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Disease Models & Mechanisms

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https://www.readbyqxmd.com/read/29084770/renal-carcinoma-kidney-progenitor-cell-chimera-organoid-as-a-novel-tumourigenesis-gene-discovery-model
#1
Qi Xu, Sanna Junttila, Andreas Scherer, Khem Raj Giri, Oona Kivelä, Ilya Skovorodkin, Juha Röning, Susan E Quaggin, Hans-Peter Marti, Jingdong Shan, Anatoly Samoylenko, Seppo J Vainio
Three-dimensional organoids provide a new way to model various diseases, including cancer. We made use of recently developed kidney organ primordia tissue engineering technologies to create novel renal organoids for cancer gene discovery. We then tested whether our novel assays can be used to examine kidney cancer development. First we identified the transcriptome profiles of quiescent embryonic metanephric mesenchymes (MM) and of MM in which the nephrogenesis program had been induced ex vivo The transcriptome profiles were then compared to the profiles of RCC patients and controls...
October 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29084769/systemic-hiv-1-infection-produces-a-unique-glial-footprint-in-humanized-mouse-brains
#2
Weizhe Li, Santhi Gorantla, Howard E Gendelman, Larisa Y Poluektova
Studies of innate glial cell responses for progressive human immunodeficiency virus type one (HIV-1) infection are limited by a dearth of human disease relevant small-animal models. To overcome this obstacle, newborn NOD/SCID/IL2Rγc(-/-) (NSG) mice were reconstituted with a humanized brain and immune systems. NSG animals of both sexes were transplanted with human neuroglial progenitors (NPC) and hematopoietic stem cells. Intraventricular injection of NPC symmetrically repopulated the mouse brain parenchyma with human astrocytes and oligodendrocytes...
October 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29084768/lyplal1-is-dispensable-for-normal-fat-deposition-in-mice
#3
Rachel A Watson, Amy S Gates, Elizabeth H Wynn, Fiona E Calvert, Amandine Girousse, Christopher J Lelliott, Inês Barroso
Genome-wide association studies (GWAS) have detected association between variants in or near the Lysophospholipase-like 1 (LYPLAL1) locus and metabolic traits, including central obesity, fatty liver and waist-hip ratio. LYPLAL1 is also known to be upregulated in the adipose tissue of obese patients. However, the physiological role of LYPLAL1 is not understood. To investigate the function of Lyplal1 in vivo we investigated the phenotype of the Lyplal1(tm1a(KOMP)Wtsi) homozygous mouse. Body composition was unaltered in Lyplal1 knockout mice as assessed by Dual-energy X-ray absorptiometry (DEXA) scanning, both on normal chow and on a high fat diet...
October 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29061563/rescue-of-atxn3-neuronal-toxicity-in-c-elegans-by-chemical-modification-of-er-stress
#4
Yasmin Fardghassemi, Arnaud Tauffenberger, Sarah Gosselin, J Alex Parker
Background: Polyglutamine expansion diseases are a group of hereditary neurodegenerative disorders that develop when a CAG repeat in the causative genes are unstably expanded above a certain threshold. The expansion of trinucleotide CAG repeats cause hereditary adult-onset neurodegenerative disorders such as Huntington's disease, dentatorubral-pallidoluysian atrophy, spinobulbar muscular atrophy and multiple forms of spinocerebellar ataxia (SCA). The most common dominantly inherited spinocerebellar ataxia is the type 3 (SCA3) also known as Machado-Joseph disease (MJD), is an autosomal dominant, progressive neurological disorder...
October 23, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29025897/a-drosophila-model-of-insulin-resistance-associated-with-the-human-trib3-q-r-polymorphism
#5
Zachary Fischer, Rahul Das, Anna Shipman, Jin-Yuan Fan, Laramie Pence, Samuel Bouyain, Leonard L Dobens
Members of the Tribbles family of proteins are conserved pseudokinases with diverse roles in cell growth and proliferation. Both Drosophila Tribbles (Trbl) and vertebrate Trib3 proteins bind to Akt kinase to block its phosphorylation-activation and reduce downstream insulin-stimulated anabolism. A single nucleotide polymorphism (SNP) variant in human Trib3, which results in a glutamine (Q) to arginine (R) missense mutation in a conserved motif at position 84, confers stronger Akt binding resulting in reduced Akt phosphorylation and is associated with a predisposition to Type II diabetes, cardiovascular disease, diabetic nephropathy, chronic kidney disease and leukemogenesis...
