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Disease Models & Mechanisms

Xin-Yu Liu, Deng-Bao Yang, Yan-Chao Xu, Marianne O L Gronning, Fang Zhang, De-Hua Wang, John R Speakman
Brandt's voles have an annual cycle of body weight and adiposity. These changes can be induced in the laboratory by manipulation of photoperiod. In the present study, male captive bred Brandt's voles aged 35 days were acclimated to a short day (SD) photoperiod (8L:16D) for 70 days. A subgroup of individuals (n=16) were implanted with transmitters to monitor physical activity and body temperature. They were then randomly allocated into long day (LD=16L:8D) (n=19: 8 with transmitters) and SD (n=18: 8 with transmitters) groups for an additional 70 days...
September 30, 2016: Disease Models & Mechanisms
Jan Olsson, Hugo Lövheim, Emma Honkala, Pekka J Karhunen, Fredrik Elgh, Eloise H Kok
Herpes simplex virus (HSV) type 1 affects a majority of the population and recent evidence suggests involvement in Alzheimer's disease aetiology.We investigated HSV (1 and 2) prevalence in the Tampere Autopsy Study (TASTY) brain samples using PCR and sero-positivity in plasma, and associations with Alzheimer's disease neuropathology.HSV was shown to be present in human brain tissue in 11/584 (1.9%) of samples in the TASTY cohort, and 6 of those samples had Alzheimer's disease neuropathological amyloid beta (Aβ) aggregations...
September 23, 2016: Disease Models & Mechanisms
David Zada, Adi Tovin, Tali Lerer-Goldshtein, Lior Appelbaum
Hypomyelination is a key symptom of the Allan-Herndon-Dudley syndrome (AHDS), a psychomotor retardation associated with mutations in the thyroid-hormone (TH) transporter MCT8. AHDS is characterized by severe intellectual deficiency, neuromuscular impairment, and brain hypothyroidism. In order to understand the mechanism for TH-dependent hypomyelination, we developed an mct8 mutant (mct8-/-) zebrafish model. The quantification of genetic markers for oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes revealed reduced differentiation of OPCs into oligodendrocytes in mct8-/- larvae and adults...
September 23, 2016: Disease Models & Mechanisms
Apoorva Mulay, Khondoker Akram, Debbie Williams, Hannah Armes, Catherine Russell, Derek Hood, Stuart Armstrong, James P Stewart, Steve D M Brown, Lynne Bingle, Colin D Bingle
Otitis media (OM) or middle ear inflammation is the most common pediatric disease and leads to significant morbidity. Although understanding of underlying disease mechanisms is hampered by complex pathophysiology it is clear that epithelial abnormalities underpin the disease. There is currently a lack of a well characterised in vitro model of the middle ear (ME) epithelium that replicates the complex cellular composition of the middle ear. Here we report the development of a novel in vitro model of mouse middle ear epithelial cells (mMECs) at air liquid interface (ALI) that recapitulates the characteristics of the native murine ME epithelium...
September 22, 2016: Disease Models & Mechanisms
Sarah J Annesley, Sui T Lay, Shawn W De Piazza, Oana Sanislav, Eleanor Hammersley, Claire Y Allan, Lisa M Francione, Minh Q Bui, Zhi-Ping Chen, Kevin R W Ngoei, Flora Tassone, Bruce E Kemp, Elsdon Storey, Andrew Evans, Danuta Z Loesch, Paul R Fisher
In combination with studies of post-mortem PD brains, pharmacological and genetic models of Parkinson's Disease (PD) have suggested that two fundamental, interacting cellular processes are impaired - proteostasis and mitochondrial respiration. We have re-examined the role of mitochondrial dysfunction in lymphoblasts isolated from patients with idiopathic PD and an age-matched control group. As previously reported for various PD cell types, the production of reactive oxygen species (ROS) by PD lymphoblasts was significantly elevated...
September 16, 2016: Disease Models & Mechanisms
Ayami Ohno Kishimoto, Yo Kishimoto, David L Young, Jinjin Zhang, Ian J Rowland, Nathan V Welham
Subepithelial changes to the vocal fold mucosa, such as fibrosis, are difficult to identify using visual assessment of the tissue surface. Moreover, without suspicion of neoplasm, mucosal biopsy is not a viable clinical option, as it carries its own risk of iatrogenic injury and scar formation. Given these challenges, we assessed the ability of high- (4.7 T) and ultrahigh-field (9.4 T) magnetic resonance imaging to resolve key vocal fold subepithelial tissue structures in the rat, an important and widely used preclinical model in vocal fold biology...
