Digital Commons Network^™

Brain-Age Prediction: Systematic Evaluation Of Site Effects, And Sample Age Range And Size, Yuetong Yu, Hao-Qi Cui, Shalaila S Haas, Faye New, Nicole Sanford, Kevin Yu, Denghuang Zhan, Guoyuan Yang, Jia-Hong Gao, Dongtao Wei, Jiang Qiu, Nerisa Banaj, Dorret I Boomsma, Alan Breier, Henry Brodaty, Randy L Buckner, Jan K Buitelaar, Dara M Cannon, Xavier Caseras, Vincent P Clark, Patricia J Conrod, Fabrice Crivello, Eveline A Crone, Udo Dannlowski, Christopher G Davey, Lieuwe De Haan, Greig I De Zubicaray, Annabella Di Giorgio, Lukas Fisch, Simon E Fisher, Barbara Franke, David C Glahn, Dominik Grotegerd, Oliver Gruber, Raquel E Gur, Ruben C Gur, Tim Hahn, Ben J Harrison, Sean Hatton, Ian B Hickie, Hilleke E Hulshoff Pol, Alec J Jamieson, Terry L Jernigan, Jiyang Jiang, Andrew J Kalnin, Sim Kang, Nicole A Kochan, Anna Kraus, Jim Lagopoulos, Luisa Lazaro, Brenna C Mcdonald, Colm Mcdonald, Katie L Mcmahon, Benson Mwangi, Fabrizio Piras, Raul Rodriguez-Cruces, Jessica Royer, Perminder S Sachdev, Theodore D Satterthwaite, Andrew J Saykin, Gunter Schumann, Pierluigi Sevaggi, Jordan W Smoller, Jair C Soares, Gianfranco Spalletta, Christian K Tamnes, Julian N Trollor, Dennis Van't Ent, Daniela Vecchio, Henrik Walter, Yang Wang, Bernd Weber, Wei Wen, Lara M Wierenga, Steven C R Williams, Mon-Ju Wu, Giovana B Zunta-Soares, Boris Bernhardt, Paul Thompson, Sophia Frangou, Ruiyang Ge, Enigma‐Lifespan Working Group

Faculty, Staff and Student Publications

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain‐age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain‐age has highlighted the need for robust and publicly available brain‐age models pre‐trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain‐age model. Here we expand this work to develop, empirically validate, and disseminate a pre‐trained brain‐age model to cover most of the human lifespan. To achieve this, we selected the …

Intratumoral Microbiome Of Adenoid Cystic Carcinomas And Comparison With Other Head And Neck Cancers, Tatiana V Karpinets, Yoshitsugu Mitani, Chia-Chi Chang, Xiaogang Wu, Xingzhi Song, Ivonne I Flores, Lauren K Mcdaniel, Yasmine M Hoballah, Fabiana J Veguilla, Renata Ferrarotto, Lauren E Colbert, Nadim J Ajami, Robert R Jenq, Jianhua Zhang, Andrew P Futreal, Adel K El-Naggar

Faculty, Staff and Student Publications

Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the …

Tractography-Based Modeling Explains Treatment Outcomes In Patients Undergoing Deep Brain Stimulation For Obsessive-Compulsive Disorder, Ron Gadot, Ningfei Li, Ben Shofty, Michelle Avendano-Ortega, Sarah Mckay, Kelly R Bijanki, Meghan E Robinson, Garrett Banks, Nicole Provenza, Eric A Storch, Wayne K Goodman, Andreas Horn, Sameer A Sheth

Faculty, Staff and Students Publications

BACKGROUND: Deep brain stimulation (DBS) is an established and expanding therapy for treatment-refractory obsessive-compulsive disorder. Previous work has suggested that a white matter circuit providing hyperdirect input from the dorsal cingulate and ventrolateral prefrontal regions to the subthalamic nucleus could be an effective neuromodulatory target.

