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Inducible expression of human C9ORF72 36x G4C2 hexanucleotide repeats is sufficient to cause RAN translation and rapid muscular atrophy in mice. Dis. Model Mech. (IF 4.651) Pub Date : 2021-01-11 F W Riemslagh; E C van der Toorn; R F M Verhagen; A Maas; L W J Bosman; R K Hukema; R Willemsen
The hexanucleotide G4C2 repeat expansion in the first intron of the C9ORF72 gene explains the majority of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) cases. Numerous studies have indicated the toxicity of dipeptide repeats (DPRs) which are produced via repeat-associated non-AUG (RAN) translation from the repeat expansion and accumulate in the brain of C9FTD/ALS patients. Mouse
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Neural crest-specific deletion of Bmp7 leads to midfacial hypoplasia, nasal airway obstruction, and disordered breathing modelling Obstructive Sleep Apnea. Dis. Model Mech. (IF 4.651) Pub Date : 2021-01-11 Pranidhi Baddam; Vivian Biancardi; Daniela M Roth; Farah Eaton; Claudine Thereza-Bussolaro; Rupasri Mandal; David S Wishart; Amy Barr; Joanna MacLean; Carlos Flores-Mir; Silvia Pagliardini; Daniel Graf
Pediatric obstructive sleep apnea (OSA), a relatively common sleep-related breathing disorder (SRBD) affecting approximately 1-5% of children, is often caused by anatomical obstruction and/or collapse of the nasal and/or pharyngeal airways. The resulting sleep disruption and intermittent hypoxia lead to various systemic morbidities. Predicting the development of OSA from craniofacial features alone
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Of numbers and movement - understanding transcription factor pathogenesis by advanced microscopy. Dis. Model Mech. (IF 4.651) Pub Date : 2020-12-29 Julia M T Auer; Jack J Stoddart; Ioannis Christodoulou; Ana Lima; Kassiani Skouloudaki; Hildegard N Hall; Vladana Vukojević; Dimitrios K Papadopoulos
Transcription factors (TFs) are life-sustaining and, therefore, the subject of intensive research. By regulating gene expression, TFs control a plethora of developmental and physiological processes, and their abnormal function commonly leads to various developmental defects and diseases in humans. Normal TF function often depends on gene dosage, which can be altered by copy-number variation or loss-of-function
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A muscle growth promoting treatment based on the attenuation of activin/myostatin signalling in young mice results in long-term testicular abnormalities. Dis. Model Mech. (IF 4.651) Pub Date : 2021-01-06 Danielle Vaughan; Robert Mitchell; Oliver Kretz; David Chambers; Maciej Lalowski; Helge Amthor; Olli Ritvos; Arja Pasternack; Antonios Matsakas; Sakthivel Vaiyapuri; Tobias B Huber; Bernd Denecke; Abir Mukherjee; Darius Widera; Ketan Patel
Activin/Myostatin signalling acts to induce skeletal muscle atrophy in adult mammals by inhibiting protein synthesis as well as promoting protein and organelle turnover. Numerous strategies have been successfully developed to attenuate the signalling properties of these molecules which result in augmenting muscle growth. However, these molecules, in particular Activin, play major roles in tissue homeostasis
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TDP-43 mislocalization drives neurofilament changes in a novel model of TDP-43 proteinopathy. Dis. Model Mech. (IF 4.651) Pub Date : 2021-01-06 Rachel Atkinson; Jacqueline Leung; James Bender; Matthew Kirkcaldie; James Vickers; Anna King
Mislocalization of the TAR DNA-binding protein 43 (TDP-43) from the nucleus to the cytoplasm is a common feature of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The downstream in vivo cellular effects of this mislocalization are not well understood. To investigate the impact of mislocalized TDP-43 on neuronal cell bodies, axons
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Mistargeting of secretory cargo in retromer-deficient cells. Dis. Model Mech. (IF 4.651) Pub Date : 2020-12-29 Sarah D Neuman; Erica L Terry; Jane E Selegue; Amy T Cavanagh; Arash Bashirullah
Intracellular trafficking is a basic and essential cellular function required for delivery of proteins to the appropriate subcellular destination; this process is especially demanding in professional secretory cells, which synthesize and secrete massive quantities of cargo proteins via regulated exocytosis. The Drosophila larval salivary glands are professional secretory cells that synthesize and secrete
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Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease. Dis. Model Mech. (IF 4.651) Pub Date : 2020-12-21 Masafumi Noguchi; Kana T Furukawa; Mitsuru Morimoto
Mammalian lungs have the ability to recognize external environments by sensing different compounds in inhaled air. Pulmonary neuroendocrine cells (PNECs) are rare, multi-functional epithelial cells currently garnering attention as intrapulmonary sensors; PNECs can detect hypoxic conditions through chemoreception. Because PNEC overactivation has been reported in patients suffering from respiratory diseases
