Medical Molecular Biology Commons^™

Ras Nanoclusters Are Cell Surface Transducers That Convert Extracellular Stimuli To Intracellular Signalling, Yong Zhou, John F Hancock

Faculty, Staff and Student Publications

Mutations of rat sarcoma virus (RAS) oncogenes (HRAS, KRAS and NRAS) can contribute to the development of cancers and genetic disorders (RASopathies). The spatiotemporal organization of RAS is an important property that warrants further investigation. In order to function, wild-type or oncogenic mutants of RAS must be localized to the inner leaflet of the plasma membrane (PM), which is driven by interactions between their C-terminal membrane-anchoring domains and PM lipids. The isoform-specific RAS-lipid interactions promote the formation of nanoclusters on the PM. As main sites for effector recruitment, these nanoclusters are biologically important. Since the spatial distribution of lipids is …

Access To Clinically Indicated Genetic Tests For Pediatric Patients With Medicaid: Evidence From Outpatient Genetics Clinics In Texas, Haley Streff, Crescenda L Uhles, Heather Fisher, Rachel Franciskovich, Rebecca O Littlejohn, Amanda Gerard, Julianna Hudnall, Hadley Stevens Smith

Faculty, Staff and Students Publications

Purpose: Little is known about how Medicaid coverage policies affect access to genetic tests for pediatric patients. Building upon and extending a previous analysis of prior authorization requests (PARs), we describe expected coverage of genetic tests submitted to Texas Medicaid and the PAR and diagnostic outcomes of those tests.

Methods: We retrospectively reviewed genetic tests ordered at 3 pediatric outpatient genetics clinics in Texas. We compared Current Procedural Terminology (CPT) codes with the Texas Medicaid fee-for-service schedule (FFSS) to determine whether tests were expected to be covered by Medicaid. We assessed completion and diagnostic yield of commonly ordered tests.

Results: …

Cognitive And Academic Performance Of Rural Zambian Youth Exposed To Hiv, Sophie Jago, Joseph Mwaba Chirwa, Mei Tan, Philip E Thuma, Elena L Grigorenko

Faculty, Staff and Students Publications

Studies focusing on children affected by HIV have shown that they have generally lower academic performance, however, few studies separate children who are HIV exposed and infected (CHEI) and those who are HIV exposed but uninfected (CHEU). Importantly, in rural sub-Saharan Africa, the majority of studies on CHEI and CHEU examine academic performance indirectly based on cognitive test scores. Therefore, studies assessing the effects of HIV on academic achievement directly for CHEI and CHEU are needed. This article evaluates the effects of HIV-infection on cognitive and academic performance by comparing CHEI (n = 82) and CHEU (n = 1045) aged …

High Molecular Diagnostic Yields And Novel Phenotypic Expansions Involving Syndromic Anorectal Malformations, Raymond Belanger Deloge, Xiaonan Zhao, Pamela N Luna, Chad A Shaw, Jill A Rosenfeld, Daryl A Scott

Faculty, Staff and Students Publications

Evidence suggests that genetic factors contribute to the development of anorectal malformations (ARMs). However, the etiology of the majority of ARMs cases remains unclear. Exome sequencing (ES) may be underutilized in the diagnostic workup of ARMs due to uncertainty regarding its diagnostic yield. In a clinical database of ~17,000 individuals referred for ES, we identified 130 individuals with syndromic ARMs. A definitive or probable diagnosis was made in 45 of these individuals for a diagnostic yield of 34.6% (45/130). The molecular diagnostic yield of individuals who initially met criteria for VACTERL association was lower than those who did not (26.8% …

The Tumor-Immune Ecosystem In Shaping Metastasis, Yang Gao, Jeffrey M Rosen, Xiang H-F Zhang

Faculty, Staff and Students Publications

A better understanding of the mechanisms regulating cancer metastasis is critical to develop new therapies and decrease mortality. Emerging evidence suggests that the interactions between tumor cells and the host immune system play important roles in establishing metastasis. Tumor cells are able to recruit immune cells, which in turn promotes tumor cell invasion, intravasation, survival in circulation, extravasation, and colonization in different organs. The tumor-host immunological interactions also generate a premetastatic niche in distant organs which facilitates metastasis. In this review, we summarize the recent findings on how tumor cells and immune cells regulate each other to coevolve and promote …

