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Disease Models & Mechanisms

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https://www.readbyqxmd.com/read/28550101/a-novel-experimental-rat-model-of-peripheral-nerve-scarring-reliably-mimicking-post-surgical-complications-and-recurring-adhesions
#1
Angela Lemke, Carina Penzenstadler, James Ferguson, Dominika Lidinsky, Rudolf Hopf, Monika Bradl, Heinz Redl, Susanne Wolbank, Thomas Hausner
Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathological processes following nerve injury and surgical interventions on peripheral nerves in human patients. Furthermore, these signs can reoccur following external neurolysis, currently the most common surgical treatment, thus leading to renewed nerve function impairment and chronic pain. To enable a successful evaluation of new therapeutic approaches, it is crucial to use a reproducible animal model that mimics the main clinical symptoms occurring in human patients...
May 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28550100/an-alternative-surgical-approach-reduces-variability-following-filament-induction-of-experimental-stroke-in-mice
#2
M Trotman-Lucas, M E Kelly, J Janus, R Fern, C L Gibson
Animal models are critical for understanding the pathology of stroke and investigating potential treatments. However, in vivo stroke models are associated, particularly in mice, with high variability in lesion volume. We investigated whether a surgical refinement where reperfusion is not reliant on the Circle of Willis reduced outcome variability. Mice underwent 60 minutes of transient middle cerebral artery occlusion avoiding ligation of the external carotid artery. During reperfusion the common carotid artery was either ligated (standard approach), or it was repaired to allow re-establishment of blood flow through the common carotid artery...
May 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28550099/viral-delivery-of-c9orf72-hexanucleotide-repeat-expansions-in-mice-lead-to-repeat-length-dependent-neuropathology-and-behavioral-deficits
#3
Saul Herranz-Martin, Jayanth Chandran, Katherine Lewis, Padraig Mulcahy, Adrian Higginbottom, Callum Walker, Isabel Martinez-Pena Y Valenzuela, Ross A Jones, Ian Coldicott, Tommaso Iannitti, Mohammed Akaaboune, Sherif F El-Khamisy, Thomas H Gillingwater, Pamela J Shaw, Mimoun Azzouz
Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, though it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here we generated two novel lines of mice that overexpress either 10 pure or 102 interrupted G4C2 repeats mediated by adeno-associated virus (AAV) and characterized relevant pathology and disease-related behavioral phenotypes...
May 26, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28546289/a-tripeptidyl-peptidase-1-is-a-binding-partner-of-gphr-golgi-ph-regulator-in-dictyostelium
#4
Maria Stumpf, Rolf Müller, Berthold Gaßen, Regina Wehrstedt, Petra Fey, Malte A Karow, Ludwig Eichinger, Gernot Glöckner, Angelika A Noegel
Mutations in tripeptidyl peptidase 1 (TPP1) have been associated with late infantile neuronal ceroid lipofuscinosis (NCL2), a neurodegenerative disorder. TPP1 is a lysosomal serine protease, which removes tripeptides from the amino terminus of proteins and is composed of an N-terminal prodomain and a catalytic domain. It is conserved in mammals, amphibians, fish and the amoeba Dictyostelium discoideum. D. discoideum harbors at least six genes encoding tripeptidyl peptidase 1, tpp1A to tpp1F We identified TPP1F as binding partner of Dictyostelium GPHR (Golgi pH regulator), which is an evolutionary highly conserved intracellular transmembrane protein...
May 25, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28546288/dynamic-changes-in-the-skeletal-muscle-proteome-during-denervation-induced-atrophy
#5
Franziska Lang, Sriram Aravamudhan, Hendrik Nolte, Clara Tuerk, Soraya Hölper, Stefan Müller, Stefan Günther, Bert Blaauw, Thomas Braun, Marcus Krüger
Loss of neuronal stimulation enhances protein breakdown and reduces protein synthesis, causing rapid muscle mass loss. To elucidate the pathophysiological adaptations that occur in atrophying muscles, we used stable isotope labelling and mass spectrometry to accurately quantify protein expression changes during denervation-induced atrophy after sciatic nerve section in the mouse gastrocnemius muscle (GAST). Additionally, mice were fed a SILAC diet containing (13)C6 lysine for four, seven, or eleven days to calculate relative levels of protein synthesis in denervated and control muscles...
