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Exploring Closed Loop Neuromodulation for the Treatment of Parkinson's Disease and Epilepsy
No full textEpilepsy and Parkinson’s Disease (PD) are of the most prevalent neurological and neurodegenerative disorders, respectively, in the world. Both of these issues present immense social and economic burdens on the affected individuals as well as the systems they interact with. Though these are highly prevalent illnesses, existing treatment methods are still unable to omit symptoms for a large proportion of individuals. Disruption in existing neurological pathways between deeper brain structures, such as the thalamus and hippocampus, and the cortex lead to many of the pathological motor symptoms observed in epileptic and parkinsonian patients. Phase-amplitude coupling (PAC) is a biological feature that demonstrates the association between the phase of low frequency oscillations and the amplitude of high frequency bands. PAC has been shown as a promising biomarker for PD (beta-gamma) and epilepsy (theta-gamma) that is subsequently altered with fluctuations in symptom severity. Existing neuromodulation techniques have yet to implement PAC as a feedback parameter for closed-loop interventions. One of the neuromodulation techniques PAC can be used for is phase-dependent stimulation (PDS); exploratory studies have identified PAC-based PDS as potential treatment solution due to the modulatory effects PDS has on PAC. This project explores PDS computationally, in the hippocampus to verify that it changes oscillatory patterns. Further, closed-loop PAC-based DBS is ideated and speculated as a potential therapy. Finally, preliminary clinical studies are presented in which ECoG signals are collected from patients with epilepsy and PD to calculate PAC patterns. PDS paradigms are also designed and applied to signals, offline, to introduce this closed-loop neuromodulation technique. Future projects will focus on the expansion of in silico work by advancing the CA3 hippocampal model with CA1 network and plasticity implementation as well as a PAC-based closed-loop DBS model. For clinical studies, the development of a real-time PAC-based PDS delivery system is in progress, as a potential implantable treatment mechanism. This project aims to exemplify closed-loop neuromodulation as a favorable therapeutic intervention for neurological disorders, specifically PAC-based PDS for epilepsy and PD
DIFFERENTIAL ROLES OF POSITIVE AND NEGATIVE SUPERCOILING IN COMPACTING THE E. COLI GENOME
No full textRecent advances in genomic technologies have allowed us to interrogate DNA functions from multiple perspectives – such as transcriptomics, proteomics, and epigenomics - across various life forms. However, to gain a holistic understanding of the cellular processes related to the genome, we must overcome the challenge of interpreting data from different modalities. This thesis examines a few examples of how integrating Hi-C, ChIP-seq, and RNA-seq data can reveal biological insights into the spatial structure of Escherichia coli (E. coli) chromosomes. We found that positive and negative supercoiling have different spatial interaction patterns and may contribute differently to genome compaction
ENHANCED RECOVERY AFTER SURGERY AT JOHNS HOPKINS HOSPITAL: A QUANTITATIVE AND QUALITATIVE ANALYSIS OF SURGICAL QUALITY IMPROVEMENT
No full textTheory: There is currently tremendous pressure to improve quality and efficiency in the U.S. healthcare system. Enhanced Recovery after Surgery (ERAS) has been increasingly adopted to reduce length of stay (LOS), surgical site infections (SSIs), and readmissions, especially in colorectal surgery, which is associated with high post-surgical morbidity and cost. In 2014, Johns Hopkins Hospital (JHH) instituted a colorectal ERAS program. It is hypothesized that ERAS implementation will be associated with improved outcomes.
Methods: The dissertation begins with a literature review of the evidentiary support for ERAS implementation and identifies current research gaps. The next manuscript presents a quantitative analysis of outcomes improvement (LOS, SSIs, and readmissions) from a two-year baseline period prior to ERAS implementation at JHH to a six-year follow-up period using techniques ranging from descriptive statistics to multivariate logistic and zero-truncated negative binomial regression. A difference-in-differences analysis is used to compare outcomes at JHH with a national sample of hospitals participating in the National Surgical Quality Improvement Project. The final manuscript is a qualitative evaluation of the ERAS implementation process based on 20 semi-structured clinician interviews to identify facilitators and barriers to implementation using methodology derived from the Consolidated Framework for Implementation Research.
Results: Quantitative findings indicate that, in a pre-post analysis, significant improvements were seen in readmission rates and SSIs at JHH, while improvements to LOS were more modest. In comparison with the national sample, improvements to SSIs were statistically equivalent, readmissions improved more notably at JHH, and LOS improved more significantly in the national sample. The qualitative analysis enabled the identification of key implementation concepts including the selection of an adaptable and evidence-based intervention, the engagement of champions, and the presence of a supportive and compatible culture.
