Digital Commons Network^™

Differential Roles Of Key Brain Regions: Ventral Tegmental Area, Locus Coeruleus, Dorsal Raphe, Nucleus Accumbens, Caudate Nucleus, And Prefrontal Cortex In Regulating Response To Methylphenidate: Insights From Neuronal And Behavioral Studies In Freely Behaving Rats, Nachum Dafny, Catherine Claussen, Emilee Frazier, Yin Liu

Faculty, Staff and Student Publications

A total of 3102 neurons were recorded before and following acute and chronic methylphenidate (MPD) administration. Acute MPD exposure elicits mainly increases in neuronal and behavioral activity in dose–response characteristics. The response to chronic MPD exposure, as compared to acute 0.6, 2.5, or 10.0 mg/kg MPD administration, elicits electrophysiological and behavioral sensitization in some animals and electrophysiological and behavioral tolerance in others when the neuronal recording evaluations were performed based on the animals’ behavioral responses, or amount of locomotor activity, to chronic MPD exposure. The majority of neurons recorded from those expressing behavioral sensitization responded to chronic MPD with further …

Maackia Amurensis Seed Lectin (Masl) And Soluble Human Podoplanin (Shpdpn) Sequence Analysis And Effects On Human Oral Squamous Cell Carcinoma (Oscc) Cell Migration And Viability, Ariel C Yin, Cayla J Holdcraft, Eamonn J Brace, Tyler J Hellmig, Sayan Basu, Saumil Parikh, Katarzyna Jachimowska, Evelyne Kalyoussef, Dylan Roden, Soly Baredes, Eugenio M Capitle, David I Suster, Alan J Shienbaum, Caifeng Zhao, Haiyan Zheng, Kevin Balcaen, Simon Devos, Jurgen Haustraete, Mahnaz Fatahzadeh, Gary S Goldberg

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Maackia amurensis lectins serve as research and botanical agents that bind to sialic residues on proteins. For example, M. amurensis seed lectin (MASL) targets the sialic acid modified podoplanin (PDPN) receptor to suppress arthritic chondrocyte inflammation, and inhibit tumor cell growth and motility. However, M. amurensis lectin nomenclature and composition are not clearly defined. Here, we sought to definitively characterize MASL and its effects on tumor cell behavior. We utilized SDS-PAGE and LC-MS/MS to find that M. amurensis lectins can be divided into two groups. MASL is a member of one group which is composed of subunits that form dimers, …

Dissecting The Potential Mechanisms Of Histone Deacetylase 1 Dependent Macrophage Phagocytosis Of Mycobacterium Tuberculosis, Owusu A. Christian

Biotechnology Theses

Histone deacetylases (HDACs) mediate the removal of acetyl groups from the histones of chromatin and regulate the expression of the genes involved in cancer development and immune cell functions. Our previous study showed that HDAC2 enhances IL-1β production by Mycobacterium tuberculosis (Mtb) infected macrophages by promoting inflammasome activation. HDAC1, on the other hand, regulates macrophage phagocytosis of Mtb. However, the mechanisms by which HDAC1 controls macrophage phagocytosis remain unclear.

Using human monocyte-derived macrophages (MDMs) and Mtb strains, we explore the mechanism of HDAC1 in macrophage phagocytosis of Mtb. Our results showed that blocking HDAC1, either chemically or genetically, …

Loss Of Lpar6 And Cab39l Dysregulates The Basal-To-Luminal Urothelial Differentiation Program, Contributing To Bladder Carcinogenesis, Sangkyou Lee, Jolanta Bondaruk, Yishan Wang, Huiqin Chen, June Goo Lee, Tadeusz Majewski, Rachel D Mullen, David Cogdell, Jiansong Chen, Ziqiao Wang, Hui Yao, Pawel Kus, Joon Jeong, Ilkyun Lee, Woonyoung Choi, Neema Navai, Charles Guo, Colin Dinney, Keith Baggerly, Cathy Mendelsohn, David Mcconkey, Richard R Behringer, Marek Kimmel, Peng Wei, Bogdan Czerniak

Faculty, Staff and Student Publications

We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term "forerunner" genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two …

