Digital Commons Network^™

N-Palmitoyl Glutamine Is A Candidate Mediator Of Cardiorespiratory Fitness, Jeremy M Robbins, Mark Benson, Anthony R P Verkerke, Gaurav Tiwari, Shuliang Deng, Prashant Rao, Usman A Tahir, Julian Avila-Pacheco, Xu Shi, Yuntian Guan, Foje-Geh Tendoh, Jacob L Barber, Patricia E Miller, Andrew S Perry, Michael E Hall, Alexis C Wood, Kent D Taylor, Wendy S Post, Stephen S Rich, Matthew Nayor, James G Wilson, Gregory D Lewis, Ravi V Shah, Jerome I Rotter, Scott A Summers, Laura M Raffield, Shingo Kajimura, Claude Bouchard, Clary B Clish, Mark A Sarzynski, Robert E Gerszten

Children’s Nutrition Research Center Staff Publications

Background: Cardiorespiratory fitness is an integrative measure of cardiometabolic health and predictor of survival, yet little is known about its molecular underpinnings. Small molecule metabolites and lipids are increasingly recognized as exercise-stimulated signaling molecules and candidate molecular transducers of cardiorespiratory fitness.

Methods: We performed nontargeted liquid chromatography mass spectrometry-based plasma metabolomics in 654 participants (mean age, 35 years; 55% women) from the HERITAGE Family Study (Health, Risk Factors, Exercise Training, and Genetics) who had cardiorespiratory fitness (maximal oxygen uptake [VO2max]) measured by cardiopulmonary exercise testing and underwent 20 weeks of supervised endurance training. Metabolite-VO2max relationships were assessed using linear regression …

Towards A Unified Gating Scheme For The Cnbd Ion Channel Family, Jenna L Lin, Baron Chanda

2020-Current year OA Pubs

Cyclic nucleotide-binding domain (CNBD) channels are critical components of numerous bioelectrical processes, including cardiac pacemaking, neuronal signaling, phototransduction in the eye, and stomatal regulation in plants. While members of this channel family share a conserved overall structure, they exhibit striking differences in voltage sensitivity. Hyperpolarization-activated cyclic nucleotide-gated channels are activated by membrane hyperpolarization, whereas ether-à-go-go channels open upon depolarization. Mutagenesis and chimeragenesis studies have revealed that some mutants display bipolar gating behavior-remaining closed at intermediate membrane potentials but capable of opening in response to both hyperpolarization and depolarization. Remarkably, in certain cases, just a few mutations are sufficient to reverse …

Β2 And Β3a Regulatory Subunits Can Coassemble In The Same Bk Channels, Yu Zhou, Vivian Gonzalez-Perez, Xiao-Ming Xia, Gopal S Kallure, Sandipan Chowdhury, Christopher J Lingle

2020-Current year OA Pubs

Ca2+- and voltage-activated BK-type K+ channels are influenced profoundly by associated regulatory subunits, including β subunits (Kcnmb1-4; β1-β4). Although overlap in expression of different BK β subunits occurs in native tissues, whether they can coassemble in the same channel complex is not known. We coexpress β2 and β3a subunits together with BK α and, through a combination of macroscopic and single-channel recordings, along with quantitative pull-down of tagged subunits, test whether coassembly can occur. We evaluate two models: (1) random mixing in which β2 and β3a subunits coassemble in the same channels, and (2) segregation in which β2 and β3a …

Pathogenesis Of Polyglutamine Diseases: Piecing Together A Complex Molecular Puzzle, Esmeralda Villavicencio Gonzalez, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Polyglutamine (polyQ) diseases, caused by a CAG repeat expansion encoding a glutamine tract in nine distinct proteins, present a complex molecular puzzle in which each piece contributes to neurodegeneration. While each of the causative proteins has a distinct function, the downstream consequences of polyQ toxicity are often similar, including protein accumulation, transcriptional dysregulation, somatic CAG repeat instability, disrupted energy homeostasis, compromised synaptic function, and selective neuronal death. This review summarizes emerging insights into how proteins with an expanded polyQ tract disrupt distinct cellular functions, and we examine a multitude of discoveries that are inspiring and reshaping novel therapeutic strategies.

