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Disease Models & Mechanisms

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https://www.readbyqxmd.com/read/27874836/whole-genome-sequence-snp-chips-and-pedigree-structure-building-demographic-profiles-in-domestic-dog-breeds-to-optimize-genetic-trait-mapping
#1
Dayna L Dreger, Maud Rimbault, Brian W Davis, Adrienne Bhatnagar, Heidi G Parker, Elaine A Ostrander
In the decade following publication of the draft genome sequence of the domestic dog, extraordinary advances with application to several fields have been credited to the canine genetic system. Taking advantage of closed breeding populations and the subsequent selection for aesthetic and behavioral characteristics, researchers have leveraged the dog as an effective natural model for the study of complex traits, such as disease susceptibility, behavior, and morphology, generating unique contributions to human health and biology...
November 17, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27874834/recovery-of-erectile-function-comparing-autologous-nerve-grafts-unseeded-conduits-schwann-cell-seeded-guidance-tubes-and-gdnf-overexpressing-schwann-cell-grafts
#2
Florian May, Alexander Buchner, Kaspar Matiasek, Boris Schlenker, Christian Stief, Norbert Weidner
Dissection of the cavernous nerves during radical prostatectomy for prostate cancer eliminates spontaneous erections. Using the rat as an experimental model, we compared the regenerative capacity of autologous nerve grafts and Schwann cell seeded nerve guides.After bilateral excision of cavernous nerve segments, cavernous nerves were reconstructed using unseeded silicon tubes (UT), nerve autografts (NA) and silicon tubes seeded with either Glial cell line-derived (GDNF)-overexpressing or green fluorescent protein (GFP)-expressing Schwann cells (SCs) (16 study nerves per group)...
November 17, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27874835/heterotypic-models-of-osteosarcoma-recapitulate-tumor-heterogeneity-and-biological-behavior
#3
Milcah C Scott, Hirotaka Tomiyasu, John R Garbe, Ingrid Cornax, Clarissa Amaya, M Gerard O'Sullivan, Subbaya Subramanian, Brad A Bryan, Jaime F Modiano
Osteosarcoma (OS) is a heterogeneous and rare disease with a disproportionate impact, as it mainly affects children and adolescents. Lamentably, more than half of patients with OS succumb to metastatic disease. Clarification of the etiology of the disease, development of better strategies to manage progression, and methods to guide personalized treatments are among the unmet health needs for OS patients. Progress in managing the disease has been hindered by the extreme heterogeneity of OS; thus, better models that accurately recapitulate the natural heterogeneity of the disease are needed...
November 3, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27799148/deregulated-expression-of-hdac9-in-b-cells-promotes-development-of-lymphoproliferative-disease-and-lymphoma
#4
V S Gil, G Bhagat, L Howell, J Zhang, C H Kim, S Stengel, F Vega, A Zelent, K Petrie
Histone Deacetylase 9 (HDAC9) is expressed in B-cells and its overexpression has been observed in B-lymphoproliferative disorders and B-cell non-Hodgkin lymphomas (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL). To study the role of HDAC9 in lymphomagenesis we generated a genetically engineered mouse (GEM) model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eμ)...
October 28, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27780828/lurbinectedin-induces-depletion-of-tumor-associated-macrophages-tam-an-essential-component-of-its-in-vivo-synergism-with-gemcitabine
#5
María Virtudes Céspedes, María José Guillén, Pedro Pablo López-Casas, Francesca Sarno, Alberto Gallardo, Patricia Álamo, Carmen Cuevas, Manuel Hidalgo, Carlos María Galmarini, Paola Allavena, Pablo Avilés, Ramón Mangues
We explored whether the combination of lurbinectedin (PM01183) with the antimetabolite gemcitabine may result in synergistic antitumor effect in pancreatic adenocarcinoma (PDA) models. We also studied the contribution of lurbinectedin to this synergism. This drug presents a dual pharmacological effect that contributes to its in vivo antitumor activity: (i) specific binding to DNA minor groove inhibiting active transcription and DNA repair; and (ii) specific depletion of tumor-associated macrophages (TAMs).We evaluated the in vivo antitumor activity of lurbinectedin, gemcitabine (as single agents) and its combination in SW-1990 and MIA PaCa-2 cell-line xenografts and in patient-derived PDA models (AVATAR)...
