Life Sciences Commons^™

A Protocol For Rapid And Parallel Isolation Of Myocytes And Non-Myocytes From Multiple Mouse Hearts., Gabriella E Farrugia, Michael A Mclellan, Kate L Weeks, Aya Matsumoto, Charles D Cohen, Crisdion Krstevski, Taylah L Gaynor, Adam C Parslow, Julie R Mcmullen, Alexander R Pinto

Faculty Research 2021

This protocol features parallel isolation of myocytes and non-myocytes from murine hearts. It was designed with considerations for (1) time required to extract cardiac cells, (2) cell viability, and (3) protocol scalability. Here, a peristaltic pump and 3D-printed elements are combined to perfuse the heart with enzymes to dissociate cells. Myocytes and non-myocytes extracted using this protocol are separated by centrifugation and/or fluorescence-activated cell sorting for use in downstream applications including single-cell omics or other bio-molecular analyses. For complete details on the use and execution of this protocol, please refer to McLellan et al. (2020).

Nuclear Pore Protein Nup210 Depletion Suppresses Metastasis Through Heterochromatin-Mediated Disruption Of Tumor Cell Mechanical Response., Ruhul Amin, Anjali Shukla, Jacqueline Jufen Zhu, Sohyoung Kim, Ping Wang, Simon Zhongyuan Tian, Andy D Tran, Debasish Paul, Steven D Cappell, Sandra Burkett, Huaitian Liu, Maxwell P Lee, Michael J Kruhlak, Jennifer E Dwyer, R Mark Simpson, Gordon L Hager, Yijun Ruan, Kent W Hunter

Faculty Research 2021

Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Here, we identify nucleoporin NUP210 as a metastasis susceptibility gene for human estrogen receptor positive (ER+) breast cancer and a cellular mechanosensor. Nup210 depletion suppresses lung metastasis in mouse models of breast cancer. Mechanistically, NUP210 interacts with LINC complex protein SUN2 which connects the nucleus to the cytoskeleton. In addition, the NUP210/SUN2 complex interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. In Nup210 knockout cells, mechanosensitive genes accumulate H3K27me3 heterochromatin modification, mediated by the polycomb repressive complex 2 …

Supervised Learning With Word Embeddings Derived From Pubmed Captures Latent Knowledge About Protein Kinases And Cancer., Vida Ravanmehr, Hannah Blau, Luca Cappelletti, Tommaso Fontana, Leigh Carmody, Ben D Coleman, Joshy George, Justin Reese, Marcin Joachimiak, Giovanni Bocci, Peter Hansen, Carol J Bult, Jens Rueter, Elena Casiraghi, Giorgio Valentini, Christopher Mungall, Tudor I Oprea, Peter N Robinson

Faculty Research 2021

Inhibiting protein kinases (PKs) that cause cancers has been an important topic in cancer therapy for years. So far, almost 8% of >530 PKs have been targeted by FDA-approved medications, and around 150 protein kinase inhibitors (PKIs) have been tested in clinical trials. We present an approach based on natural language processing and machine learning to investigate the relations between PKs and cancers, predicting PKs whose inhibition would be efficacious to treat a certain cancer. Our approach represents PKs and cancers as semantically meaningful 100-dimensional vectors based on word and concept neighborhoods in PubMed abstracts. We use information about phase …

Core-Atac: A Deep Learning Model For The Functional Classification Of Regulatory Elements From Single Cell And Bulk Atac-Seq Data., Asa Thibodeau, Shubham Khetan, Alper Eroglu, Ryan Tewhey, Michael L. Stitzel, Duygu Ucar

Faculty Research 2021

Cis-Regulatory elements (cis-REs) include promoters, enhancers, and insulators that regulate gene expression programs via binding of transcription factors. ATAC-seq technology effectively identifies active cis-REs in a given cell type (including from single cells) by mapping accessible chromatin at base-pair resolution. However, these maps are not immediately useful for inferring specific functions of cis-REs. For this purpose, we developed a deep learning framework (CoRE-ATAC) with novel data encoders that integrate DNA sequence (reference or personal genotypes) with ATAC-seq cut sites and read pileups. CoRE-ATAC was trained on 4 cell types (n = 6 samples/replicates) and accurately predicted known cis-RE functions from …