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L-type voltage-gated calcium channel agonists mitigate hearing loss and modify ribbon synapse morphology in the zebrafish model of Usher syndrome type 1. Dis. Model Mech. (IF 4.651) Pub Date : 2020-11-27 Alaa Koleilat; Joseph A Dugdale; Trace A Christenson; Jeffrey L Bellah; Aaron M Lambert; Mark A Masino; Stephen C Ekker; Lisa A Schimmenti
The mariner (myo7aa-/- ) mutant is a zebrafish model for Usher syndrome type 1 (USH1). To further characterize hair cell synaptic elements in myo7aa-/- mutants, we focused on the ribbon synapse and evaluated ultrastructure, number and distribution of immunolabeled ribbons, and postsynaptic densities. By transmission electron microscopy, we determined that myo7aa-/- zebrafish have fewer glutamatergic
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Restoration of motor learning in a mouse model of Rett syndrome following long-term treatment with a novel small-molecule activator of TrkB. Dis. Model Mech. (IF 4.651) Pub Date : 2020-11-27 Ian Adams; Tao Yang; Frank M Longo; David M Katz
Reduced expression of brain-derived neurotrophic factor (BDNF) and impaired activation of the BDNF receptor, tropomyosin receptor kinase B (TrkB; also known as Ntrk2), are thought to contribute significantly to the pathophysiology of Rett syndrome (RTT), a severe neurodevelopmental disorder caused by loss-of-function mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Previous
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Mouse models of myocardial infarction: comparing permanent ligation and ischaemia-reperfusion. Dis. Model Mech. (IF 4.651) Pub Date : 2020-11-18 Carla De Villiers; Paul R Riley
Myocardial infarction (MI) is a disease of major consequence in the modern world, causing permanent, irreversible damage to the heart. Survivors are at risk for developing further cardiovascular pathologies such as heart failure. Further study of MI injury is crucial to improve the understanding and treatment of the post-MI heart. The most commonly used model for MI in vivo is surgical ligation of
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RET inhibition in novel patient-derived models of RET-fusion positive lung adenocarcinoma reveals a role for MYC upregulation. Dis. Model Mech. (IF 4.651) Pub Date : 2020-12-14 Takuo Hayashi; Igor Odintsov; Roger S Smith; Kota Ishizawa; Allan J W Liu; Lukas Delasos; Christopher Kurzatkowski; Huichun Tai; Eric Gladstone; Morana Vojnic; Shinji Kohsaka; Ken Suzawa; Zebing Liu; Siddharth Kunte; Marissa S Mattar; Inna Khodos; Monika A Davare; Alexander Drilon; Emily Cheng; Elisa de Stanchina; Marc Ladanyi; Romel Somwar
Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of
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Hearing impairment due to Mir183/96/182 mutations suggests both loss and gain of function effects. Dis. Model Mech. (IF 4.651) Pub Date : 2020-12-14 Morag A Lewis; Francesca Di Domenico; Neil J Ingham; Haydn M Prosser; Karen P Steel
The microRNA miR-96 is important for hearing, as point mutations in humans and mice result in dominant progressive hearing loss. Mir96 is expressed in sensory cells along with Mir182 and Mir183, but the roles of these closely-linked microRNAs are as yet unknown. Here we analyse mice carrying null alleles of Mir182, and of Mir183 and Mir96 together to investigate their roles in hearing. We found that
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Head to head study of oxelumab and adalimumab in a mouse model of ulcerative colitis based on NOD/Scid IL-2Rγnull mice reconstituted with peripheral blood mononuclear cells. Dis. Model Mech. (IF 4.651) Pub Date : 2020-12-08 Henrika Jodeleit; Paula Winkelmann; Janina Caesar; Sebastian Sterz; Lesca M Holdt; Florian Beigel; Johannes Stallhofer; Simone Breiteneicher; Eckart Bartnik; Thomas Leeuw; Matthias Siebeck; Roswitha Gropp
The goal of this study was to demonstrate that the combination of patient immune profiling and testing in a humanized mouse model of ulcerative colitis (UC) may lead to patient stratification for treatment with oxelumab. First, immunological profiles of UC patients and non-UC donors were analyzed for CD4+ T cells expressing OX40 (CD134) and CD14+ monocytes expressing OX40L (CD252) by flow cytometric
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Regulation of copper homeostasis by members of the COMMD protein family. Dis. Model Mech. (IF 4.651) Pub Date : 2020-12-01 Amika Singla; Qing Chen; Kohei Suzuki; Jie Song; Alina Fedoseienko; Melinde Wijers; Adam Lopez; Daniel D Billadeau; Bart van de Sluis; Ezra Burstein
Copper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominatly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be actively recycled between the endosomal network and the plasma membrane by a molecular machinery known as
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Sensory neuron cultures derived from adult db/db mice as a simplified model to study type-2 diabetes-associated axonal regeneration defects. Dis. Model Mech. (IF 4.651) Pub Date : 2020-12-01 Cristian De Gregorio; Fernando Ezquer
