Digital Commons Network^™

Generalizability Of Neuromuscular Coordination In The Human Upper Extremity After Stroke And Its Implications In Neurorehabilitation, Manuel Portilla-Jiménez, Yoon No Gregory Hong, Komal K Kukkar, Hyung-Soon Park, Sheng Li, Jinsook Roh

Faculty, Staff and Student Publications

Background: Previous studies have shown that stroke often impairs neuromuscular coordination (i.e., muscle synergies) across various biomechanical conditions. In our previous study, we investigated the generalizability of muscle synergies between isometric and free dynamic reaching in healthy individuals. However, the extent to which muscle synergy characteristics after stroke are generalized across these conditions remains unclear.

Methods: Electromyographic signals from eight upper extremity muscles were recorded from 14 chronic stroke survivors with mild-to-severe motor impairment and eight age-range matched controls while performing isometric force generation and point-to-point dynamic reaching tasks. Non-negative matrix factorization was applied to identify muscle synergy characteristics underlying …

Landscape And Clinicopathologic Features Of Ras Pathway Mutations In Chronic Myelomonocytic Leukemia, Guillermo Montalban-Bravo, Sanam Loghavi, Ziyi Li, Kelly Chien, Rashmi Kanagal-Shamanna, Alex Bataller, Anuya Natu, Mark Gurney, Alexandre Bazinet, Danielle Hammond, Koji Sasaki, Gautam Borthakur, Mahesh Swaminathan, Courtney Dinardo, Tapan Kadia, Farhad Ravandi, Naval Daver, Nicholas Short, Naveen Pemmaraju, Ghayas Issa, Terra L Lasho, Christy M Finke, Aref Al-Kali, Clifford Csizmar, Hassan Alkhateeb, Naseema Gangat, Abhishek A Mangaonkar, Carlos Bueso-Ramos, Ayalew Tefferi, Hagop Kantarjian, Guillermo Garcia-Manero, Mrinal M Patnaik

Faculty, Staff and Student Publications

RAS pathway (RASp) mutations induce proliferative features, and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASp mutations remain unexplored. To characterize the landscape, architecture, and implications of unique RASp mutations in CMML, we evaluated a cohort of 814 patients with CMML. We identified 461 RASp mutations among 342 patients (42%). N/KRAS and CBL mutations were the most common, frequently involved the P-loop or RING domains, respectively, and frequently appeared as dominant events (63% and 65%, respectively). BRAF, NF1, and PTPN11 mutations spanned throughout the gene structure, and frequently appeared as subclonal …

Optimizing Genetic Ancestry Adjustment In Dna Methylation Studies: A Comparative Analysis Of Approaches, Kira D Höffler, Seyma Katrinli, Matthew W Halvorsen, Anne-Kristin Stavrum, Kevin S O'Connell, Alexey Shadrin, Srdjan Djurovic, Ole A Andreassen, James J Crowley, Jan Haavik, Kristen Hagen, Gerd Kvale, Kerry Ressler, Bjarne Hansen, Jair C Soares, Gabriel R Fries, Alicia K Smith, Stéphanie Le Hellard

Faculty, Staff and Student Publications

Background: Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs. The first PC is therefore often associated with factors other than ancestry.

Methods: We developed and adapted the adapted EpiAnceR+ approach, which includes (1) residualizing the CpG data overlapping with common SNPs for control …

Drug-Eluting Resorbable Scaffold Versus Balloon Angioplasty For Below-The-Knee Peripheral Artery Disease: 2-Year Results From The Life-Btk Trial., Brian G Derubertis, Ramon L Varcoe, Prakash Krishnan, Marc P Bonaca, David J O'Connor, Richard Pin, David C Metzger, Andrew Holden, Jen-Kuang Lee, Osamu Iida, Ehrin J Armstrong, Steven W C Kum, Raghu Kolluri, Danielle R Bajakian, Lawrence A Garcia, Mehdi H Shishehbor, Shawn Yu, Karine Ruster, Brad J Martinsen, Zsuzsanna Igyarto, Sahil A Parikh

