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Disease Models & Mechanisms

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https://www.readbyqxmd.com/read/28882930/renal-scar-formation-and-kidney-function-following-antibiotic-treated-murine-pyelonephritis
#1
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...
September 7, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28882929/rhob-blockade-selectively-inhibits-autoantibody-production-in-autoimmune-models-of-rheumatoid-arthritis-and-lupus
#2
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 favoring the production of pathogenic versus non-pathogenic autoantibodies. 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 model of inflammatory arthritis...
September 7, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28819044/the-parkinson-s-disease-associated-protein-dj-1-plays-a-positive-nonmitochondrial-role-in-endocytosis-in-dictyostelium-cells
#3
Suwei Chen, Sarah J Annesley, Rasha A F Jasim, Vanessa J Musco, Oana Sanislav, Paul R Fisher
The loss of function of DJ-1 caused by mutations of DJ-1 causes a form of familial Parkinson's Disease (PD). However, the role of DJ-1 in healthy and in PD cells is poorly understood. Even its subcellular localization in mammalian cells is uncertain, both cytosolic and mitochondrial locations having been reported. We show here that DJ-1 is normally located in the cytoplasm in healthy Dictyostelium discoideum cells. With its unique life cycle, straightforward genotype-phenotype relationships, experimental accesibility and genetic tractability, Dictyostelium discoideum offers an attractive model to investigate the roles of PD-associated genes...
August 17, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28819043/increased-acetylation-of-microtubules-rescues-human-tau-induced-microtubule-defects-and-neuromuscular-junction-abnormalities-in-drosophila
#4
Chuan-Xi Mao, Xue Wen, Shan Jin, Yong Q Zhang
Tau normally associates with and stabilizes microtubules (MTs), but is hyperphosphorylated and aggregated into neurofibrillary tangles in Alzheimer's disease and related neurodegenerative diseases, which are collectively known as tauopathies. MTs are regulated by different forms of post-translational modification including acetylation; acetylated MTs represent a more stable microtubule population. In our previous study, we show that inhibition of histone deacetylase 6 (HDAC6), which deacetylates tubulin at lysine 40, rescues defects in MTs and in neuromuscular junction growth caused by tau overexpression...
August 17, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28801532/activation-of-nkx2-5-calr-p53-signaling-pathway-by-hyperglycemia-induces-cardiac-remodeling-and-dysfunction-in-adult-zebrafish
#5
Sun Yanyi, Wang Qiuyun, Fang Yuehua, Wu Chunfang, Lu Guoping, Chen Zhenyue
Hyperglycemia is an independent risk factor for diabetic cardiomyopathy in humans; however, the underlying mechanisms have not been thoroughly elucidated. Zebrafish (Danio rerio) was used in this study as a novel vertebrate model to explore the signaling pathways of human adult cardiomyopathy. Hyperglycemia was induced by alternately immersing adult zebrafish in a glucose solution or water. The hyperglycemic fish gradually exhibited some hallmarks of cardiomyopathy such as myocardial hypertrophy and apoptosis, myofibril loss, fetal gene reactivation, and severe arrhythmia...
August 11, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28798136/adipose-tissue-metabolic-and-inflammatory-responses-to-stroke-are-altered-in-obese-mice
#6
Michael J Haley, Graham Mullard, Katherine A Hollywood, Garth J Cooper, Warwick B Dunn, Catherine B Lawrence
Obesity is an independent risk factor for stroke, though several clinical studies have reported that obesity improves stroke outcome. Obesity is hypothesised to aid recovery by protecting against post-stroke catabolism. We therefore assessed whether obese mice had an altered metabolic and inflammatory response to stroke. Obese ob/ob mice underwent 20 min middle cerebral artery occlusion and 24 h reperfusion. Lipid metabolism and expression of inflammatory cytokines were assessed in the plasma, liver and adipose tissue...
August 10, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28754838/the-chromatin-remodeling-bap-complex-limits-tumor-promoting-activity-of-the-hippo-pathway-effector-yki-to-prevent-neoplastic-transformation-in-drosophila-epithelia
#7
Shilin Song, Héctor Herranz, Stephen M Cohen
SWI/SNF chromatin remodeling complexes are mutated in many human cancers. In this report we make use of a Drosophila genetic model for epithelial tumor formation to explore the tumor suppressive role of SWI/SNF complex proteins. Members of the BAP complex exhibit tumor suppressor activity in tissue overexpressing the Yorkie (Yki) proto-oncogene, but not in tissue overexpressing EGFR. The BAP complex has been reported to serve as a Yki-binding cofactor to support Yki target expression. However, we observed that depletion of BAP leads to ectopic expression of Yki targets both autonomously and non-autonomously, suggesting additional indirect effects...
July 28, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28754837/p53-independent-dux4-pathology
#8
Darko Bosnakovski, Micah D Gearhart, Erik A Toso, Olivia O Recht, Anja Cucak, Abhinav K Jain, Michelle C Barton, Michael Kyba
FSHD is a genetically dominant myopathy caused by mutations that disrupt repression of the normally silent DUX4 gene, which encodes a transcription factor that has been shown to interfere with myogenesis when misexpressed at very low levels in myoblasts, and to cause cell death when overexpressed at high levels. A previous report using adeno-associated virus to deliver high levels of DUX4 to mouse skeletal muscle demonstrated severe pathology that was suppressed on a p53 knockout background, implying that DUX4 acted through the p53 pathway...
July 28, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28754836/screening-in-larval-zebrafish-reveals-tissue-specific-distributions-of-fifteen-fluorescent-compounds
#9
Yuxiao Yao, Shaoyang Sun, Fei Fei, Jingjing Wang, Youhua Wang, Ranran Zhang, Jing Wu, Lian Liu, Xiuyun Liu, Zhaomeng Cui, Qiang Li, Min Yu, Yongjun Dang, Xu Wang
Zebrafish is a prominent vertebrate model for low cost in vivo whole organism screening. In our recent screening of the distribution patterns of fluorescent compounds in live zebrafish larvae, fifteen compounds with tissue-specific distributions were identified. Several compounds were observed to accumulate in tissues where they were reported to induce side effects, and compounds with similar structures tended to be enriched in the same tissues, with minor differences. In particular, we found three novel red fluorescent bone staining dyes: purpurin, lucidin and 3-hydroxy-morindone, among which purpurin can effectively label bones in both larval and adult zebrafish, as well as in postnatal mice, without significantly affecting bone mass and density...
July 28, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28733363/lipidomic-profiling-of-patient-specific-induced-pluripotent-stem-cell-derived-hepatocyte-like-cells
#10
Mostafa Kiamehr, Leena E Viiri, Terhi Vihervaara, Kaisa M Koistinen, Mika Hilvo, Kim Ekroos, Reijo Käkelä, Katriina Aalto-Setälä
Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem cells (iPSCs) offer an alternative model for primary human hepatocytes to study lipid aberrations. However, the detailed lipid profile of HLCs is yet unknown. In the current study, functional HLCs were differentiated from iPSCs generated from dermal fibroblasts of three individuals by a 3-step protocol through definitive endoderm (DE) stage. In parallel, detailed lipidomic analyses as well as gene expression profiling of a set of lipid metabolism-related genes were performed during the entire differentiation process from iPSC to HLCs...
July 21, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28733362/loss-of-cln5-causes-altered-neurogenesis-in-a-childhood-neurodegenerative-disorder
#11
E Savchenko, Y Singh, H Konttinen, K Lejavova, L Mediavilla Santos, A Grubman, V Kärkkäinen, V Keksa-Goldsteine, N Naumenko, P Tavi, A R White, T M Malm, J Koistinaho, K M Kanninen
Neural stem/progenitor cells (NPCs) generate new neurons in the brain throughout the lifetime in an intricate process called neurogenesis. Neurogenic alterations are a common feature of several adult-onset neurodegenerative diseases. The neuronal ceroid lipofuscinoses (NCLs) are the most common group of inherited neurodegenerative diseases that mainly affect children. Pathological features of the NCLs include accumulation of lysosomal storage material, neuroinflammation, and neuronal degeneration, yet the exact cause of this group of diseases remains poorly understood...
July 21, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28714852/the-small-molecule-mimetic-agonist-trimebutine-of-adhesion-molecule-l1-contributes-to-functional-recovery-after-spinal-cord-injury-in-mice
#12
Junping Xu, Chengliang Hu, Qiong Jiang, Hongchao Pan, Huifan Shen, Melitta Schachner
Curing spinal cord injury (SCI) in mammals is a daunting task because of the lack of permissive mechanisms and strong inhibitory responses at and around the lesion. The neural cell adhesion molecule L1CAM (L1) has been shown to favor axonal regrowth and enhance neuronal survival and synaptic plasticity, and thus constitutes a viable target to promote regeneration after SCI. Since delivery of full-length L1 or its extracellular domain could encounter difficulties in translation to therapy in humans, we have identified several small organic compounds that bind to L1 and stimulate neuronal survival, neuronal migration, and neurite outgrowth in an L1-dependent manner...
July 14, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28714851/pdgfr%C3%AE-functions-in-endothelial-derived-cells-to-regulate-neural-crest-cells-and-development-of-the-great-arteries
#13
Haig Aghajanian, Young Kuk Cho, Nicholas W Rizer, Qiaohong Wang, Li Li, Karl Degenhardt, Rajan Jain
Originating as a single vessel emerging from the embryonic heart, the truncus arteriosus must septate and remodel into the aorta and pulmonary artery to support postnatal life. Defective remodeling or septation leads to abnormalities collectively known as conotruncal defects, which are associated with significant mortality and morbidity. Multiple populations of cells must interact to coordinate outflow tract remodeling, and cardiac neural crest has emerged as particularly important during this process. Abnormalities in cardiac neural crest have been implicated in the pathogenesis of multiple conotruncal defects, including persistent truncus arteriosus, double outlet right ventricle, and tetralogy of Fallot...
July 14, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28883017/nf%C3%AE%C2%BAb-signaling-in-alveolar-rhabdomyosarcoma
#14
Megan M Cleary, Atiya Mansoor, Teagan Settelmeyer, Yuichi Ijiri, Katherine J Ladner, Matthew N Svalina, Brian P Rubin, Denis C Guttridge, Charles Keller
Alveolar rhabdomyosarcoma (aRMS) is a pediatric soft tissue cancer commonly associated with a chromosomal translocation that leads to the expression of a Pax3:Foxo1 or Pax7:Foxo1 fusion protein, the developmental underpinnings of which may give clues to its therapeutic approaches. In aRMS, the NFκB-YY1-miR-29 regulatory circuit is dysregulated, resulting in repression of miR-29 and loss of the associated tumor suppressor activity. To further elucidate the role of NFκB in aRMS, we first tested 55 unique sarcoma cell lines and primary cell cultures in a large-scale chemical screen targeting diverse molecular pathways...
September 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28883016/mitochondrial-dynamics-in-parkinson-s-disease-a-role-for-%C3%AE-synuclein
#15
REVIEW
Victorio M Pozo Devoto, Tomas L Falzone
The distinctive pathological hallmarks of Parkinson's disease are the progressive death of dopaminergic neurons and the intracellular accumulation of Lewy bodies enriched in α-synuclein protein. Several lines of evidence from the study of sporadic, familial and pharmacologically induced forms of human Parkinson's disease also suggest that mitochondrial dysfunction plays an important role in disease progression. Although many functions have been proposed for α-synuclein, emerging data from human and animal models of Parkinson's disease highlight a role for α-synuclein in the control of neuronal mitochondrial dynamics...
September 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28883015/mouse-models-of-metastasis-progress-and-prospects
#16
REVIEW
Laura Gómez-Cuadrado, Natasha Tracey, Ruoyu Ma, Binzhi Qian, Valerie G Brunton
Metastasis is the spread of cancer cells from a primary tumor to distant sites within the body to establish secondary tumors. Although this is an inefficient process, the consequences are devastating as metastatic disease accounts for >90% of cancer-related deaths. The formation of metastases is the result of a series of events that allow cancer cells to escape from the primary site, survive in the lymphatic system or blood vessels, extravasate and grow at distant sites. The metastatic capacity of a tumor is determined by genetic and epigenetic changes within the cancer cells as well as contributions from cells in the tumor microenvironment...
September 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28883014/human-pluripotent-stem-cell-models-of-cardiac-disease-from-mechanisms-to-therapies
#17
REVIEW
Karina O Brandão, Viola A Tabel, Douwe E Atsma, Christine L Mummery, Richard P Davis
It is now a decade since human induced pluripotent stem cells (hiPSCs) were first described. The reprogramming of adult somatic cells to a pluripotent state has become a robust technology that has revolutionised our ability to study human diseases. Crucially, these cells capture all the genetic aspects of the patient from which they were derived. Combined with advances in generating the different cell types present in the human heart, this has opened up new avenues to study cardiac disease in humans and investigate novel therapeutic approaches to treat these pathologies...
September 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28768697/early-onset-torsion-dystonia-a-novel-high-throughput-yeast-genetic-screen-for-factors-modifying-protein-levels-of-torsina%C3%AE-e
#18
Lucía F Zacchi, John C Dittmar, Michael J Mihalevic, Annette M Shewan, Benjamin L Schulz, Jeffrey L Brodsky, Kara A Bernstein
Dystonia is the third most common movement disorder, but its diagnosis and treatment remain challenging. One of the most severe types of dystonia is early-onset torsion dystonia (EOTD). The best studied and validated EOTD-associated mutation, torsinAΔE, is a deletion of a C-terminal glutamate residue in the AAA+ ATPase torsinA. TorsinA appears to be an endoplasmic reticulum (ER)/nuclear envelope chaperone with multiple roles in the secretory pathway and in determining subcellular architecture. Many functions are disabled in the torsinAΔE variant, and torsinAΔE is also less stable than wild-type torsinA and is a substrate for ER-associated degradation...
September 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28768736/congenital-diaphragmatic-hernias-from-genes-to-mechanisms-to-therapies
#19
REVIEW
Gabrielle Kardon, Kate G Ackerman, David J McCulley, Yufeng Shen, Julia Wynn, Linshan Shang, Eric Bogenschutz, Xin Sun, Wendy K Chung
Congenital diaphragmatic hernias (CDHs) and structural anomalies of the diaphragm are a common class of congenital birth defects that are associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure. In ∼30% of CDH patients, genomic analyses have identified a range of genetic defects, including chromosomal anomalies, copy number variants and sequence variants. The affected genes identified in CDH patients include transcription factors, such as GATA4, ZFPM2, NR2F2 and WT1, and signaling pathway components, including members of the retinoic acid pathway...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28768735/therapeutic-strategies-for-spinal-muscular-atrophy-smn-and-beyond
#20
REVIEW
Melissa Bowerman, Catherina G Becker, Rafael J Yáñez-Muñoz, Ke Ning, Matthew J A Wood, Thomas H Gillingwater, Kevin Talbot
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1 A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed...
August 1, 2017: Disease Models & Mechanisms
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