Now showing items 1-20 of 13893

    • Characterization of an isoelectric focusing method for detection of IgG oligoclonal banding in paired cerebrospinal fluid and serum specimens

      Hosseini, Saman; Remaley, Alan; Beatty, Phillip; Duh, Show-Hong; Christenson, Robert H. (2024-07-28)
    • Rethinking TCT: A novel role in Bordetella immune evasion

      Rickert, David M.; Himmelberger, Riley; Scanlon, Karen; Goldman, William; Skerry, Ciaran (2024-06-23)
      We aim to identify determinants of inflammatory pathogenesis to guide the development of novel therapeutics to treat pertussis. Single cell and bulk transcriptomic studies identified NOD-like receptor signaling and peptidoglycan recognition proteins (PGLYRPs) as key elements of the hyper-inflammatory response observed in the lungs of B. pertussis infected mice. During peptidoglycan (PGN) recycling, B. pertussis releases a monomeric fragment of PGN called tracheal cytotoxin (TCT), an energy-costly and immune alarming decision. TCT contributes to tracheal cell extrusion and prevention of mucocillary clearance of pertussis, but little is known on TCT’s role in triggering immune responses. We hypothesized that TCT is a critical mediator of the host inflammatory response. To investigate the pathogenesis and immunology of TCT responses, we used a combination of over- and under- TCT releasing mutant strains, reporter assays and knockout mice. Interestingly PGN in the sacculus signals via NOD2 but TCT drives a NOD1 response. The ability of TCT to signal via NOD1 was enhanced by PGLYRP1, revealing a novel role for PGLYRPs in PGN-mediated signaling. We infected wild- type mice with TCT over- and under-producing strains, compared lung pathology and discovered that TCT promoted a less inflammatory NOD1-mediated response, diverting from a more potent NOD2 response, suggesting NOD1/2 play opposing roles in exacerbating lung pathology. These data suggest that TCT polarizes NOD responses towards a less inflammatory NOD1-response. To confirm this, we are actively performing studies in NOD1/2 knockout mice. These findings have exciting implications for pertussis vaccine development, PGN-mediated inflammatory disorders, and development of host-directed therapeutics.

      Keum, Dongil; Foxworthy, William A.; Meredith, M. Alex; Keniston, Leslie P.; Allman, Brian L.; Medina, Alexandre E. (2024-06-22)
      There is compelling evidence suggesting that FASD subjects suffer from sensory stimulus overload and can be easily distracted by unexpected sensory stimuli while trying to focus. Subjects report being uncomfortable and distracted by sensory crowded environments and show hypersensitivity to touch, smell, sound, and light. Our lab have developed a ferret model of FASD in which animals receive 3.5g/Kg of alcohol every other day between P10-P30. Using this model we have shown that developmental alcohol exposure can disrupt organization, plasticity and sensory integration in visual cortical areas. While our lab has demonstrated that developmental alcohol exposure has a major impact in striate and extrastriate visual cortex areas, much less is known about the effects of alcohol in auditory processing regions. We propose that the sensory deficits caused by developmental alcohol exposure are not restricted to visual streams and that aberrant sensory responsiveness and disrupted integrative properties would also be seen in other sensory cortical areas. Here we will present some our preliminary data based on 3 FASD and 3 control animals tested during ferret adolescence. We Investigated auditory-tactile integration in the Lateral Rostral Suprasylvian Sulcus (LRSS) and A1/AAF cortical areas.
    • Purinergic Immunosuppressive Signaling Preserves Treg Stability

      Saxena, Vikas; Shirkey, Marina W.; Piao, Wenji; Wu, Long; Kensiski, Allison; Gavzy, Samuel J.; Pettit, Sarah; Zapas, Greg; Kong, Dehe; Luo, Shunqun; et al. (2024-06-06)
      FOXP3-expressing regulatory T cells (Treg) are crucial for immune balance and tolerance, but they can lose stability, transforming into impaired Foxp3lo Tregs (exTregs), which exacerbate inflammation. Purine metabolites like adenosine and ATP are believed to play critical roles in cellular metabolism and immune responses. We hypothesized their involvement in regulating Treg stability, suggesting that disruptions in purine metabolism might lead to decreased Foxp3 expression
    • Child Support Modifications among New Orders in Maryland