Abdominal Computed Tomography Imaging Findings In Hospitalized Covid-19 Patients: A Year-Long Experience And Associations Revealed By Explainable Artificial Intelligence., Alice Scarabelli, Massimo Zilocchi, Elena Casiraghi, Pierangelo Fasani, Guido Giovanni Plensich, Andrea Alessandro Esposito, Elvira Stellato, Alessandro Petrini, Justin Reese, Peter N Robinson, Giorgio Valentini, Gianpaolo Carrafiello

Faculty Research 2021

The aim of this retrospective study is to assess any association between abdominal CT findings and the radiological stage of COVID-19 pneumonia, pulmonary embolism and patient outcomes. We included 158 adult hospitalized COVID-19 patients between 1 March 2020 and 1 March 2021 who underwent 206 abdominal CTs. Two radiologists reviewed all CT images. Pathological findings were classified as acute or not. A subset of patients with inflammatory pathology in ACE2 organs (bowel, biliary tract, pancreas, urinary system) was identified. The radiological stage of COVID pneumonia, pulmonary embolism, overall days of hospitalization, ICU admission and outcome were registered. Univariate statistical analysis …

Human Macrophage Polarization In The Response To, Alberto Marin, Kristopher Van Huss, John Corbett, Sangjin Kim, Jonathon Mohl, Bo-Young Hong, Jorge Cervantes

Faculty Research 2021

Infection with Mycobacterium leprae, the causative organism of leprosy, is still endemic in numerous parts of the world including the southwestern United States. The broad variation of symptoms in the leprosy disease spectrum range from the milder tuberculoid leprosy (paucibacillary) to the more severe and disfiguring lepromatous leprosy (multibacillary). The established thinking in the health community is that host response, rather than M. leprae strain variation, is the reason for the range of disease severity. More recent discoveries suggest that macrophage polarization also plays a significant role in the spectrum of leprosy disease but to what degree it contributes is …

Pursuit Of Precision Medicine: Systems Biology Approaches In Alzheimer's Disease Mouse Models., Brianna Gurdon, Catherine Kaczorowski

Faculty Research 2021

Alzheimer's disease (AD) is a complex disease that is mediated by numerous factors and manifests in various forms. A systems biology approach to studying AD involves analyses of various body systems, biological scales, environmental elements, and clinical outcomes to understand the genotype to phenotype relationship that potentially drives AD development. Currently, there are many research investigations probing how modifiable and nonmodifiable factors impact AD symptom presentation. This review specifically focuses on how imaging modalities can be integrated into systems biology approaches using model mouse populations to link brain level functional and structural changes to disease onset and progression. Combining imaging …

Inactive Rhomboid Proteins Rhbdf1 And Rhbdf2 (Irhoms): A Decade Of Research In Murine Models., Lisa M. Burzenski, Benjamin E. Low, Vivek Kohar, Leonard D. Shultz, Michael V. Wiles, Vishnu Hosur

Faculty Research 2021

Rhomboid proteases, first discovered in Drosophila, are intramembrane serine proteases. Members of the rhomboid protein family that are catalytically deficient are known as inactive rhomboids (iRhoms). iRhoms have been implicated in wound healing, cancer, and neurological disorders such as Alzheimer's and Parkinson's diseases, inflammation, and skin diseases. The past decade of mouse research has shed new light on two key protein domains of iRhoms-the cytosolic N-terminal domain and the transmembrane dormant peptidase domain-suggesting new ways to target multiple intracellular signaling pathways. This review focuses on recent advances in uncovering the unique functions of iRhom protein domains in normal growth and …

Spatial Concordance Of Dna Methylation Classification In Diffuse Glioma., Niels Verburg, Floris P Barthel, Kevin J Anderson, Kevin C Johnson, Thomas Koopman, Maqsood M Yaqub, Otto S Hoekstra, Adriaan A Lammertsma, Frederik Barkhof, Petra J W Pouwels, Jaap C Reijneveld, Annemieke J M Rozemuller, Jeroen A M Beliën, Ronald Boellaard, Michael D Taylor, Sunit Das, Joseph F Costello, William Peter Vandertop, Pieter Wesseling, Philip C De Witt Hamer, Roel G W Verhaak

Faculty Research 2021

BACKGROUND: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence.

