Medical Molecular Biology Commons^™

Islet Single-Cell Transcriptomic Profiling During Obesity-Induced Beta Cell Expansion In Female Mice, Peter M Masschelin, Scott A Ochsner, Sean M Hartig, Neil J Mckenna, Aaron R Cox

Faculty, Staff and Student Publications

Targeting beta cell proliferation is an appealing approach to restore glucose control in type 1 diabetes. However, the underlying mechanisms of beta cell proliferation remain incompletely understood, limiting identification of new therapeutic targets. Obesity is a naturally occurring process that potently induces human and rodent beta cell replication, representing an ideal model to study mechanisms of beta cell proliferation. We showed previously acute whole-body

Deciphering The Dark Cancer Phosphoproteome Using Machine-Learned Co-Regulation Of Phosphosites, Wen Jiang, Eric J Jaehnig, Yuxing Liao, Zhiao Shi, Tomer M Yaron-Barir, Jared L Johnson, Lewis C Cantley, Bing Zhang

Faculty, Staff and Students Publications

Mass spectrometry-based phosphoproteomics offers a comprehensive view of protein phosphorylation, yet our limited knowledge about the regulation and function of most phosphosites hampers the extraction of meaningful biological insights. To address this challenge, we integrate machine learning with phosphoproteomic data from 1195 tumor specimens spanning 11 cancer types to construct CoPheeMap, a network that maps the co-regulation of 26,280 phosphosites. By incorporating network features from CoPheeMap into a second machine learning model, namely CoPheeKSA, we achieve superior performance in predicting kinase-substrate associations. CoPheeKSA uncovers 24,015 associations between 9399 phosphosites and 104 serine/threonine kinases, shedding light on many unannotated phosphosites and …

Author Correction: Generation Of A Tree Shrew Breast Cancer Model Using Lentivirus Expressing Pik3ca-H1047r, Li Zeng, Hong-Yan Zhang, Chuan-Yu Yang, Zhuo Cheng, Qiu-Yun Jiang, Yao Luo, Yi Li, Fu-Bing Li, Ce-Shi Chen

Faculty, Staff and Students Publications

No abstract provided.

The Autophagy Protein Atg14 Safeguards Against Unscheduled Pyroptosis Activation To Enable Embryo Transport During Early Pregnancy, Pooja Popli, Arin K Oestreich, Vineet K Maurya, Marina N Rowen, Yong Zhang, Michael J Holtzman, Ramya Masand, John P Lydon, Shizuo Akira, Kelle Moley, Ramakrishna Kommagani

Faculty, Staff and Students Publications

Recurrent pregnancy loss, characterized by two or more failed clinical pregnancies, poses a significant challenge to reproductive health. In addition to embryo quality and endometrial function, proper oviduct function is also essential for successful pregnancy establishment. Therefore, structural abnormalities or inflammation resulting from infection in the oviduct may impede the transport of embryos to the endometrium, thereby increasing the risk of miscarriage. However, our understanding of the biological processes that preserve the oviductal cellular structure and functional integrity is limited. Here, we report that autophagy-related protein ATG14 plays a crucial role in maintaining the cellular integrity of the oviduct by …

Emerging Clostridioides Difficile Ribotypes Have Divergent Metabolic Phenotypes, Firas S Midani, Heather A Danhof, Nathanael Mathew, Colleen K Ardis, Kevin W Garey, Jennifer K Spinler, Robert A Britton

Faculty, Staff and Students Publications

Clostridioides difficile is a gram-positive spore-forming pathogen that commonly causes diarrheal infections in the developed world. Although C. difficile is a genetically diverse species, certain ribotypes are overrepresented in human infections, and it is unclear if metabolic adaptations are essential for the emergence of these epidemic ribotypes. To identify ribotype-specific metabolic differences, we therefore tested carbon substrate utilization by 88 C. difficile isolates and looked for differences in growth between 22 ribotypes. As expected, C. difficile was capable of growing on a variety of carbon substrates. Further, C. difficile strains clustered by phylogenetic relationship and displayed ribotype-specific and clade-specific …