      Passarella, Letitia Logan (2024-04)
      This report examines all 11,549 new orders established in 2010 and follows those new orders through 2019 to determine how many were modified. We found that one quarter (26%) of new orders were modified, and that lower order amounts were less likely to be modified.
    • Temporary Cash Assistance: 2023 Jurisdictional Snapshots

      Smith, Haley; Jackson-Brown, Tristan; Hall, Lauren A.; Passarella, Letitia Logan (2024-05)
      This document includes individual snapshots for each of Maryland’s 24 jurisdictions as well as for the state. The front of each snapshot provides a brief look at every family in a jurisdiction who received TCA in state fiscal year (SFY) 2023. The back of each snapshot provides a summary of a sample of families who left TCA between July 2016 and December 2022.
    • Tumor Microenvironmental and Cell-Intrinsic Mechanisms of Microtubule Stabilization in Breast Cancer

      Stemberger, Megan; Martin, Stuart S. (2024)
      Metastasis accounts for over 90% of breast cancer-associated mortality. Elucidating the pro-metastatic changes that occur within breast tumor cells and the surrounding tumor microenvironment (TME) is imperative for the development of antimetastatic therapies. This dissertation characterizes the effects of elevated H2O2 in the breast TME and cell-intrinsic alterations in the microtubule cytoskeleton for their impact on metastatic potential. H2O2 exposure induces -tubulin detyrosination and acetylation, two markers of poor patient prognosis, via a conserved Ca2+-dependent mechanotransduction pathway. H2O2 induces the formation of microtubule-based microtentacles (McTNs) which are enriched in detyrosinated-tubulin and acetylated-tubulin, but inhibits McTN-mediated functions of cell clustering and reattachment. This dissertation also elucidates the function of specific subsets of microtubules that have been post-translationally detyrosinated in breast cancer. Detyrosinated microtubules may provide an improved therapeutic target compared to current microtubule-stabilizing agents, which indiscriminately target all microtubules and are associated with broad side effects and inadvertently increase metastasis. Leveraging the recent discovery of the tubulin carboxypeptidase (TCP) enzyme, this study demonstrates the feasibility and functionality of lentiviral-based, constitutive TCP overexpression in mammary epithelial cells. TCP overexpression increases detyrosinated-tubulin, which is accompanied by morphological changes and enhanced cellular reattachment and migration. Collectively, this dissertation establishes that H2O2 signals in the TME induce microtubule stabilization and affect metastatic phenotypes, and provides the tools and preliminary data to continue investigating the therapeutic potential of targeting -tubulin detyrosination to reduce breast cancer metastasis.
    • Characterizing HIV-1 Genome Dimerization

      Yasin, Saif; Summer, Michael F. (2024)
      Like nearly all retroviruses, HIV-1 selectively packages two copies of its full-length genome after the formation of a dimer – a process essential not only to packaging but also reverse transcription and recombination. The dimerization process has been found to be mediated by the untranslated region of the HIV-1 transcript, the 5′-Leader, a nearly 400 nucleotide region of the RNA genome that is found to be responsible for regulating RNA fate and function. Structural methods on large RNAs like the dimeric leader (~800 nts) are notoriously limited due to the their inherent flexibility and size; however, more recent methodologies within the Summers lab have allowed us to characterize secondary structure domains within the intact leader. Using these defined structures, we can analyze how different domains of the leader influence RNA function and affect the viral life cycle. The goal of this thesis is to characterize the HIV-1 genomic dimer. We specifically looked at different domains and how they regulate dimerization and subsequent functional processes. We were specifically able to study the function of the 5′-polyadenylation signal, protein coding sequence downstream of the leader, the dimerization initiation site, and the major splice donor. We aimed to characterize processes such as dimerization, packaging, and even translation. Our work also sought to answer a long-standing question about the HIV-1 retroviral lifecycle: how could a single RNA transcript produce protein and also serve as the viral genome? We believe the process relies on the production of two different transcripts with different start sites, which modulate dimerization, but more importantly the structure at the 5′-cap which seems to subsequently dictate RNA fate. Overall, this work highlights the dynamic nature of RNA processes and how small changes in sequence can lead to dramatic changes in the HIV-1 lifecycle. We show that the role of dimerization within the HIV lifecycle is misunderstood, and still requires further characterization to understand how this structure dictates all its necessary functions. Our hope is that understanding the RNA processes involved in HIV-1 replication will allow the development of new therapeutic targets for treatment of the still ongoing HIV epidemic.
    • Recovery Support Services for Opioid Use Disorder in Maryland: A Mixed Methods Study with a Two-Paper Dissertation