METHODS: We tested this concept by attempting to retrospectively explain through predictive modeling the ranks of clinical improvement as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) in 10 patients with obsessive-compulsive disorder who underwent DBS to the ventral anterior limb of internal capsule with subsequent programming uninformed by the putative target tract.

RESULTS: Rank …

Systemic Interindividual Dna Methylation Variants In Cattle Share Major Hallmarks With Those In Humans, Wen-Jou Chang, Maria S Baker, Eleonora Laritsky, Chathura J Gunasekara, Uditha Maduranga, Justine C Galliou, Joseph W Mcfadden, Jessica R Waltemyer, Bruce Berggren-Thomas, Brianna N Tate, Hanxue Zhang, Benjamin D Rosen, Curtis P Van Tassell, George E Liu, Cristian Coarfa, Yi Athena Ren, Robert A Waterland

Faculty, Staff and Students Publications

BACKGROUND: We recently identified ~ 10,000 correlated regions of systemic interindividual epigenetic variation (CoRSIVs) in the human genome. These methylation variants are amenable to population studies, as DNA methylation measurements in blood provide information on epigenetic regulation throughout the body. Moreover, establishment of DNA methylation at human CoRSIVs is labile to periconceptional influences such as nutrition. Here, we analyze publicly available whole-genome bisulfite sequencing data on multiple tissues of each of two Holstein cows to determine whether CoRSIVs exist in cattle.

RESULTS: Focusing on genomic blocks with ≥ 5 CpGs and a systemic interindividual variation index of at least 20, …

Transcriptomic Analysis Reveals The Anti-Cancer Effect Of Gestational Mesenchymal Stem Cell Secretome, Salvatore Vaiasicca, Gianmarco Melone, David W James, Marcos Quintela, Jing Xiao, Seydou Yao, Richard H Finnell, Robert S Conlan, Lewis W Francis, Bruna Corradetti

Faculty, Staff and Students Publications

The environment created during embryogenesis contributes to reducing aberrations that drive structural malformations and tumorigenesis. In this study, we investigate the anti-cancer effect of mesenchymal stem cells (MSCs) derived from 2 different gestational tissues, the amniotic fluid (AF) and the chorionic villi (CV), with emphasis on their secretome. Transcriptomic analysis was performed on patient-derived AF- and CV-MSCs collected during prenatal diagnosis and identified both mRNAs and lncRNAs, involved in tissue homeostasis and inhibiting biological processes associated with the etiology of aggressive cancers while regulating immune pathways shown to be important in chronic disorders. Secretome enrichment analysis also identified soluble moieties …

Single-Cell Total-Rna Profiling Unveils Regulatory Hubs Of Transcription Factors, Yichi Niu, Jiayi Luo, Chenghang Zong

Faculty, Staff and Students Publications

Recent development of RNA velocity uses master equations to establish the kinetics of the life cycle of RNAs from unspliced RNA to spliced RNA (i.e., mature RNA) to degradation. To feed this kinetic analysis, simultaneous measurement of unspliced RNA and spliced RNA in single cells is greatly desired. However, the majority of single-cell RNA-seq chemistry primarily captures mature RNA species to measure gene expressions. Here, we develop a one-step total-RNA chemistry-based single-cell RNA-seq method: snapTotal-seq. We benchmark this method with multiple single-cell RNA-seq assays in their performance in kinetic analysis of cell cycle by RNA velocity. Next, with LASSO regression …

Associations Of Ambulatory Blood Pressure Measurements With High-Sensitivity Troponin And Natriuretic Peptide Levels In Sprint, Nikit Venishetty, Jarett D Berry, James A De Lemos, Elaine Wu, Minjae Lee, Paul E Drawz, Vijay Nambi, Christie M Ballantyne, Anthony A Killeen, Joachim H Ix, Michael G Shlipak, Simon B Ascher

Faculty, Staff and Students Publications

Background: Nighttime blood pressure (BP) has greater prognostic importance for cardiovascular disease (CVD) than daytime BP, but less is known about nighttime and daytime BP associations with measures of subclinical CVD.

