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2019

JMG

Articles 31 - 60 of 67

Full-Text Articles in Life Sciences

Fibronectin-Conjugated Thermoresponsive Nanobridges Generate Three Dimensional Human Pluripotent Stem Cell Cultures For Differentiation Towards The Neural Lineages., Linda Harkness, Xiaoli Chen, Zhongfan Jia, Anthony M Davies, Michael Monteiro, Peter Gray, Martin Pera Apr 2019

Fibronectin-Conjugated Thermoresponsive Nanobridges Generate Three Dimensional Human Pluripotent Stem Cell Cultures For Differentiation Towards The Neural Lineages., Linda Harkness, Xiaoli Chen, Zhongfan Jia, Anthony M Davies, Michael Monteiro, Peter Gray, Martin Pera

Faculty Research 2019

Production of 3-dimensional neural progenitor cultures from human pluripotent stem cells offers the potential to generate large numbers of cells. We utilised our nanobridge system to generate 3D hPSC aggregates for differentiation towards the neural lineage, and investigate the ability to passage aggregates while maintaining cells at a stem/progenitor stage. Over 38 days, aggregate cultures exhibited upregulation and maintenance of neural-associated markers and demonstrated up to 10 fold increase in cell number. Aggregates undergoing neural induction in the presence or absence of nanobridges demonstrated no differences in marker expression, proliferation or viability. However, aggregates formed without nanobridges were statistically ...


Integration Of Heterogeneous Functional Genomics Data In Gerontology Research To Find Genes And Pathway Underlying Aging Across Species., Jason A. Bubier, George L Sutphin, Timothy J Reynolds, Ron Korstanje, Axis Fuksman-Kumpa, Erich J Baker, Michael A Langston, Elissa J Chesler Apr 2019

Integration Of Heterogeneous Functional Genomics Data In Gerontology Research To Find Genes And Pathway Underlying Aging Across Species., Jason A. Bubier, George L Sutphin, Timothy J Reynolds, Ron Korstanje, Axis Fuksman-Kumpa, Erich J Baker, Michael A Langston, Elissa J Chesler

Faculty Research 2019

Understanding the biological mechanisms behind aging, lifespan and healthspan is becoming increasingly important as the proportion of the world's population over the age of 65 grows, along with the cost and complexity of their care. BigData oriented approaches and analysis methods enable current and future bio-gerontologists to synthesize, distill and interpret vast, heterogeneous data from functional genomics studies of aging. GeneWeaver is an analysis system for integration of data that allows investigators to store, search, and analyze immense amounts of data including user-submitted experimental data, data from primary publications, and data in other databases. Aging related genome-wide gene sets ...


Acarbose Improves Health And Lifespan In Aging Het3 Mice., David E Harrison, Randy Strong, Silvestre Alavez, Clinton M Astle, John Digiovanni, Elizabeth Fernandez, Kevin Flurkey, Michael Garratt, Jonathan A L Gelfond, Martin A Javors, Moshe Levi, Gordon J Lithgow, Francesca Macchiarini, James F Nelson, Stacey J Sukoff Rizzo, Thomas J Slaga, Timothy M Stearns, John Erby Wilkinson, Richard A Miller Apr 2019

Acarbose Improves Health And Lifespan In Aging Het3 Mice., David E Harrison, Randy Strong, Silvestre Alavez, Clinton M Astle, John Digiovanni, Elizabeth Fernandez, Kevin Flurkey, Michael Garratt, Jonathan A L Gelfond, Martin A Javors, Moshe Levi, Gordon J Lithgow, Francesca Macchiarini, James F Nelson, Stacey J Sukoff Rizzo, Thomas J Slaga, Timothy M Stearns, John Erby Wilkinson, Richard A Miller

Faculty Research 2019

To follow-up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and 2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log-rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses. The two higher doses produced 16% or 17% increases in median longevity of males, but only 4% or 5% increases in females. Age at the 90th ...


Identification Of A Novel Gene Regulating Amygdala-Mediated Fear Extinction., Ozge Gunduz-Cinar, Emma Brockway, Lauren Lederle, Troy Wilcox, Lindsay R Halladay, Ying Ding, Hyunjung Oh, Erica F Busch, Katie Kaugars, Shaun Flynn, Aaron Limoges, Olena Bukalo, Kathryn P Macpherson, Sophie Masneuf, Courtney Pinard, Etienne Sibille, Elissa J Chesler, Andrew Holmes Apr 2019

Identification Of A Novel Gene Regulating Amygdala-Mediated Fear Extinction., Ozge Gunduz-Cinar, Emma Brockway, Lauren Lederle, Troy Wilcox, Lindsay R Halladay, Ying Ding, Hyunjung Oh, Erica F Busch, Katie Kaugars, Shaun Flynn, Aaron Limoges, Olena Bukalo, Kathryn P Macpherson, Sophie Masneuf, Courtney Pinard, Etienne Sibille, Elissa J Chesler, Andrew Holmes

Faculty Research 2019

Recent years have seen advances in our understanding of the neural circuits associated with trauma-related disorders, and the development of relevant assays for these behaviors in rodents. Although inherited factors are known to influence individual differences in risk for these disorders, it has been difficult to identify specific genes that moderate circuit functions to affect trauma-related behaviors. Here, we exploited robust inbred mouse strain differences in Pavlovian fear extinction to uncover quantitative trait loci (QTL) associated with this trait. We found these strain differences to be resistant to developmental cross-fostering and associated with anatomical variation in basolateral amygdala (BLA) perineuronal ...