METHODS: We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion …

Nucleic Acid-Sensing And Interferon-Inducible Pathways Show Differential Methylation In Mz Twins Discordant For Lupus And Overexpression In Independent Lupus Samples: Implications For Pathogenic Mechanism And Drug Targeting., Miranda C Marion, Paula S Ramos, Prathyusha Bachali, Adam C Labonte, Kip D Zimmerman, Hannah C Ainsworth, Sarah E Heuer, Robert D Robl, Michelle D Catalina, Jennifer A Kelly, Timothy D Howard, Peter E Lipsky, Amrie C Grammer, Carl D Langefeld

Faculty Research 2021

Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune inflammatory disease with genomic and non-genomic contributions to risk. We hypothesize that epigenetic factors are a significant contributor to SLE risk and may be informative for identifying pathogenic mechanisms and therapeutic targets. To test this hypothesis while controlling for genetic background, we performed an epigenome-wide analysis of DNA methylation in genomic DNA from whole blood in three pairs of female monozygotic (MZ) twins of European ancestry, discordant for SLE. Results were replicated on the same array in four cell types from a set of four Danish female MZ twin pairs discordant …

Characterizing Long Covid: Deep Phenotype Of A Complex Condition., Rachel R Deer, Madeline A Rock, Nicole Vasilevsky, Leigh Carmody, Halie Rando, Alfred J Anzalone, Marc D Basson, Tellen D Bennett, Timothy Bergquist, Eilis A Boudreau, Carolyn T Bramante, James Brian Byrd, Tiffany J Callahan, Lauren E Chan, Haitao Chu, Christopher G Chute, Ben D Coleman, Hannah E Davis, Joel Gagnier, Casey S Greene, William B Hillegass, Ramakanth Kavuluru, Wesley D Kimble, Farrukh M Koraishy, Sebastian Köhler, Chen Liang, Feifan Liu, Hongfang Liu, Vithal Madhira, Charisse R Madlock-Brown, Nicolas Matentzoglu, Diego R Mazzotti, Julie A Mcmurry, Douglas S Mcnair, Richard A Moffitt, Teshamae S Monteith, Ann M Parker, Mallory A Perry, Emily Pfaff, Justin T Reese, Joel Saltz, Robert A Schuff, Anthony E Solomonides, Julian Solway, Heidi Spratt, Gary S Stein, Anupam A Sule, Umit Topaloglu, George D Vavougios, Liwei Wang, Melissa A Haendel, Peter N Robinson

Faculty Research 2021

BACKGROUND: Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or "long COVID"), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies.

METHODS: The Human Phenotype Ontology …

Community Oncologists' Perceptions And Utilization Of Large-Panel Genomic Tumor Testing., Eric C Anderson, Alexandra C Hinton, Christine W Lary, Anny T H R Fenton, Andrey Antov, Emily A Edelman, Petra Helbig, Kate Reed, Susan Miesfeldt, Christian A Thomas, Michael J Hall, J Scott Roberts, Jens Rueter, Paul K J Han, Mcgi Working Group

Faculty Research 2021

PURPOSE: Large-panel genomic tumor testing (GTT) is an emerging technology with great promise but uncertain clinical value. Previous research has documented variability in academic oncologists' perceptions and use of GTT, but little is known about community oncologists' perceptions of GTT and how perceptions relate to clinicians' intentions to use GTT.

