MEDICA@MUSC (Medical University of South Carolina)
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The Genomics of CHAMP1: Insights into their Cell-Type Specificity and Developmental Trajectories
Get PDFChromosome alignment maintaining phosphoprotein 1(CHAMP1) is a gene that encodes a zinc finger protein that is involved in in the maintenance of kinetochore-microtubule attachment and regulating chromosome segregation in mitosis. (Itoh et al., 2011) CHAMP1 mutations have been shown to be major risk factors for neurodevelopmental disorders (NDDs) and autism spectrum disorder (ASD).(Asakura et al., 2021; Isidor et al., 2016; Levy et al., 2022) Although there is information on the link between CHAMP1 mutations and NDD, the role of CHAMP1 in regulating processes of human cortical development, namely, neurogenesis, proliferation, and electrophysiological properties of newly born neurons, is unknown. This study aimed to investigate the cell type trajectory of CHAMP1 during early stages of human brain development. We hypothesized that CHAMP1 plays a key role in the early stage of human brain development, and we expected CHAMP1 expression to be highly enriched in apical radial glia (aRG) and other proliferative cell types such as outer/basal radial glia (oRG). We also hypothesized that CHAMP1, POGZ, and REV7 are co-expressed. This will be investigated, by using and integrating human forebrain organoids (Uzquiano et al., 2022) and fetal brain tissue (Herring et al., 2022) development single cell omic datasets. We found that CHAMP1 is expressed in aRG as well as other early proliferative cell types. We found that CHAMP1, POGZ, and MAD2L2 follow similar expression patterns via expression plots and percentage of number of cells of the expressed genes
Increasing Engagement and Awareness of Wellness for People with Autism Specturm Disorder and other Intellectual Disabilities with the Piece It Together Program
Get PDFIGF-II Regulates Lysyl Oxidase Propeptide and Mediates its Effects in part via Basic Helix-Loop-Helix E40
No full textProblem Statement:
Pulmonary fibrosis (PF) is a clinically severe and commonly fatal complication of Systemic Sclerosis (SSc). Our group has previously reported profibrotic roles for Insulin-like Growth Factor II (IGF-II) and Lysyl Oxidase (LOX) in SSc-PF.
Approach, Materials, Methods:
We sought to identify downstream regulatory mediators related to IGF-II signaling. In the present work, we show that SSc lung tissues have higher baseline levels of the total (N-glycosylated/unglycosylated) LOX-Propeptide (LOX-PP) than normal lung tissues.
Major Findings:
LOX-PP mediated changes which were consistent with the extracellular matrix (ECM) deregulation implicated in SSc-PF progression. Furthermore, Tolloid-like 1 (TLL1) and Bone Morphogenetic Protein 1 (BMP1), enzymes that can cleave ProLOX to release LOX-PP were increased in SSc lung fibrosis and the bleomycin (BLM)-induced murine lung fibrosis model, respectively. In addition, IGF-II regulated the levels of ProLOX, active LOX, LOX-PP, as well as BMP1 and isoforms of TLL1. The Class E Basic Helix-Loop-Helix protein 40 (BHLHE40) transcription factor localizes to the nucleus in response to IGF-II. BHLHE40 silencing downregulated TLL1 isoforms and LOX-PP and restored significant features of ECM deregulation triggered by IGF-II.