Heart and Vascular Articles

BACKGROUND: Limited treatment options exist for infrapopliteal disease in patients with chronic limb-threatening ischemia (CLTI), a condition associated with a high risk of limb loss. Interventional management of diseased infrapopliteal vessels with percutaneous transluminal angioplasty (PTA) is associated with high rates of restenosis and reintervention. In the LIFE-BTK randomized controlled trial (Pivotal Investigation of Safety and Efficacy of BRS Treatment-Below the Knee), the drug-eluting resorbable scaffold (DRS) demonstrated superior 12-month efficacy compared with PTA in a selected CLTI population with predominantly noncomplex, mildly to moderately calcified lesions. This report presents the 2-year safety and efficacy outcomes of the Esprit BTK …

Effect Of Age On Isth-Bat Scores And Low Vwf Diagnosis In The Zimmerman Program, Ferdows Atiq, Jorge Di Paola, Et Al.

2020-Current year OA Pubs

An essential component of low von Willebrand factor (VWF)/type 1 von Willebrand disease (VWD) diagnosis is to identify patients with an increased bleeding phenotype, as most individuals with VWF levels in the 30 to 50 IU/dL range do not bleed. The International Society on Thrombosis and Haemostasis-bleeding assessment tool (ISTH-BAT), widely used for assessing bleeding severity, has recently been shown to be age dependent. Although age may also influence ISTH-BAT scores in individuals with VWF levels between 30 and 50 IU/dL, and subsequently affect low VWF diagnosis, this relationship has not been investigated. Therefore, we analyzed 325 participants from the …

The Effect Of Telehealth-Based Medical Nutrition Therapy On Cardiovascular Disease Risk Factors In A Rural Population: A Secondary Analysis Of Outcomes Related To Nutrition, Health And Well-Being From The Healthy Rural Hearts Randomised Controlled Trial, Tracy L. Schumacher, Erin D. Clarke, Jaimee Herbert, Anna Jansson, Chris Oldmeadow, Megan E. Rollo, Penny Milson, Carissa Alderton, Leanne J. Brown, Jennifer T. May Phd, Rn, Anp-Bc, Annabelle Williams, Michelle Guppy, Shanthi Ramanathan, John Attia, Clare E. Collins

Publications

BACKGROUND: Adults in rural Australia are at elevated risk of cardiovascular disease (CVD). To date, no intervention trials have evaluated the impact of dietitian delivered nutrition therapy using telehealth exclusively in patients recruited in the primary care setting. The primary aim was to assess effectiveness of telehealth delivered Medical Nutrition Therapy (MNT) on change in dietary intake energy, reported as percent energy derived from nutrient-dense (core) foods. Secondary aims included assessment of the intervention effects on percentage weight loss, quality of life, health literacy and patient engagement in their health (patient activation).

METHODS: This was a secondary data analysis of …

Advancements In Prenatal Genetic Screening And Testing: Emerging Technologies And Evolving Applications, Mona M Makhamreh, Mei Ling Chong, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

Advancements in genomic technologies have transformed prenatal genetic testing, offering more accurate, comprehensive, and noninvasive approaches to reproductive care. This review provides an in-depth overview of current methodologies and emerging innovations, including expanded carrier screening (ECS), cell-free DNA (cfDNA) testing, chromosomal microarray analysis (CMA), and sequencing-based diagnostics. We highlight how next-generation sequencing (NGS) technologies have revolutionized carrier screening and fetal genome analysis, enabling detection of a broad spectrum of genetic conditions. The clinical implementation of cfDNA has expanded from common aneuploidies to include copy number variants (CNVs), and single-gene disorders. Diagnostic testing has similarly evolved, with genome sequencing outperforming traditional …

Inhibition Of Osteosarcoma Lung Metastases By Β-Glucan And Cd40 Agonist Is Mediated By Activation Of Macrophages And Nk Cells, Pradeep Shrestha, Rejeena Shrestha, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Background: Osteosarcoma (OS) lung metastases remain a significant therapeutic challenge. Innate immune activation is a promising therapeutic approach. Innate immune agonists can modulate the tumor immune microenvironment and improve therapeutic response.

