Genetic Phenomena Commons^™

The Mitochondrial Protease Lonp1 Promotes Proteasome Inhibitor Resistance In Multiple Myeloma, Laure Maneix, Melanie A Sweeney, Sukyeong Lee, Polina Iakova, Shannon E Moree, Ergun Sahin, Premal Lulla, Sarvari V Yellapragada, Francis T F Tsai, Andre Catic

Faculty, Staff and Students Publications

Multiple myeloma and its precursor plasma cell dyscrasias affect 3% of the elderly population in the US. Proteasome inhibitors are an essential part of several standard drug combinations used to treat this incurable cancer. These drugs interfere with the main pathway of protein degradation and lead to the accumulation of damaged proteins inside cells. Despite promising initial responses, multiple myeloma cells eventually become drug resistant in most patients. The biology behind relapsed/refractory multiple myeloma is complex and poorly understood. Several studies provide evidence that in addition to the proteasome, mitochondrial proteases can also contribute to protein quality control outside of …

Phenytoin Inhibits Cell Proliferation Through Microrna-196a-5p In Mouse Lip Mesenchymal Cells, Hiroki Yoshioka, Sai Shankar Ramakrishnan, Akiko Suzuki, Junichi Iwata

Faculty, Staff and Student Publications

Cleft lip (CL) is one of the most common birth defects. It is caused by either genetic mutations or environmental factors. Recent studies suggest that environmental factors influence the expression of noncoding RNAs [e.g., microRNA (miRNA)], which can regulate the expression of genes crucial for cellular functions. In this study, we examined which miRNAs are associated with CL. Among 10 candidate miRNAs (miR-98-3p, miR-101a-3p, miR-101b-3p, miR-141-3p, miR-144-3p, miR-181a-5p, miR-196a-5p, miR-196b-5p, miR-200a-3p, and miR-710) identified through our bioinformatic analysis of CL-associated genes, overexpression of miR-181a-5p, miR-196a-5p, miR-196b-5p, and miR-710 inhibited cell proliferation through suppression of genes associated with CL in cultured …

Investigating The Role Of Znf384 Rearrangements In Acute Leukemia, Kirsten Dickerson

Theses and Dissertations (ETD)

Chromosomal rearrangements involving ZNF384 are the defining lesion in 5% of pediatric and adult B-cell acute lymphoblastic leukemia and tumors are characterized by aberrant myeloid marker expression. Additionally, ZNF384 rearrangements are the defining lesion in nearly half of pediatric B/myeloid mixed phenotype acute leukemia. These fusions juxtapose full-length ZNF384 to the N terminal portion of a diverse range of partners, most often, transcription factors or epigenetic modifiers. It has been shown that ZNF384-rearranged tumors have a distinct gene expression profile that is consistent between disease groups and N terminal partners. Genomic analyses of patient tumors has shown that ZNF384 fusions …

Calcium Ions Trigger The Exposure Of Phosphatidylserine On The Surface Of Necrotic Cells, Yoshitaka Furuta, Omar Pena-Ramos, Zao Li, Lucia Chiao, Zheng Zhou

Faculty, Staff and Students Publications

Intracellular Ca2+ level is under strict regulation through calcium channels and storage pools including the endoplasmic reticulum (ER). Mutations in certain ion channel subunits, which cause mis-regulated Ca2+ influx, induce the excitotoxic necrosis of neurons. In the nematode Caenorhabditis elegans, dominant mutations in the DEG/ENaC sodium channel subunit MEC-4 induce six mechanosensory (touch) neurons to undergo excitotoxic necrosis. These necrotic neurons are subsequently engulfed and digested by neighboring hypodermal cells. We previously reported that necrotic touch neurons actively expose phosphatidylserine (PS), an "eat-me" signal, to attract engulfing cells. However, the upstream signal that triggers PS externalization remained elusive. Here we …

Patterns Of Cilia Gene Dysregulations In Major Psychiatric Disorders, Wedad Alhassen, Siwei Chen, Marquis Vawter, Brianna Kay Robbins, Henry Nguyen, Thant Nyi Myint, Yumiko Saito, Anton Schulmann, Surya M. Nauli, Olivier Civelli, Pierre Baldi, Amal Alachkar

