48670 research outputs found
Sort by
Imaging And Manipulating Cells And Their Interactions With Trimethoprim-Based Tools
No full textDetecting and manipulating cells and their interactions is a broad goal of chemical biology with potential translational impact. For example, detecting live bacteria in vertebrate animals is a crucial advance for infection diagnosis. Similarly, monitoring engineered mammalian cells is important when developing new cellular therapies. Beyond detecting a specific cell population, controlling cell-cell interactions is a fast- developing research area with practical applications. Immune-mediated therapeutics such as checkpoint inhibitors drive the interaction of immune cells with cancer cells. Similarly, chimeric antigen receptor (CAR) T cells use combinations of protein domains to build a sense-and-respond architecture into a therapeutic paradigm based on cell-cell interactions. Still, challenges remain for maximizing the potential of immunotherapies including on-target, off-tumor toxicity. Development of molecular technologies to fine- tune temporal and spatial dynamics of protein expression could bolster efficacy while reducing toxicity. Here, small-molecule systems may offer unique value in both detecting and manipulating cell interactions as they are facile to iterate, easily permeate cells, and may be less expensive than other modalities. Trimethoprim (TMP) is an antibiotic that reversibly inhibits bacterial dihydrofolate reductase (DHFR) with 10,000-fold selectivity over the mammalian DHFR homologue. Such a large therapeutic window renders TMP inert in mammalian cells and makes it an ideal molecular chassis for building new chemical biology platforms. In this thesis, I detail advances in two TMP- based molecular tools. First, I describe a two-cell system that can regulate protein expression based on the selective activation of a TMP prodrug. Initial proof-of-concept studies employ a bacterial nitroreductase enzyme while later studies use a human cancer target, fibroblast activation protein, for the catalytic uncaging of a steric protecting group on the TMP. Second, I describe the development and application of a TMP-based PET radiotracer, [11C]-TMP, and determine whether it can image drug- resistant bacteria. In vitro and bioinformatic approaches uncover a DHFR redundancy pattern that allows TMP-resistant bacteria to be imaged by [11C]-TMP. Together, these tools may serve as powerful approaches to both image pathologic processes and manipulate future engineered molecular technologies
Do Boards Matter to Institutional Change? The Role of Governing Boards in Strategy Change at Small, Private Women\u27s Higher Education Institutions
No full textSmall, private, women’s colleges served an important role historically and continue to do so today. The number remaining after the advent of general coeducation at private colleges and universities provide a niche in the diversity of higher education institutions. Many of the women’s colleges that remain today undertook significant changes in strategy to survive as dedicated single-sex institutions. Governing boards are central to intentional change efforts as they are responsible for mission and, by extension, strategy. Women’s college transitions are well studied, but the literature gives short shrift to the role of the boards in strategy change. Using qualitative methods through comparative case studies of Bay Path University and Agnes Scott College, this research describes the role of governing boards and board leaders at small, private, women’s colleges which leaned into their missions and identities to embark on strategy change. The research questions and case study analyses focused on how boards came to frame the need for strategy change, what the boards and the board chairs did and how they related to key stakeholders, and how the boards’ own work evolved. The findings demonstrate that governing boards and especially the board chairs are critically important to strategy change and that the boards’ work evolves to a higher plane with strategy change. The findings point to implications for practice for governing board chairs, other trustees, and institutional presidents. The research fills a gap in the literature on governing boards and trustees. Implications for practice are translatable not only to other niche college subsets with targeted missions and students, but more broadly to the many small, private, tuition-dependent colleges that share the challenges of declining enrollments, small endowments, and competition
Anderson-Bernoulli Localization on 2D and 3D Lattice