Diabetic neuropathy (DN) is an early, common complication of diabetes mellitus (DM) leading to chronic pain, sensory loss and muscle atrophy. Due to its multifactorial etiology, neuron in vitro cultures have been proposed as simplified systems for DN studies. However, the most used models currently available do not recreate the chronic and systemic damage suffered by peripheral neurons of type-2 DM
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Interpreting the pathogenicity of Joubert Syndrome missense variants in Caenorhabditis elegans. Dis. Model Mech. (IF 4.651) Pub Date : 2020-11-24 Karen I Lange; Sofia Tsiropoulou; Katarzyna Kucharska; Oliver E Blacque
Ciliopathies are inherited disorders caused by defects in motile and non-motile (primary) cilia. Ciliopathy syndromes and associated gene variants are often highly pleiotropic and represent exemplars for interrogating genotype-phenotype correlations. Towards understanding disease mechanisms in the context of ciliopathy mutations, we have employed a leading model organism for cilia and ciliopathy research
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Impaired muscle morphology in a Drosophila model of myosin storage myopathy was supressed by overexpression of an E3 ubiquitin ligase. Dis. Model Mech. (IF 4.651) Pub Date : 2020-11-24 Martin Dahl-Halvarsson; Montse Olive; Malgorzata Pokrzywa; Michaela Norum; Katarina Ejeskär; Homa Tajsharghi
Myosin is vital for body movement and heart contractility. Mutations in MYH7, encoding slow/ß-cardiac myosin heavy chain, are an important cause of hypertrophic and dilated cardiomyopathy, as well as skeletal muscle disease. A dominant missense mutation (R1845W) in MYH7 has been reported in several unrelated cases with myosin storage myopathy. We have developed a Drosophila model for a myosin storage
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Duchenne muscular dystrophy (DMD) cardiomyocyte-secreted exosomes promote the pathogenesis of DMD-associated cardiomyopathy. Dis. Model Mech. (IF 4.651) Pub Date : 2020-11-13 Melanie Gartz; Chien-Wei Lin; Mark A Sussman; Michael W Lawlor; Jennifer L Strande
Cardiomyopathy is a leading cause of early mortality in Duchenne muscular dystrophy (DMD). There is a need to gain a better understanding of the molecular pathogenesis for the development effective therapies. Exosomes (exo) are secreted vesicles and exert effects via their RNA, lipid and protein cargo. The role of exosomes in disease pathology is unknown. Exosomes derived from stem cells have demonstrated
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Chronic administration of P2X7 receptor antagonist JNJ-47965567 delays disease onset and progression, and improves motor performance in ALS SOD1G93A female mice. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-30 Cristina Ruiz-Ruiz; Nuria García-Magro; Pilar Negredo; Carlos Avendaño; Anindya Bhattacharya; Marc Ceusters; Antonio G García
Neuroinflammation is one of the main physiopathological mechanisms of amyotrophic lateral sclerosis (ALS), produced by the chronic activation of microglia in the CNS. This process is triggered by the persistent activation of the ATP-gated P2X7 receptor (P2RX7, hereafter referred to as P2X7R). The present study aimed to evaluate the effects of the chronic treatment with the P2X7R antagonist JNJ-47965567
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Cellular and animal models for facioscapulohumeral muscular dystrophy. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-28 Alec M DeSimone; Justin Cohen; Monkol Lek; Angela Lek
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy and presents with weakness of the facial, scapular and humeral muscles, which frequently progresses to the lower limbs and truncal areas, causing profound disability. Myopathy results from epigenetic de-repression of the D4Z4 microsatellite repeat array on chromosome 4, which allows misexpression of
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3D quantification of changes in pancreatic islets in mouse models of diabetes type I and II. Dis. Model Mech. (IF 4.651) Pub Date : 2020-11-06 Urmas Roostalu; Jacob Lercke Skytte; Casper Gravesen Salinas; Thomas Klein; Niels Vrang; Jacob Jelsing; Jacob Hecksher-Sørensen
Diabetes is characterized by rising levels in blood glucose and is often associated with a progressive loss of insulin producing beta cells. Recent studies have demonstrated that it is possible to regenerate new beta cells through proliferation of existing beta cells or trans-differentiation of other cell types into beta cells, raising hope that diabetes can be cured through restoration of functional
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Deletion of Yy1 in mouse lung epithelium unveils molecular mechanisms governing pleuropulmonary blastoma pathogenesis. Dis. Model Mech. (IF 4.651) Pub Date : 2020-11-06 Kim Landry-Truchon; Nicolas Houde; Mickaël Lhuillier; Louis Charron; Alice Hadchouel; Christophe Delacourt; William D Foulkes; Louise Galmiche-Rolland; Lucie Jeannotte
Pleuropulmonary blastoma (PPB) is a very rare pediatric lung disease. It can progress from abnormal epithelial cysts to an aggressive sarcoma with poor survival. PPB diagnosis is difficult as it can be confounded with other cystic lung disorders like congenital pulmonary airway malformations (CPAM). PPB is associated with mutations in DICER1 that perturb the microRNA (miRNA) profile in lung. How DICER1
