Digital Commons Network^™

Association Between Hemoglobin A1c And Pediatric Asthma Control, Hewlett Pham, Rachelle Koehl, Han Woo, Tianshi David Wu, Anna Yue Qiu, Emily P Brigham, Nadia N Hansel, Meredith C Mccormack

Faculty, Staff and Students Publications

Purpose: To examine the relationship between Hemoglobin A1c (HbA1c) and asthma outcomes in an urban cohort of children with asthma.

Methods: The AIRWEIGHS Study was a randomized controlled clinical trial of an air cleaner intervention testing the hypothesis that overweight/obese children would experience greater improvement in asthma control compared to normal weight children. The study enrolled 164 children with asthma from Baltimore, MD and assessed HbA1c levels and asthma outcomes during clinic visits at baseline and three months. HbA1c levels were analyzed as a continuous measure and categorized as either normal (< 5.7%) or consistent with pre-diabetes (≥5.7%). Asthma outcomes included standardized questionnaires, spirometry, and fractional exhaled nitric oxide (FeNO). Generalized Estimating Equation (GEE) regression models were used to analyze the association between the HbA1c and asthma outcomes.

Results: Participants included 164 children with an average …

External Validation Of A Novel Cancer-Associated Venous Thromboembolism Risk Assessment Score In A Safety-Net Hospital, Karlynn N Dulberger, Jennifer La, Ang Li, Saran Lotfollahzadeh, Asha Jose, Nhan V Do, Mary T Brophy, J Michael Gaziano, Katya Ravid, Vipul C Chitalia, Nathanael R Fillmore

Faculty, Staff and Students Publications

Background: Cancer-associated thrombosis (CAT) is a leading cause of death in patients diagnosed with cancer. However, pharmacologic thromboprophylaxis use in cancer patients must be carefully evaluated due to a 2-fold increased risk of experiencing a major bleeding event within this population. The electronic health record CAT (EHR-CAT) risk assessment model (RAM) was recently developed, and reports improved performance over the widely used Khorana score. Extensive RAM external validation is crucial to determine accuracy across diverse patient populations prior to clinical utilization.

Objectives: To externally validate EHR-CAT using data from 2103 patients with cancer at the Boston Medical Center (BMC), New …

Evaluation Of Real-World Evidence To Assess Effectiveness Outcomes Of Janus Kinase Inhibitors For Rheumatoid Arthritis: A Systematic Review Of Us Studies, Chandler Gandy, Shadi Bazzazzadehgan, Sebastian Bruera, Yinan Huang

Faculty, Staff and Students Publications

Objective: This review summarized the real-world effectiveness outcomes of Janus kinase inhibitors (JAKi) for rheumatoid arthritis (RA) based on observational studies.

Methods: A systematic review followed PRISMA guidelines, with searches conducted in PubMed, Embase, and CINAHL from each database's inception to June 2, 2023. Studies were included if they evaluated real-world effectiveness outcomes of JAKi for US RA patients. Search terms included "RA", "JAKi", and "real-world". All citations were imported into COVIDENCE platform. Two reviewers independently performed title/abstract screening and full-text eligibility. For each article, study characteristics and effectiveness measures focusing on treatment pattern, clinical response, and patient-reported outcomes (PROs) …

Baseline Predictors For 28-Day Covid-19 Severity And Mortality Among Hospitalized Patients: Results From The Impacc Study, Jintong Hou, Benjamin Haslund-Gourley, Joann Diray-Arce, Annmarie Hoch, Nadine Rouphael, Patrice M Becker, Alison D Augustine, Al Ozonoff, Leying Guan, Steven H Kleinstein, Bjoern Peters, Elaine Reed, Matt Altman, Charles R Langelier, Holden Maecker, Seunghee Kim, Ruth R Montgomery, Florian Krammer, Michael Wilson, Walter Eckalbar, Steven E Bosinger, Ofer Levy, Hanno Steen, Lindsey B Rosen, Lindsey R Baden, Esther Melamed, Lauren I R Ehrlich, Grace A Mccomsey, Rafick P Sekaly, Joanna Schaenman, Albert C Shaw, David A Hafler, David B Corry, Farrah Kheradmand, Mark A Atkinson, Scott C Brakenridge, Nelson I Agudelo Higuita, Jordan P Metcalf, Catherine L Hough, William B Messer, Bali Pulendran, Kari C Nadeau, Mark M Davis, Ana Fernandez Sesma, Viviana Simon, Monica Kraft, Chris Bime, Carolyn S Calfee, David J Erle, Impacc Network, Lucy F Robinson, Charles B Cairns, Elias K Haddad, Mary Ann Comunale