Pharmacy Faculty Articles and Research

Primary cilia function as cells' antennas to detect and transduce external stimuli and play crucial roles in cell signaling and communication. The vast majority of cilia genes that are causally linked with ciliopathies are also associated with neurological deficits, such as cognitive impairments. Yet, the roles of cilia dysfunctions in the pathogenesis of psychiatric disorders have not been studied. Our aim is to identify patterns of cilia gene dysregulation in the four major psychiatric disorders: schizophrenia (SCZ), autism spectrum disorder (ASD), bipolar disorder (BP), and major depressive disorder (MDD). For this purpose, we acquired differentially expressed genes (DEGs) from the …

A Peek Inside The Machines Of Bacterial Nucleotide Excision Repair, Thanyalak Kraithong, Silas Hartley, David Jeruzalmi, Danaya Pakotiprapha

Publications and Research

Double stranded DNA (dsDNA), the repository of genetic information in bacteria, archaea and eukaryotes, exhibits a surprising instability in the intracellular environment; this fragility is exacerbated by exogenous agents, such as ultraviolet radiation. To protect themselves against the severe consequences of DNA damage, cells have evolved at least six distinct DNA repair pathways. Here, we review recent key findings of studies aimed at understanding one of these pathways: bacterial nucleotide excision repair (NER). This pathway operates in two modes: a global genome repair (GGR) pathway and a pathway that closely interfaces with transcription by RNA polymerase called transcription-coupled repair (TCR). …

Cerebellar Coordination Of Neuronal Communication In Cerebral Cortex, Samuel S Mcafee, Yu Liu, Roy V Sillitoe, Detlef H Heck

Duncan NRI Faculty and Staff Publications

Cognitive processes involve precisely coordinated neuronal communications between multiple cerebral cortical structures in a task specific manner. Rich new evidence now implicates the cerebellum in cognitive functions. There is general agreement that cerebellar cognitive function involves interactions between the cerebellum and cerebral cortical association areas. Traditional views assume reciprocal interactions between one cerebellar and one cerebral cortical site, via closed-loop connections. We offer evidence supporting a new perspective that assigns the cerebellum the role of a coordinator of communication. We propose that the cerebellum participates in cognitive function by modulating the coherence of neuronal oscillations to optimize communications between multiple …

Contribution Of The Human Microbiome And Proteus Mirabilis To Onset And Progression Of Rheumatoid Arthritis: Potential For Targeted Therapy, Jessica Kerpez, Marc Kesselman, Michelle Demory Beckler

Internet Journal of Allied Health Sciences and Practice

The human microbiome has been shown to play a role in the regulation of human health, behavior, and disease. Data suggests that microorganisms that co-evolved within humans have an enhanced ability to prevent the development of a large spectrum of immune-related disorders but may also lead to the onset of conditions when homeostasis is disrupted. In many conditions, a link between dysbiosis (microbial imbalance or microbiome upset) has been identified and associated with immune conditions such as rheumatoid arthritis (RA). This review provides insight into how an individual’s unique microbiome, combined with a genetic predisposition and environmental factors may lead …

Mimicking The Effect Of Prolactin On Stat3/Stat5 Activity In Breast Cancer, Jennifer N. Barbuto, Sarah R. Walker

Honors Theses and Capstones

Signal transducers and activators of transcription (STAT) 3 and 5 are commonly constitutively activated in breast cancer. STAT5 can outcompete STAT3 and reduce cell proliferation and metastasis. STAT5 activation is stimulated by prolactin, a natural hormone that can be harmful at high levels. The aim of this study is to identify some possible previously developed drugs that mimic the effect of prolactin and STAT5 without the added risk in MDA-MB231 breast cancer cells. Using the CLUE database query app and STAT5 up- and downregulation signatures, three drugs (X, K, and M) were chosen based on their similarity in signatures to …

Chromosome Xq23 Is Associated With Lower Atherogenic Lipid Concentrations And Favorable Cardiometabolic Indices, Pradeep Natarajan, Akhil Pampana, Sarah E. Graham, Sanni Ruotsalainen, Paul S. De Vries, Jai G. Broome, Juan M. Peralta, John Blangero, Joanne E. Curran, James P. Pirruccello