      Park, Eunsong; Unick, George Jay (2024)
      The alarming fatality rates associated with opioid use disorder (OUD) in the United States have triggered an increased level of public concern and awareness. Recognizing the urgency of addressing this crisis, adopting a fundamental proactive approach becomes imperative. Offering recovery support services (RSS) for individuals with OUD, in addition to treatment, emerges as a strategic pathway to guide society away from the opioid crisis. This two-paper dissertation is dedicated to comprehensively exploring RSS for individuals with OUD within Maryland. The first paper investigated the provision status of RSS across the local jurisdictions in Maryland. This investigation involved virtual interviews with key informants, examination of pertinent written documents, and online searches. While all jurisdictions had at least one service provider offering services for Mutual Support Groups, Care Coordination/Case Management, Medical Assistance Transportation, Harm Reduction, and Peer Support Services, considerable disparities in provision were observed among the twenty-four jurisdictions for the remaining RSS categories, RCC, WRC, Recovery Housing, Homeless Shelters, and Supported Employment Services. The second paper examined the associations between the provision of RSS, county-level covariates, and opioid overdose admission among jurisdictions in Maryland. In the second paper, the analysis incorporated the provision of RSS, the results from the first paper and secondary data including the Maryland State Emergency Department Database, Healthcare Cost and Utilization Project (2016-2020). Counties with more RSS were positively associated with opioid overdose admissions, compared to counties with fewer RSS. Drug overdose death rate, patient capacity rate, single-parent household rate, and non-Hispanic White rate were also positively associated with opioid overdose admissions. Notably, a significant reduction in opioid overdose admissions was observed in the year 2020 compared to the reference year, 2016.
    • Electromyographic activity and perceived exertion during the performance of a training protocol with internal focus direction in the bench press exercise

      Nascimento, P.H.F.; Lanza, Marcel B.; Andrade, A.G.P.; Caldeira, C.N.; Diniz, R.C.R.; Chagas, M.H.; Lima, F.V (2024-06-26)
    • Differences in Neuromechanical Factors Affecting Explosive Torque Production During Knee Extension: A Preliminary Comparative Study of Males and Females.

      Lanza, Marcel B.; Frakes, Nathan; Lateef, Shabnam; Baghi, Raziyeh; Rao, Sanjana; Zhang, Li-Qun; Gray, Vicki L. (2024-06-26)
    • Saliva Levels of IL-18 in Healthy and Peri-implantitis Patients

      Kachlan, Mamdouh; Masri, Radi, 1975- (2024)
      Title of Thesis: Saliva Levels of IL-18 in healthy and peri-implantitis patients Purpose: Peri-implantitis is a common problem that occurs in 9.25% in functioning implants and approximately 20% of patients. Our understanding of the etiology of Peri-implantitis is limited. Understanding molecular mechanisms associated with peri-implantitis may help in developing and improving treatments for peri-implantitis. The purpose of this study was to assess the levels of IL-18 in saliva of healthy patients and patients diagnosed with peri-implantitis. Materials and Methods: Institutional Review Board approval was obtained. Unstimulated saliva was collected from a total of 24 subjects (peri-implantitis n=14, healthy n=10). Saliva was collected from subjects using 15 ml tubes every minute for 5 minutes. Collected saliva were then centrifuged for 5 minutes at 10,000 x g. The aliquot layer was collected and immediately stored at -80°C until analysis. The concentration level of IL-18 was measured using high-sensitivity enzyme-linked immunoabsorbent assays (ELISA). All statistical analyses were performed using Microsoft® Excel®. Statistical comparisons were tested for normality followed by the Mann Whitney U test. Results: Twenty-four subjects with 33 implants were analyzed. Twenty-two implants were diagnosed with peri-implantitis, while the remaining 11 were healthy controls. The Median values of IL-18 analytes were 1.92 pg/ml for peri-implantitis and 2.23 pg/ml for healthy control. The range was 8.58 pg/ml for peri-implantitis (min 0.079 pg/ml – max 8.66 pg/ml). The range was 21.26 pg/ml for healthy control (min 1.13 pg/ml – max 22.39 pg/ml). The mean was 5.47 pg/ml for healthy control and 2.61 pg/ml for peri-implantitis. The standard deviation was 6.80 pg/ml for healthy control and 2.04 pg/ml for peri-implantitis. Conclusions: In non-smoking patients not suffering from diabetes or other inflammatory disease, it appears that the levels of IL-18 are comparable to those of healthy patients.
    • EAP Evidence: In-Person, Worksite and Online Delivery Options All Are Important to Supporting Workplace Mental Health

