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Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a mouse model of Snyder-Robinson Syndrome. Dis. Model Mech. (IF 4.3) Pub Date : 2024-03-11 Oluwaseun Akinyele, Anushe Munir, Marie A Johnson, Megan S Perez, Yuan Gao, Jackson R Foley, Ashley Nwafor, Yijen Wu, Tracy Murray-Stewart, Robert A Casero, Hulya Bayir, Dwi U Kemaladewi
Snyder-Robinson Syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene encoding spermine synthase and aberrant polyamine metabolism. SRS is characterized by intellectual disability, thin habitus, seizure, low muscle tone/hypotonia, and osteoporosis. Progress towards understanding and treating SRS requires a model that recapitulates human mutations and disease presentations
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Key considerations to improve the normalization, interpretation and reproducibility of morbidity data in mammalian models of viral disease. Dis. Model Mech. (IF 4.3) Pub Date : 2024-03-05 Jessica A Belser, Troy J Kieran, Zoë A Mitchell, Xiangjie Sun, Kristin Mayfield, Terrence M Tumpey, Jessica R Spengler, Taronna R Maines
Viral pathogenesis and therapeutic screening studies that utilize small mammalian models rely on the accurate quantification and interpretation of morbidity measurements, such as weight and body temperature, which can vary depending on the model, agent and/or experimental design used. As a result, morbidity-related data are frequently normalized within and across screening studies to aid with their
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Telomere length is an epigenetic trait - Implications for the use of telomerase-deficient organisms to model human disease. Dis. Model Mech. (IF 4.3) Pub Date : 2024-03-05 Catarina M Henriques, Miguel Godinho Ferreira
Telomere length, unlike most genetic traits, is epigenetic, in the sense that it is not fully coded by the genome. Telomeres vary in length and randomly assort to the progeny leaving some individuals with longer and others with shorter telomeres. Telomerase activity counteracts this by extending telomeres in the germline and during embryogenesis but sizeable variances remain in telomere length. This
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Functional and In-silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases. Dis. Model Mech. (IF 4.3) Pub Date : 2024-03-04 Eli Matsell, Jens Peter Andersen, Robert S Molday
P4-ATPases flip lipids from the exoplasmic to cytoplasmic leaflet of cell membranes, a property crucial for many biological processes. Mutations in P4-ATPases are associated with severe inherited and complex human disorders. We have determined the expression, localization, and ATPase activity of four variants in ATP8A2, the P4-ATPase associated with the neurodevelopmental disorder known as cerebellar
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A common cellular response to broad splicing perturbations is characterized by metabolic transcript downregulation driven by the Mdm2-p53 axis. Dis. Model Mech. (IF 4.3) Pub Date : 2024-03-01 Jade E Varineau, Eliezer Calo
Disruptions in core cellular processes elicit stress responses that drive cell-state changes leading to organismal phenotypes. Perturbations in the splicing machinery cause widespread mis-splicing, resulting in p53-dependent cell-state changes that give rise to cell-type-specific phenotypes and disease. However, a unified framework for how cells respond to splicing perturbations, and how this response
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Targeted irradiation in an autochthonous mouse model of pancreatic cancer. Dis. Model Mech. (IF 4.3) Pub Date : 2024-02-29 Mathias Tesson, Katrina Stevenson, Saadia A Karim, Colin Nixon, Anthony J Chalmers, Owen J Sansom, Eric O'Neil, Keaton Jones, Jennifer P Morton
The value of radiotherapy in the treatment of pancreatic cancer has been the subject of much debate but limited preclinical research. We hypothesise that the poor translation of radiation research into clinical trials of radiotherapy in pancreatic cancer is due, in part, to inadequate preclinical study models. Here, we have developed and refined methods for targeted irradiation in autochthonous mouse
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Postnatal Zika virus infection leads to morphological and cellular alterations within the neurogenic niche. Dis. Model Mech. (IF 4.3) Pub Date : 2024-02-28 Jéssica C C G Ferreira, Raissa R Christoff, Tailene Rabello, Raiane O Ferreira, Carolina Batista, Pedro Junior Pinheiro Mourão, Átila D Rossi, Luiza M Higa, Maria Bellio, Amilcar Tanuri, Patricia P Garcez
The Zika virus received significant attention in 2016, following a declaration by the World Health Organization of an epidemic in the Americas, in which infections were associated with microcephaly. Indeed, prenatal Zika virus infection is detrimental to fetal neural stem cells and can cause premature cell loss and neurodevelopmental abnormalities in newborn infants, collectively described as congenital