Methods: Among 897 Systolic Blood Pressure Intervention Trial Study (SPRINT) participants with 24-hour ambulatory BP monitoring obtained near the 27-month study visit, 849 (95%) had N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) measured at the 24-month study visit. Multivariable linear regression analyses were performed to evaluate the associations of nighttime and daytime BP with cardiac biomarker levels.

Results: The mean age was 69 ± 12 …

The Effect Of Cesarean Delivery On The Neonatal Gut Microbiome In An Under-Resourced Population In The Bronx, Ny, Usa, Sandra E Reznik, Ayodele J Akinyemi, David Harary, Mariam S Latuga, Mamta Fuloria, Maureen J Charron

SKMC Student Presentations and Publications

BACKGROUND: Neonatal and early-life gut microbiome changes are associated with altered cardiometabolic and immune development. In this study, we explored Cesarean delivery effects on the gut microbiome in our high-risk, under-resourced Bronx, NY population.

RESULTS: Fecal samples from the Bronx MomBa Health Study (Bronx MomBa Health Study) were categorized by delivery mode (vaginal/Cesarean) and analyzed via 16 S rRNA gene sequencing at four timepoints over the first two years of life. Bacteroidota organisms, which have been linked to decreased risk for obesity and type 2 diabetes, were relatively reduced by Cesarean delivery, while Firmicutes organisms were increased. Organisms belonging to …

Set-Based Tests For Genetic Association Studies With Interval-Censored Competing Risks Outcomes, Zhichao Xu, Jaihee Choi, Ryan Sun

Faculty, Staff and Student Publications

Over the past decade, massive genetic compendiums such as the UK Biobank have gathered extensive genetic and phenotypic data that hold the potential to provide unparalleled insight into the genetic etiologies of various complex diseases. However, much of the disease information is collected as time-to-event outcomes in interval-censored form, and conventional tools for genetic association analysis are often not available for this type of data. For example, set-based inference for common and rare variants analysis is a fundamental investigation in germline genetics studies, but there is a lack of approaches that can perform set-based testing when the interval-censored outcome of …

Dansyl Fluorophore Functionalized Hierarchically Structured Mesoporous Silica Nanoparticles As Novel Latent Fingerprint Development Agents, Lais F A M Oliveira, Lais V A T Da Silva, Artur F Sonsin, Meclycia S Alves, Cristiane V Costa, Jeane C S Melo, Nicholas Ross, Paul T Wady, Thomas Zinn, Ticiano G Do Nascimento, Eduardo J S Fonseca, Alexandro M L De Assis, A Robert Hillman, Adriana S Ribeiro

Faculty, Staff and Student Publications

A nanostructured hybrid material based on mesoporous silica nanoparticles (MCM-41) functionalized with chitosan and a fluorescent dye (dansylglycine), designated MCM-41@Ch@DnsGly, was synthesized and characterized with a view to its application for the visualization of latent fingerprints. These nanoparticles were applied as latent fingerprint developers for marks on surfaces of diverse chemical composition, topography, optical characteristics, and spatially variant nature, typical of forensically challenging evidence. For quality assessment of the enhanced fingermarks, the developed images were analyzed holistically using the UK Home Office scale, forensic protocols and, in terms of their constituent features (minutiae), using forensic software. Across a substantive collection …

Multiparametric Mri-Based Radiomic Models For Early Prediction Of Response To Neoadjuvant Systemic Therapy In Triple-Negative Breast Cancer, Rania M Mohamed, Bikash Panthi, Beatriz E Adrada, Medine Boge, Rosalind P Candelaria, Huiqin Chen, Mary S Guirguis, Kelly K Hunt, Lei Huo, Ken-Pin Hwang, Anil Korkut, Jennifer K Litton, Tanya W Moseley, Sanaz Pashapoor, Miral M Patel, Brandy Reed, Marion E Scoggins, Jong Bum Son, Alastair Thompson, Debu Tripathy, Vicente Valero, Peng Wei, Jason White, Gary J Whitman, Zhan Xu, Wei Yang, Clinton Yam, Jingfei Ma, Gaiane M Rauch