Control Of Clostridioides Difficile Virulence And Physiology By The Flagellin Homeostasis Checkpoint Flic-Fliw-Csra In The Absence Of Motility, Duolong Zhu, Katherine J Wozniak, Firas Midani, Shaohui Wang, Xingmin Sun, Robert A Britton

Faculty, Staff and Students Publications

Mutations affecting Clostridioides difficile flagellin (FliC) have been shown to be hypervirulent in animal models and display increased toxin production and alterations in central metabolism. The regulation of flagellin levels in bacteria is governed by a tripartite regulatory network involving fliC, fliW, and csrA, which creates a feedback system to regulate flagella production. Through genomic analysis of C. difficile clade 5 strains (non-motile), we identified they have jettisoned many of the genes required for flagellum biosynthesis yet retain the major flagellin gene fliC and regulatory gene fliW. We therefore investigated the roles of fliC, fliW …

Exploratory Co-Design On Electronic Health Record Nursing Summaries: Case Study, Suhyun Park, Jenna L Marquard, Robin R Austin, Christie L Martin, David S Pieczkiewicz, Connie W Delaney

The Brown Foundation: Institute of Molecular Medicine

Background: Although electronic health record nursing summaries aim to provide a concise overview of patient data, they often fall short of meeting nurses' information needs, leading to underutilization. This gap arises from a lack of involvement of nurses in the design of health information technologies.

Objective: The purpose of this exploratory co-design case study was to solicit insights from nurses regarding nursing summary design considerations, including key information types and the preferred design prototype.

Methods: We recruited clinical nurses (N=33) from 7 inpatient units at a university hospital in the Midwestern United States using a purposive sampling method. We used …

Roles Of The Survivin Bir Domain In Cellular Apoptosis And Proliferation: An In Silico Study, Silviatun Nihayah, Septelia Inawati Wanandi, Linda Erlina, Resda Akhra Syahrani

Makara Journal of Science

Survivin is an antiapoptotic protein that is highly expressed in cancer cells. We investigated the dual roles of the Bacu-lovirus IAP Repeats (BIR) domain within survivin, encompassing both apoptosis and proliferation, through an in silico study. The protein-protein interaction (PPI) network of survivin was analyzed using Cytoscape software. Functional enrichment (FE) analysis and data from the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to identify the implicated signaling pathways. The binding affinity of the BIR domain with the targeted proteins was visualized via molecular docking analysis. Drawing insights from the PPI network and FE analysis, we identified two …

Novel Signaling Pathways Involved In Ybx1 Role In Hepatocellular Carcinoma, Yamile Abuchard Anaya, Ana Ayala Pazzi, Dennis Kwabiah, Veerababu Nagati, Ricardo Pequeno Bracho, Kyle Doxtater, Subhash C. Chauhan, Manish K. Tripathi

Research Symposium

Background: The most prevalent type of liver cancer is hepatocellular carcinoma (HCC), and socioeconomic and health disparities have a major impact on both its incidence and fatality rates. HCC rates are typically greater in areas with poor access to healthcare, high obesity rates, and a high frequency of infectious diseases. Because of risk factors include diabetes, non-alcoholic fatty liver disease (NAFLD), and Hepatitis B and C, HCC is particularly common in the Rio Grande Valley (RGV). The burden of HCC in this underprivileged area is made worse by McAllen, Texas, which regrettably holds the distinction of being the most obese …

Dysregulation Of Cholesterol Metabolism And Sorafenib Drug Resistance In Hepatocellular Carcinoma, Veerababu Nagati, Dennis Kwabiah, Yamile Abuchard Anaya, Ana Ayala Pazzi, Manish K. Tripathi