School of Medicine Publications

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and …

A Conceptual Proposal For The Epigenetically Causal Relationship Between Parental Ptsd And Inflammatory Disease In Post Hoc Offspring., Emma Griffith

Williams Honors College, Honors Research Projects

Could a combat veteran's horrific experiences in early-2000s Afghanistan have a direct, biological impact his now-adult daughter's risk of a heart attack later in her life? This concept would have been unapologetically mocked a mere twenty years ago, and it has only been in the past decade that the new field of epigenetics has revealed a distinct possibility for this event to actually take place—for parents' experiences to profoundly influence the biology of their children. The major objective of this research project is to argue for the legitimacy of this theoretical phenomenon by discussing the latest data regarding PTSD's interaction …

Cornelia De Lange Syndrome Research From 1953 To 2020: A Bibliometric Analysis, Dr. Mirza Muhammad Naseer, Dr. Abu Waris

Library Philosophy and Practice (e-journal)

The present study was conducted to explore various aspects of Cornelia de Lange Syndrome (CdLS) research publications including annual scientific productivity, top contributing authors and their impact, top contributing countries and organizations, most relevant sources of publication, highly cited documents, and most frequently used words. Bibliometric methods were used to investigate these aspects of CdLS research publications. Results of the study disclosed that the annual scientific productivity of CdLS literature is increasing gradually with the passage of time. A. Selicorni contributed the highest number of publications (45) to CdLS literature while I. D. Krantz had the highest impact in the …

Rapid Induction Of The Unfolded Protein Response And Apoptosis By Estrogen Mimic Ttc-352 For The Treatment Of Endocrine-Resistant Breast Cancer, Balkees Abderrahman, Philipp Y Maximov, Ramona F Curpan, Sean W Fanning, Jay S Hanspal, Ping Fan, Charles E Foulds, Yue Chen, Anna Malovannaya, Antrix Jain, Rui Xiong, Geoffrey L Greene, Debra A Tonetti, Gregory R J Thatcher, V Craig Jordan

Faculty, Staff and Students Publications

Patients with long-term estrogen-deprived breast cancer (BC), after resistance to tamoxifen or aromatase inhibitors develops, can experience tumor regression when treated with estrogens. Estrogen’s anti-tumor effect is attributed to apoptosis via the estrogen receptor (ER). Estrogen treatment can have unpleasant gynecological and non-gynecological adverse events thus the development of safer estrogenic agents remains a clinical priority. Here, we study synthetic selective estrogen mimics (SEMs) BMI-135 and TTC-352, and the naturally-occurring estrogen estetrol (E4), which are proposed as safer estrogenic agents compared to 17β-estradiol (E2), for the treatment of endocrine-resistant BC. TTC-352 and E4 are being evaluated in BC clinical trials. …

Deep Learning For Automated Analysis Of Cellular And Extracellular Components Of The Foreign Body Response In Multiphoton Microscopy Images, Mattia Sarti, Maria Parlani, Luis Diaz-Gomez, Antonios G Mikos, Pietro Cerveri, Stefano Casarin, Eleonora Dondossola

Faculty, Staff and Student Publications

The Foreign body response (FBR) is a major unresolved challenge that compromises medical implant integration and function by inflammation and fibrotic encapsulation. Mice implanted with polymeric scaffolds coupled to intravital non-linear multiphoton microscopy acquisition enable multiparametric, longitudinal investigation of the FBR evolution and interference strategies. However, follow-up analyses based on visual localization and manual segmentation are extremely time-consuming, subject to human error, and do not allow for automated parameter extraction. We developed an integrated computational pipeline based on an innovative and versatile variant of the U-Net neural network to segment and quantify cellular and extracellular structures of interest, which is …

Carving The Path To Allogeneic Car T Cell Therapy In Acute Myeloid Leukemia, Oren Pasvolsky, May Daher, Gheath Alatrash, David Marin, Naval Daver, Farhad Ravandi, Katy Rezvani, Elizabeth Shpall, Partow Kebriaei