Micrornas In Prostate Cancer Liquid Biopsies: Early Detection, Prognosis, And Treatment Monitoring, Seyyed Mohammad Yaghoubi, Erfan Zare, Sina Jafari Dargahlou, Maryam Jafari, Mahdiye Azimi, Maedeh Khoshnazar, Solmaz Shirjang, Behzad Mansoori

Student Papers, Posters & Projects

Prostate cancer (PCa) is a common malignancy in men worldwide, with incidence projected to rise in the coming years. Traditional screening and diagnostic methods, such as prostate-specific antigen (PSA) testing and biopsy, face limitations in specificity and invasiveness. Circulating microRNAs (miRNAs) have emerged as stable, non-invasive biomarkers obtainable via liquid biopsies (blood, urine, semen) that could transform PCa management. These small regulatory RNAs reflect underlying tumor biology and are detectable at early disease stages, enabling improved early detection when used alongside or in place of PSA. Distinct miRNA expression patterns correlate with tumor aggressiveness. For example, miR-141 and miR-375 are …

Anti-Csf-1r Therapy With Combined Immuno-Chemotherapy Coordinate An Adaptive Immune Response To Eliminate Macrophage Enriched Triple Negative Breast Cancers, Diego A Pedroza, Xueying Yuan, Fengshuo Liu, Hilda L Chan, Christina Zhang, William Bowie, Alex J Smith, Sebastian J Calderon, Nadia Lieu, Weiguo Wu, Paul Porter, Poonam Sarkar, Na Zhao, Constanze V Oehler, Ondrej Peller, M Waleed Gaber, Qian Zhu, Charles M Perou, Xiang H-F Zhang, Jeffrey M Rosen

Faculty, Staff and Students Publications

Women diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory low-dose Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic Trp53 null TNBC transplantable syngeneic models that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along …

Bromodomain And Extra-Terminal Protein Inhibitors Modulate Natural Killer Cell Function And Differentiation., Eric S. Geanes, Gage Greening, Maria Aggelakopoulou, Linh Huyen Truong, Santosh Khanal, Cas Lemaster, Marc L. Herman, Rebecca Mclennan, Persephone Borrow, Todd Bradley

Manuscripts, Articles, Book Chapters and Other Papers

Natural killer (NK) cells are integral to the innate immune system, playing a crucial role in immune surveillance and the rapid response to virally infected and tumor cells. Epigenetic gene expression regulation significantly influences NK cell function and differentiation. Using a high-throughput small-molecule drug screening approach, we identified bromodomain and extra-terminal domain (BET) inhibitors (BETi) as potent modulators of NK cell function, reducing proinflammatory cytokine secretion while increasing markers of NK cell maturation and cytotoxicity. During NK lineage specification from hematopoietic stem cells, we demonstrated that BETi reduced NK cell fate and promoted increased myeloid cell differentiation. Moreover, differentiated NK …

Impaired Complement Regulation Drives Chronic Lung Allograft Dysfunction After Lung Transplantation, Hrishikesh S. Kulkarni, Laneshia K. Tague, Fuyi Liao, Zhiyi Liu, Lorena Garnica, Nishanth R. Shankar, Xiaobo Wu, Dequan Zhou, Yan Tao, Victoria E. Davis, Cory T. Bernardt, Derek E. Byers, Chad A. Witt, Daniel Kreisel, John P. Atkinson, Andrew E. Gelman, Et Al.

2020-Current year OA Pubs

A greater understanding of chronic lung allograft dysfunction (CLAD) pathobiology, the primary cause of death after lung transplantation (LTx), is needed to improve outcomes. The complement system links innate to adaptive immune responses and is activated early after lung transplantation to form C3 convertase, a critical enzyme that cleaves the central complement component C3. We hypothesized that LTx recipients with a genetic predisposition to enhanced complement activation have worse CLAD-free survival mediated through increased adaptive alloimmunity. We interrogated a known functional C3 polymorphism (C3 R102G) that increases complement activation through impaired C3 convertase inactivation in 2 independent LTx recipient cohorts. …