Conclusion:
Our findings indicate that IGF-II, BHLHE40 and LOX-PP may serve as targets of therapeutic intervention to halt SSc-PF progression
Developing Educational Resources for Clinicians and Caregivers to Increase Use of Aquatic-Based Therapy in Occupational Therapy
Get PDFBackground: Aquatic therapy (AT) is a specialized intervention using the medium of water with therapeutic intent toward rehabilitation of specific physical and functional goals (Güeita-Rodríguez et al., 2019). AT benefits include increased joint mobility and muscle flexibility, improved head and neck control, increased attention and eye contact, improved tolerance of physical contact, and sensorimotor integration in the pediatric population (Kucher et al., 2015; Vonder Hulls et al., 2006). Physical therapists and occupational therapists (PT, OT) integrate AT into treatment plans supplemental to traditional practice. Occupational therapists facilitate performance patterns and directly influence children’s occupations of play, leisure, and social participation through integration of meaningful activities in an aquatic environment to ultimately promote functional outcomes. An occupational therapy (OT) doctoral capstone needs assessment identified gaps in knowledge of AT and opportunities for the development of evidenced-based educational resources. The International Classification of Functioning, Disability, and Health (ICF) framework guided the creation of these educational resources to promote client participation in AT programs as a supplement to traditional OT services at an outpatient pediatric therapy clinic. Aim: The purpose of this OT doctoral capstone project was to create educational resources to increase attention, awareness and accessibility of AT among clinicians and caregivers. Methods: Participants of a 10-week aquatic therapy program included 8 pediatric clinicians and 25 clients. Two anonymous REDCap surveys were administered to investigate perceptions, experiences, and knowledge about AT following implementation of project deliverables. Six clinicians and six caregivers completed responses to their respective survey. Results: Clinicians reported primary benefits of AT include sensory processing (100%, n=6), physical/motor development (100%, n=6), and water safety (100%, n=6) skills while caregivers reported benefits in sensory processing (100%, n=6), water safety (100%, n=6), and functional independence/life skills (100%, n=6). All clinicians and caregivers strongly agreed or agreed the resources provided increased their knowledge and understanding of AT. Clinicians strongly agreed or agreed (100%, n=6) they are comfortable explaining the benefits of AT to patient caregivers as a result of this project. Clinicians also reported these educational resources will be helpful to give to caregivers upon referral to AT in the future (100%, n=6). All caregivers strongly agreed (100%, n=6) AT benefits their child in addition to traditional therapy and reported interest in additional AT programs for their child. Conclusion: Evidence-based AT resources were a beneficial addition to the AT clinician training and clinic resource library. Clinicians feel confident referring patients for supplemental AT and have increased knowledge on AT benefits, hydrodynamic properties of water, aquatic sensory integration, equipment use, and treatment ideas. Educational handouts shared with caregivers facilitated understanding of the unique benefits AT provides to children with diverse needs in addition to land-based pediatric therapy.
References
Güeita-Rodríguez, J., Florencio, L. L., Arias-Buría, J. L., Lambeck, J., Fernández-de-Las-Peñas, C., & Palacios-Ceña, D. (2019). Content comparison of aquatic therapy outcome measures for children with neuromuscular and neurodevelopmental disorders using the international classification of functioning, disability, and health. International Journal of Environmental Research and Public Health, 16(21), 4263. https://doi.org/10.3390/ijerph16214263
Kucher, G., Moore, K., Rodia, R., & Szczech Moser, C. (2015). Aquatic therapy for children: Edited by christy szczech moser, PhD, OTR, FAOTA. Journal of Occupational Therapy, Schools & Early Intervention, 8(4), 277-291. https://doi.org/10.1080/19411243.2015.1113104
Vonder Hulls, D. S., Walker, L. K., & Powell, J. M. (2006). Clinicians\u27 perceptions of the benefits of aquatic therapy for young children with autism: A preliminary study. Physical & Occupational Therapy in Pediatrics, 26(1-2), 13-22. https://doi.org/10.1080/J006v26n01_0
HSP27 and GpX1: Important Regulators in Porphyromonas gingivalis-Driven Selective Autophagy in Human Gingival Epithelial Cells