Human Nk Cell Development In Hil-7 And Hil-15 Knockin Nod/Scid/Il2rgko Mice., Masashi Matsuda, Rintaro Ono, Tomonori Iyoda, Takaho Endo, Makoto Iwasaki, Mariko Tomizawa-Murasawa, Yoriko Saito, Akiko Kaneko, Kanako Shimizu, Daisuke Yamada, Narumi Ogonuki, Takashi Watanabe, Manabu Nakayama, Yoko Koseki, Fuyuko Kezuka-Shiotani, Takanori Hasegawa, Hiromasa Yabe, Shunichi Kato, Atsuo Ogura, Leonard D. Shultz, Osamu Ohara, Masaru Taniguchi, Haruhiko Koseki, Shin-Ichiro Fujii, Fumihiko Ishikawa Apr 2019

Human Nk Cell Development In Hil-7 And Hil-15 Knockin Nod/Scid/Il2rgko Mice., Masashi Matsuda, Rintaro Ono, Tomonori Iyoda, Takaho Endo, Makoto Iwasaki, Mariko Tomizawa-Murasawa, Yoriko Saito, Akiko Kaneko, Kanako Shimizu, Daisuke Yamada, Narumi Ogonuki, Takashi Watanabe, Manabu Nakayama, Yoko Koseki, Fuyuko Kezuka-Shiotani, Takanori Hasegawa, Hiromasa Yabe, Shunichi Kato, Atsuo Ogura, Leonard D. Shultz, Osamu Ohara, Masaru Taniguchi, Haruhiko Koseki, Shin-Ichiro Fujii, Fumihiko Ishikawa

Faculty Research 2019

The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies ...


Robust Mouse Tracking In Complex Environments Using Neural Networks., Brian Q Geuther, Sean P Deats, Kai J Fox, Stephen A Murray, Robert E Braun, Jacqueline K White, Elissa J Chesler, Cathleen Lutz, Vivek Kumar Mar 2019

Robust Mouse Tracking In Complex Environments Using Neural Networks., Brian Q Geuther, Sean P Deats, Kai J Fox, Stephen A Murray, Robert E Braun, Jacqueline K White, Elissa J Chesler, Cathleen Lutz, Vivek Kumar

Faculty Research 2019

The ability to track animals accurately is critical for behavioral experiments. For video-based assays, this is often accomplished by manipulating environmental conditions to increase contrast between the animal and the background in order to achieve proper foreground/background detection (segmentation). Modifying environmental conditions for experimental scalability opposes ethological relevance. The biobehavioral research community needs methods to monitor behaviors over long periods of time, under dynamic environmental conditions, and in animals that are genetically and behaviorally heterogeneous. To address this need, we applied a state-of-the-art neural network-based tracker for single mice. We compare three different neural network architectures across visually diverse ...


Identification Of A Functional Non-Coding Variant In The Gaba, Megan K Mulligan, Timothy Abreo, Sarah M Neuner, Cory Parks, Christine E Watkins, M Trevor Houseal, Thomas M Shapaker, Michael Hook, Haiyan Tan, Xusheng Wang, Jesse Ingels, Junmin Peng, Lu Lu, Catherine Kaczorowski, Camron D Bryant, Gregg E Homanics, Robert W Williams Mar 2019

Identification Of A Functional Non-Coding Variant In The Gaba, Megan K Mulligan, Timothy Abreo, Sarah M Neuner, Cory Parks, Christine E Watkins, M Trevor Houseal, Thomas M Shapaker, Michael Hook, Haiyan Tan, Xusheng Wang, Jesse Ingels, Junmin Peng, Lu Lu, Catherine Kaczorowski, Camron D Bryant, Gregg E Homanics, Robert W Williams

Faculty Research 2019

GABA type-A (GABA-A) receptors containing the α2 subunit (GABRA2) are expressed in most brain regions and are critical in modulating inhibitory synaptic function. Genetic variation at the GABRA2 locus has been implicated in epilepsy, affective and psychiatric disorders, alcoholism and drug abuse. Gabra2 expression varies as a function of genotype and is modulated by sequence variants in several brain structures and populations, including F2 crosses originating from C57BL/6J (B6J) and the BXD recombinant inbred family derived from B6J and DBA/2J. Here we demonstrate a global reduction of GABRA2 brain protein and mRNA in the B6J strain relative to ...