Cholesterol Efflux Protein, Abca1, Supports Anticancer Functions Of Myeloid Immune Cells, Shruti V Bendre, Yu Wang, Basel Hajyousif, Rajendra K C, Shounak G Bhogale, Dhanya Pradeep, Natalia Krawczynska, Claire P Schane, Erin Weisser, Avni Singh, Simon Han, Hannah Kim, Lara Kockaya, Anasuya Das Gupta, Adam T Nelczyk, Hashni Epa Vidana Gamage, Yifan Fei, Desirée Rodríguez-Casiano, Xingyu Guo, Haoyun Li, Ryan J Deaton, Fei Mo, Maria Sverdlov, Peter H Gann, Saurabh Sinha, Sahil Sahni, Kun Wang, Kevin Van Bortle, Emad Tajkorshid, Wendy A Woodward, Wonhwa Cho, Erik R Nelson

Faculty, Staff and Student Publications

Breast and other solid tumors respond poorly to immune therapy. Myeloid cells (MCs) such as macrophages contribute to resistance. Established clinical evidence links cholesterol to cancer outcomes, with MC function being regulated by cholesterol metabolism. We screened MC-expressed regulators of cholesterol homeostasis linked to survival and identified the cholesterol efflux protein ABCA1. ABCA1 activity increases anticancer functions of macrophages: enhancing tumor infiltration, decreasing angiogenic potential, reducing efferocytosis, and improving support of CD8+ T cell activity. Mechanistically, different AKT isoforms are involved, through both PI3K-dependent and PI3K-independent mechanisms. Highlighting the clinical relevance of our findings are correlations between ABCA1 in macrophages …

Nf2 Loss Malignantly Transforms Human Pancreatic Acinar Cells And Enhances Cell Fitness Under Environmental Stress, Yi Xu, Michael H Nipper, Angel A Dominguez, Chenhui He, Francis E Sharkey, Sajid Khan, Han Xu, Daohong Zhou, Lei Zheng, Yu Luan, Jun Liu, Pei Wang

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) occurs as a complex, multifaceted event driven by the interplay of tumor-permissive genetic mutations, the nature of the cellular origin, and microenvironmental stress. In this study, using primary human pancreatic acinar 3D organoids, we performed a CRISPR-KO screen targeting 199 potential tumor suppressors curated from clinical PDAC samples. Our data revealed significant enrichment of a list of candidate genes, with neurofibromatosis type 2 associated gene (NF2) emerging as the top target. Functional validation confirmed that loss of NF2 promoted the transition of PDAC to an invasive state, potentially through extracellular matrix modulation. NF2 inactivation …

Amyloid Β-Cholesterol Interplay: Removal Of Cholesterol From The Membranes To Catalyze Aggregation And Amyloid Pathology, Rishiram Baral, Ruan Van Deventer, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42-residue form of the amyloid-β peptide) peptides in pathological aggregates is considered one of the major molecular mechanisms in the development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that …

Differential Sensitivity Of Leukocyte Populations To Staphylococcus Aureus Biofilm, Nichole D. Brandquist, Tammy Kielian

Journal Articles: Pathology and Microbiology

Staphylococcus aureus is a leading cause of prosthetic joint infection (PJI) typified by biofilm formation. Anti-inflammatory granulocytic myeloid-derived suppressor cells (G-MDSCs) represent the main leukocyte population in a mouse model of S. aureus PJI, followed by neutrophils (PMNs), and macrophages (Mφs), which is also seen during human PJI. Defining how each leukocyte population responds to S. aureus biofilm vs planktonic bacteria could have important implications for how S. aureus evades immune detection to facilitate biofilm persistence. This study compared the kinetics of leukocyte death and relationship to mitochondrial ROS (mtROS) production following exposure to planktonic S. aureus or biofilm. Mφs …

Factors Affecting Detection And Quantification Of Schistosoma Haematobium Eggs In Pooled Urine Samples, Abraham Degarege, Bruno Levecke, Christopher R. Bilder, David Brett-Major, Abebe Animut, Yohannes Negash, M. Jana Broadhurst, Tzeyu L. Michaud, Berhanu Erko

Journal Articles: Epidemiology

BACKGROUND: Building on our previous work showing that pooled urine testing can rapidly detect Schistosoma haematobium infections but has limited sensitivity in low-intensity settings or with large pool sizes, this study evaluated how urine volume, pool size, infection intensity, and diagnostic method affect the detection and quantification of S. haematobium eggs in pooled samples.