May 25, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28495673/parallel-imaging-of-drosophila-embryos-for-quantitative-analysis-of-genetic-perturbations-of-the-ras-pathway
#6
Yogesh Goyal, Thomas J Levario, Henry H Mattingly, Susan Holmes, Stanislav Y Shvartsman, Hang Lu
The Ras pathway patterns the poles of the Drosophila embryo by downregulating the levels and activity of a DNA-binding transcriptional repressor Capicua (Cic). We demonstrate that the spatiotemporal pattern of Cic during this signaling event can be harnessed for functional studies of the Ras-pathway mutations from human diseases. Our approach relies on a new microfluidic device that enables parallel imaging of Cic dynamics in dozens of live embryos. We found that although the pattern of Cic in early embryos is complex, it can be accurately approximated by a product of one spatial profile and one time-dependent amplitude...
May 11, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28483796/imaging-of-viral-neuroinvasion-in-the-zebrafish-reveals-that-sindbis-and-chikungunya-viruses-favour-different-entry-routes
#7
Gabriella Passoni, Christelle Langevin, Nuno Palha, Bryan C Mounce, Valérie Briolat, Pierre Affaticati, Elodie De Job, Jean-Stéphane Joly, Marco Vignuzzi, Maria-Carla Saleh, Philippe Herbomel, Pierre Boudinot, Jean-Pierre Levraud
Alphaviruses, such as chikungunya (CHIKV) and Sindbis virus (SINV), are vector‑borne pathogens that cause acute illnesses in humans and are sometimes associated with neuropathies, especially in infants and elderly patients. Little is known about their entry mechanism in the central nervous system (CNS), even for SINV, which has been used extensively as a model for viral encephalopathies. We previously established a CHIKV infection model in the optically transparent zebrafish larva; here we describe a new SINV infection model in this host...
May 8, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28450472/paneth-cell-disruption-induced-necrotizing-enterocolitis-requires-live-bacteria-and-occurs-independent-of-tlr4-signaling
#8
Jessica R White, Huiyu Gong, Brock Pope, Patrick Schlievert, Steven J McElroy
OBJECTIVE: Necrotizing enterocolitis (NEC) remains a leading cause of morbidity and mortality in premature infants. Both human surgical specimens and animal models suggest a potential involvement of Paneth cells in NEC pathogenesis. Paneth cells play critical roles in epithelial homeostasis, innate immunity, and host-microbial interactions. Yet, the complex interplay between Paneth cell disruption, epithelial barrier dysfunction, and microbial-driven inflammation remains unclear in the immature intestine...
April 27, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28424158/generation-of-a-multipurpose-prdm16-allele-by-targeted-trapping
#9
A Strassman, F Schnütgen, Q Dai, J C Jones, A C Gomez, L Pitstick, N E Holton, R Moskal, E R Leslie, H von Melchner, D R Beier, B C Bjork
Gene trap mutagenesis is a powerful tool to create loss-of-function mutations in mice and other model organisms. Modifications of traditional gene trap cassettes, including addition of conditional features in the form of Flip-excision (FlEx) arrays enabling directional gene trap cassette inversions by Cre and Flpe site-specific recombinases, greatly enhanced their experimental potential. By taking advantage of these conditional gene trap cassettes, we developed a generic strategy for generating conditional mutations and validated this strategy in mice carrying a multipurpose allele of the Prdm16 transcription factor gene...
April 19, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28389479/characterization-of-drosophila-saposin-related-mutants-as-a-model-for-lysosomal-sphingolipid-storage-diseases
#10
Julia Sellin, Heike Schulze, Marie Paradis, Dominic Gosejacob, Cyrus Papan, Andrej Shevchenko, Olympia Ekaterina Psathaki, Achim Paululat, Melanie Thielisch, Konrad Sandhoff, Michael Hoch
Sphingolipidoses are inherited diseases belonging to the class of lysosomal storage diseases (LSDs), which are characterized by the accumulation of indigestible material in the lysosome caused by specific defects in the lysosomal degradation machinery. While some LSDs can be efficiently treated by enzyme replacement therapy (ERT), this is not possible if the nervous system is affected due to the presence of the blood brain barrier. Sphingolipidoses in particular often present as severe, untreatable forms of LSDs with massive sphingolipid and membrane accumulation in lysosomes, neurodegeneration, and very short life expectancy...