Conclusions: ERAS has been successfully implemented at JHH and is a potentially powerful quality improvement tool for colorectal surgery. Organizations considering ERAS should first assess their local implementation environment and identify specific goals aligned with the components and capabilities of the pathway. Other surgical quality improvement strategies, including the adoption of minimally invasive surgical approaches, may also significantly impact surgical outcomes
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
DESIGN, SYNTHESIS, AND VALIDATION OF GANGLIOSIDE PROBES TO REVEAL GANGLIOSIDE-PROTEIN INTERACTOME
No full textGangliosides are glycosphingolipids that contain one or more sialic acids residues. Gangliosides are present, primarily on cell surfaces of every cell and tissue type in mammals, but are most abundantly found in the brain. In the brain, >90% of ganglioside consist of these four complex gangliosides: GM1, GD1a, GD1b, and GT1b. Gangliosides have been associated with diverse molecular signaling pathways involved in human disease such as cancer, diabetes, neurodegeneration, and many others. Gangliosides regulate cell physiology in normal and disease states through ganglioside-protein interactions. While some of these interactions have been reported, the entirety of the ganglioside-protein interactome has not been fully resolved. There is a strong need for the development of tools to unbiasedly detect ganglioside specific and protein specific interactions at the proteome-wide scale.
Herein, we present the synthesis, delivery, validation, and mass spectrometry proteomics results of bifunctional click and crosslinking ganglioside probes. The synthesis of the bifunctional probes proceeded in few steps with relatively minimal loss. The protocols for synthesizing these probes are adaptable for many diverse gangliosides. The delivery of the probes selectively to outer plasma membrane of mammalian cells in culture was performed with methyl-β-cyclodextrin as a carrier. Fluorescent confocal microscopy with fluorophore-clicked probes reveal distinct membranous staining indicative of successful delivery to the plasma membrane. Finally, gangliosides probes were delivered and crosslinked on the cell surface in two human derived cell lines of interest, the neuroblastoma cell line SH-SY5Y and epidermoid carcinoma cell line A431. Mass spectrometry proteomics of crosslinked ganglioside-proteins revealed over 2,000 protein hits found in our samples. Analyses of these protein pathways revealed diverse networks of cell surface regulation in which gangliosides may be playing a role
EXAMINING HETEROGENEITY OF CELLULAR SENESCENCE WITH MULTIPLEXING IMMUNOLABELING
No full textAging has become an arising prominent problem that has received more and more attention. Cellular senescence is thought to be a key contributor to the aging process. A deeper understanding of cellular senescence could lead to the development of novel therapies to promote healthy aging and prevent or treat age-related diseases. However, cellular senescence is a heterogeneous phenomenon that can vary in terms of its triggers, phenotypes, and functional consequences, which poses a challenge to the development of therapies targeting senescence. Here, we try to reveal the heterogeneity with the single-cell imaging analysis platform and figure out some different subpopulations of senescent cells with morphological characteristics and protein expressions
Institutional Repository Use of Vendor-Based Solutions Relating to Technical Knowledge and Digital Curation
No full textInstitutional repositories (IRs) are digital collections that curate and disseminate the intellectual output of an institution. They play a significant role in the open access movement and in providing access to research and scholarly outputs. Vendor-based systems (VBSs) are a popular option for managing IRs. VBSs offer a number of advantages, including scalability, security, and support. However, they are expensive and require a high degree of technical knowledge for staff to extend the IR collections into digital preservation workflows. This paper examines the impact of VBSs on digital curation and preservation in IRs. The paper begins by providing an overview of IRs and VBSs. It then discusses the benefits and drawbacks of VBSs relating to the executable connectivity for digital curation and preservation by digital librarians. Finally, the paper presents the results of a survey that gauged current technical knowledge and other aspects of those working in the librarian roles of digital curation/preservation, asset management, and institutional repository management of scholarly digital assets. The analysis of the survey suggests several factors that inhibit IRs from utilizing VBSs to their fullest for digital curation and preservation. Overall, a VBS is a valuable tool for digital curation and preservation in IRs if gaps in technical knowledge, increased resources, and stakeholder support are improved
An Interpretable Machine Learning Model to Explore Relationships between Drought Indices and Ecological Drought Impacts in the Cheyenne River Basin, USA
No full textRangeland ecosystems across the United States have significant biological, economic, and cultural value. However, the increasing frequency and severity of droughts across the country may lead to unforeseen impacts on these ecosystems. To address this challenge, this study aimed to identify relationships between drought indices and vegetation health in the