October 12, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28993314/mecp2-regulates-tnfa-during-zebrafish-embryonic-development-and-acute-inflammation
#6
M van der Vaart, O Svoboda, B G Weijts, R Espín-Palazón, V Sapp, T Pietri, M Bagnat, A R Muotri, D Traver
Mutations in MECP2 cause Rett syndrome, a severe neurological disorder with autism-like features. Duplication of MECP2 also causes severe neuropathology. Both diseases display immunological abnormalities that suggest a role for MeCP2 in controlling immune and inflammatory responses. Here, we used mecp2-null zebrafish to study the potential function of Mecp2 as an immunological regulator. Mecp2-deficiency resulted in an increase in neutrophil infiltration and upregulated expression of the pro- and anti-inflammatory cytokines Il1b and Il10 as a secondary response to disturbances in tissue homeostasis...
October 9, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28982681/early-neonatal-loss-of-inhibitory-synaptic-input-to-the-spinal-motor-neurons-confers-spina-bifida-like-leg-dysfunction-in-a-chicken-model
#7
Md Sakirul Islam Khan, Hiroaki Nabeka, Farzana Islam, Tetsuya Shimokawa, Shouichiro Saito, Xuan Li, Soichiro Kawabe, Fumihiko Hamada, Tetsuya Tachibana, Seiji Matsuda
Spina bifida aperta (SBA), one of the most common congenital malformations, causes lifelong neurological complications particularly in terms of motor dysfunction. Fetuses with SBA exhibit voluntary leg movements in utero and during early neonatal life but these disappear within the first few weeks after birth. However, the pathophysiological sequence underlying such motor dysfunction remains unclear. Additionally, because important insights have yet to be obtained from human cases, an appropriate animal model is essential...
October 5, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28982680/chronic-psychosocial-stress-disturbs-long-bone-growth-in-adolescent-mice
#8
S Foertsch, M Haffner-Luntzer, J Kroner, F Gross, K Kaiser, M Erber, S O Reber, A Ignatius
Although a strong association between psychiatric and somatic disorders is generally accepted, little is known regarding the interrelation between mental and skeletal health. While depressive disorders were shown to be strongly associated with osteoporosis and increased fracture risk, evidence from post-traumatic stress disorder (PTSD) patients is less consistent. Therefore, the present study investigated the influence of chronic psychosocial stress on bone using a well-established murine model for PTSD. 7-week-old C57BL/6N mice were subjected to chronic subordinate colony housing (CSC) for 19 days, whereas control mice were singly housed...
October 5, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28982679/evaluation-of-human-dermal-fibroblasts-directly-reprogrammed-to-adipocyte-like-cells-as-a-metabolic-disease-model
#9
Jian-Hua Chen, Kim Jee Goh, Nuno Rocha, Matthijs P Groeneveld, Marina Minic, Timothy G Barrett, David Savage, Robert K Semple
Adipose tissue is the primary tissue affected in most single gene forms of severe insulin resistance, and growing evidence has implicated it as a site where many risk alleles for insulin resistance identified in population-wide studies may exert their effect. There is thus increasing need for human adipocyte models in which to interrogate the function of known and emerging genetic risk variants, yet primary adipocyte cultures, existing immortalised cell lines, and stem-cell based models all have significant biological or practical limitations...
October 5, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28982678/functional-assays-for-the-assessment-of-the-pathogenicity-of-variants-in-gosr2-an-er-to-golgi-snare-involved-in-progressive-myoclonus-epilepsies
#10
Jörn M Völker, Mykola Dergai, Luciano A Abriata, Yves Mingard, Daniel Ysselstein, Dimitri Krainc, Matteo Dal Peraro, Gabriele Fischer von Mollard, Dirk Fasshauer, Judith Koliwer, Michael Schwake
Progressive myoclonus epilepsies (PME) are inherited disorders characterized by myoclonus, generalized tonic-clonic seizures, and ataxia. One of the genes that are associated with PME is the ER-to-Golgi Qb-SNARE GOSR2, which forms a SNARE complex with Syntaxin5, Bet1 and Sec22b. Most PME patients are homo-zygous for a p.Gly144Trp mutation and develop similar clinical presentations. Recently, a patient who was compound heterozygous for the p.Gly144Trp and a novel p.Lys164del mutation was identified. Since this patient presented with a milder disease phenotype, we hypothesized that the p...