April 7, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28381495/dietary-reversal-of-neuropathy-in-a-murine-model-of-prediabetes-and-the-metabolic-syndrome
#11
Lucy M Hinder, Phillipe D O'Brien, John M Hayes, Carey Backus, Andrew P Solway, Catrina Sims-Robinson, Eva L Feldman
Patients with the metabolic syndrome, defined as obesity, dyslipidemia, hypertension, and impaired glucose tolerance (IGT), can develop the same macro- and microvascular complications as patients with type 2 diabetes, including peripheral neuropathy. In type 2 diabetes, glycemic control has little effect on the development and progression of peripheral neuropathy, suggesting that other metabolic syndrome components may contribute to the presence of neuropathy. A parallel phenomenon is observed in patients with prediabetes and the metabolic syndrome, where improvement in weight and dyslipidemia more closely correlates with restoration of nerve function than improvement in glycemic status...
April 5, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28363987/progesterone-induced-neuroprotection-in-reperfusion-promoted-mitochondrial-dysfunction-following-focal-cerebral-ischemia-in-rats
#12
Syed Suhail Andrabi, Suhel Parvez, Heena Tabassum
Alterations in mitochondrial permeability transition and organelle damage are key players in the development of cerebral ischemic tissue injury due to associated modifications in ATP turnover and cellular apoptosis/necrosis. Early restoration of blood flow and improvement of mitochondrial function might reverse the situation and help in recovery following an onset of stroke. Mitochondria and related bioenergetics can be effectively used as pharmacological targets. Progesterone (P4), one of the promising neurosteroids, has been found neuroprotective in various models of neurological diseases through a number of mechanisms...
March 31, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28348140/a-classification-system-for-zebrafish-adipose-tissues
#13
James E N Minchin, John F Rawls
The zebrafish model system offers significant utility for in vivo imaging of adipose tissue (AT) dynamics, and screening to identify chemical and genetic modifiers of adiposity. In particular, AT can be accurately quantified in live zebrafish using fluorescent lipophilic dyes (FLDs). Although, this methodology offers considerable promise, the comprehensive identification and classification of zebrafish ATs has not been performed. Here we utilize FLDs and in vivo imaging to systematically identify, classify and quantify the zebrafish AT pool...
March 27, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28331058/slga-the-homologue-of-the-human-schizophrenia-associated-prodh-gene-acts-in-clock-neurons-to-regulate-drosophila-aggression
#14
Liesbeth Zwarts, Veerle Vulsteke, Edgar Buhl, James J L Hodge, Patrick Callaerts
Mutations in proline dehydrogenase (PRODH) are linked to behavioral alterations in schizophrenia and as part of DiGeorge and velo-cardio-facial syndromes, but the role of PRODH in their etiology remains unclear. We here establish a Drosophila model to study the role of PRODH in behavioral disorders. We determine the distribution of the Drosophila PRODH homolog slgA in the brain and show that knock-down and overexpression of human PRODH and slgA in the lateral neurons ventral (LNv) lead to altered aggressive behavior...
March 22, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28331057/upregulation-of-distinct-collagen-transcripts-in-post-surgery-scar-tissue-a-study-of-conjunctival-fibrosis
#15
Li-Fong Seet, Li Zhen Toh, Stephanie W L Chu, Sharon N Finger, Jocelyn L L Chua, Tina T Wong
Excessive accumulation of collagen is often used to assess the development of fibrosis. This study aims to identify collagen genes that define fibrosis in the conjunctiva following glaucoma filtration surgery (GFS). Using the mouse model of GFS, we have identified collagen transcripts that were upregulated in the fibrotic phase of wound healing via RNA-seq. The top three highest induced collagen transcripts belong to Col8a1, Col11a1 and Col8a2 Further validation of the Col8a1, Col11a1 and Col8a2 transcripts revealed their increase by 67-, 54- and 18-folds respectively in the fibrotic phase, compared to 12-fold for Col1a1, the most commonly evaluated collagen gene for fibrosis...
