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Disease Models & Mechanisms

Sara Carbajo-Pescador, David Porras, María Victoria García-Mediavilla, Susana Martínez-Flórez, María Juarez-Fernández, María José Cuevas, José Luis Mauriz, Javier González-Gallego, Esther Nistal, Sonia Sánchez-Campos
Childhood obesity has reached epidemic levels, representing one of the most serious public health concerns associated with metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). There is limited clinical experience for pediatric NAFLD patients and the therapeutic options are very scarce. The aim of this study is to evaluate the benefits of exercise on gut microbiota composition and functionality balance and its repercussion on early obesity and NAFLD onset in an in vivo model. 21 days old male Wistar rats fed with control or high fat diet (HFD) were subjected to a combined aerobic and resistance training protocol...
April 10, 2019: Disease Models & Mechanisms
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. 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 protocols. Here, we demonstrate that fully differentiated human SH-SY5Y neuroblastoma cells grown in three-dimensional cell culture develop Lewy body-like pathology upon exposure to exogenous α-synuclein species...
March 29, 2019: Disease Models & Mechanisms
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 cancer. The cell-of-origin of pancreatic ductal adenocarcinoma (PDAC) has been controversial and recent progress suggested acinar cells as a 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 to introduce genetic engineering in tree shrew pancreatic acinar cells to explore the driver mutation essential for malignant transformation and to establish a novel tree shrew PDAC model, because we found that lentivirus could selectively infect acinar cells in tree shrew pancreas...
March 25, 2019: Disease Models & Mechanisms
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 for normal lifespan as well as metabolic and immune homeostasis. Flies lacking fat body fs(1)h exhibit short lifespan, increased expression of immune target genes, an inability to metabolize triglyceride, and low basal AKT activity, mostly resulting from systemic defects in insulin signaling...
March 25, 2019: Disease Models & Mechanisms
Roberta Resaz, Francesca Rosa, Federica Grillo, Luca Basso, Daniela Segalerba, Andrea Puglisi, Maria Carla Bosco, Luca Mastracci, Carlo E Neumaier, Luigi Varesio, Alessandra Eva
Purpose: Hepatocellular adenomas (HCA) are benign tumors whose most serious complications are hemorrhage and malignant transformation to hepatocellular carcinoma (HCC). Among various subtypes of HCA, β-catenin-activated (bHCA) are at greater risk of malignant transformation. Magnetic Resonance Imaging (MRI) is an important tool to differentiate benign and malignant hepatic lesions, and preclinical experimental approaches may help develop a method to identify MRI features associated with bHCA. HCA are associated to various pathologies, including Glycogen Storage Disease 1a (GSD1a)...
March 21, 2019: Disease Models & Mechanisms
Ao Zhang, Mei Wu, Junliang Tan, Ning Yu, Mengchang Xu, Xutong Yu, Wei Liu, Yiyue Zhang
Benzene exposure is associated with various hematological disorders, especially leukemia. The reactive metabolite of benzene, 1,4-Benzoquinone (BQ), generated in bone marrow (BM), is suggested to be a key molecule in mediating benzene-induced hematotoxicity and carcinogenicity. Yet, its pathogenic role remains largely unknown due to lack of suitable vertebrate whole-organism models. Here, we present an in vivo study to reveal the effect of BQ exposure on hematotoxicity in zebrafish. From embryonic stages to adulthood, BQ exposure suppressed erythroid and lymphoid hematopoiesis but abnormally accumulated myeloid cells and precursors, which resembles benzene-induced cytopenia and myeloid dysplasia in humans...
March 19, 2019: Disease Models & Mechanisms
Lauren Brilli Skvarca, Hwa In Han, Eugenel B Espiritu, Maria A Missinato, Elizabeth R Rochon, Michael D McDaniels, Abha S Bais, Beth L Roman, Joshua S Waxman, Simon C Watkins, Alan J Davidson, Michael Tsang, Neil A Hukriede
Acute kidney injury (AKI) is a serious disorder for which there are limited treatment options. Following injury, native nephrons display limited regenerative capabilities, relying on the dedifferentiation and proliferation of renal tubular epithelial cells (RTECs) that survive the insult. Previously, we identified 4-(phenylthio)butanoic acid (PTBA), a histone deacetylase inhibitor (HDI) that enhances renal recovery and showed that PTBA treatment increased RTEC proliferation and reduced renal fibrosis. Here, we investigated the regenerative mechanisms of PTBA in zebrafish models of larval renal injury and adult cardiac injury...
