Life Sciences Commons^™

New Statistical Method Identifies Cytokines That Distinguish Stool Microbiomes., Dake Yang, Jethro Johnson, Xin Zhou, Elena Deych, Berkley Shands, Blake Hanson, Erica Sodergren, George M. Weinstock, William D Shannon

Faculty Research 2019

Regressing an outcome or dependent variable onto a set of input or independent variables allows the analyst to measure associations between the two so that changes in the outcome can be described by and predicted by changes in the inputs. While there are many ways of doing this in classical statistics, where the dependent variable has certain properties (e.g., a scalar, survival time, count), little progress on regression where the dependent variable are microbiome taxa counts has been made that do not impose extremely strict conditions on the data. In this paper, we propose and apply a new regression model …

Genetic Perturbations Of Disease Risk Genes In Mice Capture Transcriptomic Signatures Of Late-Onset Alzheimer's Disease., Ravi S Pandey, Leah C. Graham, Asli Uyar, Christoph Preuss, Gareth R Howell, Gregory W. Carter

Faculty Research 2019

BACKGROUND: New genetic and genomic resources have identified multiple genetic risk factors for late-onset Alzheimer's disease (LOAD) and characterized this common dementia at the molecular level. Experimental studies in model organisms can validate these associations and elucidate the links between specific genetic factors and transcriptomic signatures. Animal models based on LOAD-associated genes can potentially connect common genetic variation with LOAD transcriptomes, thereby providing novel insights into basic biological mechanisms underlying the disease.

METHODS: We performed RNA-Seq on whole brain samples from a panel of six-month-old female mice, each carrying one of the following mutations: homozygous deletions of Apoe and Clu; …

Urolithiasis Is A Risk Factor For Uroseptic Shock And Acute Kidney Injury In Patients With Urinary Tract Infection., Chih-Yen Hsiao, Tsung-Hsien Chen, Yi-Chien Lee, Meng-Chang Hsiao, Peir-Haur Hung, Yih-Yuan Chen, Ming-Cheng Wang

Faculty Research 2019

Urinary tract infection (UTI) is a common complication in patients with urolithiasis. This study aimed to compare clinical manifestations and treatment outcomes among UTI patients with or without urolithiasis. It also focused on identifying relationships among urolithiasis, uroseptic shock, and acute kidney injury (AKI). This retrospective study enrolled hospitalized UTI patients who underwent imaging in an acute care setting from January 2006 to March 2015. Of 662 participants enrolled, 113 (17.1%) had urolithiasis, 107 (16.2%) developed uroseptic shock, and 184 (27.8%) developed AKI. A multivariate logistic regression analysis showed that in UTI patients, urolithiasis is associated with an increased risk …

Estimating Heritability And Genetic Correlations From Large Health Datasets In The Absence Of Genetic Data., Gengjie Jia, Yu Li, Hanxin Zhang, Ishanu Chattopadhyay, Anders Boeck Jensen, David R Blair, Lea Davis, Peter N Robinson, Torsten Dahlén, Søren Brunak, Mikael Benson, Gustaf Edgren, Nancy J Cox, Xin Gao, Andrey Rzhetsky

Faculty Research 2019

Typically, estimating genetic parameters, such as disease heritability and between-disease genetic correlations, demands large datasets containing all relevant phenotypic measures and detailed knowledge of family relationships or, alternatively, genotypic and phenotypic data for numerous unrelated individuals. Here, we suggest an alternative, efficient estimation approach through the construction of two disease metrics from large health datasets: temporal disease prevalence curves and low-dimensional disease embeddings. We present eleven thousand heritability estimates corresponding to five study types: twins, traditional family studies, health records-based family studies, single nucleotide polymorphisms, and polygenic risk scores. We also compute over six hundred thousand estimates of genetic, environmental …

Comparative Analysis Of Metabolome Of Rice Seeds At Three Developmental Stages Using A Recombinant Inbred Line Population., Kang Li, Dehong Wang, Liang Gong, Yuanyuan Lyu, Hao Guo, Wei Chen, Cheng Jin, Xianqing Liu, Chuanying Fang, Jie Luo