Research Symposium

Background: Hepatocellular carcinoma (HCC) is among the most prevalent cancers and a leading cause of cancer-related deaths worldwide. Sorafenib, a multikinase inhibitor, serves as a key first-line treatment for HCC when surgical intervention is not an option. However, primary and acquired resistance to sorafenib has significantly limited its effectiveness, reducing the disease control rate. Dysregulation of numerous genes that influence cancer cell proliferation, survival, and drug resistance contributes to this challenge. Identifying the molecular drivers of sorafenib resistance remains critical to improving treatment outcomes. Several factors, including activation of oncogenic pathways (e.g., Akt/mTOR), hypoxia, cholesterol metabolism, EMT, multidrug resistance, and …

Uca1 As A Key Regulator Of The Warburg Effect During Anoikis Resistance In Colorectal Cancer Metastasis, Ricardo Pequeno Bracho, Salique Hassan Shaham, Yamile Abuchard Anaya, Sophia Leslie, Kyle Doxtater, Subhash Chauhan, Bilal Hafeez, Tamer Oraby, Manish K. Tripathi

Research Symposium

Colorectal carcinoma (CRC) is the second leading cause of cancer-related mortality in the United States. While localized CRC has a 90% five-year survival rate, this drops sharply to 14% upon metastasis. Metastasis occurs in approximately 40–50% of CRC cases and requires cancer cells to acquire anoikis resistance—a critical adaptation allowing survival after detachment from the extracellular matrix, enabling migration and colonization of secondary sites. Understanding the molecular mechanisms driving anoikis resistance, particularly those linked to altered glucose metabolism, is essential for developing targeted therapies for metastatic CRC.

Cancer cells frequently exhibit the Warburg Effect, a metabolic adaptation favoring glycolysis over …

Sequence Variants In Hectd1 Result In A Variable Neurodevelopmental Disorder, Gazelle Zerafati-Jahromi, Elias Oxman, Hieu D Hoang, Wu-Lin Charng, Tanvitha Kotla, Weimin Yuan, Keito Ishibashi, Sonia Sebaoui, Kathryn Luedtke, Bryce Winrow, Rebecca D Ganetzky, Anna Ruiz, Carmen Manso-Basúz, Nino Spataro, Peter Kannu, Taryn Athey, Christina Peroutka, Caitlin Barnes, Richard Sidlow, George Anadiotis, Kari Magnussen, Irene Valenzuela, Alejandro Moles-Fernandez, Seth Berger, Christina L Grant, Eric Vilain, Gudny A Arnadottir, Patrick Sulem, Telma S Sulem, Kari Stefansson, Shavonne Massey, Natalie Ginn, Annapurna Poduri, Alissa M D'Gama, Rozalia Valentine, Sara K Trowbridge, Chaya N Murali, Rachel Franciskovich, Yen Tran, Bryn D Webb, Kim M Keppler-Noreuil, April L Hall, Bobbi Mcgivern, Kristin G Monaghan, Maria J Guillen Sacoto, Dustin Baldridge, Gary A Silverman, Sonika Dahiya, Tychele N Turner, Tim Schedl, Joshua G Corbin, Stephen C Pak, Irene E Zohn, Christina A Gurnett

Faculty, Staff and Students Publications

Dysregulation of genes encoding the homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases has been linked to cancer and structural birth defects. One member of this family, the HECT-domain-containing protein 1 (HECTD1), mediates developmental pathways, including cell signaling, gene expression, and embryogenesis. Through GeneMatcher, we identified 14 unrelated individuals with 15 different variants in HECTD1 (10 missense, 3 frameshift, 1 nonsense, and 1 splicing variant) with neurodevelopmental disorders (NDDs), including autism, attention-deficit/hyperactivity disorder, and epilepsy. Of these 15 HECTD1 variants, 10 occurred de novo, 3 had unknown inheritance, and 2 were compound heterozygous. While all individuals in this cohort displayed …

2024 Lifetime Achievement Award: Biology Unbalanced: Genes, Gene Dosage, And Disease Susceptibility, James R Lupski

Faculty, Staff and Students Publications

This article is based on the address given by the author at the 2024 meeting of The American Society of Human Genetics (ASHG) in Denver, CO. A video of the original address can be found at the ASHG website.