September 16, 2016: Disease Models & Mechanisms
Silvia Hayer, Gregor Bauer, Martin Willburger, Katharina Sinn, Farideh Alasti, Roberto Plasenzotti, Tetyana Shvets, Birgit Niederreiter, Constantin Aschauer, Guenter Steiner, Bruno K Podesser, Josef S Smolen, Kurt Redlich
Chronic inflammation of articular joints causing bone and cartilage destructions consequently leads to functional impairment or loss of mobility in affected joints from patients with Rheumatoid Arthritis (RA). Even successful treatment with complete resolution of synovial inflammatory processes did not lead to full reversibility of joint functionality pointing to the crucial contribution of irreversibly damaged structural compartments such as bone or cartilage destruction on joint mobility. In this context, we investigated the impact of the distinct components including synovial inflammation, bone erosion or cartilage damage as well as the effect of a TNF blockade on functional impairment in human tumor necrosis factor transgenic (hTNFtg) mice, a chronic inflammatory, erosive animal model of Rheumatoid Arthritis (RA)...
September 16, 2016: Disease Models & Mechanisms
Galen W Heyne, Joshua L Everson, Lydia J Ansen-Wilson, Cal G Melberg, Dustin M Fink, Kia F Parins, Padydeh Doroodchi, Caden M Ulschmid, Robert J Lipinski
Holoprosencephaly (HPE) is a common and severe human developmental abnormality marked by malformations of the forebrain and face. While several genetic mutations have been linked to HPE, phenotypic outcomes range dramatically and most cases cannot be attributed to a specific cause. Gene-environment interaction has been invoked as a premise to explain the etiological complexity of HPE but identification of interacting factors has been extremely limited. Here, we demonstrate that mutations in Gli2, which encodes a Hedgehog pathway transcription factor, can cause or predispose to HPE depending upon gene dosage...
September 1, 2016: Disease Models & Mechanisms
Karl-F Bergeron, Chloé M A Nguyen, Tatiana Cardinal, Baptiste Charrier, David W Silversides, Nicolas Pilon
Waardenburg syndrome is a neurocristopathy characterized by a combination of skin/hair depigmentation and inner ear defects. In the type 4 form, these defects are comorbid with Hirschsprung disease, a disorder marked by an absence of neural ganglia in the distal colon triggering functional intestinal obstruction. Here, we report that the Spot mouse line - obtained through an insertional mutagenesis screen for genes involved in neural crest cell (NCC) development - is a model for Waardenburg syndrome type 4...
September 1, 2016: Disease Models & Mechanisms
Insa Bultmann-Mellin, Jeroen Essers, Paula M van Heijingen, Harald von Melchner, Gerhard Sengle, Anja Sterner-Kock
LTBP‑4L and LTBP‑4S are two isoforms of the extracellular matrix protein latent transforming growth factor β-binding protein 4 (LTBP‑4). The mutational inactivation of both isoforms causes autosomal recessive cutis laxa type 1C (ARCL1C) in humans and an ARCL1C‑like phenotype in Ltbp4(‑/-) mice, both characterized by high postnatal mortality and severely affected elastogenesis. However, genetic data in mice suggest isoform-specific functions for Ltbp-4 because Ltbp4S(‑/-) mice, solely expressing Ltbp‑4L, survive to adulthood...
September 1, 2016: Disease Models & Mechanisms
Sabela Diaz-Castroverde, Almudena Gómez-Hernández, Silvia Fernández, Gema García-Gómez, Marianna Di Scala, Gloria González-Aseguinolaza, Elisa Fernández-Millán, Águeda González-Rodríguez, María García-Bravo, Pierre Chambon, Carmen Álvarez, Liliana Perdomo, Nuria Beneit, Oscar Escribano, Manuel Benito
Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. Previous in vitro data showed that insulin receptor isoform A, but not B, favours basal glucose uptake through its specific association with endogenous GLUT1/2 in murine hepatocytes and beta cells. With this background, we hypothesized that hepatic expression of insulin receptor isoform A in a mouse model of type 2 diabetes could potentially increase the glucose uptake of these cells decreasing the hyperglycaemia and therefore ameliorating the diabetic phenotype...
August 24, 2016: Disease Models & Mechanisms
Jennifer M I Daenzer, Patricia P Jumbo-Lucioni, Marquise L Hopson, Kerry R Garza, Emily L Ryan, Judith L Fridovich-Keil
Classic galactosemia (CG) is a potentially lethal inborn error of metabolism that results from profound loss of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme in the Leloir pathway of galactose metabolism. Neonatal detection and dietary restriction of galactose minimize or resolve the acute sequelae of CG, but fail to prevent the long-term complications experienced by a majority of patients. One of the substrates of GALT, galactose-1-phosphate (Gal-1P), accumulates to high levels in affected infants, especially following milk exposure, and has been proposed as the key mediator of acute and long-term pathophysiology in CG...
August 24, 2016: Disease Models & Mechanisms
Changwen Zhang, Jillian L Ellis, Chunyue Yin
Alcoholic liver disease (ALD) results from alcohol overconsumption and is among the leading causes of liver-related morbidity and mortality worldwide. Elevated expression of vascular endothelial growth factor (VEGF) and its receptors has been observed in ALD, but how it contributes to ALD pathophysiology is unclear. Here we investigated the impact of VEGF signaling inhibition on an established zebrafish model of acute alcoholic liver injury. VEGF-receptor 2/Kdrl activity was blocked by chemical inhibitor treatment or by genetic mutation...