Methods: Using an experimental syngeneic OS lung metastasis BALB/c mouse model with K7M3-luc OS cells, we evaluated the antitumor effects of yeast-derived particulate β-glucan in prevention and therapeutic settings. We then assessed whether the CD40 agonist (CD40a) in combination with β-glucan increased therapeutic response in two different immune-competent mouse models of OS lung tumor burden.

Results: In the pretreatment settings, mice treated with β-glucan prior to OS cell infusion …

Integrated Single-Cell Multiomic Profiling Of Caudate Nucleus Suggests Key Mechanisms In Alcohol Use Disorder, Nicholas C Green, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

Alcohol use disorder (AUD) induces complex transcriptional and regulatory changes across multiple brain regions including the caudate nucleus, which remains understudied. Using paired single-nucleus RNA-seq and ATAC-seq on caudate samples from 143 human postmortem brains, including 74 with AUD, we identified 17 distinct cell types. A significant portion of the alcohol-related differences in gene expression were accompanied by a corresponding difference in chromatin accessibility within the gene. We observed transcriptional differences in medium spiny neurons that impact RNA metabolism and immune response pathways. A small cluster of D1/D2 hybrid neurons showed AUD-induced differences distinct from the D1 and D2 types, …

Development And Validation Of Clinical Screening Systems For Cushing Disease In The United States, Jorge E. Salcedo-Sifuentes, Sonal Mehta, Carter M. Suryadevara, Marvin Bergsneider, Kevin C. J. Yuen, Paul A. Gardner, Julie M. Silverstein, Albert H. Kim, James J. Evans, Garni Barkhoudarian, Juan C. Fernandez-Miranda, William T. Couldwell, Robert C. Rennert, Varun R. Kshettry, Kyle C. Wu, Carolina Benjamin, Gabriel Zada, Michael R. Chicoine, Jamie J. Van Gompel, Michael P. Catalino, Michael Karsy, Adam Mamelak, Ildiko Torok, Trevor Low, Won Kim, Donato R. Pacione, Nidhi Agrawal

Department of Neurosurgery Faculty Papers

PURPOSE: Clinical screening systems (CSSs) for Cushing syndrome (CS) validated in Europe have not been evaluated for CS or Cushing disease (CD) in the United States (US). We aimed to evaluate existing CSSs in US patients and develop two new symptom-based CSSs to identify patients with high pre-test probability of disease warranting referral for definitive biochemical workup-one for broad CS screening and one specifically for CD.

METHODS: Data were obtained from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID)-comprising 615 patients who underwent transnasal transsphenoidal resection for CD at one of 11 US pituitary centers, the Centers …

Ligand-Receptor Interactions Induce And Mediate Regulatory Functions Of Batf3+ B Cells, Hui Yan, Rui Wang, Suryavathi Viswanadhapalli, Christian Cervantes, Funan He, Shuai Wu, Azad Khosh, Weiwei Luo, Jingwei Wang, Maria J Fernandez, Uday P Pratap, Mustafa Khan, Karli Hinton, Sai Eashan Vankamamidi, Dariela Perez, Carlos E Rivera, Harshita B Gupta, Fushun Zhang, Zhenqing Ye, Yidong Chen, Xiao-Dong Li, Gangadhara R Sareddy, Hong Zan, Yue Li, Exing Wang, Evelien M Bunnik, Guangming Zhong, Christopher A Hunter, Ross M Kedl, Zhinan Yin, Booki Min, Diako Ebrahimi, Siyuan Zheng, Tyler J Curiel, Yan Xiang, Ratna K Vadlamudi, Paolo Casali, Zhenming Xu

Faculty, Staff and Student Publications

B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined receptor signals, and assessed their regulatory capacities and specificities through in silico analysis of ligand-receptor interactions. Consequently, we identified a B cell subset that expressed cytokine interleukin-27 (IL-27) and chemokine CXCL10. Through the IL-27–IL-27 receptor interaction, these IL-27/CXCL10-producing B cells targeted CD40-activated B cells in vitro and, upon induction by immunization and viral infection, optimized antibody responses and antiviral immunity in vivo. Also present in breast cancer tumors and retained there through CXCL10-CXCR3 …