Cheyenne River Basin, USA, using machine learning (ML) and explainable artificial intelligence (XAI) methods. Using Terra Moderate Resolution Imaging Spectroradiometers (MODIS), University of Idaho Gridded Surface Meteorological Dataset (gridMET), and Daymet data, the study employed XGBoost Regressor and Extra Trees Regressor models in unison with SHapley
Additive exPlanations (SHAP) to evaluate predictive performance and the connections between drought indices, environmental variables, and the Normalized Difference Vegetation Index (NDVI). Tests of model performance demonstrated that the XGBoost model performed moderately well at predicting NDVI and was therefore useful for further XAI analysis with SHAP. SHAP explainer results showed that the Palmer Drought Severity Index (PDSI), the 90-day Standardized Precipitation Index (SPI), and snow water equivalent (SWE), were the most important predictors of NDVI values and are therefore closely associated with vegetation health in the study area. The findings of this study first demonstrate the feasibility and usefulness of applying XAI, an underutilized method in the drought space, to study ecological drought indicators. Secondly, results provide an understanding of which commonly used drought indices correlate with effects on vegetation health in the study area, as well as the specific directionality of these relationships. These results can be used to inform drought research and monitoring practices and anticipate ecological drought impacts in the Cheyenne River Basin
“If There Is No Struggle, There Is No Progress”: Industrial Slavery and the Novel in the Late-Abolition Americas
No full textNo Struggle, No Progress’ explores how antislavery authors refashioned the political novel to diagnose the failures of their movement and imagine previously unthinkable resolutions. As the “Age of Revolutions” appeared to pass them by, activist writers in what I term the Late-Abolition Americas – the post-1848 US, Cuba, and Brazil – were faced with an exceptional challenge: how to continue to the fight when the march of human progress, the basis of their politics and worldview, appeared not only to have stalled but drastically reversed course. Far from withering away, a highly-developed racial slavery had consolidated its grip on the Late-Abolition world. Narrative fiction emerged as a crucial space in which to cope with this collective trauma and speculate on future worlds not been foreclosed by the zombie-like persistence of slavery. Starting in the mid-1850s US, my first chapter argues that Harriet Beecher Stowe’s Dred: A Tale of the Dismal Swamp (1856) exploits novelistic conventions such as character system and point of view to stage the death of older antislavery paradigms and consider the maroon commune as a potential vehicle for emancipation and Black citizenship. After the US Civil War, the Cuban independence struggle breaks out in Cuba against a Spanish empire dependent on plantation slavery. In this matrix, Francisco Calcagno’s Romualdo, One of Many (1869) unfolds a bleak counterfactual in which the pursuit of abolition through legal channels is not simply outdated but has always been ineffectual, leaving free and enslaved Blacks no choice but marronage. At the end of the era, hopes for winning black citizenship are transmuted into a reactionary allegory in the Brazilian Joaquim Macedo’s Pai-Raiol, The Conjurer (1869). This text diagnoses Industrial Slavery as a national cancer, but only to ultimately imagine the excision of Afro-Brazilians from the body politic. Rather than the egalitarian multiracial societies imagined by Stowe and others, the post-slavery world at the end of No Struggle, No Progress predicts the anti-Black biopolitics that tragically unite post-abolition Brazil, post-colonial Cuba, and the Jim Crow South
Compressive Capacity of Cold-Formed Steel High Strength Low-Alloy Lipped Channels with Intermediate Stiffeners
No full textWe report herein a set of compression tests on high strength low alloy (HSLA) cold-formed steel steel sections intended for use as piles. The specimens are lipped channels with outer cross-section dimensions of 6 in. wide and 4 in. deep, and include 1 in. lips and feature two intermediate flat hat-shaped stiffeners in the web, one intermediate stiffener in the flange, and return lips. The HSLA employed has a measured mean yield stress of 100.5 ksi and a nominal thickness of 0.075 in. The compression tests were conducted between rigid steel end platens and resulted in highly repeatable strengths at all studied lengths: 12 in., 24 in. and 48 in. Mean peak strength for the shortest 12 in. long specimens was 85.3 kips, followed by 80.1 kips for the 24 in. long specimens, and 74.1 kips for the 48 in. long specimens. Tested strengths were compared to predictions using the Direct Strength Method of AISI S100 and assuming either simply supported or clamped end boundary conditions. Although the test conditions only use end bearing, best agreement is still found when assuming clamped end boundary conditions, mean test-to-predicted ratio is 1.16 assuming simple ends and 0.97 assuming clamped ends. In addition, work to summarize measured geometric imperfections, comparisons against a set of companion tests using advanced high strength sheet steels, and potential future work items are all discussed.Verco Decking, Inc