METHODS: Community oncology physicians (N = 58) participating in a statewide initiative aimed at improving access to large-panel GTT completed surveys assessing their confidence in using GTT, attitudes regarding the value of GTT, perceptions of barriers to GTT implementation, and future intentions to use GTTs. Descriptive and multivariable regression analyses …

Immuno-Transcriptomic Profiling Of Extracranial Pediatric Solid Malignancies., Andrew S Brohl, Sivasish Sindiri, Jun S Wei, David Milewski, Hsien-Chao Chou, Young K Song, Xinyu Wen, Jeetendra Kumar, Hue V Reardon, Uma S Mudunuri, Jack R Collins, Sushma Nagaraj, Vineela Gangalapudi, Manoj Tyagi, Yuelin J Zhu, Katherine E Masih, Marielle E Yohe, Jack F Shern, Yue Qi, Udayan Guha, Daniel Catchpoole, Rimas J Orentas, Igor B Kuznetsov, Nicolas J Llosa, John A Ligon, Brian K Turpin, Daniel G Leino, Shintaro Iwata, Irene L Andrulis, Jay S Wunder, Silvia R C Toledo, Paul S Meltzer, Ching C Lau, Beverly A Teicher, Heather Magnan, Marc Ladanyi, Javed Khan

Faculty Research 2021

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. …

Selection Shapes The Landscape Of Functional Variation In Wild House Mice., Raman Akinyanju Lawal, Uma P Arora, Beth L Dumont

Faculty Research 2021

BACKGROUND: Through human-aided dispersal over the last ~ 10,000 years, house mice (Mus musculus) have recently colonized diverse habitats across the globe, promoting the emergence of new traits that confer adaptive advantages in distinct environments. Despite their status as the premier mammalian model system, the impact of this demographic and selective history on the global patterning of disease-relevant trait variation in wild mouse populations is poorly understood.

RESULTS: Here, we leveraged 154 whole-genome sequences from diverse wild house mouse populations to survey the geographic organization of functional variation and systematically identify signals of positive selection. We show that a significant …

Relating Multivariate Shapes To Genescapes Using Phenotype-Biological Process Associations For Craniofacial Shape., Jose D Aponte, David C Katz, Daniela M Roth, Marta Vidal-García, Wei Liu, Fernando Andrade, Charles C Roseman, Stephen A Murray, James Cheverud, Daniel Graf, Ralph S Marcucio, Benedikt Hallgrímsson

Faculty Research 2021

Realistic mappings of genes to morphology are inherently multivariate on both sides of the equation. The importance of coordinated gene effects on morphological phenotypes is clear from the intertwining of gene actions in signaling pathways, gene regulatory networks, and developmental processes underlying the development of shape and size. Yet, current approaches tend to focus on identifying and localizing the effects of individual genes and rarely leverage the information content of high-dimensional phenotypes. Here, we explicitly model the joint effects of biologically coherent collections of genes on a multivariate trait - craniofacial shape - in a sample of n = 1145 …

An Asp To Strike Out Cancer? Therapeutic Possibilities Arising From Aspartate's Emerging Roles In Cell Proliferation And Survival., Iiro Taneli Helenius, Hanumantha Rao Madala, Jing-Ruey Joanna Yeh

Faculty Research 2021

A better understanding of the metabolic constraints of a tumor may lead to more effective anticancer treatments. Evidence has emerged in recent years shedding light on a crucial aspartate dependency of many tumor types. As a precursor for nucleotide synthesis, aspartate is indispensable for cell proliferation. Moreover, the malate-aspartate shuttle plays a key role in redox balance, and a deficit in aspartate can lead to oxidative stress. It is now recognized that aspartate biosynthesis is largely governed by mitochondrial metabolism, including respiration and glutaminolysis in cancer cells. Therefore, under conditions that suppress mitochondrial metabolism, including mutations, hypoxia, or chemical inhibitors, …