No full textPorphyromonas gingivalis, a major, host-adapted, oral pathobiont, evades canonical host pathogen clearance in human-primary-gingival-epithelial-cells (GECs) by initiating a non-canonical variant of autophagy consisting of Microtubule-associated-protein-1A/1B-light-chain-3 (LC3)-rich replicative autophagosomes. Simultaneously, P. gingivalis inhibits oxidative-stress, including extracellular-ATP (eATP)-mediated reactive-oxygen-species (ROS) production, via phosphorylating Heat-Shock-Protein-27 (HSP27) with the bacterial nucleoside-diphosphate-kinase (Ndk) and via inducing Glutathione-Peroxidase-1 (GpX1) in a glutamine (Gln) metabolism-mediated manner. Here, we have mechanistically identified how the host anti-stress molecules HSP27 and GpX1 abet P. gingivalis’ autophagic survival in GECs. Specifically, we define that P. gingivalis-mediated induction of HSP27 is crucial for the recruitment of the LC3-isoform, LC3C, to drive the formation of live P. gingivalis-containing, Beclin-1-ATG14-rich, autophagosomes that are redox-sensitive and non-degrading. Additionally, HSP27 depletion of infected GECs, accompanied by eATP-treatment, removed protracted Beclin-1-ATG14 partnering and significantly decreased live intracellular P. gingivalis levels. These events were partially restored via treatments with the antioxidant N-acetyl cysteine (NAC), which rescued the cellular redox-environment independent of HSP27. Moreover, the temporal-phosphorylation of HSP27 by the bacterial Ndk resulted in HSP27 tightly binding with LC3C, hindering LC3C canonical-cleavage, extending Beclin-1-ATG14 associations, and halting canonical-autophagosomal-maturation. Separately, P. gingivalis was found to induce GpX1 to partner with LC3C following autophagosomal formation. This partnering induces Akt phosphorylation on Ser473, which then phosphorylated the maturation modulator UV-Radiation-Resistant-Associated-Gene-Protein (UVRAG) to further inhibit canonical maturation of P. gingivalis-specific autophagosomes. Additionally, the negative effects of GpX1 depletion of infected GECs, accompanied by eATP-treatment, reverted when concurrently treated with exogenous-Gln, the major precursor of Gln metabolism, which P. gingivalis also alters to increase Glutathione (GSH) synthesis in GECs. HSP27 and GpX1 depletions of infected GECs and gingiva-mimicking organotypic-culture-systems resulted in the collapse of P. gingivalis-mediated autophagosomes. GpX1-KO mouse models confirmed that the depletion of these host molecules abolished P. gingivalis-induced LC3C-specific autophagic-flux and human-gingival-biopsy-specimens were utilized to reconfirm the pro-bacterial interactions in P. gingivalis-associated periodontitis. These findings pinpoint how HSP27 and GpX1 are influenced by P. gingivalis to pleiotropically serve as major platform-molecules, redox-regulators, and stepwise-modulators of LC3C to mediate pro-bacterial autophagy. Thus, our findings can determine specific molecular strategies for interfering with the host-adapted P. gingivalis’ successful mucosal colonization and oral dysbiosis
The Role of Cellular Senescence in Alzheimer’s Disease Progression
No full textAlzheimer\u27s disease (AD) is a neurodegenerative disorder linked to abnormal protein buildup in the brain and neuroinflammation. Aging is the greatest risk factor for AD, while lifestyle and environmental factors can also contribute to AD pathogenesis. Cellular senescence is a hallmark of aging that has been implicated in AD. However, the mechanisms whereby senescent cells affect brain aging and AD pathogenesis are largely unknown. This study aimed to define the role of cellular senescence in brain aging and AD progression.
We used C57/BL6 (WT) mice to evaluate senescence in healthy brains and 5xFAD mice, a common model used to study AD, to evaluate senescence in AD brains. To assess senescence during healthy brain aging and AD progression, we tested these models at various ages for evaluating senescence and senescence-mediated neuroinflammation. We further depleted senescent cells using the senolytic drug ABT-263 to examine the role of senescence in AD progression. Additionally, we used two models to examine stress-induced senescence in AD: ionizing radiation (IR) and a high-fat diet (HFD).
Our studies confirmed that AD phenotypes exacerbate age-associated cognitive decline and AD progression during aging and that these changes are associated with increased senescence. Removal of senescent cells by senolytic ABT-263 reduced AD pathogenesis. In vitro studies demonstrated that IR induces senescence and promotes the senescence-associated secretory phenotype, which includes pro-inflammatory cytokines, in microglia. A whole-brain IR in vivo model supported these findings. IR-exposed mice exhibited age-associated cognitive deficits in WT mice and AD progression in 5xFAD mice, which were associated with increased senescence-mediated neuroinflammation. Our second model, the HFD, also induced cognitive decline and AD progression, which were associated with increased senescence and other AD-associated features. Metformin mitigated HFD-induced pathological phenotypes in 5xFAD mice. JC10 and MitoSOX red assays revealed that HFD conditions promoted mitochondrial dysfunction and oxidative stress in BV-2 microglia cells, and metformin prevented these HFD-induced changes.