March 19, 2019: Disease Models & Mechanisms
Laura Martorano, Margherita Peron, Claudio Laquatra, Elisa Lidron, Nicola Facchinello, Giacomo Meneghetti, Natascia Tiso, Andrea Rasola, Daniele Ghezzi, Francesco Argenton
Mitochondrial DNA depletion syndromes (MDS) are a group of rare autosomal recessive disorders with early onset and no cure available. MDS are caused by mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance, and characterized by both a strong reduction of mtDNA content and severe mitochondrial defects in affected tissues. Mutations in MPV17 , a nuclear gene encoding a mitochondrial inner membrane protein, have been associated with hepatocerebral forms of MDS. Zebrafish mpv17 null mutant lacks the guanine-based reflective skin cells named iridophores and represents a promising model to clarify the role of Mpv17...
March 4, 2019: Disease Models & Mechanisms
Emily J Jones, Zoe J Matthews, Lejla Gul, Padhmanand Sudhakar, Agatha Treveil, Devina Divekar, Jasmine Buck, Tomasz Wrzesinski, Matthew Jefferson, Stuart D Armstrong, Lindsay J Hall, Alastair J M Watson, Simon R Carding, Wilfried Haerty, Federica Di Palma, Ulrike Mayer, Penny P Powell, Isabelle Hautefort, Tom Wileman, Tamas Korcsmaros
Paneth cells are key epithelial cells providing an antimicrobial barrier and maintaining integrity of the small intestinal stem cell niche. Paneth cell abnormalities are unfortunately detrimental to gut health and often associated with digestive pathologies such as Crohn's disease or infections. Similar alterations are observed in individuals with impaired autophagy, a process which recycles cellular components. The direct effect of autophagy-impairment on Paneth cells has not been analysed. To investigate this, we generated a mouse model lacking Atg16l1 specifically in intestinal epithelial cells making these cells impaired in autophagy...
February 27, 2019: Disease Models & Mechanisms
Danny N Legge, Alex P Shephard, Tracey J Collard, Alexander Greenhough, Adam C Chambers, Richard W Clarkson, Christos Paraskeva, Ann C Williams
To decrease bowel cancer incidence and improve survival, we need to understand the mechanisms that drive tumorigenesis. Recently BCL-3 (a key regulator of NF-κB signalling) has been recognised as an important oncogenic player in solid tumours. Although reported to be over-expressed in a subset of colorectal cancers (CRC), the role of BCL-3 expression in colorectal tumorigenesis remains poorly understood. Despite evidence in the literature that BCL-3 may interact with β-catenin it is perhaps surprising, given the importance of deregulated Wnt/β-catenin signalling in colorectal carcinogenesis, that the functional significance of this interactions is not known...
February 21, 2019: Disease Models & Mechanisms
Laura E Kuil, Nynke Oosterhof, Samuël N Geurts, Herma C van der Linde, Erik Meijering, Tjakko J van Ham
Microglia are brain resident macrophages, which have specialized functions important in brain development and in disease. They colonize the brain in early embryonic stages, but few factors that drive the migration of yolk sac macrophages (YSMs) into the embryonic brain , or regulate their acquisition of specialized properties are currently known.Here, we present a CRISPR/Cas9-based in vivo reverse genetic screening pipeline to identify new microglia regulators using zebrafish. Zebrafish larvae are particularly suitable due to their external development, transparency and conserved microglia features...
February 14, 2019: Disease Models & Mechanisms
A Havighorst, Y Zhang, E Farmaki, V Kaza, I Chatzistamou, H Kiaris
Endoplasmic reticulum (ER) stress has been causatively linked to the onset of various pathologies. However, if and how inherent variations in the resulting unfolded protein response (UPR) affect the predisposition to ER stress-associated metabolic conditions remains to be established. By using genetically diverse deer mice ( Peromyscus maniculatus ) as a model, we show that the profile of tunicamycin-induced UPR in fibroblasts isolated at puberty varies between individuals and predicts deregulation of lipid metabolism and diet-induced hepatic steatosis later in life...