Thbs1 Regulates Skeletal Muscle Mass In A Tgfβ-Smad2/3-Atf4-Dependent Manner, Davy Vanhoutte, Tobias G Schips, Rachel A Minerath, Jiuzhou Huo, Naga Swathi Sree Kavuri, Vikram Prasad, Suh-Chin Lin, Michael J Bround, Michelle A Sargent, Christopher M Adams, Jeffery D Molkentin

Faculty, Staff and Students Publications

Loss of muscle mass is a feature of chronic illness and aging. Here, we report that skeletal muscle-specific thrombospondin-1 transgenic mice (Thbs1 Tg) have profound muscle atrophy with age-dependent decreases in exercise capacity and premature lethality. Mechanistically, Thbs1 activates transforming growth factor β (TGFβ)-Smad2/3 signaling, which also induces activating transcription factor 4 (ATF4) expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to facilitate muscle atrophy. Indeed, myofiber-specific inhibition of TGFβ-receptor signaling represses the induction of ATF4, normalizes ALP and UPS, and partially restores muscle mass in Thbs1 Tg mice. Similarly, myofiber-specific deletion of Smad2 and Smad3 …

Astrocytic Slc4a4 Regulates Blood-Brain Barrier Integrity In Healthy And Stroke Brains Via A Ccl2-Ccr2 Pathway And No Dysregulation, Qi Ye, Juyeon Jo, Chih-Yen Wang, Heavin Oh, Jiangshan Zhan, Tiffany J Choy, Kyoung In Kim, Angelo D'Alessandro, Yana K Reshetnyak, Sung Yun Jung, Zheng Chen, Sean P Marrelli, Hyun Kyoung Lee

Faculty, Staff and Student Publications

Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests that ion homeostasis is a cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates …

Pulmonary Hypertension And Hyperglycemia-Not A Sweet Combination, Or Bruck, L M Pandit

Faculty, Staff and Students Publications

Hyperglycemia and pulmonary hypertension (PH) share common pathological pathways that lead to vascular dysfunction and resultant cardiovascular complications. These shared pathologic pathways involve endothelial dysfunction, inflammation, oxidative stress, and hormonal imbalances. Individuals with hyperglycemia or pulmonary hypertension also possess shared clinical factors that contribute to increased morbidity from both diseases. This review aims to explore the relationship between PH and hyperglycemia, highlighting the mechanisms underlying their association and discussing the clinical implications. Understanding these common pathologic and clinical factors will enable early detection for those at-risk for complications from both diseases, paving the way for improved research and targeted therapeutics.

Cosmetic Penile Enhancement Procedures: An Smsna Position Statement, Landon Trost, Daniel N Watter, Serge Carrier, Mohit Khera, Faysal A Yafi, Helen L Bernie, Matthew Ziegelmann, Tobias Köhler

Faculty, Staff and Students Publications

Background: Penile cosmetic enhancement procedures have been performed for many years with varying success. However, they have historically been relegated to niche areas of sexual medicine, with limited data, and have not achieved mainstream adoption. More recently, the topic has been increasingly discussed within academic congresses due to availability of novel techniques, therapies, and procedures. Given their distinctive nature, the Sexual Medicine Society of North America (SMSNA) felt that it was pertinent to develop formal position statements to help guide both patients and sexual medicine providers on the current state of the scientific literature and to give recommendations for future …

Intouch Week Of May 27, 2024, New York Medical College

InTouch

• NYMC Honors the Class of 2024 at 165^th Commencement Ceremonies
• NYMC Research Well Represented at Touro Research Day
• NYMC Student Recognized with Prestigious U.S. Public Health Award
• Palliative Medicine Education Provides Essential Knowledge
• Student Spotlight: Vasiliki Gregory Lead Authors Study on Extending Heart Transplantation Procurement Time

Glioblastoma Disrupts Cortical Network Activity At Multiple Spatial And Temporal Scales, Jochen Meyer, Kwanha Yu, Estefania Luna-Figueroa, Benjamin Deneen, Jeffrey Noebels