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Smad4 restricts injury-provoked biliary proliferation and carcinogenesis. Dis. Model Mech. (IF 4.3) Pub Date : 2024-02-28 William B Alexander, Wenjia Wang, Margaret A Hill, Michael R O'Dell, Luis I Ruffolo, Bing Guo, Katherine M Jackson, Nicholas Ullman, Scott C Friedland, Matthew N McCall, Ankit Patel, Nathania Figueroa-Guilliani, Mary Georger, Brian A Belt, Christa L Whitney-Miller, David C Linehan, Patrick J Murphy, Aram F Hezel
Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly
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PTCH1-mutant human cerebellar organoids exhibit altered neural development and recapitulate early medulloblastoma tumorigenesis. Dis. Model Mech. (IF 4.3) Pub Date : 2024-02-27 Max J van Essen, Elizabeth J Apsley, Joey Riepsaame, Ruijie Xu, Paul A Northcott, Sally A Cowley, John Jacob, Esther B E Becker
Patched 1 (PTCH1) is the primary receptor for the sonic hedgehog (SHH) ligand and negatively regulates SHH signalling, an essential pathway in human embryogenesis. Loss-of-function mutations in PTCH1 are associated with altered neuronal development and the malignant brain tumour medulloblastoma. As a result of differences between murine and human development, molecular and cellular perturbations that
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Tracking cell layer contribution during repair of the tympanic membrane. Dis. Model Mech. (IF 4.3) Pub Date : 2024-02-23 Olivia M Dinwoodie, Abigail S Tucker, Juan Fons-Romero
The tympanic membrane (or ear drum) sits at the interface between the middle and external ear. The membrane is composed of three layers: an outer ectodermally-derived layer, a middle neural crest-derived fibroblast layer with contribution from the mesoderm-derived vasculature, and an inner endodermally-derived mucosal layer. These layers form a thin sandwich that is often perforated as a consequence
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The Mexican Biobank Project promotes genetic discovery, inclusive science and local capacity building. Dis. Model Mech. (IF 4.3) Pub Date : 2024-02-01 Mashaal Sohail, Andrés Moreno-Estrada
Diversifying genotype-phenotype databases is essential to understanding complex trait and disease etiology across different environments and genetic ancestries. The rise of biobanks across the world is helping reveal the genetic and environmental architecture of multiple disease traits but the diversity they capture remains limited. To help close this gap, the Mexican Biobank (MXB) Project was recently
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Validity of Xiphophorus fish as models for human disease. Dis. Model Mech. (IF 4.3) Pub Date : 2024-02-01 Manfred Schartl, Yuan Lu
Platyfish and swordtails of the genus Xiphophorus provide a well-established model for melanoma research and have become well known for this feature. Recently, modelling approaches for other human diseases in Xiphophorus have been developed or are emerging. This Review provides a comprehensive summary of these models and discusses how findings from basic biological and molecular studies and their translation
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Establishing mouse and human oral esophageal organoids to investigate the tumor immune response. Dis. Model Mech. (IF 4.3) Pub Date : 2024-01-23 Yuan Jiang, Hua Zhao, Shuai Kong, Dan Zhou, Jinxiu Dong, Yulan Cheng, Shuo Zhang, Fei Wang, Andrew Kalra, Nina Yang, Dan-Dan Wei, Jian Chen, Yuan-Wei Zhang, De-Chen Lin, Stephen J Meltzer, Yan-Yi Jiang
Organoid culture systems are very powerful models that recapitulate in vivo organ development and disease pathogenesis, offering great promise in basic research, drug screening and precision medicine. However, the application of organoids derived from patients with cancer to immunotherapeutic research is a relatively untapped area. Esophageal cancer is one of the most lethal malignancies worldwide
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Histological and functional characterization of 3D human skin models mimicking the inflammatory skin diseases psoriasis and atopic dermatitis. Dis. Model Mech. (IF 4.3) Pub Date : 2024-01-22 Jasmin Scheurer, Birgit Sauer, Jule Focken, Martina Giampetraglia, Annika Jäger, Christian M Schürch, Bettina Weigelin, Birgit Schittek
Three-dimensional (3D) human skin equivalents have emerged as valuable tools in skin research, replacing animal experimentation and precluding the need for patient biopsies. In this study, we advanced 3D skin equivalents to model the inflammatory skin diseases atopic dermatitis and psoriasis by cytokine stimulation, and were successful in integrating TH1 T cells into skin models to develop an immunocompetent
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Kif6 regulates cilia motility and polarity in brain ependymal cells. Dis. Model Mech. (IF 4.3) Pub Date : 2024-01-18 Maki Takagishi, Yang Yue, Ryan S Gray, Kristen J Verhey, John B Wallingford
