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https://www.readbyqxmd.com/read/28098219/combined-lrrk2-mutation-aging-and-chronic-low-dose-oral-rotenone-as-a-model-of-parkinson-s-disease
#1
Hui-Fang Liu, Philip Wing-Lok Ho, Gideon Chi-Ting Leung, Colin Siu-Chi Lam, Shirley Yin-Yu Pang, Lingfei Li, Michelle Hiu-Wai Kung, David Boyer Ramsden, Shu-Leong Ho
Aging, genetics and environmental toxicity are important etiological factors in Parkinson's disease (PD). However, its pathogenesis remains unclear. A major obstacle is the lack of an appropriate experimental model which incorporates genetic susceptibility, aging and prolonged environmental toxicity. Here, we explored the interplay amongst these factors using mutant LRRK2(R1441G) (leucine-rich-repeat-kinase-2) knockin mice. We found that mutant primary cortical and mesencephalic dopaminergic neurons were more susceptible to rotenone-induced ATP deficiency and cell death...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28097237/oxidized-camkii-promotes-asthma-through-the-activation-of-mast-cells
#2
Jingjing Qu, Danh C Do, Yufeng Zhou, Elizabeth Luczak, Wayne Mitzner, Mark E Anderson, Peisong Gao
Oxidation of calmodulin-dependent protein kinase II (ox-CaMKII) by ROS has been associated with asthma. However, the contribution of ox-CaMKII to the development of asthma remains to be fully characterized. Here, we tested the effect of ox-CaMKII on IgE-mediated mast cell activation in an allergen-induced mouse model of asthma using oxidant-resistant CaMKII MMVVδ knockin (MMVVδ) mice. Compared with WT mice, the allergen-challenged MMVVδ mice displayed less airway hyperresponsiveness (AHR) and inflammation...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28096221/efficient-crispr-cas9-assisted-gene-targeting-enables-rapid-and-precise-genetic-manipulation-of-mammalian-neural-stem-cells
#3
Raul Bardini Bressan, Pooran Singh Dewari, Maria Kalantzaki, Ester Gangoso, Mantas Matjusaitis, Claudia Garcia-Diaz, Carla Blin, Vivien Grant, Harry Bulstrode, Sabine Gogolok, William C Skarnes, Steven M Pollard
Mammalian neural stem (NS) cell lines provide a tractable model for discovery across stem cell and developmental biology, regenerative medicine and neuroscience. They can be derived from foetal or adult germinal tissues and continuously propagated in vitro as adherent monolayers. NS cells are clonally expandable, genetically stable, and easily transfectable - experimental attributes compatible with targeted genetic manipulations. However, gene targeting - so critical for functional studies of embryonic stem cells - has not been exploited to date in NS cells...
January 17, 2017: Development
https://www.readbyqxmd.com/read/28094771/orphan-gpr182-suppresses-erk-mediated-intestinal-proliferation-during-regeneration-and-adenoma-formation
#4
Daniel O Kechele, R Eric Blue, Bailey Zwarycz, Scott T Espenschied, Amanda T Mah, Marni B Siegel, Charles M Perou, Shengli Ding, Scott T Magness, P Kay Lund, Kathleen M Caron
Orphan GPCRs provide an opportunity to identify potential pharmacological targets, yet their expression patterns and physiological functions remain challenging to elucidate. Here, we have used a genetically engineered knockin reporter mouse to map the expression pattern of the Gpr182 during development and adulthood. We observed that Gpr182 is expressed at the crypt base throughout the small intestine, where it is enriched in crypt base columnar stem cells, one of the most active stem cell populations in the body...
January 17, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28053051/rom1-converts-y141c-prph2-associated-pattern-dystrophy-to-retinitis-pigmentosa
#5
Shannon M Conley, Michael W Stuck, Jamie N Watson, Muna I Naash
Mutations in peripherin 2 (PRPH2), also known as retinal degeneration slow/RDS, lead to various retinal degenerations including retinitis pigmentosa (RP) and macular/pattern dystrophy (MD/PD). PRPH2-associated disease is often characterized by a phenotypic variability even within families carrying the same mutation, raising interest in potential modifiers. PRPH2 oligomerizes with its homologue rod outer segment (OS) membrane protein 1 (ROM1), and non-pathogenic PRPH2/ROM1 mutations, when present together, lead to digenic RP...
