Digital Commons Network^™

Adaptive Filters At The First Olfactory Synapse, Elizabeth H Moss, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

The olfactory system is able to filter odor representations based on attention and learning. Two PLoS Biology studies reveal how short axon cells in the olfactory bulb integrate cholinergic input from the basal forebrain to dynamically regulate olfactory input.

Diagnostic Yield Of Exome Sequencing For Pregnancies With And Without Fetal Anomalies And For Stillbirth, Roni Zemet, Christian M Parobek, April D Adams, Mohamad Ali Maktabi, Lena Shay, Linyan Meng, Pengfei Liu, Hongzheng Dai, Fan Xia, Christine Eng, Ignatia B Van Den Veyver, Liesbeth Vossaert

Duncan NRI Faculty and Staff Publications

Objective: Exome sequencing (ES) benefits the genetic work-up for fetuses with structural anomalies, but data on its utility for fetuses without anomalies and stillbirths is more limited. We report our experience with prenatal ES for all three indications.

Method: We retrospectively reviewed results from 344 trio-ES performed for fetuses with structural anomalies (N = 262), stillbirths (N = 39), and fetuses without anomalies (N = 43), many of which had a relevant family history. We classified pathogenic variants (P), likely pathogenic variants (LP), or variants of uncertain significance (VUS) favoring pathogenicity in a gene consistent with the fetal phenotype as …

Synthetic Zfta Fusions Pinpoint Disordered Protein Domain Acquisition As A Mechanism Of Brain Tumorigenesis, A Arabzade, H K Shirnekhi, S Varadharajan, S M Ippagunta, A H Phillips, N Laboe, D W Baggett, Wahiduzzaman, M Jo, T Zheng, R Pathak, D Gee, D Bhimsaria, H Wu, X Gao, J Liu, E Emanus, A Bland, A Kardian, A Hancock, B Holcomb, T Wright, T Bugbee, H Sun, M Zhai, E Caesar, M Park, S Tripathi, A Shirinifard, K Lowe, A Khalighifar, R A Petersen, S King, D Stabley, A Pitre, G E Campbell, C-G Park, W T Freyaldenhoven, B Chandra, Y Xia, E Bonten, A Achari, S Kandikonda, A Carisey, S B Pounds, J Xu, D W Ellison, B Deneen, K C Bertrand, R W Kriwacki, S C Mack

Children’s Nutrition Research Center Staff Publications

Over 95% of ependymomas that arise in the cortex are driven by a gene fusion involving the zinc finger translocation-associated (ZFTA) protein. Here, using super-resolution and lattice light-sheet microscopy, we demonstrate that the most frequent fusion variant, ZFTA-RELA (ZR), forms dynamic nuclear condensates that are required for oncogene expression and tumorigenesis. Mutagenesis studies of ZR reveal a key intrinsically disordered region (IDR) in RELA that governs condensate formation. Condensate-modulating IDR mutations introduced into ZR impaired its genomic occupancy at oncogenic loci and inhibited the recruitment of transcriptional effector proteins, such as MED1, BRD4 and RNA polymerase II. Using nuclear magnetic …

A Consensus Guide To Preclinical Indirect Calorimetry Experiments, Alexander S Banks, David B Allison, Thierry Alquier, Ansarullah, Steven N Austad, Johan Auwerx, Julio E Ayala, Joseph A Baur, Stefania Carobbio, Gary A Churchill, Morten Dall, Rafael De Cabo, Jose Donato, Nathalia R V Dragano, Carol F Elias, Anthony W Ferrante, Brian N Finck, Jose E Galgani, Zachary Gerhart-Hines, Laurie J Goodyear, Justin L Grobe, Rana K Gupta, Kirk M Habegger, Sean M Hartig, Andrea L Hevener, Steven B Heymsfield, Corey D Holman, Martin Hrabě De Angelis, David E James, Lawrence Kazak, Jae Bum Kim, Martin Klingenspor, Xingxing Kong, Sander Kooijman, Louise Lantier, K C Kent Lloyd, James C Lo, Irfan J Lodhi, Paul S Maclean, Owen P Mcguinness, Gema Medina-Gómez, Raghavendra G Mirmira, Christopher D Morrison, Gregory J Morton, Timo D Müller, Yoshihiro Ogawa, David Pajuelo-Reguera, Matthew J Potthoff, Nathan Qi, Marc L Reitman, Patrick C N Rensen, Jan Rozman, Jennifer M Rutkowsky, Kei Sakamoto, Philipp E Scherer, Gary J Schwartz, Radislav Sedlacek, Mohammed Selloum, Saame Raza Shaikh, Shuai Chen, Gerald I Shulman, Vojtěch Škop, Alexander A Soukas, John R Speakman, Bruce M Spiegelman, Gregory R Steinberg, Katrin J Svensson, John P Thyfault, Tony Tiganis, Paul M Titchenell, Nigel Turner, Licio A Velloso, Antonio Vidal-Puig, Christopher S Ward, Ashley S Williams, Christian Wolfrum, Allison W Xu, Ying Xu, Juleen R Zierath, International Indirect Calorimetry Consensus Committee (Iiccc)