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is often treated with neoadjuvant systemic therapy (NAST). We investigated if radiomic models based on multiparametric Magnetic Resonance Imaging (MRI) obtained early during NAST predict pathologic complete response (pCR). We included 163 patients with stage I-III TNBC with multiparametric MRI at baseline and after 2 (C2) and 4 cycles of NAST. Seventy-eight patients (48%) had pCR, and 85 (52%) had non-pCR. Thirty-six multivariate models combining radiomic features from dynamic contrast-enhanced MRI and diffusion-weighted imaging had an area under the receiver operating characteristics curve (AUC) > 0.7. The top-performing model combined 35 radiomic features of relative difference between …

Patient-Reported Quality Of Life At Diagnosis In Adolescent And Young Adults With Cancer, Goldy C George, Clark Andersen, Xiaohui Tang, Elizabeth Rodriguez, Midhat Jafry, Maria C Swartz, Sairah Ahmed, Carlos H Barcenas, J Andrew Livingston, Michael E Roth, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

Background: The overall landscape of health-related quality of life (HRQoL) has not been thoroughly investigated in adolescents and young adults (AYAs) with cancer. Data are also lacking on how well HRQoL at the time of cancer diagnosis can prognosticate long-term survival in AYA survivors.

Patients and methods: We included 3,497 survivors of AYA cancer (age 15-39 years at diagnosis) who completed the Short-Form 12 Health Survey (SF-12) HRQoL questionnaire at diagnosis. Physical component summary (PCS) and mental component summary (MCS) scores were generated, with scores < 50 representing poor HRQoL. Differences in HRQoL by patient characteristics and tumor type were investigated using violin plots and t tests/analysis of variance. The effect of HRQoL on overall survival was assessed using Kaplan-Meier plots and Cox proportional hazards models.

Results: Overall mean PCS and MCS scores in this racially/ethnically diverse cohort (64% White, 19% …

Learning To Express Reward Prediction Error-Like Dopaminergic Activity Requires Plastic Representations Of Time, Ian Cone, Claudia Clopath, Harel Z Shouval

Faculty, Staff and Student Publications

The dominant theoretical framework to account for reinforcement learning in the brain is temporal difference learning (TD) learning, whereby certain units signal reward prediction errors (RPE). The TD algorithm has been traditionally mapped onto the dopaminergic system, as firing properties of dopamine neurons can resemble RPEs. However, certain predictions of TD learning are inconsistent with experimental results, and previous implementations of the algorithm have made unscalable assumptions regarding stimulus-specific fixed temporal bases. We propose an alternate framework to describe dopamine signaling in the brain, FLEX (Flexibly Learned Errors in Expected Reward). In FLEX, dopamine release is similar, but not identical …

27-Hydroxycholesterol Acts On Estrogen Receptor Α Expressed By Pomc Neurons In The Arcuate Nucleus To Modulate Feeding Behavior, Hui Ye, Xiaohua Yang, Bing Feng, Pei Luo, Valeria C Torres Irizarry, Leslie Carrillo-Sáenz, Meng Yu, Yongjie Yang, Benjamin P Eappen, Marcos David Munoz, Nirali Patel, Sarah Schaul, Lucas Ibrahimi, Penghua Lai, Xinyue Qi, Yuliang Zhou, Maya Kota, Devin Dixit, Madeline Mun, Chong Wee Liew, Yuwei Jiang, Chunmei Wang, Yanlin He, Pingwen Xu

