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Disease Models & Mechanisms

Maria R Replogle, Virinchipuram S Sreevidya, Vivian M Lee, Michael D Laiosa, Kurt R Svoboda, Ava J Udvadia
The neural crest (NC) is a transient population of embryonic progenitors that are implicated in a diverse range of congenital birth defects and pediatric syndromes. The broad spectrum of NC-related disorders can be attributed to the wide variety of differentiated cell types arising from the NC. In vitro models of NC development provide a powerful platform for testing the relative contributions of intrinsic and extrinsic factors mediating NC differentiation under normal and pathogenic conditions. Although differentiation is a dynamic process that unfolds over time, currently, there is no well-defined chronology that characterizes the in vitro progression of NC differentiation towards specific cell fates...
November 8, 2018: Disease Models & Mechanisms
Jennifer E Hewitt, Amelia K Pollard, Leila Lesanpezeshki, Colleen S Deane, Christopher J Gaffney, Timothy Etheridge, Nathaniel J Szewczyk, Siva A Vanapalli
Muscle strength is a key clinical parameter used to monitor the progression of human muscular dystrophies including Duchenne and Becker muscular dystrophies. Although Caenorhabditis elegans is an established genetic model for studying mechanisms and treatments of muscular dystrophies, analogous strength-based measurements in this disease model are lacking. Here we describe the first demonstration of the direct measurement of muscular strength in dystrophin-deficient C. elegans mutants using a micropillar-based force measurement system called NemaFlex...
November 5, 2018: Disease Models & Mechanisms
Denver D Britto, Barbara Wyroba, Wenxuan Chen, Rhoswen A Lockwood, Khanh B Tran, Peter R Shepherd, Chris J Hall, Kathryn E Crosier, Philip S Crosier, Jonathan W Astin
Tumour angiogenesis has long been a focus of anti-cancer therapy, however, anti-angiogenic cancer treatment strategies have had limited clinical success. Tumour-associated myeloid cells are believed to play a role in the resistance of cancer towards anti-angiogenesis therapy, but the mechanisms by which they do this are unclear. A zebrafish embryonic xenograft model has been developed to investigate the mechanisms of tumour angiogenesis and as an assay to screen anti-angiogenic compounds. In this study, we used cell ablation techniques to remove either macrophages or neutrophils and assessed their contribution towards zebrafish xenograft angiogenesis by quantitating levels of graft vascularisation...
November 5, 2018: Disease Models & Mechanisms
Chana Yagil, Ronen Varadi-Levi, Yoram Yagil
The mechanisms underlying diabetes remain unresolved. The Cohen Diabetic rat represents a model of diet-induced diabetes in which the disease is induced after exposure to a diabetogenic diet (DD) in the diabetes sensitive (CDs/y) but not in the resistant (CDr/y) strain. Diet imposes a metabolic strain that leads to diabetes in the appropriate genetic background. We previously identified through whole genome linkage analysis a diabetes-related QTL on RNO4 which incorporates NADH dehydrogenase (ubiquinone) 1 alpha sub-complex 4 ( Ndufa4 ), a nuclear gene that affects mitochondrial function...
October 25, 2018: Disease Models & Mechanisms
Troy A McDiarmid, Vinci Au, Aaron D Loewen, Joseph Liang, Kota Mizumoto, Donald G Moerman, Catharine H Rankin
Our ability to sequence genomes has vastly surpassed our ability to interpret the genetic variation we discover. This presents a major challenge in the clinical setting, where the recent application of whole exome and whole genome sequencing has uncovered thousands of genetic variants of uncertain significance. Here, we present a strategy for targeted human gene replacement and phenomic characterization based on CRISPR-Cas9 genome engineering in the genetic model organism Caenorhabditis elegans that will facilitate assessment of the functional conservation of human genes and structure-function analysis of disease-associated variants with unprecedented precision...
October 25, 2018: Disease Models & Mechanisms
Henrika Jodeleit, Omar Al-Amodi, Janina Caesar, Christina Villarroel Aguilera, Lesca Holdt, Roswitha Gropp, Florian Beigel, Matthias Siebeck
Glucose is the preferred source of energy in activated inflammatory cells. Glucose uptake into the cell is ensured by a family of glucose uptake transporters (GLUT) which have been identified as off target molecules of the HIV protease inhibitor ritonavir. In this study, we examined the effect of ritonavir on inflammation in vitro and in vivo Peripheral blood mononuclear cells (PBMC) were activated with anti CD3 in the presence or absence of ritonavir and analyzed by flow cytometric analysis. Frequencies of CD4+ cells were significantly affected by ritonavir (CD69+ p=3E-05; CD134 p=4E-06; CD25+ p= E-07; central memory p=0...
