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https://www.readbyqxmd.com/read/29021349/activation-of-autophagy-ameliorates-cardiomyopathy-in-mybpc3-targeted-knockin-mice
#1
Sonia R Singh, Antonia T L Zech, Birgit Geertz, Silke Reischmann-Düsener, Hanna Osinska, Maksymilian Prondzynski, Elisabeth Krämer, Qinghang Meng, Charles Redwood, Jolanda van der Velden, Jeffrey Robbins, Saskia Schlossarek, Lucie Carrier
BACKGROUND: Alterations in autophagy have been reported in hypertrophic cardiomyopathy (HCM) caused by Danon disease, Vici syndrome, or LEOPARD syndrome, but not in HCM caused by mutations in genes encoding sarcomeric proteins, which account for most of HCM cases. MYBPC3, encoding cMyBP-C (cardiac myosin-binding protein C), is the most frequently mutated HCM gene. METHODS AND RESULTS: We evaluated autophagy in patients with HCM carrying MYBPC3 mutations and in a Mybpc3-targeted knockin HCM mouse model, as well as the effect of autophagy modulators on the development of cardiomyopathy in knockin mice...
October 2017: Circulation. Heart Failure
https://www.readbyqxmd.com/read/29020614/gene-editing-in-rat-embryonic-stem-cells-to-produce-in%C3%A2-vitro-models-and-in%C3%A2-vivo-reporters
#2
Yaoyao Chen, Sonia Spitzer, Sylvia Agathou, Ragnhildur Thora Karadottir, Austin Smith
Rat embryonic stem cells (ESCs) offer the potential for sophisticated genome engineering in this valuable biomedical model species. However, germline transmission has been rare following conventional homologous recombination and clonal selection. Here, we used the CRISPR/Cas9 system to target genomic mutations and insertions. We first evaluated utility for directed mutagenesis and recovered clones with biallelic deletions in Lef1. Mutant cells exhibited reduced sensitivity to glycogen synthase kinase 3 inhibition during self-renewal...
October 10, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29019003/role-of-dynein-axonemal-heavy-chain-6-gene-expression-as-a-possible-biomarker-for-huntington-s-disease-a-translational-study
#3
Lorena B Areal, Lorraine P Pereira, Fabiola M Ribeiro, Isabella G Olmo, Marcelo R Muniz, Maria do Carmo Rodrigues, Patrik F Costa, Cristina Martins-Silva, Stephen S G Ferguson, Daniela A M Guimarães, Rita G W Pires
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive deficits, and psychiatric symptoms. The primary genetic cause is an expansion of cytosine adenine guanine (CAG) nucleotides of the huntingtin gene, which codes an important protein involved with neuronal signaling. The severity of HD correlates with the number of CAG repeats and individuals with longer expansions have an earlier onset and more severe symptoms. A microarray study conducted by our research group showed alteration in DNAH6 gene (encoding dynein axonemal heavy chain 6)...
October 10, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28984573/sleep-homeostasis-regulated-by-5ht2b-receptor-in-a-small-subset-of-neurons-in-the-dorsal-fan-shaped-body-of-drosophila
#4
Yongjun Qian, Yue Cao, Bowen Deng, Guang Yang, Jiayun Li, Rui Xu, Dandan Zhang, Juan Huang, Yi Rao
Our understanding of molecular mechanisms underlying sleep homeostasis is limited. We have taken a systematic approach to study neural signaling by the transmitter 5-hydroxytryptamine (5-HT) in Drosophila. We have generated knockout and knockin lines for Trh, the 5-HT synthesizing enzyme and all five 5-HT receptors, making it possible for us to determine their expression patterns and to investigate their functional roles. Loss of the Trh, 5HT1a or 5HT2b gene decreased sleep time whereas loss of the Trh or 5HT2b gene diminished sleep rebound after sleep deprivation...
October 6, 2017: ELife
https://www.readbyqxmd.com/read/28973913/period2-3-utr-and-microrna-24-regulate-circadian-rhythms-by-repressing-period2-protein-accumulation
#5
Seung-Hee Yoo, Shihoko Kojima, Kazuhiro Shimomura, Nobuya Koike, Ethan D Buhr, Tadashi Furukawa, Caroline H Ko, Gabrielle Gloston, Christopher Ayoub, Kazunari Nohara, Bryan A Reyes, Yoshiki Tsuchiya, Ook-Joon Yoo, Kazuhiro Yagita, Choogon Lee, Zheng Chen, Shin Yamazaki, Carla B Green, Joseph S Takahashi
We previously created two PER2::LUCIFERASE (PER2::LUC) circadian reporter knockin mice that differ only in the Per2 3'-UTR region: Per2::Luc, which retains the endogenous Per2 3'-UTR and Per2::LucSV, where the endogenous Per2 3'-UTR was replaced by an SV40 late poly(A) signal. To delineate the in vivo functions of Per2 3'-UTR, we analyzed circadian rhythms of Per2::LucSV mice. Interestingly, Per2::LucSV mice displayed more than threefold stronger amplitude in bioluminescence rhythms than Per2::Luc mice, and also exhibited lengthened free-running periods (∼24...