Children’s Nutrition Research Center Staff Publications

Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data …

Randomized Trial: Peppermint Oil (Menthol) Pharmacokinetics In Children And Effects On Gut Motility In Children With Functional Abdominal Pain: 540 Mg Vs. 900 Mg Dose Comparison, Robert J Shulman, Bruno P Chumpitazi, Daniel Gonzalez, Uttam Garg, Salma Musaad, Jiali Wen, Gregory L Kearns

Children’s Nutrition Research Center Staff Publications

Aims: There is a paucity of information on the pharmacokinetics (PK) and pharmacodynamics (PD) of menthol, the active ingredient in peppermint oil (PMO). We studied the PK of menthol (540 and 900 mg) in children and measured their effects on gut transit/contractility.

Methods: Children 7-12 years of age with functional abdominal pain underwent wireless motility capsule (WMC) testing. One week later, they were randomized to 540 mg or 900 mg of oral enteric-coated PMO. Blood was sampled over 24 h to determine menthol PK. The WMC test was repeated while they took their respective dose (180 mg thrice or 180 …

A Metabolomics Study Of Cardiac Dysfunction In Hyperglycemia: Findings From The Atherosclerosis Risk In Communities (Aric) Study And The Hispanic Community Health Study/Study Of Latinos (Hchs/Sol), Yilin Yoshida, Ngoc Quynh Nguyen, Eun Hye Moon, Casey Rebholz, Hicham Skali, Victoria Arthur, Justin B Echouffo-Tcheugui, Christie Ballantyne, Elizabeth Selvin, Amil Shah, Robert Kaplan, Carlos J Rodriguez, Qibin Qi, Susan Cheng, Bing Yu

Faculty, Staff and Student Publications

Objective: Hyperglycemic states (prediabetes and diabetes) are associated with heart failure (HF) risk. We aimed to identify distinct metabolites for subclinical cardiac dysfunction, a precursor of HF, in hyperglycemic or euglycemic individuals.

Research design and methods: We conducted cross-sectional and prospective analyses of 2,492 HF-free participants from the Atherosclerosis Risk in Communities (ARIC) study visit 5, 2011-2013. A total of 1,297 participants were hyperglycemic (assessed on the basis of hemoglobin A1c >5.7%, fasting glucose >100 mg/dL, use of diabetes medication, or diagnosis), and 1,195 were euglycemic. We used logistic regression for analysis of association between 790 metabolites and cardiac dysfunction, …

Replication Of Blood Dna Methylomic Signatures Associated With Cerebrospinal Fluid Levels Of Ykl-40 And Nfl Biomarkers, Timo Kaleck, Rafael Campos-Martin, Amanda Cano, Maria Victoria Fernández, Pamela Martino-Adami, Luca Kleineidam, Victor M Andrade Fuentes, Kumar P Tripathi, Kayenat Parveen, Raquel Puerta, Itziar De Rojas, Kishore A Ravichandran, Oliver Peters, Julian Hellmann-Regen, Josef Priller, Maria Gemenetzi, Anja Schneider, Jens Wiltfang, Emrah Düzel, Katharina Buerger, Robert Perneczky, Stefan Teipel, Christoph Laske, Frederic Brosseron, Marta Marquié, Daniel La Van Den Hove, Mercè Boada, Michael T Heneka, Michael Wagner, Natalie Marchant, Jean-Charles Lambert, Ruth Frikke-Schmidt, Frank Jessen, Agustín Ruiz, Alfredo Ramirez

Faculty, Staff and Student Publications

No abstract provided.