February 7, 2019: Disease Models & Mechanisms
Qiqi Yang, Chuan Yan, Xu Wang, Zhiyuan Gong
Cancer cachexia affects up to 80% of the patients with advanced solid cancer and leads to excessive muscle wasting. Here, using an inducible zebrafish HCC model driven by oncogenic kras G12V , we observed a progressive muscle wasting phenotype in adult zebrafish, characterized by significant loss of body weight and muscle fibers. By differential feeding, we observed that overfeeding caused fatty liver, accelerated carcinogenesis and muscle wasting. Interestingly, leptin, an obesity hormone, was upregulated in oncogenic hepatocytes and overfeeding groups...
February 4, 2019: Disease Models & Mechanisms
Daniel Sobrido-Cameán, Diego Robledo, Laura Sánchez, María Celina Rodicio, Antón Barreiro-Iglesias
Classical neurotransmitters are mainly known for their roles as neuromodulators, but they also play important roles in the control of developmental and regenerative processes. Here, we used the lamprey model of spinal cord injury to study the effect of serotonin in axon regeneration at the level of individually identifiable descending neurons. Pharmacological and genetic manipulations after a complete spinal cord injury showed that endogenous serotonin inhibits axonal regeneration in identifiable descending neurons through the activation of serotonin 1A receptors and a subsequent decrease in cAMP levels...
February 1, 2019: Disease Models & Mechanisms
Sandra Muñoz-Braceras, Alba R Tornero-Écija, Olivier Vincent, Ricardo Escalante
Members of the VPS13 family are associated with various human diseases. In particular, the loss of function of VPS13A leads to chorea-acanthocytosis (ChAc), a rare neurodegenerative disease without available curative treatments. Autophagy has been considered a promising therapeutic target because the absence of VPS13A causes a defective autophagy flux. However, the mechanistic details of this deficiency are unknown. Here, we identified Rab7A as an interactor of one of the VPS13 family members in Dictyostelium discoideum and we showed that this interaction is conserved between the human homologs VPS13A and RAB7A in HeLa cells...
February 1, 2019: Disease Models & Mechanisms
Michelle Stewart, Petrina Lau, Gareth Banks, Rasneer Sonia Bains, Enrico Castroflorio, Peter L Oliver, Christine L Dixon, Michael C Kruer, Dimitri M Kullmann, Abraham Acevedo-Arozena, Sara E Wells, Silvia Corrochano, Patrick M Nolan
Loss of function mutations in the human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and ex vivo studies have implicated FRRS1L in AMPA receptor biogenesis, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse Frrs1l null mutant...
January 28, 2019: Disease Models & Mechanisms
Alexandria T M Blackburn, Rachel K Miller
Congenital anomalies of the kidney and urinary tract (CAKUT) occur in ∼1/500 live births and are a leading cause of pediatric kidney failure. With an average wait time of 3-5 years for a kidney transplant, the need is high for the development of new strategies aimed at reducing the incidence of CAKUT and preserving renal function. Next-generation sequencing has uncovered a significant number of putative causal genes, but a simple and efficient model system to examine the function of CAKUT genes is needed...
April 9, 2019: Disease Models & Mechanisms
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 establish the fly as a valid model in cancer research through different scientific periods.
April 1, 2019: Disease Models & Mechanisms
Monica J Justice
Disease Models & Mechanisms (DMM) is delighted to announce that the winner of the DMM Prize 2018 is Wenqing Zhou, for her paper entitled 'Neutrophil-specific knockout demonstrates a role for mitochondria in regulating neutrophil motility in zebrafish' (Zhou et al., 2018a). The prize of $1000 is awarded to the first author of the paper that is judged by the journal's editors to be the most outstanding contribution to the journal that year. To be considered for the prize, the first author must be a student or a postdoc of no more than 5 years standing...
March 26, 2019: Disease Models & Mechanisms
Melissa C Chubak, Kevin C J Nixon, Max H Stone, Nicholas Raun, Shelby L Rice, Mohammed Sarikahya, Spencer G Jones, Taylor A Lyons, Taryn E Jakub, Roslyn L M Mainland, Maria J Knip, Tara N Edwards, Jamie M Kramer
Technology has led to rapid progress in the identification of genes involved in neurodevelopmental disorders such as intellectual disability (ID), but our functional understanding of the causative genes is lagging. Here, we show that the SWI/SNF chromatin remodelling complex is one of the most over-represented cellular components disrupted in ID. We investigated the role of individual subunits of this large protein complex using targeted RNA interference in post-mitotic memory-forming neurons of the Drosophila mushroom body (MB)...
March 25, 2019: Disease Models & Mechanisms
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