October 2, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28973536/the-mitochondrial-metallochaperone-sco1-maintains-ctr1-at-the-plasma-membrane-to-preserve-copper-homeostasis-in-the-murine-heart
#6
Zakery N Baker, Kimberly Jett, Aren Boulet, Amzad Hossain, Paul A Cobine, Byung-Eun Kim, Amr M El Zawily, Ling Lee, Glen F Tibbits, Michael J Petris, Scot C Leary
SCO1 is a ubiquitously expressed, mitochondrial protein with essential roles in cytochrome c oxidase (COX) assembly and the regulation of copper homeostasis. SCO1 patients present with severe forms of early onset disease, and ultimately succumb from liver, heart or brain failure. However, the inherent susceptibility of these tissues to SCO1 mutations and the clinical heterogeneity observed across SCO1 pedigrees remain poorly understood phenomena. To further address this issue, we generated Sco1hrt/hrt and Sco1stm/stm mice in which Sco1 was specifically deleted in heart and striated muscle, respectively...
September 4, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28949038/parkinsonism-without-dopamine-neuron-degeneration-in-aged-l-dopa-responsive-dystonia-knockin-mice
#7
Samuel J Rose, Porter Harrast, Christine Donsante, Xueliang Fan, Valerie Joers, Malú G Tansey, H A Jinnah, Ellen J Hess
BACKGROUND: Recent neuroimaging studies implicate nigrostriatal degeneration as a critical factor in producing late-onset parkinsonism in patients with l-dopa-responsive dystonia-causing mutations. However, postmortem anatomical studies do not reveal neurodegeneration in l-dopa-responsive dystonia patients. These contrasting findings make it unclear how parkinsonism develops in l-dopa-responsive dystonia mutation carriers. METHODS: We prospectively assessed motor dysfunction, responses to dopaminergic challenge, and dopamine neuron degeneration with aging in a validated knockin mouse model bearing a l-dopa-responsive dystonia-causing mutation found in humans...
September 26, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28943315/nlrp3-phosphorylation-is-an-essential-priming-event-for-inflammasome-activation
#8
Nan Song, Zhao-Shan Liu, Wen Xue, Zhao-Fang Bai, Qian-Yi Wang, Jiang Dai, Xin Liu, Yi-Jiao Huang, Hong Cai, Xiao-Yan Zhan, Qiu-Ying Han, Hongxia Wang, Yuan Chen, Hui-Yan Li, Ai-Ling Li, Xue-Min Zhang, Tao Zhou, Tao Li
Many infections and stress signals can rapidly activate the NLRP3 inflammasome to elicit robust inflammatory responses. This activation requires a priming step, which is thought to be mainly for upregulating NLRP3 transcription. However, recent studies report that the NLRP3 inflammasome can be activated independently of transcription, suggesting that the priming process has unknown essential regulatory steps. Here, we report that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event and is essential for NLRP3 inflammasome activation...
October 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28943089/ehd-proteins-cooperate-to-generate-caveolar-clusters-and-to-maintain-caveolae-during-repeated-mechanical-stress
#9
Ivana Yeow, Gillian Howard, Jessica Chadwick, Carolina Mendoza-Topaz, Carsten G Hansen, Benjamin J Nichols, Elena Shvets
Caveolae introduce flask-shaped convolutions into the plasma membrane and help to protect the plasma membrane from damage under stretch forces. The protein components that form the bulb of caveolae are increasingly well characterized, but less is known about the contribution of proteins that localize to the constricted neck. Here we make extensive use of multiple CRISPR/Cas9-generated gene knockout and knockin cell lines to investigate the role of Eps15 Homology Domain (EHD) proteins at the neck of caveolae...
October 9, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28935707/the-eutheria-specific-mir-290-mir-371-cluster-modulates-placental-growth-and-maternal-fetal-transport
#10
Alireza Paikari, Cassandra Belair, Danial Saw, Robert Blelloch
A family of vertebrate-specific microRNAs called the ESCC microRNAs arises from two genetic loci in mammals, the miR-290/miR-371 and miR-302 loci. While the miR-302 locus is found broadly among vertebrates, the miR-290/miR-371 locus is unique to eutheria (placental mammals), suggesting a role in placental development. Here, we evaluate that role. A knockin reporter for the mouse miR-290 cluster gene is expressed throughout the embryo until gastrulation at which time it becomes specifically expressed in extraembryonic tissues and the germline...