Drivers Of Frequent Emergency Department Use In Socioeconomically Disadvantaged Older Adults: A Qualitative Study, Anita Chary, Annika Bhananker, Michelle Suh, David Leavitt, Elise Brickhouse, Shreya Tamma, Jose Ramirez, Mariana Rios, Aanand D Naik, Margaret Samuels-Kalow, Naomi George

Faculty, Staff and Student Publications

Background: The emergency department (ED) is the safety net for and a common point of healthcare access for socioeconomically disadvantaged older adults. Little is known about socioeconomically disadvantaged older ED patients' perspectives on their health, healthcare access, and ED use. Such insights could guide tailored interventions to address unmet clinical and health-related social needs (HRSN).

Methods: We performed a qualitative study with older adults in a single public safety net hospital ED. We interviewed patients age 60+ who had ≥ 4 ED 4 visits in the past year. Semi-structured interviews explored perceived health needs and motivations underlying ED visits. We …

Identifying Geographic Cold Spots Of Pcos Diagnosis In Texas: A Spatial Analysis Of Underdiagnosis And Rural Disparities, Ryan Ramphul, Geethika Yalavarthy, Jooyeon Lee

Faculty, Staff and Student Publications

Context: Polycystic ovary syndrome (PCOS) is a common yet underdiagnosed endocrine disorder with substantial reproductive and metabolic consequences. Although disparities in PCOS care have been documented, few studies have employed spatial methods to identify areas of potential underdiagnosis.

Objective: This study uses geospatial analysis to detect cold spots of PCOS clinical encounters across Texas and investigates neighborhood characteristics associated with these areas.

Methods: We analyzed inpatient and outpatient encounter data from the Texas Public Use Data File (PUDF) between 2018 and 2024 to identify PCOS-related visits (International Classification of Diseases, revision 10: E28.2). ZIP code tabulation area (ZCTA)-level PCOS encounter …

Maternal Sleep Disorders And Maternal And Birth Outcomes: A Retrospective Us Claims-Based Study, Anayeli Herrera Morales, Audrey C Choh, Cici X Bauer, Stefan A Czerwinski, Miryoung Lee

Faculty, Staff and Student Publications

Introduction: Sleep disturbances are commonly reported during pregnancy and have been associated with adverse maternal, fetal, and neonatal outcomes. However, self-reported sleep disturbances may not be accurately reflected in the prevalence of clinically diagnosed sleep disorders.

Methods: Using Optum's de-identified Clinformatics Data Mart Database, we conducted a cross-sectional study of 93,767 American women who were pregnant with singletons between January 1, 2015 and June 30, 2021, to (1) determine the prevalence of clinically diagnosed sleep disorders and breathing abnormalities; (2) examine their associations with maternal health outcomes; and (3) examine their associations with birth outcomes. Sleep disorders and breathing abnormalities …

Genome-Wide Association Study Provides Novel Insight Into The Genetic Architecture Of Severe Obesity, Mohanraj Krishnan, Mohammad Yaser Anwar, Anne E Justice, Geetha Chittoor, Hung-Hsin Chen, Rashedeh Roshani, Alyssa Scartozzi, Rachel R Dickerson, Roelof A J Smit, Michael H Preuss, Nathalie Chami, Benjamin S Hadad, Esteban J Parra, Miguel Cruz, Qin Hui, Peter W F Wilson, Yan V Sun, Xiaoyu Zhang, Gregorio V Linchangco, Sharon L R Kardia, Jessica D Faul, David R Weir, Lawrence F Bielak, Heather M Highland, Kristin L Young, Baiyu Qi, Yujie Wang, Myriam Fornage, Christopher Haiman, Iona Cheng, Ulrike Peters, Charles Kooperberg, Steven Buyske, Joseph B Mccormick, Susan P Fisher-Hoch, Frida Lona-Durazo, Jesus Peralta, Jamie Gomez-Zamudio, Stephen S Rich, Kendra R Ferrier, Ethan M Lange, Christopher R Gignoux, Eimear E Kenny, Genevieve L Wojcik, Kelly Cho, Michael J Gaziano, Luc Djousse, Shuwei Liu, Dhananjay Vaidya, Renée De Mutsert, Navya S Josyula, Christopher R Bauer, Wei Zhao, Ryan W Walker, Jennifer A Smith, Leslie A Lange, Mariah C Meyer, Ching-Ti Liu, Lisa R Yanek, Miryoung Lee, Laura M Raffield, Ruth J F Loos, Penny Gordon-Larsen, Jennifer E Below, Kari E North, Mariaelisa Graff