Factors That Influence Response Classifications In Chemotherapy Treated Patient-Derived Xenografts (Pdx)., Joan Malcolm, Timothy M Stearns, Susan Airhart, Joel H. Graber, Carol J Bult Mar 2019

Factors That Influence Response Classifications In Chemotherapy Treated Patient-Derived Xenografts (Pdx)., Joan Malcolm, Timothy M Stearns, Susan Airhart, Joel H. Graber, Carol J Bult

Faculty Research 2019

In this study, we investigated the impact of initial tumor volume, rate of tumor growth, cohort size, study duration, and data analysis method on chemotherapy treatment response classifications in patient-derived xenografts (PDXs). The analyses were conducted on cisplatin treatment response data for 70 PDX models representing ten cancer types with up to 28-day study duration and cohort sizes of 3-10 tumor-bearing mice. The results demonstrated that a 21-day dosing study using a cohort size of eight was necessary to reliably detect responsive models (i.e., tumor volume ratio of treated animals to control between 0.1 and 0.42)-independent ...


Genomic Inversions And Golga Core Duplicons Underlie Disease Instability At The 15q25 Locus., Flavia A M Maggiolini, Stuart Cantsilieris, Pietro D'Addabbo, Michele Manganelli, Bradley P Coe, Beth L Dumont, Ashley D Sanders, Andy Wing Chun Pang, Mitchell R Vollger, Orazio Palumbo, Pietro Palumbo, Maria Accadia, Massimo Carella, Evan E Eichler, Francesca Antonacci Mar 2019

Genomic Inversions And Golga Core Duplicons Underlie Disease Instability At The 15q25 Locus., Flavia A M Maggiolini, Stuart Cantsilieris, Pietro D'Addabbo, Michele Manganelli, Bradley P Coe, Beth L Dumont, Ashley D Sanders, Andy Wing Chun Pang, Mitchell R Vollger, Orazio Palumbo, Pietro Palumbo, Maria Accadia, Massimo Carella, Evan E Eichler, Francesca Antonacci

Faculty Research 2019

Human chromosome 15q25 is involved in several disease-associated structural rearrangements, including microdeletions and chromosomal markers with inverted duplications. Using comparative fluorescence in situ hybridization, strand-sequencing, single-molecule, real-time sequencing and Bionano optical mapping analyses, we investigated the organization of the 15q25 region in human and nonhuman primates. We found that two independent inversions occurred in this region after the fission event that gave rise to phylogenetic chromosomes XIV and XV in humans and great apes. One of these inversions is still polymorphic in the human population today and may confer differential susceptibility to 15q25 microdeletions and inverted duplications. The inversion breakpoints ...


Toward Regeneration Of The Heart: Bioengineering Strategies For Immunomodulation., Arianna Ferrini, Molly M Stevens, Susanne Sattler, Nadia Rosenthal Mar 2019

Toward Regeneration Of The Heart: Bioengineering Strategies For Immunomodulation., Arianna Ferrini, Molly M Stevens, Susanne Sattler, Nadia Rosenthal

Faculty Research 2019

Myocardial Infarction (MI) is the most common cardiovascular disease. An average-sized MI causes the loss of up to 1 billion cardiomyocytes and the adult heart lacks the capacity to replace them. Although post-MI treatment has dramatically improved survival rates over the last few decades, more than 20% of patients affected by MI will subsequently develop heart failure (HF), an incurable condition where the contracting myocardium is transformed into an akinetic, fibrotic scar, unable to meet the body's need for blood supply. Excessive inflammation and persistent immune auto-reactivity have been suggested to contribute to post-MI tissue damage and exacerbate HF ...


Combined Congenic Mapping And Nuclease-Based Gene Targeting For Studying Allele-Specific Effects Of Tnfrsf9 Within The Idd9.3 Autoimmune Diabetes Locus., Matthew H Forsberg, Bardees Foda, David V. Serreze, Yi-Guang Chen Mar 2019

Combined Congenic Mapping And Nuclease-Based Gene Targeting For Studying Allele-Specific Effects Of Tnfrsf9 Within The Idd9.3 Autoimmune Diabetes Locus., Matthew H Forsberg, Bardees Foda, David V. Serreze, Yi-Guang Chen

Faculty Research 2019

Rodent complex trait genetic studies involving a cross between two inbred strains are usually followed by congenic mapping to refine the loci responsible for the phenotype. However, progressing from a chromosomal region to the actual causal gene remains challenging because multiple polymorphic genes are often closely linked. The goal of this study was to develop a strategy that allows candidate gene testing by allele-specific expression without prior knowledge of the credible causal variant. Tnfrsf9 (encoding CD137) is a candidate gene for the Idd9.3 type 1 diabetes (T1D) susceptibility locus in the nonobese diabetic (NOD) mouse model. A C57BL/10Sn ...


Quantitative Evaluation Of Ontology Design Patterns For Combining Pathology And Anatomy Ontologies., Sarah M Alghamdi, Beth A. Sundberg, John P Sundberg, Paul N Schofield, Robert Hoehndorf Mar 2019

Quantitative Evaluation Of Ontology Design Patterns For Combining Pathology And Anatomy Ontologies., Sarah M Alghamdi, Beth A. Sundberg, John P Sundberg, Paul N Schofield, Robert Hoehndorf

Faculty Research 2019

Data are increasingly annotated with multiple ontologies to capture rich information about the features of the subject under investigation. Analysis may be performed over each ontology separately, but recently there has been a move to combine multiple ontologies to provide more powerful analytical possibilities. However, it is often not clear how to combine ontologies or how to assess or evaluate the potential design patterns available. Here we use a large and well-characterized dataset of anatomic pathology descriptions from a major study of aging mice. We show how different design patterns based on the MPATH and MA ontologies provide orthogonal axes ...