Faculty, Staff and Students Publications

The emergence of glioblastoma in cortical tissue initiates early and persistent neural hyperexcitability with signs ranging from mild cognitive impairment to convulsive seizures. The influence of peritumoral synaptic density, expansion dynamics, and spatial contours of excess glutamate upon higher order neuronal network modularity is unknown. We combined cellular and widefield imaging of calcium and glutamate fluorescent reporters in two glioblastoma mouse models with distinct synaptic microenvironments and infiltration profiles. Functional metrics of neural ensembles are dysregulated during tumor invasion depending on the stage of malignant progression and tumor cell proximity. Neural activity is differentially modulated during periods of accelerated and …

Generation Of Oviductal Glycoprotein 1 Cre Mouse Model For The Study Of Secretory Epithelial Cells Of The Oviduct, Emily A Mcglade, Jiude Mao, Kalli K Stephens, Andrew M Kelleher, Lisette A Maddison, Miranda L Bernhardt, Francesco J Demayo, John P Lydon, Wipawee Winuthayanon

Faculty, Staff and Students Publications

The epithelial cell lining of the oviduct plays an important role in oocyte pickup, sperm migration, preimplantation embryo development, and embryo transport. The oviduct epithelial cell layer comprises ciliated and nonciliated secretory cells. The ciliary function has been shown to support gamete and embryo movement in the oviduct, yet secretory cell function has not been well characterized. Therefore, our goal was to generate a secretory cell-specific Cre recombinase mouse model to study the role of the oviductal secretory cells. A knock-in mouse model, Ovgp1Cre:eGFP, was created by expressing Cre from the endogenous Ovgp1 (oviductal glycoprotein 1) locus, with enhanced green …

Plasmonic Nano-Aperture Label-Free Imaging Of Single Small Extracellular Vesicles For Cancer Detection, Nareg Ohannesian, Mohammad Sadman Mallick, Jianzhong He, Yawei Qiao, Nan Li, Simona F Shaitelman, Chad Tang, Eileen H Shinn, Wayne L Hofstetter, Alexei Goltsov, Manal M Hassan, Kelly K Hunt, Steven H Lin, Wei-Chuan Shih

Faculty, Staff and Student Publications

BACKGROUND: Small extracellular vesicle (sEV) analysis can potentially improve cancer detection and diagnostics. However, this potential has been constrained by insufficient sensitivity, dynamic range, and the need for complex labeling.

METHODS: In this study, we demonstrate the combination of PANORAMA and fluorescence imaging for single sEV analysis. The co-acquisition of PANORAMA and fluorescence images enables label-free visualization, enumeration, size determination, and enables detection of cargo microRNAs (miRs).

RESULTS: An increased sEV count is observed in human plasma samples from patients with cancer, regardless of cancer type. The cargo miR-21 provides molecular specificity within the same sEV population at the single …

Genetic Or Pharmacological Ghsr Blockade Has Sexually Dimorphic Effects In Rodents On A High-Fat Diet, András H Lékó, Adriana Gregory-Flores, Renata C N Marchette, Juan L Gomez, Janaina C M Vendruscolo, Vez Repunte-Canonigo, Vicky Choung, Sara L Deschaine, Kimberly E Whiting, Shelley N Jackson, Maria Paula Cornejo, Mario Perello, Zhi-Bing You, Michael Eckhaus, Karuna Rasineni, Kim D Janda, Barry Zorman, Pavel Sumazin, George F Koob, Michael Michaelides, Pietro P Sanna, Leandro F Vendruscolo, Lorenzo Leggio

