Medicine and Health Sciences Commons^™

Racipe: A Computational Tool For Modeling Gene Regulatory Circuits Using Randomization., Bin Huang, Dongya Jia, Jingchen Feng, Herbert Levine, José N Onuchic, Mingyang Lu

Faculty Research 2018

BACKGROUND: One of the major challenges in traditional mathematical modeling of gene regulatory circuits is the insufficient knowledge of kinetic parameters. These parameters are often inferred from existing experimental data and/or educated guesses, which can be time-consuming and error-prone, especially for large networks.

RESULTS: We present a user-friendly computational tool for the community to use our newly developed method named random circuit perturbation (RACIPE), to explore the robust dynamical features of gene regulatory circuits without the requirement of detailed kinetic parameters. Taking the network topology as the only input, RACIPE generates an ensemble of circuit models with distinct randomized parameters …

Glioma Through The Looking Glass: Molecular Evolution Of Diffuse Gliomas And The Glioma Longitudinal Analysis Consortium., The Glass Consortium, Hoon Kim, Roel G W Verhaak

Faculty Research 2018

Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal Analysis …

Jnk2 Deficiency Increases The Rate Of Glaucomatous Neurodegeneration In Ocular Hypertensive Dba/2j Mice., Jeffrey M. Harder, Pete A. Williams, Ileana Soto, Nicole E Foxworth, Kimberly A Fernandes, Nelson F Freeburg, Richard T Libby, Simon W M John

Faculty Research 2018

The cJun N-terminal kinases (JNKs; JNK1, JNK2, and JNK3) promote degenerative processes after neuronal injury and in disease. JNK2 and JNK3 have been shown to promote retinal ganglion cell (RGC) death after optic nerve injury. In their absence, long-term survival of RGC somas is significantly increased after mechanical optic nerve injury. In glaucoma, because optic nerve damage is thought to be a major cause of RGC death, JNKs are an important potential target for therapeutic intervention. To assess the role of JNK2 and JNK3 in an ocular hypertensive model of glaucoma, null alleles of Jnk2 and Jnk3 were backcrossed into …

Oocyte Stage-Specific Effects Of Mtor Determine Granulosa Cell Fate And Oocyte Quality In Mice., Jing Guo, Teng Zhang, Yueshuai Guo, Tao Sun, Hui Li, Xiaoyun Zhang, Hong Yin, Guangyi Cao, Yaoxue Yin, Hao Wang, Lanying Shi, Xuejiang Guo, Jiahao Sha, John J. Eppig, You-Qiang Su

Faculty Research 2018

MTOR (mechanistic target of rapamycin) is a widely recognized integrator of signals and pathways key for cellular metabolism, proliferation, and differentiation. Here we show that conditional knockout (cKO) of Mtor in either primordial or growing oocytes caused infertility but differentially affected oocyte quality, granulosa cell fate, and follicular development. cKO of Mtor in nongrowing primordial oocytes caused defective follicular development leading to progressive degeneration of oocytes and loss of granulosa cell identity coincident with the acquisition of immature Sertoli cell-like characteristics. Although Mtor was deleted at the primordial oocyte stage, DNA damage accumulated in oocytes during their later growth, and …

Increased Reactive Oxygen Species And Cell Cycle Defects Contribute To Anemia In The Rasa3 Mutant Mouse Model S, Emily S Hartman, Elena C Brindley, Julien Papoin, Steven L. Ciciotte, Yue Zhao, Luanne L. Peters, Lionel Blanc

Faculty Research 2018

RASA3 is a Ras GTPase activating protein that plays a critical role in blood formation. The autosomal recessive mouse model scat (severe combined anemia and thrombocytopenia) carries a missense mutation in Rasa3. Homozygotes present with a phenotype characteristic of bone marrow failure that is accompanied by alternating episodes of crisis and remission. The mechanism leading to impaired erythropoiesis and peripheral cell destruction as evidenced by membrane fragmentation in scat is unclear, although we previously reported that the mislocalization of RASA3 to the cytosol of reticulocytes and mature red cells plays a role in the disease. In this study, we …