Faculty Research 2019

Plants are considered an important food and nutrition source for humans. Despite advances in plant seed metabolomics, knowledge about the genetic and molecular bases of rice seed metabolomes at different developmental stages is still limited. Here, using Zhenshan 97 (ZS97) and Minghui 63 (MH63), we performed a widely targeted metabolic profiling in seeds during grain filling, mature seeds and germinating seeds. The diversity between MH63 and ZS97 was characterized in terms of the content of metabolites and the metabolic shifting across developmental stages. Taking advantage of the ultra-high-density genetic map of a population of 210 recombinant inbred lines (RILs) derived …

Assessment Of Bones Deficient In Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences., Lukas Altinbas, Nicole Bormann, Daniel Lehmann, Sarah Jeuthe, Dag Wulsten, Uwe Kornak, Peter N Robinson, Britt Wildemann, Georgios Kararigas

Faculty Research 2019

Defects in the extracellular matrix protein fibrillin-1 that perturb transforming growth factor beta (TGFβ) bioavailability lead to Marfan syndrome (MFS). MFS is an autosomal-dominant disorder, which is associated with connective tissue and skeletal defects, among others. To date, it is unclear how biological sex impacts the structural and functional properties of bone in MFS. The aim of this study was to investigate the effects of sex on bone microarchitecture and mechanical properties in mice with deficient fibrillin-1, a model of human MFS. Bones of 11-week-old male and female Fbn1^mgR/mgR mice were investigated. Three-dimensional micro-computed tomography of femora and vertebrae …

Pedia: Prioritization Of Exome Data By Image Analysis., Tzung-Chien Hsieh, Martin A Mensah, Jean T Pantel, Dione Aguilar, Omri Bar, Allan Bayat, Luis Becerra-Solano, Heidi B Bentzen, Saskia Biskup, Oleg Borisov, Oivind Braaten, Claudia Ciaccio, Marie Coutelier, Kirsten Cremer, Magdalena Danyel, Svenja Daschkey, Hilda David Eden, Koenraad Devriendt, Sandra Wilson, Sofia Douzgou, Dejan Đukić, Nadja Ehmke, Christine Fauth, Björn Fischer-Zirnsak, Nicole Fleischer, Heinz Gabriel, Luitgard Graul-Neumann, Karen W Gripp, Yaron Gurovich, Asya Gusina, Nechama Haddad, Nurulhuda Hajjir, Yair Hanani, Jakob Hertzberg, Konstanze Hoertnagel, Janelle Howell, Ivan Ivanovski, Angela Kaindl, Tom Kamphans, Susanne Kamphausen, Catherine Karimov, Hadil Kathom, Anna Keryan, Alexej Knaus, Sebastian Köhler, Uwe Kornak, Alexander Lavrov, Maximilian Leitheiser, Gholson J Lyon, Elisabeth Mangold, Purificación Marín Reina, Antonio Martinez Carrascal, Diana Mitter, Laura Morlan Herrador, Guy Nadav, Markus Nöthen, Alfredo Orrico, Claus-Eric Ott, Kristen Park, Borut Peterlin, Laura Pölsler, Annick Raas-Rothschild, Linda Randolph, Nicole Revencu, Christina Ringmann Fagerberg, Peter N Robinson, Stanislav Rosnev, Sabine Rudnik, Gorazd Rudolf, Ulrich Schatz, Anna Schossig, Max Schubach, Or Shanoon, Eamonn Sheridan, Pola Smirin-Yosef, Malte Spielmann, Eun-Kyung Suk, Yves Sznajer, Christian T Thiel, Gundula Thiel, Alain Verloes, Irena Vrecar, Dagmar Wahl, Ingrid Weber, Korina Winter, Marzena Wiśniewska, Bernd Wollnik, Ming W Yeung, Max Zhao, Na Zhu, Johannes Zschocke, Stefan Mundlos, Denise Horn, Peter M Krawitz

Faculty Research 2019

PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists.

METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds.

