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Molecular changes in alveolar epithelial cells during influenza virus infection
No full textAnnual influenza virus infection represents a concern for public health and a financial burden as it results in approximately 500,000 deaths and 5,000,000 hospitalizations as reported by the World Health Organization (WHO). Influenza virus infection begins with the attachment and entry of alveolar epithelial cells within the respiratory tract of susceptible hosts. During infection, influenza virus hijacks the cellular machinery in order to replicate its genome and produce new progeny virions to spread the infection. As not all alveolar epithelial cells are infected during influenza virus replication, we queried what the transcriptomic differences were between directly infected epithelial cells compared to bystander uninfected epithelial cells isolated from mice at day three post infection with a green fluorescent protein expressing A/Puerto Rico/8/1934 influenza virus. Using RNA sequencing, we identified the downregulation of Wnt signaling during influenza virus infection and our studies suggest that this might be a host response to initiate repair mechanisms necessary to restore lung function. We have also identified a novel transcript, Heatr9 that we found to be upregulated following influenza virus infection and whose expression plays a role in chemokine ligand induction and release. Beyond differences in protein coding genes, we also show that the long noncoding RNA profile of influenza virus infected epithelial cells is unique and that Zfas1, a long noncoding RNA found to be induced following influenza virus infection, plays a role in preventing apoptosis, a mechanism that may benefit viral replication in vivo in the highly inflammatory environment of the lung. These studies demonstrate the novel effects of direct influenza virus infection compared to mere exposure to an inflammatory environment and offer a platform for future studies to explore the specific pathways and interactions between influenza virus and host cells.Ph.D., Microbiology and Immunology -- Drexel University, 201
Computational Modeling of a Geometrically Tunable Blood Shunt for Norwood Recipients
No full textThe low availability of suitable heart transplants requires the use of palliative treatments for infants with severe congenital heart defects. Out of every 10,000 live births, 2-4 infants have a severe form of congenital heart defect characterized by a single functional ventricle. In order to survive, these infants require the first of a series of palliative surgeries---the Norwood procedure---within hours or days after birth. The modified Blalock-Taussig shunt (MBTS) is one type of shunt used in the Norwood procedure to redirect blood flow. With this shunt, the single functional ventricle performs the work of two ventricles. The proper growth and development of the infant depends on a delicate balance of blood flow between the body and the lungs, the ratio of which is determined by the size, orientation, and conditions of the shunt. A model of the MBTS in a neonatal aortic arch is developed and evaluated using computational fluid dynamics. Parameters are modified individually to study their effect in steady-state, including multiple shunt geometries and a range of physiological conditions. Additionally, time-variant simulations are conducted to simulate the dynamics over the duration of a heartbeat. In comparison to a model of the healthy anatomy, the MBTS model creates more complex fluid patterns that have higher amounts of shear stress. These factors indicate less overall cardiac efficiency. Variations to the shunt diameter are used to validate the model against well-established concepts. Geometry variations with additional curvature and flaring had more pulmonary flow, which suggested more favorable uniform flow behaviors. Results of the physiological variations connect the significance of low cardiac output with blood oxygenation and poor clinical outcomes. The impact of moderate shunt dysfunction is found to be relatively minor. The inlet behavior of the time-variant simulations corresponds to a neonatal heartbeat, but the results do not mimic realistic fluid behavior over the entire duration because of limitations in the boundary conditions.M.S., Biomedical Engineering -- Drexel University, 201
Data-driven Whole Building Energy Forecasting Model for Data Predictive Control
No full textIn the United States, the buildings sector accounted for about 41% of primary energy consumption. Building control and operation strategies have a great impact on building energy efficiency and the development of building-grid integration. Model predictive control (MPC) has received extensive attention from researchers in the field of whole building control and operation strategies. To develop MPC for whole building control and operation, high-fidelity building energy forecasting model is one of the most critical components. Data-driven energy forecasting model is typically developed using statistical methods to capture the relationship between building energy consumption and collected building data, such as operation data. MPC built with a data-driven model is also termed as data predictive control (DPC). Due to the surge of machine learning and the