Comparison Of Deep Learning And Traditional Machine Learning Models For Predicting Mild Cognitive Impairment Using Plasma Proteomic Biomarkers, Kesheng Wang, Donald A. Adjeroh, Wei Fang, Suzy M. Walter, Danqing Xiao, Ubolrat Piamjariyakul, Chun Xu

Health & Biomedical Sciences Faculty Publications

Mild cognitive impairment (MCI) is a clinical condition characterized by a decline in cognitive ability and progression of cognitive impairment. It is often considered a transitional stage between normal aging and Alzheimer’s disease (AD). This study aimed to compare deep learning (DL) and traditional machine learning (ML) methods in predicting MCI using plasma proteomic biomarkers. A total of 239 adults were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort along with a pool of 146 plasma proteomic biomarkers. We evaluated seven traditional ML models (support vector machines (SVMs), logistic regression (LR), naïve Bayes (NB), random forest (RF), k-nearest neighbor …

Caloric Restriction And Telomere Preservation In Tert Knockout Adipocyte Progenitors Does Not Rescue Mice From Metabolic Dysfunction Due To A Tert Function In Adipocyte Mitochondria, Zhanguo Gao, Yongmei Yu, Kristin Eckel-Mahan, Mikhail G Kolonin

The Brown Foundation: Institute of Molecular Medicine

Inactivation of telomerase (TERT) in adipocyte progenitor cells (APC) expedites telomere attrition, and the onset of diabetes in mice fed high-fat diet (HFD), which promotes APC over-proliferation and replicative senescence. Here, we show that time-restricted feeding or caloric restriction in the postnatal development of mice subsequently subjected to HFD prevents telomere attrition but not glucose intolerance. This metabolic effect of dietary intervention was not observed for mice with TERT KO in endothelial or myeloid cells. To characterize the telomere-independent effects of TERT in the APC lineage, we analyzed mice with TERT knockout in mature adipocytes (AD-TERT-KO), which do not proliferate …

Reevaluating Anti-Inflammatory Therapy: Targeting Senescence To Balance Anti-Cancer Efficacy And Vascular Disease, Bernardo Casso-Chapa, Norma Alicia Vazquez González, Nhat-Tu Le, Nicolas L Palaskas, Kevin T Nead, Lydia P Eutsey, Venkata S K Samanthapudi, Abigail M Osborn, Jonghae Lee, Gilbert Mejia, Oanh Hoang, Steven H Lin, Anita Deswal, Joerg Herrmann, Guangyu Wang, James L Kirkland, Sunil Krishnan, Xander H T Wehrens, Eduardo N Chini, Syed Wamique Yusuf, Cezar A Iliescu, Abhishek Jain, Jared K Burks, Erin Seeley, Philip L Lorenzi, Khanh M Chau, Keila C Ostos-Mendoza, Isabella M Grumbach, Paul S Brookes, Nordin M J Hanssen, Menno P J De Winther, Laurent Yvan-Charvet, Sivareddy Kotla, Keri Schadler, Jun-Ichi Abe

The Brown Foundation: Institute of Molecular Medicine

Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially …

Assessing Predictions On Fitness Effects Of Missense Variants In Hmbs In Cagi6, Jing Zhang, Lisa Kinch, Panagiotis Katsonis, Olivier Lichtarge, Milind Jagota, Yun S Song, Yuanfei Sun, Yang Shen, Nurdan Kuru, Onur Dereli, Ogun Adebali, Muttaqi Ahmad Alladin, Debnath Pal, Emidio Capriotti, Maria Paola Turina, Castrense Savojardo, Pier Luigi Martelli, Giulia Babbi, Rita Casadio, Fabrizio Pucci, Marianne Rooman, Gabriel Cia, Matsvei Tsishyn, Alexey Strokach, Zhiqiang Hu, Warren Van Loggerenberg, Frederick P Roth, Predrag Radivojac, Steven E Brenner, Qian Cong, Nick V Grishin