The Brown Foundation: Institute of Molecular Medicine

Severe obesity (SevO) is a primary driver of cardiovascular diseases (CVD), cardiometabolic diseases (CMD) and several cancers, with a disproportionate impact on marginalized populations. SevO is an understudied global health disease, limiting knowledge about its mechanisms and impacts. In genome-wide association study (GWAS) meta-analyses of the tail end of the BMI distribution (≥95th percentile BMI) and two SevO phenotypes [Obesity Class III BMI ≥ 40 kg/m2 and Obesity Class IV BMI ≥ 50 kg/m2] in 159,359 individuals across eleven ancestrally diverse population-based studies followed by replication in 480,897 individuals across six ancestrally diverse studies, we identified and replicated three novel …

Utilization Of Outpatient Mental Health Services During And 2 Years After The Covid-19 Pandemic, Michelle A Hayek, Hye-Chung Kum, Sulki Park, Robert Ohsfeldt, Mark A Lawley, Michelle J Bovin

The Brown Foundation: Institute of Molecular Medicine

Objective: Analyze the impact of COVID-19 on outpatient mental health (OP-MH) utilization patterns, particularly telehealth, across eight different MH conditions with a 2-year follow-up.

Methods: This population-based cohort study uses a 5% random sample of Medicare beneficiaries aged ≥18 and newly diagnosed with one of the eight MH disorders: psychotic, depressive, bipolar, anxiety, trauma-related, substance-use, other MH disorders, and two or more MH disorders. Monthly OP-MH utilization patterns were compared among patients in 2020-2021 newly diagnosed in 2019 to comparable prepandemic cohorts newly diagnosed in 2017. Multiple logistic regression models were conducted to examine differences in telehealth utilization across MH …

Deepmvp: Deep Learning Models Trained On High-Quality Data Accurately Predict Ptm Sites And Variant-Induced Alterations, Bo Wen, Chenwei Wang, Kai Li, Ping Han, Matthew V Holt, Sara R Savage, Jonathan T Lei, Yongchao Dou, Zhiao Shi, Yi Li, Bing Zhang

Center on Aging Staff Publications

Post-translational modifications (PTMs) are critical regulators of protein function, and their disruption is a key mechanism by which missense variants contribute to disease. Accurate PTM site prediction using deep learning can help identify PTM-altering variants, but progress has been limited by the lack of large, high-quality training datasets. Here, we introduce PTMAtlas, a curated compendium of 397,524 PTM sites generated through systematic reprocessing of 241 public mass-spectrometry datasets, and DeepMVP, a deep learning framework trained on PTMAtlas to predict PTM sites for phosphorylation, acetylation, methylation, sumoylation, ubiquitination and N-glycosylation. DeepMVP substantially outperforms existing tools across all six PTM types. Its …

Five-Year Change In Sleep Duration And Incident Alzheimer’S Disease And Related Dementias Among Lower-Income Older Adults, Hui Shi, Loren Lipworth, Qian Xiao, Xijing Han, Michael Mumma, Laura M Keohane, Danxia Yu, Corey J Bolton, Derek B Archer, Timothy J Hohman, Kelsie M Full

Faculty, Staff and Student Publications

Introduction: Little is known about change in sleep duration over time and Alzheimer's Disease and Related Dementias (ADRD) risk.

Methods: ADRD cases were identified among Southern Community Cohort Study participants enrolled in Medicare. Sleep duration was reported at enrollment and first study follow-up and categorized (short (< 7 hours), recommended (7-9) and long (> 9)), change was calculated between timepoints. Adjusted Cox proportional hazards regression was used to estimate hazard ratios (HRs, 95% CIs) for incident ADRD.

Results: We identified 2,093 ADRD cases among 17,945 participants. Compared to maintaining optimal sleep duration (7-9 hours) over 5 years, suboptimal changes were associated with 20-69% greater ADRD risk: adjusted …

Steroid Hormone Biosynthesis And Dietary Related Metabolites Associated With Excessive Daytime Sleepiness, Tariq Faquih, Kaitlin S Potts, Pavithra Nagarajan, Bing Yu, Robert Kaplan, Carmen R Isasi, Qibin Qi, Kent D Taylor, Peter Y Liu, Satu J Strausz, Hanna M Ollila, Tianyi Huang, Russell P Tracy, Craig Johnson, Stephen S Rich, Clary B Clish, Jerome I Rotter, Susan Redline, Tamar Sofer, Heming Wang

Faculty, Staff and Student Publications

Background: Excessive daytime sleepiness (EDS) is a complex sleep problem that affects approximately 33% of the United States population. Although EDS usually occurs in conjunction with insufficient sleep and other sleep and circadian disorders, recent studies have shown unique genetic markers and metabolic pathways underlying EDS. Here, we aimed to further elucidate the biological profile of EDS using large-scale single- and pathway-level metabolomics analyses.

