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Get PDFA young field medic in Vietnam tries his hardest save his men among the chaos of war.
Articles, stories, and other compositions in this archive were written by participants in the Mighty Pen Project. The program, developed by author David L. Robbins, and in partnership with Virginia Commonwealth University and the Virginia War Memorial in Richmond, Virginia, offers veterans and their family members a customized twelve-week writing class, free of charge. The program encourages, supports, and assists participants in sharing their stories and experiences of military experience so both writer and audience may benefit
Damaged Goods
Get PDFI’m ready to go back now // to a place that’s far away-
Short poem about home, and returning to it
Trans* Educators in Early Childhood through Secondary (PK-12) Schools: An Exhaustive Literature Review
Get PDFThis literature review provides documentation and analysis for 22 years of empirical, English-language research on trans* educators in early childhood through secondary (PK-12) education. A total of 87 publications from six different continents provide a basis for researchers and policymakers interested in better understanding this historically marginalized population. Findings include a diverse array of methodological and theoretical approaches as well as several meta-level findings concerning the varied circumstances of trans* educators. There is a need for additional research to address persistent gaps as well as for sweeping policy change and collective action to improve the unacceptable conditions of trans* educators
To Honor Their Courage and Commitment
Get PDFTwo veterans from different eras keep memories alive through archival work.
So many of the pictures were fading, curling, and cracking. Add a few years, and the history captured in light and shadow will be lost, like so many veterans and the stories they never told.
I commit mine to paper so they won’t be forgotten.
Articles, stories, and other compositions in this archive were written by participants in the Mighty Pen Project. The program, developed by author David L. Robbins, and in partnership with Virginia Commonwealth University and the Virginia War Memorial in Richmond, Virginia, offers veterans and their family members a customized twelve-week writing class, free of charge. The program encourages, supports, and assists participants in sharing their stories and experiences of military experience so both writer and audience may benefit
Intervertebral Lateral Bending Moment Differences in the Lumbar Spine of Baseball Pitchers Across Throwing Velocities
Get PDFIntroduction Baseball pitching imposes substantial mechanical demands on the lumbar spine, a crucial link in the kinetic chain responsible for transferring energy from the lower body to the upper extremity. While increased pitch velocity is associated with greater trunk forces the specific intervertebral loading patterns during high-velocity pitching remain unclear. This study investigates differences in lateral bending moments across lumbar spinal segments between collegiate pitchers throwing at high versus low velocities.
Methods Twenty right-handed collegiate pitchers were divided into two groups: high-velocity (n = 10, 90.3 ± 1.6 mph) and low-velocity (n = 10, 81.6 ± 1.1 mph). Motion capture and external ground reaction forces from an open-access pitching dataset were processed using OpenSim. A thoracolumbar model and inverse dynamics analysis was used to compute lateral bending moments at six intervertebral joints (T12/L1 to L5/S1). Statistical parametric mapping (SPM) was used to compare moment waveforms between groups across a time-normalized window centered around maximum shoulder external rotation.
Results SPM analysis revealed significant group differences at L5/S1 (p = 0.014) and L3/L4 (p = 0.009), with high-velocity pitchers showing average peak moments approximately 28% higher at L5/S1, and 24% higher at L3/L4. Additionally, the T12/L1 segment showed multiple significant intervals (p = 0.025–0.016) of increased loading in the fast group. These peaks occurred primarily during late cocking and early acceleration, consistent with the proposed high trunk demands during segmental separation and force transfer.
Conclusions These findings confirm that high-velocity pitchers experience
greater and more temporally concentrated lateral bending loads at key lumbar and thoracolumbar junctions. This suggests that enhanced spinal engagement plays a role in generating higher throwing speeds. From a performance standpoint, these insights highlight the importance of trunk control and spinal stability in energy transfer. From an injury prevention perspective, the increased and localized loading observed in high-velocity throwers emphasizes the need for targeted strength, mobility, and recovery strategies to mitigate the risk of overuse injuries to the lumbar spine
Lung Disposition and Efficacy of Small Molecule and mRNA-based Macrophage-targeting Nanoformulations in Models of Osteosarcoma Lung Metastases
No full textOsteosarcoma (OS) is the most common primary bone malignancy across all age groups, with a high propensity for metastasizing to the lungs. Pulmonary metastases, referred to as osteosarcoma lung metastases (OSLM), represent the leading cause of mortality in OS patients. Despite aggressive multi-agent chemotherapy regimens, such as the standard MAP protocol (methotrexate, doxorubicin, and cisplatin), outcomes for patients with OSLM remain poor, with five-year survival rates as low as 20–30%. Existing therapies are further limited by systemic toxicity, poor lung drug distribution, and a lack of effective immunotherapeutic responses, highlighting the urgent need for improved and localized treatment options.
This dissertation investigates a novel therapeutic strategy that combines local pulmonary administration (PA) with nanotechnology-based macrophage-targeting immunotherapies to shift the tumor microenvironment (TME) toward an antitumorigenic phenotype. Tumor-associated macrophages (TAMs) are highly abundant in OSLM and play a crucial role in maintaining an immunosuppressive, tumor-promoting environment. In this work, we explored two immunotherapeutic approaches to modulate TAM activity: (1) PLX-3397, and it liposomal formulation (L-PLX), a colony-stimulating factor 1 receptor inhibitor (CSF-1Ri), and (2) lipid nanoparticle (LNP) formulations encapsulating reporter mRNA (Fluc or eGFP).
In Aim# 01, we evaluated the pharmacokinetic (PK) profile of PLX following pulmonary administration in vivo, along with its efficacy in reprogramming TAMs in vitro and comparing it to L-PLX. In Aim #02, we designed and optimized mRNA LNP formulations for targeted transfection of macrophages and other cells within the OSLM TME, assessing their performance in vitro and in vivo, including a 3D spheroid model.
Collectively, this work demonstrates that local lung delivery of TAM-targeted nano-immunotherapies can enhance lung tissue exposure, reduce systemic toxicity, and promote a favorable immune response in the TME. These findings offer strong preclinical support for the clinical development of inhaled nanomedicine-based immunotherapies as adjuvant treatments for metastatic osteosarcoma
Exploring the Role of Transcription Factor Nrf1 in Autophagy and Inhibiting the Nrf1 Bounce-Back Response
Get PDFCells exposed to proteotoxic stress invoke adaptive responses aimed at restoring proteostasis. Our previous studies have established a firm role for the transcription factor Nuclear factor-erythroid derived-2-related factor-1 (Nrf1) in responding to proteotoxic stress elicited by inhibition of cellular proteasome. Following proteasome inhibition, Nrf1 mediates the synthesis of new proteasomes, thus enabling cells to mitigate proteotoxic stress. Here, we report that under similar circumstances, multiple components of the autophagy-lysosomal pathway (ALP) were transcriptionally upregulated in an Nrf1-dependent fashion, thus providing the cells with an additional route to cope with proteasome insufficiency. In response to proteasome inhibitors, Nrf1-deficient cells exhibited profound defects in inducing autophagy and clearing aggresomes. This phenomenon was also recapitulated in NGLY1 knockout cells, where Nrf1 is known to be non-functional. Conversely, overexpression of Nrf1 induced ALP genes and endowed the cells with an increased capacity to clear aggresomes. Overall, our results significantly expand the role of Nrf1 in shaping the cellular response to proteotoxic stress.
Proteasome inhibitors, ixazomib, carfilzomib, and bortezomib, are FDA-approved and currently used in clinics to treat multiple myeloma and mantle cell lymphoma. However, over time, patients often develop resistance to proteasome inhibitors, rendering them less effective as a treatment. The transcription factor Nrf1 induces proteasome and autophagy-lysosomal pathway (ALP) genes in response to proteasome inhibition, thus making proteasome inhibitors less effective. To improve the efficacy of proteasome inhibitors, it is necessary to identify drugs that can attenuate the Nrf1-mediated bounce-back response. Here, we found that anthracyclines, such as doxorubicin, synergized with proteasome inhibitors. Anthracyclines were able to attenuate Nrf1 transcriptional activity and increase cancer cell death. Moreover, we found that anthracyclines inhibited Nrf1\u27s ability to bind to antioxidant response elements (AREs) of target genes for the proteasome and ALP. Interestingly, we also saw that aclarubicin, a non-DNA damage-inducing anthracycline, was also able to attenuate the Nrf1-mediated bounce-back response. Our work provides a mechanistic explanation of the synergy between anthracyclines and proteasome inhibitors in cancer cell lines, and these findings could lead to future preclinical and clinical studies for this combinational treatment
DEVELOPMENT OF CHIMERIC ANTIGENS FOR THE DETECTION AND PREVENTION OF EHRLICHIOSIS
No full textEhrlichiosis is a significant tick-borne zoonotic disease affecting both humans and companion animals, with increasing prevalence across the United States. Despite its public health importance, no effective vaccine exists for Ehrlichia, and current diagnostic methods remain limited by sensitivity, specificity, and accessibility challenges. This study explores innovative approaches to address these gaps by identifying, testing, and optimizing antigenic targets for vaccine and diagnostic development. Immunoprecipitation and LC-MS/MS analyses identified over 50 candidate antigens from Ehrlichia chaffeensis and Ehrlichia canis. Focused evaluation revealed that outer membrane proteins, including P28, P30, and Omp-1C, demonstrated robust immunogenicity and infection-blocking efficacy. A chimeric vaccine construct, HVR1-CHI, incorporating hypervariable regions from multiple Ehrlichia strains, exhibited superior performance, achieving up to 97-100% infection blocking in vitro. Furthermore, HVR1-CHI was successfully co-administered with chimeric Lyme vaccinogens Chv2M and BAF, supporting its potential integration into a multi-pathogen vaccine formulation. Chimeric constructs incorporating immunodominant regions of TRP47, TRP36, and Omp-1H were developed for diagnostics to improve sensitivity and specificity across diverse Ehrlichia species. Additionally, the importance of evaluating diagnostic specificity through multifaceted serum panel characterizations was emphasized, given the limitations of current diagnostic standards. Future directions include in vivo validation of vaccine efficacy using animal models, refinement of diagnostic tools for broader applicability, and detailed investigation of vaccine mechanisms to guide next-generation designs. By addressing critical challenges in preventing and detecting Ehrlichiosis, this work provides a foundation for advancing tick-borne disease management and mitigating its impact on human and animal health
LIMB-GIRDLE MUSCULAR DYSTROPHY: ALTERNATIVE DIAGNOSTICS AND GENE THERAPY EVALUATION
No full textLimb-girdle muscular dystrophy (LGMD) is a neuromuscular disorder clinically characterized by progressive proximal muscle wasting leading to significant loss of ambulation. There are 29 different subtypes (most inherited in an autosomal recessive pattern), each linked to a unique causative gene. Despite the immense symptom burden, there are currently no approved LGMD-specific gene therapies. Obtaining a genetic diagnosis is typically completed with next-generation sequencing (NGS) gene panels or whole exome sequencing (WES). However, genomic DNA testing often results in low diagnostic yield that is complicated by variants of unknown significance (VUS). To determine pathogenicity of these variants, we proposed performing RNA sequencing (RNA-seq) using patient muscle tissue to evaluate transcriptomic consequences of identified variants. To evaluate this assertion, we performed RNA-seq with muscle tissue derived from 12 genetically undiagnosed individuals with a limb-girdle phenotype. When paired with WES, RNA-seq enabled reclassification of one VUS to pathogenic and provided evidence to support reclassification based on aberrant splicing caused by another candidate disease VUS. Confirming pathogenicity of these VUS can confirm the disease gene, leading to appropriate patient diagnosis with a specific LGMD subtype. LGMD diagnosis is an essential qualifier that can permit a patient to be eligible for clinical trials evaluating impending gene replacement therapies, none of which have yet achieved FDA approval. These potentially curative therapies are incredibly powerful “one-and-done” treatments, meaning patients are infused/injected with the cloned vector only once. The therapies therefore require an optimal dose high enough for efficient treatment, but not enough to trigger adverse immune reactions. To elucidate the optimal dosing, we propose using asymptomatic carriers of autosomal recessive LGMD to define haplosufficiency in each disease state. We explored the transcriptomic and proteomic profiles for carriers of LGMD subtypes R1, R9, and R3 to determine relative protein expression and functionality for the respective causative gene. We determined carriers had about 1/3 CAPN3 and SGCA protein expression for LGMDR1 and R3, respectively, compared to healthy controls without any detectable pathogenic variations in any LGMD genes. LGMDR9 carriers had about 50% FKRP enzymatic functionality compared to healthy controls. These metrics could translate to the minimal effective dosing to restore a haplosufficient state in LGMD patients. Evaluation of gene therapy success also requires robust disease-specific gene markers that proxy protein restoration. To begin this exploration, I performed differential gene expression analysis for LGMDR1, R9 and R3 affected individuals. Each subtype was compared to a control group and normalized to a myotonic dystrophy background to provide disease specificity. I found several uniquely dysregulated genes, including sarcomeric and calcium-binding genes for LGMDR1, circadian clock genes for LGMDR9, and epidermal/connective tissue genes in LGMDR3. These results prompt further in vivo experimentation to evaluate gene candidacy as a disease marker
Faculty Recital, Ruta Smedina Starke, piano, video
Get PDFFaculty Recital VideoRuta Smedina-Starke, pianoSunday, September 7, 2025 at 4:00 p.m.Sonia Vlahcevic Concert HallW.E. Singleton Center for the Performing Arts922 Park Avenue | Richmond, Virgini