Thanatomicrobiome Composition Profiling As A Tool For Forensic Investigation., Wei Zhou, Yingnan Bian

Faculty Research 2018

Thanatomicrobiome, or the postmortem microbiome, has been recognized as a useful microbial marker of the time and location of host death. In this mini-review, we compare the experimental methods commonly applied to thanatomicrobiome studies to the state-of-the-art methodologies in the microbiome field. Then, we review present findings in thanatomicrobiome studies, focusing on the diversity of the thanatomicrobiome composition and prediction models that have been proposed. Finally, we discuss potential improvements and future directions of the field.

Acclimation And Institutionalization Of The Mouse Microbiota Following Transportation., Dan R Montonye, Aaron C Ericsson, Susheel B Busi, Cathleen Lutz, Keegan Wardwell, Craig L Franklin

Faculty Research 2018

Using animal models, the gut microbiota has been shown to play a critical role in the health and disease of many organ systems. Unfortunately, animal model studies often lack reproducibility when performed at different institutions. Previous studies in our laboratory have shown that the gut microbiota of mice can vary with a number of husbandry factors leading us to speculate that differing environments may alter gut microbiota, which in turn may influence animal model phenotypes. As an extension of these studies, we hypothesized that the shipping of mice from a mouse producer to an institution will result in changes in …

Systematic Analysis Of Copy Number Variation Associated With Congenital Diaphragmatic Hernia., Qihui Zhu, Frances A High, Chengsheng Zhang, Eliza Cerveira, Meaghan K Russell, Mauro Longoni, Maliackal P Joy, Mallory Ryan, Adam Mil-Homens, Lauren Bellfy, Caroline M Coletti, Pooja Bhayani, Regis Hila, Jay M Wilson, Patricia K Donahoe, Charles Lee

Faculty Research 2018

Congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and hypoplasia of the lungs, is one of the most common and severe birth defects, and is associated with high morbidity and mortality rates. There is growing evidence demonstrating that genetic factors contribute to CDH, although the pathogenesis remains largely elusive. Single-nucleotide polymorphisms have been studied in recent whole-exome sequencing efforts, but larger copy number variants (CNVs) have not yet been studied on a large scale in a case control study. To capture CNVs within CDH candidate regions, we developed and tested a targeted array comparative genomic hybridization platform to …

Reconstructing The Molecular Life History Of Gliomas., Floris P Barthel, Pieter Wesseling, Roel G W Verhaak

Faculty Research 2018

At the time of their clinical manifestation, the heterogeneous group of adult and pediatric gliomas carries a wide range of diverse somatic genomic alterations, ranging from somatic single-nucleotide variants to structural chromosomal rearrangements. Somatic abnormalities may have functional consequences, such as a decrease, increase or change in mRNA transcripts, and cells pay a penalty for maintaining them. These abnormalities, therefore, must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model of gliomagenesis consisting of the following five consecutive phases that glioma cells have traversed prior to clinical manifestation: (I) initial growth; …

Profiling Of Epidermal Lipids In A Mouse Model Of Dermatitis: Identification Of Potential Biomarkers., Jackeline Franco, Christina Ferreira, Tiago J Paschoal Sobreira, John P Sundberg, Harm Hogenesch

Faculty Research 2018

Lipids are important structural and functional components of the skin. Alterations in the lipid composition of the epidermis are associated with inflammation and can affect the barrier function of the skin. SHARPIN-deficient cpdm mice develop a chronic dermatitis with similarities to atopic dermatitis in humans. Here, we used a recently-developed approach named multiple reaction monitoring (MRM)-profiling and single ion monitoring to rapidly identify discriminative lipid ions. Shorter fatty acyl residues and increased relative amounts of sphingosine ceramides were observed in cpdm epidermis compared to wild type mice. These changes were accompanied by downregulation of the Fasn gene which encodes fatty …