Just-In-Time Adaptive Intervention To Improve Hiv Prevention And Substance Use In Youth Experiencing Homelessness (My-Ride): Protocol For A Randomized Controlled Trial, Diane Santa Maria, Nikhil Padhye, Michael Businelle, Natasha Slesnick, Stefani Ricondo, Marguerita Lightfoot

Faculty, Staff and Students Publications

Background: Youth who are experiencing homelessness face a higher risk of HIV infection compared to their housed peers, and suicide and overdose remain the leading causes of death among homeless youth. Just-in-Time Adaptive Interventions (JITAIs) are gaining momentum for HIV prevention and substance use research. Yet, most interventions for homeless youth have not addressed modifiable real-time factors.

Objective: This paper describes the development and implementation of a randomized attention-controlled trial to assess the efficacy of motivating youth to reduce infections, disconnections, and emotional dysregulation (MY-RIDE), a JITAI to improve HIV prevention and substance use in homeless youth.

Methods: This study …

The Effect Of Type 2 Diabetes Genetic Predisposition On Non-Cardiovascular Comorbidities, Ana Luiza Arruda, Ozvan Bocher, Henry J Taylor, Davis Cammann, Satoshi Yoshiji, Xianyong Yin, Chi Zhao, Jingchun Chen, Alexis C Wood, Ken Suzuki, Josep M Mercader, Cassandra N Spracklen, James B Meigs, Marijana Vujkovic, George Davey Smith, Jerome I Rotter, Benjamin F Voight, Andrew P Morris, Eleftheria Zeggini

Faculty, Staff and Students Publications

Type 2 diabetes is associated with a range of non-cardiovascular non-oncologic comorbidities. To move beyond associations and evaluate causal effects between type 2 diabetes genetic predisposition and 21 comorbidities, we apply Mendelian randomization analysis using genome-wide association studies across multiple genetic ancestries. Additionally, leveraging eight mechanistic clusters of type 2 diabetes genetic profiles, each representing distinct biological pathways, we investigate causal links between cluster-stratified type 2 diabetes genetic predisposition and comorbidity risk. We identify causal effects of type 2 diabetes genetic predisposition driven by distinct genetic clusters. For example, the risk-increasing effects of type 2 diabetes genetic predisposition on cataracts …

Sti Testing And Diagnosis Rates Among Patients With Mpox In 2 Populous Us Cities, 2022, Shauna H Gunaratne, Karen J Vigil, Simian Huang, Nina Kumenda, Jacob Mclean, Clare Delaurentis, Delivette Castor, Jason Zucker

Faculty, Staff and Student Publications

Background: Mpox is recognized as a sexually transmitted infection, and the 2022 epidemic and 2024 resurgence of mpox cases through sexual transmission highlighted the need for sexually transmitted infection (STI) testing. Our objective was to observe rates of STI testing and STI diagnoses in patients with confirmed mpox in Houston, Texas and New York City, New York (NY).

Methods: This was a retrospective cohort study involving manual review of confirmed mpox cases at three large clinical centers in Houston, Texas and New York City, NY. Descriptive statistics were calculated for rates of STI testing and new diagnoses of syphilis, chlamydia …

Germline Determinants Of Toxicity And Efficacy In Patients With Large B-Cell Lymphoma Treated With Car T-Cell Therapy, Paolo Strati, Amanda Brandt, Anath C Lionel, Jared Henderson, Jason R Westin, Sherry Adkins, Elizabeth J Shpall, Partow Kebriaei, Jeremy Ramdial, Neeraj Saini, Sairah Ahmed, Christopher Flowers, Sattva S Neelapu, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

Background: Recent data have suggested that germline genetic aberrations can affect outcomes in patients with large B-cell lymphoma (LBCL) treated with chimeric antigen receptor T-cell therapy (CART). However, a comprehensive analysis of germline determinants of response and toxicity after CART has not yet been described.