Cardiac Phenotype In Mouse Models Of Systemic Autoimmunity., Chandan Sanghera, Lok Man Wong, Mona Panahi, Amalia Sintou, Muneer G. Hasham, Susanne Sattler Mar 2019

Cardiac Phenotype In Mouse Models Of Systemic Autoimmunity., Chandan Sanghera, Lok Man Wong, Mona Panahi, Amalia Sintou, Muneer G. Hasham, Susanne Sattler

Faculty Research 2019

Patients suffering from systemic autoimmune diseases are at significant risk of cardiovascular complications. This can be due to systemically increased levels of inflammation leading to accelerated atherosclerosis, or due to direct damage to the tissues and cells of the heart. Cardiac complications include an increased risk of myocardial infarction, myocarditis and dilated cardiomyopathy, valve disease, endothelial dysfunction, excessive fibrosis, and bona fide autoimmune-mediated tissue damage by autoantibodies or auto-reactive cells. There is, however, still a considerable need to better understand how to diagnose and treat cardiac complications in autoimmune patients. A range of inducible and spontaneous mouse models of systemic ...


Variable Outcomes Of Human Heart Attack Recapitulated In Genetically Diverse Mice., Ekaterina Salimova, Kristen J Nowak, Ana C Estrada, Milena B Furtado, Elyshia Mcnamara, Quang Nguyen, Lois Balmer, Christoph Preuss, Jeffrey W Holmes, Mirana Ramialison, Grant Morahan, Nadia Rosenthal Mar 2019

Variable Outcomes Of Human Heart Attack Recapitulated In Genetically Diverse Mice., Ekaterina Salimova, Kristen J Nowak, Ana C Estrada, Milena B Furtado, Elyshia Mcnamara, Quang Nguyen, Lois Balmer, Christoph Preuss, Jeffrey W Holmes, Mirana Ramialison, Grant Morahan, Nadia Rosenthal

Faculty Research 2019

Clinical variation in patient responses to myocardial infarction (MI) has been difficult to model in laboratory animals. To assess the genetic basis of variation in outcomes after heart attack, we characterized responses to acute MI in the Collaborative Cross (CC), a multi-parental panel of genetically diverse mouse strains. Striking differences in post-MI functional, morphological, and myocardial scar features were detected across 32 CC founder and recombinant inbred strains. Transcriptomic analyses revealed a plausible link between increased intrinsic cardiac oxidative phosphorylation levels and MI-induced heart failure. The emergence of significant quantitative trait loci for several post-MI traits indicates that utilizing CC ...


Systems Genetics Of Sensation Seeking., Price E. Dickson, Tyler A Roy, Kathryn A. Mcnaughton, Troy Wilcox, Padam Kumar, Elissa J Chesler Mar 2019

Systems Genetics Of Sensation Seeking., Price E. Dickson, Tyler A Roy, Kathryn A. Mcnaughton, Troy Wilcox, Padam Kumar, Elissa J Chesler

Faculty Research 2019

Sensation seeking is a multifaceted, heritable trait which predicts the development of substance use and abuse in humans; similar phenomena have been observed in rodents. Genetic correlations among sensation seeking and substance use indicate shared biological mechanisms, but the genes and networks underlying these relationships remain elusive. Here, we used a systems genetics approach in the BXD recombinant inbred mouse panel to identify shared genetic mechanisms underlying substance use and preference for sensory stimuli, an intermediate phenotype of sensation seeking. Using the operant sensation seeking (OSS) paradigm, we quantified preference for sensory stimuli in 120 male and 127 female mice ...


Recommended Housing Densities For Research Mice: Filling The Gap In Data-Driven Alternatives., Karen L. Svenson, Beverly J Paigen Mar 2019

Recommended Housing Densities For Research Mice: Filling The Gap In Data-Driven Alternatives., Karen L. Svenson, Beverly J Paigen

Faculty Research 2019

Space recommendations for mice made in the Guide for Care and Use of Laboratory Animals have not changed since 1972, despite important improvements in husbandry and caging practices. The 1996 version of the Guide put forth a challenge to investigators to produce new data evaluating the effects of space allocation on the well-being of mice. In this review, we summarize many studies published in response to this challenge. We distinguish between studies using ventilated or nonventilated caging systems and those evaluating reproductive performance or general well-being of adult mice. We discuss how these studies might affect current housing density considerations ...