January 4, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28035926/pleiotropic-effect-of-human-apoe4-on-cerebral-ceramide-and-saturated-fatty-acid-levels
#6
Sandra den Hoedt, Carola I F Janssen, Guiseppe Astarita, Daniele Piomelli, Frank P J Leijten, Simone M Crivelli, Adrie J M Verhoeven, Helga E de Vries, Jochen Walter, Pilar Martinez-Martinez, Eric J G Sijbrands, Amanda J Kiliaan, Monique T Mulder
BACKGROUND: Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the ɛ4 allele is a risk factor for late onset Alzheimer's disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD. OBJECTIVE: To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet. METHODS: Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months...
December 30, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28017374/biallelic-mutations-in-mypn-encoding-myopalladin-are-associated-with-childhood-onset-slowly-progressive-nemaline-myopathy
#7
Satoko Miyatake, Satomi Mitsuhashi, Yukiko K Hayashi, Enkhsaikhan Purevjav, Atsuko Nishikawa, Eriko Koshimizu, Mikiya Suzuki, Kana Yatabe, Yuzo Tanaka, Katsuhisa Ogata, Satoshi Kuru, Masaaki Shiina, Yoshinori Tsurusaki, Mitsuko Nakashima, Takeshi Mizuguchi, Noriko Miyake, Hirotomo Saitsu, Kazuhiro Ogata, Mitsuru Kawai, Jeffrey Towbin, Ikuya Nonaka, Ichizo Nishino, Naomichi Matsumoto
Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy...
January 5, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27986254/inhibition-of-na-k-cl-cotransporter-isoform-1-reduces-lung-injury-induced-by-ischemia-reperfusion
#8
Chou-Chin Lan, Chung-Kan Peng, Shih-En Tang, Hsueh-Ju Lin, Sung-Sen Yang, Chin-Pyng Wu, Kun-Lun Huang
OBJECTIVES: Ischemia-reperfusion acute lung injury is characterized by increased vascular permeability, lung edema, and neutrophil sequestration. Ischemia-reperfusion acute lung injury occurs in lung transplantation and other major surgical procedures. Effective regulation of alveolar fluid balance is critical for pulmonary edema. Sodium-potassium-chloride co-transporter regulates alveolar fluid and is associated with inflammation. We hypothesized that sodium-potassium-chloride co-transporter is important in ischemia-reperfusion acute lung injury...
January 2017: Journal of Thoracic and Cardiovascular Surgery
https://www.readbyqxmd.com/read/27974160/capturing-and-manipulating-activated-neuronal-ensembles-with-cane-delineates-a-hypothalamic-social-fear-circuit
#9
Katsuyasu Sakurai, Shengli Zhao, Jun Takatoh, Erica Rodriguez, Jinghao Lu, Andrew D Leavitt, Min Fu, Bao-Xia Han, Fan Wang
We developed a technology (capturing activated neuronal ensembles [CANE]) to label, manipulate, and transsynaptically trace neural circuits that are transiently activated in behavioral contexts with high efficiency and temporal precision. CANE consists of a knockin mouse and engineered viruses designed to specifically infect activated neurons. Using CANE, we selectively labeled neurons that were activated by either fearful or aggressive social encounters in a hypothalamic subnucleus previously known as a locus for aggression, and discovered that social-fear and aggression neurons are intermixed but largely distinct...
November 23, 2016: Neuron
https://www.readbyqxmd.com/read/27939582/new-transgenic-mouse-lines-for-selectively-targeting-astrocytes-and-studying-calcium-signals-in-astrocyte-processes-in-situ-and-in%C3%A2-vivo
#10
Rahul Srinivasan, Tsai-Yi Lu, Hua Chai, Ji Xu, Ben S Huang, Peyman Golshani, Giovanni Coppola, Baljit S Khakh
Astrocytes exist throughout the nervous system and are proposed to affect neural circuits and behavior. However, studying astrocytes has proven difficult because of the lack of tools permitting astrocyte-selective genetic manipulations. Here, we report the generation of Aldh1l1-Cre/ERT2 transgenic mice to selectively target astrocytes in vivo. We characterized Aldh1l1-Cre/ERT2 mice using imaging, immunohistochemistry, AAV-FLEX-GFP microinjections, and crosses to RiboTag, Ai95, and new Cre-dependent membrane-tethered Lck-GCaMP6f knockin mice that we also generated...