Faculty, Staff and Students Publications

The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake …

Validation Of Human Telomere Length Multi-Ancestry Meta-Analysis Association Signals Identifies Pop5 And Kbtbd6 As Human Telomere Length Regulation Genes, Rebecca Keener, Surya B Chhetri, Carla J Connelly, Margaret A Taub, Matthew P Conomos, Joshua Weinstock, Bohan Ni, Benjamin Strober, Stella Aslibekyan, Paul L Auer, Lucas Barwick, Lewis C Becker, John Blangero, Eugene R Bleecker, Jennifer A Brody, Brian E Cade, Juan C Celedon, Yi-Cheng Chang, L Adrienne Cupples, Brian Custer, Barry I Freedman, Mark T Gladwin, Susan R Heckbert, Lifang Hou, Marguerite R Irvin, Carmen R Isasi, Jill M Johnsen, Eimear E Kenny, Charles Kooperberg, Ryan L Minster, Take Naseri, Satupa'itea Viali, Sergei Nekhai, Nathan Pankratz, Patricia A Peyser, Kent D Taylor, Marilyn J Telen, Baojun Wu, Lisa R Yanek, Ivana V Yang, Christine Albert, Donna K Arnett, Allison E Ashley-Koch, Kathleen C Barnes, Joshua C Bis, Thomas W Blackwell, Eric Boerwinkle, Esteban G Burchard, April P Carson, Zhanghua Chen, Yii-Der Ida Chen, Dawood Darbar, Mariza De Andrade, Patrick T Ellinor, Myriam Fornage, Bruce D Gelb, Frank D Gilliland, Jiang He, Talat Islam, Stefan Kaab, Sharon L R Kardia, Shannon Kelly, Barbara A Konkle, Rajesh Kumar, Ruth J F Loos, Fernando D Martinez, Stephen T Mcgarvey, Deborah A Meyers, Braxton D Mitchell, Courtney G Montgomery, Kari E North, Nicholette D Palmer, Juan M Peralta, Benjamin A Raby, Susan Redline, Stephen S Rich, Dan Roden, Jerome I Rotter, Ingo Ruczinski, David Schwartz, Frank Sciurba, M Benjamin Shoemaker, Edwin K Silverman, Moritz F Sinner, Nicholas L Smith, Albert V Smith, Hemant K Tiwari, Ramachandran S Vasan, Scott T Weiss, L Keoki Williams, Yingze Zhang, Elad Ziv, Laura M Raffield, Alexander P Reiner, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Hematology And Hemostasis Working Group, Topmed Structural Variation Working Group, Marios Arvanitis, Carol W Greider, Rasika A Mathias, Alexis Battle

Faculty, Staff and Student Publications

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of …

Brain Cell-Type Shifts In Alzheimer’S Disease, Autism, And Schizophrenia Interrogated Using Methylomics And Genetics, Chloe X Yap, Daniel D Vo, Matthew G Heffel, Arjun Bhattacharya, Cindy Wen, Yuanhao Yang, Kathryn E Kemper, Jian Zeng, Zhili Zheng, Zhihong Zhu, Eilis Hannon, Dorothea Seiler Vellame, Alice Franklin, Christa Caggiano, Brie Wamsley, Daniel H Geschwind, Noah Zaitlen, Alexander Gusev, Bogdan Pasaniuc, Jonathan Mill, Chongyuan Luo, Michael J Gandal

Faculty, Staff and Student Publications

Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer's disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer's disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial …

Evaluating Performance And Applications Of Sample-Wise Cell Deconvolution Methods On Human Brain Transcriptomic Data, Rujia Dai, Tianyao Chu, Ming Zhang, Xuan Wang, Alexandre Jourdon, Feinan Wu, Jessica Mariani, Flora M Vaccarino, Donghoon Lee, John F Fullard, Gabriel E Hoffman, Panos Roussos, Yue Wang, Xusheng Wang, Dalila Pinto, Sidney H Wang, Chunling Zhang, Psychencode Consortium, Chao Chen, Chunyu Liu

Faculty, Staff and Student Publications

Sample-wise deconvolution methods estimate cell-type proportions and gene expressions in bulk tissue samples, yet their performance and biological applications remain unexplored, particularly in human brain transcriptomic data. Here, nine deconvolution methods were evaluated with sample-matched data from bulk tissue RNA sequencing (RNA-seq), single-cell/nuclei (sc/sn) RNA-seq, and immunohistochemistry. A total of 1,130,767 nuclei per cells from 149 adult postmortem brains and 72 organoid samples were used. The results showed the best performance of dtangle for estimating cell proportions and bMIND for estimating sample-wise cell-type gene expressions. For eight brain cell types, 25,273 cell-type eQTLs were identified with deconvoluted expressions (decon-eQTLs). The …