Integrative Annotation And Knowledge Discovery Of Kinase Post-Translational Modifications And Cancer-Associated Mutations Through Federated Protein Ontologies And Resources., Liang-Chin Huang, Karen E Ross, Timothy R Baffi, Harold J. Drabkin, Krzysztof J Kochut, Zheng Ruan, Peter D'Eustachio, Daniel Mcskimming, Cecilia Arighi, Chuming Chen, Darren A Natale, Cynthia Smith, Pascale Gaudet, Alexandra C Newton, Cathy Wu, Natarajan Kannan

Faculty Research 2018

Many bioinformatics resources with unique perspectives on the protein landscape are currently available. However, generating new knowledge from these resources requires interoperable workflows that support cross-resource queries. In this study, we employ federated queries linking information from the Protein Kinase Ontology, iPTMnet, Protein Ontology, neXtProt, and the Mouse Genome Informatics to identify key knowledge gaps in the functional coverage of the human kinome and prioritize understudied kinases, cancer variants and post-translational modifications (PTMs) for functional studies. We identify 32 functional domains enriched in cancer variants and PTMs and generate mechanistic hypotheses on overlapping variant and PTM sites by aggregating information …

Genomic Profiling Of Two Histologically Distinct Rare Urothelial Cancers In A Clinical Setting To Identify Potential Therapeutic Options For Treatment And Management Of Disease., Andrew N Hesse, William Fabricius, Christian A Thomas, Ramesh Gaindh, Robert Christman, Pavalan Selvam, Matthew Prego, Gregory Lewis, Jasmina Uvalic, Daniel Bergeron, Shelbi Burns, Bridgette Sisson, Kevin Kelly, Jens Rueter, Honey V Reddi

Faculty Research 2018

Molecular profiling of urothelial cancers for therapeutic and prognostic potential has been very limited due to the absence of cancer-specific targeted therapies. We describe here 2 clinical cases with a histological diagnosis of an invasive sarcomatoid and a poorly differentiated carcinoma favoring urothelial with some neuroendocrine differentiation, two of the rarer types of urothelial cancers, which were evaluated for mutations in 212 genes for single-nucleotide variants and copy-number variants and 53 genes for fusions associated with solid tumors. In both cases, we identified variants in 2 genes, Case Rep Oncol 2018 Mar 27; 11(1):196-205.

The Innate Immune Response To Ischemic Injury: A Multiscale Modeling Perspective., Elena Dimitrova, Leslie A Caromile, Reinhard Laubenbacher, Linda H Shapiro

Faculty Research 2018

BACKGROUND: Cell death as a result of ischemic injury triggers powerful mechanisms regulated by germline-encoded Pattern Recognition Receptors (PRRs) with shared specificity that recognize invading pathogens and endogenous ligands released from dying cells, and as such are essential to human health. Alternatively, dysregulation of these mechanisms contributes to extreme inflammation, deleterious tissue damage and impaired healing in various diseases. The Toll-like receptors (TLRs) are a prototypical family of PRRs that may be powerful anti-inflammatory targets if agents can be designed that antagonize their harmful effects while preserving host defense functions. This requires an understanding of the complex interactions and consequences …

Nkx2-5 Regulates Human Cardiomyogenesis Via A Hey2 Dependent Transcriptional Network., David J Anderson, David I Kaplan, Katrina M Bell, Katerina Koutsis, John M Haynes, Richard J Mills, Dean G Phelan, Elizabeth L Qian, Ana Rita Leitoguinho, Deevina Arasaratnam, Tanya Labonne, Elizabeth S Ng, Richard P Davis, Simona Casini, Robert Passier, James E Hudson, Enzo R Porrello, Mauro W Costa, Arash Rafii, Clare L Curl, Lea M Delbridge, Richard P Harvey, Alicia Oshlack, Michael M Cheung, Christine L Mummery, Stephen Petrou, Andrew G Elefanty, Edouard G Stanley, David A Elliott