October 20, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27736740/photoperiod-induced-obesity-in-the-brandt-s-vole-lasiopodomys-brandtii-a-model-of-healthy-obesity
#6
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
https://www.readbyqxmd.com/read/27664134/pharmacological-and-bbb-targeted-genetic-therapies-for-thyroid-hormone-dependent-hypomyelination
#7
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
https://www.readbyqxmd.com/read/27660200/an-in-vitro-model-of-murine-middle-ear-epithelium
#8
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
https://www.readbyqxmd.com/read/27638668/immortalized-parkinson-s-disease-lymphocytes-have-enhanced-mitochondrial-respiratory-activity
#9
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
https://www.readbyqxmd.com/read/27638666/preservation-of-cartilage-and-bone-architecture-is-the-most-important-aspect-for-maintaining-functionality-in-longstanding-experimental-arthritis
#10
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
https://www.readbyqxmd.com/read/27821603/preclinical-models-for-obesity-research
#11
REVIEW
Perry Barrett, Julian G Mercer, Peter J Morgan
A multi-dimensional strategy to tackle the global obesity epidemic requires an in-depth understanding of the mechanisms that underlie this complex condition. Much of the current mechanistic knowledge has arisen from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. These experimental models mimic certain aspects of the human condition and its root causes, particularly the over-consumption of calories and unbalanced diets. As with human obesity, obesity in rodents is the result of complex gene-environment interactions...
November 1, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27821602/drug-screening-using-model-systems-some-basics
#12
EDITORIAL
Ross Cagan
An increasing number of laboratories that focus on model systems are considering drug screening. Executing a drug screen is complicated enough. But the path for moving initial hits towards the clinic requires a different knowledge base and even a different mindset. In this Editorial I discuss the importance of doing some homework before you start screening. 'Lead hits', 'patentable chemical space' and 'druggability' are all concepts worth exploring when deciding which screening path to take. I discuss some of the lessons I learned that may be useful as you navigate the screening matrix...
November 1, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27664135/hsv-presence-in-brains-of-individuals-without-dementia-the-tasty-brain-series
#13
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 the prevalence of HSV type 1 and 2 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, of which six had Alzheimer's disease neuropathological amyloid beta (Aβ) aggregations...
November 1, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27638667/high-and-ultrahigh-field-magnetic-resonance-imaging-of-na%C3%A3-ve-injured-and-scarred-vocal-fold-mucosae-in-rats
#14
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...
November 1, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27585883/upregulation-of-the-nr2f1-a830082k12rik-gene-pair-in-murine-neural-crest-cells-results-in-a-complex-phenotype-reminiscent-of-waardenburg-syndrome-type-4
#15
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 and hair depigmentation, and inner ear defects. In the type 4 form, these defects show comorbidity 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...
November 1, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27562100/acute-and-long-term-outcomes-in-a-drosophila-melanogaster-model-of-classic-galactosemia-occur-independently-of-galactose-1-phosphate-accumulation
#16
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 the 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 minimizes or resolves the acute sequelae of CG, but fails 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...
November 1, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27736748/rat-models-of-spinal-cord-injury-from-pathology-to-potential-therapies
#17
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
https://www.readbyqxmd.com/read/27736747/rheumatoid-arthritis-identifying-and-characterising-polymorphisms-using-rat-models
#18
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
https://www.readbyqxmd.com/read/27736746/from-integrative-genomics-to-systems-genetics-in-the-rat-to-link-genotypes-to-phenotypes
#19
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
https://www.readbyqxmd.com/read/27736745/exploring-human-disease-using-the-rat-genome-database
#20
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; http://rgd.mcw.edu) 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
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