Ga4gh: International Policies And Standards For Data Sharing Across Genomic Research And Healthcare., Heidi L Rehm, Angela J H Page, Lindsay Smith, Jeremy B Adams, Gil Alterovitz, Lawrence J Babb, Maxmillian P Barkley, Michael Baudis, Michael J S Beauvais, Tim Beck, Jacques S Beckmann, Sergi Beltran, David Bernick, Alexander Bernier, James K Bonfield, Tiffany F Boughtwood, Guillaume Bourque, Sarion R Bowers, Anthony J Brookes, Michael Brudno, Matthew H Brush, David Bujold, Tony Burdett, Orion J Buske, Moran N Cabili, Daniel L Cameron, Robert J Carroll, Esmeralda Casas-Silva, Debyani Chakravarty, Bimal P Chaudhari, Shu Hui Chen, J Michael Cherry, Justina Chung, Melissa Cline, Hayley L Clissold, Robert M Cook-Deegan, Mélanie Courtot, Fiona Cunningham, Miro Cupak, Robert M Davies, Danielle Denisko, Megan J Doerr, Lena I Dolman, Edward S Dove, L Jonathan Dursi, Stephanie O M Dyke, James A Eddy, Karen Eilbeck, Kyle P Ellrott, Susan Fairley, Khalid A Fakhro, Helen V Firth, Michael S Fitzsimons, Marc Fiume, Paul Flicek, Ian M Fore, Mallory A Freeberg, Robert R Freimuth, Lauren A Fromont, Jonathan Fuerth, Clara L Gaff, Weiniu Gan, Elena M Ghanaim, David Glazer, Robert C Green, Malachi Griffith, Obi L Griffith, Robert L Grossman, Tudor Groza, Jaime M Guidry Auvil, Roderic Guigó, Dipayan Gupta, Melissa A Haendel, Ada Hamosh, David P Hansen, Reece K Hart, Dean Mitchell Hartley, David Haussler, Rachele M Hendricks-Sturrup, Calvin W L Ho, Ashley E Hobb, Michael M Hoffman, Oliver M Hofmann, Petr Holub, Jacob Shujui Hsu, Jean-Pierre Hubaux, Sarah E Hunt, Ammar Husami, Julius O Jacobsen, Saumya S Jamuar, Elizabeth L Janes, Francis Jeanson, Aina Jené, Amber L Johns, Yann Joly, Steven J M Jones, Alexander Kanitz, Kazuto Kato, Thomas M Keane, Kristina Kekesi-Lafrance, Jerome Kelleher, Giselle Kerry, Seik-Soon Khor, Bartha M Knoppers, Melissa A Konopko, Kenjiro Kosaki, Martin Kuba, Jonathan Lawson, Rasko Leinonen, Stephanie Li, Michael F Lin, Mikael Linden, Xianglin Liu, Isuru Udara Liyanage, Javier Lopez, Anneke M Lucassen, Michael Lukowski, Alice L Mann, John Marshall, Michele Mattioni, Alejandro Metke-Jimenez, Anna Middleton, Richard J Milne, Fruzsina Molnár-Gábor, Nicola Mulder, Monica C Munoz-Torres, Rishi Nag, Hidewaki Nakagawa, Jamal Nasir, Arcadi Navarro, Tristan H Nelson, Ania Niewielska, Amy Nisselle, Jeffrey Niu, Tommi H Nyrönen, Brian D O'Connor, Sabine Oesterle, Soichi Ogishima, Vivian Ota Wang, Laura A D Paglione, Emilio Palumbo, Helen E Parkinson, Anthony A Philippakis, Angel D Pizarro, Andreas Prlic, Jordi Rambla, Augusto Rendon, Renee A Rider, Peter N Robinson, Kurt W Rodarmer, Laura Lyman Rodriguez, Alan F Rubin, Manuel Rueda, Gregory A Rushton, Rosalyn S Ryan, Gary I Saunders, Helen Schuilenburg, Torsten Schwede, Serena Scollen, Alexander Senf, Nathan C Sheffield, Neerjah Skantharajah, Albert V Smith, Heidi J Sofia, Dylan Spalding, Amanda B Spurdle, Zornitza Stark, Lincoln D Stein, Makoto Suematsu, Patrick Tan, Jonathan A Tedds, Alastair A Thomson, Adrian Thorogood, Timothy L Tickle, Katsushi Tokunaga, Juha Törnroos, David Torrents, Sean Upchurch, Alfonso Valencia, Roman Valls Guimera, Jessica Vamathevan, Susheel Varma, Danya F Vears, Coby Viner, Craig Voisin, Alex H Wagner, Susan E Wallace, Brian P Walsh, Marc S Williams, Eva C Winkler, Barbara J Wold, Grant M Wood, J Patrick Woolley, Chisato Yamasaki, Andrew D Yates, Christina K Yung, Lyndon J Zass, Ksenia Zaytseva, Junjun Zhang, Peter Goodhand, Kathryn North, Ewan Birney