March 22, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28325753/mouse-model-for-inherited-renal-fibrosis-associated-with-endoplasmic-reticulum-stress
#16
Sian E Piret, Eric Olinger, Anita A C Reed, M Andrew Nesbit, Tertius A Hough, Liz Bentley, Olivier Devuyst, Roger Cox, Rajesh V Thakker
Renal fibrosis is a common feature of renal failure resulting from multiple aetiologies, including diabetic nephropathy, hypertension and inherited renal disorders. However, the mechanisms of renal fibrosis are incompletely understood and we therefore explored these by establishing a mouse model for a renal tubular disorder, referred to as autosomal dominant tubulointerstitial kidney disease (ADTKD) due to missense uromodulin (UMOD) mutations (ADTKD-UMOD). ADTKD-UMOD, which is associated with retention of mutant uromodulin in the endoplasmic reticulum (ER) of renal thick ascending limb cells, is characterized by hyperuricemia, interstitial fibrosis, inflammation, and renal failure, and we used targeted homologous recombination to generate a knock-in mouse model with an ADTKD-causing missense cysteine to arginine uromodulin mutation (C125R)...
March 21, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28280001/a-rapid-and-effective-method-for-screening-sequencing-and-reporter-verification-of-engineered-frameshift-mutations-in-zebrafish
#17
Sergey V Prykhozhij, Shelby L Steele, Babak Razaghi, Jason N Berman
Clustered Regularly Interspaced Palindromic Repeats (CRISPR)/Cas9 adaptive immunity against pathogens in bacteria has been adapted for genome editing and applied in zebrafish (Danio rerio) to generate frameshift mutations in protein-coding genes. Although there are methods to detect, quantify and sequence CRISPR/Cas9-induced mutations, identifying mutations in F1 heterozygous fish remains challenging. Additionally, sequencing a mutation and assuming that it causes a frameshift does not prove causality because of possible alternative translation start sites and potential effects of mutations on splicing...
March 9, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28258125/a-drosophila-model-of-dominant-inclusion-body-myopathy-3-shows-diminished-myosin-kinetics-that-reduce-muscle-power-and-yield-myofibrillar-defects
#18
Jennifer A Suggs, Girish C Melkani, Bernadette M Glasheen, Mia M Detor, Anju Melkani, Nathan P Marsan, Douglas M Swank, Sanford I Bernstein
Inclusion body myopathy type 3 (IBM-3) patients display congenital joint contractures with early-onset muscle weakness that becomes more severe in adults. The disease arises from an autosomal dominant point mutation causing an E706K substitution in myosin heavy chain type IIa. We previously expressed the corresponding myosin mutation (E701K) in homozygous Drosophila indirect flight muscles and recapitulated the myofibrillar degeneration and inclusion bodies observed in the human disease. We also found that purified E701K myosin has dramatically reduced actin-sliding velocity and ATPase levels...
March 3, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28468939/modelling-amyotrophic-lateral-sclerosis-progress-and-possibilities
#19
REVIEW
Philip Van Damme, Wim Robberecht, Ludo Van Den Bosch
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects the motor system and presents with progressive muscle weakness. Most patients survive for only 2-5 years after disease onset, often due to failure of the respiratory muscles. ALS is a familial disease in ∼10% of patients, with the remaining 90% developing sporadic ALS. Over the past decade, major advances have been made in our understanding of the genetics and neuropathology of ALS. To date, around 20 genes are associated with ALS, with the most common causes of typical ALS associated with mutations in SOD1, TARDBP, FUS and C9orf72 Advances in our understanding of the genetic basis of ALS have led to the creation of different models of this disease...
May 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28468938/the-role-of-ca-2-signaling-in-parkinson-s-disease
#20
REVIEW
Sofia V Zaichick, Kaitlyn M McGrath, Gabriela Caraveo
Across all kingdoms in the tree of life, calcium (Ca(2+)) is an essential element used by cells to respond and adapt to constantly changing environments. In multicellular organisms, it plays fundamental roles during fertilization, development and adulthood. The inability of cells to regulate Ca(2+) can lead to pathological conditions that ultimately culminate in cell death. One such pathological condition is manifested in Parkinson's disease, the second most common neurological disorder in humans, which is characterized by the aggregation of the protein, α-synuclein...
May 1, 2017: Disease Models & Mechanisms
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