      Attridge, Mark (Employee Assistance Professionals Association (EAPA), 2024-06)
      This cover story highlights the fourth installment in the EAP Evidence research series. It continues with a critical analysis of contemporary approaches to providing employee assistance services. New findings are featured from a 2023 survey study (n = 164 EA professionals in a global sample) conducted on the delivery modality options of human in-person, human via technology, and non-human computerized digital tools. Examples of core services within each area were rated for their importance to supporting employer goals concerning workplace mental health. All three kinds of services had a majority of professionals considering it important. Self-service digital tools for employees received the lowest ratings. However, people working at internal staff model EAPs placed more value on workplace service delivery than did people working for external vendor providers of EA services. Major review studies in the research literature are also described to provide context for interpreting the study results.
    • Extra! Extra! Read All About It: A National Dental Survey of the Emergency Room Physician

      Jackson, Courtney Moore; Tordik, Patricia (2024)
      Introduction: Physicians are the first point of contact for patients who present to the ED with dental pain, infection, and trauma. This study determined the Physician's knowledge gap when assessing and rendering care to the ED dental patient. Methods: 81 American College of Emergency Physicians (ACEP) ED physician members were surveyed online using Qualtrics.TM The sample group was questioned about their comfort level when assessed and rendered care for dental pain, infection, and trauma. If satisfied with support when assessed and rendered, Chi-square and Fisher’s exact test analysis was undertaken using contingency tables. Results: The survey associated assessment and rendered care for dental trauma and severe local odontogenic infection. This is influenced by satisfaction with dental education (10x odds more comfortable), years in practice, and ACEP affiliation. Conclusions: This survey presented an opportunity for advancement in physician management of trauma and infection. Continuing medical education courses for ED physicians with dental emergencies could include instruction and guidelines on assessing and rendering care for dental trauma and severe dental disease.
    • Characterization of Pseudomonas aeruginosa lipid A structural variants in cystic fibrosis

      Hofstaedter, Casey; Ernst, Robert K. (2024)
      Pseudomonas aeruginosa is the most common Gram-negative bacteria to cause chronic lung infection in people with cystic fibrosis (pwCF), leading to structural lung damage and progressive pulmonary decline. P. aeruginosa in the CF lung undergoes numerous genetic and phenotypic changes, adapting to the airway environment while establishing chronic infection. The work presented in this thesis characterizes one specific P. aeruginosa adaptation that occurs during CF lung infection: lipid A structural modification. Lipid A is the membrane anchor of lipopolysaccharide (LPS) (i.e., endotoxin), which comprises approximately 75% of the outer membrane of Gram-negative bacteria and is a potent agonist of toll-like receptor (TLR)-4, an innate immune receptor. The structure of P. aeruginosa lipid A is intimately linked with its recognition by TLR4 and the subsequent immune response. We hypothesize that lipid A structural alteration is beneficial for P. aeruginosa survival and pathogenesis by manipulating the host immune response during lung infection. Using a cohort of CF-derived P. aeruginosa isolates, we identify lipid A structural variation in isolates from 20% of pwCF. These lipid A structural alterations are driven by non-synonymous mutations in three lipid A genes: lpxO1, lpxO2, and pagL. We then characterize two P. aeruginosa lipid A enzymes encoded by lpxO1 and lpxO2 that can be mutated during chronic lung infection in CF. These two lipid A enzymes have distinct functions, mediating lipid A 2-hydroxylation in a site-specific manner. We also characterize P. aeruginosa isolates obtained from another inflammatory lung disease, diffuse panbronchiolitis, which result in the synthesis of structurally-distinct lipid A structures, suggesting that lipid A structural variation is not CF-specific. Lastly, we evaluate the impact of P. aeruginosa lipid A structure on host immune recognition and response. In vivo P. aeruginosa lacks PagL-mediated lipid A deacylation, which subsequently induces a stronger cytokine response. P. aeruginosa lipid A that lacks LpxO2-mediated 2-hydroxylation has reduced inflammatory potential, whereas LpxO1-mediated 2-hydroxylation has no measurable impact. This demonstrates distinct roles for each of the lipid A 2-hydroyxlation enzymes during in vivo P. aeruginosa infection. Taken together, P. aeruginosa lipid A structure plays an important role in pathogenesis during lung infection.
    • Comprehensive U.S. Federal Boys’ and Men’s Health Policy: Examining Barriers and Strategies Through a Mixed Methods Policy Delphi