Phase Separation In Biology And Disease; Current Perspectives And Open Questions, Steven Boeynaems, Shasha Chong, Jörg Gsponer, Liam Holt, Dragomir Milovanovic, Diana M Mitrea, Oliver Mueller-Cajar, Bede Portz, John F Reilly, Christopher D Reinkemeier, Benjamin R Sabari, Serena Sanulli, James Shorter, Emily Sontag, Lucia Strader, Jeanne Stachowiak, Stephanie C Weber, Michael White, Huaiying Zhang, Markus Zweckstetter, Shana Elbaum-Garfinkle, Richard Kriwacki

Faculty, Staff and Students Publications

In the past almost 15 years, we witnessed the birth of a new scientific field focused on the existence, formation, biological functions, and disease associations of membraneless bodies in cells, now referred to as biomolecular condensates. Pioneering studies from several laboratories [reviewed in [1–3]] supported a model wherein biomolecular condensates associated with diverse biological processes form through the process of phase separation. These and other findings that followed have revolutionized our understanding of how biomolecules are organized in space and time within cells to perform myriad biological functions, including cell fate determination, signal transduction, endocytosis, regulation …

Novel And Replicated Clinical And Genetic Risk Factors For Toxicity From High-Dose Methotrexate In Pediatric Acute Lymphoblastic Leukemia, Mark Zobeck, M Brooke Bernhardt, Kala Y Kamdar, Karen R Rabin, Philip J Lupo, Michael E Scheurer

Faculty, Staff and Students Publications

STUDY OBJECTIVE: Methotrexate (MTX) is a key component of treatment for high-risk pediatric acute lymphoblastic leukemia (ALL) but may cause acute kidney injury and prolonged hospitalization due to delayed clearance. The purpose of this study is to identify clinical and genetic factors that may predict which children are at risk for creatinine increase and prolonged MTX clearance.

DESIGN: We conducted a single-center, retrospective cohort study of pediatric patients with ALL who received 4000-5000 mg/m

MAIN RESULTS: Hispanic ethnicity, body mass index (BMI) < 3%, BMI between 85%-95%, and Native American genetic ancestry were found to be associated with an increased risk for creatinine elevation. Older age, Black race, and use of the intensive monitoring protocol were associated with a decreased risk for creatinine elevation. Older age, B- compared to T-ALL, and the minor alleles of rs2838958/SLC19A1 and rs7317112/ABCC4 were associated with an increased risk for delayed clearance. Black race, MTX dose reduction, and the minor allele of rs2306283/SLCO1B1 were found to be associated with a decreased risk for delayed clearance.

CONCLUSIONS: These predictors of MTX toxicities may allow for more precise individualized toxicity risk prediction.

B-Complex Vitamins For Patients With Tango2-Deficiency Disorder, Sarah E Sandkuhler, Lilei Zhang, Joshua K Meisner, Lina Ghaloul-Gonzalez, Cheyenne M Beach, David Harris, Pascale De Lonlay, Seema R Lalani, Christina Y Miyake, Samuel J Mackenzie

Faculty, Staff and Students Publications

No abstract provided.

Excess Folic Acid Intake Increases Dna De Novo Point Mutations, Xuanye Cao, Jianfeng Xu, Ying L Lin, Robert M Cabrera, Qiuying Chen, Chaofan Zhang, John W Steele, Xiao Han, Steven S Gross, Bogdan J Wlodarczyk, James R Lupski, Wei Li, Hongyan Wang, Richard H Finnell, Yunping Lei

Faculty, Staff and Students Publications

No abstract provided.

Does The Potocki-Lupski Syndrome Convey The Autism Spectrum Disorder Phenotype? Case Report And Scoping Review, Oksana I Talantseva, Galina V Portnova, Raisa S Romanova, Daria A Martynova, Olga V Sysoeva, Elena L Grigorenko

Faculty, Staff and Students Publications

Potocki-Lupski Syndrome (PTLS) is a rare condition associated with a duplication of 17p11.2 that may underlie a wide range of congenital abnormalities and heterogeneous behavioral phenotypes. Along with developmental delay and intellectual disability, autism-specific traits are often reported to be the most common among patients with PTLS. To contribute to the discussion of the role of autism spectrum disorder (ASD) in the PTLS phenotype, we present a case of a female adolescent with a de novo dup(17) (p11.2p11.2) without ASD features, focusing on in-depth clinical, behavioral, and electrophysiological (EEG) evaluations. Among EEG features, we found the atypical peak-slow wave patterns …