October 5, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29125828/comprehensive-analysis-of-gene-expression-patterns-in-friedreich-s-ataxia-fibroblasts-by-rna-sequencing-reveals-altered-levels-of-protein-synthesis-factors-and-solute-carriers
#11
Jill Sergesketter Napierala, Yanjie Li, Yue Lu, Kevin Lin, Lauren A Hauser, David R Lynch, Marek Napierala
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease usually caused by large homozygous expansions of GAA repeat sequences in intron 1 of the frataxin (FXN) gene. FRDA patients homozygous for GAA expansions have low FXN mRNA and protein levels when compared with heterozygous carriers or healthy controls. Frataxin is a mitochondrial protein involved in iron-sulfur cluster synthesis, and many FRDA phenotypes result from deficiencies in cellular metabolism due to lowered expression of FXN Presently, there is no effective treatment for FRDA, and biomarkers to measure therapeutic trial outcomes and/or to gauge disease progression are lacking...
November 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29125827/early-cerebellar-deficits-in-mitochondrial-biogenesis-and-respiratory-chain-complexes-in-the-kiko-mouse-model-of-friedreich-ataxia
#12
Hong Lin, Jordi Magrane, Amy Rattelle, Anna Stepanova, Alexander Galkin, Elisia M Clark, Yi Na Dong, Sarah M Halawani, David R Lynch
Friedreich ataxia (FRDA), the most common recessive inherited ataxia, results from deficiency of frataxin, a small mitochondrial protein crucial for iron-sulphur cluster formation and ATP production. Frataxin deficiency is associated with mitochondrial dysfunction in FRDA patients and animal models; however, early mitochondrial pathology in FRDA cerebellum remains elusive. Using frataxin knock-in/knockout (KIKO) mice and KIKO mice carrying the mitoDendra transgene, we show early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in this FRDA model...
November 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29125826/lysyl-oxidases-regulate-fibrillar-collagen-remodelling-in-idiopathic-pulmonary-fibrosis
#13
Gavin Tjin, Eric S White, Alen Faiz, Delphine Sicard, Daniel J Tschumperlin, Annabelle Mahar, Eleanor P W Kable, Janette K Burgess
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with few effective therapeutic options. Structural remodelling of the extracellular matrix [i.e. collagen cross-linking mediated by the lysyl oxidase (LO) family of enzymes (LOX, LOXL1-4)] might contribute to disease pathogenesis and represent a therapeutic target. This study aimed to further our understanding of the mechanisms by which LO inhibitors might improve lung fibrosis. Lung tissues from IPF and non-IPF subjects were examined for collagen structure (second harmonic generation imaging) and LO gene (microarray analysis) and protein (immunohistochemistry and western blotting) levels...
November 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29125825/understanding-the-aetiology-and-resolution-of-chronic-otitis-media-from-animal-and-human-studies
#14
REVIEW
Mahmood F Bhutta, Ruth B Thornton, Lea-Ann S Kirkham, Joseph E Kerschner, Michael T Cheeseman
Inflammation of the middle ear, known clinically as chronic otitis media, presents in different forms, such as chronic otitis media with effusion (COME; glue ear) and chronic suppurative otitis media (CSOM). These are highly prevalent diseases, especially in childhood, and lead to significant morbidity worldwide. However, much remains unclear about this disease, including its aetiology, initiation and perpetuation, and the relative roles of mucosal and leukocyte biology, pathogens, and Eustachian tube function...
November 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29125824/intraluminal-valves-development-function-and-disease
#15
REVIEW
Xin Geng, Boksik Cha, Md Riaj Mahamud, R Sathish Srinivasan
The circulatory system consists of the heart, blood vessels and lymphatic vessels, which function in parallel to provide nutrients and remove waste from the body. Vascular function depends on valves, which regulate unidirectional fluid flow against gravitational and pressure gradients. Severe valve disorders can cause mortality and some are associated with severe morbidity. Although cardiac valve defects can be treated by valve replacement surgery, no treatment is currently available for valve disorders of the veins and lymphatics...