Faculty, Staff and Students Publications

Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of …

Monoallelic De Novo Ajap1 Loss-Of-Function Variants Disrupt Trans-Synaptic Control Of Neurotransmitter Release, Simon Früh, Sami Boudkkazi, Peter Koppensteiner, Vita Sereikaite, Li-Yuan Chen, Diego Fernandez-Fernandez, Pascal D Rem, Daniel Ulrich, Jochen Schwenk, Ziyang Chen, Elodie Le Monnier, Thorsten Fritzius, Sabrina M Innocenti, Valérie Besseyrias, Luca Trovò, Michal Stawarski, Emanuela Argilli, Elliott H Sherr, Bregje Van Bon, Erik-Jan Kamsteeg, Maria Iascone, Alba Pilotta, Maria R Cutrì, Mahshid S Azamian, Andrés Hernández-García, Seema R Lalani, Jill A Rosenfeld, Xiaonan Zhao, Tiphanie P Vogel, Herda Ona, Daryl A Scott, Peter Scheiffele, Kristian Strømgaard, Mehdi Tafti, Martin Gassmann, Bernd Fakler, Ryuichi Shigemoto, Bernhard Bettler

Faculty, Staff and Students Publications

Adherens junction–associated protein 1 (AJAP1) has been implicated in brain diseases; however, a pathogenic mechanism has not been identified. AJAP1 is widely expressed in neurons and binds to γ-aminobutyric acid type B receptors (GBRs), which inhibit neurotransmitter release at most synapses in the brain. Here, we show that AJAP1 is selectively expressed in dendrites and trans-synaptically recruits GBRs to presynaptic sites of neurons expressing AJAP1. We have identified several monoallelic AJAP1 variants in individuals with epilepsy and/or neurodevelopmental disorders. Specifically, we show that the variant p.(W183C) lacks binding to GBRs, resulting in the inability to recruit them. Ultrastructural analysis revealed …

Development Of A Simple And Accurate Polymerase Chain Reaction Screen For Human Papillomavirus In College Students, Emily Bishop, Owen Smith, Paul E. Richardson

Journal of the South Carolina Academy of Science

Human Papillomavirus (HPV) is, according to the CDC, the most common sexually transmitted infection (STI) with many infections developing in a person's late teens or early 20’s. HPV is a nonenveloped, relatively small, icosahedral DNA virus that infects squamous epithelial cells. This infection can happen in genital, anal, and oral cavities. 90% of these infections will self-clear in two years according to the CDC. Of the 10% of infections that do not clear in two years, they could develop into carcinomas later in life. The goal of this developmental research is to create a polymerase chain reaction (PCR) that can …

Challenges Of Spatially Resolved Metabolism In Cancer Research, Andrew N. Lane, Richard M. Higashi, Teresa W-M Fan

Markey Cancer Center Faculty Publications

Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing the basis for flux analysis. As the diversity of stable isotope-enriched compounds is very high, and with newer approaches to multiplexing, the coverage of metabolism is now very extensive. However, as the complexity of the model increases, including more kinds of interacting cell types and interorgan communication, the analytical complexity also increases. Further, as studies move further …

A Crisis In Clinical Research, David S Hong, Patricia Lorusso, Mario Sznol

Faculty, Staff and Student Publications

The clinical research pipeline is critical to ensuring continued development of novel treatments that can offer patients with cancer safe and effective options. Unfortunately, progress has slowed since the COVID-19 pandemic due to uncovered, systemic inefficiencies across critical processes. Towards initiating discussion on how to reinvigorate clinical research, the Society for Immunotherapy of Cancer (SITC) hosted a virtual summit that characterized issues and formed potential solutions. This commentary serves to highlight the crisis facing clinical research as well as stimulate field-wide discussion on how to better serve patients into the future.