METHODS: Between July 2022 and April 2023, 2,134 urine samples from school-age children living in three regional states of Ethiopia were individually examined by deploying urine filtration microscopy (UFM). Subsequently, 5, 10, 20 and 40 individual samples were strategically pooled and examined by deploying UFM and …

African Domestic Poultry Genetic Resources, Diversity, And Unique Features, Tadelle Dessie, Christian K. Tiambo, Liveness J. Banda, Raman Akinyanju Lawal, Sheila C. Ommeh, Timothy Gondwe, Esatu Wondmeneh, Matthew A. Adeleke, Olivier Hanotte

Faculty Research 2026

This chapter provides a detailed account of African domestic poultry genetic resources, their diversity, and unique features. It aims to bring together information to provide a comprehensive picture of the topic. Section 7.1 introduces African poultry genetic resources, their importance, and previous interventions conducted to better utilize this important resource. Section 7.2 deals with the origin of poultry genetic resources and their dispersal into Africa. The introduction of domesticated chickens into Africa is not well documented. Although indigenous birds have several adaptive traits and associated genes that are important in the tropics, the real value of indigenous chicken breeds is …

Educational Efficacy Of Training Videos And Simulators For Teaching Basic Mouse Experimental Skills To Novice Veterinary Students., Atsushi Tsukamoto, Thum Su Zan, Makie Nitta, Hiromitsu Yoshida, Hirotaka Katahira, Yoshiharu Fujita, Satoshi Takagi, Shinichiro Nakamura

Faculty Research 2026

Alternative educational tools, such as training videos and simulators, are recommended in the education of laboratory animal science. However, evidence supporting their educational utility in the training of rodent experimental techniques remains limited. In this study, we assessed the utility of alternative educational tools in the practice of laboratory animal science for novice veterinary students. 149 students participated in a stepwise program beginning with lectures, followed by preparatory learning sessions using training videos and two types of mouse simulators (a silicone-based model and fabric toy mouse), and then hands-on training with live mice. The program covered basic techniques: habituation, restraint, …

Overcoming Egfr-Mediated Dendritic Cell Dysfunction To Enhance Anti-Tumor Immunity In Egfr-Mutant Nsclc By Precisely Targeting Cd73 With Ph-Responsive Nanocarriers., Xiaoling Shang, Xudong Geng, Zixu Wang, Shumin Yuan, Shanshan Ding, Ni Liu, Xinchun Ma, Xuan Sun, Huimin Wang, Ying Sun, Xun Qu, Guangwen Ren, Yong Qiang Li, Xiuwen Wang, Yanguo Liu

Faculty Research 2026

EGFR mutations remain a major challenge in immunotherapy for non-small cell lung cancer (NSCLC), with poor responses to immune checkpoint inhibitors driven by mechanisms associated with EGFR mutation-mediated tumor microenvironment (TME) modulation. This study reveals that EGFR mutations prominently impaired dendritic cell (DC) maturation, disrupting their capacity to effectively prime CD8+ T cells and thereby compromising anti-tumor immune responses. By application of clinical specimen analyses, multi-omics approaches, and in vivo mouse models, this work demonstrates that EGFR mutations elicited adenosine production through the ERK/c-Jun signaling axis in tumor cells, establishing an immunosuppressive TME that impeded maturation and antigen presentation of …

Cxcr6+ Natural Killer Cell Immunotherapy Preserves Cd4+ T Helper Cells In Humanized Mice, Naushad Khan, Kayla Frank, Silke Paust

Faculty Research 2026

Human immunodeficiency virus (HIV) persists despite antiretroviral therapy because long-lived viral reservoirs are not eliminated, and ongoing or rebound infection contributes to progressive loss of CD4⁺ T helper cells. Natural killer (NK) cells can acquire adaptive, antigen-experienced functions, including recall responses to HIV envelope protein, suggesting that defined NK-cell subsets may be therapeutically useful against HIV. Because HIV-responsive adaptive NK-cell activity is enriched among CXC chemokine receptor 6-positive (CXCR6⁺) NK cells, we tested whether CXCR6⁺ NK cells provide enhanced antiviral activity and CD4⁺ T-cell protection compared with CXCR6⁻ NK cells. In co-cultures with HIV-infected …