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Modeling neurodegeneration in Caenorhabditiselegans. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-26 Kim A Caldwell; Corey W Willicott; Guy A Caldwell
The global burden of neurodegenerative diseases underscores the urgent need for innovative strategies to define new drug targets and disease-modifying factors. The nematode Caenorhabditis elegans has served as the experimental subject for multiple transformative discoveries that have redefined our understanding of biology for ∼60 years. More recently, the considerable attributes of C. elegans have
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Myh6-driven Cre-recombinase activates the DNA damage response and the cell-cycle in the myocardium in the absence of loxP sites. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-08 Xinrui Wang; Amelia Lauth; Tina C Wan; John W Lough; John A Auchampach
Regeneration of muscle in the damaged myocardium is a major objective of cardiovascular research, for which purpose many investigators utilize mice containing transgenes encoding Cre-recombinase to recombine loxP-flanked target genes. An unfortunate side-effect of the Cre-loxP model is the propensity of Cre-recombinase to inflict off-target DNA damage, which has been documented in various eukaryotic
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Modulating the ER stress response attenuates neurodegeneration in a C. elegans model of spinal muscular atrophy. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-08 James J Doyle; Celine Vrancx; Claudia Maios; Audrey Labarre; Shunmoogum A Patten; J Alex Parker
Spinal muscular atrophy is (SMA) is a devastating, autosomal recessive neuromuscular disease resulting in muscle atrophy, neurodegeneration, and is the leading genetic cause of infant death. SMA arises when there are homozygous deletion mutations in the human SMN1 gene, leading to a decrease in corresponding SMN1 protein. Although SMN1 is expressed across multiple tissue types, much of the previous
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Predicting experimental success: A retrospective case-control study using the rat intraluminal thread model of stroke. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-22 Lisa Liebenstund; Mark Coburn; Christina Fitzner; Antje Willuweit; Karl-Josef Langen; Jingjin Liu; Michael Veldeman; Anke Höllig
The poor translational success rate of preclinical stroke research may partly be due to inaccurate modelling of the disease. We provide data on transient middle cerebral artery occlusion (tMCAO) experiments including detailed intraoperative monitoring to elaborate predictors indicating experimental success (ischemia without occurrence of confounding pathologies).The tMCAO monitoring data (bilateral
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Heterogeneity in clone dynamics within and adjacent to intestinal tumours identified by Dre-mediated lineage tracing. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-22 Ann-Sofie Thorsen; Doran Khamis; Richard Kemp; Mathilde Colombé; Filipe C Lourenço; Edward Morrissey; Douglas Winton
Somatic models of tissue pathology commonly utilise induction of gene specific mutations in mice mediated by spatiotemporal regulation of Cre recombinase. Subsequent investigation of the onset and development of disease can be limited by the inability to track changing cellular behaviours over time. Here a lineage tracing approach based on ligand dependent activation of Dre recombinase that can be
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CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-12 S Schuster; E Heuten; A Velic; J Admard; M Synofzik; S Ossowski; B Macek; S Hauser; L Schöls
C-terminus of HSC70-interacting protein (CHIP) encoded by the gene STUB1 is a co-chaperone and E3 ligase that acts as a key regulator of cellular protein homeostasis. Mutations in STUB1 cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16) with widespread neurodegeneration manifesting as spastic-ataxic gait disorder, dementia and epilepsy. CHIP-/- mice display severe cerebellar atrophy
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Alcoholic hepatitis and metabolic disturbance in female mice : a more tractable model than Nrf2-/- animals. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-16 Lozan Sheriff; Reenam S Khan; Raquel Saborano; Richard Wilkin; Nguyet-Thin Luu; Ulrich L Gunther; Stefan G Hubscher; Philip N Newsome; Patricia F Lalor
Alcoholic hepatitis (AH) is the dramatic acute presentation of alcoholic liver disease, with a 28-day mortality of 15% in severe cases. Research into AH has been hampered by the lack of effective and reproducible murine models that can be operated under different regulatory frameworks internationally. The liquid Lieber-deCarli (LdC) diet has been used as a means of ad libitum delivery of alcohol, but