Methods: Metabolomics data were available for 877 metabolites in 6071 individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). EDS was assessed using the Epworth Sleepiness Scale (ESS) questionnaire. We performed linear regression for each …

Proximity-Dependent Proteomics And Network Analysis Of Adenylyl Cyclase Isoforms 5, 6, And 9 In Cardiomyocytess, Taeyeop Park, Yong Li, Neha Arora, Anibal Garza-Carbajal, Karen Colwill, Cassandra J Wong, Yong Zhou, Carmen W Dessauer

Faculty, Staff and Student Publications

cAMP influences multiple aspects of cardiac biology, including the regulation of contraction, relaxation, and overall stress responses. The functional outcomes of cAMP are driven by the spatial arrangement of enzymes that produce and degrade cAMP (adenylyl cyclase [AC] and phosphodiesterase, respectively), together with the downstream targets of cAMP. We performed proximity-dependent biotin identification (BioID) of near-neighbor interactions proteomics in cardiomyocytes to generate proximity maps for three cardiac AC isoforms. Processing and trafficking functions were the most common gene ontology terms for ACs, with AC5 and AC6 generating unique proximal protein sets compared to AC9. AC5/6 proximal proteins showed significant localization …

Buprenorphine Salivary Gland Accumulation Sustaining High Oral Fluid Exposure And Increasing The Risk Of Streptococcus Mutans Biofilm Formation, Zicong Zheng, Jie Chen, Songpol Srinual, Vesna Tumbas Šaponjac, Taijun Yin, Bing-Yan Wang, Rongjin Sun, Ming Hu

Faculty, Staff and Student Publications

Objectives: The US Food and Drug Administration (FDA) issued a warning about buprenorphine-induced dental caries of unknown mechanism in 2022. To investigate the potential mechanism, the association between local buprenorphine exposure and dental biofilm formation will be explored in this study.

Methods: Female F344 rats were dosed with sublingual buprenorphine film or intravenous injection to explore the oral cavity exposure of the buprenorphine. The buprenorphine distribution in salivary glands after the sublingual and intravenous administration was also evaluated. To investigate the effects of buprenorphine exposure on dental caries formation, buprenorphine's impact on the biofilm formation of S. mutans in vitro …

Folliculin Deletion In The Mouse Kidney Results In Cystogenesis Of The Loops Of Henle Via Aberrant Tfeb Activation, Ola Shalaby, Tomoko Ohmori, Koichiro Miike, Shunsuke Tanigawa, Luh Ade Wilan Krisna, Alessia Calcagnì, Andrea Ballabio, Yoshiaki Kubota, Laura S Schmidt, W Marston Linehan, Takaaki Ito, Masaya Baba, Ryuichi Nishinakamura

Duncan NRI Faculty and Staff Publications

The mammalian kidney contains numerous nephrons connected to the collecting ducts, and each nephron consists of a glomerulus, a proximal tubule, the loop of Henle (LoH), and a distal tubule. Folliculin (FLCN) is a causative gene for Birt-Hogg-Dubé syndrome, which is characterized by a variety of manifestations, including renal cysts and cancer. Although deletion of Flcn in the mouse collecting duct and distal nephron leads to cyst formation, its precise role in the entire nephron remains unclear. Herein, nephron-specific Flcn knockout mice exhibited cystogenesis along the entire nephron segments, most prominent in the LoH, preceded by an irregularly shaped lumen …

Coenzyme Q Headgroup Intermediates Can Ameliorate A Mitochondrial Encephalopathy, Guangbin Shi, Claire Miller, Sota Kuno, Alejandro G Rey Hipolito, Salsabiel El Nagar, Giulietta M Riboldi, Megan Korn, Wyatt C Tran, Zixuan Wang, Lia Ficaro, Tao Lin, Quentin Spillier, Begoña Gamallo-Lana, Drew R Jones, Matija Snuderl, Soomin C Song, Adam C Mar, Alexandra L Joyner, Roy V Sillitoe, Robert S Banh, Michael E Pacold

Duncan NRI Faculty and Staff Publications

Decreased brain levels of coenzyme Q10 (CoQ10), an endogenously synthesized lipophilic antioxidant1,2, underpin encephalopathy in primary CoQ10 deficiencies3,4 and are associated with common neurodegenerative diseases and the ageing process5,6. CoQ10 supplementation does not increase CoQ10 pools in the brain or in other tissues. The recent discovery of the mammalian CoQ10 headgroup synthesis pathway, in which 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) makes 4-hydroxymandelate (4-HMA) to synthesize the CoQ10 headgroup precursor 4-hydroxybenzoate (4-HB)7, offers an opportunity to pharmacologically restore CoQ10 synthesis and mechanistically treat CoQ10 deficiencies. To test whether 4-HMA …

Current Controversies In Prenatal Diagnosis 2: Conventional Postmortem Examination Remains The Gold Standard For The Anatomical Examination Of Fetal Loss, J Ciaran Hutchinson, Lorraine Potocki, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

A comprehensive postmortem examination is an essential component of a work-up after stillbirth. Its findings can support accurate counseling of parents about causes and risk of recurrence. It also supports providers' decisions about most appropriate testing and management plans for future pregnancy to prevent recurrence. Informing parents about fetal autopsy and obtaining their consent is challenging, and conducting a fetal autopsy requires expertise that is, not universally available. Newer non-invasive or minimally invasive methods such as postmortem MRI and targeted biopsies can replace or supplement autopsies, but one must recognize that expertise in these methods is likewise not broadly available. …

Prenatal Genetic Consultation And Testing, Sarah Araji, Lauren Westerfield, Roni Zemet, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

The evolution of prenatal genetic testing has transformed prenatal diagnosis into a more precise and individualized approach. Advanced tools such as chromosomal microarray analysis and exome sequencing have enabled the prenatal diagnosis of more genetic conditions, including anomalies and disorders eligible for fetal therapy. When in utero therapy is considered, accurate genetic diagnosis is essential for guiding providers' and patients' decisions regarding management and outcomes. This chapter reviews available prenatal genetic screens and tests, their indications, and counseling strategies. It also explores genetic abnormalities associated with fetal structural anomalies and their implications for decision-making in fetal interventions.

Mechanisms Underlying Treatment-Resistant Depression: Exploring Sex-Based Biological Differences, Francisco E R Da Silva, Atakan Yucel, Antonio P M Menezes, Ana C Ruiz, Marcela C Carbajal Tamez, Tatiana Barichello, Giselli Scaini, Joao Quevedo

Faculty, Staff and Student Publications

Treatment-resistant depression (TRD) represents a severe and complex subtype of major depressive disorder (MDD), affecting approximately 30% of patients who fail to respond adequately to multiple standard antidepressant therapies. While the pathophysiology of TRD remains incompletely understood, emerging evidence suggests that sex-based biological differences might influence its onset, progression, and treatment response. Women are disproportionately affected by depression and are more likely to experience residual symptoms and treatment resistance, potentially due to hormonal fluctuations, immune system differences, and variations in brain circuitry and neuroplasticity. This narrative explores the current literature on the mechanisms underlying TRD, with a particular emphasis on …

Immune Impacts Of Fire Smoke Exposure, Mary M Johnson, Abhinav Kaushik, Olivia A Kline, Eric M Smith, Xiaoying Zhou, Yagiz Pat, Laura Buergi, Juan Aguilera, Shifaa Alkotob, Elisabeth M Simonin, Alberto Favaro, Miguel Couto, Oscar Bennett, R Sharon Chinthrajah, Ella Parsons, Mohamed Shamji, Marshall Burke, Melissa Bondy, Mubeccel Akdis, Cezmi A Akdis, Kari C Nadeau

Faculty, Staff and Student Publications

Fire smoke exposure has become a global health concern and is associated with increased morbidity and mortality. There is a lack of understanding of the specific immune mechanisms involved in smoke exposure with preventative and targeted interventions needed. After exposure to fire smoke, which includes PM2.5, toxic metals and per- and polyfluoroalkyl substances (PFAS), epidemiology-based studies demonstrate increases in respiratory (e.g. asthma exacerbations), cardiac (e.g. myocardial infarctions, arrhythmias), neurologic (e.g. stroke) and pregnancy-related (e.g. low birthweight, premature births) outcomes. However, mechanistic studies exploring how smoke exposure disrupts cellular homeostasis are lacking. Therefore, we collected blood from smoke-exposed individuals (n …

Outcomes In Systemic Sclerosis-Associated Interstitial Lung Disease Based On Serological Profiles With A Focus On Anticentromere And Anti-Rna Polymerase Iii Antibodies, Elizabeth R Volkmann, Shervin Assassi, Christopher P Denton, Rozeta Simonovska, Steven Sambevski, Margarida Alves, Elana J Bernstein

Faculty, Staff and Student Publications

Objective: We aimed to compare the progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) based on serological status.

Methods: In a posthoc analysis of the SENSCIS trial (nintedanib vs placebo in SSc-ILD; ClinicalTrials.gov: NCT02597933), we analyzed the rate of decline in forced vital capacity (FVC) over 52 weeks in 3 subsets: (1) positive for anticentromere antibody (ACA), (2) positive for anti-RNA polymerase III antibody (ARA), and (3) negative for ACA, ARA, and antitopoisomerase I antibody (ATA).

Results: Among study participants who underwent baseline serological evaluation, 32/549 (5.8%) were ACA positive, 98/528 (18.6%) were ARA positive, and 127/526 (24.1%) were …

Ixekizumab Improves Signs, Symptoms, And Quality Of Life In Patients With Axial Spondyloarthritis Irrespective Of Symptom Duration, Victoria Navarro-Compán, John D Reveille, Proton Rahman, José A Maldonado-Cocco, Marina Magrey, Rebecca Bolce, Tommaso Panni, Andris Kronbergs, Martin Rudwaleit

Faculty, Staff and Student Publications

Introduction: The objective of this study was to assess treatment response to ixekizumab, an interleukin-17A antagonist, by shorter versus longer symptom duration (< 5 years vs. ≥ 5 years) in patients with radiographic axial spondyloarthritis (r-axSpA) and non-radiographic axial spondyloarthritis (nr-axSpA) up to 52 weeks.

Methods: This post hoc analysis used data from three randomized, placebo-controlled trials including patients with r-axSpA from COAST-V [biologic disease-modifying anti-rheumatic drug (bDMARD)-naïve] and COAST-W (tumor necrosis factor inhibitor-experienced) and patients with nr-axSpA from COAST-X (bDMARD-naïve). Patients received ixekizumab (80 mg every 2 or 4 weeks) or placebo through Week 16 and ixekizumab to Week 52. Assessments included the Assessment in SpondyloArthritis international Society 40% improvement (ASAS40) and Axial Spondyloarthritis Disease Activity Score (ASDAS) low disease activity …

Rna-Binding Proteins Mediate The Maturation Of Chromatin Topology During Differentiation, Bondita Dehingia, Małgorzata Milewska-Puchała, Marcin Janowski, Mahmoud-Reza Rafiee, Misbah Abbas, Aleksandra Piotrowska, Jan Senge, Piotr Blaut, Dietrich Walsh, Jacqueline Severino, Debadeep Chaudhury, Sajjad Iqbal, Rogelio Montiel-Manriquez, Sylwia Jankowska, Peyman Zare, Wolfgang Huber, Jianliang Xu, Rafael Casellas, Timo Zimmermann, Paweł Dłotko, Jeroen Krijgsveld, Aleksandra Pękowska

Faculty, Staff and Student Publications

Topologically associating domains (TADs) and chromatin architectural loops impact promoter-enhancer interactions, with CCCTC-binding factor (CTCF) defining TAD borders and loop anchors. TAD boundaries and loops progressively strengthen upon embryonic stem (ES) cell differentiation, underscoring the importance of chromatin topology in ontogeny. However, the mechanisms driving this process remain unclear. Here we show a widespread increase in CTCF-RNA-binding protein (RBP) interactions upon ES to neural stem (NS) cell differentiation. While dispensable in ES cells, RBPs reinforce CTCF-anchored chromatin topology in NS cells. We identify Pantr1, a non-coding RNA, as a key facilitator of CTCF-RBP interactions, promoting chromatin maturation. Using acute CTCF …

The Antifungal Mechanism Of Entv-Derived Peptides Is Associated With A Reduction In Extracellular Vesicle Release, Giuseppe Buda De Cesare, Melissa R Cruz, Shane A Cristy, Luis A Vega, Robert Zarnowski, Antonino Zito, Shantanu Guha, David R Andes, Danielle A Garsin, Michael C Lorenz