Motile cilia on ependymal cells lining brain ventricular walls beat in concert to generate laminar cerebrospinal fluid (CSF) flow. Dyneins and kinesins are ATPase microtubule motor proteins that promote the rhythmic beating of cilia axonemes. Despite common consensus about the importance of axonemal dynein motor proteins, little is known about how kinesin motors contribute to cilia motility. Here,
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Standardization of zebrafish drug testing parameters for muscle diseases. Dis. Model Mech. (IF 4.3) Pub Date : 2024-01-18 Muthukumar Karuppasamy, Katherine G English, Clarissa A Henry, M Chiara Manzini, John M Parant, Melissa A Wright, Avnika A Ruparelia, Peter D Currie, Vandana A Gupta, James J Dowling, Lisa Maves, Matthew S Alexander
Skeletal muscular diseases predominantly affect skeletal and cardiac muscle, resulting in muscle weakness, impaired respiratory function and decreased lifespan. These harmful outcomes lead to poor health-related quality of life and carry a high healthcare economic burden. The absence of promising treatments and new therapies for muscular disorders requires new methods for candidate drug identification
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A Zika virus protein expression screen in Drosophila to investigate targeted host pathways during development. Dis. Model Mech. (IF 4.3) Pub Date : 2024-01-12 Nichole Link, J Michael Harnish, Brooke Hull, Shelley Gibson, Miranda Dietze, Uchechukwu E Mgbike, Silvia Medina-Balcazar, Priya S Shah, Shinya Yamamoto
In the past decade, Zika virus (ZIKV) emerged as a global public health concern. While adult infections are typically mild, maternal infection can lead to adverse fetal outcomes. Understanding how ZIKV proteins disrupt development can provide insights into the molecular mechanisms of disease caused by this virus including microcephaly. In this study, we generated a toolkit to ectopically express ZIKV
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Face valid phenotypes in a mouse model of the most common mutation in EEF1A2 related neurodevelopmental disorder, E122K. Dis. Model Mech. (IF 4.3) Pub Date : 2024-01-05 Grant F Marshall, Melissa Fasol, Faith C J Davies, Matthew Le Seelleur, Alejandra Fernandez Alvarez, Cavan Bennett-Ness, Alfredo Gonzalez-Sulser, Catherine M Abbott
De novo heterozygous missense mutations in EEF1A2, encoding neuromuscular translation-elongation factor eEF1A2, are associated with developmental and epileptic encephalopathies. We used CRISPR/ Cas9 to recapitulate the most common mutation, E122K, in mice. Although E122K heterozygotes were not observed to have convulsive seizures, they exhibit frequent electrographic seizures and EEG abnormalities
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Conditional in vivo deletion of LYN kinase has little effect on a BRCA1 loss-of-function-associated mammary tumour model. Dis. Model Mech. (IF 4.3) Pub Date : 2023-12-26 Giusy Tornillo, Lauren Warrington, Howard Kendrick, Adam T Higgins, Trevor Hay, Sam Beck, Matthew J Smalley
LYN kinase is expressed in BRCA1 loss-of-function-dependent mouse mammary tumours, in the cells of origin of such tumours, and in human breast cancer. Suppressing LYN kinase activity in BRCA1-defective cell lines, as well as in in vitro cultures of Brca1-null mouse mammary tumours, is deleterious to their growth. Here, we have examined the interaction between LYN kinase and BRCA1 loss-of-function in
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Inescapable foot shock induces PTSD-like phenotype and negatively impacts adult murine bone. Dis. Model Mech. (IF 4.3) Pub Date : 2023-12-22 Sara J Sidles, Ryan R Kelly, Kirsten D Kelly, Jessica D Hathaway-Schrader, Stephanie K Khoo, Jeffrey A Jones, James J Cray, Amanda C LaRue
Post-traumatic stress disorder (PTSD) is associated with osteopenia, osteoporosis, and increased fracture risk in the clinical population. Yet, the development of preclinical models to study PTSD-induced bone loss remains limited. In this study, we present a novel model of PTSD in adult female C57BL/6 mice, employing inescapable foot shock (IFS) and social isolation, which demonstrates high face and
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Transcriptional profiling of zebrafish identifies host factors controlling susceptibility to Shigella flexneri. Dis. Model Mech. (IF 4.3) Pub Date : 2023-12-22 Vincenzo Torraca, Richard J White, Ian M Sealy, Maria Mazon-Moya, Gina Duggan, Alexandra Willis, Elisabeth M Busch-Nentwich, Serge Mostowy
Shigella flexneri is a human-adapted pathovar of Escherichia coli that can invade the intestinal epithelium, causing inflammation and bacillary dysentery. Although an important human pathogen, the host response to S. flexneri has not been fully described. Zebrafish larvae represent a valuable model to study human infections in vivo. Here we use a Shigella-zebrafish infection model to generate mRNA
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eNOS plays essential roles in the developing heart and aorta linked to disruption of Notch signalling. Dis. Model Mech. (IF 4.3) Pub Date : 2023-12-19 Lorraine Eley, Rachel V Richardson, Ahlam Alqahtani, Bill Chaudhry, Deborah J Henderson