No full textThe Anderson model describes the behaviour of electrons inside a piece of metal with uniform impurity. The Anderson-Bernoulli model is a special case of the Anderson model where the potential has Bernoulli distribution. We consider Anderson-Bernoulli localization on d dimensional lattice for d=2,3. For d=2, we prove that, if the potential has symmetric Bernoulli distribution and the disorder is large, then localization happens outside a small neighborhood of finitely many energies. For d=3, we prove that localization happens at the bottom of the spectrum
Injectable Hydrogels to Deliver Extracellular Vesicles for Treatment After Myocardial Infarction
No full textThere is a tremendous clinical need to develop new therapies to limit the progression to heart failure after myocardial infarction (MI). Recent studies have suggested that extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) can mediate cardioprotection and preserve function post-MI due to their key roles in paracrine signaling with angiogenic, proliferative, anti-inflammatory, and anti-apoptotic effects via transfer of proteins and miRNAs. Despite this interest, there are still challenges related to EV scale-up, sustained delivery, and analysis in clinically-relevant animal models that need to be addressed prior to their translation. With these considerations in mind, the overall goals of this dissertation were to (i) develop injectable hydrogels, which allow localization and sustained release, for minimally invasive delivery of EVs to the heart, (ii) scale-up production of MSC-EVs to generate doses required for preclinical large animal studies, and (iii) investigate the timing of EV presentation on cardiac repair. First, three MSC culture systems (tissue culture plastic, microcarriers in a spinner flask, and perfusion bioreactor) were explored towards scaling up EV production to generate large doses. MSC-EVs were characterized for size, distribution, yield, morphology, content and in vitro potential, which motivated microcarriers to create large doses for pre-clinical studies. The therapeutic potential of MSC-EVs delivered from injectable hydrogels was then investigated in a porcine MI model, which indicated improvements in infarct area with EV delivery. Secondly, extended delivery of EVs through an interpenetrating network (IPN) hydrogel was studied with metabolic labeling to understand the timing, release, and biodistribution of MSC-EVs. The therapeutic potential of extended MSC-EV delivery was studied in a rat model of MI, with the IPN delivery of EVs improving outcomes of vascularization over controls. Finally, a radiopaque hydrogel system was developed to evaluate hydrogel localization after injection via a SPECT/CT imaging system towards clinical translation. Overall, this thesis highlights the importance of cell culture conditions for scale-up of MSC-EVs for cardiac repair and the use of injectable hydrogels as a therapeutic delivery vehicle towards translation of these therapeutics for clinical use
Discontinuous Predicates as Partial Deletion in Cantonese
Get PDFProviding novel evidence from discontinuous predicates in Cantonese, this paper argues that partial deletion applies to the word level. A number of disyllabic verbs in Cantonese may appear as discontinuous strings where the two syllables are separated by suffixes and/or phrasal elements. We propose that their derivation involves a conspiracy of multiple operations in Narrow Syntax and in the Phonological Form (PF): (i) verb movement in Narrow Syntax creates copies; (ii) affixes induce a PF syllable deletion rule on the higher copy; (iii) partial Copy Deletion applies to the lower copy. Consequently, partial deletion not only applies to phrasal constituents (Fanselow and Cavar 2002), but also to words/heads. We also maintain a relatively conservative understanding of Copy Deletion by scattering the deletion to a PF deletion rule and Copy Deletion, where the partial effect is due to disruption of the latter by the former
Mirror Principle Violations in Greek Prefixed Verbal Complexes
Get PDFThis study investigates the formation of prefixed verbal complexes in Greek. I provide evidence that, in their base position, prepositional prefixes (henceforth, prefixes) are generated in [Spec, VP], below Tense. However, after spell-out, they surface in a position preceding Tense, showing a case of Mirror Principle violations. I argue that the traditional Head Movement (Koopman 1984, Travis 1984, Baker 1985) is inadequate to model the linear order of morphemes in prefixed verbal complexes. Instead, they require the use of two main mechanisms: the syntactic operation of Generalized Head Movement (Arregi and Pietraszko 2018, 2019), which unifies upward and downward head movement by creating a single complex head, and the postsyntactic operation of Merger (Matushansky 2006, Harizanov 2014, Martinovic 2019), which combines a head with its specifier
Cot in the Act: Speaker Ethnicity Conditions Lexical Identification in the Context of the Low-Back Merger in New York City English