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Identification of MYOM2 as a candidate gene in hypertrophic cardiomyopathy and tetralogy of fallot and its functional evaluation in the Drosophila heart. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-08 Emilie Auxerre-Plantié; Tanja Nielsen; Marcel Grunert; Olga Olejniczak; Andreas Perrot; Cemil Özcelik; Dennis Harries; Faramarz Matinmehr; Cristobal Dos Remedios; Christian Mühlfeld; Theresia Kraft; Rolf Bodmer; Georg Vogler; Silke R Sperling
The causal genetic underpinnings of congenital heart diseases, which are often complex and with multigenic background, are still far from understood. Moreover, there are also predominantly monogenic heart defects, such as cardiomyopathies, with known disease genes for the majority of cases. In this study, we identified mutations in myomesin 2 (MYOM2) in patients with Tetralogy of Fallot (TOF), the
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Akkermansia muciniphila promotes type H vessels formation and bone fracture healing by reducing gut permeability and inflammation. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-08 Jiang-Hua Liu; Tao Yue; Zhong-Wei Luo; Jia Cao; Zi-Qi Yan; Ling Jin; Teng-Fei Wan; Ci-Jun Shuai; Zheng-Guang Wang; Yong Zhou; Ran Xu; Hui Xie
Improving revascularization is one of the major measures in fracture treatment. Moderate local inflammation triggers angiogenesis, whereas systemic inflammation hampers angiogenesis. Previous studies showed that Akkermansia muciniphila (A. muc), a gut probiotic, ameliorates systemic inflammation by tightening intestinal barrier. In this study, fractured mice intragastrically administrated with A. muc
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Imbalanced cellular metabolism compromises cartilage homeostasis and joint function in a mouse model of mucolipidosis type III gamma. Dis. Model Mech. (IF 4.651) Pub Date : 2020-10-06 Lena M Westermann; Lutz Fleischhauer; Jonas Vogel; Zsuzsa Jenei-Lanzl; Nataniel Floriano Ludwig; Lynn Schau; Fabio Morellini; Anke Baranowsky; Timur A Yorgan; Giorgia Di Lorenzo; Michaela Schweizer; Bruna de Souza Pinheiro; Nicole Ruas Guarany; Fernanda Sperb-Ludwig; Fernanda Visioli; Thiago Oliveira Silva; Jamie Soul; Gretl Hendrickx; J Simon Wiegert; Ida V D Schwartz; Hauke Clausen-Schaumann; Frank
Mucolipidosis type III (MLIII) gamma is a rare inherited lysosomal storage disorder caused by mutations in GNPTG encoding the γ-subunit of GlcNAc-1-phosphotransferase, the key enzyme ensuring proper intracellular location of multiple lysosomal enzymes. Patients with MLIII gamma typically present with osteoarthritis and joint stiffness, suggesting cartilage involvement. Using Gnptg ko mice as a model
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Cells expressing PAX8 are the main source of homeostatic regeneration of adult endometrial epithelium and give rise to serous endometrial carcinoma. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-30 Dah-Jiun Fu; Andrea J De Micheli; Mallikarjun Bidarimath; Lora H Ellenson; Benjamin D Cosgrove; Andrea Flesken-Nikitin; Alexander Yu Nikitin
Humans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells. However, their location and hierarchy remain debatable. A number of recent studies have suggested the presence of stem cells in the mouse endometrial epithelium. At the same time, it has been reported this tissue can be regenerated by stem cells of stromal/mesenchymal
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Differential physiological role of BIN1 isoforms in skeletal muscle development, function and regeneration. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-29 Ivana Prokic; Belinda S Cowling; Candice Kutchukian; Christine Kretz; Hichem Tasfaout; Vincent Gache; Josiane Hergueux; Olivia Wendling; Arnaud Ferry; Anne Toussaint; Christos Gavriilidis; Vasugi Nattarayan; Catherine Koch; Jeanne Lainé; Roy Combe; Laurent Tiret; Vincent Jacquemond; Fanny Pilot-Storck; Jocelyn Laporte
Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here we focus on the cellular and physiological roles of amphiphysin 2 (BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies (CNM), that is ubiquitously expressed and has skeletal muscle-specific
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Progenitor death drives retinal dysplasia and neuronal degeneration in a mouse model of Atrip-Seckel syndrome. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-15 Gabriel E Matos-Rodrigues; Pedro B Tan; Maurício Rocha-Martins; Clara F Charlier; Anielle L Gomes; Felipe Cabral-Miranda; Paulius Grigaravicius; Thomas G Hofmann; Pierre-Olivier Frappart; Rodrigo A P Martins
Seckel syndrome is a type of microcephalic primordial dwarfism (MPD) that is characterized by growth retardation and neurodevelopmental defects, including reports of retinopathy. Mutations in key mediators of the replication stress response, the mutually dependent partners ATR or ATRIP, are among the known causes of Seckel syndrome. However, it remains unclear how their deficiency disrupts the development
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A novel mouse model of Duchenne muscular dystrophy carrying a multi-exonic Dmd deletion exhibits progressive muscular dystrophy and early-onset cardiomyopathy. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-21 Tatianna Wai Ying Wong; Abdalla Ahmed; Grace Yang; Eleonora Maino; Sydney Steiman; Elzbieta Hyatt; Parry Chan; Kyle Lindsay; Nicole Wong; Diane Golebiowski; Joel Schneider; Paul Delgado-Olguín; Evgueni A Ivakine; Ronald D Cohn