advances of building automation system (BAS), data-driven energy forecasting model and DPC for building control are increasingly studied in academia and applied in industry. However, three gaps impede the development of high-fidelity and cost-effective data-driven building energy forecasting models and predictive control strategies: Gap 1: Active learning, the key to defy data bias in building operation data, is hardly studied and applied to the area of data-driven building energy forecasting modeling; Gap 2: Feature selection to defy high data dimensionality is widely applied to building energy modeling process but there lacks a systematic and scalable methodology; Gap 3: Active learning and feature selection have not been systematically integrated for whole building DPC application. In this dissertation, to address the three gaps mentioned above, three research objectives are proposed: Objective 1: Develop active learning strategies in the application of data-driven building energy forecasting modeling to defy data bias; Objective 2: Develop a systematic feature selection procedure in the application of data-driven building energy forecasting modeling to defy high data dimensionality; Objective 3: Develop an integrated active learning and feature selection framework for data-driven building energy forecasting modeling used for whole building DPC application. In this thesis, the integrated framework of active learning and feature selection is developed to improve the performance of data-driven building energy forecasting modeling that can be used for future DPC applications. The framework provides a systematic methodology and automatic workflow that starts with collecting raw data from BAS to the establishment of data-driven energy models and DPC controllers. The developed strategies and framework are evaluated in a number of virtual and real building testbeds. Improved performance is observed from the building energy forecasting models built using the developed active learning strategy, systematic feature selection procedure, and integrated framework of active learning and feature selection, respectively. A DPC controller is also developed using an energy forecasting model built with the developed framework. Using virtual testbeds, the developed DPC controller is demonstrated to have better performance, in terms of total electricity cost, peak load shifting capability, and average CPU time, which further shows the effectiveness of the developed framework.Ph.D., Architectural Engineering -- Drexel University, 201
The Impacts of Kindergarten Transition
No full textCurrent national practices demand that public educators demonstrate accountability for academic achievement for all PK through 12th grade students. These high demands make it necessary for children to enter kindergarten prepared for the social, emotional, and academic requirements placed on them. The purpose of this qualitative research descriptive case study was to determine how kindergarten transition and screening assessments are used to help serve children's academic needs as they enter kindergarten. This study examined the importance of kindergarten readiness and how the kindergarten transition process prepares children for kindergarten. This research study explored the value of, and uses for, pre-kindergarten screening assessments. This research is important to parents, teachers, administrators, pre-school providers and policy-makers as it informs the benefits and challenges of providing a quality pre-school experience for all four-year-old children as preparation to more formal schooling. This research study answered the following questions: 1) How do parents use information from kindergarten transition activities and screening assessments to help prepare their children for kindergarten? 2) What transition activities do teachers believe are most beneficial in preparing children for kindergarten? 3) How is information from kindergarten screening exams used to help children attain academic success in kindergarten? 4) What challenges do parents, teachers, and administrators overcome in order to help children prepare for kindergarten? This qualitative research descriptive case study highlights the need for kindergarten readiness. The study demonstrates how activities designed to increase kindergarten readiness help children become more successful in the academic setting. This study focuses on the question of what factors influence kindergarten readiness. This research gives teachers and administrators ideas for interventions for students who experience difficulty with academic material upon entering school. This research provides information on how to interpret the results of kindergarten screening assessments. This study provides educators and parents many different best practices for applying the knowledge gained from kindergarten screening assessments at home and in the classroom. The findings from this qualitative research study demonstrate that parents, teachers and administrators value the variety of transition activities offered to their children. The results suggest that transition events and the screening assessment help children become prepared for the academic, social, and emotional demands of kindergarten. The findings demonstrate the need to provide quality opportunities for transition of children entering school for the first time.Ed.D., Educational Leadership and Management -- Drexel University, 201
Analysis of Genomic Structures Involved in 22q Deletion Syndrome
No full textThe 22q11.2 Deletion Syndrome (22q11DS) is a congenital malformation disorder and the most frequent microdeletion syndrome in humans [1]. It has a prevalence of 1 in every 3000 live births [1,2] and 1 in every 1000 pregnancies [3]. Significant medical issues afflict affected individuals. Medical issues may include: congenital cardiac defects (~75%), immune deficiencies, speech/language defects, intellectual disabilities, and a 25-30% risk for developing schizophrenia in adolescence or adulthood [2]. The causative deletion of 22q11DS occurs as a de novo event in meiosis and 90% of affected individuals have a hemizygous 3 million base pair (Mbp) deletion in the chromosome 22q11.2 region [2]. The mechanism responsible for the deletion is non-allelic homologous recombination (NAHR) between surrounding low copy repeats, specific to chromosome 22 (LCR22s) [4,5]. There are 8 LCRs on chromosome 22, labeled alphabetically from LCRA to LCRH from centromere to telomere on the long (q) arm [5]. The LCR22s are comprised of sequence modules of varying lengths containing interspersed genes and pseudogenes. Sequence analysis of these modules reveal a complex organization of duplicated modules. The most frequent ~3Mbp deletion is immediately flanked by LCRA and LCRD, two of the largest LCR22s at approximately 240kbp each [2,5,9]. LCRA and LCRD consist of a direct, highly homologous (>99% sequence identity) 160kbp repeat [6,9,10]. The combination of large, near-identical segments makes the LCR22s substrates in non-allelic homologous recombination (NAHR), leading to genomic rearrangements. Unfortunately, these characteristics also make the LCR22s difficult to reliably sequence and identify rearrangement breakpoints within the homologous chromosome 22 LCRs in individuals with 22q11DS. While significant progress has been made toward elucidating genomic structures of 22q11.2 and mechanisms involved in leading to the causative deletion, any predisposing structures and the exact location of deletion breakpoints remain unknown. Currently, there is no complete and specific model of the NAHR mechanism. Such a model would require completely contiguous LCR22 modules on each chromosome 22 homolog in the parent containing the homologous recombination, along with the resulting 22q11.2 deletion-containing haplotype within this parent's 22q11DS proband. Numerous genomic disorders arise from NAHR of LCRs specific to other chromosomes [6,7,8]. Predisposition to Williams-Beuren syndrome [11] and 16p12.1 microdeletions [12] has been linked to copy number variation of subunits within LCRs. Copy number variation in LCR22 modules has yet to be linked to predisposition to 22q11DS, as the complex arrangement and large size of the LCR22s has made the identification of any NAHR-driving sequences difficult. To complicate matters, the last two human genome reference assembly builds, hg19 (GRCh37) and hg38 (GRCh38.p11), contain large gaps in sequence, predominantly in LCRA. Additionally, LCRB contains an AT-rich palindrome in the center of its mapped location, leaving mischaracterized sequence [13,14]. The sum of gaps, large identical stretches of sequence modules, tandem repeats, and variants of all classes and sizes makes it difficult to define where chromosomal breakage and exchange occurs leading to the 3Mbp deletion. These same characteristics hamper identification of any specific LCR22 configurations responsible that might lead to increased risk for NAHR. Duplicate modules in LCRs are assigned orientations based on the orientation of the module in the human genome reference and typically, the "forward" or "direct" orientation is denoted from the reference module. Flanking LCRs with inverted modules may influence inter- or intrachromosomal rearrangements creating inversion polymorphisms [15,16]. If present, inversions can hamper the meiotic pairing of homologous chromosomes and are predisposing factors in NAHR [19]. Additionally, variations in LCR22s may influence NAHR events but a larger cohort of individuals is required for confirmation of this association [21]. It is possible that any combination of inversions and/or other variants predispose to the events leading to NAHR, highlighting the importance of large-scale population-based studies exhaustively detailing every aspect of the 22q11.2 region. The remaining issues in the 22q11DS region cannot be solved with current sequencing technologies. While whole-genome NGS approaches have enabled thousands of human genomes to be sequenced, the technologies are still not sufficient to completely sequence a whole genome end-to-end revealing phased chromosomes, without leaving gaps in structurally complex regions. Combinations of genome mapping and phased sequencing technologies have shown promising results in previous studies but have yet to be applied to as complex a region as 22q11.2. With the current state of whole-genome approaches, optimizing complementary mapping and sequencing technologies to resolve structural variations in this extremely complex region of the genome while discerning parental origin, will provide an innovative and comprehensive approach to understanding the mechanism giving rise to the 22q11DS. Here the development of a comprehensive whole-genome approach is described, leveraging the increased sensitivity afforded by long single molecule optical mapping on nanochannel arrays coupled with 10xGenomics (10xG) Linked-Read whole-genome sequencing and the CRISPR-Cas9 labeling system. This combination of technologies, along with novel informatics approaches, will elucidate the previously unmapped structure and variation of the chromosome 22 LCRs and surrounding regions. This will provide enhanced insight into the role of variable genetic structures in producing 22q11DS and its associated phenotypes. Our lab's preliminary studies show variability in LCR22 structures that have never been observed before taking place via the 160kbp modules. Typical sequencing approaches fail because the 160kbp modules cause read pile-ups and are not able to discriminate between LCRA- and LCRD-specific sequences. The proposed approach may determine if specific haplotypes predominate in the parent-of-deletion-origin. This approach will likely represent a paradigm, providing resources for the analysis of numerous other significant regions of the genome that have failed accurate detection because of the presence and complexity of other LCRs, many of which cause disease. The added advantage of mapping as an upfront technology to drive sequencing is observed in its high-throughput nature. One can map whole human genomes in less than one week. This enables fast and efficient use of time in determining large-scale structures of LCR22s. Using this information, assembled and/or mapped sequence data may be placed to the proper high-homology LCR22 modules. The coordinates of the deletion breakpoint may be honed-in on, by using three different methods. First, nucleotide differences between LCR22-specific modules in 22q11.2 may be identified and optically mapped using targeted gRNAs using the CRISPR-Cas9 labeling system. To obtain sequence-based information and changes from the reference genome, the medium-range heterozygous variant linking ability of 10xG allows for the crossing from accessible and known mapped regions into unknown, highly-repetitive regions. Finally, label polymorphisms between repeat copies in the 22q11.2, of which may be detected using the DLE-1 optical mapping labeling system, are used to distinguish individual duplicons. By incorporating these methods, the complex configurations in 22q11.2 were disentangled and locally contiguous haplotypes were produced per LCR22 region. Using this information, insight into the genetic mechanisms involved in recombination leading to the predominant 22q11.2 deletion was gained. Overall, this work has resulted in the production of effective mapping and sequencing approaches for use in other difficult to analyze genomic regions and for the eventual creation of pre-diagnostic tests that might potentially aid in preconception screening for 22q11DS risk. This platform has many advantages over the systematic use and expense of current sequencing technologies, which fail to resolve the 22q11.2 region altogether. Using our methods, NAHR has been observed for the first time and may be applied to future genomes, enabling the direct observation of genomic structures participating in NAHR leading to the 22q11.2 deletion.Ph.D., Biomedical Science -- Drexel University, 201
Role of Meniscus Micromechanics in Joint Function and Osteoarthritis
No full textThe meniscus, a crescent-shaped fibrocartilage located between the femur and tibia ends of the knee, is an essential component of knee joint, responsible for stability, load transmission and lubrication. The unique biomechanical function of the meniscus is endowed by its hierarchically structured extracellular matrix (ECM). The knee meniscus has very limited self-healing capabilities, especially in the inner avascular, proteoglycan-rich zone. Currently, the mechanical knowledge of meniscus is mostly limited to the tissue level, so it is unclear how such unique ECM structure across multiple length scales endows the tissue with its specialized mechanical properties. The first part of the dissertation studied the anisotropy and heterogeneity of the micromechanical properties of the meniscus ECM in normal joint function as well as during maturation by using innovative atomic force microscopy (AFM) based nanomechanical tools. The systematic structure-mechanics understanding of the meniscus can serve as benchmark for understanding meniscus biomechanical function, documenting disease progression and designing tissue repair strategies. Injuries in the meniscus often lead to the development of post-traumatic osteoarthritis (PTOA) which is the most prevalent form of osteoarthritis (OA) among the younger population. Among different types of PTOA repair and amelioration, small molecule treatment has been considered as one target since it plays a critical role not only in signaling pathway, but also in extracellular matrix. The second part of the dissertation was to investigate the role of decorin, a major small leucine rich proteoglycan (SLPR), in meniscus dysfunction induced PTOA progression. After destabilization of medial meniscus (DMM) surgery, decorin knockout mice underwent accelerated aggrecan loss and cartilage damage, signifying increased susceptibility