The Tfiis N-Terminal Domain (Tnd): A Transcription Assembly Module At The Interface Of Order And Disorder, Katerina Cermakova, Vaclav Veverka, H Courtney Hodges

Faculty, Staff and Students Publications

Interaction scaffolds that selectively recognize disordered protein strongly shape protein interactomes. An important scaffold of this type that contributes to transcription is the TFIIS N-terminal domain (TND). The TND is a five-helical bundle that has no known enzymatic activity, but instead selectively reads intrinsically disordered sequences of other proteins. Here, we review the structural and functional properties of TNDs and their cognate disordered ligands known as TND-interacting motifs (TIMs). TNDs or TIMs are found in prominent members of the transcription machinery, including TFIIS, super elongation complex, SWI/SNF, Mediator, IWS1, SPT6, PP1-PNUTS phosphatase, elongin, H3K36me3 readers, the transcription factor MYC, and …

Uncovering Novel Regulators Of Memory Using C Elegans Genetic And Genomic Analysis, Katie L Brandel-Ankrapp, Rachel N Arey

Faculty, Staff and Students Publications

How organisms learn and encode memory is an outstanding question in neuroscience research. Specifically, how memories are acquired and consolidated at the level of molecular and gene pathways remains unclear. In addition, memory is disrupted in a wide variety of neurological disorders; therefore, discovering molecular regulators of memory may reveal therapeutic targets for these disorders. C. elegans are an excellent model to uncover molecular and genetic regulators of memory. Indeed, the nematode's invariant neuronal lineage, fully mapped genome, and conserved associative behaviors have allowed the development of a breadth of genetic and genomic tools to examine learning and memory. In …

Role Of Ribosome Recycling Factor In Natural Termination And Translational Coupling As A Ribosome Releasing Factor, Yoshio Inokuchi, Fabio Quaglia, Akikazu Hirashima, Yoshihiro Yamamoto, Hideko Kaji, Akira Kaji

Department of Biochemistry and Molecular Biology Faculty Papers

The role of ribosome recycling factor (RRF) of E. coli was studied in vivo and in vitro. We used the translational coupling without the Shine-Dalgarno sequence of downstream ORF (d-ORF) as a model system of the RRF action in natural termination of protein synthesis. For the in vivo studies we used the translational coupling by the adjacent coat and lysis genes of RNA phage GA sharing the termination and initiation (UAAUG) and temperature sensitive RRF. The d-ORF translation was measured by the expression of the reporter lacZ gene connected to the 5'-terminal part of the lysis gene. The results showed …

Prenatal Detection Of A Foxf1 Deletion In A Fetus With Acdmpv And Hydronephrosis, Katarzyna Bzdęga, Anna Kutkowska-Kaźmierczak, Gail H Deutsch, Izabela Plaskota, Marta Smyk, Magdalena Niemiec, Artur Barczyk, Ewa Obersztyn, Jan Modzelewski, Iwona Lipska, Paweł Stankiewicz, Marzena Gajecka, Małgorzata Rydzanicz, Rafał Płoski, Tomasz Szczapa, Justyna A Karolak

Faculty, Staff and Students Publications

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by the arrest of fetal lung formation, resulting in neonatal death due to acute respiratory failure and pulmonary arterial hypertension. Heterozygous single-nucleotide variants or copy-number variant (CNV) deletions involving the FOXF1 gene and/or its lung-specific enhancer are found in the vast majority of ACDMPV patients. ACDMPV is often accompanied by extrapulmonary malformations, including the gastrointestinal, cardiac, or genitourinary systems. Thus far, most of the described ACDMPV patients have been diagnosed post mortem, based on histologic evaluation of the lung tissue and/or genetic testing. Here, …

Identification Of Small-Molecule Inhibitors Of The Salmonella Frab Deglycase Using A Live-Cell Assay, Anice Sabag-Daigle, Erin F Boulanger, Pankajavalli Thirugnanasambantham, Jamison D Law, Alex J Bogard, Edward J Behrman, Venkat Gopalan, Brian M M Ahmer

Faculty, Staff and Student Publications

Nontyphoidal salmonellosis is one of the most significant foodborne diseases in the United States and globally. There are no vaccines available for human use to prevent this disease, and only broad-spectrum antibiotics are available to treat complicated cases of the disease. However, antibiotic resistance is on the rise and new therapeutics are needed. We previously identified the Salmonella fraB gene, that mutation of causes attenuation of fitness in the murine gastrointestinal tract. The FraB gene product is encoded in an operon responsible for the uptake and utilization of fructose-asparagine (F-Asn), an Amadori product found in several human foods. Mutations in …