Duchenne muscular dystrophy (DMD) is a life-threatening neuromuscular disease caused by the lack of dystrophin, resulting in progressive muscle wasting and locomotor dysfunctions. By adulthood, almost all patients also develop cardiomyopathy, which is the primary cause of death in DMD. Although there has been extensive effort in creating animal models to study treatment strategies for DMD, most fail
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Fibrodysplasia ossificans progressiva: current concepts from bench to bedside. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-21 Arun-Kumar Kaliya-Perumal; Tom J Carney; Philip W Ingham
Heterotopic ossification (HO) is a disorder characterised by the formation of ectopic bone in soft tissue. Acquired HO typically occurs in response to trauma and is relatively common, yet its aetiology remains poorly understood. Genetic forms, by contrast, are very rare, but provide insights into the mechanisms of HO pathobiology. Fibrodysplasia ossificans progressiva (FOP) is the most debilitating
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Neonatal and infant immunity for tuberculosis vaccine development: importance of age-matched animal models. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-15 Laylaa Ramos; Joan K Lunney; Mercedes Gonzalez-Juarrero
Neonatal and infant immunity differs from that of adults in both the innate and adaptive arms, which are critical contributors to immune-mediated clearance of infection and memory responses elicited during vaccination. The tuberculosis (TB) research community has openly admitted to a vacuum of knowledge about neonatal and infant immune responses to Mycobacterium tuberculosis (Mtb) infection, especially
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A novel hypomorphic allele of Spag17 causes primary ciliary dyskinesia phenotypes in mice. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-08 Zakia Abdelhamed; Marshall Lukacs; Sandra Cindric; Heymut Omran; Rolf W Stottmann
Primary ciliary dyskinesia (PCD) is a human condition of dysfunctional motile cilia characterized by recurrent lung infection, infertility, organ laterality defects, and partially penetrant hydrocephalus. We recovered a mouse mutant from a forward genetic screen that developed many of the hallmark phenotypes of PCD. Whole exome sequencing identified this primary ciliary dyskinesia only (Pcdo) allele
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Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-21 Katie Lloyd,Stamatia Papoutsopoulou,Emily Smith,Philip Stegmaier,Francois Bergey,Lorna Morris,Madeleine Kittner,Hazel England,Dave Spiller,Mike H R White,Carrie A Duckworth,Barry J Campbell,Vladimir Poroikov,Vitor A P Martins Dos Santos,Alexander Kel,Werner Muller,D Mark Pritchard,Chris Probert,Michael D Burkitt,
Objective: Inflammatory bowel diseases cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs which alter NF-κB signalling and may be repositioned for use in inflammatory bowel disease.Design: The SysmedIBD consortium
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Teleological Role of L-2-Hydroxyglutarate Dehydrogenase in the Kidney. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-14 Garrett Brinkley,Hyeyoung Nam,Eunhee Shim,Richard Kirkman,Anirban Kundu,Suman Karki,Yasaman Heidarian,Jason M Tennessen,Juan Liu,Jason W Locasale,Tao Guo,Shi Wei,Jennifer Gordetsky,Teresa L Johnson-Pais,Devin Absher,Dinesh Rakheja,Anil K Challa,Sunil Sudarshan
L-2-hydroxyglutarate (L-2HG) is an oncometabolite found elevated in renal tumors. However, this molecule may have physiologic roles that extend beyond its association with cancer as L-2HG levels are elevated in response to hypoxia and during Drosophila larval development. L-2HG is known to be metabolized by L-2HG dehydrogenase (L2HGDH), and loss of L2HGDH leads to elevated L-2HG levels. Despite being
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Ammonia inhibits energy metabolism in astrocytes in a rapid and glutamate dehydrogenase 2-dependent manner. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-11 Leonie Drews,Marcel Zimmermann,Philipp Westhoff,Dominik Brilhaus,Rebecca E Poss,Laura Bergmann,Constanze Wiek,Peter Brenneisen,Roland P Piekorz,Tabea Mettler-Altmann,Andreas P M Weber,Andreas S Reichert
Astrocyte dysfunction is a primary factor in hepatic encephalopathy (HE) impairing neuronal activity under hyperammonemia. In particular the early events causing ammonia-induced toxicity to astrocytes are not well understood. Using established cellular HE models, we show that mitochondria rapidly undergo fragmentation in a reversible manner upon hyperammonemia. Further, within a timescale of minutes
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An HIV-Tat inducible mouse model system of childhood HIV-associated nephropathy. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-11 Pingtao Tang,Jharna R Das,Jinliang Li,Jing Yu,Patricio E Ray