to OA. Since decorin and biglycan are two structurally similar SLRPs, the inducible knockout of decorin / biglycan or both has been studied to delineate the roles of decorin and biglycan during OA progression. By using the inducible knockout mice, mice can develop normally before the surgery, thus the decorin's role during OA progression can be isolated from biological development. By deleting decorin or biglycan expression at the time of DMM surgery, decorin appears to play a more dominating role than biglycan, as illustrated by its more severe phenotype in inducible knockout model and elevated expression in wild type cartilage under OA condition. These results underlined decorin for serving as an indispensable constituent to the structural and functional integrity of cartilage ECM, and set a basis for developing decorin-based cartilage regeneration and repair strategies.Ph.D., Biomedical Science -- Drexel University, 201
Potential of the flavonoid Apigenin in regulating immune cell functions during neuroinflammation in a RelB-dependent manner
No full textApigenin, a well-documented health promoting agent, belongs to a group of low-molecular weight phyto-pigments called flavonoids that are present ubiquitously in a variety of plants, vegetables and herbs. The chemo-protective effects of Apigenin can be largely attributed towards its anti-inflammatory properties that have been studied in various cell types including the cells of the immune system such as dendritic cells (DCs). DCs are the most potent antigen presenting cells that form an important link between the innate and adaptive branches of the immune system through their ability to capture and present both pathogens and self-antigens and initiate either an immunogenic or tolerogenic response. Any dysregulation in this function causes an immune imbalance leading to disorders that are specially devastating in immune privileged location like the central nervous system. In order to establish the potential utility of Apigenin as a therapeutic agent against neuroinflammatory diseases, we tested and found that Apigenin treatment ameliorated disease severity, progression and relapse of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 and SJL mouse models of multiple sclerosis. An increased retention of DCs and other myeloid cells in the periphery correlated with decreased immune cell infiltration and reduced demyelination in the treated mice. Apigenin possibly exerts its effects through shifting the DC modulated T-cell responses from Th1 and Th17 type towards Th2 and Treg directed responses evident through the decrease in T-bet, IFN-γ (Th1), IL-17 (Th17) and increase in IL-4 (Th2), IL-10, TGF-β and FoxP3 (Treg) expression. Mechanistically, Apigenin treatment reduced cytoplasmic RelB expression in presence of LPS in human peripheral blood DCs, which is central to DC maturation, its antigen presentation capabilities and DC-mediated T cell activation. TNF-α, CD40, and IL-23, downstream targets of RelB were also reduced upon Apigenin treatment in these cells. These results provide key information about the molecular events controlled by Apigenin in its regulation of DC activity marking its potential as a therapy for neuroinflammatory disease.Ph.D., Biomedical Science -- Drexel University, 201
The New Age of Stigma and Social Support: A Mixed-Methods Analysis of Social Media Communication about Mental Health
No full textBackground/Purpose: Mental illness is highly stigmatized and viewed negatively by the public. Stigma is associated with several poor health outcomes for persons living with mental illness, which can be mitigated through social support. Media exposure shapes the public’s knowledge, attitudes, and beliefs. Therefore, people may develop stigmatizing attitudes through media exposure. Studies of mental illness stigma have historically focused on traditional media, such as print news, which often perpetuate stigma. The purpose of this dissertation is to provide novel methods through which to examine mental illness stigma and social support by exploring these topics across multiple social media platforms. Methodology: This dissertation employed Twitter, Instagram, and qualitative interview data to explore mental illness stigma and social support through current events, geographic location, and responses to the culture of social media. This mixed-methods approach used content analysis of social media and qualitative interview data, as well as machine learning techniques, to describe the ways in which stigma and social support manifest on these platforms. Results: We found that social media content contained both overt and covert mental illness stigma and that some of this stigma was counteracted by displays of social support, which were prominent during high volume communication periods on social media. However, stigma on social media demonstrated a potential to be internalized as self-stigma, which was shown to be discouraging to support-seeking on these platforms. Conclusions: This research demonstrates the need for mental health advocacy on social media at both the individual and organizational levels. Considering these findings, advocates should mobilize on social media during current events related to mental health. Advocacy should be defined by stigma reduction, displays of social support, and encouragement of support seeking on these platforms.Dr.P.H., Community Health and Prevention -- Drexel University, 201