RESULTS: …

The Jax Synteny Browser For Mouse-Human Comparative Genomics., Georgi Kolishovski, Anna Lamoureux, Paul Hale, Joel E Richardson, Jill M. Recla, Omoluyi Adesanya, Allen K. Simons, Govindarajan Kunde-Ramamoorthy, Carol J Bult

Faculty Research 2019

Visualizing regions of conserved synteny between two genomes is supported by numerous software applications. However, none of the current applications allow researchers to select genome features to display or highlight in blocks of synteny based on the annotated biological properties of the features (e.g., type, function, and/or phenotype association). To address this usability gap, we developed an interactive web-based conserved synteny browser, The Jackson Laboratory (JAX) Synteny Browser. The browser allows researchers to highlight or selectively display genome features in the reference and/or the comparison genome according to the biological attributes of the features. Although the current implementation for the …

Differential Functions Of Splicing Factors In Mammary Transformation And Breast Cancer Metastasis., Sunghee Park, Mattia Brugiolo, Martin Akerman, Shipra Das, Laura M Urbanski, Adam Geier, Anil K Kesarwani, Martin Fan, Nathan Leclair, Kuan-Ting Lin, Leo Hu, Ian Hua, Joshy George, Senthil K Muthuswamy, Adrian R Krainer, Olga Anczuków

Faculty Research 2019

Misregulation of alternative splicing is a hallmark of human tumors, yet to what extent and how it contributes to malignancy are only beginning to be unraveled. Here, we define which members of the splicing factor SR and SR-like families contribute to breast cancer and uncover differences and redundancies in their targets and biological functions. We identify splicing factors frequently altered in human breast tumors and assay their oncogenic functions using breast organoid models. We demonstrate that not all splicing factors affect mammary tumorigenesis in MCF-10A cells. Specifically, the upregulation of SRSF4, SRSF6, or TRA2β disrupts acinar morphogenesis and promotes cell …

Mia-Sig: Multiplex Chromatin Interaction Analysis By Signal Processing And Statistical Algorithms., Minji Kim, Meizhen Zheng, Simon Zhongyuan Tian, Byoungkoo Lee, Jeffrey Chuang, Yijun Ruan

Faculty Research 2019

The single-molecule multiplex chromatin interaction data are generated by emerging 3D genome mapping technologies such as GAM, SPRITE, and ChIA-Drop. These datasets provide insights into high-dimensional chromatin organization, yet introduce new computational challenges. Thus, we developed MIA-Sig, an algorithmic solution based on signal processing and information theory. We demonstrate its ability to de-noise the multiplex data, assess the statistical significance of chromatin complexes, and identify topological domains and frequent inter-domain contacts. On chromatin immunoprecipitation (ChIP)-enriched data, MIA-Sig can clearly distinguish the protein-associated interactions from the non-specific topological domains. Together, MIA-Sig represents a novel algorithmic framework for multiplex chromatin interaction analysis.

Characterization Of Mucosal Dysbiosis Of Early Colonic Neoplasia., Bo-Young Hong, Takayasu Ideta, Bruno S Lemos, Yuichi Igarashi, Yuliana Tan, Michael Disiena, Allen Mo, John W Birk, Faripour Forouhar, Thomas J Devers, George M. Weinstock, Daniel W Rosenberg

Faculty Research 2019

Aberrant crypt foci (ACF) are the earliest morphologically identifiable lesions in the colon that can be detected by high-definition chromoendoscopy with contrast dye spray. Although frequently associated with synchronous adenomas, their role in colorectal tumor development, particularly in the proximal colon, is still not clear. The goal of this study was to evaluate the profile of colon-adherent bacteria associated with proximal ACF and to investigate their relationship to the presence and subtype of synchronous polyps present throughout the colon. Forty-five subjects undergoing a screening or surveillance colonoscopy were included in this retrospective study. Bacterial cells adherent to the epithelia of …

The Firre Locus Produces A Trans-Acting Rna Molecule That Functions In Hematopoiesis., Jordan P Lewandowski, James C Lee, Taeyoung Hwang, Hongjae Sunwoo, Jill M Goldstein, Abigail F Groff, Nydia P Chang, William Mallard, Adam Williams, Jorge Henao-Meija, Richard A Flavell, Jeannie T Lee, Chiara Gerhardinger, Amy J Wagers, John L Rinn