eNOS (NOS3) is the enzyme that generates nitric oxide, a signalling molecule and regulator of vascular tone. Loss of eNOS function is associated with increased susceptibility to atherosclerosis, hypertension, thrombosis and stroke. Aortopathy and cardiac hypertrophy have also been found in eNOS null mice, but their aetiology is unclear. We evaluated eNOS nulls before and around birth for cardiac defects
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Physiological stress improves stem cell modeling of dystrophic cardiomyopathy. Dis. Model Mech. (IF 4.3) Pub Date : 2023-12-05 Dominic E Fullenkamp, Alexander B Willis, Jodi L Curtin, Ansel P Amaral, Kyle T Dittloff, Sloane I Harris, Ivana A Chychula, Cory W Holgren, Paul W Burridge, Brenda Russell, Alexis R Demonbreun, Elizabeth M McNally
Heart failure contributes to Duchenne muscular dystrophy (DMD), which arises from mutations that ablate dystrophin, rendering the plasma membrane prone to disruption. Cardiomyocyte membrane breakdown in DMD patients yields a serum injury profile similar to other types of myocardial injury with the release of creatinine kinase and troponin isoforms. Human induced pluripotent stem cell-derived cardiomyocytes
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Longitudinal assessment of skeletal muscle functional mechanics in the DE50-MD dog model of Duchenne Muscular Dystrophy. Dis. Model Mech. (IF 4.3) Pub Date : 2023-12-05 Dominique O Riddell, John C W Hildyard, Rachel C M Harron, Frances Taylor-Brown, Joe N Kornegay, Dominic J Wells, Richard J Piercy
Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is associated with fatal muscle degeneration and atrophy. Patients have progressive reductions in skeletal muscle strength and resistance to eccentric muscle stretch. We assessed tibiotarsal joint (TTJ) flexor and extensor force dynamics, and resistance of dystrophic muscle to eccentric stretch in the DE50-MD dog model of
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Membrane transporters in cell physiology, cancer metabolism and drug response. Dis. Model Mech. (IF 4.3) Pub Date : 2023-12-01 Sara Alam, Emily Doherty, Paula Ortega-Prieto, Julia Arizanova, Louise Fets
By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types
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Inborn errors of amino acid metabolism - from underlying pathophysiology to therapeutic advances. Dis. Model Mech. (IF 4.3) Pub Date : 2023-11-23 Shira G Ziegler, Jiyoung Kim, Jeffrey T Ehmsen, Hilary J Vernon
Amino acids are organic molecules that serve as basic substrates for protein synthesis and have additional key roles in a diverse array of cellular functions, including cell signaling, gene expression, energy production and molecular biosynthesis. Genetic defects in the synthesis, catabolism or transport of amino acids underlie a diverse class of diseases known as inborn errors of amino acid metabolism
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Neurofibromatosis 1 (NF1) mutation results in impaired function of human induced pluripotent stem cell-derived microglia. Dis. Model Mech. (IF 4.3) Pub Date : 2023-11-22 Leonard D Kuhrt,Edyta Motta,Nirmeen Elmadany,Hannah Weidling,Raphaela Fritsche-Guenther,Ibrahim E Efe,Olivia Cobb,Jit Chatterjee,Lucy G Boggs,Marina Schnauß,Sebastian Diecke,Marcus Semtner,Corina Anastasaki,David H Gutmann,Helmut Kettenmann
Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by germline mutations in the NF1 gene. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could reflect the effect of NF1 mutation on microglia function. Using heterozygous Nf1-mutant mice, we previously demonstrated that impaired purinergic signaling
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APOL1-G2 accelerates nephrocyte cell death by inhibiting the autophagy pathway. Dis. Model Mech. (IF 4.3) Pub Date : 2023-11-16 Jun-Yi Zhu,Jin-Gu Lee,Yulong Fu,Joyce van de Leemput,Patricio E Ray,Zhe Han
People of African ancestry carrying the APOL1 risk alleles (RA) G1 or G2 are at high risk of developing kidney diseases through not fully understood mechanisms that impair the function of podocytes. It is also not clear whether the APOL1-G1 and G2 RA affect these cells through similar mechanisms. Previously, we developed transgenic Drosophila fly lines expressing either the human APOL1 reference allele
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Genetic background determines severity of Loxl1-mediated systemic and ocular elastosis in mice. Dis. Model Mech. (IF 4.3) Pub Date : 2023-11-13 Maria F Suarez,Heather M Schmitt,Megan S Kuhn,TeddiJo Watkins,Kristyn M Hake,Tara Weisz,Edward J Flynn,Michael H Elliott,Michael A Hauser,W Daniel Stamer
Pseudoexfoliation syndrome (PEX) is a systemic, age-related disorder characterized by elastosis and extracellular matrix deposits. Its most significant ocular manifestation is an aggressive form of glaucoma associated with variants in the gene encoding lysyl oxidase-like 1 (LOXL1). Depending upon the population, variants in LOXL1 can impart risk or protection for PEX, suggesting the importance of genetic