Reversible Male Contraception By Targeted Inhibition Of Serine/Threonine Kinase 33, Angela F Ku, Kiran L Sharma, Hai Minh Ta, Courtney M Sutton, Kurt M Bohren, Yong Wang, Srinivas Chamakuri, Ruihong Chen, John M Hakenjos, Ravikumar Jimmidi, Katarzyna Kent, Feng Li, Jian-Yuan Li, Lang Ma, Chandrashekhar Madasu, Murugesan Palaniappan, Stephen S Palmer, Xuan Qin, Matthew B Robers, Banumathi Sankaran, Zhi Tan, Yasmin M Vasquez, Jian Wang, Jennifer Wilkinson, Zhifeng Yu, Qiuji Ye, Damian W Young, Mingxing Teng, Choel Kim, Martin M Matzuk

Faculty, Staff and Students Publications

Men or mice with homozygous serine/threonine kinase 33 (STK33) mutations are sterile owing to defective sperm morphology and motility. To chemically evaluate STK33 for male contraception with STK33-specific inhibitors, we screened our multibillion-compound collection of DNA-encoded chemical libraries, uncovered potent STK33-specific inhibitors, determined the STK33 kinase domain structure bound with a truncated hit CDD-2211, and generated an optimized hit CDD-2807 that demonstrates nanomolar cellular potency (half-maximal inhibitory concentration = 9.2 nanomolar) and favorable metabolic stability. In mice, CDD-2807 exhibited no toxicity, efficiently crossed the blood-testis barrier, did not accumulate in brain, and induced a reversible contraceptive effect that …

Profiling Complex Repeat Expansions In Rfc1 In Parkinson’S Disease, Pilar Alvarez Jerez, Kensuke Daida, Abigail Miano-Burkhardt, Hirotaka Iwaki, Laksh Malik, Guillaume Cogan, Mary B Makarious, Roisin Sullivan, Jana Vandrovcova, Jinhui Ding, J Raphael Gibbs, Androo Markham, Mike A Nalls, Rupesh K Kesharwani, Fritz J Sedlazeck, Bradford Casey, John Hardy, Henry Houlden, Cornelis Blauwendraat, Andrew B Singleton, Kimberley J Billingsley

Faculty, Staff and Students Publications

A biallelic (AAGGG) expansion in the poly(A) tail of an AluSx3 transposable element within the gene RFC1 is a frequent cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and more recently, has been reported as a rare cause of Parkinson's disease (PD) in the Finnish population. Here, we investigate the prevalence of RFC1 (AAGGG) expansions in PD patients of non-Finnish European ancestry in 1609 individuals from the Parkinson's Progression Markers Initiative study. We identified four PD patients carrying the biallelic RFC1 (AAGGG) expansion and did not identify any carriers in controls.

Pancreatic Cancer And Venous Thromboembolism, Teagan Prouse, Mohammad A. Mohammad, Sonali Ghosh, Narender Kumar, Ma Lorena Duhaylungsod, Rinku Majumder, Samarpan Majumder

School of Graduate Studies Faculty Publications

Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all pancreatic cancers and is the most fatal of all cancers. The treatment response from combination chemotherapies is far from satisfactory and surgery remains the mainstay of curative strategies. These challenges warrant identifying effective treatments for combating this deadly cancer. PDAC tumor progression is associated with the robust activation of the coagulation system. Notably, cancer-associated thrombosis (CAT) is a significant risk factor in PDAC. CAT is a concept whereby cancer cells promote thromboembolism, primarily venous thromboembolism (VTE). Of all cancer types, PDAC is associated with the highest risk of developing …

Dynamic Cbct Imaging Using Prior Model-Free Spatiotemporal Implicit Neural Representation (Pmf-Stinr), Hua-Chieh Shao, Tielige Mengke, Tinsu Pan, You Zhang

Faculty, Staff and Student Publications

Objective. Dynamic cone-beam computed tomography (CBCT) can capture high-spatial-resolution, time-varying images for motion monitoring, patient setup, and adaptive planning of radiotherapy. However, dynamic CBCT reconstruction is an extremely ill-posed spatiotemporal inverse problem, as each CBCT volume in the dynamic sequence is only captured by one or a few x-ray projections, due to the slow gantry rotation speed and the fast anatomical motion (e.g. breathing).Approach. We developed a machine learning-based technique, prior-model-free spatiotemporal implicit neural representation (PMF-STINR), to reconstruct dynamic CBCTs from sequentially acquired x-ray projections. PMF-STINR employs a joint image reconstruction and registration approach to address the …