Methods: Genome-wide genotyping was performed in 170 patients with LBCL treated with standard of care axicabtagene ciloleucel. Polygenic risk score instruments for blood cell traits and inflammatory markers were obtained from the PGS Catalog and analyzed using PRSice-2. Exploratory gene-based and genome-wide association study analyses were performed. Genetic ancestry of the patients with LBCL was …

Comprehensive Analysis Of The Tumor Targeting Efficiency Of Functionalized Nanoparticles In An Immunocompetent Environment, Nolan Jackson, Nasry Bouzeineddine, Daniel Cecchi, Safara Holder, Katrina Gee, Wayne Beckham, Sameh Basta, Sunil Krishnan, Devika B Chithrani

Faculty, Staff and Student Publications

The success of nanoparticle-based cancer therapeutics relies on their efficient tumor uptake and retention. Given this, improving nanoparticle localization in tumors is paramount to maximize their therapeutic potential. A common approach to achieve this is to functionalize nanoparticles with active targeting moieties that bind to specific tumor-associated receptors. Among these, arginine-glycine-aspartic acid (RGD) peptides have shown a potential to promote tumor accumulation by targeting the ανβ3 integrin receptor, a receptor commonly overexpressed by tumors owing to its role in promoting angiogenesis, metastasis and proliferation. Yet, its efficacy is commonly assessed using immunocompromised mice models. While useful, these models do not …

Polychlorinated Biphenyls Alter Estrogen Receptor Β-Mediated Epigenetic Regulation, Promoting Endometriosis, Yuri Park, Nuri Sung, Eunsu Kim, Jaeyeong Jeong, Juhee Sim, Mi Jin Park, John P Lydon, Xiaoming Guan, Sang Jun Han

Faculty, Staff and Students Publications

Endometriosis is a pathological condition characterized by the ectopic growth of endometrial cells, leading to chronic pelvic pain and infertility. Epidemiological studies have associated exposure to dioxin-like polychlorinated biphenyls, particularly PCB126, with an increased risk of endometriosis. However, the underlying mechanisms of this association remain poorly understood. We utilized a surgically induced endometriosis mouse model and human endometrial cell lines to assess the impact of PCB126 on endometriosis progression. Mice were exposed to environmentally relevant doses of PCB126. Endometriotic lesion growth, estrogen receptor signaling, receptor tyrosine kinase activity, and gene expression changes induced by PCB126-mediated elevation of DNA methyltransferase 3A …

Dual Targeting Of Orphan Nuclear Receptors Nr4a1 And Nr4a2 For Nonhormonal Endometriosis Therapy, Wai Ning Tiffany Tsui, Yuri Park, Srijana Upadhyay, Da Mi Kim, Lei Zhang, Gus Wright, Amanuel Hailemariam, Arafat Rahman Oany, Sang Jun Han, Stephen Safe

Faculty, Staff and Students Publications

Previous studies show that orphan nuclear receptor 4A1 (NR4A1) regulates endometriotic cell growth, survival, estrogen receptor β (ERβ), mechanistic target of rapamycin signaling and fibrosis. NR4A2 is also expressed in epithelial and stromal derived endometriotic cells, and in this study the effects of 1,1-bis(3'-indolyl)-(3,5-disubstitutedphenyl)methane (DIM-3,5) dual NR4A1/nuclear receptor 4A2 (NR4A2) ligands and knockdown of NR4A1 and NR4A2 were investigated. The dual NR4A1/2 DIM-3,5 analogs inhibited previously identified proendometriotic pathways and gene products, and they also inhibited TWIST1 and multiple markers associated with epithelial-to-mesenchymal transition (EMT). The results show that both NR4A1 and NR4A2 regulate the same pathways, including endometriotic cell …