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High-fat diet induces C-reactive protein secretion, promoting lung adenocarcinoma via immune microenvironment modulation. Dis. Model Mech. (IF 4.3) Pub Date : 2023-11-09 Wei-Lun Hsu,Yun-Ting Hsieh,Wei-Ming Chen,Min-Hui Chien,Wei-Jia Luo,Jung-Hsuan Chang,Kevin Devlin,Kang-Yi Su
To understand the effects of a high-fat diet (HFD) on lung cancer progression and biomarkers, we here used an inducible mutant epidermal growth factor receptor (EGFR)-driven lung cancer transgenic mouse model fed a regular diet (RD) or HFD. The HFD lung cancer (LC-HFD) group exhibited significant tumor formation and deterioration, such as higher EGFR activity and proliferation marker expression, compared
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Ascorbate protects human kidney organoids from damage induced by cell-free hemoglobin. Dis. Model Mech. (IF 4.3) Pub Date : 2023-11-09 Julie Bejoy, Justin M Farry, Eddie S Qian, Curtis H Dearing, Lorraine B Ware, Julie A Bastarache, Lauren E Woodard
Sepsis-associated acute kidney injury is associated with high morbidity and mortality in critically ill patients. Cell-free hemoglobin (CFH) is released into the circulation of patients with severe sepsis and the levels of CFH are independently associated with mortality. CFH treatment increased cytotoxicity in the human tubular epithelial cell line HK-2. To better model the intact kidney, we cultured
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The importance of figures in scientific 'show and tell'. Dis. Model Mech. (IF 4.3) Pub Date : 2023-11-08 Julija Hmeljak,Kirsty Hooper
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Pluripotent stem cell-derived neural progenitor cells can be used to model effects of IL-6 on human neurodevelopment. Dis. Model Mech. (IF 4.3) Pub Date : 2023-11-03 Kseniia Sarieva,Felix Hildebrand,Theresa Kagermeier,Zeynep Yentür,Katharina Becker,Simone Mayer
Maternal immune activation (MIA) increases the risks for neurodevelopmental disorders in offspring through inflammatory cytokines, including interleukin-6 (IL-6). We therefore aimed to establish a human two-dimensional (2D) in vitro neural model to investigate the effects of IL-6 exposure on neurodevelopment. IL-6 signal transduction requires two receptors: interleukin-6 signal transducer (IL6ST) and
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Nuclear mechanosensing of the aortic endothelium in health and disease. Dis. Model Mech. (IF 4.3) Pub Date : 2023-11-01 Aarren J Mannion,Lars Holmgren
The endothelium, the monolayer of endothelial cells that line blood vessels, is exposed to a number of mechanical forces, including frictional shear flow, pulsatile stretching and changes in stiffness influenced by extracellular matrix composition. These forces are sensed by mechanosensors that facilitate their transduction to drive appropriate adaptation of the endothelium to maintain vascular homeostasis
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How metals fuel fungal virulence, yet promote anti-fungal immunity. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-31 Alanoud Alselami,Rebecca A Drummond
Invasive fungal infections represent a significant global health problem, and present several clinical challenges, including limited treatment options, increasing rates of antifungal drug resistance and compounding comorbidities in affected patients. Metals, such as copper, iron and zinc, are critical for various biological and cellular processes across phyla. In mammals, these metals are important
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Pax3 lineage-specific deletion of Gpr161 is associated with spinal neural tube and craniofacial malformations during embryonic development. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-27 Sung-Eun Kim, Pooja J Chothani, Rehana Shaik, Westley Pollard, Richard H Finnell
Sonic hedgehog (Shh) signaling is the morphogen signaling that regulates embryonic craniofacial and neural tube development. G protein-coupled receptor 161 (Gpr161) is a negative regulator of Shh signaling, and its inactivation in mice results in embryo lethality associated with craniofacial and neural tube defects (NTDs). However, the structural defects of later embryonic stages in Gpr161 null mice
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Correction: Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-23 Dah-Jiun Fu,Andrea J De Micheli,Blaine A Harlan,Mallikarjun Bidarimath,Lora H Ellenson,Benjamin D Cosgrove,Andrea Flesken-Nikitin,Alexander Yu Nikitin
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The roles of JAK2/STAT3 signaling in fusion of the secondary palate. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-17 Naoki Yoshida, Toshihiro Inubushi, Takumi Hirose, Gozo Aoyama, Hiroshi Kurosaka, Takashi Yamashiro