Impact Of Combinatorial Histone Modifications On Acetyllysine Recognition By The Atad2 And Atad2b Bromodomains, Margaret Phillips, Kiera L Malone, Brian W Boyle, Cameron Montgomery, Isabelle A Kressy, Faith M Joseph, Kathleen M Bright, Samuel P Boyson, Sunsik Chang, Jay C Nix, Nicolas L Young, Victoria Jeffers, Seth Frietze, Karen C Glass

Faculty, Staff and Students Publications

The ATPase family AAA+ domain containing 2 (ATAD2) protein and its paralog ATAD2B have a C-terminal bromodomain (BRD) that functions as a reader of acetylated lysine residues on histone proteins. Using a structure–function approach, we investigated the ability of the ATAD2/B BRDs to select acetylated lysine among multiple histone post-translational modifications. The ATAD2B BRD can bind acetylated histone ligands that also contain adjacent methylation or phosphorylation marks, while the presence of these modifications significantly weakened the acetyllysine binding activity of the ATAD2 BRD. Our structural studies provide mechanistic insights into how ATAD2/B BRD-binding pocket residues coordinate the acetyllysine group in …

Gte: A Graph Learning Framework For Prediction Of T-Cell Receptors And Epitopes Binding Specificity, Feng Jiang, Yuzhi Guo, Hehuan Ma, Saiyang Na, Wenliang Zhong, Yi Han, Tao Wang, Junzhou Huang

Faculty, Staff and Student Publications

The interaction between T-cell receptors (TCRs) and peptides (epitopes) presented by major histocompatibility complex molecules (MHC) is fundamental to the immune response. Accurate prediction of TCR–epitope interactions is crucial for advancing the understanding of various diseases and their prevention and treatment. Existing methods primarily rely on sequence-based approaches, overlooking the inherent topology structure of TCR–epitope interaction networks. In this study, we present , a novel heterogeneous Graph neural network model based on inductive learning to capture the topological structure between TCRs and Epitopes. Furthermore, we address the challenge of constructing negative samples within the graph by proposing a dynamic edge …

Viral Reprogramming Of Host Transcription Initiation, Nathan A. Ungerleider, Claire Roberts, Tina M. O’Grady, Trang T. Nguyen, Melody Baddoo, Jia Wang, Eman Ishaq, Monica Concha, Meggie Lam, Jordan Bass, Truong D. Nguyen, Nick Van Otterloo, Nadeeshika Wickramarachchige-Dona, Dorota Wyczechowska, Maria Morales, Tianfang Ma, Yan Dong, Erik K. Flemington

School of Medicine Faculty Publications

Viruses are master remodelers of the host cell environment in support of infection and virus production. For example, viruses typically regulate cell gene expression through modulating canonical cell promoter activity. Here, we show that Epstein Barr virus (EBV) replication causes ‘de novo’ transcription initiation at 29674 new transcription start sites throughout the cell genome. De novo transcription initiation is facilitated in part by the unique properties of the viral pre-initiation complex (vPIC) that binds a TATT[T/A]AA, TATA box-like sequence and activates transcription with minimal support by additional transcription factors. Other de novo promoters are driven by the viral transcription factors, …

Androgen Deprivation Induces Neuroendocrine Phenotypes In Prostate Cancer Cells Through Creb1/Ezh2-Mediated Downregulation Of Rest, Dayong Zheng, Yan Zhang, Sukjin Yang, Ning Su, Michael Bakhoum, Guoliang Zhang, Samira Naderinezhad, Zhengmei Mao, Zheng Wang, Ting Zhou, Wenliang Li

Faculty, Staff and Student Publications

Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor …

Photochemical And Biological Dual-Effects Enhance The Inhibition Of Photosensitizers For Tumour Growth, Huiyu Niu, Yang Liu, Yafu Wang, Yonggang Yang, Ge Wang, Tony D James, Jonathan L Sessler, Hua Zhang