Co-Activation Of Macrophages And T Cells Contribute To Chronic Gvhd In Human Il-6 Transgenic Humanised Mouse Model., Rintaro Ono, Takashi Watanabe, Eiryo Kawakami, Makoto Iwasaki, Mariko Tomizawa-Murasawa, Masashi Matsuda, Yuho Najima, Shinsuke Takagi, Saera Fujiki, Rumi Sato, Yoshiki Mochizuki, Hisahiro Yoshida, Kaoru Sato, Hiromasa Yabe, Shunichi Kato, Yoriko Saito, Shuichi Taniguchi, Leonard D. Shultz, Osamu Ohara, Masayuki Amagai, Haruhiko Koseki, Fumihiko Ishikawa Mar 2019

Co-Activation Of Macrophages And T Cells Contribute To Chronic Gvhd In Human Il-6 Transgenic Humanised Mouse Model., Rintaro Ono, Takashi Watanabe, Eiryo Kawakami, Makoto Iwasaki, Mariko Tomizawa-Murasawa, Masashi Matsuda, Yuho Najima, Shinsuke Takagi, Saera Fujiki, Rumi Sato, Yoshiki Mochizuki, Hisahiro Yoshida, Kaoru Sato, Hiromasa Yabe, Shunichi Kato, Yoriko Saito, Shuichi Taniguchi, Leonard D. Shultz, Osamu Ohara, Masayuki Amagai, Haruhiko Koseki, Fumihiko Ishikawa

Faculty Research 2019

BACKGROUND: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence.

METHODS: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34

FINDINGS: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of ...


Update On The Human And Mouse Lipocalin (Lcn) Gene Family, Including Evidence The Mouse Mup Cluster Is Result Of An "Evolutionary Bloom"., Georgia Charkoftaki, Yewei Wang, Monica Mcandrews, Elspeth A Bruford, David C Thompson, Vasilis Vasiliou, Daniel W Nebert Feb 2019

Update On The Human And Mouse Lipocalin (Lcn) Gene Family, Including Evidence The Mouse Mup Cluster Is Result Of An "Evolutionary Bloom"., Georgia Charkoftaki, Yewei Wang, Monica Mcandrews, Elspeth A Bruford, David C Thompson, Vasilis Vasiliou, Daniel W Nebert

Faculty Research 2019

Lipocalins (LCNs) are members of a family of evolutionarily conserved genes present in all kingdoms of life. There are 19 LCN-like genes in the human genome, and 45 Lcn-like genes in the mouse genome, which include 22 major urinary protein (Mup) genes. The Mup genes, plus 29 of 30 Mup-ps pseudogenes, are all located together on chromosome (Chr) 4; evidence points to an "evolutionary bloom" that resulted in this Mup cluster in mouse, syntenic to the human Chr 9q32 locus at which a single MUPP pseudogene is located. LCNs play important roles in physiological processes by binding and transporting small ...


A Large Crispr-Induced Bystander Mutation Causes Immune Dysregulation., Dimitre R Simeonov, Alexander J Brandt, Alice Y Chan, Jessica T Cortez, Zhongmei Li, Jonathan M Woo, Youjin Lee, Claudia M B Carvalho, Alyssa C Indart, Theodore L Roth, James Zou, Andrew P May, James R Lupski, Mark S Anderson, F William Buaas, Daniel S Rokhsar, Alexander Marson Feb 2019

A Large Crispr-Induced Bystander Mutation Causes Immune Dysregulation., Dimitre R Simeonov, Alexander J Brandt, Alice Y Chan, Jessica T Cortez, Zhongmei Li, Jonathan M Woo, Youjin Lee, Claudia M B Carvalho, Alyssa C Indart, Theodore L Roth, James Zou, Andrew P May, James R Lupski, Mark S Anderson, F William Buaas, Daniel S Rokhsar, Alexander Marson

Faculty Research 2019

A persistent concern with CRISPR-Cas9 gene editing has been the potential to generate mutations at off-target genomic sites. While CRISPR-engineering mice to delete a ~360 bp intronic enhancer, here we discovered a founder line that had marked immune dysregulation caused by a 24 kb tandem duplication of the sequence adjacent to the on-target deletion. Our results suggest unintended repair of on-target genomic cuts can cause pathogenic "bystander" mutations that escape detection by routine targeted genotyping assays.


Identification Of Pre-Symptomatic Gene Signatures That Predict Resilience To Cognitive Decline In The Genetically Diverse Ad-Bxd Model., Sarah M Neuner, Sarah E Heuer, Ji-Gang Zhang, Vivek M. Philip, Catherine Kaczorowski Feb 2019

Identification Of Pre-Symptomatic Gene Signatures That Predict Resilience To Cognitive Decline In The Genetically Diverse Ad-Bxd Model., Sarah M Neuner, Sarah E Heuer, Ji-Gang Zhang, Vivek M. Philip, Catherine Kaczorowski

Faculty Research 2019

Across the population, individuals exhibit a wide variation of susceptibility or resilience to developing Alzheimer's disease (AD). Identifying specific factors that promote resilience would provide insight into disease mechanisms and nominate potential targets for therapeutic intervention. Here, we use transcriptome profiling to identify gene networks present in the pre-symptomatic AD mouse brain relating to neuroinflammation, brain vasculature, extracellular matrix organization, and synaptic signaling that predict cognitive performance at an advanced age. We highlight putative drivers of these observed relationships, including


