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From Cowboy-Astronaut-Rockstar to Family Medicine
Get PDFThe author submitted this entry in the Creative Non-Fiction category (Amateur division) for the 2025 On My Own Time™ (OMOT) Art Show.Self-reflection on the meaning behind a common childhood dream career
Development of the Multicultural Curriculum Appraisal (MCCA): A Process to Promote Multicultural Infusion into APA Accredited Doctoral Program Curriculum
Get PDFThe current American Psychological Association's standard for Diversity Education and Training in doctoral-level accredited Health Service Psychology programs is sparce and lacks a measurable expectation of programs. There is no published research on broad application or outcomes of this standard across Health Service Psychology curricula. To address any variation in the interpretation of the diversity education and training standard, we created an audit tool, the Multicultural Curriculum Appraisal (MCCA) Tool, to capture the amount of multicultural education and training present in today's psychology programs. One important step is to understand the how much multicultural content psychology instructors are incorporating into their course syllabi. Another essential step is to identify the areas, within a syllabus, that contain multicultural content. Lastly, it is critical to understand any potential barriers to multicultural infusion identified by psychology instructors. Our study surveyed doctoral level instructors (n=55) and audited their course syllabi (n=92). The primary aim was to explore the influence of instructor identity on the amount of multicultural content in a course. We expected instructors who identified with historically marginalized groups to have more multicultural infusion into their courses. This studies secondary aim examined barriers to multicultural infusion using three types of barriers: institutional, instructor and student. We anticipated participants who identified instructor barriers to have lower scores than participants who selected other barrier types. Contrary to expectations, participants with marginalized identities and those who selected instructor barriers did not have significantly different scores than their peers. Participants who were trained as counseling psychologists, taught at counseling psychology programs, were younger, ranked themselves lower on a national subjective socioeconomic scale, and in the early career stage demonstrated higher scores on the Multicultural Curriculum Appraisal. Additionally, participants who identified institutional barriers also demonstrated higher scores on the Multicultural Curriculum Appraisal. This study lays the groundwork for future research designed to better understand and correct for the variation between instructors, academic programs, and psychology disciplines and understand the potential influences of instructor identity and barriers in multicultural education and training in psychology curricula
Please Die in the Sun
Get PDFThe author submitted this entry in the Open Verse Poetry category (Amateur division) for the 2025 On My Own Time™ (OMOT) Art Show.A dying patient staring longingly out of the window
Pilot Treatment Development: Improving Adolescent Suicide Risk Through a Standardized Brief Group Sleep Intervention
Get PDFSuicide is a leading cause of death in adolescents. Development of sustainable interventions targeting modifiable suicide risk factors is essential. Sleep disturbances, another pervasive problem for adolescents, have emerged as salient predictors of suicidality. CBT for Insomnia (CBT-I) is the gold-standard for insomnia treatment and is effective in reducing suicidality in adults. The few CBT-I adaptations for adolescents are promising, but exclude for suicidality, are inconsistent with intervention content, and impractical for "real-world" settings. The current multi-method study examined the feasibility, acceptability, and initial evidence of benefit for a brief, group CBT-I adapted for adolescents (N=87, M=14.7 years) in a suicidality treatment program (CBT-IA). We hypothesized CBT-IA would be deemed feasible, acceptable, and both subjective and objective measures of sleep would show improvement across treatment using a pre-posttest design. Measures of subjective sleep, objective (actigraphy) sleep, and suicidality were collected at admission, week one and four, and discharge. Findings relevant to feasibility indicated high rates of subjective measures completion (80.5%) and most CBT-IA sessions (88.5%), but lower compliance with actigraphy (23%). Acceptability of CBT-IA was indicated by adolescents reporting it was helpful and enjoyable. Paired samples t-tests indicated initial evidence of benefit for improving suicidality, subjective sleep quality, and one objective sleep marker (all p<.01). Limitations to this study include the homogenous sample and limited objective data. However, we identified barriers to obtaining actigraphy data and improved yield by the end of the study. This study also offers extended value beyond the data reported here: control group data were simultaneously gathered, and 1- and 6-month follow-ups for both groups are ongoing. This additional data will contribute to a future, more rigorous controlled trial design. This novel study was developed and tested in a real-world setting and CBT-IA provides the opportunity to reduce health-care burden, increase care accessibility, and save lives
Fucose in the Time of Cholera: Host Cell Glycoproteins and Glycolipids Play Opposing Roles in Cholera Intoxication
Get PDFCholera toxin (CT) is the etiological agent of cholera. Here we report that multiple classes of fucosylated glycoconjugates function in CT binding and intoxication of intestinal epithelial cells. In Colo205 cells, knockout of B3GNT5, the enzyme required for synthesis of lacto- and neolacto-series glycosphingolipids (GSLs), reduces CT binding but sensitizes cells to intoxication. Overexpressing B3GNT5 to generate more fucosylated GSLs confers significant protection against intoxication, indicating that fucosylated GSLs act as decoy receptors for CT. Knockout of B3GALT5, causes increased production of fucosylated O-linked and N-linked glycoproteins, and leads to increased CT binding and intoxication. Knockout of B3GNT5 in B3GALT5 KO cells eliminates production of fucosylated GSLs but increases intoxication, identifying fucosylated glycoproteins as functional receptors for CT. These findings provide insight into molecular determinants regulating CT sensitivity of host cells
The Role of Progranulin in Frontotemporal Dementia
Get PDFFrontotemporal dementia (FTD) is one of the most common forms of presenile dementia with a cost per patient per year greater than Alzheimer's disease. FTD is a highly heritable disease, and one of the most common genetic causes is heterozygous loss-of-function mutations in GRN, the gene that encodes the protein progranulin. In order to treat GRN-FTD, our lab developed small molecule enhancers of GRN expression which boost progranulin back to healthy levels. However, there was no robust phenotype in progranulin haploinsufficient models against which to test our progranulin enhancing drugs. To this end, I utilized a technique called LysoIP followed by tandem-mass-tag mass spectrometry to define robust lysosomal proteomic aberrations in progranulin haploinsufficient cells in both Grn heterozygous mouse models as well as GRN-FTD patient derived fibroblasts. This led to the discovery that progranulin haploinsufficiency leads to decreases in dozens of lysosomal proteins whose complete loss-of-function mutations lead to lysosomal storage disorders. I further utilized our lead compound to correct this aberrant lysosomal proteome in both mouse and human cells, restoring key lysosomal proteins to control levels and demonstrating the capability of our drug to not only boost progranulin, but to boost overall lysosomal biogenesis as well
Investigating the Role of KIBRA-Dependent Synaptic Function on Hippocampal and Cortical Network Mechanisms Underlying Complex Cognition
Get PDFRevealing how molecular interactions within single cells contribute to experience-dependent changes in circuit-level neural activity across large-scale brain networks is a significant challenge in neuroscience. Disorders of complex cognition have substantial genetic contributions and ultimately manifest via emergent properties of dysfunctional neural networks. Thus, an integrated understanding of how molecular and synaptic perturbations contribute to circuit function/plasticity will be invaluable in interpreting neuropsychiatric disorders as a feature emerging from network activity.
Here I investigate in vivo network dysfunction following the removal of the synaptic scaffolding protein KIBRA. Variants in the KIBRA gene are linked to normal variation in human memory performance, and mice lacking Kibra show substantial impairment in learning and memory in addition to impaired synaptic plasticity. KIBRA is a synaptically localized scaffolding protein that regulates AMPA receptor trafficking. In addition, KIBRA and the protein complexes it organizes are associated with multiple neuropsychiatric disorders known to have synaptic/circuit etiologies. However, the role of KIBRA in regulating circuit dynamics is unknown. Thus, elucidating KIBRA's role in experience-dependent changes in network function is likely to reveal fundamental links between plasticity, memory, and neurological disorders. Particularly relevant for the study of network-level memory processes are hippocampal sharp-wave/ripple (SWR) events, which are brief high-frequency oscillations that occur during offline states. Considerable evidence implicates SWRs as a mechanism for memory consolidation and retrieval in both rodents and humans, and synaptic plasticity is implicated in encoding recent experience in SWRs. To determine whether KIBRA-dependent plasticity mechanisms regulate behaviorally relevant circuit dynamics, I monitored simultaneous neural activity in both the hippocampus (HC) and frontal cortex (ACC) of mice with forebrain-specific deletion of KIBRA (KIBRA cKO) using in vivo electrophysiology in freely behaving mice before and after a novel experience.
I found minimal gross differences in baseline hippocampal network function between WT and KIBRA cKO mice. When we examined SWR properties before experience, I found that most fundamental properties of SWR events and associated hippocampal network dynamics are intact in KIBRA cKO mice. However, when we quantified SWR properties during and after experience, KIBRA cKO mice failed to show experience-dependent modifications of SWR properties observed in WT mice that are consistent with information updating. Additionally, I found multiple lines of evidence demonstrating that adult KIBRA cKO mice may have impaired experience-dependent oscillatory dynamics during active behavior that may impact memory encoding and maintenance. These findings indicate a failure of hippocampal circuits to properly synchronize in response to experience in the absence of KIBRA and reveal network-level mechanisms by which KIBRA function may regulate memory consolidation.
In Chapter 1, I review the relevant literature to provide a foundation to build upon when interpreting this dissertation's data. Next, in Chapter 2, I demonstrated that while most fundamental properties of remote sharp wave-ripple events and associated oscillatory dynamics are intact, experience-dependent changes in these circuit dynamics that support memory consolidation are impaired. In Chapter 3, I present data that implicates KIBRA in neural activity during active encoding processes, laying the groundwork for future questions. In Chapter 4, I discuss the implications of this work and future directions
Identifying Consequences of In Vivo Neural Activity on Hippocampal Synaptic Function
Get PDFSince the inception of the field, neurobiology has gained valuable insights into the cellular and molecular mechanisms of learning and memory. However, a complete understanding of how we learn and remember information remains at the frontier of neuroscience research. In particular, the cellular changes that occur in vivo during brief and novel behavioral epochs are poorly understood. Identifying the neural plasticity changes that facilitate learning and memory will not only provide crucial insights into the fundamental processes of normal brain function but also help understand neurological disorders. Here, I employ a temporally precise marker of neuronal activity, CaMPARI2, to label active CA1 hippocampal neurons in vivo, followed by immediate acute slice preparation and electrophysiological quantification of synaptic properties. Recently active neurons in the superficial sublayer of stratum pyramidale displayed larger post-synaptic responses at excitatory synapses from area CA3, with no change in pre-synaptic release probability. In contrast, in vivo activity weakened both pre- and post-synaptic excitatory weights onto pyramidal cells in the deep sublayer. These bidirectional synaptic changes were also observed at excitatory synapses in the SLM sublayer though failed to reach statistical significance and low sample numbers precluded any firm conclusions regarding plasticity changes at these synapses. In vivo activity of deep and superficial neurons within sharp-wave ripples was bidirectionally changed across experience, consistent with the observed changes in synaptic weights. These findings reveal novel, fundamental mechanisms through which the hippocampal network is modified by experience to store information
Responding to medical errors: implementing the modern ethical paradigm
Get PDFTuesday, January 14, 2025; noon to 1 p.m. (Central Time); Room NS2.100A or via Zoom. "Responding to Medical Errors: Implementing the Modern Ethical Paradigm". Thomas H. Gallagher, M.D., Professor and Associate Chair in the Department of Medicine and Professor in the Department of Bioethics and Humanities, University of Washington School of Medicine.Dramatic changes are underway around expectations for how healthcare organizations and providers should respond when patients are harmed by their healthcare. Historical efforts focused on the "disclosure" of errors to patients and perhaps making proactive offers of financial compensation have given way to comprehensive, principled, and systematic initiatives for responding to harm with accountability, compassion, and transparency. These initiatives, known as Communication and Resolution Programs (CRPs), are becoming much more widely adopted. Unfortunately, most suffer from highly inconsistent implementation that blunts their impact. This presentation will address the ethical underpinnings of CRPs, lessons learned from CRP adoption across hundreds of organizations, key unanswered questions, and a vision for the future.UT Southwestern--Program in Ethic
Mycobacterium tuberculosis Lipids Activate Neurons and Trigger Cough
Get PDFPulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and a transmission mechanism. While nociceptive neurons innervating the lungs trigger the cough reflex and some bacteria produce neuron-targeting molecules, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating molecule that induces cough is unknown. Here, I identified the Mtb glycolipid sulfolipid-1 (SL-1) as a nociceptive-activating and cough-inducing molecule. I also demonstrated that phenolic glycolipid (PGL), which is uniquely produced by the hypervirulent Mtb HN878, activates nociceptive neurons. Finally, I determined that a GPCR mediates SL-1 activity, independent of TRPV1. This work demonstrates a novel molecular mechanism for cough induction by a virulent human pathogen via its production of complex lipids to induce a cough response