Parg Is Essential For Polθ-Mediated Dna End-Joining By Removing Repressive Poly-Adp-Ribose Marks, Umeshkumar Vekariya, Leonid Minakhin, Gurushankar Chandramouly, Mrityunjay Tyagi, Tatiana Kent, Katherine Sullivan-Reed, Jessica Atkins, Douglas Ralph, Margaret Nieborowska-Skorska, Anna-Mariya Kukuyan, Hsin-Yao Tang, Richard T. Pomerantz, Tomasz Skorski

Department of Biochemistry and Molecular Biology Faculty Papers

DNA polymerase theta (Polθ)-mediated end-joining (TMEJ) repairs DNA double-strand breaks and confers resistance to genotoxic agents. How Polθ is regulated at the molecular level to exert TMEJ remains poorly characterized. We find that Polθ interacts with and is PARylated by PARP1 in a HPF1- independent manner. PARP1 recruits Polθ to the vicinity of DNA damage via PARylation dependent liquid demixing, however, PARylated Polθ cannot perform TMEJ due to its inability to bind DNA. PARG-mediated de-PARylation of Polθ reactivates its DNA binding and end-joining activities. Consistent with this, PARG is essential for TMEJ and the temporal recruitment of PARG to DNA …

Emerging Biomedical And Clinical Applications Of 3d-Printed Poly(Lactic Acid)-Based Devices And Delivery Systems, Allan John R Barcena, Prashanth Ravi, Suprateek Kundu, Karthik Tappa

Faculty, Staff and Student Publications

Poly(lactic acid) (PLA) is widely used in the field of medicine due to its biocompatibility, versatility, and cost-effectiveness. Three-dimensional (3D) printing or the systematic deposition of PLA in layers has enabled the fabrication of customized scaffolds for various biomedical and clinical applications. In tissue engineering and regenerative medicine, 3D-printed PLA has been mostly used to generate bone tissue scaffolds, typically in combination with different polymers and ceramics. PLA's versatility has also allowed the development of drug-eluting constructs for the controlled release of various agents, such as antibiotics, antivirals, anti-hypertensives, chemotherapeutics, hormones, and vitamins. Additionally, 3D-printed PLA has recently been used …

Emergent Emm4 Group A Streptococcus Evidences A Survival Strategy During Interaction With Immune Effector Cells, Chioma M Odo, Luis A Vega, Piyali Mukherjee, Sruti Debroy, Anthony R Flores, Samuel A Shelburne

Faculty, Staff and Student Publications

The major gram-positive pathogen group A Streptococcus (GAS) is a model organism for studying microbial epidemics as it causes waves of infections. Since 1980, several GAS epidemics have been ascribed to the emergence of clones producing increased amounts of key virulence factors such as streptolysin O (SLO). Herein, we sought to identify mechanisms underlying our recently identified temporal clonal emergence among emm4 GAS, given that emergent strains did not produce augmented levels of virulence factors relative to historic isolates. By creating and analyzing isoallelic strains, we determined that a conserved mutation in a previously undescribed gene encoding a putative carbonic …

Intrinsically Disordered Membrane Anchors Of Rheb, Rhoa, And Diras3 Small Gtpases: Molecular Dynamics, Membrane Organization, And Interactions, Chase M Hutchins, Alemayehu A Gorfe

Faculty, Staff and Student Publications

Protein structure has been well established to play a key role in determining function; however, intrinsically disordered proteins and regions (IDPs and IDRs) defy this paradigm. IDPs and IDRs exist as an ensemble of structures rather than a stable 3D structure yet play essential roles in many cell-signaling processes. Nearly all Ras superfamily GTPases are tethered to membranes by a lipid tail at the end of a flexible IDR. The sequence of the IDR is a key determinant of membrane localization, and interaction between the IDR and the membrane has been shown to affect signaling in RAS proteins through the …

Psmd11 Loss-Of-Function Variants Correlate With A Neurobehavioral Phenotype, Obesity, And Increased Interferon Response, Wallid Deb, Cory Rosenfelt, Virginie Vignard, Jonas Johannes Papendorf, Sophie Möller, Martin Wendlandt, Maja Studencka-Turski, Benjamin Cogné, Thomas Besnard, Léa Ruffier, Bérénice Toutain, Léa Poirier, Silvestre Cuinat, Amy Kritzer, Amy Crunk, Janette Dimonda, Jaime Vengoechea, Sandra Mercier, Lotte Kleinendorst, Mieke M Van Haelst, Linda Zuurbier, Telma Sulem, Hildigunnur Katrínardóttir, Rún Friðriksdóttir, Patrick Sulem, Kari Stefansson, Berglind Jonsdottir, Shimriet Zeidler, Margje Sinnema, Alexander P A Stegmann, Natali Naveh, Cara M Skraban, Christopher Gray, Jill R Murrell, Sedat Isikay, Davut Pehlivan, Daniel G Calame, Jennifer E Posey, Mathilde Nizon, Kirsty Mcwalter, James R Lupski, Bertrand Isidor, François V Bolduc, Stéphane Bézieau, Elke Krüger, Sébastien Küry, Frédéric Ebstein