Get PDFThis paper reports on an experiment designed to measure how listeners\u27s perceptions of speaker age and ethnicity condition identification of lexical items with THOUGHT/LOT vowels in New York City English (NYCE). Several independent studies have recently reported evidence of THOUGHT-lowering and/or LOT/THOUGHT merging in NYCE led by younger non-White speakers. Spoken corpus data by Wong (2012), Becker (2010) and Haddican et al. (2021) suggest rapid THOUGHT lowering, particularly in Asian and Latinx communities. Similarly, younger Asian and Latinx NYCE speakers favor merged LOT/THOUGHT responses in controlled homophony judgment tasks (Johnson 2010, Haddican et al. 2016). Moreover, matched-guise results by Becker (2014) suggest that raised THOUGHT is associated mainly with older White speakers. Unaddressed in this literature is whether listeners use perceived social information about the speaker--i.e. perceptions of age and ethnicity--in their phonemic categorization of low back vowels in comprehension of NYCE (Rubin 1992, Hay, Warren and Drager 2006, Koops 2011). Here, we report results from a forced-choice lexical identification experiment intended to investigate this. Consistent with previous production and matched guise results, judges tended to misidentify LOT auditory stimulus items as THOUGHT more often when the item was accompanied by a photo of an Asian speaker than a White speaker. The analysis revealed no effect for the age comparison. The results suggest that NYCE-native listeners actively use social information about speaker ethnicity in the categorization of LOT/THOUGHT items in comprehension
Matrix Operators in Georgian Indexical Shift
Get PDFThis paper examines indexical shift in Georgian (South Caucasian), which has been noted but understudied in the literature. I argue that its matrix-level shift provides evidence in favour of the shifty operator theory (Anand and Nevins, 2004; Shklovsky and Sudo, 2014; Deal, 2020, i.a.). In these approaches, an embedded indexical is interpreted against a non-utterance context whose parameters are determined by an operator. Crucially, this operator is distinct from the verb that introduces it, which logically allows for the operator to merge freely in the structure. This prediction is evidenced by shifted indexicals in Georgian matrix clauses
Deciphering the Heterogeneity of HIV Reservoir Immunology: A Single-Cell Perspective
No full textSince its initial documentation in 1981, the acquired immunodeficiency syndrome (AIDS) epidemic has impacted more than 70 million people. As the causative agent of AIDS, human immunodeficiency virus (HIV) is a retrovirus that integrates a copy of its viral genome (termed provirus) into the genome of target cells known as CD4+ T cells. With antiretroviral therapy (ART), persons living with HIV (PLWH) can suppress viral replication and prevent progression to AIDS. However, ART is usually a lifelong requirement as interruption can lead to viral rebound via transcription at the integrated viral genome. During early HIV infection, some infected cells can enter a quiescent state that results in a state of infection known as latency. Persistent infection and reversible latency are characteristics of the HIV reservoir. As a result, there is no universally accessible cure for HIV. A functional cure of HIV – which is to suppress viral replication without ART – is a primary goal of HIV cure research. Such a strategy requires an in-depth understanding of the HIV reservoir but many CD4+ T cells, each with different function and phenotype, contribute to the collective HIV reservoir that is located throughout different tissue environments. To address this challenge, this study deciphers the reservoir through the lens of tissue versus blood compartmentalization at a subset resolution to address the impact of residency and circulation as well as with a novel single-cell approach to enable a comprehensive analysis of the HIV reservoir during ART. While the characteristics of integration were generally the same across compartments, there was a lack of overlap between tissues and blood to suggest the existence of sub-reservoirs where there may be unique reservoirs based on residency status. Furthermore, the single-cell profiling revealed extensive heterogeneity between and within individuals with some infected cells displaying a poised signature for reactivation. These results provided a clearer picture of the HIV reservoir to come closer to the goal of a functional cure that can effectively target latency across the location and phenotypic diversity of the HIV reservoir
Penn Library\u27s LJS 439 - [Book on the configuration of the orb]. (Video Orientation)
No full texthttps://repository.upenn.edu/sims_video/1184/thumbnail.jp