Faculty Research 2019

RNA has been classically known to play central roles in biology, including maintaining telomeres, protein synthesis, and in sex chromosome compensation. While thousands of long noncoding RNAs (lncRNAs) have been identified, attributing RNA-based roles to lncRNA loci requires assessing whether phenotype(s) could be due to DNA regulatory elements, transcription, or the lncRNA. Here, we use the conserved X chromosome lncRNA locus Firre, as a model to discriminate between DNA- and RNA-mediated effects in vivo. We demonstrate that (i) Firre mutant mice have cell-specific hematopoietic phenotypes, and (ii) upon exposure to lipopolysaccharide, mice overexpressing Firre exhibit increased levels of pro-inflammatory cytokines …

Evaluation Of 16s Rrna Gene Sequencing For Species And Strain-Level Microbiome Analysis., Jethro Johnson, Daniel Spakowicz, Bo-Young Hong, Lauren M Petersen, Patrick Demkowicz, Lei Chen, Shana Leopold, Blake M Hanson, Hanako O Agresta, Mark Gerstein, Erica Sodergren, George M. Weinstock

Faculty Research 2019

The 16S rRNA gene has been a mainstay of sequence-based bacterial analysis for decades. However, high-throughput sequencing of the full gene has only recently become a realistic prospect. Here, we use in silico and sequence-based experiments to critically re-evaluate the potential of the 16S gene to provide taxonomic resolution at species and strain level. We demonstrate that targeting of 16S variable regions with short-read sequencing platforms cannot achieve the taxonomic resolution afforded by sequencing the entire (~1500 bp) gene. We further demonstrate that full-length sequencing platforms are sufficiently accurate to resolve subtle nucleotide substitutions (but not insertions/deletions) that exist between …

Cisplatin-Resistant Triple-Negative Breast Cancer Subtypes: Multiple Mechanisms Of Resistance., David P. Hill, Akeena Harper, Joan Malcolm, Monica Mcandrews, Susan Mockus, Sara E. Patterson, Timothy Reynolds, Erich J Baker, Carol J Bult, Elissa J Chesler, Judith A. Blake

Faculty Research 2019

BACKGROUND: Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies.

METHODS: In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated …

Split Selectable Markers., Nathaniel L. Jillette, Menghan Du, Jacqueline Jufen Zhu, Peter Cardoz, Albert W Cheng

Faculty Research 2019

Selectable markers are widely used in transgenesis and genome editing for selecting engineered cells with a desired genotype but the variety of markers is limited. Here we present split selectable markers that each allow for selection of multiple "unlinked" transgenes in the context of lentivirus-mediated transgenesis as well as CRISPR-Cas-mediated knock-ins. Split marker gene segments fused to protein splicing elements called "inteins" can be separately co-segregated with different transgenic vectors, and rejoin via protein trans-splicing to reconstitute a full-length marker protein in host cells receiving all intended vectors. Using a lentiviral system, we create and validate 2-split Hygromycin, Puromycin, Neomycin …

Plantsimlab - A Modeling And Simulation Web Tool For Plant Biologists., S Ha, E Dimitrova, S Hoops, D Altarawy, M Ansariola, D Deb, J Glazebrook, R Hillmer, H Shahin, F Katagiri, J Mcdowell, M Megraw, J Setubal, B M Tyler, Reinhard Laubenbacher

Faculty Research 2019

BACKGROUND: At the molecular level, nonlinear networks of heterogeneous molecules control many biological processes, so that systems biology provides a valuable approach in this field, building on the integration of experimental biology with mathematical modeling. One of the biggest challenges to making this integration a reality is that many life scientists do not possess the mathematical expertise needed to build and manipulate mathematical models well enough to use them as tools for hypothesis generation. Available modeling software packages often assume some modeling expertise. There is a need for software tools that are easy to use and intuitive for experimentalists.

RESULTS: …

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. …

Editorial: Long Non-Coding Rnas And Immunity., Grace J Kwon, Jorge Henao-Mejia, Adam Williams

Faculty Research 2019

No abstract provided.

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

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

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 fat diets. …

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 effectors, …

(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 results …

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

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 …

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 …

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=114 …

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

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

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 in …