Cleft palate has a multifactorial etiology. In palatal fusion, the contacting medial edge epithelium (MEE) forms the epithelial seam, which is subsequently removed with the reduction of p63. Failure in this process results in a cleft palate. We herein report the involvement of janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling in palatal fusion and that folic
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Identification of histone deacetylase inhibitors as neutrophil recruitment modulators in zebrafish using a chemical library screen. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-13 Sijia Fan,Jinlong Jiang,Huan Zhang,Cuihong Wang,Shang Kong,Tingting Zhao,Ling Meng,Yang Liu,Jingjing Qin,Xiuqin Rong,Zhenting He,Qinke He,Ke He,Ketong Chen,Ling Lei,Xinyu Hai,Hong Nie,Chunguang Ren
Tissue injury-induced neutrophil recruitment is a prerequisite for the initiation and amplification of inflammatory responses. Although multiple proteases and enzymes involved in post-translational modification (PTM) of proteins regulate leukocyte recruitment, an unbiased functional screen of enzymes regulating inflammatory leukocyte recruitment has yet to be undertaken. Here, using a zebrafish tail
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Microenvironment-dependent growth of Sezary cells in humanized IL-15 mice. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-13 Jie Gao,Shumei Ren,Gabrielle Choonoo,Guoying Chen,Davor Frleta,Jun Zhong,Namita Gupta,Prachi Sharma,Adelekan Oyejide,Gurinder S Atwal,Lynn Macdonald,Andrew Murphy,Frank Kuhnert
Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small-animal models. Here, we demonstrate that IL-15 is a critical CTCL growth factor. Importantly, an immunodeficient knock-in mouse model genetically engineered to express human IL-15 uniquely supported the growth of SS patient samples relative
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TReATS: A novel method for TAT-Cre Recombinase-mediated floxed Allele modification in ex vivo Tissue Slices. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-13 Sek-Shir Cheong, Tiago C Luis, Michelle Stewart, Rosie Hillier, Matthew Hind, Charlotte H Dean
Precision-Cut Lung Slices (PCLS) are used for a variety of applications. However, methods to manipulate genes in PCLS are currently limited. We developed a novel method, TAT-Cre Recombinase-mediated floxed Allele modification in Tissue Slices (TReATS), to induce highly effective and temporally controlled gene deletion or activation in ex vivo PCLS. Treatment of PCLS from Rosa26-flox-stop-flox-EYFP
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A Novel drosophila model targets Eiger/TNFα to alleviate obesity-related insulin resistance and macrophage infiltration. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-13 Zhasmine Mirzoyan, Alice Valenza, Sheri Zola, Carola Bonfanti, Lorenzo Arnaboldi, Nicholas Ferrari, John Pollard, Valeria Lupi, Matteo Cassinelli, Matteo Frattaroli, Mehtap Sahin, Maria Enrica Pasini, Paola Bellosta
Obesity is associated with various metabolic disorders, such as insulin resistance and adipose tissue inflammation (ATM), characterized by macrophage infiltration into adipose cells. This study presents a novel Drosophila model (OBL) to investigate the mechanisms underlying these obesity-related pathologies. We employed genetic manipulation to reduce ecdysone levels to prolong the larval stage. These
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Playing the genetic lottery: an interview with Kiran Musunuru. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-10 Kiran Musunuru
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A genetic mosaic mouse model illuminates the pre-malignant progression of basal-like breast cancer. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-10 Jianhao Zeng, Shambhavi Singh, Xian Zhou, Ying Jiang, Eli Casarez, Kristen A Atkins, Kevin A Janes, Hui Zong
Basal-like breast cancer (BLBC) is highly aggressive, often characterized by BRCA1 and p53 deficiency. Although conventional mouse models enabled the investigation of BLBC at malignant stages, its initiation and pre-malignant progression remain under-studied. Here, we leveraged a mouse genetic system known as Mosaic Analysis with Double Markers (MADM) to study BLBC initiation by generating rare GFP+
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Altered binding affinity of SIX1-Q177R correlates with enhanced WNT5A and WNT pathway effector expression in Wilms tumor. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-10 Matthew J Stevenson, Sabrina K Phanor, Urvi Patel, Stephen S Gisselbrecht, Martha L Bulyk, Lori L O'Brien
Wilms tumors present as an amalgam of varying proportions of tissues normally located within the developing kidney, one being the nephrogenic blastema comprised of multipotent nephron progenitor cells (NPCs). A recurring missense mutation, Q177R, in NPC transcription factors SIX1 and SIX2 is most correlated with tumors of blastemal histology and is significantly associated with relapse. Yet, the transcriptional