Towards Large Scale Automated Cage Monitoring - Diurnal Rhythm And Impact Of Interventions On In-Cage Activity Of C57bl/6j Mice Recorded 24/7 With A Non-Disrupting Capacitive-Based Technique., Karin Pernold, F Iannello, Benjamin E. Low, M Rigamonti, G Rosati, F Scavizzi, J Wang, M Raspa, Michael V. Wiles, B Ulfhake Feb 2019

Towards Large Scale Automated Cage Monitoring - Diurnal Rhythm And Impact Of Interventions On In-Cage Activity Of C57bl/6j Mice Recorded 24/7 With A Non-Disrupting Capacitive-Based Technique., Karin Pernold, F Iannello, Benjamin E. Low, M Rigamonti, G Rosati, F Scavizzi, J Wang, M Raspa, Michael V. Wiles, B Ulfhake

Faculty Research 2019

BACKGROUND AND AIMS: Automated recording of laboratory animal's home cage behavior is receiving increasing attention since such non-intruding surveillance will aid in the unbiased understanding of animal cage behavior potentially improving animal experimental reproducibility.

MATERIAL AND METHODS: Here we investigate activity of group held female C57BL/6J mice (mus musculus) housed in standard Individually Ventilated Cages across three test-sites: Consiglio Nazionale delle Ricerche (CNR, Rome, Italy), The Jackson Laboratory (JAX, Bar Harbor, USA) and Karolinska Insititutet (KI, Stockholm, Sweden). Additionally, comparison of female and male C57BL/6J mice was done at KI. Activity was recorded using a capacitive-based sensor ...


Knockdown Of Heterochromatin Protein 1 Binding Protein 3 Recapitulates Phenotypic, Cellular, And Molecular Features Of Aging., Sarah M Neuner, Shengyuan Ding, Catherine C Kaczorowski Feb 2019

Knockdown Of Heterochromatin Protein 1 Binding Protein 3 Recapitulates Phenotypic, Cellular, And Molecular Features Of Aging., Sarah M Neuner, Shengyuan Ding, Catherine C Kaczorowski

Faculty Research 2019

Identifying genetic factors that modify an individual's susceptibility to cognitive decline in aging is critical to understanding biological processes involved and mitigating risk associated with a number of age-related disorders. Recently, heterochromatin protein 1 binding protein 3 (Hp1bp3) was identified as a mediator of cognitive aging. Here, we provide a mechanistic explanation for these findings and show that targeted knockdown of Hp1bp3 in the hippocampus by 50%-75% is sufficient to induce cognitive deficits and transcriptional changes reminiscent of those observed in aging and Alzheimer's disease brains. Specifically, neuroinflammatory-related pathways become activated following Hp1bp3 knockdown in combination with ...


Metformin Intervention Prevents Cardiac Dysfunction In A Murine Model Of Adult Congenital Heart Disease., Julia C Wilmanns, Raghav Pandey, Olivia Hon, Anjana Chandran, Jan M Schilling, Elvira Forte, Qizhu Wu, Gael Cagnone, Preeti Bais, Vivek M. Philip, David Coleman, Heidi Kocalis, Stuart K Archer, James T Pearson, Mirana Ramialison, Joerg Heineke, Hemal H Patel, Nadia Rosenthal, Milena B Furtado, Mauro W Costa Feb 2019

Metformin Intervention Prevents Cardiac Dysfunction In A Murine Model Of Adult Congenital Heart Disease., Julia C Wilmanns, Raghav Pandey, Olivia Hon, Anjana Chandran, Jan M Schilling, Elvira Forte, Qizhu Wu, Gael Cagnone, Preeti Bais, Vivek M. Philip, David Coleman, Heidi Kocalis, Stuart K Archer, James T Pearson, Mirana Ramialison, Joerg Heineke, Hemal H Patel, Nadia Rosenthal, Milena B Furtado, Mauro W Costa

Faculty Research 2019

OBJECTIVE: Congenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown.

METHODS: We used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention ...


Genome Assembly And Gene Expression In The American Black Bear Provides New Insights Into The Renal Response To Hibernation., Anuj Srivastava, Vishal Kumar Sarsani, Ian Fiddes, Susan Sheehan, Rita L Seger, Mary Barter, Selena Neptune-Bear, Charlotte Lindqvist, Ron Korstanje Feb 2019

Genome Assembly And Gene Expression In The American Black Bear Provides New Insights Into The Renal Response To Hibernation., Anuj Srivastava, Vishal Kumar Sarsani, Ian Fiddes, Susan Sheehan, Rita L Seger, Mary Barter, Selena Neptune-Bear, Charlotte Lindqvist, Ron Korstanje

Faculty Research 2019

The prevalence of chronic kidney disease (CKD) is rising worldwide and 10-15% of the global population currently suffers from CKD and its complications. Given the increasing prevalence of CKD there is an urgent need to find novel treatment options. The American black bear (Ursus americanus) copes with months of lowered kidney function and metabolism during hibernation without the devastating effects on metabolism and other consequences observed in humans. In a biomimetic approach to better understand kidney adaptations and physiology in hibernating black bears, we established a high-quality genome assembly. Subsequent RNA-Seq analysis of kidneys comparing gene expression profiles in black ...