Pan-Cancer Molecular Subtypes Of Metastasis Reveal Distinct And Evolving Transcriptional Programs, Yiqun Zhang, Fengju Chen, Chad J Creighton

Faculty, Staff and Students Publications

Molecular mechanisms underlying cancer metastasis span diverse tissues of origin. Here, we synthesize and collate the transcriptomes of patient-derived xenografts and patient tumor metastases, and these data collectively represent 38 studies and over 3,000 patients and 4,000 tumors. We identify four expression-based subtypes of metastasis transcending tumor lineage. The first subtype has extensive copy alterations, higher expression of MYC transcriptional targets and DNA repair genes, and bromodomain inhibitor response association. The second subtype has higher expression of genes involving metabolism and prostaglandin synthesis and regulation. The third subtype has evidence of neuronal differentiation, higher expression of DNA and histone methylation …

Fixitfelix: Improving Genomic Analysis By Fixing Reference Errors, Sairam Behera, Jonathon Lefaive, Peter Orchard, Medhat Mahmoud, Luis F Paulin, Jesse Farek, Daniela C Soto, Stephen C J Parker, Albert V Smith, Megan Y Dennis, Justin M Zook, Fritz J Sedlazeck

Faculty, Staff and Students Publications

The current version of the human reference genome, GRCh38, contains a number of errors including 1.2 Mbp of falsely duplicated and 8.04 Mbp of collapsed regions. These errors impact the variant calling of 33 protein-coding genes, including 12 with medical relevance. Here, we present FixItFelix, an efficient remapping approach, together with a modified version of the GRCh38 reference genome that improves the subsequent analysis across these genes within minutes for an existing alignment file while maintaining the same coordinates. We showcase these improvements over multi-ethnic control samples, demonstrating improvements for population variant calling as well as eQTL studies.

Identification Of And Mechanistic Insights Into Sars-Cov-2 Main Protease Non-Covalent Inhibitors: An In-Silico Study, Jian-Xin Shen, Wen-Wen Du, Yuan-Ling Xia, Zhi-Bi Zhang, Ze-Fen Yu, Yun-Xin Fu, Shu-Qun Liu

Faculty, Staff and Student Publications

The indispensable role of the SARS-CoV-2 main protease (Mpro) in the viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order to identify the non-covalent Mpro inhibitors, we performed a comprehensive study using a combined computational strategy. We first screened the ZINC purchasable compound database using the pharmacophore model generated from the reference crystal structure of Mpro complexed with the inhibitor ML188. The hit compounds were then filtered by molecular docking and predicted parameters of drug-likeness and pharmacokinetics. The final molecular dynamics (MD) simulations identified three effective candidate inhibitors (ECIs) capable of maintaining …

Differential Regulation Of H3k9/H3k14 Acetylation By Small Molecules Drives Neuron-Fate-Induction Of Glioma Cell, Xincheng Liu, Cui Guo, Tiandong Leng, Zhen Fan, Jialuo Mai, Jiehong Chen, Jinhai Xu, Qianyi Li, Bin Jiang, Ke Sai, Wenzhuo Yang, Jiayu Gu, Jingyi Wang, Shuxin Sun, Zhijie Chen, Yingqian Zhong, Xuanming Liang, Chaoxin Chen, Jing Cai, Yuan Lin, Jiankai Liang, Jun Hu, Guangmei Yan, Wenbo Zhu, Wei Yin

Faculty, Staff and Student Publications

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple …

Drug-Like Small Molecules That Inhibit Expression Of The Oncogenic Microrna-21, Matthew D Shortridge, Bhawna Chaubey, Huanyu J Zhang, Thomas Pavelitz, Venkata Vidadala, Changyan Tang, Gregory L Olsen, George A Calin, Gabriele Varani

Faculty, Staff and Student Publications

We report the discovery of drug-like small molecules that bind specifically to the precursor of the oncogenic and pro-inflammatory microRNA-21 with mid-nanomolar affinity. The small molecules target a local structure at the Dicer cleavage site and induce distinctive structural changes in the RNA, which correlate with specific inhibition of miRNA processing. Structurally conservative single nucleotide substitutions eliminate the conformational change induced by the small molecules, which is also not observed in other miRNA precursors. The most potent of these compounds reduces cellular proliferation and miR-21 levels in cancer cell lines without inhibiting kinases or classical receptors, while closely related compounds …