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Glycosphingolipids linked to elevated neurotransmission and neurodegeneration in a Drosophila model of Niemann Pick Type C. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-10 Anna E Eberwein, Swarat S Kulkarni, Emma Rushton, Kendal Broadie
The lipid storage disease Niemann Pick Type C (NPC) causes neurodegeneration owing primarily to loss of NPC1. Here, we employ a Drosophila model to test links between glycosphingolipids, neurotransmission, and neurodegeneration. We find npc1a nulls have elevated neurotransmission at the glutamatergic neuromuscular junction (NMJ), which is phenocopied in brainiac (brn) mutants impairing mannosylglucosylceramide
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Transcriptomic analysis of diabetic kidney disease and neuropathy in mouse models of type 1 and type 2 diabetes. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-04 Sarah E Elzinga, Stephanie A Eid, Brett A McGregor, Dae-Gyu Jang, Lucy M Hinder, Jacqueline R Dauch, John M Hayes, Hongyu Zhang, Kai Guo, Subramaniam Pennathur, Matthias Kretzler, Frank C Brosius, Emily J Koubek, Eva L Feldman, Junguk Hur
Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are common complications of type 1 (T1D) and type 2 (T2D) diabetes. However, the mechanisms underlying pathogenesis of these complications are unclear. In this study, we optimized a streptozotocin-induced db/+ murine model of T1D and compared it to our established db/db T2D mouse model of the same C57BLKS/J background. Glomeruli
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Innovating spinal muscular atrophy models in the therapeutic era. Dis. Model Mech. (IF 4.3) Pub Date : 2023-10-03 Ilaria Signoria, W Ludo van der Pol, Ewout J N Groen
Spinal muscular atrophy (SMA) is a severe, monogenetic, neuromuscular disease. A thorough understanding of its genetic cause and the availability of robust models has led to the development and approval of three gene-targeting therapies. This is a unique and exciting development for the field of neuromuscular diseases, many of which remain untreatable. The development of therapies for SMA not only
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FUS-NLS mutation causes neurodevelopmental and systemic metabolic alterations. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-29 Zeinab Ali, Juan M Godoy-Corchuelo, Aurea B Martins-Bach, Irene Garcia-Toledo, Luis C Fernández-Beltrán, Remya R Nair, Shoshana Spring, Brian J Nieman, Irene Jimenez-Coca, Rasneer S Bains, Hamish Forrest, Jason P Lerch, Karla Miller, Elizabeth M C Fisher, Thomas J Cunningham, Silvia Corrochano
Mutations in the ubiquitously expressed DNA/RNA binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). While most FUS mutation studies have focused on motor neuron degeneration, little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity
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Efficient genetic editing of human intestinal organoids using ribonucleoprotein-based CRISPR. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-29 Nefeli Skoufou-Papoutsaki, Sam Adler, Paula D'Santos, Liz Mannion, Shenay Mehmed, Richard Kemp, Amy Smith, Francesca Perrone, Komal Nayak, Alasdair Russell, Matthias Zilbauer, Douglas J Winton
Organoids combined with genetic editing strategies, the potential to offer rapid and efficient investigation of gene function in many models of human disease. However, to date, the editing efficiency of organoids with the use of non-viral electroporation methods has been only up to 30%, with implications for the subsequent need for selection including turnaround time and exhaustion or adaptation of
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Sodium butyrate, a pan-histone deacetylase inhibitor, does not protect spinal motor neurons from AMPA-induced excitotoxic degeneration in vivo. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-26 Mara Prior-González, Rafael Lazo-Gómez, Ricardo Tapia
Motor neuron loss is the primary pathological hallmark of amyotrophic lateral sclerosis ALS the most prevalent of motoneuron disorders which are a group of lethal neurodegenerative diseases. Currently, there are no effective treatments that stop the progression of these disorders. Histone deacetylase 4 HDAC4 is one of several factors involved in nerve-muscle communication during motoneuron loss. HDAC4
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Supporting the translation of multiscale research in rare disease. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-22 Kirsty M Hooper,Julija Hmeljak
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Crossroads in virology: current challenges and future perspectives in the age of emerging viruses. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-20 Sumana Sanyal
Ongoing global health challenges posed by emerging and re-emerging viruses have highlighted the critical importance of understanding virus-host interactions in countering these threats. Environmental changes, urbanisation and ecological disruption, coupled with the adaptable nature of viruses, facilitates the emergence and spread of new viruses. This Editorial emphasises the urgency of a concerted