Enhancing The Efficacy Of Glycolytic Blockade In Cancer Cells Via Rad51 Inhibition., John J Wilson, Kin-Hoe Chow, Nathan J Labrie, Jane Branca, Thomas J. Sproule, Bryant R A Perkins, Elise E Wolf, Mauro W Costa, Grace Stafford, Christine Rosales, Kevin D Mills, Derry C. Roopenian, Muneer G. Hasham Feb 2019

Enhancing The Efficacy Of Glycolytic Blockade In Cancer Cells Via Rad51 Inhibition., John J Wilson, Kin-Hoe Chow, Nathan J Labrie, Jane Branca, Thomas J. Sproule, Bryant R A Perkins, Elise E Wolf, Mauro W Costa, Grace Stafford, Christine Rosales, Kevin D Mills, Derry C. Roopenian, Muneer G. Hasham

Faculty Research 2019

Targeting the early steps of the glycolysis pathway in cancers is a well-established therapeutic strategy; however, the doses required to elicit a therapeutic effect on the cancer can be toxic to the patient. Consequently, numerous preclinical and clinical studies have combined glycolytic blockade with other therapies. However, most of these other therapies do not specifically target cancer cells, and thus adversely affect normal tissue. Here we first show that a diverse number of cancer models - spontaneous, patient-derived xenografted tumor samples, and xenografted human cancer cells - can be efficiently targeted by 2-deoxy-D-Glucose (2DG), a well-known glycolytic inhibitor. Next, we tested the ...


Ccne1 Amplification Is Associated With Poor Prognosis In Patients With Triple Negative Breast Cancer., Zi-Ming Zhao, Susan E Yost, Katherine E Hutchinson, Sierra Min Li, Yate-Ching Yuan, Javad Noorbakhsh, Zheng Liu, Charles Warden, Radia M Johnson, Xiwei Wu, Jeffrey H Chuang, Yuan Yuan Jan 2019

Ccne1 Amplification Is Associated With Poor Prognosis In Patients With Triple Negative Breast Cancer., Zi-Ming Zhao, Susan E Yost, Katherine E Hutchinson, Sierra Min Li, Yate-Ching Yuan, Javad Noorbakhsh, Zheng Liu, Charles Warden, Radia M Johnson, Xiwei Wu, Jeffrey H Chuang, Yuan Yuan

Faculty Research 2019

BACKGROUND: Triple negative breast cancer (TNBC) is aggressive with limited treatment options upon recurrence. Molecular discordance between primary and metastatic TNBC has been observed, but the degree of biological heterogeneity has not been fully explored. Furthermore, genomic evolution through treatment is poorly understood. In this study, we aim to characterize the genomic changes between paired primary and metastatic TNBCs through transcriptomic and genomic profiling, and to identify genomic alterations which may contribute to chemotherapy resistance.

METHODS: Genomic alterations and mRNA expression of 10 paired primary and metastatic TNBCs were determined through targeted sequencing, microarray analysis, and RNA sequencing. Commonly mutated ...


The Gene Ontology Resource: 20 Years And Still Going Strong., Gene Ontology Consortium Jan 2019

The Gene Ontology Resource: 20 Years And Still Going Strong., Gene Ontology Consortium

Faculty Research 2019

The Gene Ontology resource (GO; http://geneontology.org) provides structured, computable knowledge regarding the functions of genes and gene products. Founded in 1998, GO has become widely adopted in the life sciences, and its contents are under continual improvement, both in quantity and in quality. Here, we report the major developments of the GO resource during the past two years. Each monthly release of the GO resource is now packaged and given a unique identifier (DOI), enabling GO-based analyses on a specific release to be reproduced in the future. The molecular function ontology has been refactored to better represent the ...


Expansion Of The Human Phenotype Ontology (Hpo) Knowledge Base And Resources., Sebastian Köhler, Leigh Carmody, Nicole Vasilevsky, Julius O B Jacobsen, Daniel Danis, Jean-Philippe Gourdine, Michael Gargano, Nomi L Harris, Nicolas Matentzoglu, Julie A Mcmurry, David Osumi-Sutherland, Valentina Cipriani, James P Balhoff, Tom Conlin, Hannah Blau, Gareth Baynam, Richard Palmer, Dylan Gratian, Hugh Dawkins, Michael Segal, Anna C Jansen, Ahmed Muaz, Willie H Chang, Jenna Bergerson, Stanley J F Laulederkind, Zafer Yüksel, Sergi Beltran, Alexandra F Freeman, Panagiotis I Sergouniotis, Daniel Durkin, Andrea L Storm, Marc Hanauer, Michael Brudno, Susan M. Bello, Murat Sincan, Kayli Rageth, Matthew T Wheeler, Renske Oegema, Halima Lourghi, Maria G Della Rocca, Rachel Thompson, Francisco Castellanos, James Priest, Charlotte Cunningham-Rundles, Ayushi Hegde, Ruth C Lovering, Catherine Hajek, Annie Olry, Luigi Notarangelo, Morgan Similuk, Xingmin A Zhang, David Gómez-Andrés, Hanns Lochmüller, Hélène Dollfus, Sergio Rosenzweig, Shruti Marwaha, Ana Rath, Kathleen Sullivan, Cynthia Smith, Joshua D Milner, Dorothée Leroux, Cornelius F Boerkoel, Amy Klion, Melody C Carter, Tudor Groza, Damian Smedley, Melissa A Haendel, Chris Mungall, Peter N Robinson Jan 2019