Faculty Research 2018

Congenital heart defects can be caused by mutations in genes that guide cardiac lineage formation. Here, we show deletion of NKX2-5, a critical component of the cardiac gene regulatory network, in human embryonic stem cells (hESCs), results in impaired cardiomyogenesis, failure to activate VCAM1 and to downregulate the progenitor marker PDGFRα. Furthermore, NKX2-5 null cardiomyocytes have abnormal physiology, with asynchronous contractions and altered action potentials. Molecular profiling and genetic rescue experiments demonstrate that the bHLH protein HEY2 is a key mediator of NKX2-5 function during human cardiomyogenesis. These findings identify HEY2 as a novel component of the NKX2-5 cardiac transcriptional …

Functional Redundancy Of Dicer Cofactors Tarbp2 And Prkra During Murine Embryogenesis Does Not Involve Mirna Biogenesis., Sri Ramulu N Pullagura, F William Buaas, Nichelle Gray, Lindsey C Krening, Anuj Srivastava, Robert E Braun

Faculty Research 2018

Several in vitro studies have suggested that canonical microRNA (miRNA) biogenesis requires the DICER cofactors TARBP2 and PRKRA for processing of pre-miRNAs to mature miRNAs. To investigate the roles of TARBP2 and PRKRA in miRNA biogenesis in vivo, and to determine possible functional redundancy, we first compared the phenotypes of Tarbp2 and Prkra single and double mutants. In contrast to Dicer ^-/- embryos, which die by embryonic day 7.5 (E7.5), single Tarbp2 ^-/- and Prkra ^-/- mice survive beyond E7.5 and either die perinatally or survive and exhibit cranial/facial abnormalities, respectively. In contrast, only a few Tarbp2 ^-/- ; …

Ddr: Efficient Computational Method To Predict Drug-Target Interactions Using Graph Mining And Machine Learning Approaches., Rawan S Olayan, Haitham Ashoor, Vladimir B Bajic

Faculty Research 2018

Motivation: Finding computationally drug-target interactions (DTIs) is a convenient strategy to identify new DTIs at low cost with reasonable accuracy. However, the current DTI prediction methods suffer the high false positive prediction rate.

Results: We developed DDR, a novel method that improves the DTI prediction accuracy. DDR is based on the use of a heterogeneous graph that contains known DTIs with multiple similarities between drugs and multiple similarities between target proteins. DDR applies non-linear similarity fusion method to combine different similarities. Before fusion, DDR performs a pre-processing step where a subset of similarities is selected in a heuristic process to …

Fusorsv: An Algorithm For Optimally Combining Data From Multiple Structural Variation Detection Methods., Timothy Becker, Wan-Ping Lee, Joseph Leone, Qihui Zhu, Chengsheng Zhang, Silvia Liu, Jack Sargent, Kritika Shanker, Adam Mil-Homens, Eliza Cerveira, Mallory Ryan, Jane Cha, Fabio C P Navarro, Timur Galeev, Mark Gerstein, Ryan E Mills, Dong-Guk Shin, Charles Lee, Ankit Malhotra

Faculty Research 2018

Comprehensive and accurate identification of structural variations (SVs) from next generation sequencing data remains a major challenge. We develop FusorSV, which uses a data mining approach to assess performance and merge callsets from an ensemble of SV-calling algorithms. It includes a fusion model built using analysis of 27 deep-coverage human genomes from the 1000 Genomes Project. We identify 843 novel SV calls that were not reported by the 1000 Genomes Project for these 27 samples. Experimental validation of a subset of these calls yields a validation rate of 86.7%. FusorSV is available at https://github.com/TheJacksonLaboratory/SVE . Genome Biol 2018 Mar 20; …

Disease Ontology: Improving And Unifying Disease Annotations Across Species., Susan M. Bello, Mary Shimoyama, Elvira Mitraka, Stanley J F Laulederkind, Cynthia Smith, Janan T. Eppig, Lynn M Schriml

Faculty Research 2018

Model organisms are vital to uncovering the mechanisms of human disease and developing new therapeutic tools. Researchers collecting and integrating relevant model organism and/or human data often apply disparate terminologies (vocabularies and ontologies), making comparisons and inferences difficult. A unified disease ontology is required that connects data annotated using diverse disease terminologies, and in which the terminology relationships are continuously maintained. The Mouse Genome Database (MGD, http://www.informatics.jax.org), Rat Genome Database (RGD, http://rgd.mcw.edu) and Disease Ontology (DO, http://www.disease-ontology.org) projects are collaborating to augment DO, aligning and incorporating disease terms used by MGD and RGD, and improving DO as a tool for …

Aberrant Glyrs-Hdac6 Interaction Linked To Axonal Transport Deficits In Charcot-Marie-Tooth Neuropathy., Zhongying Mo, Xiaobei Zhao, Huaqing Liu, Qinghua Hu, Xu-Qiao Chen, Jessica Pham, Na Wei, Ze Liu, Jiadong Zhou, Robert W. Burgess, Samuel L Pfaff, C Thomas Caskey, Chengbiao Wu, Ge Bai, Xiang-Lei Yang

Faculty Research 2018

Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease's specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset. An HDAC6 inhibitor used to restore α-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice. These results link …

Primary Hepatic Neuroendocrine Carcinoma: Report Of Two Cases And Literature Review., Zi-Ming Zhao, Jin Wang, Ugochukwu C Ugwuowo, Liming Wang, Jeffrey P Townsend

Faculty Research 2018

Background: Primary hepatic neuroendocrine carcinoma (PHNEC) is extremely rare. The diagnosis of PHNEC remains challenging-partly due to its rarity, and partly due to its lack of unique clinical features. Available treatment options for PHNEC include surgical resection of the liver tumor(s), radiotherapy, liver transplant, transcatheter arterial chemoembolization (TACE), and administration of somatostatin analogues.

Case presentation: We report two male PHNEC cases and discuss the diagnosis and treatment options. Both cases presented with abdominal pain; case two also presented with symptoms of jaundice. The initial diagnosis for both cases was poorly differentiated grade 3 small-cell neuroendocrine carcinoma, based on imaging characteristics …

Sarnaclust: Semi-Automatic Detection Of Rna Protein Binding Motifs From Immunoprecipitation Data., Ivan Dotu, Scott I Adamson, Benjamin Coleman, Cyril Fournier, Emma Ricart-Altimiras, Eduardo Eyras, Jeffrey H Chuang

Faculty Research 2018

RNA-protein binding is critical to gene regulation, controlling fundamental processes including splicing, translation, localization and stability, and aberrant RNA-protein interactions are known to play a role in a wide variety of diseases. However, molecular understanding of RNA-protein interactions remains limited; in particular, identification of RNA motifs that bind proteins has long been challenging, especially when such motifs depend on both sequence and structure. Moreover, although RNA binding proteins (RBPs) often contain more than one binding domain, algorithms capable of identifying more than one binding motif simultaneously have not been developed. In this paper we present a novel pipeline to determine …

Müller Glia-Derived Prss56 Is Required To Sustain Ocular Axial Growth And Prevent Refractive Error., Seyyedhassan Paylakhi, Cassandre Labelle-Dumais, Nicholas G Tolman, Michael A Sellarole, Yusef Seymens, Joseph Saunders, Hesham Lakosha, Wilhelmine N De Vries, Andrew C Orr, Piotr Topilko, Simon W M John, K Saidas Nair

Faculty Research 2018

A mismatch between optical power and ocular axial length results in refractive errors. Uncorrected refractive errors constitute the most common cause of vision loss and second leading cause of blindness worldwide. Although the retina is known to play a critical role in regulating ocular growth and refractive development, the precise factors and mechanisms involved are poorly defined. We have previously identified a role for the secreted serine protease PRSS56 in ocular size determination and PRSS56 variants have been implicated in the etiology of both hyperopia and myopia, highlighting its importance in refractive development. Here, we use a combination of genetic …

Humanized Mice In Studying Efficacy And Mechanisms Of Pd-1-Targeted Cancer Immunotherapy., Minan Wang, Li-Chin Yao, Mingshan Cheng, Danying Cai, Jan Martinek, Chong-Xian Pan, Wei Shi, Ai-Hong Ma, Ralph W De Vere White, Susan Airhart, Edison T Liu, Jacques Banchereau, Michael A Brehm, Dale L Greiner, Leonard D. Shultz, Karolina Palucka, James G. Keck

Faculty Research 2018

Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg- Prkdc^scidIL2rg^tm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34⁺ hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patient-derived xenografts [PDX; non-small cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). …

Differential Human Gut Microbiome Assemblages During Soil-Transmitted Helminth Infections In Indonesia And Liberia., Bruce A Rosa, Taniawati Supali, Lincoln Gankpala, Yenny Djuardi, Erliyani Sartono, Yanjiao Zhou, Kerstin Fischer, John Martin, Rahul Tyagi, Fatorma K Bolay, Peter U Fischer, Maria Yazdanbakhsh, Makedonka Mitreva

Faculty Research 2018

BACKGROUND: The human intestine and its microbiota is the most common infection site for soil-transmitted helminths (STHs), which affect the well-being of ~ 1.5 billion people worldwide. The complex cross-kingdom interactions are not well understood.

RESULTS: A cross-sectional analysis identified conserved microbial signatures positively or negatively associated with STH infections across Liberia and Indonesia, and longitudinal samples analysis from a double-blind randomized trial showed that the gut microbiota responds to deworming but does not transition closer to the uninfected state. The microbiomes of individuals able to self-clear the infection had more alike microbiome assemblages compared to individuals who remained infected. …

A Commensal Strain Of Staphylococcus Epidermidis Protects Against Skin Neoplasia., Teruaki Nakatsuji, Tiffany H Chen, Anna M Butcher, Lynnie L Trzoss, Sang-Jip Nam, Karina T Shirakawa, Wei Zhou, Julia Oh, Michael Otto, William Fenical, Richard L Gallo

Faculty Research 2018

We report the discovery that strains of Staphylococcus epidermidis produce 6-N-hydroxyaminopurine (6-HAP), a molecule that inhibits DNA polymerase activity. In culture, 6-HAP selectively inhibited proliferation of tumor lines but did not inhibit primary keratinocytes. Resistance to 6-HAP was associated with the expression of mitochondrial amidoxime reducing components, enzymes that were not observed in cells sensitive to this compound. Intravenous injection of 6-HAP in mice suppressed the growth of B16F10 melanoma without evidence of systemic toxicity. Colonization of mice with an S. epidermidis strain producing 6-HAP reduced the incidence of ultraviolet-induced tumors compared to mice colonized by a control …

Exploring Autophagy With Gene Ontology., Paul Denny, Marc Feuermann, David P. Hill, Ruth C Lovering, Helene Plun-Favreau, Paola Roncaglia

Faculty Research 2018

Autophagy is a fundamental cellular process that is well conserved among eukaryotes. It is one of the strategies that cells use to catabolize substances in a controlled way. Autophagy is used for recycling cellular components, responding to cellular stresses and ridding cells of foreign material. Perturbations in autophagy have been implicated in a number of pathological conditions such as neurodegeneration, cardiac disease and cancer. The growing knowledge about autophagic mechanisms needs to be collected in a computable and shareable format to allow its use in data representation and interpretation. The Gene Ontology (GO) is a freely available resource that describes …

Identifying Noncoding Risk Variants Using Disease-Relevant Gene Regulatory Networks., Long Gao, Yasin Uzun, Peng Gao, Bing He, Xiaoke Ma, Jiahui Wang, Shizhong Han, Kai Tan

Faculty Research 2018

Identifying noncoding risk variants remains a challenging task. Because noncoding variants exert their effects in the context of a gene regulatory network (GRN), we hypothesize that explicit use of disease-relevant GRNs can significantly improve the inference accuracy of noncoding risk variants. We describe Annotation of Regulatory Variants using Integrated Networks (ARVIN), a general computational framework for predicting causal noncoding variants. It employs a set of novel regulatory network-based features, combined with sequence-based features to infer noncoding risk variants. Using known causal variants in gene promoters and enhancers in a number of diseases, we show ARVIN outperforms state-of-the-art methods that use …

Humanizing The Mdx Mouse Model Of Dmd: The Long And The Short Of It., Nora Yucel, Alex C Chang, John W Day, Nadia Rosenthal, Helen M Blau

Faculty Research 2018

Duchenne muscular dystrophy (DMD) is a common fatal heritable myopathy, with cardiorespiratory failure occurring by the third decade of life. There is no specific treatment for DMD cardiomyopathy, in large part due to a lack of understanding of the mechanisms underlying the cardiac failure. Mdx mice, which have the same dystrophin mutation as human patients, are of limited use, as they do not develop early dilated cardiomyopathy as seen in patients. Here we summarize the usefulness of the various commonly used DMD mouse models, highlight a model with shortened telomeres like humans, and identify directions that warrant further investigation. NPJ …

Activation Of Serine One-Carbon Metabolism By Calcineurin Aβ1 Reduces Myocardial Hypertrophy And Improves Ventricular Function., Laura Padrón-Barthe, María Villalba-Orero, Jesús M Gómez-Salinero, Rebeca Acín-Pérez, Sara Cogliati, Marina López-Olañeta, Paula Ortiz-Sánchez, Elena Bonzón-Kulichenko, Jesús Vázquez, Pablo García-Pavía, Nadia Rosenthal, José Antonio Enríquez, Enrique Lara-Pezzi

Faculty Research 2018

BACKGROUND: In response to pressure overload, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. This pathological hypertrophy is mediated, among others, by the phosphatase calcineurin and is characterized by metabolic changes that impair energy production by mitochondria.

OBJECTIVES: The authors aimed to determine the role of the calcineurin splicing variant CnAβ1 in the context of cardiac hypertrophy and its mechanism of action.

METHODS: Transgenic mice overexpressing CnAβ1 specifically in cardiomyocytes and mice lacking the unique C-terminal domain in CnAβ1 (CnAβ1Δi12 mice) were used. Pressure overload hypertrophy was induced by transaortic constriction. Cardiac function was measured …

The Polo-Like Kinase 1 Inhibitor Volasertib Synergistically Increases Radiation Efficacy In Glioma Stem Cells., Jianwen Dong, Soon Young Park, Nghi Nguyen, Ravesanker Ezhilarasan, Emmanuel Martinez-Ledesma, Shaofang Wu, Verlene Henry, Yuji Piao, Ningyi Tiao, David Brunell, Clifford Stephan, Roel G W Verhaak, Erik Sulman, Veerakumar Balasubramaniyan, John F De Groot

Faculty Research 2018

Background: Despite the availability of hundreds of cancer drugs, there is insufficient data on the efficacy of these drugs on the extremely heterogeneous tumor cell populations of glioblastoma (GBM).

Results: The PKIS of 357 compounds was initially evaluated in 15 different GSC lines which then led to a more focused screening of the 21 most highly active compounds in 11 unique GSC lines using HTS screening for cell viability. We further validated the HTS result with the second-generation PLK1 inhibitor volasertib as a single agent and in combination with ionizing radiation (IR).

Conclusions: Our results reinforce the potential therapeutic efficacy …