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OPA1 deficiency impairs oxidative metabolism in cycling cells, underlining a translational approach for degenerative diseases. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-20 Aurélie M C Millet,Corentin Coustham,Camille Champigny,Marlène Botella,Christine Demeilliers,Anne Devin,Anne Galinier,Pascale Belenguer,Joel Bordeneuve-Guibé,Noélie Davezac
Dominant optic atrophy is an optic neuropathy with varying clinical symptoms and progression. A severe disorder is associated with certain OPA1 mutations and includes additional symptoms for >20% of patients. This underscores the consequences of OPA1 mutations in different cellular populations, not only retinal ganglionic cells. We assessed the effects of OPA1 loss of function on oxidative metabolism
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The Drosophila homolog of APP promotes Dscam expression to drive axon terminal growth, revealing interaction between Down syndrome genes. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-15 Sarah Pizzano,Gabriella R Sterne,Macy W Veling,L Amanda Xu,Ty Hergenreder,Bing Ye
Down syndrome (DS) is caused by triplication of human chromosome 21 (HSA21). Although several HSA21 genes have been found to be responsible for aspects of DS, whether and how HSA21 genes interact with each other is poorly understood. DS patients and animal models present with a number of neurological changes, including aberrant connectivity and neuronal morphology. Previous studies have indicated that
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Stromal matrix directs corneal fibroblasts to re-express keratocan after injury and transplantation. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-13 Ana C Acosta, Mei Sun, Nabeel Zafrullah, Marcel Y Avila, Curtis E Margo, Edgar M Espana
Every tissue has an extracellular matrix (ECM) with certain properties unique to it - the tissue 'niche' - that are necessary for normal function. A distinct specific population of quiescent keratocan-expressing keratocytes populate the corneal stroma during homeostasis to maintain corneal function. However, during wound healing, when there is alteration of the niche conditions, keratocytes undergo
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Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-11 Nicole M Sayles, Jill S Napierala, Josef Anrather, Nadège Diedhiou, Jixue Li, Marek Napierala, Hélène Puccio, Giovanni Manfredi
Cardiomyopathy is often fatal in Friedreich Ataxia (FA). However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). Conditional cardiac knockout mouse models of FXN show transcriptional and metabolic profiles of the mitochondrial integrated stress response (ISRmt), which could play an adaptive role. However, ISRmt has not
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Using Drosophila to model a variant of unknown significance in the human cardiogenic gene Nkx2.5. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-11 TyAnna L Lovato, Brenna Blotz, Cayleen Bileckyj, Christopher A Johnston, Richard M Cripps
Sequencing of human genome samples has unearthed genetic variants for which functional testing is necessary to validate their clinical significance. We used the Drosophila system to analyze a variant of unknown significance in the human congenital heart disease gene, Nkx2.5. We generated an R321N allele of the Nkx2.5 ortholog tinman (tin) to model a human K158N variant and tested its function in vitro
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The dual lipid desaturase/hydroxylase DEGS2 controls phytoceramide levels necessary to counter intestinal inflammation. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-08 Ran Song,Aaron Fond,Xiaohong Li,Miao Tang,Xiaoming Zhan,Ruth Gordillo,Eva Marie Y Moresco,Bruce Beutler,Emre E Turer
Intestinal immunity is dependent on barrier function to maintain quiescence. The mechanisms for the maintenance of this barrier are not fully understood. Delta 4-desaturase, sphingolipid 2 (DEGS2) is a lipid desaturase and hydroxylase that catalyzes the synthesis of ceramide and phytoceramide from dihydroceramide. Using a forward genetic approach, we found and validated a mutation in Degs2 as causative
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Increase in brain glycogen levels ameliorates disease phenotype and rescues neurodegeneration in the Drosophila model of Huntington's disease. Dis. Model Mech. (IF 4.3) Pub Date : 2023-09-08 Akanksha Onkar, Deepashree Sheshadri, Anupama Rai, Arjit Kant Gupta, Nitin Gupta, Subramaniam Ganesh
Under normal physiological conditions, the mammalian brain contains very little glycogen, most of which is stored in astrocytes. However, the aging brain and subareas of the brain in patients with neurodegenerative disorders tend to accumulate glycogen, the cause and significance of which remain largely unexplored. Using cellular models, we have recently demonstrated a neuroprotective role for neuronal