Faculty, Staff and Student Publications

Despite advances in the understanding of the genetic landscape of acute myeloid leukemia (AML) and the addition of targeted biological and epigenetic therapies to the available armamentarium, achieving long-term disease-free survival remains an unmet need. Building on growing knowledge of the interactions between leukemic cells and their bone marrow microenvironment, strategies to battle AML by immunotherapy are under investigation. In the current review we describe the advances in immunotherapy for AML, with a focus on chimeric antigen receptor (CAR) T cell therapy. CARs constitute powerful immunologic modalities, with proven clinical success in B-Cell malignancies. We discuss the challenges and possible …

A Novel Statistical Method For Interpreting The Pathogenicity Of Rare Variants, Jun Wang, Hehe Liu, Renae Elaine Bertrand, Alejandro Sarrion-Perdigones, Yezabel Gonzalez, Koen J T Venken, Rui Chen

Faculty, Staff and Students Publications

PURPOSE: To achieve the ultimate goal of personalized treatment of patients, accurate molecular diagnosis and precise interpretation of the impact of genetic variants on gene function is essential. With sequencing cost becoming increasingly affordable, the accurate distinguishing of benign from pathogenic variants becomes the major bottleneck. Although large normal population sequence databases have become a key resource in filtering benign variants, they are not effective at filtering extremely rare variants.

METHODS: To address this challenge, we developed a novel statistical test by combining sequencing data from a patient cohort with a normal control population database. By comparing the expected and …

Novel Mutations In The Gtpbp3 Gene For Mitochondrial Disease And Characteristics Of Related Phenotypic Spectrum: The First Three Cases From China, Hui-Ming Yan, Zhi-Mei Liu, Bei Cao, Victor Wei Zhang, Yi-Duo He, Zheng-Jun Jia, Hui Xi, Jing Liu, Fang Fang, Hua Wang

Faculty, Staff and Students Publications

Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) caused by mutations in GTPBP3 gene is a rare mitochondrial disease, and this disorder identified from the Chinese population has not been described thus far. Here, we report a case series of three patients with COXPD23 caused by GTPBP3 mutations, from a severe to a mild phenotype. The main clinical features of these patients include lactic acidosis, myocardial damage, and neurologic symptoms. Whole genome sequencing and targeted panels of candidate human mitochondrial genome revealed that patient 1 was a compound heterozygote with novel mutations c.413C > T (p. A138V) and c.509_510del (p. E170Gfs∗42) in GTPBP3 …

Protein-Functionalized Poly(Ethylene Glycol) Hydrogels As Scaffolds For Monolayer Organoid Culture, Reid L Wilson, Ganesh Swaminathan, Khalil Ettayebi, Carolyn Bomidi, Xi-Lei Zeng, Sarah E Blutt, Mary K Estes, K Jane Grande-Allen

Faculty, Staff and Students Publications

Stem cell-derived, organotypic in vitro models, known as organoids, have emerged as superior alternatives to traditional cell culture models due to their unparalleled ability to recreate complex physiological and pathophysiological processes. For this reason, they are attractive targets of tissue-engineering efforts, as constructs that include organoid technology would be expected to better simulate the many functions of the desired tissue or organ. While the 3D spheroidal architecture that is the default architecture of most organoid models may be preferred for some applications, 2D monolayer arrangements remain the preferred organization for many applications in tissue engineering. Therefore, in this work, we …

Identification Of Deep-Intronic Splice Mutations In A Large Cohort Of Patients With Inherited Retinal Diseases, Xinye Qian, Jun Wang, Meng Wang, Austin D Igelman, Kaylie D Jones, Yumei Li, Keqing Wang, Kerry E Goetz, David G Birch, Paul Yang, Mark E Pennesi, Rui Chen

Faculty, Staff and Students Publications

High throughput sequencing technologies have revolutionized the identification of mutations responsible for a diverse set of Mendelian disorders, including inherited retinal disorders (IRDs). However, the causal mutations remain elusive for a significant proportion of patients. This may be partially due to pathogenic mutations located in non-coding regions, which are largely missed by capture sequencing targeting the coding regions. The advent of whole-genome sequencing (WGS) allows us to systematically detect non-coding variations. However, the interpretation of these variations remains a significant bottleneck. In this study, we investigated the contribution of deep-intronic splice variants to IRDs. WGS was performed for a cohort …