Faculty, Staff and Student Publications

Candida albicans, an opportunistic fungal pathogen, causes systemic and superficial infections, especially in immunocompromised patients. Treatment of fungal infections is complicated by limited antifungal options and the development of drug resistance. Previous work from our group demonstrated the efficacy of the anti-virulence peptide EntV and shorter variants against C. albicans infection in various animal models, including mouse models of oropharyngeal candidiasis and disseminated infection and a rat venous catheter model. However, the mechanism of action, which abrogates fungal virulence without fungicidal or fungistatic activity, has remained unknown. We used a combination of cell biological, biochemical, genomic, and genetic approaches to …

Trop2 Expression In Salivary Gland Adenoidcystic Carcinoma (Acc) According To Histologic Subtype: Therapeutic Implications, Juliana Mota Siqueira, Yoshitsugu Mitani, Mario L Marques-Piubelli, Camilla Oliveira Hoff, Flavia Bonini, Luana Guimaraes De Sousa, Mutsumi Mitani, Giovanna Lopes Carvalho, Fabio Daumas Nunes, Leandro Luongo Matos, Shiaw-Yih Lin, Michael T Spiotto, Ehab Y Hanna, Daniel J Mcgrail, Adel K El-Naggar, Renata Ferrarotto

Faculty, Staff and Student Publications

Background: Adenoid cystic carcinoma (ACC) is a common salivary gland carcinoma with high recurrence and distant metastasis rates. Currently, there is no standard systemic treatment available. TROP2 is a transmembrane glycoprotein involved in the oncogenesis of several tumors that can be therapeutically targeted by a TROP2-antibody-drug conjugate (ADC). We aimed to characterize TROP2 expression in ACC and assess TROP2 as a potential therapeutic target.

Methods: TROP2 immunohistochemistry was performed in a tissue microarray including 165 ACC of salivary gland. The tumors were grouped according to the histological pattern as non-solid, solid + non-solid, or solid. TROP2 protein expression in ACC …

Wuse-Oil Compound 03 Mitigates Radiation-Induced Oral Mucositis By Modulating Oral Microbiota To Mediate Tlr4/Nf-Κb Pathway And Inhibit M1 Macrophage Polarization, Liqun Jia, Rong Huang, Chen Chen, Feng Teng, Tian Gu, Huafeng Liu, Li Ma, Ye Feng, Jingyi Long, Zihan Jin, Dong Li, Dongmei Chen, Yanni Lou

Faculty, Staff and Student Publications

Background: Radiation-induced oral mucositis (RIOM) is a prevalent condition among patients with head and neck cancer undergoing radiotherapy. It is characterized by a high incidence and severe symptoms that significantly compromise patients' quality of life. Currently, there exists no consensus regarding an effective treatment modality. Wuse-oil Compound 03 (WC03), a Traditional Chinese Herbal Medicine, demonstrates potential in managing RIOM.

Purpose: This study aims to investigate the efficacy of WC03 in treating RIOM through the modulation of oral microbiota and associated biological pathways.

Study design: Mechanism study experimental design.

Methods: A rat model of RIOM was established via radiation exposure. WC03 …

Auricular Point Acupressure For Older Adults With Chronic Low Back Pain: A Randomized Controlled Trial, Jennifer Kawi, Chao Hsing Yeh, Nada Lukkahatai, Hulin Wu, Natalia E Morone, Ronald Glick, Elizabeth A Schlenk, Claudia Campbell, Johannes Thrul, Xinran Huang, Hongyu Wang, Hejingzi Monica Jia, Paul Christo, Constance Johnson

Faculty, Staff and Student Publications

Objective: Efficacious modalities are limited in chronic low back pain (cLBP). We determined the efficacy of auricular point acupressure (APA) in older adults with cLBP.

Design: 3-arm randomized controlled trial.

Setting: Baltimore, Maryland.

Participants: Participants, ≥60 years with cLBP, were randomized (1:1:1) to APA with ear points targeted to cLBP (T-APA, n = 92), points nontargeted to cLBP (NT-APA, n = 91), or waitlist education control (n = 89), and followed up to 6 months (6M). Participants in the APA groups received 4 weekly APA sessions; the education control group received 4 weekly educational sessions.

Intervention: APA.

Main outcomes and …