Background: Modern antiretroviral therapies (ART) have decreased the prevalence of HIV-associated nephropathy (HIVAN). Nonetheless, we continue to see children and adolescents with HIVAN all over the world. Furthermore, once HIVAN is established in children, it is difficult to revert its long-term progression, and we need better animal models of childhood HIVAN to test new treatments.Objectives. To
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Cell and animal models of SARS-CoV-2 pathogenesis and immunity. Dis. Model Mech. (IF 4.651) Pub Date : 2020-09-01 Sarah R Leist,Alexandra Schäfer,David R Martinez
The spread of the novel virus SARS coronavirus 2 (SARS-CoV-2) was explosive, with cases first identified in December 2019, and >22 million people infected and >775,000 deaths as of August 2020. SARS-CoV-2 can cause severe respiratory disease in humans leading to coronavirus disease 2019 (COVID-19). The development of effective clinical interventions, such as antivirals and vaccines that can limit or
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Pathological evaluation of rats carrying in-frame mutations in the dystrophin gene: A new model of Becker muscular dystrophy. Dis. Model Mech. (IF 4.651) Pub Date : 2020-08-28 Naomi Teramoto,Hidetoshi Sugihara,Keitaro Yamanouchi,Katsuyuki Nakamura,Koichi Kimura,Tomoko Okano,Takanori Shiga,Taku Shirakawa,Masafumi Matsuo,Tetsuya Nagata,Masao Daimon,Takashi Matsuwaki,Masugi Nishihara
Dystrophin, encoded by the DMD gene on the X chromosome, stabilizes the sarcolemma by linking the actin cytoskeleton with the dystrophin-glycoprotein complex (DGC). In-frame mutations in DMD cause a milder form of X-linked muscular dystrophy, called Becker muscular dystrophy (BMD), characterized by the reduced expression of truncated dystrophin. So far, no animal model with in-frame mutations in Dmd
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Machine learning discriminates a movement disorder in a zebrafish model of Parkinson's disease. Dis. Model Mech. (IF 4.651) Pub Date : 2020-08-28 G L Hughes,M A Lones,M Bedder,P D Currie,S L Smith,M E Pownall
Animal models of human disease provide an in vivo system that can reveal molecular mechanisms by which mutations cause pathology, and, moreover, have the potential to provide a valuable tool for drug development. Here we have developed a zebrafish model of Parkinson's disease (PD) together with a novel method to screen for movement disorders in adult fish, pioneering a more efficient drug testing route
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The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model. Dis. Model Mech. (IF 4.651) Pub Date : 2020-08-28 Éva Saskői,Zoltán Hujber,Gábor Nyírő,István Likó,Barbara Mátyási,Gábor Petővári,Katalin Mészáros,Attila L Kovács,László Patthy,Shreyas Supekar,Hao Fan,Gergely Sváb,László Tretter,Arunabh Sarkar,Aamir Nazir,Anna Sebestyén,Attila Patócs,Anil Mehta,Krisztina Takács-Vellai
The conserved B-subunit of succinate dehydrogenase (SDH) participates in the TCA cycle and mitochondrial electron transport. The Arg230His mutation in SDHB causes heritable pheochromocytoma/paraganglioma (PPGL). In C. elegans, we generated an in vivo PPGL model (SDHB-1 Arg244His; equivalent to human Arg230His) which manifests delayed development, shortened lifespan, attenuated ATP production and reduced
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Sex-dependent effect of APOE on Alzheimer's disease and other age-related neurodegenerative disorders. Dis. Model Mech. (IF 4.651) Pub Date : 2020-08-27 Julia Gamache,Young Yun,Ornit Chiba-Falek
The importance of apolipoprotein E (APOE) in late-onset Alzheimer's disease (LOAD) has been firmly established, but the mechanisms through which it exerts its pathogenic effects remain elusive. In addition, the sex-dependent effects of APOE on LOAD risk and endophenotypes have yet to be explained. In this Review, we revisit the different aspects of APOE involvement in neurodegeneration and neurological
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Integrating fish models in tuberculosis vaccine development. Dis. Model Mech. (IF 4.651) Pub Date : 2020-08-23 Anni K Saralahti,Meri I E Uusi-Mäkelä,Mirja T Niskanen,Mika Rämet
Tuberculosis is a chronic infection by Mycobacterium tuberculosis that results in over 1.5 million deaths worldwide each year. Currently, there is only one vaccine against tuberculosis, the Bacillus Calmette-Guérin (BCG) vaccine. Despite widespread vaccination programmes, over 10 million new M. tuberculosis infections are diagnosed yearly, with almost half a million cases caused by antibiotic-resistant
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Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish. Dis. Model Mech. (IF 4.651) Pub Date : 2020-08-20 Jelmer Hoeksma,Gerard C M van der Zon,Peter Ten Dijke,Jeroen den Hertog
Zebrafish models are well established tools for investigating underlying mechanisms of diseases. Here, we identified cercosporamide, a metabolite from the fungus Ascochyta aquiliqiae, as a potent bone morphogenetic protein receptor (BMPR) type I kinase inhibitor through a zebrafish embryo phenotypic screen. The developmental defects in zebrafish, including lack of the ventral fin induced by cercosporamide