Completion Rates For Ecological Momentary Assessments Of Food Intake During Pregnancy And Post Partum: Descriptive Study, Sarah Annalise Sanders, Serwaa Omowale, Andrea Casas, Alexis Kiyanda, Abigail Smith Kosbie, Yu-Hsuan Lai, Meredith Wallace, Stephen Rathbun, Tiffany Gary-Webb, Esa Davis, Lora Burke, Dara Méndez

Faculty, Staff and Student Publications

Background: The collection of dietary behavior data is crucial in childbearing populations. In addition to observed inequities in perinatal dietary intake and quality, burdensome assessment methods (eg, 24-h dietary recall) may limit research participation for some groups. Ecological momentary assessment (EMA) is associated with reduced recall bias and participant convenience, but there is a dearth of studies with diverse cohorts.

Objective: Our aim is to describe participant completion of food intake items in EMA surveys, overall and across individual characteristics (eg, prepregnancy BMI).

Methods: Using secondary EMA data from participants in a longitudinal study, we report average completion rates of …

Synaptic Transmission Promotes Brain Metastatic Outgrowth In Breast Cancer, Jayanta Mondal, Patrick Nylund, Prit Benny Malgulwar, William E Johnson, Jason T Huse

Faculty, Staff and Student Publications

This work demonstrates that normal neuron-to-neuron signaling machinery is hijacked by metastasizing cancer cells during their outgrowth in the central nervous system.

Quiescent Oxphos-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend On Bcl-Xl For Survival, Slawomir Andrzejewski, Marie Winter, Leandro Encarnacao Garcia, Olusiji Akinrinmade, Francisco Madeira Marques, Emmanouil Zacharioudakis, Anna Skwarska, Julio Aguirre-Ghiso, Marina Konopleva, Guangrong Zheng, Susan A Fineberg, Daohong Zhou, Evripidis Gavathiotis, Tao Wang, Eugen Dhimolea

Faculty, Staff and Student Publications

The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling, …

Barriers And Facilitators Of Implementing A Community Workshop Series To Mitigate Maternal-Child Food Insecurity: A Mixed-Methods Re-Aim Evaluation, Kristen Herlosky, Ana Baumann, Et Al.

2020-Current year OA Pubs

BACKGROUND: Community-led workshops offer promising health education models to advance maternal-child health equity by providing culturally congruent spaces for information sharing, resource access, and social support building. This study aimed to (1) document the participatory co-creation of a Community Workshop Series with topics across the Nurturing Care Framework domains (health, nutrition, early learning, security/safety, responsive caregiving) to mitigate maternal-child food insecurity, (2) evaluate CWS effectiveness in increasing participants' knowledge across the Nurturing Care Framework, and (3) identify CWS implementation barriers and facilitators.

METHODS: The study employed two-phases: Phase One engaged members of a Community Advisory Board in participatory research to …

Hydroxyapatite Microspheres Induce Durable Pleurodesis And Are Rapidly Cleared By Pleural Osteoclasts, Yusuke Tanaka, Yuki Takahashi, Yuma Shindo, Lori B. Pitstick, Steven L. Teitelbaum, Wei Zou, Xiangning Wang, Jason C. Woods, Kathryn A. Wikenheiser-Brokamp, Francis X. Mccormack

2020-Current year OA Pubs

Talc pleurodesis is highly effective for preventing recurrence of pneumothorax and pleural effusion, but it can be complicated by dissemination, acute lung injury, lead exposure, and foreign body-induced chronic inflammation and pain. Our objective is to develop a safe, biodegradable, contaminant-free particle for pleurodesis. We used mouse models of pneumothorax and malignant pleural effusion to compare the efficacy and safety of pleurodesis with talc and hydroxyapatite microspheres (HAM). Intrapleural instillation of microspheres induced pleural adhesions, fibrosis, and symphysis as effectively as talc and resulted in more durable protection from experimental pneumothorax. HAM and talc both induced an osteoclastogenic, inflammatory, and …

Gabaergic Interneurons Contribute To The Fatal Seizure Phenotype Of Cln2 Disease Mice, Keigo Takahashi, Nicholas R. Rensing, Elizabeth M. Eultgen, Letitia L. Williams, Sophie H. Wang, Hemanth R. Nelvagal, Steven Q. Le, Marie S. Roberts, Balraj Doray, Edward B. Han, Patricia I. Dickson, Michael Wong, Mark S. Sands, Jonathan D. Cooper

2020-Current year OA Pubs

The cellular etiology of seizures in CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), remains elusive. Given that Cln2R207X/R207X mice display fatal spontaneous seizures and an early loss of several cortical GABAergic interneuron populations, we hypothesized that these 2 events might be causally related. To study the cell-autonomous effects of interneuron-specific TPP1 deficiency, we first generated transgenic mice expressing loxP-flanked lysosomal membrane-tethered TPP1 (TPP1LAMP1 mice) on the Cln2R207X/R207X genetic background, and then crossed TPP1LAMP1 mice with Vgat-Cre mice. These Vgat-Cre; TPP1LAMP1 mice accumulated storage material in cortical and striatal interneurons. Vgat-Cre; …

Implementation Mapping To Identify Best Practices For Implementing Population-Wide Genomic Screening Programs: Protocol For The Focus (Facilitating The Implementation Of Population-Wide Genomic Screening) Study, Megan Roberts, Jarrod Marable, Kimberly Foss, Cason Whitcomb, Deborah Cragun, Adam Buchanan, Miranda Hallquist, Nathaniel Baker, Rebecca Bosch, Derek W Craig, Ingrid Wagner, Maria Fernandez, Chanita Hughes-Halbert, Caitlin Allen

Faculty, Staff and Student Publications

Background: Population-wide genomic screening (PGS) for genetic conditions such as hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia presents opportunities to reduce morbidity and mortality among the 1%-2% of the population at elevated risk for these serious, preventable diseases. With decreasing sequencing costs and growing support from national bodies, there are increasing numbers of PGS programs in the United States. However, guidelines and strategies to support implementation are limited, especially regarding equitable access to PGS. Contextual factors, such as organizational structures and processes, impact PGS implementation, often failing to benefit underrepresented populations. To address these challenges, we …

Impact Of Obicetrapib On Major Adverse Cardiovascular Events In High-Risk Patients: A Pooled Analysis, Stephen J Nicholls, Adam J Nelson, Kausik K Ray, Christie M Ballantyne, Marc Ditmarsch, Douglas Kling, Andrew Hsieh, Michael Szarek, John J Kastelein, Michael H Davidson

Faculty, Staff and Students Publications

Background: The cholesteryl ester transfer protein inhibitor obicetrapib decreases levels of atherogenic lipids and raises high-density lipoprotein cholesterol (HDL-C).

Objectives: In this study, we sought to determine the effect of obicetrapib on cardiovascular events.

Methods: The effects of 10 mg obicetrapib and placebo daily on major adverse cardiovascular event (MACE) rates were investigated in a pooled analysis of 354 patients with heterozygous familial hypercholesterolemia (HeFH) and 2,530 patients with atherosclerotic cardiovascular disease (ASCVD) over 365 days. The association between on-treatment lipids and MACE were also investigated.

Results: The cohort (mean age 66 years, 36% female, ASCVD 82%, HeFH 27%, diabetes …

Performance Evaluation Of A Commercial Multiplex Pathogen Panel For Detection Of Bacteria In Sputum Specimens From Non-Icu Patients With Suspected Lower Respiratory Tract Infection, Madeline Gemoules, Tristan T Timbrook, Elizabeth Neuner, Rebekah E Dumm, Tamara Krekel

2020-Current year OA Pubs

Rapid diagnostic testing can improve pathogen detection and lead to targeted antibiotics. The BioFire FilmArray Pneumonia Panel (BFPP) is a multiplex PCR that has displayed strong concordance with traditional microbiologic techniques. However, most existing literature focuses on deep respiratory specimens, and there is sparse literature on performance in sputum specimens. This retrospective, single-center study included adult patients between 1 September 2022 and 31 August 2024 who had collection of a BFPP with standard of care (SOC) culture from a sputum specimen on a non-intensive care unit (ICU) floor or in the emergency department if admitted to a non-ICU floor. Out …

Fate Mapping Of Peripherally-Derived Macrophages After Traumatic Brain Injury In Mice Reveals A Long-Lasting Population With A Distinct Transcriptomic Signature, Maria Serena Paladini, Benjamin A Yang, Kristof A Torkenczy, Elma S Frias, Xi Feng, Karen Krukowski, Rene Sit, Maurizio Morri, Wendy Lam, Valentina Pedoia, Stefka Tyanova, Marco Colonna, Amber L Nolan, Susanna Rosi

2020-Current year OA Pubs

Traumatic brain injury (TBI) is an environmental risk factor for dementia and long-term neurological deficits, posing a significant public health challenge. TBI-induced neuroinflammation involves both brain-resident microglia and peripheral monocyte-derived macrophages (MDMs). Previous research has shown that MDMs contribute to the development of long-term memory deficits, yet their long-term behavior following brain infiltration remains unclear. To address this, our study uses two complementary fate-mapping mouse lines, CCR2-creERT2 and Ms4a3-cre, for precise and lasting tracking of MDMs in vivo. Here we show that MDMs persist in the brain for at least 8 months post-TBI in both male and female mice. MDMs …

Genetics-Nutrition Interactions Control Diurnal Enhancer-Promoter Dynamics And Liver Lipid Metabolism, Dishu Zhou, Ying Chen, Panpan Liu, Kun Zhu, Juliet Holder-Haynes, S Julie-Ann Lloyd, Cam Mong La, Inna I Astapova, Seunghee Choa, Ying Xiong, Hosung Bae, Marlene Aguilar, Hongyuan Yang, Yu A An, Zheng Sun, Mark A Herman, Xia Gao, Liming Pei, Cholsoon Jang, Joshua D Rabinowitz, Samer G Mattar, Yongyou Zhang, Dongyin Guan

Faculty, Staff and Student Publications

The circadian clock controls 24-h rhythmic processes. However, how genetic variations outside clock genes impact peripheral diurnal rhythms remains largely unknown. Here, we find that genetic variation contributes to different diurnal patterns of hepatic gene expression in both humans and mice. Nutritional challenges alter the rhythmicity of gene expression in mouse liver in a strain-specific manner. Remarkably, genetics and nutrition interdependently control more than 80% of rhythmic gene and enhancer-promoter interactions (E-PIs), with a noncanonical clock regulator, estrogen-related receptor gamma (ESRRγ), emerging as a top transcription factor during motif mining. Knockout of Esrrγ abolishes strain-specific metabolic processes in response to …

Genetic Underpinnings Of The Heterogeneous Impact Of Obesity On Lipid Levels And Cardiovascular Disease, Daeeun Kim, Heather M Highland, Roelof A J Smit, Micah R Hysong, Victoria L Buchanan, Kristin L Young, Chi Zhao, Cassandra N Spracklen, Tuomas O Kilpeläinen, Boya Guo, Burcu F Darst, Yanwei Cai, Zhe Wang, Jessica Lundin, Sonja I Berndt, Joann E Manson, Eirini Marouli, Leslie Lange, Ethan Lange, Myriam Fornage, Christopher R Gignoux, Christopher A Haiman, Stephen S Rich, Steven Buyske, Ruth J F Loos, Charles Kooperberg, Ulrike Peters, Christy L Avery, Penny Gordon-Larsen, Mariaelisa Graff, Laura M Raffield, Kari E North

Faculty, Staff and Student Publications

Background: Obesity is thought to increase cardiovascular disease (CVD) risk partly through dyslipidemia. Yet, obesity's effects on dyslipidemia are not uniform. Understanding the shared genetic basis between obesity and lipid traits can provide insight into this heterogeneity and its implications for CVD risk.

Methods: We examined local genetic correlations between three lipid measures [high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG)] and body mass index (BMI) using genome-wide association study summary statistics from European ancestry UK Biobank participants. We identified genomic loci with opposing genetic effects on obesity and dyslipidemia risk (protective BMI-lipid loci) and those with …