December 21, 2016: Neuron
https://www.readbyqxmd.com/read/27932475/intercalated-cell-depletion-and-vacuolar-h-atpase-mistargeting-in-an-ae1-r607h-knockin-model
#11
Rizwan Mumtaz, Francesco Trepiccione, J Christopher Hennings, Antje K Huebner, Bettina Serbin, Nicolas Picard, A K M Shahid Ullah, Teodor G Păunescu, Diane E Capen, Rawad M Lashhab, Isabelle Mouro-Chanteloup, Seth L Alper, Carsten A Wagner, Emmanuelle Cordat, Dennis Brown, Dominique Eladari, Christian A Hübner
Distal nephron acid secretion is mediated by highly specialized type A intercalated cells (A-ICs), which contain vacuolar H(+)-ATPase (V-type ATPase)-rich vesicles that fuse with the apical plasma membrane on demand. Intracellular bicarbonate generated by luminal H(+) secretion is removed by the basolateral anion-exchanger AE1. Chronically reduced renal acid excretion in distal renal tubular acidosis (dRTA) may lead to nephrocalcinosis and renal failure. Studies in MDCK monolayers led to the proposal of a dominant-negative trafficking mechanism to explain AE1-associated dominant dRTA...
December 8, 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27926877/ptbp1-and-ptbp2-serve-both-specific-and-redundant-functions-in-neuronal-pre-mrna-splicing
#12
John K Vuong, Chia-Ho Lin, Min Zhang, Liang Chen, Douglas L Black, Sika Zheng
Families of alternative splicing regulators often contain multiple paralogs presumed to fulfill different functions. Polypyrimidine tract binding proteins PTBP1 and PTBP2 reprogram developmental pre-mRNA splicing in neurons, but how their regulatory networks differ is not understood. To compare their targeting, we generated a knockin allele that conditionally expresses PTBP1. Bred to a Ptbp2 knockout, the transgene allowed us to compare the developmental and molecular phenotypes of mice expressing only PTBP1, only PTBP2, or neither protein in the brain...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27898095/efficient-generation-of-orthologous-point-mutations-in-pigs-via-crispr-assisted-ssodn-mediated-homology-directed-repair
#13
Kankan Wang, Xiaochun Tang, Yan Liu, Zicong Xie, Xiaodong Zou, Mengjing Li, Hongming Yuan, Hongsheng Ouyang, Huping Jiao, Daxin Pang
Precise genome editing in livestock is of great value for the fundamental investigation of disease modeling. However, genetically modified pigs carrying subtle point mutations were still seldom reported despite the rapid development of programmable endonucleases. Here, we attempt to investigate single-stranded oligonucleotides (ssODN) mediated knockin by introducing two orthologous pathogenic mutations, p.E693G for Alzheimer's disease and p.G2019S for Parkinson's disease, into porcine APP and LRRK2 loci, respectively...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27864306/the-transactivation-domains-of-the-p53-protein
#14
Nitin Raj, Laura D Attardi
The p53 tumor suppressor is a transcriptional activator, with discrete domains that participate in sequence-specific DNA binding, tetramerization, and transcriptional activation. Mutagenesis and reporter studies have delineated two distinct activation domains (TADs) and specific hydrophobic residues within these TADs that are critical for their function. Knockin mice expressing p53 mutants with alterations in either or both of the two TADs have revealed that TAD1 is critical for responses to acute DNA damage, whereas both TAD1 and TAD2 participate in tumor suppression...
November 18, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27847984/knock-knock-knockin-%C3%A2-on-critical-care-s-door
#15
EDITORIAL
Alberto García-Salido, Ana Serrano-González
No abstract text is available yet for this article.
November 15, 2016: Intensive Care Medicine
https://www.readbyqxmd.com/read/27826658/a-tbc1d1-ser231ala-knockin-mutation-partially-impairs-aicar-but-not-exercise-induced-muscle-glucose-uptake-in-mice
#16
Qiaoli Chen, Bingxian Xie, Sangsang Zhu, Ping Rong, Yang Sheng, Serge Ducommun, Liang Chen, Chao Quan, Min Li, Kei Sakamoto, Carol MacKintosh, Shuai Chen, Hong Yu Wang
AIMS/HYPOTHESIS: TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) is a Rab GTPase-activating protein (RabGAP) that has been implicated in regulating GLUT4 trafficking. TBC1D1 can be phosphorylated by the AMP-activated protein kinase (AMPK) on Ser(231), which consequently interacts with 14-3-3 proteins. Given the key role for AMPK in regulating insulin-independent muscle glucose uptake, we hypothesised that TBC1D1-Ser(231) phosphorylation and/or 14-3-3 binding may mediate AMPK-governed glucose homeostasis...
February 2017: Diabetologia
https://www.readbyqxmd.com/read/27807834/crispr-cas-mediated-knockin-in-human-pluripotent-stem-cells
#17
Nipun Verma, Zengrong Zhu, Danwei Huangfu
Fluorescent reporter and epitope-tagged human pluripotent stem cells (hPSCs) greatly facilitate studies on the pluripotency and differentiation characteristics of these cells. Unfortunately traditional procedures to generate such lines are hampered by a low targeting efficiency that necessitates a lengthy process of selection followed by the removal of the selection cassette. Here we describe a procedure to generate fluorescent reporter and epitope tagged hPSCs in an efficient one-step process using the CRISPR/Cas technology...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27780040/functional-coordination-of-wave-and-wasp-in-c-%C3%A2-elegans-neuroblast-migration
#18
Zhiwen Zhu, Yongping Chai, Yuxiang Jiang, Wenjing Li, Huifang Hu, Wei Li, Jia-Wei Wu, Zhi-Xin Wang, Shanjin Huang, Guangshuo Ou
Directional cell migration is critical for metazoan development. We define two molecular pathways that activate the Arp2/3 complex during neuroblast migration in Caenorhabditis elegans. The transmembrane protein MIG-13/Lrp12 is linked to the Arp2/3 nucleation-promoting factors WAVE or WASP through direct interactions with ABL-1 or SEM-5/Grb2, respectively. WAVE mutations partially impaired F-actin organization and decelerated cell migration, and WASP mutations did not inhibit cell migration but enhanced migration defects in WAVE-deficient cells...
October 24, 2016: Developmental Cell
https://www.readbyqxmd.com/read/27775852/cotinine-administration-improves-impaired-cognition-in-the-mouse-model-of-fragile-x-syndrome
#19
Marta Pardo, Eleonore Beurel, Richard S Jope
Cotinine is the major metabolite of nicotine and has displayed some capacity for improving cognition in mouse models following chronic administration. We tested if acute cotinine treatment is capable of improving cognition in the mouse model of Fragile X syndrome, Fmr1(-/-) knockout mice, and if this is related to inhibition by cotinine treatment of glycogen synthase kinase-3β (GSK3β), which is abnormally active in Fmr1(-/-) mice. Acute cotinine treatment increased the inhibitory serine-phosphorylation of GSK3β and the activating phosphorylation of AKT, which can mediate serine-phosphorylation of GSK3β, in both wild-type and Fmr1(-/-) mouse hippocampus...
October 24, 2016: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27769098/expression-of-noggin-and-gremlin1-and-its-implications-in-fine-tuning-bmp-activities-in-mouse-cartilage-tissues
#20
Xiaodan Yu, Hiroko Kawakami, Naoyuki Tahara, Merissa Olmer, Shinichi Hayashi, Ryutaro Akiyama, Anindya Bagchi, Martin Lotz, Yasuhiko Kawakami
Increasing evidence supports the idea that bone morphogenetic proteins (BMPs) regulate cartilage maintenance in the adult skeleton. The aim of this study is to obtain insight into the regulation of BMP activities in the adult skeletal system. We analyzed expression of Noggin and Gremlin1, BMP antagonists that are known to regulate embryonic skeletal development, in the adult skeletal system by Noggin-LacZ and Gremlin1-LacZ knockin reporter mouse lines. Both reporters are expressed in the adult skeleton in a largely overlapping manner with some distinct patterns...
October 21, 2016: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
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