Faculty, Staff and Students Publications

This paper presents an evaluation of predictions submitted for the "HMBS" challenge, a component of the sixth round of the Critical Assessment of Genome Interpretation held in 2021. The challenge required participants to predict the effects of missense variants of the human HMBS gene on yeast growth. The HMBS enzyme, critical for the biosynthesis of heme in eukaryotic cells, is highly conserved among eukaryotes. Despite the application of a variety of algorithms and methods, the performance of predictors was relatively similar, with Kendall's tau correlation coefficients between predictions and experimental scores around 0.3 for a majority of submissions. Notably, the …

The Glu86 Residue In Tbx4 Proves Critical For Human Lung Development, Przemyslaw Szafranski, Tomasz Gambin, Gail Deutsch, Salma A Nassef, Mary Clay Bailey, Debra L Kearney, Paweł Stankiewicz

Faculty, Staff and Students Publications

T-box transcription factors are a group of evolutionarily conserved T-box-containing regulators of mesoderm specification and development. Heterozygous single nucleotide variants (SNVs) or copy-number variant (CNV) deletions involving dosage-sensitive TBX4 have been associated with pulmonary arterial hypertension (PAH), ischiocoxopodopatellar syndrome with or without PAH, and lethal lung developmental disorders (LLDDs), including acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD), and other unspecified primary pulmonary hypoplasias. Loss- and gain-of-function variants have been proposed to cause pediatric PAH and LLDDs, and adult forms of PAH, respectively. Of more than 50 missense SNVs scattered across the entire TBX4, only three have been reported in patients …

Cagi6 Id Panel Challenge: Assessment Of Phenotype And Variant Predictions In 415 Children With Neurodevelopmental Disorders (Ndds), Maria Cristina Aspromonte, Alessio Del Conte, Shaowen Zhu, Wuwei Tan, Yang Shen, Yexian Zhang, Qi Li, Maggie Haitian Wang, Giulia Babbi, Samuele Bovo, Pier Luigi Martelli, Rita Casadio, Azza Althagafi, Sumyyah Toonsi, Maxat Kulmanov, Robert Hoehndorf, Panagiotis Katsonis, Amanda Williams, Olivier Lichtarge, Su Xian, Wesley Surento, Vikas Pejaver, Sean D Mooney, Uma Sunderam, Rajgopal Srinivasan, Alessandra Murgia, Damiano Piovesan, Silvio C E Tosatto, Emanuela Leonardi

Faculty, Staff and Students Publications

The Genetics of Neurodevelopmental Disorders Lab in Padua provided a new intellectual disability (ID) Panel challenge for computational methods to predict patient phenotypes and their causal variants in the context of the Critical Assessment of the Genome Interpretation, 6th edition (CAGI6). Eight research teams submitted a total of 30 models to predict phenotypes based on the sequences of 74 genes (VCF format) in 415 pediatric patients affected by Neurodevelopmental Disorders (NDDs). NDDs are clinically and genetically heterogeneous conditions, with onset in infant age. Here, we assess the ability and accuracy of computational methods to predict comorbid phenotypes based on clinical …

Genomic Balancing Act: Deciphering Dna Rearrangements In The Complex Chromosomal Aberration Involving 5p152, 2q311, And 18q2132, Zain Dardas, Dana Marafi, Ruizhi Duan, Jawid M Fatih, Omnia F El-Rashidy, Christopher M Grochowski, Claudia M B Carvalho, Shalini N Jhangiani, Weimin Bi, Haowei Du, Richard A Gibbs, Jennifer E Posey, Daniel G Calame, Maha S Zaki, James R Lupski

Faculty, Staff and Students Publications

Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and a terminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses …