBCA (1 mM-1s-1 vs 3 mM-1s-1), respectively. In vivo injection resulted in significant decrease in tumor T1 (15%) within 1 hour of injection and complete signal recovery after 4 hours. Good relaxation and delivery properties and the presence of multiple surface reactive groups can facilitate application of the developed uSPIO, as a universal MRI-compatible nanocarrier platform.
HER2(+) metastatic breast cancer (mBC) is one of the most aggressive and lethal cancer type among female. Targeted therapeutic approaches such as trastuzumab and antibody-drug conjugates (ADC) lack long-term efficacy against HER2(+) mBC or can cause severe systematic toxicity due to off-target effects. A Pretargeting delivery platform can minimize toxicity and increases therapeutic localization by separating the single delivery step into a pretargeting step of biomarker followed by the therapeutic delivery step. We have successfully developed a click-chemistry based pretargeting platform for HER2(+) BC with PET-MR image guidance. Trastuzumab and newly developed uSPIO carrier are selected as pretargeting and delivery component, respectively. Confocal imaging confirmed an enhanced internalization associated with pretargeting strategy. An enhanced tumor accumulation as well as the tumor to organ accumulation ratio at up to 24hr post uSPIO injection was observed in pretargeted mice. 40% local T1 decrease in pretargeted tumors was observed within 4hr, and an overall of 15% T1 drop retained for 24hr post uSPIO injection. The prolonged tumor retention and increased tumor to organ accumulation ratio establish a solid foundation for pretargeted delivery approach for in vivo applications
NEMATIC ORDER AND TOPOLOGICAL DEFECTS IN CELL MONOLAYERS GUIDED BY TOPOGRAPHY
No full textMany types of living cells display long-range orientational order, resembling nematic liquid crystals. They also form disordered regions known as topological defects, where a broad range of interesting biological properties have been observed including aggregation and cell death. I aim to study the effects of topological defects on various types of cells. For this, I design topographically patterned substrates to guide two-dimensional cell alignment and induce topological defects with alternating circular and hyperbolic alignment. I measure the alignment and density distribution of 3T6 and EpH-4 cells. 3T6 cells exhibit shape changes and density variation near the topological defects, reaching a higher density near circular defects and remaining at a low density near hyperbolic defects.
I perform experiments to test two possible mechanisms for the observed density variation: collective migration or a spatially varying division rate. I study the cells' dynamics near circular defects, finding a lack of collective motion. To further suppress collective motion, I increase the ridge height. I find that the density variation near defects is enhanced on the substrates with taller ridges, which can be explained by a shape-dependent cell division rate. The results establish a connection between the order, shape, and density in the cell sheets. They suggest that density variation is driven not by collective migration but by the shape changes of cells near the circular defects.
With these micropatterned substrates I generate controlled 3D structures in 3T3 cell sheets, inspired by the design of liquid crystal elastomer actuators. I develop a method to induce the detachment of cell layers from the substrates. Upon release from substrates that induce uniform cell alignment, the cell sheet contract anisotropically, with a greater degree of contraction along the cells' nematic director. I also grow cells on substrates with spatial variations in the alignment and find that they can generate 3D structures as a result of this anisotropic contraction.
In summary, using concepts from liquid crystal physics, I explore the relationship between shape and order in cell sheets, and I provide examples of how to use this concept to create programmable cell layers
The Lives of Things in Ashurnasirpal II’s Northwest Palace at Nimrud, Iraq
No full textFrom the time of its inception by Ashurnasirpal II (883–859 BCE) to its abandonment after 612, the Northwest Palace at Nimrud, Iraq, facilitated and participated in enduring engagements between diverse constellations of inhabitants and visitors, human and nonhuman alike. And yet, scholars regularly neglect the palace’s historical depth, instead focusing their inquiries on narrow moments of the palace’s long life, such as the reigns of certain kings. The dissertation argues that this constricted gaze risks obfuscating the palace’s persistent and messy past, which permeated any given present and future. In three case studies, this dissertation dives into the palace’s dynamic and complex histories to explore the ever-emerging entanglements of the palace’s things with human and nonhuman interlocutors.
The first case study considers the polychronic nature of the Banquet Stele, a stone commemorative monument prominently located outside the Throne Room. The monument’s material durability and central position ensured its continuous engagement with the palace’s inhabitants long after the commemorated event. The chapter argues that the stele transformed from a monument memorializing a past event to a monument obscuring it.
The second case study takes a phenomenological approach to examine the small decorative and figural garment embellishments that adorned the figures carved in bas-relief on the palace’s walls. I argue that the garment decorations evoked the “Internationalizing” identity of the Late Bronze Age, which created tensions between the “Assyrianizing” identity of the Assyrian elite. I then consider the garments’ miniature human-headed lions and genii in relation to their monumental counterparts on the palace’s walls and stationed at doorways. I argue that the miniature and monumental representations had a co-constitutive connection to enūma eliš, which may have compromised their apotropaic efficacy.
The final case study delves into the complex entanglements among gender performativity, identity symbols, and materials. The Assyrian king defined his masculinity upon the emasculation of defeated foreign rulers. This chapter argues that ivory came to embody a subordinated masculinity resulting from the material’s role as a royal symbol of Levantine kingship