October 15, 2018: Disease Models & Mechanisms
Zachary R Stromberg, Angelica Van Goor, Graham A J Redweik, Meghan J Wymore Brand, Michael J Wannemuehler, Melha Mellata
Most Escherichia coli strains in the human intestine are harmless. However, enterohemorrhagic E coli (EHEC) is a foodborne pathogen that causes intestinal disease in humans. Conventionally-reared (CONV) mice are inconsistent models for human infections with EHEC because they are often resistant to E coli colonization in part due to their gastrointestinal (GI) microbiota. Although antibiotic manipulation of the mouse microbiota has been a common means to overcome colonization resistance, these models have limitations...
September 28, 2018: Disease Models & Mechanisms
Alexander T Young, Kien N Ly, Callum Wilson, Klaus Lehnert, Russell G Snell, Suzanne J Reid, Jessie C Jacobsen
Brain dopamine-serotonin vesicular transport disease is a rare disease caused by autosomal recessive mutations in the SLC18A2 gene, which encodes the VMAT2 protein. VMAT2 is a membrane protein responsible for vesicular transport of monoamines, and its disruption negatively affects neurotransmission. This results in a severe neurodevelopmental disorder affecting motor skills, development, and causes muscular hypotonia. The condition was initially described in a consanguineous Saudi Arabian family with affected siblings homozygous for a P387L mutation...
September 28, 2018: Disease Models & Mechanisms
Kevin K L Lee, Emma Peskett, Charlotte M Quinn, Rosanna Aiello, Liliya Adeeva, Dale A Moulding, Philip Stanier, Erwin Pauws
FGFR2c regulates many aspects of craniofacial and skeletal development. Mutations in the FGFR2 gene are causative for multiple forms of syndromic craniosynostosis, including Crouzon syndrome. Paradoxically, mouse studies have shown that both the activation ( Fgfr2c C342Y ; a mouse model for human Crouzon syndrome), as well as the removal ( Fgfr2c null ) of the FGFR2c isoform can drive suture abolishment. This study aims to address the downstream effects of pathogenic FGFR2c signalling by studying the effects of Fgfr2c overexpression...
September 28, 2018: Disease Models & Mechanisms
Margarita Parada-Kusz, Cristina Penaranda, Elliott J Hagedorn, Anne Clatworthy, Anil V Nair, Jonathan E Henninger, Christoph Ernst, Brian Li, Raquel Riquelme, Humberto Jijon, Eduardo J Villablanca, Leonard I Zon, Deborah Hung, Miguel L Allende
Xenografts of the hematopoietic system are extremely useful as disease models and for translational research. Zebrafish xenografts have been widely used to monitor blood cancer cell dissemination and homing due to the optical clarity of embryos and larvae, which allow unrestricted in vivo visualization of migratory events. Here, we have developed a xenotransplantation technique that transiently generates hundreds of hematopoietic tissue chimeric embryos by transplanting murine bone marrow cells into zebrafish blastulae...
September 28, 2018: Disease Models & Mechanisms
Clémentine Le Magnen, Renu K Virk, Aditya Dutta, Jaime Yeji Kim, Sukanya Panja, Zoila A Lopez-Bujanda, Andrea Califano, Charles G Drake, Antonina Mitrofanova, Cory Abate-Shen
While it is known that inflammation plays a critical role in prostate tumorigenesis, the underlying processes are not well understood. Based on analysis of genetically-engineered mouse models combined with correlative analysis of expression profiling data from human prostate tumors, we demonstrate a reciprocal relationship between inflammation and the status of the NKX3.1 homeobox gene associated with prostate cancer initiation. We find that cancer initiation in aged Nkx3.1 mutant mice correlates with enrichment of specific immune populations and increased expression of immunoregulatory genes...
September 28, 2018: Disease Models & Mechanisms
Nicolas Floc'h, Maria Luisa Guerriero, Antonio Ramos-Montoya, Barry R Davies, Jonathan Cairns, Natasha A Karp
The high attrition rate of preclinical agents entering oncology clinical trials has been associated with poor understanding of the heterogeneous patient response arising from limitations in the pre-clinical pipeline with cancer models. PDX models have been shown to better recapitulate the patient drug response. However, the platform of evidence generated to support clinical development in a drug discovery project typically employs a limited number of models, which may not accurately predict the response at a population level...
September 25, 2018: Disease Models & Mechanisms
S J Tunster, M Van de Pette, H D J Creeth, L Lefebvre, R M John
Beckwith-Wiedemann syndrome (BWS) is a complex imprinting disorder involving fetal overgrowth and placentomegaly and associated with a variety of genetic and epigenetic mutations affecting expression of imprinted genes on human chromosome 11p15.5. Most BWS cases are linked to loss of methylation at the Imprint Control Region 2 (ICR2) within this domain, which in mice regulates the silencing of several maternally expressed imprinted genes. Modelling this disorder in mice is confounded by the unique embryonic requirement for Ascl2 which is imprinted in mice but not humans...