Can Angiotensin Ii Affect The Inflammatory Response Of Human Dental Pulp Cells In Vitro?, Bella Luna Colombini-Ishikiriama, Thiago José Dionisio, Thais Francini Garbieri, Rafaela Alves Da Silva, Sandra Helena Penha Oliveira, Vanessa Soares Lara, Andrew S Greene, Carlos Ferreira Dos Santos

Faculty Research 2026

OBJECTIVE: This study aimed to evaluate the capacity of fibroblasts from permanent and deciduous dental pulp to express inflammatory mediators when exposed to bacterial and inflammatory antigens. It also sought to assess the presence of components of the renin-angiotensin system (RAS) and the potential modulatory role of ANG-II in this response.

METHODOLOGY: Fibroblasts were cultured from the pulp of permanent and deciduous teeth obtained from three adult and four pediatric donors with informed consent. Cells were stimulated with Porphyromonas gingivalis and Escherichia coli lipopolysaccharides (LPS) either alone or in combination with ANG-II and, in some cases, with IL-1β. Gene expression …

Z Variant Heterozygosity In Alpha-1 Antitrypsin Deficiency: Disease Risk And Treatment Implications, Craig P. Hersh, Jeffrey H. Teckman, Pavel Strnad, Aaron Hakim, Tomás P. Carroll, Ian P. Hall, Auyon J. Ghosh, Igor Barjaktarevic, Noel G. Mcelvaney, Joseph E. Kaserman, David A. Lomas, Charlie Strange, M Bradley Drummond, Stephen I. Rennard, Kathi E. Hanna, Virginia C. Clark, Monica P. Goldklang, Peg Iverson, Andrew A. Wilson

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Individuals heterozygous for alpha-1 antitrypsin deficiency (AATD) have one copy of the normal "M" allele and one copy of an abnormal allele ("Z", "S", or another variant) in the SERPINA1 gene. Historically, evidence has been lacking to support the concept that heterozygotes are at increased risk for liver and/or lung complications compared to individuals homozygous for the M allele. However, growing evidence suggests that inheritance of a single Z allele increases the risk of disease in some individuals. The Alpha-1 Foundation convened a workshop on October 27, 2023, in Bethesda, Maryland that included stakeholders from the research, pharmaceutical, and …

Biomechanical Integrity Of The Female Pelvic Floor: A Comparison Of Military And Civilian Women, Vladimir Egorov, Peter Takacs, Vincent Lucente, Heather Van Raalte, Joy A. Greer, Noune Sarvazyan

Department of Obstetrics & Gynecology Faculty Publications

Introduction

The health of the pelvic floor depends on the integrity of its muscles, connective tissue, ligaments, and their innervation. The female pelvic floor may be more vulnerable to repetitive heavy loads in a military environment than the male pelvic floor because of anatomical and physiological differences. The study aim was to identify and explore possible differences in the female pelvic floor conditions between active military and civilian women with similar demographics.To identify and explore possible differences in the conditions of the female pelvic floor between active military women and civilian women with similar demographics.

Materials and Methods

Military active …

Cgas-Sting Dependent Type I Ifn Reduces Leptospira Interrogans Renal Colonization In Mice., Suman Gupta, James Matsunaga, Bridget Ratitong, Andrew Manion, Sana Ismaeel, Diogo G Valadares, A Phillip West, Nagaraj Kerur, Christian Stehlik, Andrea Dorfleutner, Jargalsaikhan Dagvadorj, Jenifer Coburn, Andrea J Wolf, Meghan A Morrissey, Suzanne L Cassel, David A Haake, Fayyaz S Sutterwala

Faculty Research 2026

Leptospira interrogans is the major causative agent of leptospirosis. Humans, canines and agricultural animals are susceptible to Leptospira species and can develop fulminant disease. Rodents serve as reservoir hosts in which the bacteria colonize the renal tubules and are excreted in the urine. The host immune response to Leptospira spp. remains poorly defined. We show that L. interrogans induces a robust type I interferon (IFN) response in human and murine macrophages that is dependent on the cytosolic dsDNA sensor Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of IFN Genes (STING) signaling pathway. Further, we show that mice deficient in the …