      Gilgoff, Jon; Wagner, Fernando A. (2024)
      Background: Boys’ and men’s poor physical and behavioral health outcomes, as well as social determinants of health, have been extensively researched. Disparities facing marginalized subgroups are particularly severe. Federal U.S. policy responses have been lacking, as has research on policy inaction. This study examined barriers to comprehensive federal boys’ and men’s health policy (CFBMHP), and strategies for policy adoption. Methods: The study engaged a diverse, national, purposive sample of 16 key stakeholders with expertise in health and gender using a two-round mixed methods Policy Delphi. In round one interviews, participants described reasons for the lack of CFBMHP and conditions that would facilitate adoption. After using Braun and Clarke’s reflexive thematic analysis, 46 proposed strategies were presented via survey for assessment by importance and feasibility. Survey data analysis computed means for each strategy and overall themes. Results: Key themes with top-rated strategies by both importance and feasibility were: 1. Getting at the root with structural problems that impede CFBMHP, 2. Addressing bias with strength-based intersectional approaches (Strategy – take a strength-based approach, not just focus on negative things boys and men bring to the table), 3. Increasing societal value of boys’ and men’s health – Addressing patriarchy and “which men?” concerns (Strategies – stress how men’s health benefits women’s, family, and community health; stress that many boys’ and men’s deaths are preventable), 4. Engaging boys and men effectively in health services and advocacy (Strategy – implement regular holistic health check-ups beginning in adolescence), 5. Creating momentum through strategic communication, coalition, and consensus building (Strategy – highlight successes of relevant existing federal policies). The most highly rated themes across importance and feasibility were three and four. Discussion: Greater dialogue among key stakeholders appears needed around issue framing so more see this as a social problem in need of policy action. Clearer commitments to women’s, family, and community health, and addressing health disparities facing marginalized men, may increase policy support. Future research may increase study duration and sample, including impacted boys and men, mirroring multi-year consultation processes undertaken in countries that then enacted comprehensive men’s health policies.
    • Advancing Genetic Studies in Latin American Populations: Enhancing Imputation and Investigating X Chromosome Associations with Alzheimer’s Disease

      French, Jennifer; O'Connor, Timothy D. (2024)
      Estimating genetic risk factors of diseases is challenging in diverse populations underrepresented in genomic studies. Genome-wide association studies (GWAS) are commonly used to discover genetic risk loci associated with health and disease. However, the majority of participants in GWAS are of European descent. These studies rely on imputation and many existing imputation reference panels are largely composed of individuals of European ancestry, resulting in lower imputation quality in underrepresented populations. The studies comprising this dissertation investigate how the composition of imputation reference panels affects imputation quality in four target Latin American cohorts. We achieve this through comparing imputation quality for chromosomes 7 and X when altering the imputation reference panel by: 1) increasing the number of Latin American individuals; 2) excluding either Latin American, African, or European individuals, or 3) increasing the Indigenous American (IA) admixture proportions of included Latin Americans. We found that increasing the number of Latin Americans in the reference panel improved imputation quality in the four cohorts; however, for some there were differences between chromosomes 7 and X. Finally, increasing Indigenous American (IA)-like admixture proportions in the reference panel increased imputation quality at different levels in the populations. The difference in imputation results between populations and chromosomes suggests that existing and future reference panels containing Latin American individuals are likely to perform differently in different Latin American populations, consistent with what we know of the varying population structure and ancestry proportions of the Latin Americans. As a further investigation, we imputed 87,393 variants on the X chromosome for 49,405 Latin American individuals and conducted a GWAS and X chromosome-wide association study (XWAS) in a Caribbean cohort. We identified 3 autosomal and 17 X-chromosome variants significantly associated with Alzheimer’s disease. Future studies are required to replicate X chromosome findings and include more robust X chromosome data for more diverse Latin American populations. This work highlights the importance of not treating Latin Americans as a homogenous population and taking population structure and the X chromosome into account when studying these populations.
    • Defining the Role of SLC35A2 in Cortical Development and Epilepsy

      Elziny, Soad; Crino, Peter B. (2024)
      Epilepsy is a common neurological disorder (3.4 million adults and 470,000 children) defined by recurrent seizures. Medically intractable (drug resistant) epilepsy affects approximately one-third of adults and 20-25% of children. Intractable epilepsy is often the result of germline gene mutations e.g., ion channels, kinases, neurotransmitter receptor subunits, identified in patient blood. Interestingly, recent studies have revealed somatic mosaicism associated with epilepsy in which variants are focally present in a subset of brain cells and cause epilepsy-associated focal malformations of cortical development (MCD). SLC35A2, was recently identified in a substantial fraction focal cortical dysplasia type 1a specimens. SLC35A2 encodes UGT-1, a transmembrane UDP-galactose transporter that facilitates movement of UDP-galactose from the cytosol to the lumen of the Golgi apparatus. Further, the variant allele frequency (VAF) in somatic SLC35A2 patients appears to correlate with severity in phenotype i.e., higher allelic burden is associated with greater morbidity. Patients exhibit a range of phenotypes including MRI confirmed FCD, intractable seizures, and intellectual disability. Germline variants in SLC35A2 are categorized under congenital disorders of glycosylation (CDG) and are implicated in an X-linked developmental and epileptic encephalopathy. All pathogenic variants, both somatic and germline, prevent UDP-galactose from being transported across the Golgi membrane and thus lead to aberrant glycosylated proteoglycans. Solute carrier families (SLCs) are the largest family of transmembrane transporters of sugars and a portion of these genes are implicated in epilepsy, neurodegenerative diseases, and autism spectrum disorder. To date, no study has addressed the effects of SLC35A2 knockout (KO) on neuronal morphology, protein glycosylation, or cortical lamination in a mouse model despite SLC35A2 mutations being recognized as a common cause of drug resistant epilepsy. I hypothesize that Slc35a2 KO results in disrupted neuronal Golgi structure, aberrant dendritic arborization, altered glycosylation profiles, aberrant cortical lamination, and disrupted network integrity. I will test this hypothesis under 4 specific aims: 1) To define the consequences of Slc35a2 KO in vitro on Golgi structure and dendritic arborization, 2) To demonstrate that Slc35a2 KO results in aberrant glycosylation profiles in mouse neurons, 3) To demonstrate that Slc35a2 KO in vivo alters cortical lamination and network integrity in mice using in utero electroporation, and 4) To establish 2 conditional KO (cKO) mouse lines of Slc35a2 and demonstrate that they alter cortical architecture and network integrity.
    • Sex-Dependent Differences in Alcohol-Induced Alpha-Tubulin Acetylation in Different Regions of the Mouse Brain

      Elesinnla, Abosede; Kristian, Tibor (2024)
      Downstream products of alcohol metabolism can impact the level of acetylated alpha-tubulin through the production of acetyl-CoA and the effects of acetylase alpha-tubulin N acetyltransferase1 (ATAT1) and deacetylase histone deacetylase6 (HDAC6) expressions. To determine the impact of ethanol intake on the modulation of tubulin acetylation in the brain, we administered ethanol to mice for different durations and examined their brain tissues. We used wild-type and HDAC6 null adult male and female mice. The control groups received PBS, and the treatment groups received ethanol (20% in PBS, 2g/kg) intraperitoneally. We analyzed the acetyl-CoA and CoA metabolites using high-performance liquid-chromatography (HPLC) methods. Furthermore, we determined changes in the acetylated alpha-tubulin levels and the enzymes regulating alpha-tubulin acetylation by western blots. We observed sex-related changes in the ethanol-induced hyperacetylation of alpha-tubulin in mice cerebellum and hippocampus. These differences can be attributed to the changes in the ethanol-induced expression levels of the acetylase/deacetylase enzymes.