August 24, 2016: Disease Models & Mechanisms
Carolina Uggenti, Kit Briant, Anne-Kathrin Streit, Steven Thomson, Yee Hui Koay, Richard A Baines, Eileithyia Swanton, Forbes D Manson
Autosomal recessive bestrophinopathy (ARB) is a retinopathy caused by mutations in the bestrophin-1 protein which is thought to function as a Ca(2+)-gated Cl(-) channel in the basolateral surface of the retinal pigment epithelium (RPE). Using a stably-transfected polarised epithelial cell model, we show that 4 ARB mutant bestrophin-1 proteins were mislocalised and subjected to proteasomal degradation. In contrast to the wildtype bestrophin-1, each of the 4 mutant proteins also failed to conduct Cl(-) ions in transiently transfected cells as determined by whole-cell patch-clamp...
August 12, 2016: Disease Models & Mechanisms
Mary P Colasanto, Shai Eyal, Payam Mohassel, Michael Bamshad, Carsten Bonnemann, Elazar Zelzer, Anne M Moon, Gabrielle Kardon
In the vertebrate limb over 40 muscles are arranged in a precise pattern of attachment via muscle connective tissue and tendon to bone and provide an extensive range of motion. How the development of somite-derived muscle is coordinated with the development of lateral plate-derived muscle connective tissue, tendon, and bone to assemble a functional limb musculoskeletal system is a long-standing question. Mutations in the T-box transcription factor, TBX3, have previously been identified as the genetic cause of ulnar-mammary syndrome (UMS), characterized by distinctive defects in posterior forelimb bones...
August 4, 2016: Disease Models & Mechanisms
Jacob Kjell, Lars Olson
A long-standing goal of spinal cord injury research is to develop effective spinal cord repair strategies for the clinic. Rat models of spinal cord injury provide an important mammalian model in which to evaluate treatment strategies and to understand the pathological basis of spinal cord injuries. These models have facilitated the development of robust tests for assessing the recovery of locomotor and sensory functions. Rat models have also allowed us to understand how neuronal circuitry changes following spinal cord injury and how recovery could be promoted by enhancing spontaneous regenerative mechanisms and by counteracting intrinsic inhibitory factors...
October 1, 2016: Disease Models & Mechanisms
Anthony C Y Yau, Rikard Holmdahl
Rheumatoid arthritis is a chronic inflammatory joint disorder characterised by erosive inflammation of the articular cartilage and by destruction of the synovial joints. It is regulated by both genetic and environmental factors, and, currently, there is no preventative treatment or cure for this disease. Genome-wide association studies have identified ∼100 new loci associated with rheumatoid arthritis, in addition to the already known locus within the major histocompatibility complex II region. However, together, these loci account for only a modest fraction of the genetic variance associated with this disease and very little is known about the pathogenic roles of most of the risk loci identified...
October 1, 2016: Disease Models & Mechanisms
Aida Moreno-Moral, Enrico Petretto
Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points...
October 1, 2016: Disease Models & Mechanisms
Mary Shimoyama, Stanley J F Laulederkind, Jeff De Pons, Rajni Nigam, Jennifer R Smith, Marek Tutaj, Victoria Petri, G Thomas Hayman, Shur-Jen Wang, Omid Ghiasvand, Jyothi Thota, Melinda R Dwinell
Rattus norvegicus, the laboratory rat, has been a crucial model for studies of the environmental and genetic factors associated with human diseases for over 150 years. It is the primary model organism for toxicology and pharmacology studies, and has features that make it the model of choice in many complex-disease studies. Since 1999, the Rat Genome Database (RGD; has been the premier resource for genomic, genetic, phenotype and strain data for the laboratory rat. The primary role of RGD is to curate rat data and validate orthologous relationships with human and mouse genes, and make these data available for incorporation into other major databases such as NCBI, Ensembl and UniProt...
October 1, 2016: Disease Models & Mechanisms
Bart Ellenbroek, Jiun Youn
Rodents (especially Mus musculus and Rattus norvegicus) have been the most widely used models in biomedical research for many years. A notable shift has taken place over the last two decades, with mice taking a more and more prominent role in biomedical science compared to rats. This shift was primarily instigated by the availability of a much larger genetic toolbox for mice, particularly embryonic-stem-cell-based targeting technology for gene disruption. With the recent emergence of tools for altering the rat genome, notably genome-editing technologies, the technological gap between the two organisms is closing, and it is becoming more important to consider the physiological, anatomical, biochemical and pharmacological differences between rats and mice when choosing the right model system for a specific biological question...
October 1, 2016: Disease Models & Mechanisms
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