Peculiarities Of Phosphatidylserine Externalization By Nano- And Microsecond Electric Pulses, Mantas Silkunas, Alayna Enos, Iurii Semenov, Giedre Silkuniene, Eleni Zivla, Olga N. Pakhomova, Andrei G. Pakhomov

Bioelectrics Publications

Phosphatidylserine (PS) externalization is a hallmark of apoptosis but can also be triggered within seconds by pulsed electric fields (PEFs). Whether PS reaches the outer leaflet by lateral migration through electropores or indirectly through Ca²⁺-dependent signaling and scramblase activation remains debated. We used total internal reflection fluorescence (TIRF) microscopy with Annexin V-Alexa Fluor 568 and/or bovine lactadherin-FITC to resolve PS externalization in HEK293 cells placed on an indium tin oxide (ITO) transparent electrode. PEF exposures produced discrete PS-positive puncta ("freckles") within ~ 10 s after a 20-µs pulse (1.2-2.5 kV/cm) or with a ~ 1-min delay after a …

Stim1-Dependent Treg Dysfunction Promotes Cardiometabolic Hfpef: Insights From Patients And Animal Studies, Balaji Srinivas, Alluri Kiran, Hongmei Peng, Jiang Xu, Paula Fortuno, Jennifer May, Ismail El Moudden, Nour-Eddine Rhaleb, John M. Herre, Raymond L. Benza, Khalid Matrougui

Department of Biomedical and Translational Sciences Faculty Publications

Background

Heart failure with preserved ejection fraction (HFpEF) arises from chronic cardiometabolic and vascular stress and is increasingly recognized as an inflammatory syndrome with immune dysregulation. Regulatory T cells (Tregs) are critical modulators of cardiovascular inflammation, yet the mechanisms driving Treg dysfunction in HFpEF remain poorly defined. stromal interaction molecule 1 (STIM1)-dependent calcium signaling is a key stress-responsive pathway in immune cells; however, its role in Treg maladaptation during HFpEF remains unknown.

Methods

Circulating Tregs from patients with and without HFpEF were analyzed for abundance, STIM1 expression, and stress-associated signaling pathways. To establish causality, mice with Treg-specific deletion of STIM1 …

Mouse Alport Podocytes Are Susceptible To Aav9 Transduction In Vivo, Meei-Hua Lin, Kohei Omachi, Joshua F Begin, Jennifer L Richardson, Jeffrey H Miner

2020-Current year OA Pubs

INTRODUCTION: Alport syndrome features a defective glomerular basement membrane (GBM) due to variants in COL4A3, COL4A4, and COL4A5. The most severe forms, which lack the GBM's collagen α3α4α5(IV) network, progress from hematuria in early childhood to proteinuria, chronic kidney disease, and kidney failure by the age of ∼30. As a monogenic disease without specific treatments, and with podocytes being the only glomerular cells that synthesize collagen α3α4α5(IV), the ability to efficiently deliver genes to Alport podocytes could open up new possibilities for treatment.

METHODS: As a proof-of-concept study, we investigated whether podocytes in X-linked Alport mice were susceptible to transduction …

Immortalization And Characterization Of Schwann Cell Lines Derived From Nf1-Associated Cutaneous Neurofibromas, Hua Li, Angela Hirbe, Et Al.

2020-Current year OA Pubs

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition in which patients are heterozygous for a disruptive pathogenic variant in the NF1 gene. The most characteristic feature of the condition NF1 is the neurofibroma, a benign, multi-cellular tumor which initiates when a cell of the Schwann cell lineage gains a somatic pathogenic variant of the other NF1 allele. Neurofibromas developing at nerve termini in the skin are termed "cutaneous" neurofibromas (cNFs), while those developing within larger nerves are termed "plexiform." Most patients develop cNFs beginning in late childhood or early adulthood, continuing throughout life at variable rates. Some patients may …

Cutibacterium Adaptation To Life On Humans Provides A Potential C Acnes Infection Biomarker, Md Shafiuddin, Wen-Chi Huang, Gabriel William Prather, Jeffrey Ryan Anton, Andrew Lawrence Martin, Sydney Brianna Sillart, Jonathan Z Tang, Michael R Vittori, Michael J Prinsen, Jessica Jane Ninneman, Chandrashekhara Manithody, Jeffrey P Henderson, Alexander W Aleem, Ma Xenia Garcia Ilagan, William H Mccoy 4th

2020-Current year OA Pubs

Propionibacteriaceae appear to have adapted to life on humans during the domestication of cattle. These microbial immigrants formed the genus Cutibacterium, and a descendent of those microbial trailblazers (C acnes) now dominates 25% of human skin. C acnes colonization of human skin requires the protein RoxP. Although all Cutibacteria encode this adaptation to life on humans, nothing like RoxP has been found in any other organism. In this study, we report an extensive assessment of 21 RoxP orthologs, which identified conserved molecular surfaces linked to heme-dependent oligomerization and low pH stability. Our investigation suggests how RoxP helps C acnes dominate …

Diverse Misfolding Mutant Digestive Enzymes Cause Chronic Pancreatitis Through Common Pathways, Steven J Wilhelm, Grace E Curry, Neel Matiwala, Jianguo Lin, Tran Quach, Mark E Lowe, Miklós Sahin-Tóth, Xunjun K Xiao

2020-Current year OA Pubs

BACKGROUND & AIMS: Increasing evidence suggests that protein misfolding and proteotoxicity is an important mechanism of chronic pancreatitis (CP) in patients with genetic variants. Two mouse models carrying misfolding digestive enzyme variants, CPA1 N256K and PNLIP T221M, recapitulate the human CP phenotype. We hypothesized that both models develop CP through similar disease mechanisms.

METHODS: We conducted a comprehensive analysis of mice aged 1 to 6 months using histology, immunohistochemistry, protein immunoblotting, quantitative polymerase chain reaction (qPCR), transmission electron microscopy (TEM), and RNA sequencing (RNA-seq) analysis to characterize pancreatic pathological changes.

RESULTS: Both homozygous models exhibited CP hallmarks, including progressive acinar …

Coordinated Regulation Of Capping Protein By Carmil And V-1/Myotrophin, John A Hammer, John A Cooper

2020-Current year OA Pubs

Capping Protein (CP) plays a central role in controlling actin filament dynamics in almost all eukaryotic cell types by virtue of its ability to block monomer addition and loss at the barbed end of the actin filament. Like other proteins that control actin assembly, CP is subject to regulation. Here we focus on two direct regulators of CP-CARMIL and V-1/Myotrophin. Specifically, we review recent biochemical, structural, imaging, and cell biological data that argue these two proteins cooperate to create a regulatory cycle for CP that controls its availability, activity, and site of action in the cell. Finally, we discuss unresolved …

Dysregulated Lactate Metabolism Synergizes With Als Genetic Risk Factors To Accelerate Motor Decline, Shweta Tendulkar, Tong Wu, Amy Strickland, Amber R. Hackett, Yurie Sato-Yamada, Xianrong Mao, Yo Sasaki, Jeffrey Milbrandt, A. Joseph Bloom, Aaron Diantonio

2020-Current year OA Pubs

Neurons rely on glial 'lactate shuttling' for metabolic support, which declines with aging and in neurodegenerative disease. Full disruption of lactate shuttling in peripheral nerves causes progressive axon degeneration, but we were interested to understand how partial disruption, a scenario more relevant to aging and disease, contributes to neurodegeneration risk. Pyruvate and lactate are interconverted by lactate dehydrogenases (LDHA and LDHB) in both lactate producing and consuming cells. We therefore began by investigating Ldhb knockout mice (loss of LDHA, the dominant LDH in liver and muscle, caused embryonic lethality), and discovered that they develop progressive neuromuscular junction atrophy and functional …

Oculomics And Ai: The Eye As A Biomarker For Health Span, Joy Le Yi Wong, Rajendra S Apte, Et Al.

2020-Current year OA Pubs

As the world's population ages, the focus of healthcare is shifting from extending life span to promoting health span. There is an unmet need to identify sensitive and reliable markers of health span through more cost-effective and non-invasive methods, to enable early and effective intervention on modifiable aging factors. The eye offers a unique window into systemic health, providing direct visualization of the body's vascular and neural health. This review presents an overview of how various ocular structures can serve as biomarkers of health span-drawing on insights from ocular imaging, metabolomics, and proteomics, with evidence from basic science, animal models, …