Faculty, Staff and Students Publications

Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy. PSMD11 loss-of-function variants caused early-onset syndromic intellectual disability and neurodevelopmental delay with recurrent obesity in 10 unrelated children. Our findings demonstrate that the cognitive impairment observed in these individuals could be …

Full-Length Αiibβ3 Cryo-Em Structure Reveals Intact Integrin Initiate-Activation Intrinsic Architecture, Tong Huo, Hongjiang Wu, Zeinab Moussa, Mehmet Sen, Valerie Dalton, Zhao Wang

Faculty, Staff and Students Publications

Integrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation and a proven drug-target for antithrombotic therapies. Here we resolve the cryoEM structures of the full-length αIIbβ3, which covers three distinct states along the activation pathway. Firstly, we obtain the αIIbβ3 structure at 3Å resolution in the inactive state, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the ligand-binding domain tucked in a specific angle proximity to the TM region. After the addition of a Mn2+ agonist, we resolve two coexisting structures representing two new states between inactive and active state. Our structures show …

Msl2 Variants Lead To A Neurodevelopmental Syndrome With Lack Of Coordination, Epilepsy, Specific Dysmorphisms, And A Distinct Episignature, Remzi Karayol, Maria Carla Borroto, Sadegheh Haghshenas, Anoja Namasivayam, Jack Reilly, Michael A Levy, Raissa Relator, Jennifer Kerkhof, Haley Mcconkey, Maria Shvedunova, Andrea K Petersen, Kari Magnussen, Christiane Zweier, Georgia Vasileiou, André Reis, Juliann M Savatt, Meghan R Mulligan, Louise S Bicknell, Gemma Poke, Aya Abu-El-Haija, Jessica Duis, Vickie Hannig, Siddharth Srivastava, Elizabeth Barkoudah, Natalie S Hauser, Myrthe Van Den Born, Uri Hamiel, Noa Henig, Hagit Baris Feldman, Shane Mckee, Ingrid P C Krapels, Yunping Lei, Albena Todorova, Ralitsa Yordanova, Slavena Atemin, Mihael Rogac, Vivienne Mcconnell, Anna Chassevent, Kristin W Barañano, Vandana Shashi, Jennifer A Sullivan, Angela Peron, Maria Iascone, Maria P Canevini, Jennifer Friedman, Iris A Reyes, Janell Kierstein, Joseph J Shen, Faria N Ahmed, Xiao Mao, Berta Almoguera, Fiona Blanco-Kelly, Konrad Platzer, Ariana-Berenike Treu, Juliette Quilichini, Alexia Bourgois, Nicolas Chatron, Louis Januel, Christelle Rougeot, Deanna Alexis Carere, Kristin G Monaghan, Justine Rousseau, Kenneth A Myers, Bekim Sadikovic, Asifa Akhtar, Philippe M Campeau

Faculty, Staff and Students Publications

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding …

The Multifaceted Role Of Neutrophils In Nsclc In The Era Of Immune Checkpoint Inhibitors, Shucheng Miao, Bertha Leticia Rodriguez, Don L Gibbons