Faculty, Staff and Students Publications

Introduction: The coronavirus disease 2019 (COVID-19) pandemic threatened public health and placed a significant burden on medical resources. The Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study collected clinical, demographic, blood cytometry, serum receptor-binding domain (RBD) antibody titers, metabolomics, targeted proteomics, nasal metagenomics, Olink, nasal viral load, autoantibody, SARS-CoV-2 antibody titers, and nasal and peripheral blood mononuclear cell (PBMC) transcriptomics data from patients hospitalized with COVID-19. The aim of this study is to select baseline biomarkers and build predictive models for 28-day in-hospital COVID-19 severity and mortality with most predictive variables while prioritizing routinely collected variables.

Methods: We analyzed 1102 …

Utility Of Microbial Cell-Free Dna Sequencing In The Diagnosis Of Mycobacterial Infections In A Quaternary Care Center, Fernando H Centeno, Todd Lasco, Ahmed M Hamdi, Mayar Al Mohajer

Faculty, Staff and Students Publications

We examine the performance of microbial cell-free DNA (mcfDNA) next-generation sequencing (NGS) testing on patients admitted to a quaternary care hospital in Houston, Texas. The test was 75.0% sensitive and 97.8% specific for all mycobacterial infections. mcfDNA NGS results led to adjustments in antimicrobial therapy for seven of nine patients with positive results.

Impact Of A Cerebrospinal Fluid Diagnostic Stewardship Intervention On Quantity Of Tests, Length Of Stay, Antibiotic Prescriptions, And Cost, Aaron Pathak, Sabra Shay, Todd Lasco, Mayar Al Mohajer

Faculty, Staff and Students Publications

Redundant and low-value cerebrospinal fluid analysis for suspected meningitis can increase costs and antimicrobial use. Our diagnostic stewardship intervention limited available infectious disease cerebrospinal fluid assays to seven common tests, including a multiplex polymerase chain reaction panel. There was no significant difference in the cost of testing or clinical outcomes.

The Utilization Of Microbial Cell-Free Dna Next-Generation Sequencing For The Detection Of Human Herpesvirus-8 In A Quaternary Care Center, Rebecca Berger, Jennifer Jacobe, Fernando H Centeno, Todd Lasco, Mayar Al Mohajer

Faculty, Staff and Students Publications

Background: Human herpesvirus-8 (HHV8) can present with cutaneous or extracutaneous manifestations. While violaceous skin lesions characterize cutaneous Kaposi sarcoma, extracutaneous HHV8 is challenging to diagnose due to nonspecific symptoms.

Objectives: We evaluated the role of microbial cell-free DNA next-generation sequencing (mcfDNA NGS) in diagnosing HHV8-related illness.

Design: Retrospective analysis.

Methods: Between 2017 and 2024, we reviewed the medical charts of 10 immunosuppressed patients at a quaternary care center who had positive HHV8 mcfDNA NGS results.

Results: The clinical and laboratory turnaround times of mcfDNA NGS were 3 and 1 days, respectively (8.5 and 7 days for immunohistochemistry vs 5.5 and …

Candidiasis Epidemiology And Outcomes Including Emergence Of Candida Auris From A Large, Southern Us Metro Area: A Six-Year Evaluation, Ricky Huynh-Phan, Ardath Plauche, William L Musick, Kady Phe, Wesley J Hoffman, Mayar Al Mohajer, Todd Lasco, Nicholas D Beyda, Taryn A Eubank, Kevin W Garey

Faculty, Staff and Students Publications

Background: Invasive candidiasis including candidemia is a common healthcare-associated infections with significant morbidity and mortality. The USA does not have mandatory national surveillance for mucocutaneous or invasive candidiasis which complicates estimation of epidemiology and outcomes. The aim of this project was to describe the epidemiology, mortality, and Candida-associated hospital readmissions in hospitalized patients with Candida species infections.

Methods: This secondary database analysis used clinical microbiology data from adults hospitalized at three large health systems (25-hospitals) in the Greater Houston area totaling over 1.6 million hospitalization days per year from 2018 to 2023. Proportion and rates of Candida cultures per …

Investigating Socioeconomic Deprivation And Antibiotic Prescribing Among Older Medicare Patients Using An Instrumental Variable Approach, Mayar Al Mohajer, David Slusky, David Nix, Catia Nicodemo

Faculty, Staff and Students Publications

Background: Socioeconomic deprivation has been associated with antibiotic overprescription in the US; however, prior studies could not quantify a causal relationship due to endogeneity. This study examines how socioeconomic deprivation is related to the rate of antibiotic days supplied to older Medicare Part D beneficiaries, utilizing an Instrumental Variable (IV) approach.

Methods: Data from the Medicare Part D and the Social Deprivation Index (SDI) repositories were analyzed. To address potential endogeneity and omitted variable bias in the relationship between SDI and antibiotic prescribing, we used the maximum Earned Income Tax Credit as an IV. Bivariate Moran's I assessed the spatial …

Toward Improving Retention In Hiv Care After Pregnancy: Lessons From A Post-Pandemic Cohort In The United States, Alexandra H Latham, Andrea Lugo Morales, Elizabeth Barba Gutierrez, Michael Jochum, Sarah Conrad, Eva H Clark, Kassandra Goytia, Megan Alam, Jessica Gerard, Jennifer Mckinney

Faculty, Staff and Students Publications

Introduction: People living with HIV (PLWH) often experience low rates of retention in HIV care (RIC) and suboptimal viral suppression postpartum. Understanding contemporary barriers to RIC is crucial to identify risk factors for loss to care and thereby improve support during this vulnerable transition. This work aimed to identify factors associated with adequate RIC, defined as two HIV care visits ≥90 days apart in the first year postpartum.

Methods: Electronic records were retrospectively reviewed for PLWH who delivered from 2019 to 2023 and received prenatal care within a single county health system. Variables were collected related to both maternal and …

Inclusion Of Patient-Centered, Non-Microbiological Endpoints And Biomarkers In Tuberculosis Drug Trials, Andrew R Dinardo, Wilbert Sabiiti, Stephen H Gillespie, Sophia B Georghiou, Norbert Heinrich, Norbert Hittel, Sami Taghlabi, Danna Carrero Longlax, Mikashmi Kohli, Ursula Panzner, Collins Musia, Christoph Lange, Anca Vasiliu, Rob J W Arts, Anna M Mandalakas, Morten Ruhwald, Lieven J Stuyver, Reinout Van Crevel

Faculty, Staff and Students Publications

Tuberculosis drug trials are primarily designed to identify antibiotic regimens with the strongest potency to kill Mycobacterium tuberculosis. However, microbiologic cure is not synonymous with improved health and recovery. Beyond antimicrobial efficacy, parameters such as morbidity and mortality related to lung function, cardiovascular health, and cancer should be prioritized. This narrative review emphasizes the critical need to emphasize clinical outcomes as much, if not more, than microbiological endpoints. We examine the underlying pathophysiological mechanisms and determinants of non-microbiological outcomes in tuberculosis, providing a synthesis of current knowledge. While there is growing evidence for some biomarkers to risk stratify TB …

Gut Microbial Community Structure Of The Adult Citrus Root Weevil Diaprepes Abbreviatus, Imilce A Rodriguez-Fernandez, Tasha M Santiago-Rodriguez, Paola G Figueroa-Pratts, Keislamarí Cintrón-Berríos, Nichole D Rodriguez-Cornier, Gary A Toranzos

Faculty, Staff and Students Publications

Diaprepes abbreviatus is an agricultural pest known to affect around 270 plant species across the Caribbean and the United States, posing significant challenges to pest management. Chemical control dominates management, but environmental and health concerns motivate microbiome-informed alternatives. However, limited information exists on the gut anatomy, physicochemical environment, and microbial composition of D. abbreviatus. In this study, we provide the first comprehensive characterization of the gut morphology, pH, and microbiota of adult D. abbreviatus in both females and males collected in Puerto Rico. Using dye-based gut tracing, we identified foregut, midgut, and hindgut or posterior gut compartments, and confirmed the …

Transposable Element Activity Captures Human Pluripotent Cell States, Florencia Levin-Ferreyra, Srikanth Kodali, Yingzhi Cui, Alison R S Pashos, Patrizia Pessina, Justin Brumbaugh, Bruno Di Stefano

Faculty, Staff and Students Publications

Human pluripotent stem cells (hPSCs) exist in multiple, transcriptionally distinct states and serve as powerful models for studying human development. Despite their significance, the molecular determinants and pathways governing these pluripotent states remain incompletely understood. Here, we demonstrate that transposable elements act as sensitive indicators of distinct pluripotent cell states. We engineered hPSCs with fluorescent reporters to capture the temporal expression dynamics of two state-specific transposable elements, LTR5_Hs, and MER51B. This dual reporter system enables real-time monitoring and isolation of stem cells transitioning from naïve to primed pluripotency and further towards differentiation, serving as a more accurate readout of pluripotency …

Age-Related Variations In Hba1c Improvemecnts: Insights From A Telehealth-Supported Community-Based Intervention, Laura Porterfield, Xiaoying Yu, Amber B Amspoker, Craig A Johnston, Aanand D Naik, Salim S Virani, Christie M Ballantyne, Ashok Balasubramanyam, Elizabeth M Vaughan

Faculty, Staff and Students Publications

Background and objectives: We previously demonstrated that a telehealth-supported community health worker (CHW) intervention significantly improved clinical outcomes in diabetes care. However, the extent to which these benefits vary across different age groups remains unclear. This study evaluated the effectiveness of a CHW-led multidimensional diabetes intervention in reducing HbA1c across age groups.

Research design and methods: We conducted a retrospective analysis of 10 studies (n = 301) that focused on low-income Hispanic adults with or at risk for type 2 diabetes. The intervention included CHW-participant coaching via mobile Health (mHealth), monthly CHW-led group education, and bidirectional mHealth feedback among …

Promotion Of Hiv Clearance By Sensitization Of Hiv Reservoirs To Cell Death, Min Li, Baichao Sun, Jing Dong, Jian-Rong Li, Laurie J Minze, Min Chen, Chao Cheng, Jin Wang

Faculty, Staff and Students Publications

Introduction: HIV integrates its proviral DNA into the host genome to establish persistent infection. To promote HIV clearance, we have designed an approach for selective elimination of host cells harboring replication-competent HIV (SECH), through inhibition of autophagy and anti-apoptotic molecules during viral reactivation. SECH approach can clear HIV-infected cells in approximately 50% humanized mice. However, the mechanisms for the resistance of reservoirs to depletion in mice with failure in HIV clearance are unclear.

Methods: We have performed single cell transcriptome analyses of HIV-infected T cells that escaped the treatments, in order to identify cellular pathways that could be targeted to …

Reliable Rna-Seq Analysis From Ffpe Specimens As A Means To Accelerate Cancer-Related Health Disparities Research, Mitchell J Frederick, Dannelys Perez-Bello, Pedram Yadollahi, Patricia Castro, Alan Frederick, Andrew Frederick, Rashid A Osman, Fonma Essien, Imelda Yebra, Ashley Hamlin, Thomas J Ow, Heath D Skinner, Vlad C Sandulache

Faculty, Staff and Students Publications

Whole transcriptome sequencing (WTS/ RNA-Seq) is a ubiquitous tool for investigating cancer biology. RNA isolated from frozen sources limits possible studies for analysis of associations with phenotypes or clinical variables requiring long-term follow-up. Although good correlations are reported in RNA-Seq data from paired frozen and formalin fixed paraffin embedded (FFPE) samples, uncertainties regarding RNA quality, methods of extraction, and data reliability are hurdles to utilization of archival samples. We compared three different platforms for performing RNA-seq using archival FFPE oropharyngeal squamous carcinoma (OPSCC) specimens stored up to 20 years, as part of an investigation of transcriptional profiles related to health …

Inhibition Of Ribosome Biogenesis In Vivo Causes P53-Dependent Death And P53-Independent Dysfunction, Charles J Cho, Thanh Nguyen, Amala K Rougeau, Yang-Zhe Huang, Sarah To, Xiaobo Lin, Supuni Thalalla Gamage, Jordan L Meier, Jason C Mills

Faculty, Staff and Students Publications

Background & aims: Although it is well-known that ribosomes are critical for cell function, and their synthesis (known as ribosome biogenesis [RiBi]) is energy-intensive, surprisingly little is known about RiBi in vivo in adult tissue.

Methods: Using a mouse model with conditional deletion of Nat10, an essential gene for RiBi and subsequent translation of mRNA, we investigated the effects of RiBi blockade in vivo, with a focus on pancreatic acinar cells during homeostasis and tumorigenesis.

Results: We observed an unexpected latency of several weeks between Nat10 deletion and onset of structural and functional abnormalities and p53-dependent acinar cell death. Although …

Relationships Of Personality Traits With The Taxonomic Composition Of The Gut Microbiome Among Psychiatric Inpatients, William Orme, Sandra L Grimm, Divya S N Vella, J Christopher Fowler, B Christopher Frueh, Benjamin L Weinstein, Joseph Petrosino, Cristian Coarfa, Alok Madan

Faculty, Staff and Students Publications

Objective: Through the brain-gut-microbiome axis, myriad psychological functions that affect behavior share a dynamic, bidirectional relationship with the intestinal microbiome. Little is known about the relationship between personality-a stable construct that influences social- and health-related behaviors-and the bacterial ecosystem. The authors of this exploratory study examined the relationship between general and maladaptive personality traits and the composition of the gut microbiome.

Methods: In total, 105 psychiatric inpatients provided clinical data and fecal samples. Personality traits were measured with the five-factor model of personality, the Structured Clinical Interview for DSM-IV Axis II Personality Disorders, and the Personality Inventory for DSM-5; 16S …

Paternal Upd (15) With Disease-Causing Mutation And Small Supernumerary Ring Chromosome 15: A Case Report, David Lee Curtis, Nasim Bekheirnia, Lorraine Potocki, Ludmila Matyakhina, Mir Reza Bekheirnia

Faculty, Staff and Students Publications

Uniparental disomy (UPD) constitutes an unconventional mode of inheritance that disrupts the typical biparental genetic contribution and may result in phenotypic abnormalities. This report centers on a patient diagnosed with Bartter syndrome Type 1, attributed to a homozygous pathogenic variant in SLC12A1 unmasked by mosaic paternal UPD of chromosome 15. We hypothesize that this pattern (or constellation) emerged from a trisomy rescue event, resulting in two distinct cell lines. Concurrently, the unmasking of a pathogenic paternal SLC12A1 variant by trisomy rescue resulted in the manifestation of Bartter syndrome Type 1. The maternally derived ring chromosome 15 and its impact on …

Experiences From Dual Genome Next-Generation Sequencing Panel Testing For Mitochondrial Disorders: A Comprehensive Molecular Diagnosis, Elizabeth Gorman, Hongzheng Dai, Yanming Feng, William James Craigen, David C Y Chen, Fan Xia, Linyan Meng, Pengfei Liu, Robert Rigobello, Arpita Neogi, Christine M Eng, Yue Wang

Faculty, Staff and Students Publications

Introduction: The molecular diagnosis of mitochondrial disorders is complicated by phenotypic variability, genetic heterogeneity, and the complexity of mitochondrial heteroplasmy. Next-generation sequencing (NGS) of the mitochondrial genome in combination with a targeted panel of nuclear genes associated with mitochondrial disease provides the highest likelihood of obtaining a comprehensive molecular diagnosis. To assess the clinical utility of this approach, we describe the results from a retrospective review of patients having dual genome panel testing for mitochondrial disease.

Methods: Dual genome panel testing by NGS was performed on a cohort of 1,509 unrelated affected individuals with suspected mitochondrial disorders. This test included …

Purely Cystic Intraosseous Meningioma Of The Skull: A Radiologic Conundrum And Histologic Challenge, Diego Rojas, Arman Kavoussi, Ashley Rose Ricciardelli, Alex Flores, Sricharan Gopakumar, Luis Carrete, Hsiang-Chih Lu, Alex W Brenner, Akash J Patel

Faculty, Staff and Students Publications

Background: Intraosseous meningiomas and cystic meningiomas are two rare subtypes of meningiomas. Meningiomas can develop with characteristics encompassing both cystic and intraosseous, termed intraosseous cystic meningiomas, that pose a diagnostic challenge.

Case description: We report the case of a 41-year-old woman with a history of hearing loss presented with a left frontal mass that had been present for 12 years. Her history of hearing loss was in the setting of ear infections bilaterally since she was a teenager and was being evaluated by ear, nose, and throat specialists at the time. Initial cranial computed tomography (CT) identified a skull lesion …

Approved Car-T Therapies Have Reproducible Efficacy And Safety In Clinical Practice, Daniel Goyco Vera, Hiral Waghela, Mohamed Nuh, Jonathan Pan, Premal Lulla

Faculty, Staff and Students Publications

CAR-T cell therapy has established itself as a highly effective treatment for hematological malignancies. There are currently six commercial CAR-T products that have been FDA approved for diseases such as B-ALL, LBCL, MCL, FL, MM, and CLL/SLL. "Real-world" studies allow us to evaluate outcomes from the general population to determine their efficacy and safety compared to those who were included in the original trials. Based on several well conducted "Real-world" studies that represent diverse populations, we report that outcomes from the original trials that led to the approval of these therapies are comparable to those in practice.

Addressing Unprofessional Behaviors In The Clinical Learning Environment: Lessons From A Multi-Year Virtual, Intergenerational, Interdisciplinary Workshop, Stacey Rose, Anita Kusnoor, Phuong Huynh, Jocelyn Greely, Yesenia Rojas-Khalil, Doris Kung, Anne Gill, Nadia Ismail, Nital Appelbaum

Faculty, Staff and Students Publications

INTRODUCTION: Optimizing the clinical learning environment (CLE) is a medical education priority nationwide.

MATERIALS AND METHODS: We developed a virtual, one-hour workshop engaging students, housestaff and faculty in small-group discussions of five case scenarios adapted from reported unprofessional behaviors in the CLE, plus didactics regarding mistreatment, microaggressions and bystander interventions.

RESULTS: Over two sessions (2021-2022), we engaged 340 students and 73 faculty/housestaff facilitators. Post-session surveys showed significant improvement in participants' ability to recognize and respond to challenges in the CLE.

DISCUSSION: Our innovative workshop, including scenarios derived from institutional reports of unprofessional behaviors, advanced participants' knowledge and commitment to improve …

Transition To Enteral Triazole Antifungal Therapy For Pediatric Invasive Candidiasis: Secondary Analysis Of A Multicenter Cohort Study Conducted By The Pediatric Fungal Network, Robert F T Bucayu, Craig L K Boge, Inci Yildirim, Martha Avilés-Robles, Surabhi B Vora, David M Berman, Tanvi S Sharma, Lillian Sung, Elio Castagnola, Debra L Palazzi, Lara Danziger-Isakov, Dwight E Yin, Emmanuel Roilides, Gabriela Maron, Alison C Tribble, Pere Soler-Palacin, Eduardo López-Medina, José Romero, Kiran Belani, Antonio C Arrieta, Fabianne Carlesse, Dawn Nolt, Natasha Halasa, Daniel Dulek, Sujatha Rajan, William J Muller, Monica I Ardura, Alice Pong, Blanca E Gonzalez, Christine M Salvatore, Anna R Huppler, Catherine Aftandilian, Mark J Abzug, Arunaloke Chakrabarti, Michael Green, Irja Lutsar, Elizabeth D Knackstedt, Sarah K Johnson, William J Steinbach, Brian T Fisher, Rachel L Wattier

Faculty, Staff and Students Publications

Of 319 children with invasive candidiasis, 67 (21%) transitioned from intravenous to enteral antifungal therapy. Eight (12%) transitioned back to intravenous antifungal therapy, one due to perceived treatment failure defined by clinical progression or worsening. Global treatment response at study completion was successful in 66 participants who transitioned to enteral therapy.

Dlk-Dependent Axonal Mitochondrial Fission Drives Degeneration After Axotomy, Jorge Gómez-Deza, Matthew Nebiyou, Mor R Alkaslasi, Francisco M Nadal-Nicolás, Preethi Somasundaram, Anastasia L Slavutsky, Wei Li, Michael E Ward, Trent A Watkins, Claire E Le Pichon

Faculty, Staff and Students Publications

Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrate that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We find that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related …

Age-Dependent Regulation Of Axoglial Interactions And Behavior By Oligodendrocyte Ankyring, Xiaoyun Ding, Yu Wu, Anna Vainshtein, Victoria Rodriguez, Emily Ricco, James T Okoh, Yanhong Liu, Daniel C Kraushaar, Elior Peles, Matthew N Rasband

Faculty, Staff and Students Publications

The bipolar disorder (BD) risk gene ANK3 encodes the scaffolding protein AnkyrinG (AnkG). In neurons, AnkG regulates polarity and ion channel clustering at axon initial segments and nodes of Ranvier. Disruption of neuronal AnkG causes BD-like phenotypes in mice. During development, AnkG is also expressed at comparable levels in oligodendrocytes and facilitates the efficient assembly of paranodal junctions. However, the physiological roles of glial AnkG in the mature nervous system, and its contributions to BD-like phenotypes, remain unexplored. Here, we show that oligodendroglia-specific AnkG conditional knockout results in destabilization of axoglial interactions in aged but not young adult mice. In …