November 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29046322/pumilio2-deficient-mice-show-a-predisposition-for-epilepsy
#16
Philipp Follwaczny, Rico Schieweck, Therese Riedemann, Antonia Demleitner, Tobias Straub, Anna H Klemm, Martin Bilban, Bernd Sutor, Bastian Popper, Michael A Kiebler
Epilepsy is a neurological disease that is caused by abnormal hypersynchronous activities of neuronal ensembles leading to recurrent and spontaneous seizures in human patients. Enhanced neuronal excitability and a high level of synchrony between neurons seem to trigger these spontaneous seizures. The molecular mechanisms, however, regarding the development of neuronal hyperexcitability and maintenance of epilepsy are still poorly understood. Here, we show that pumilio RNA-binding family member 2 (Pumilio2; Pum2) plays a role in the regulation of excitability in hippocampal neurons of weaned and 5-month-old male mice...
November 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28954734/overexpression-of-microrna-722-fine-tunes-neutrophilic-inflammation-by-inhibiting-rac2-in-zebrafish
#17
Alan Y Hsu, Decheng Wang, Theodore Gurol, Wenqing Zhou, Xiaoguang Zhu, Hsiu-Yi Lu, Qing Deng
Neutrophilic inflammation is essential for defending against invading pathogens, but can also be detrimental in many clinical settings. The hematopoietic-specific small Rho-GTPase Rac2 regulates multiple pathways that are essential for neutrophil activation, including adhesion, migration, degranulation and production of reactive oxygen species. This study tested the hypothesis that partially suppressing rac2 in zebrafish neutrophils by using a microRNA (miRNA) would inhibit neutrophil migration and activation, which would reduce the immunological damage caused by systemic inflammation...
November 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28882930/renal-scar-formation-and-kidney-function-following-antibiotic-treated-murine-pyelonephritis
#18
Patrick D Olson, Lisa K McLellan, Alice Liu, Kelleigh L Briden, Kristin M Tiemann, Allyssa L Daugherty, Keith A Hruska, David A Hunstad
We present a new preclinical model to study treatment, resolution and sequelae of severe ascending pyelonephritis. Urinary tract infection (UTI), primarily caused by uropathogenic Escherichia coli (UPEC), is a common disease in children. Severe pyelonephritis is the primary cause of acquired renal scarring in childhood, which may eventually lead to hypertension and chronic kidney disease in a small but important fraction of patients. Preclinical modeling of UTI utilizes almost exclusively females, which (in most mouse strains) exhibit inherent resistance to severe ascending kidney infection; consequently, no existing preclinical model has assessed the consequences of recovery from pyelonephritis following antibiotic treatment...
November 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28882929/rhob-blockade-selectively-inhibits-autoantibody-production-in-autoimmune-models-of-rheumatoid-arthritis-and-lupus
#19
Laura Mandik-Nayak, James B DuHadaway, Jennifer Mulgrew, Elizabeth Pigott, Kaylend Manley, Summer Sedano, George C Prendergast, Lisa D Laury-Kleintop
During the development of autoimmune disease, a switch occurs in the antibody repertoire of B cells so that the production of pathogenic rather than non-pathogenic autoantibodies is enabled. However, there is limited knowledge concerning how this pivotal step occurs. Here, we present genetic and pharmacological evidence of a positive modifier function for the vesicular small GTPase RhoB in specifically mediating the generation of pathogenic autoantibodies and disease progression in the K/BxN preclinical mouse model of inflammatory arthritis...
November 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28993312/mmp-14-overexpression-correlates-with-the-neurodegenerative-process-in-familial-amyloidotic-polyneuropathy
#20
Diana Martins, João Moreira, Nádia Pereira Gonçalves, Maria João Saraiva
Levels of matrix metalloproteases (MMPs) can be differentially regulated in response to injury or neurological diseases. For instance, it is known that selective and short-term inhibition of MMP-14, a membrane-type 1 MMP, accelerates axon regeneration. Because axon growth and regeneration is impaired in familial amyloidotic polyneuropathy (FAP), a neurodegenerative disorder characterized by misfolding and deposition of mutant transthyretin (TTR) in the peripheral nervous system (PNS), we presently investigated the expression levels and the potential role for MMP-14 in this condition...
October 1, 2017: Disease Models & Mechanisms
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