Faculty Research 2021

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight …

Three Decades Of The Human Genome Organization., Charles Lee, Stylianos E Antonarakis, Ada Hamosh, John Burn

Faculty Research 2021

The Human Genome Organization (HUGO) was initially established in 1988 to help integrate international scientific genomic activity and to accelerate the diffusion of knowledge from the efforts of the human genome project. Its founding President was Victor McKusick. During the late 1980s and 1990s, HUGO organized lively gene mapping meetings to accurately place genes on the genome as chromosomes were being sequenced. With the completion of the Human Genome Project, HUGO went through some transitions and self-reflection. In 2020, HUGO (which hosts a large annual scientific meeting and comprises the renowned HUGO Gene Nomenclature Committee [HGNC], responsible for naming genes, …

Victor Mckusick And His Short Course., Charles Wray, Gregory A. Cox, David Valle

Faculty Research 2021

The Short Course in Human and Mammalian Genetics and Genomics (aka the "Short Course" or the "Bar Harbor course") is one of Victor McKusick's landmark contributions to medical genetics. Conceived in 1959 as a way to increase the contribution of genetic advances to medicine, it has directly affected more than 7000 students and 600 participating faculty from around the world. Now, more than 10 years after his death, it continues to be a vibrant disseminator of genetics, and genomics knowledge for medicine, a catalytic agent for ongoing research and a source of collegiality in our field. What an extraordinary gift!

A Missense Mutation In Pitx2 Leads To Early-Onset Glaucoma Via Nrf2-Yap1 Axis., Yeming Yang, Xiao Li, Jieping Wang, Junkai Tan, Bernie Fitzmaurice, Patsy M. Nishina, Kuanxiang Sun, Wanli Tian, Wenjing Liu, Xuyang Liu, Bo Chang, Xianjun Zhu

Faculty Research 2021

Glaucoma is a leading cause of blindness, affecting 70 million people worldwide. Owing to the similarity in anatomy and physiology between human and mouse eyes and the ability to genetically manipulate mice, mouse models are an invaluable resource for studying mechanisms underlying disease phenotypes and for developing therapeutic strategies. Here, we report the discovery of a new mouse model of early-onset glaucoma that bears a transversion substitution c. G344T, which results in a missense mutation, p. R115L in PITX2. The mutation causes an elevation in intraocular pressure (IOP) and progressive death of retinal ganglion cells (RGC). These ocular phenotypes recapitulate …

Hippocampal And Thalamic Afferents Form Distinct Synaptic Microcircuits In The Mouse Infralimbic Frontal Cortex., Kourtney Graham, Nelson Spruston, Erik B Bloss

Faculty Research 2021

The selection of goal-directed behaviors is supported by neural circuits located within the frontal cortex. Frontal cortical afferents arise from multiple brain areas, yet the cell-type-specific targeting of these inputs is unclear. Here, we use monosynaptic retrograde rabies mapping to examine the distribution of afferent neurons targeting distinct classes of local inhibitory interneurons and excitatory projection neurons in mouse infralimbic frontal cortex. Interneurons expressing parvalbumin, somatostatin, or vasoactive intestinal peptide receive a large proportion of inputs from the hippocampus, while interneurons expressing neuron-derived neurotrophic factor receive a large proportion of inputs from thalamic regions. A similar dichotomy is present among …

Dna Methylation-Calling Tools For Oxford Nanopore Sequencing: A Survey And Human Epigenome-Wide Evaluation., Yang Liu, Wojciech Rosikiewicz, Ziwei Pan, Nathaniel L. Jillette, Ping Wang, Aziz Taghbalout, Jonathan Foox, Christopher Mason, Martin Carroll, Albert Cheng, Sheng Li

Faculty Research 2021

BACKGROUND: Nanopore long-read sequencing technology greatly expands the capacity of long-range, single-molecule DNA-modification detection. A growing number of analytical tools have been developed to detect DNA methylation from nanopore sequencing reads. Here, we assess the performance of different methylation-calling tools to provide a systematic evaluation to guide researchers performing human epigenome-wide studies.