Faculty, Staff and Student Publications

Lung cancer is the most common cause of cancer-related death in both males and females in the U.S. and non-small-cell lung cancer (NSCLC) accounts for 85%. Although the use of first- or second-line immune checkpoint inhibitors (ICIs) exhibits remarkable clinical benefits, resistance to ICIs develops over time and dampens the efficacy of ICIs in patients. Tumor-associated neutrophils (TANs) have an important role in modulating the tumor microenvironment (TME) and tumor immune response. The major challenge in the field is to characterize the TANs in NSCLC TME and understand the link between TAN-related immunosuppression with ICI treatment response. In this review, …

Inverted Triplications Formed By Iterative Template Switches Generate Structural Variant Diversity At Genomic Disorder Loci, Christopher M Grochowski, Jesse D Bengtsson, Haowei Du, Mira Gandhi, Ming Yin Lun, Michele G Mehaffey, Kyunghee Park, Wolfram Höps, Eva Benito, Patrick Hasenfeld, Jan O Korbel, Medhat Mahmoud, Luis F Paulin, Shalini N Jhangiani, James Paul Hwang, Sravya V Bhamidipati, Donna M Muzny, Jawid M Fatih, Richard A Gibbs, Matthew Pendleton, Eoghan Harrington, Sissel Juul, Anna Lindstrand, Fritz J Sedlazeck, Davut Pehlivan, James R Lupski, Claudia M B Carvalho

Faculty, Staff and Students Publications

The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. …

Longitudinal Program Evaluation Of An Inter-Institutional Mentorship Network For Pediatric Rheumatology Using A Quality Improvement Framework, Kristen Hayward, Alexi Grom, Eyal Muscal, Peter A Nigrovic, Kelly A Rouster-Stevens, Kaveh Ardalan, Linda Hiraki, L Nandini Moorthy

Faculty, Staff and Students Publications

BACKGROUND: The American College of Rheumatology (ACR)/Childhood Arthritis and Rheumatology Research Alliance (CARRA) Mentoring Interest Group (AMIGO) is an inter-institutional mentorship program launched to target mentorship gaps within pediatric rheumatology. Initial program evaluation indicated increased mentorship access. Given the small size of the pediatric rheumatology workforce, maintaining a consistent supply of mentors was a potential threat to the longevity of the network. Our aims were to: (i) describe the sustainability of AMIGO over the period 2011-2018, (ii) highlight ongoing benefits to participants, and (iii) describe challenges in the maintenance of a mentorship network.

METHODS: A mixed-methods approach centered on a …

Persistent Interruption In Parvalbuminpositive Inhibitory Interneurons: Biophysical And Mathematical Mechanisms, Carol M. Upchurch, Christopher J. Knowlton, Simon Chamberland, Carmen C. Canavier

School of Graduate Studies Faculty Publications

Persistent activity in excitatory pyramidal cells (PYRs) is a putative mechanism for maintaining memory traces during working memory. We have recently demonstrated persistent interruption of firing in fastspiking parvalbumin-expressing interneurons (PV-INs), a phenomenon that could serve as a substrate for persistent activity in PYRs through disinhibition lasting hundreds of milliseconds. Here, we find that hippocampal CA1 PV-INs exhibit type 2 excitability, like striatal and neocortical PV-INs. Modeling and mathematical analysis showed that the slowly inactivating potassium current KV1 contributes to type 2 excitability, enables the multiple firing regimes observed experimentally in PV-INs, and provides a mechanism for robust persistent interruption …

Adjunctive Therapy With An Oral H2s Donor Provides Additional Therapeutic Benefit Beyond Sglt2 Inhibition In Cardiometabolic Heart Failure With Preserved Ejection Fraction, Jake E. Doiron, Huijing Xia, Xiaoman Yu, Alexandra R. Nevins, Kyle B. Lapenna, Thomas E. Sharp, Traci T. Goodchild, Timothy D. Allerton, Mona Elgazzaz, Eric Lazartigues, Sanjiv J. Shah, Zhen Li, David J. Lefer

School of Graduate Studies Faculty Publications

Background and Purpose: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S donor in two preclinical models of cardiometabolic HFpEF was investigated. Experimental Approach: Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H2S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or …