August 29, 2018: Disease Models & Mechanisms
Paulina M Strzelecka, Anna M Ranzoni, Ana Cvejic
Probing cellular population diversity at single-cell resolution became possible only in recent years. The popularity of single-cell 'omic' approaches, which allow researchers to dissect sample heterogeneity and cell-to-cell variation, continues to grow. With continuous technological improvements, single-cell omics are becoming increasingly prevalent and contribute to the discovery of new and rare cell types, and to the deciphering of disease pathogenesis and outcome. Animal models of human diseases have significantly facilitated our understanding of the mechanisms driving pathologies and resulted in the development of more efficient therapies...
November 5, 2018: Disease Models & Mechanisms
Masanori Takahashi, Masaru Tamura, Shigeru Sato, Kiyoshi Kawakami
Omphalocele is a human congenital anomaly in ventral body wall closure and may be caused by impaired formation of the primary abdominal wall (PAW) and/or defects in abdominal muscle development. Here, we report that mice doubly deficient in homeobox genes Six4 and Six5 showed the same ventral body wall closure defects as those seen in human omphalocele. SIX4 and SIX5 were localized in surface ectodermal cells and somatic mesoderm-derived mesenchymal and coelomic epithelial cells (CECs) in the PAW. Six4-/- ;Six5-/- fetuses exhibited a large omphalocele with protrusion of both the liver and intestine, or a small omphalocele with protrusion of the intestine, with complete penetrance...
October 25, 2018: Disease Models & Mechanisms
Rachel Hackett, O Claire Moulton
No abstract text is available yet for this article.
October 24, 2018: Disease Models & Mechanisms
Sergey V Prykhozhij, Jason N Berman
The zebrafish is an increasingly popular model organism for human genetic disease research. CRISPR/Cas9-based approaches are currently used for multiple gene-editing purposes in zebrafish, but few studies have developed reliable ways to introduce precise mutations. Point mutation knock-in using CRISPR/Cas9 and single-stranded oligodeoxynucleotides (ssODNs) is currently the most promising technology for this purpose. Despite some progress in applying this technique to zebrafish, there is still a great need for improvements in terms of its efficiency, optimal design of sgRNA and ssODNs and broader applicability...
October 24, 2018: Disease Models & Mechanisms
Olga S Blomberg, Lorenzo Spagnuolo, Karin E de Visser
Metastatic disease is the leading cause of death in cancer patients. Metastasis formation involves a cascade of events for which the underlying mechanisms are still poorly understood. During the metastatic cascade, cancer cells tightly interact with the immune system and they influence each other, both in the tumor microenvironment and systemically. The crosstalk between cancer and immune cells adds another layer of complexity to our understanding of metastasis formation, but at the same time opens new therapeutic opportunities for cancer patients...
October 24, 2018: Disease Models & Mechanisms
Georgina Askeland, Marie Rodinova, Hana Štufková, Zaneta Dosoudilova, Monika Baxa, Petra Smatlikova, Bozena Bohuslavova, Jiri Klempir, The Duong Nguyen, Anna Kuśnierczyk, Magnar Bjørås, Arne Klungland, Hana Hansikova, Zdenka Ellederova, Lars Eide
Huntington's disease (HD) is a monogenic, progressive, neurodegenerative disorder with currently no available treatment. The Libechov transgenic minipig model for HD (TgHD) displays neuroanatomical similarities to humans and exhibits slow disease progression, and is therefore more powerful than available mouse models for the development of therapy. The phenotypic characterization of this model is still ongoing, and it is essential to validate biomarkers to monitor disease progression and intervention. In this study, the behavioral phenotype (cognitive, motor and behavior) of the TgHD model was assessed, along with biomarkers for mitochondrial capacity, oxidative stress, DNA integrity and DNA repair at different ages (24, 36 and 48 months), and compared with age-matched controls...
October 24, 2018: Disease Models & Mechanisms
Zaid Tanvir, Ralph F Nelson, Kathleen DeCicco-Skinner, Victoria P Connaughton
Prolonged hyperglycemia can alter retinal function, ultimately resulting in blindness. Adult zebrafish adults exposed to alternating conditions of 2% glucose/0% glucose display a 3× increase in blood sugar levels. After 4 weeks of treatment, electroretinograms (ERGs) were recorded from isolated, perfused, in vitro eyecups. Control animals were exposed to alternating 2% mannitol/0% mannitol (osmotic control) or to alternating water (0% glucose/0% glucose; handling control). Two types of ERGs were recorded: (1) native ERGs measured using white-light stimuli and medium without synaptic blockers; and (2) spectral ERGs measured with an AMPA/kainate receptor antagonist, isolating photoreceptor-to-ON-bipolar-cell synapses, and a spectral protocol that separated red (R), green (G), blue (B) and UV cone signals...
October 22, 2018: Disease Models & Mechanisms
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