RESULTS: We compare seven analytic tools for detecting DNA methylation from nanopore long-read sequencing data generated from human natural DNA at a whole-genome scale. We evaluate the per-read and per-site performance of CpG methylation prediction across different genomic contexts, CpG site coverage, and computational resources consumed by each …

Genetic Differences In Dorsal Hippocampus Acetylcholinesterase Activity Predict Contextual Fear Learning Across Inbred Mouse Strains., Sean M Mooney-Leber, Dana Zeid, Prescilla Garcia-Trevizo, Laurel R Seemiller, Molly A. Bogue, Stephen C. Grubb, Gary Peltz, Thomas J Gould

Faculty Research 2021

Learning is a critical behavioral process that is influenced by many neurobiological systems. We and others have reported that acetylcholinergic signaling plays a vital role in learning capabilities, and it is especially important for contextual fear learning. Since cholinergic signaling is affected by genetic background, we examined the genetic relationship between activity levels of acetylcholinesterase (AChE), the primary enzyme involved in the acetylcholine metabolism, and learning using a panel of 20 inbred mouse strains. We measured conditioned fear behavior and AChE activity in the dorsal hippocampus, ventral hippocampus, and cerebellum. Acetylcholinesterase activity varied among inbred mouse strains in all three …

Cultivation Of Common Bacterial Species And Strains From Human Skin, Oral, And Gut Microbiota., Elizabeth Fleming, Victor Pabst, Zoe Scholar, Ruoyun Xiong, Anita Y Voigt, Wei Zhou, Amelia Hoyt, Rachel Hardy, Anna Peterson, Ryan Beach, Yvette Ondouah-Nzutchi, Jinhong Dong, Lucinda Bateman, Suzanne D Vernon, Julia Oh

Faculty Research 2021

BACKGROUND: Genomics-driven discoveries of microbial species have provided extraordinary insights into the biodiversity of human microbiota. In addition, a significant portion of genetic variation between microbiota exists at the subspecies, or strain, level. High-resolution genomics to investigate species- and strain-level diversity and mechanistic studies, however, rely on the availability of individual microbes from a complex microbial consortia. High-throughput approaches are needed to acquire and identify the significant species- and strain-level diversity present in the oral, skin, and gut microbiome. Here, we describe and validate a streamlined workflow for cultivating dominant bacterial species and strains from the skin, oral, and gut …

Uncovering Disease Mechanisms In A Novel Mouse Model Expressing Humanized Apoeε4 And Trem2*R47h., Kevin P Kotredes, Adrian Oblak, Ravi S Pandey, Peter Bor-Chian Lin, Dylan Garceau, Harriet M. Jackson, Asli Uyar, Rita O'Rourke, Sarah O'Rourke, Cynthia Ingraham, Daria Bednarycek, Melisa Belanger, Zackary Cope, Kate E Foley, Benjamin A Logsdon, Lara M Mangravite, Stacey J Sukoff Rizzo, Paul R Territo, Gregory W. Carter, Michael Sasner, Bruce T Lamb, Gareth R Howell

Faculty Research 2021

Late-onset Alzheimer's disease (AD; LOAD) is the most common human neurodegenerative disease, however, the availability and efficacy of disease-modifying interventions is severely lacking. Despite exceptional efforts to understand disease progression via legacy amyloidogenic transgene mouse models, focus on disease translation with innovative mouse strains that better model the complexity of human AD is required to accelerate the development of future treatment modalities. LOAD within the human population is a polygenic and environmentally influenced disease with many risk factors acting in concert to produce disease processes parallel to those often muted by the early and aggressive aggregate formation in popular mouse …

Novel Phosphatidylserine-Binding Molecule Enhances Antitumor T-Cell Responses By Targeting Immunosuppressive Exosomes In Human Tumor Microenvironments., Maulasri Bhatta, Gautam N Shenoy, Jenni L Loyall, Brian D Gray, Meghana Bapardekar, Alexis Conway, Hans Minderman, Raymond J Kelleher, Beatriz M Carreno, Gerald Linette, Leonard D. Shultz, Kunle Odunsi, Sathy V Balu-Iyer, Koon Yan Pak, Richard B Bankert