Expansion Of The Human Phenotype Ontology (Hpo) Knowledge Base And Resources., Sebastian Köhler, Leigh Carmody, Nicole Vasilevsky, Julius O B Jacobsen, Daniel Danis, Jean-Philippe Gourdine, Michael Gargano, Nomi L Harris, Nicolas Matentzoglu, Julie A Mcmurry, David Osumi-Sutherland, Valentina Cipriani, James P Balhoff, Tom Conlin, Hannah Blau, Gareth Baynam, Richard Palmer, Dylan Gratian, Hugh Dawkins, Michael Segal, Anna C Jansen, Ahmed Muaz, Willie H Chang, Jenna Bergerson, Stanley J F Laulederkind, Zafer Yüksel, Sergi Beltran, Alexandra F Freeman, Panagiotis I Sergouniotis, Daniel Durkin, Andrea L Storm, Marc Hanauer, Michael Brudno, Susan M. Bello, Murat Sincan, Kayli Rageth, Matthew T Wheeler, Renske Oegema, Halima Lourghi, Maria G Della Rocca, Rachel Thompson, Francisco Castellanos, James Priest, Charlotte Cunningham-Rundles, Ayushi Hegde, Ruth C Lovering, Catherine Hajek, Annie Olry, Luigi Notarangelo, Morgan Similuk, Xingmin A Zhang, David Gómez-Andrés, Hanns Lochmüller, Hélène Dollfus, Sergio Rosenzweig, Shruti Marwaha, Ana Rath, Kathleen Sullivan, Cynthia Smith, Joshua D Milner, Dorothée Leroux, Cornelius F Boerkoel, Amy Klion, Melody C Carter, Tudor Groza, Damian Smedley, Melissa A Haendel, Chris Mungall, Peter N Robinson

Faculty Research 2019

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data ...


Pdx Finder: A Portal For Patient-Derived Tumor Xenograft Model Discovery., Nathalie Conte, Jeremy C Mason, Csaba Halmagyi, Steven Neuhauser, Abayomi Mosaku, Galabina Yordanova, Aikaterini Chatzipli, Dale A. Begley, Debra M Krupke, Helen Parkinson, Terrence F Meehan, Carol J Bult Jan 2019

Pdx Finder: A Portal For Patient-Derived Tumor Xenograft Model Discovery., Nathalie Conte, Jeremy C Mason, Csaba Halmagyi, Steven Neuhauser, Abayomi Mosaku, Galabina Yordanova, Aikaterini Chatzipli, Dale A. Begley, Debra M Krupke, Helen Parkinson, Terrence F Meehan, Carol J Bult

Faculty Research 2019

Patient-derived tumor xenograft (PDX) mouse models are a versatile oncology research platform for studying tumor biology and for testing chemotherapeutic approaches tailored to genomic characteristics of individual patients' tumors. PDX models are generated and distributed by a diverse group of academic labs, multi-institution consortia and contract research organizations. The distributed nature of PDX repositories and the use of different metadata standards for describing model characteristics presents a significant challenge to identifying PDX models relevant to specific cancer research questions. The Jackson Laboratory and EMBL-EBI are addressing these challenges by co-developing PDX Finder, a comprehensive open global catalog of PDX models ...


The Mouse Gene Expression Database (Gxd): 2019 Update., Constance M. Smith, Terry F. Hayamizu, Jacqueline H. Finger, Susan M. Bello, Ingeborg J. Mccright, Jingxia Xu, Richard M. Baldarelli, Jonathan S Beal, Jeffrey Campbell, Lori E. Corbani, Pete J. Frost, Jill R Lewis, Sharon C Giannatto, Dave Miers, David R. Shaw, James A. Kadin, Joel E Richardson, Cynthia Smith, Martin Ringwald Jan 2019

The Mouse Gene Expression Database (Gxd): 2019 Update., Constance M. Smith, Terry F. Hayamizu, Jacqueline H. Finger, Susan M. Bello, Ingeborg J. Mccright, Jingxia Xu, Richard M. Baldarelli, Jonathan S Beal, Jeffrey Campbell, Lori E. Corbani, Pete J. Frost, Jill R Lewis, Sharon C Giannatto, Dave Miers, David R. Shaw, James A. Kadin, Joel E Richardson, Cynthia Smith, Martin Ringwald

Faculty Research 2019

The mouse Gene Expression Database (GXD) is an extensive, well-curated community resource freely available at www.informatics.jax.org/expression.shtml. Covering all developmental stages, GXD includes data from RNA in situ hybridization, immunohistochemistry, RT-PCR, northern blot and western blot experiments in wild-type and mutant mice. GXD's gene expression information is integrated with the other data in Mouse Genome Informatics and interconnected with other databases, placing these data in the larger biological and biomedical context. Since the last report, the ability of GXD to provide insights into the molecular mechanisms of development and disease has been greatly enhanced by ...