The Role of Store-Operated Calcium Channels in Peripheral Sensitization
No full textChronic pain is a common and debilitating condition that afflicts more than 100 million Americans and is often poorly managed. Peripheral and central sensitization processes are believed to play key roles in the pathogenesis of chronic pain. However, candidate molecules involved in these processes remain unclear. Store-operated calcium channels (SOCs) are highly calcium-selective channels mediating calcium entry in various cell types. We have reported that SOC inhibition by YM-58483 attenuates chronic pain. Our previous study showed that SOCs are expressed in dorsal horn neurons and play a critical role in central sensitization. However, it remains elusive whether SOCs contribute to peripheral sensitization. Here we demonstrate that SOCs are expressed in dorsal root ganglion (DRG) neurons and that both STIM1 and STIM2 are important components mediating SOC entry (SOCE). While Orai1 is the only subunit mediating SOCE in most cell types, we found that Orai1 and Orai3 are responsible for SOCE in DRG neurons. Importantly, SOC activation by thapsigargin increases neuronal excitability, which is abolished by double knockdown of Orai1/3. To further determine the peripheral mechanisms of SOCs in inflammatory pain, we generated carrageenan- and CFA-induced pain models and found that Orai1 is involved in carrageenan- and CFA-induced inflammatory pain. Moreover, we demonstrate that SOC function in DRG neurons is potentiated by PGE2, an important inflammatory mediator, which was mediated through EP1 and its downstream PKC cascade. Orai1 deficiency completely abolished PGE2-induced SOCE increase in DRG neurons. Consistently, PGE2-induced pain hypersensitivity is significantly attenuated in Orai1KO mice compared with wildtype littermates. Taken together, our findings suggest that SOCs exert an excitatory action in DRG neurons and are important in peripheral sensitization during chronic pain. Our study also provides new insights into how PGE2 mediates inflammatory pain.Ph.D., Pharmacology and Physiology -- Drexel University, 201
The Impact of Autism Traits and Psychosis Traits on Mentalizing in Individuals with and without Autism Spectrum Disorder
No full textDisruptions in social processes cause significant impairment in autism spectrum disorder (ASD) and psychotic spectrum disorders (PSDs; Chisholm, Lin, Abu-Akel, & Wood, 2015). These conditions share aspects of behavioral expressions and genetic and environmental risk factors. Furthermore, the behaviors and cognitive styles that characterize ASD and PSDs are conceptualized as dimensional traits (autism traits and psychosis traits, respectively) present in the general population at non-clinical levels (i.e., levels that do not cause impairments in everyday functioning). One specific social cognitive process disrupted in ASD and PSDs is mentalizing - an ability that is important for the perception and understanding of others (Crespi & Badcock, 2008). Relative levels of autism traits and psychosis traits within individuals are potentially useful for understanding intact and impaired mentalizing. In individuals without clinical diagnoses, high levels of both autism traits and psychosis traits produce a "normalizing" effect on mentalizing performance, such that individuals with high levels of both sets of traits performed similarly to individuals with low levels of traits (Abu-Akel, Wood, Hansen, & Apperly, 2015). However, it is unknown whether this normalizing effect extends to individuals with clinical conditions, and such knowledge will be useful for understanding the nature of social functioning across conditions. The current study embraced a dimensional transdiagnostic approach by examining self-reported autism traits, psychosis traits, and mentalizing accuracy and levels of mentalizing in 76 adolescents and young adults with (n = 32) and without (n = 44) ASD. We hypothesized that each set of traits would negatively affect performance on the mentalizing tasks (i.e., high levels of either autism traits or psychosis traits would be related to less accurate mental state attributions and more atypical levels of mentalizing) and that concordant levels of both sets of traits (i.e., both low or both high) would be associated with a normalizing effect on mentalizing. Results showed a negative main effect of autism traits on mentalizing accuracy but not on mentalizing levels. Psychosis traits were not associated with either mentalizing accuracy or levels. Contrary to our hypothesis, we found an enhancing negative effect of concordant high levels of autism traits and psychosis traits on mentalizing levels, such that as levels of both sets of traits increased, mentalizing levels decreased. We found a similar enhancing negative effect of traits on mentalizing accuracy; however, this result did not reach statistical significance. Results from this study contribute to the conceptualization of psychopathology as arising from combinations of dimensional traits within individuals and may inform the personalization of social cognition interventions for individuals with distinct profiles of traits.Ph.D., Psychology -- Drexel University, 201