Faculty Research 2021

BACKGROUND: The human tumor microenvironment (TME) is a complex and dynamic milieu of diverse acellular and cellular components, creating an immunosuppressive environment, which contributes to tumor progression. We have previously shown that phosphatidylserine (PS) expressed on the surface of exosomes isolated from human TMEs is causally linked to T-cell immunosuppression, representing a potential immunotherapeutic target. In this study, we investigated the effect of ExoBlock, a novel PS-binding molecule, on T-cell responses in the TME.

METHODS: We designed and synthesized a new compound, (ZnDPA)

RESULTS: ExoBlock was able to bind PS with high avidity and was found to consistently and significantly …

The Jackson Laboratory Nathan Shock Center: Impact Of Genetic Diversity On Aging., Ron Korstanje, Luanne L. Peters, Laura Robinson, Stephen D Krasinski, Gary Churchill

Faculty Research 2021

Healthspan is a complex trait, influenced by many genes and environmental factors that accelerate or delay aging, reduce or increase disease risk, and extend or reduce lifespan. Thus, assessing the role of genetic variation in aging requires an experimental strategy capable of modeling the genetic and biological complexity of human populations. The goal of the The Jackson Laboratory Nathan Shock Center (JAX NSC) is to provide research resources and training for geroscience investigators that seek to understand the role of genetics and genetic diversity on the fundamental process of aging and diseases of human aging using the laboratory mouse as …

A Reversal In Hair Cell Orientation Organizes Both The Auditory And Vestibular Organs., Basile Tarchini

Faculty Research 2021

Sensory hair cells detect mechanical stimuli with their hair bundle, an asymmetrical brush of actin-based membrane protrusions, or stereocilia. At the single cell level, stereocilia are organized in rows of graded heights that confer the hair bundle with intrinsic directional sensitivity. At the organ level, each hair cell is precisely oriented so that its intrinsic directional sensitivity matches the direction of mechanical stimuli reaching the sensory epithelium. Coordinated orientation among neighboring hair cells usually ensures the delivery of a coherent local group response. Accordingly, hair cell orientation is locally uniform in the auditory and vestibular cristae epithelia in birds and …

Identification Of The Adult Hematopoietic Liver As The Primary Reservoir For The Recruitment Of Pro-Regenerative Macrophages Required For Salamander Limb Regeneration., Ryan J Debuque, Andrew J Hart, Gabriela H Johnson, Nadia Rosenthal, James W Godwin

Faculty Research 2021

The lack of scar-free healing and regeneration in many adult human tissues imposes severe limitations on the recovery of function after injury. In stark contrast, salamanders can functionally repair a range of clinically relevant tissues throughout adult life. The impressive ability to regenerate whole limbs after amputation, or regenerate following cardiac injury, is critically dependent on the recruitment of (myeloid) macrophage white blood cells to the site of injury. Amputation in the absence of macrophages results in regeneration failure and scar tissue induction. Identifying the exact hematopoietic source or reservoir of myeloid cells supporting regeneration is a necessary step in …

Dti2vec: Drug-Target Interaction Prediction Using Network Embedding And Ensemble Learning., Maha A Thafar, Rawan S Olayan, Somayah Albaradei, Vladimir B Bajic, Takashi Gojobori, Magbubah Essack, Xin Gao

Faculty Research 2021

Drug-target interaction (DTI) prediction is a crucial step in drug discovery and repositioning as it reduces experimental validation costs if done right. Thus, developing in-silico methods to predict potential DTI has become a competitive research niche, with one of its main focuses being improving the prediction accuracy. Using machine learning (ML) models for this task, specifically network-based approaches, is effective and has shown great advantages over the other computational methods. However, ML model development involves upstream hand-crafted feature extraction and other processes that impact prediction accuracy. Thus, network-based representation learning techniques that provide automated feature extraction combined with traditional ML …