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Longitudinal neuroanatomical and behavioral analyses show phenotypic drift and variability in the Ts65Dn mouse model of Down syndrome. Dis. Model Mech. (IF 4.651) Pub Date : 2020-08-17 Patricia R Shaw,Jenny A Klein,Nadine M Aziz,Tarik F Haydar
Mouse models of Down syndrome (DS) have been invaluable tools for advancing knowledge of the underlying mechanisms of intellectual disability in people with DS. The Ts(1716)65Dn (Ts65Dn) mouse is one of the most commonly used models as it recapitulates many of the phenotypes seen in individuals with DS, including neuroanatomical changes and impaired learning and memory. In this study, we utilize rigorous
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DMM Outstanding Paper Prize 2019 winner: Alessandro Bailetti. Dis. Model Mech. (IF 4.651) Pub Date : 2020-08-14 Rachel Hackett
Disease Models & Mechanisms (DMM) is delighted to announce (with apologies for the delay) that the winner of the DMM Prize 2019 is Alessandro Bailetti, for his paper entitled 'Enhancer of Polycomb and the Tip60 complex repress hematological tumor initiation by negatively regulating JAK/STAT pathway activity' ( Bailetti et al., 2019). The prize of $1000 is awarded to the first author of the paper that
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Temporal patterning in neural progenitors: from Drosophila development to childhood cancers. Dis. Model Mech. (IF 4.651) Pub Date : 2020-07-22 Cédric Maurange
The developing central nervous system (CNS) is particularly prone to malignant transformation, but the underlying mechanisms remain unresolved. However, periods of tumor susceptibility appear to correlate with windows of increased proliferation, which are often observed during embryonic and fetal stages and reflect stereotypical changes in the proliferative properties of neural progenitors. The temporal
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Neuromuscular disease modeling on a chip. Dis. Model Mech. (IF 4.651) Pub Date : 2020-07-07 Jeffrey W Santoso,Megan L McCain
Organs-on-chips are broadly defined as microfabricated surfaces or devices designed to engineer cells into microscale tissues with native-like features and then extract physiologically relevant readouts at scale. Because they are generally compatible with patient-derived cells, these technologies can address many of the human relevance limitations of animal models. As a result, organs-on-chips have
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A novel pancreatic cancer model originated from transformation of acinar cells in adult tree shrew, a primate-like animal. Dis. Model Mech. (IF 4.651) Pub Date : 2019-04-15 Qiu Tu,Dong Yang,Xianning Zhang,Xintong Jia,Sanqi An,Lanzhen Yan,Hongjuan Dai,Yuhua Ma,Chengwei Tang,Weimin Tong,Zongliu Hou,Longbao Lv,Jing Tan,Xudong Zhao
Pancreatic cancer is one of the most lethal common cancers. The cell of origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial, and recent evidence suggested acinar cells as the most probable candidate. However, the genetic alterations driving the transformation of pancreatic acinar cells in fully mature animals remain to be deciphered. In this study, lentivirus was used as a tool
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Recapitulating Parkinson's disease pathology in a three-dimensional human neural cell culture model. Dis. Model Mech. (IF 4.651) Pub Date : 2019-04-09 Teresa R Taylor-Whiteley,Christine L Le Maitre,James A Duce,Caroline F Dalton,David P Smith
Extensive loss of dopaminergic neurons and aggregation of the protein α-synuclein into ubiquitin-positive Lewy bodies represents a major neuropathological hallmark of Parkinson's disease (PD). At present, the generation of large nuclear-associated Lewy bodies from endogenous wild-type α-synuclein, translationally regulated under its own promoter in human cell culture models, requires costly and time-consuming
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fs(1)h controls metabolic and immune function and enhances survival via AKT and FOXO in Drosophila. Dis. Model Mech. (IF 4.651) Pub Date : 2019-04-04 Jessica Sharrock,Alicia Estacio-Gomez,Jake Jacobson,Katrin Kierdorf,Tony D Southall,Marc S Dionne
The Drosophila fat body is the primary organ of energy storage as well as being responsible for the humoral response to infection. Its physiological function is of critical importance to the survival of the organism; however, many molecular regulators of its function remain ill-defined. Here, we show that the Drosophila melanogaster bromodomain-containing protein FS(1)H is required in the fat body
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One hundred years of Drosophila cancer research: no longer in solitude. Dis. Model Mech. (IF 4.651) Pub Date : 2019-04-01 Santiago Nahuel Villegas
When Mary Stark first described the presence of tumours in the fruit fly Drosophila melanogaster in 1918, would she ever have imagined that flies would become an invaluable organism for modelling and understanding oncogenesis? And if so, would she have expected it to take 100 years for this model to be fully accredited? This Special Article summarises the efforts and achievements of Drosophilists to