We conclude that age-associated and stress-induced senescence promotes brain aging and AD progression. Additionally, our findings demonstrated that metformin mitigated HFD-induced senescence and AD progression and may do so by preventing mitochondrial dysfunction and oxidative stress, which are major drivers of senescence
Exploring the Intersection of Flourishing and the Social Determinants of Heath Among Medical, Physician Assistant, and Nurse Practitioner Students: A Mixed-Methods Study
No full textBurnout and poor mental health are pervasive among clinical health professions students and are leading causes of attrition. While knowledge about burnout prevention and resilience training continue to grow, there is a significant gap in understanding how students define flourishing and what factors promote flourishing among students. This dissertation is a compendium of five manuscripts. The first is an integrative review of the drivers and barriers of clinical health profession student flourishing that was used to inform the development of an exploratory sequential mixed-methods study resulting in the remaining four manuscripts. Manuscripts two and three explore the use of a novel, self-weighted scoring approach to the Secure Flourish Index that accounts for individual values in the measurement of flourishing. The fourth manuscript explores the relationship between the social determinants of health and student flourishing. The fifth manuscript integrates interview data with the survey results to further explain student perceptions and values of the domains of flourishing accounting for the social determinants of health. The findings from manuscript two shows a difference in mean flourishing when individual values are applied to the domains to create a weighted score as compared to the traditional scoring approach. Manuscript three shows that social and economic needs as well as avoidant coping style are highly negatively correlated with student flourishing. Manuscript four shows that on average, students have at least one unmet social determinant of health need and that students with higher needs are significantly more likely to consider leaving training than those with low needs. Manuscript five shows that students define flourishing in multiple unique ways, however many of these definitions include reference to personal growth, multi-factorial thriving, and a balance between happiness and success. Additionally, students across all levels of SDOH need (no current unmet needs through three or more unmet needs) experience financial stress throughout training and depend largely on their support network for coping with both academic and personal stress. Student’s individual values, intrinsic characteristics, and social and economic needs are all intertwined with their ability to flourish through training and should be considered when developing wellness instruments for screening as well as interventions
Invasive and Non-invasive Pressure-Volume Loop Analysis in Children with Heart Disease: Validation, Clinical Utility in Predicting Outcomes, and Heart Failure Phenotyping
No full textThe most severe form of congenital heart disease includes patients with single right ventricle (SRV) physiology who exhibit 40% mortality by 5 years of age. These patients are all at very high risk for heart failure. Therapies proven to be efficacious in adults do not appear to improve heart failure in SRV patients. The reason behind this disparity is unclear due to inability of investigators to assess the effects of drugs on these patients’ non-invasively. The goals of our research were to develop and validate non-invasive surrogates for contractility, afterload, and ventricular stiffness in children, then, utilize those measures to better understand these patients’ physiology, predict their outcomes, and evaluate drug effects on their cardiovascular system.
We utilized three-dimensional echocardiography and non-invasive blood pressure measurements to develop novel non-invasive assessments contractility and afterload. We validated these measurements against reference-standard measures obtained using invasive microconductance derived pressure-volume loop analysis. We utilized these measurements to assess drug effects in previous SRV clinical trials. We found that heart failure drugs, including enalapril and digoxin, did not change SRV patients’ myocardial mechanics as hypothesized, leading to negative clinical trials.
To assess diastolic function, we utilized spectral Doppler, tissue Doppler, and three-dimensional echocardiography to develop a novel non-invasive assessment of ventricular stiffness and again validated it against the reference-standard. We used this measure to perform the first identification of Fontan patients with high ventricular stiffness with preserved ejection fraction and showed their exercise tolerance was decreased compared to controls and their systolic dysfunction counterparts. We next discovered a novel Fontan phenotype, those patients’ low ventricular stiffness. We showed that these patients had worse outcomes in the post-operative period after all three palliative operations and worse exercise tolerance compared to controls.
We concluded that the non-invasive measures of cardiac mechanics we developed and validated were useful for understanding physiology, predicting outcomes, and determining drug effects in children with congenital heart disease. We utilized these measures to perform novel identifications of both a high stiffness and a low stiffness phenotype in the SRV population. Future studies should validate these phenotypes utilizing invasive assessments and tissue-based studies
Predicting Access Barriers and Facilitators to Pediatric Specialty Care among Children with Complex Chronic Conditions
Get PDFChildren with complex chronic conditions (CCC) face healthcare inequities when accessing pediatric specialty care. Social or economic barriers may exacerbate the challenges faced by families with a child/children with CCC and include increased geographical distance to specialty services, familial poverty, inadequate neighborhood resources, and food insecurity. Understanding how social and economic factors may impact equitable access to care are essential in improving health outcomes for children with CCC. The first manuscript in this compendium is an integrative review focused on the barriers and facilitators of accessing pediatric specialty care for rural dwelling children with CCC. The second manuscript presents a retrospective chart review conducted to understand the impact of neighborhood-level barriers and facilitators on the time from specialty referral to specialty appointment. The third manuscript in this compendium describes a qualitative descriptive assessment using semi-structured key informant interviews with parents of children with CCC in rural South Carolina