Faculty, Staff and Student Publications

Photosensitizers typically rely on a singular photochemical reaction to generate reactive oxygen species, which can then inhibit or eradicate lesions. However, photosensitizers often exhibit limited therapeutic efficiency due to their reliance on a single photochemical effect. Herein, we propose a new strategy that integrates the photochemical effect (type-I photochemical effect) with a biological effect (proton sponge effect). To test our strategy, we designed a series of photosensitizers (ZZ-sers) based on the naphthalimide molecule. ZZ-sers incorporate both a p-toluenesulfonyl moiety and weakly basic groups to activate the proton sponge effect while simultaneously strengthening the type-I photochemical effect, resulting in enhanced …

The Inform (International Framework For Rehabilitation Medics) Project To Strengthen The Medical Specialty, Man Hung, Himani Patel, Samantha Lee, Justin Nguyen, Amir Mohajeri

Faculty, Staff and Student Publications

(1) Background: This study examines vitamin D’s impact on dental caries to inform prevention strategies, given its critical role in bone and calcium regulation, vital for dental health. (2) Methods: Data from 18,683 participants of the National Health and Nutrition Examination Survey (NHANES) 2011–2016 were analyzed. NHANES collects U.S. population data through interviews, physical exams, and tests, including vitamin D levels and dental health assessed using both the decayed, missing, and filled teeth (DMFT) index and the presence of untreated dental caries. Vitamin D levels were measured according to serum 25(OH)D concentrations, and the analyses adjusted for confounders such as …

Twist1 Drives Cytotoxic Cd8+ T-Cell Exhaustion Through Transcriptional Activation Of Cd274 (Pd-L1) Expression In Breast Cancer Cells, Xiaobin Yu, Jianming Xu

Faculty, Staff and Students Publications

In breast cancer, epithelial-mesenchymal transition (EMT) is positively associated with programmed death ligand 1 (PD-L1) expression and immune escape, and TWIST1 silences ERα expression and induces EMT and cancer metastasis. However, how TWIST1 regulates PD-L1 and immune evasion is unknown. This study analyzed TWIST1 and PD-L1 expression in breast cancers, investigated the mechanism for TWIST1 to regulate PD-L1 transcription, and assessed the effects of TWIST1 and PD-L1 in cancer cells on cytotoxic CD8+ T cells. Interestingly, TWIST1 expression is correlated with high-level PD-L1 expression in ERα-negative breast cancer cells. The overexpression and knockdown of TWIST1 robustly upregulate and downregulate PD-L1 …

Nanobodies In The Fight Against Infectious Diseases: Repurposing Nature's Tiny Weapons, Dina Mohamed Moustafa, Soha S. Rizk, Shahira A. Elbanna, Hanzada Tawfik Nour El-Din, Ahmed Sherif Attia

Dentistry

Nanobodies are the smallest known antigen-binding molecules to date. Their small size, good tissue penetration, high stability and solubility, ease of expression, refolding ability, and negligible immunogenicity in the human body have granted them excellence over conventional antibodies. Those exceptional attributes of nanobodies make them promising candidates for various applications in biotechnology, medicine, protein engineering, structural biology, food, and agriculture. This review presents an overview of their structure, development methods, advantages, possible challenges, and applications with special emphasis on infectious diseases-related ones. A showcase of how nanobodies can be harnessed for applications including neutralization of viruses and combating antibiotic-resistant bacteria …

Age-Specific Induction Of Mutant P53 Drives Clonal Hematopoiesis And Acute Myeloid Leukemia In Adult Mice, Rasoul Pourebrahim, Rafael Heinz Montoya, Hiroki Akiyama, Lauren Ostermann, Shayuan Khazaei, Muharrem Muftuoglu, Natalia Baran, Ran Zhao, Tom Lesluyes, Bin Liu, Joseph D Khoury, Mihai Gagea, Peter Van Loo, Michael Andreeff

Faculty, Staff and Student Publications

The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML vs. lymphoma development. In this context, age-related changes in hematopoietic stem …

Selective Refueling Of Car T Cells Using Ada1 And Cd26 Boosts Antitumor Immunity, Yue Hu, Abhijit Sarkar, Kevin Song, Sara Michael, Magnus Hook, Ruoning Wang, Andras Heczey, Xiaotong Song

Faculty, Staff and Student Publications

Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR T cells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR T cells, improving migration and resistance to transforming growth factor β1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor …