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Full-Text Articles in Life Sciences

Growth Differentiation Factor 11 Locally Controls Anterior-Posterior Patterning Of The Axial Skeleton., Joonho Suh, Je-Hyun Eom, Na-Kyung Kim, Kyung Mi Woo, Jeong-Hwa Baek, Hyun-Mo Ryoo, Se-Jin Lee, Yun-Sil Lee Dec 2019

Growth Differentiation Factor 11 Locally Controls Anterior-Posterior Patterning Of The Axial Skeleton., Joonho Suh, Je-Hyun Eom, Na-Kyung Kim, Kyung Mi Woo, Jeong-Hwa Baek, Hyun-Mo Ryoo, Se-Jin Lee, Yun-Sil Lee

Faculty Research 2019

Growth and differentiation factor 11 (GDF11) is a transforming growth factor β family member that has been identified as the central player of anterior-posterior (A-P) axial skeletal patterning. Mice homozygous for Gdf11 deletion exhibit severe anterior homeotic transformations of the vertebrae and craniofacial defects. During early embryogenesis, Gdf11 is expressed predominantly in the primitive streak and tail bud regions, where new mesodermal cells arise. On the basis of this expression pattern of Gdf11 and the phenotype of Gdf11 mutant mice, it has been suggested that GDF11 acts to specify positional identity along the A-P axis either by local changes in ...


Increased Interactions And Engulfment Of Dendrites By Microglia Precede Purkinje Cell Degeneration In A Mouse Model Of Niemann Pick Type-C., Larisa Kavetsky, Kayla K Green, Bridget R Boyle, Fawad A K Yousufzai, Zachary M Padron, Sierra E Melli, Victoria L Kuhnel, Harriet M. Jackson, Rosa E Blanco, Gareth R Howell, Ileana Soto Oct 2019

Increased Interactions And Engulfment Of Dendrites By Microglia Precede Purkinje Cell Degeneration In A Mouse Model Of Niemann Pick Type-C., Larisa Kavetsky, Kayla K Green, Bridget R Boyle, Fawad A K Yousufzai, Zachary M Padron, Sierra E Melli, Victoria L Kuhnel, Harriet M. Jackson, Rosa E Blanco, Gareth R Howell, Ileana Soto

Faculty Research 2019

Niemann Pick Type-C disease (NPC) is an inherited lysosomal storage disease (LSD) caused by pathogenic variants in the Npc1 or Npc2 genes that lead to the accumulation of cholesterol and lipids in lysosomes. NPC1 deficiency causes neurodegeneration, dementia and early death. Cerebellar Purkinje cells (PCs) are particularly hypersensitive to NPC1 deficiency and degenerate earlier than other neurons in the brain. Activation of microglia is an important contributor to PCs degeneration in NPC. However, the mechanisms by which activated microglia promote PCs degeneration in NPC are not completely understood. Here, we are demonstrating that in the Npc1nmf164 mouse cerebellum, microglia ...


Bmp Signaling Mediates Glioma Stem Cell Quiescence And Confers Treatment Resistance In Glioblastoma., Rohit Sachdeva, Megan Wu, Kevin C Johnson, Hyunsoo Kim, Angela Celebre, Uswa Shahzad, Maya Srikanth Graham, John A Kessler, Jeffrey Chuang, Jason Karamchandani, Markus Bredel, Roel G W Verhaak, Sunit Das Oct 2019

Bmp Signaling Mediates Glioma Stem Cell Quiescence And Confers Treatment Resistance In Glioblastoma., Rohit Sachdeva, Megan Wu, Kevin C Johnson, Hyunsoo Kim, Angela Celebre, Uswa Shahzad, Maya Srikanth Graham, John A Kessler, Jeffrey Chuang, Jason Karamchandani, Markus Bredel, Roel G W Verhaak, Sunit Das

Faculty Research 2019

Despite advances in therapy, glioblastoma remains an incurable disease with a dismal prognosis. Recent studies have implicated cancer stem cells within glioblastoma (glioma stem cells, GSCs) as mediators of therapeutic resistance and tumor progression. In this study, we investigated the role of the transforming growth factor-β (TGF-β) superfamily, which has been found to play an integral role in the maintenance of stem cell homeostasis within multiple stem cell systems, as a mediator of stem-like cells in glioblastoma. We find that BMP and TGF-β signaling define divergent molecular and functional identities in glioblastoma, and mark relatively quiescent and proliferative GSCs, respectively ...


Early-Life Dna Methylation Profiles Are Indicative Of Age-Related Transcriptome Changes., Niran Hadad, Dustin R Masser, Laura Blanco-Berdugo, David R Stanford, Willard M Freeman Oct 2019

Early-Life Dna Methylation Profiles Are Indicative Of Age-Related Transcriptome Changes., Niran Hadad, Dustin R Masser, Laura Blanco-Berdugo, David R Stanford, Willard M Freeman

Faculty Research 2019

BACKGROUND: Alterations to cellular and molecular programs with brain aging result in cognitive impairment and susceptibility to neurodegenerative disease. Changes in DNA methylation patterns, an epigenetic modification required for various CNS functions are observed with brain aging and can be prevented by anti-aging interventions, but the relationship of altered methylation to gene expression is poorly understood.

RESULTS: Paired analysis of the hippocampal methylome and transcriptome with aging of male and female mice demonstrates that age-related differences in methylation and gene expression are anti-correlated within gene bodies and enhancers. Altered promoter methylation with aging was found to be generally un-related to ...


Debutant Ios App And Gene-Disease Complexities In Clinical Genomics And Precision Medicine., Zeeshan Ahmed, Saman Zeeshan, Ruoyun Xiong, Bruce T Liang Oct 2019

Debutant Ios App And Gene-Disease Complexities In Clinical Genomics And Precision Medicine., Zeeshan Ahmed, Saman Zeeshan, Ruoyun Xiong, Bruce T Liang

Faculty Research 2019

BACKGROUND: The last decade has seen a dramatic increase in the availability of scientific data, where human-related biological databases have grown not only in count but also in volume, posing unprecedented challenges in data storage, processing, analysis, exchange, and curation. Next generation sequencing (NGS) advancements have facilitated and accelerated the process of identifying genetic variations. Adopting NGS with Whole-Genome and RNA sequencing in a diagnostic context has the potential to improve disease-risk detection in support of precision medicine and drug discovery. Several bioinformatics pipelines have been developed to strengthen variant interpretation by efficiently processing and analyzing sequence data, whereas many ...


3d Extracellular Matrix Microenvironment In Bioengineered Tissue Models Of Primary Pediatric And Adult Brain Tumors., Disha Sood, Min D Tang-Schomer, Dimitra Pouli, Craig Mizzoni, Nicole Raia, Albert Tai, Knarik Arkun, Julian Wu, Lauren D Black, Bjorn Scheffler, Irene Georgakoudi, Dennis A Steindler, David L Kaplan Oct 2019

3d Extracellular Matrix Microenvironment In Bioengineered Tissue Models Of Primary Pediatric And Adult Brain Tumors., Disha Sood, Min D Tang-Schomer, Dimitra Pouli, Craig Mizzoni, Nicole Raia, Albert Tai, Knarik Arkun, Julian Wu, Lauren D Black, Bjorn Scheffler, Irene Georgakoudi, Dennis A Steindler, David L Kaplan

Faculty Research 2019

Dynamic alterations in the unique brain extracellular matrix (ECM) are involved in malignant brain tumors. Yet studies of brain ECM roles in tumor cell behavior have been difficult due to lack of access to the human brain. We present a tunable 3D bioengineered brain tissue platform by integrating microenvironmental cues of native brain-derived ECMs and live imaging to systematically evaluate patient-derived brain tumor responses. Using pediatric ependymoma and adult glioblastoma as examples, the 3D brain ECM-containing microenvironment with a balance of cell-cell and cell-matrix interactions supports distinctive phenotypes associated with tumor type-specific and ECM-dependent patterns in the tumor cells' transcriptomic ...


A Mutation In Mouse Krüppel-Like Factor 15 Alters The Gut Microbiome And Response To Obesogenic Diet., Karen L. Svenson, Lauren L Long, Steven L. Ciciotte, Mark D Adams Sep 2019

A Mutation In Mouse Krüppel-Like Factor 15 Alters The Gut Microbiome And Response To Obesogenic Diet., Karen L. Svenson, Lauren L Long, Steven L. Ciciotte, Mark D Adams

Faculty Research 2019

We identified a mouse strain, HLB444, carrying an N-ethyl-N-nitrosourea (ENU)-induced mutation in a highly conserved C2H2 zinc-finger DNA binding motif of the transcriptional regulator KLF15 that exhibits resistance to diet-induced obesity. Characterization of the HLB444 mutant model on high-fat and chow diets revealed a number of phenotypic differences compared to wild-type controls. When fed a high fat diet, HLB444 had lower body fat, resistance to hepatosteatosis, lower circulating glucose and improved insulin sensitivity compared to C57BL/6J controls. Gut microbial profiles in HLB444 generated from 16S rRNA sequencing of fecal samples differed from controls under both chow and high ...


C57bl/6 Substrain Differences In Pharmacological Effects After Acute And Repeated Nicotine Administration., Lois S Akinola, Bryan Mckiver, Wisam Toma, Andy Z X Zhu, Rachel F Tyndale, Vivek Kumar, M Imad Damaj Sep 2019

C57bl/6 Substrain Differences In Pharmacological Effects After Acute And Repeated Nicotine Administration., Lois S Akinola, Bryan Mckiver, Wisam Toma, Andy Z X Zhu, Rachel F Tyndale, Vivek Kumar, M Imad Damaj

Faculty Research 2019

Tobacco smoking is the major cause of disability and death in the United States and around the world. In addition, tobacco dependence and addiction express themselves as complex behaviors involving an interplay of genetics, environment, and psychological state. Mouse genetic studies could potentially elucidate the novel genes and/or gene networks regulating various aspects of nicotine dependence. Using the closely related C57BL/6 (B6) mice substrains, recent reports have noted phenotypic differences within C57BL/6J (B6J) and C57BL/6N (B6N) mice for some drugs of abuse: alcohol, opiates, and cocaine. However, the differences in nicotine's effects have not yet ...


Enhanced Crispr-Based Dna Demethylation By Casilio-Me-Mediated Rna-Guided Coupling Of Methylcytosine Oxidation And Dna Repair Pathways., Aziz Taghbalout, Menghan Du, Nathaniel L. Jillette, Wojciech Rosikiewicz, Abhijit Rath, Christopher D Heinen, Sheng Li, Albert Cheng Sep 2019

Enhanced Crispr-Based Dna Demethylation By Casilio-Me-Mediated Rna-Guided Coupling Of Methylcytosine Oxidation And Dna Repair Pathways., Aziz Taghbalout, Menghan Du, Nathaniel L. Jillette, Wojciech Rosikiewicz, Abhijit Rath, Christopher D Heinen, Sheng Li, Albert Cheng

Faculty Research 2019

Here we develop a methylation editing toolbox, Casilio-ME, that enables not only RNA-guided methylcytosine editing by targeting TET1 to genomic sites, but also by co-delivering TET1 and protein factors that couple methylcytosine oxidation to DNA repair activities, and/or promote TET1 to achieve enhanced activation of methylation-silenced genes. Delivery of TET1 activity by Casilio-ME1 robustly alters the CpG methylation landscape of promoter regions and activates methylation-silenced genes. We augment Casilio-ME1 to simultaneously deliver the TET1-catalytic domain and GADD45A (Casilio-ME2) or NEIL2 (Casilio-ME3) to streamline removal of oxidized cytosine intermediates to enhance activation of targeted genes. Using two-in-one effectors or modular ...


Ak002, A Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody That Induces Antibody-Dependent Cell-Mediated Cytotoxicity Against Human Eosinophils And Inhibits Mast Cell-Mediated Anaphylaxis In Mice., Bradford A Youngblood, Emily C Brock, John Leung, Rustom Falahati, Paul J Bryce, Jessica Bright, Jason Williams, Leonard D. Shultz, Dale L Greiner, Michael A Brehm, Christopher Bebbington, Nenad Tomasevic Sep 2019

Ak002, A Humanized Sialic Acid-Binding Immunoglobulin-Like Lectin-8 Antibody That Induces Antibody-Dependent Cell-Mediated Cytotoxicity Against Human Eosinophils And Inhibits Mast Cell-Mediated Anaphylaxis In Mice., Bradford A Youngblood, Emily C Brock, John Leung, Rustom Falahati, Paul J Bryce, Jessica Bright, Jason Williams, Leonard D. Shultz, Dale L Greiner, Michael A Brehm, Christopher Bebbington, Nenad Tomasevic

Faculty Research 2019

INTRODUCTION: Pathologic accumulation and activation of mast cells and eosinophils are implicated in allergic and inflammatory diseases. Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is an inhibitory receptor selectively expressed on mast cells, eosinophils and, at a lower extent, basophils. When engaged with an antibody, Siglec-8 can induce apoptosis of activated eosinophils and inhibit mast cell activation. AK002 is a humanized, non-fucosylated IgG1 anti-Siglec-8 antibody undergoing clinical investigation for treatment of allergic, inflammatory, and proliferative diseases. Here we examine the human tissue selectivity of AK002 and evaluate the in vitro, ex vivo, and in vivo activity of AK002 on eosinophils and ...


(Epi)Genomic Heterogeneity Of Pancreatic Islet Function And Failure In Type 2 Diabetes., Nathan Lawlor, Michael L. Stitzel Sep 2019

(Epi)Genomic Heterogeneity Of Pancreatic Islet Function And Failure In Type 2 Diabetes., Nathan Lawlor, Michael L. Stitzel

Faculty Research 2019

BACKGROUND: Pancreatic Islets of Langerhans are heterogeneous tissues consisting of multiple endocrine cell types that carry out distinct yet coordinated roles to regulate blood glucose homeostasis. Islet dysfunction and specifically failure of the beta cells to secrete adequate insulin are known precursors to type 2 diabetes (T2D) onset. However, the exact genetic, (epi)genomic, and environmental mechanisms that contribute to islet failure, and ultimately to T2D pathogenesis, require further elucidation.

SCOPE OF REVIEW: This review summarizes efforts and advances in dissection of the complex genetic underpinnings of islet function and resilience in T2D pathogenesis. In this review, we will highlight ...


Visual Discrimination, Serial Reversal, And Extinction Learning In The, Price E. Dickson, Guy Mittleman Aug 2019

Visual Discrimination, Serial Reversal, And Extinction Learning In The, Price E. Dickson, Guy Mittleman

Faculty Research 2019

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy and the most common neuromuscular disorder. In addition to neuromuscular consequences, some individuals with DMD experience global intellectual dysfunction and executive dysfunction of unknown mechanistic origin. The cognitive profile of the mdx mouse, the most commonly used mouse model of DMD, has been incompletely characterized and has never been assessed using the touchscreen operant conditioning paradigm. The touchscreen paradigm allows the use of protocols that are virtually identical to those used in human cognitive testing and may, therefore, provide the most translational paradigm for quantifying mouse cognitive function ...


Genetic Determinants Of Gut Microbiota Composition And Bile Acid Profiles In Mice., Julia H Kemis, Vanessa Linke, Kelsey L Barrett, Frederick J Boehm, Lindsay L Traeger, Mark P Keller, Mary E Rabaglia, Kathryn L Schueler, Donald S Stapleton, Daniel M Gatti, Gary A Churchill, Daniel Amador-Noguez, Jason D Russell, Brian S Yandell, Karl W Broman, Joshua J Coon, Alan D Attie, Federico E Rey Aug 2019

Genetic Determinants Of Gut Microbiota Composition And Bile Acid Profiles In Mice., Julia H Kemis, Vanessa Linke, Kelsey L Barrett, Frederick J Boehm, Lindsay L Traeger, Mark P Keller, Mary E Rabaglia, Kathryn L Schueler, Donald S Stapleton, Daniel M Gatti, Gary A Churchill, Daniel Amador-Noguez, Jason D Russell, Brian S Yandell, Karl W Broman, Joshua J Coon, Alan D Attie, Federico E Rey

Faculty Research 2019

The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct ...


Spontaneous Mutations Of The Zpld1 Gene In Mice Cause Semicircular Canal Dysfunction But Do Not Impair Gravity Receptor Or Hearing Functions., Sarath Vijayakumar, Sherri M Jones, Timothy A Jones, Cong Tian, Kenneth R. Johnson Aug 2019

Spontaneous Mutations Of The Zpld1 Gene In Mice Cause Semicircular Canal Dysfunction But Do Not Impair Gravity Receptor Or Hearing Functions., Sarath Vijayakumar, Sherri M Jones, Timothy A Jones, Cong Tian, Kenneth R. Johnson

Faculty Research 2019

The cupula is a gelatinous membrane overlying the crista ampullaris of the semicircular canal, important for sensing rotation of the head and critical for normal balance. Recently the zona pellucida like domain containing 1 protein (ZPLD1, also known as cupulin) was identified in the cupula of fish. Here, we describe two new spontaneous mutations in the mouse Zpld1 gene, which were discovered by the circling behavior of mutant mice, an indicator of balance dysfunction. The Zpld1 mutant mice exhibited normal hearing function as assessed by auditory brainstem response (ABR) measurements, and their otolithic organs appeared normal. In the inner ear ...


A First Genetic Portrait Of Synaptonemal Complex Variation., Richard J Wang, Beth L Dumont, Peicheng Jing, Bret A Payseur Aug 2019

A First Genetic Portrait Of Synaptonemal Complex Variation., Richard J Wang, Beth L Dumont, Peicheng Jing, Bret A Payseur

Faculty Research 2019

The synaptonemal complex (SC) is a proteinaceous scaffold required for synapsis and recombination between homologous chromosomes during meiosis. Although the SC has been linked to differences in genome-wide crossover rates, the genetic basis of standing variation in SC structure remains unknown. To investigate the possibility that recombination evolves through changes to the SC, we characterized the genetic architecture of SC divergence on two evolutionary timescales. Applying a novel digital image analysis technique to spermatocyte spreads, we measured total SC length in 9,532 spermatocytes from recombinant offspring of wild-derived mouse strains with differences in this fundamental meiotic trait. Using this ...


Hepsin-Mediated Processing Of Uromodulin Is Crucial For Salt-Sensitivity And Thick Ascending Limb Homeostasis., Eric Olinger, Jennifer Lake, Susan Sheehan, Guglielmo Schiano, Tomoaki Takata, Natsuko Tokonami, Huguette Debaix, Francesco Consolato, Luca Rampoldi, Ron Korstanje, Olivier Devuyst Aug 2019

Hepsin-Mediated Processing Of Uromodulin Is Crucial For Salt-Sensitivity And Thick Ascending Limb Homeostasis., Eric Olinger, Jennifer Lake, Susan Sheehan, Guglielmo Schiano, Tomoaki Takata, Natsuko Tokonami, Huguette Debaix, Francesco Consolato, Luca Rampoldi, Ron Korstanje, Olivier Devuyst

Faculty Research 2019

Uromodulin is a zona pellucida-type protein essentially produced in the thick ascending limb (TAL) of the mammalian kidney. It is the most abundant protein in normal urine. Defective uromodulin processing is associated with various kidney disorders. The luminal release and subsequent polymerization of uromodulin depend on its cleavage mediated by the serine protease hepsin. The biological relevance of a proper cleavage of uromodulin remains unknown. Here we combined in vivo testing on hepsin-deficient mice, ex vivo analyses on isolated tubules and in vitro studies on TAL cells to demonstrate that hepsin influence on uromodulin processing is an important modulator of ...


Texp: Deconvolving The Effects Of Pervasive And Autonomous Transcription Of Transposable Elements., Fabio Cp Navarro, Jacob Hoops, Lauren Bellfy, Eliza Cerveira, Qihui Zhu, Chengsheng Zhang, Charles Lee, Mark B Gerstein Aug 2019

Texp: Deconvolving The Effects Of Pervasive And Autonomous Transcription Of Transposable Elements., Fabio Cp Navarro, Jacob Hoops, Lauren Bellfy, Eliza Cerveira, Qihui Zhu, Chengsheng Zhang, Charles Lee, Mark B Gerstein

Faculty Research 2019

The Long interspersed nuclear element 1 (LINE-1) is a primary source of genetic variation in humans and other mammals. Despite its importance, LINE-1 activity remains difficult to study because of its highly repetitive nature. Here, we developed and validated a method called TeXP to gauge LINE-1 activity accurately. TeXP builds mappability signatures from LINE-1 subfamilies to deconvolve the effect of pervasive transcription from autonomous LINE-1 activity. In particular, it apportions the multiple reads aligned to the many LINE-1 instances in the genome into these two categories. Using our method, we evaluated well-established cell lines, cell-line compartments and healthy tissues and ...


Pras: Predicting Functional Targets Of Rna Binding Proteins Based On Clip-Seq Peaks., Jianan Lin, Yuping Zhang, Wayne N Frankel, Zhengqing Ouyang Aug 2019

Pras: Predicting Functional Targets Of Rna Binding Proteins Based On Clip-Seq Peaks., Jianan Lin, Yuping Zhang, Wayne N Frankel, Zhengqing Ouyang

Faculty Research 2019

RNA-protein interaction plays important roles in post-transcriptional regulation. Recent advancements in cross-linking and immunoprecipitation followed by sequencing (CLIP-seq) technologies make it possible to detect the binding peaks of a given RNA binding protein (RBP) at transcriptome scale. However, it is still challenging to predict the functional consequences of RBP binding peaks. In this study, we propose the Protein-RNA Association Strength (PRAS), which integrates the intensities and positions of the binding peaks of RBPs for functional mRNA targets prediction. We illustrate the superiority of PRAS over existing approaches on predicting the functional targets of two related but divergent CELF (CUGBP, ELAV-like ...


Transcriptome Profiling Of Brain Myeloid Cells Revealed Activation Of Itgal, Trem1, And Spp1 In Western Diet-Induced Obesity., Hongtian Yang, Leah C. Graham, Alaina M Reagan, Weronika Grabowska, William H. Schott, Gareth R Howell Aug 2019

Transcriptome Profiling Of Brain Myeloid Cells Revealed Activation Of Itgal, Trem1, And Spp1 In Western Diet-Induced Obesity., Hongtian Yang, Leah C. Graham, Alaina M Reagan, Weronika Grabowska, William H. Schott, Gareth R Howell

Faculty Research 2019

BACKGROUND: Environmental factors are critical in the development of age-related cognitive decline and dementia. A western diet (WD) can cause nutrient deficiency and inflammation that could impact cognition directly. It is increasingly recognized that innate immune responses by brain myeloid cells, such as resident microglia, and infiltrating peripheral monocytes/macrophages may represent an essential link between a WD, cognitive decline, and dementia. Our previous data demonstrated that chronic consumption of a WD induced inflammation through brain myeloid cells in aging mice and a mouse model of Alzheimer's disease (AD). However, the subtypes of myeloid cells that contribute to the ...


Doxorubicin-Induced Cardiotoxicity In Collaborative Cross (Cc) Mice Recapitulates Individual Cardiotoxicity In Humans., Caroline J Zeiss, Daniel M Gatti, Olga Toro-Salazar, Crystal Davis, Cathleen M Lutz, Francis Spinale, Timothy M Stearns, Milena B Furtado, Gary A Churchill Aug 2019

Doxorubicin-Induced Cardiotoxicity In Collaborative Cross (Cc) Mice Recapitulates Individual Cardiotoxicity In Humans., Caroline J Zeiss, Daniel M Gatti, Olga Toro-Salazar, Crystal Davis, Cathleen M Lutz, Francis Spinale, Timothy M Stearns, Milena B Furtado, Gary A Churchill

Faculty Research 2019

Anthracyclines cause progressive cardiotoxicity whose ultimate severity is individual to the patient. Genetic determinants contributing to this variation are difficult to study using current mouse models. Our objective was to determine whether a spectrum of anthracycline induced cardiac disease can be elicited across 10 Collaborative Cross mouse strains given the same dose of doxorubicin. Mice from ten distinct strains were given 5 mg/kg of doxorubicin intravenously once weekly for 5 weeks (total 25 mg/kg). Mice were killed at acute or chronic timepoints. Body weight was assessed weekly, followed by terminal complete blood count, pathology and a panel of ...


Sox2-Dependent 3d Chromatin Interactomes In Transcription, Neural Stem Cell Proliferation And Neurodevelopmental Diseases., Chia-Lin Wei, Silvia K Nicolis, Yanfen Zhu, Miriam Pagin Aug 2019

Sox2-Dependent 3d Chromatin Interactomes In Transcription, Neural Stem Cell Proliferation And Neurodevelopmental Diseases., Chia-Lin Wei, Silvia K Nicolis, Yanfen Zhu, Miriam Pagin

Faculty Research 2019

In our article, we asked whether Sox2, a transcription factor important in brain development and disease, is involved in gene regulation through its action on long-range interactions between promoters and distant enhancers. Our findings highlight that Sox2 shapes a genome-wide network of promoter-enhancer interactions, acting by direct binding to these elements. Sox2 loss affects the three-dimensional (3D) genome and decreases the activity of a subset of genes involved in Sox2-bound interactions. At least one of such downregulated genes, Socs3, is critical for long-term neural stem cell maintenance. These results point to the possibility of identifying a transcriptional network downstream to ...


Meox2 Haploinsufficiency Accelerates Axonal Degeneration In Dba/2j Glaucoma., Rebecca A Buchanan, Kate E Foley, Keating W. Pepper, Alaina M Reagan, Kelly J Keezer, Amanda A Hewes, Cory A Diemler, Christoph Preuss, Ileana Soto, Simon W M John, Gareth R Howell Aug 2019

Meox2 Haploinsufficiency Accelerates Axonal Degeneration In Dba/2j Glaucoma., Rebecca A Buchanan, Kate E Foley, Keating W. Pepper, Alaina M Reagan, Kelly J Keezer, Amanda A Hewes, Cory A Diemler, Christoph Preuss, Ileana Soto, Simon W M John, Gareth R Howell

Faculty Research 2019

Purpose: Glaucoma is a complex disease with major risk factors including advancing age and increased intraocular pressure (IOP). Dissecting these earliest events will likely identify new avenues for therapeutics. Previously, we performed transcriptional profiling in DBA/2J (D2) mice, a widely used mouse model relevant to glaucoma. Here, we use these data to identify and test regulators of early gene expression changes in DBA/2J glaucoma.

Methods: Upstream regulator analysis (URA) in Ingenuity Pathway Analysis was performed to identify potential master regulators of differentially expressed genes. The function of one putative regulator, mesenchyme homeobox 2 (Meox2), was tested using a ...


Rapid Growth Is A Dominant Predictor Of Hepcidin Suppression And Declining Ferritin In Gambian Infants., Andrew E Armitage, Schadrac C Agbla, Modupeh Betts, Ebrima A Sise, Momodou W Jallow, Ellen Sambou, Bakary Darboe, Archibald Worwui, George M. Weinstock, Martin Antonio, Sant-Rayn Pasricha, Andrew M Prentice, Hal Drakesmith, Momodou K Darboe, Brenda Anna Kwambana-Adams Aug 2019

Rapid Growth Is A Dominant Predictor Of Hepcidin Suppression And Declining Ferritin In Gambian Infants., Andrew E Armitage, Schadrac C Agbla, Modupeh Betts, Ebrima A Sise, Momodou W Jallow, Ellen Sambou, Bakary Darboe, Archibald Worwui, George M. Weinstock, Martin Antonio, Sant-Rayn Pasricha, Andrew M Prentice, Hal Drakesmith, Momodou K Darboe, Brenda Anna Kwambana-Adams

Faculty Research 2019

Iron deficiency and iron deficiency anemia are highly prevalent in low-income countries, especially among young children. Hepcidin is the major regulator of systemic iron homeostasis. It controls dietary iron absorption, dictates whether absorbed iron is made available in circulation for erythropoiesis and other iron-demanding processes, and predicts response to oral iron supplementation. Understanding how hepcidin is itself regulated is therefore important, especially in young children. We investigated how changes in iron-related parameters, inflammation and infection status, seasonality, and growth influenced plasma hepcidin and ferritin concentrations during infancy using longitudinal data from two birth cohorts of infants in rural Gambia (n ...


Spatial Chromatin Architecture Alteration By Structural Variations In Human Genomes At The Population Scale., Michal Sadowski, Agnieszka Kraft, Przemyslaw Szalaj, Michal Wlasnowolski, Zhonghui Tang, Yijun Ruan, Dariusz Plewczynski Jul 2019

Spatial Chromatin Architecture Alteration By Structural Variations In Human Genomes At The Population Scale., Michal Sadowski, Agnieszka Kraft, Przemyslaw Szalaj, Michal Wlasnowolski, Zhonghui Tang, Yijun Ruan, Dariusz Plewczynski

Faculty Research 2019

BACKGROUND: The number of reported examples of chromatin architecture alterations involved in the regulation of gene transcription and in disease is increasing. However, no genome-wide testing has been performed to assess the abundance of these events and their importance relative to other factors affecting genome regulation. This is particularly interesting given that a vast majority of genetic variations identified in association studies are located outside coding sequences. This study attempts to address this lack by analyzing the impact on chromatin spatial organization of genetic variants identified in individuals from 26 human populations and in genome-wide association studies.

RESULTS: We assess ...


Enabling Global Clinical Collaborations On Identifiable Patient Data: The Minerva Initiative., Christoffer Nellåker, Fowzan S Alkuraya, Gareth Baynam, Raphael A Bernier, Francois P J Bernier, Vanessa Boulanger, Michael Brudno, Han G Brunner, Jill Clayton-Smith, Benjamin Cogné, Hugh J S Dawkins, Bert B A Devries, Sofia Douzgou, Tracy Dudding-Byth, Evan E Eichler, Michael Ferlaino, Karen Fieggen, Helen V Firth, David R Fitzpatrick, Dylan Gration, Tudor Groza, Melissa Haendel, Nina Hallowell, Ada Hamosh, Jayne Hehir-Kwa, Marc-Phillip Hitz, Mark Hughes, Usha Kini, Tjitske Kleefstra, R Frank Kooy, Peter Krawitz, Sébastien Küry, Melissa Lees, Gholson J Lyon, Stanislas Lyonnet, Julien L Marcadier, Stephen Meyn, Veronika Moslerová, Juan M Politei, Cathryn C Poulton, F Lucy Raymond, Margot R F Reijnders, Peter N Robinson, Corrado Romano, Catherine M Rose, David C G Sainsbury, Lyn Schofield, Vernon R Sutton, Marek Turnovec, Anke Van Dijck, Hilde Van Esch, Andrew O M Wilkie Jul 2019

Enabling Global Clinical Collaborations On Identifiable Patient Data: The Minerva Initiative., Christoffer Nellåker, Fowzan S Alkuraya, Gareth Baynam, Raphael A Bernier, Francois P J Bernier, Vanessa Boulanger, Michael Brudno, Han G Brunner, Jill Clayton-Smith, Benjamin Cogné, Hugh J S Dawkins, Bert B A Devries, Sofia Douzgou, Tracy Dudding-Byth, Evan E Eichler, Michael Ferlaino, Karen Fieggen, Helen V Firth, David R Fitzpatrick, Dylan Gration, Tudor Groza, Melissa Haendel, Nina Hallowell, Ada Hamosh, Jayne Hehir-Kwa, Marc-Phillip Hitz, Mark Hughes, Usha Kini, Tjitske Kleefstra, R Frank Kooy, Peter Krawitz, Sébastien Küry, Melissa Lees, Gholson J Lyon, Stanislas Lyonnet, Julien L Marcadier, Stephen Meyn, Veronika Moslerová, Juan M Politei, Cathryn C Poulton, F Lucy Raymond, Margot R F Reijnders, Peter N Robinson, Corrado Romano, Catherine M Rose, David C G Sainsbury, Lyn Schofield, Vernon R Sutton, Marek Turnovec, Anke Van Dijck, Hilde Van Esch, Andrew O M Wilkie

Faculty Research 2019

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital ...


A Mathematical Model Of Combined Cd8 T Cell Costimulation By 4-1bb (Cd137) And Ox40 (Cd134) Receptors., Anna Konstorum, Anthony T Vella, Adam J Adler, Reinhard C Laubenbacher Jul 2019

A Mathematical Model Of Combined Cd8 T Cell Costimulation By 4-1bb (Cd137) And Ox40 (Cd134) Receptors., Anna Konstorum, Anthony T Vella, Adam J Adler, Reinhard C Laubenbacher

Faculty Research 2019

Combined agonist stimulation of the TNFR costimulatory receptors 4-1BB (CD137) and OX40(CD134) has been shown to generate supereffector CD8 T cells that clonally expand to greater levels, survive longer, and produce a greater quantity of cytokines compared to T cells stimulated with an agonist of either costimulatory receptor individually. In order to understand the mechanisms for this effect, we have created a mathematical model for the activation of the CD8 T cell intracellular signaling network by mono- or dual-costimulation. We show that supereffector status is generated via downstream interacting pathways that are activated upon engagement of both receptors, and ...


Computational Processing And Quality Control Of Hi-C, Capture Hi-C And Capture-C Data., Peter Hansen, Michael Gargano, Jochen Hecht, Jonas Ibn-Salem, Guy Karlebach, Johannes T Roehr, Peter N Robinson Jul 2019

Computational Processing And Quality Control Of Hi-C, Capture Hi-C And Capture-C Data., Peter Hansen, Michael Gargano, Jochen Hecht, Jonas Ibn-Salem, Guy Karlebach, Johannes T Roehr, Peter N Robinson

Faculty Research 2019

Hi-C, capture Hi-C (CHC) and Capture-C have contributed greatly to our present understanding of the three-dimensional organization of genomes in the context of transcriptional regulation by characterizing the roles of topological associated domains, enhancer promoter loops and other three-dimensional genomic interactions. The analysis is based on counts of chimeric read pairs that map to interacting regions of the genome. However, the processing and quality control presents a number of unique challenges. We review here the experimental and computational foundations and explain how the characteristics of restriction digests, sonication fragments and read pairs can be exploited to distinguish technical artefacts from ...


Identifying And Ranking Potential Driver Genes Of Alzheimer's Disease Using Multiview Evidence Aggregation., Sumit Mukherjee, Thanneer M Perumal, Kenneth Daily, Solveig K Sieberts, Larsson Omberg, Christoph Preuss, Gregory W. Carter, Lara M Mangravite, Benjamin A Logsdon Jul 2019

Identifying And Ranking Potential Driver Genes Of Alzheimer's Disease Using Multiview Evidence Aggregation., Sumit Mukherjee, Thanneer M Perumal, Kenneth Daily, Solveig K Sieberts, Larsson Omberg, Christoph Preuss, Gregory W. Carter, Lara M Mangravite, Benjamin A Logsdon

Faculty Research 2019

MOTIVATION: Late onset Alzheimer's disease is currently a disease with no known effective treatment options. To better understand disease, new multi-omic data-sets have recently been generated with the goal of identifying molecular causes of disease. However, most analytic studies using these datasets focus on uni-modal analysis of the data. Here, we propose a data driven approach to integrate multiple data types and analytic outcomes to aggregate evidences to support the hypothesis that a gene is a genetic driver of the disease. The main algorithmic contributions of our article are: (i) a general machine learning framework to learn the key ...


Genomic Data Analysis Workflows For Tumors From Patient-Derived Xenografts (Pdxs): Challenges And Guidelines., Xing Yi Woo, Anuj Srivastava, Joel H Graber, Vinod Yadav, Vishal Kumar Sarsani, Allen K. Simons, Glen L Beane, Stephen C. Grubb, Guruprasad Ananda, Rangjiao Liu, Grace Stafford, Jeffrey Chuang, Susan Airhart, Radha Krishna Murthy Karuturi, Joshy George, Carol J Bult Jul 2019

Genomic Data Analysis Workflows For Tumors From Patient-Derived Xenografts (Pdxs): Challenges And Guidelines., Xing Yi Woo, Anuj Srivastava, Joel H Graber, Vinod Yadav, Vishal Kumar Sarsani, Allen K. Simons, Glen L Beane, Stephen C. Grubb, Guruprasad Ananda, Rangjiao Liu, Grace Stafford, Jeffrey Chuang, Susan Airhart, Radha Krishna Murthy Karuturi, Joshy George, Carol J Bult

Faculty Research 2019

BACKGROUND: Patient-derived xenograft (PDX) models are in vivo models of human cancer that have been used for translational cancer research and therapy selection for individual patients. The Jackson Laboratory (JAX) PDX resource comprises 455 models originating from 34 different primary sites (as of 05/08/2019). The models undergo rigorous quality control and are genomically characterized to identify somatic mutations, copy number alterations, and transcriptional profiles. Bioinformatics workflows for analyzing genomic data obtained from human tumors engrafted in a mouse host (i.e., Patient-Derived Xenografts; PDXs) must address challenges such as discriminating between mouse and human sequence reads and accurately ...


Clinical Data: Sources And Types, Regulatory Constraints, Applications., Stanley C Ahalt, Christopher G Chute, Karamarie Fecho, Gustavo Glusman, Jennifer Hadlock, Casey Overby Taylor, Emily R Pfaff, Peter N Robinson, Harold Solbrig, Casey Ta, Nicholas Tatonetti, Chunhua Weng Jul 2019

Clinical Data: Sources And Types, Regulatory Constraints, Applications., Stanley C Ahalt, Christopher G Chute, Karamarie Fecho, Gustavo Glusman, Jennifer Hadlock, Casey Overby Taylor, Emily R Pfaff, Peter N Robinson, Harold Solbrig, Casey Ta, Nicholas Tatonetti, Chunhua Weng

Faculty Research 2019

Access to clinical data is critical for the advancement of translational research. However, the numerous regulations and policies that surround the use of clinical data, although critical to ensure patient privacy and protect against misuse, often present challenges to data access and sharing. In this article, we provide an overview of clinical data types and associated regulatory constraints and inferential limitations. We highlight several novel approaches that our team has developed for openly exposing clinical data.