Orthogonal And Multiplexable Genetic Perturbations With An Engineered Prime Editor And A Diverse Rna Array, Qichen Yuan, Hongzhi Zeng, Tyler C Daniel, Qingzhuo Liu, Yongjie Yang, Emmanuel C Osikpa, Qiaochu Yang, Advaith Peddi, Liliana M Abramson, Boyang Zhang, Yong Xu, Xue Gao

Faculty, Staff and Students Publications

Programmable and modular systems capable of orthogonal genomic and transcriptomic perturbations are crucial for biological research and treating human genetic diseases. Here, we present the minimal versatile genetic perturbation technology (mvGPT), a flexible toolkit designed for simultaneous and orthogonal gene editing, activation, and repression in human cells. The mvGPT combines an engineered compact prime editor (PE), a fusion activator MS2-p65-HSF1 (MPH), and a drive-and-process multiplex array that produces RNAs tailored to different types of genetic perturbation. mvGPT can precisely edit human genome via PE coupled with a prime editing guide RNA and a nicking guide RNA, activate endogenous gene expression …

Vaccines Targeting P53 Mutants Elicit Anti-Tumor Immunity, Dafei Chai, Xu Wang, Chunmei Fan, Junhao Wang, Jing Ming Lim, Xinfang Yu, Ken H Young, Yong Li

Faculty, Staff and Students Publications

The p53 tumor suppressor is commonly mutated in cancer; however, there are no effective treatments targeting p53 mutants. A DNA vaccine gWIZ-S237G targeting the p53 S237G mutant, which is highly expressed in A20 murine tumor cells, was developed and administered intramuscularly via electroporation, either alone or in combination with PD1 blockade. The anti-p53-S237G immunization elicited a robust protective response against subcutaneous A20 tumors and facilitated the infiltration of immune cells including CD8+ T cells, NK cells, and DCs. The vaccine enhanced the induction and maturation of CD11c+, CD103+CD11c+, and CD8+CD11c+ cells, which in turn promoted tumor-specific antibody production, as well …

Role Of Nf2 Mutation In The Development Of Eleven Different Cancers, Shervin Hosseingholi Nouri, Vijay Nitturi, Elizabeth Ledbetter, Collin W English, Sean Lau, Tiemo J Klisch, Akash J Patel

Faculty, Staff and Students Publications

Background/Objectives: With the rise in prevalence of diagnostic genetic techniques like RNA sequencing and whole exome sequencing (WES), as well as biological treatment regiments for cancer therapy, several genes have been implicated in carcinogenesis. This review aims to update our understanding of the Neurofibromatosis 2 (NF2) gene and its role in the pathogenesis of various cancers. Methods: A comprehensive search of five online databases yielded 43 studies that highlighted the effect of sporadic NF2 mutations on several cancers, including sporadic meningioma, ependymoma, schwannoma, mesothelioma, breast cancer, hepatocellular carcinoma, prostate cancer, glioblastoma, thyroid cancer, and melanoma. Of note were key biological …

Aperiodic Spectral Slope Tracks The Effects Of Brain State On Saliency Responses In The Human Auditory Cortex, Madaline Mocchi, Eleonora Bartoli, John Magnotti, Jan Willem De Gee, Brian Metzger, Bailey Pascuzzi, Raissa Mathura, Suhruthaa Pulapaka, Wayne Goodman, Sameer Sheth, Matthew J Mcginley, Kelly Bijanki

Faculty, Staff and Students Publications

Alteration of responses to salient stimuli occurs in a wide range of brain disorders and may be rooted in pathophysiological brain state dynamics. Specifically, tonic and phasic modes of activity in the reticular activating system (RAS) influence, and are influenced by, salient stimuli, respectively. The RAS influences the spectral characteristics of activity in the neocortex, shifting the balance between low- and high-frequency fluctuations. Aperiodic '1/f slope' has emerged as a promising composite measure of these brain state dynamics. However, the relationship of 1/f slope to state-dependent processes, such as saliency, is less explored, particularly intracranially in humans. Here, we record …