September 21, 2017: Development
https://www.readbyqxmd.com/read/28918039/crispr-cas9-mediated-knockin-application-in-cell-therapy-a-non-viral-procedure-for-bystander-treatment-of-glioma-in-mice
#11
Oscar Meca-Cortés, Marta Guerra-Rebollo, Cristina Garrido, Salvador Borrós, Nuria Rubio, Jeronimo Blanco
The use of non-viral procedures, together with CRISPR/Cas9 genome-editing technology, allows the insertion of single-copy therapeutic genes at pre-determined genomic sites, overcoming safety limitations resulting from random gene insertions of viral vectors with potential for genome damage. In this study, we demonstrate that combination of non-viral gene delivery and CRISPR/Cas9-mediated knockin via homology-directed repair can replace the use of viral vectors for the generation of genetically modified therapeutic cells...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28913802/design-and-assembly-of-crispr-cas9-reagents-for-gene-knockout-targeted-insertion-and-replacement-in-wheat
#12
Tomáš Čermák, Shaun J Curtin
Advances in cereal transformation along with the completion of the wheat genome sequence assembly have increased the demand for tools that perform targeted and specific modifications in this crop plant. This protocol demonstrates the construction of reagents using a comprehensive genome engineering kit to create single and multiple gene "knockouts," site-specific chromosome deletions and gene replacement or "knockins" including the use of geminivirus replicons (GVRs). The reagents allow for both easy construction of simple genome engineering vectors, and "mix and match" swapping of components such as the Cas9, guide RNA and donor template cassettes for gene targeting...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28884202/gcg-creert2-knockin-mice-as-a-tool-for-genetic-manipulation-in-pancreatic-alpha-cells
#13
Chiyo Shiota, Krishna Prasadan, Ping Guo, Joseph Fusco, Xiangwei Xiao, George K Gittes
AIMS/HYPOTHESIS: The Cre/loxP system, which enables tissue-specific manipulation of genes, is widely used in mice for diabetes research. Our aim was to develop a new Cre-driver mouse line for the specific and efficient manipulation of genes in pancreatic alpha cells. METHODS: A Gcg (CreERT2) knockin mouse, which expresses a tamoxifen-inducible form of Cre from the endogenous preproglucagon (Gcg) gene locus, was generated by homologous recombination. The new Gcg (CreERT2) mouse line was crossed to the Rosa26 (tdTomato) (R26 (tdTomato) ) Cre reporter mouse line in order to evaluate the tissue specificity, efficiency and tamoxifen dependency of Gcg (CreERT2) -mediated recombination...
September 7, 2017: Diabetologia
https://www.readbyqxmd.com/read/28880886/the-osteogenic-cell-surface-marker-bril-ifitm5-is-dispensable-for-bone-development-and-homeostasis-in-mice
#14
Alexa Patoine, Abdallah Husseini, Bahar Kasaai, Marie-Hélène Gaumond, Pierre Moffatt
BRIL (bone-restricted IFITM-like), is a short transmembrane protein expressed almost exclusively in osteoblasts. Although much is known about its bone-restricted gene expression pattern and protein biochemical and topological features, little information is available for BRIL physiological function. Two autosomal dominant forms of osteogenesis imperfecta (OI) are caused by distinct, but recurrent mutations in the BRIL gene. Yet, the underlying mechanisms by which those mutations lead to OI are still poorly understood...
2017: PloS One
https://www.readbyqxmd.com/read/28878123/the-r213g-polymorphism-in-sod3-protects-against-allergic-airway-inflammation
#15
Rohit Gaurav, Jason T Varasteh, Michael R Weaver, Sean R Jacobson, Laura Hernandez-Lagunas, Qing Liu, Eva Nozik-Grayck, Hong Wei Chu, Rafeul Alam, Børge G Nordestgaard, Camilla J Kobylecki, Shoaib Afzal, Geoffrey L Chupp, Russell P Bowler
Oxidative stress is important in the pathogenesis of allergic asthma. Extracellular superoxide dismutase (EC-SOD; SOD3) is the major antioxidant in lungs, but its role in allergic asthma is unknown. Here we report that asthmatics have increased SOD3 transcript levels in sputum and that a single nucleotide polymorphism (SNP) in SOD3 (R213G; rs1799895) changes lung distribution of EC-SOD, and decreases likelihood of asthma-related symptoms. Knockin mice analogous to the human R213G SNP had lower airway hyperresponsiveness, inflammation, and mucus hypersecretion with decreased interleukin-33 (IL-33) in bronchoalveolar lavage fluid and reduced type II innate lymphoid cells (ILC2s) in lungs...
September 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/28870220/the-type-vi-adenylyl-cyclase-protects-cardiomyocytes-from-%C3%AE-adrenergic-stress-by-a-pka-stat3-dependent-pathway
#16
Yu-Shuo Wu, Chien-Chang Chen, Chen-Li Chien, Hsing-Lin Lai, Si-Tse Jiang, Yong-Cyuan Chen, Lin-Ping Lai, Wei-Fan Hsiao, Wen-Pin Chen, Yijuang Chern
BACKGROUND: The type VI adenylyl cyclase (AC6) is a main contributor of cAMP production in the heart. The amino acid (aa) sequence of AC6 is highly homologous to that of another major cardiac adenylyl cyclase, AC5, except for its N-terminus (AC6-N, aa 1-86). Activation of AC6, rather than AC5, produces cardioprotective effects against heart failure, while the underlying mechanism remains to be unveiled. Using an AC6-null (AC6(-/-)) mouse and a knockin mouse with AC6-N deletion (AC6 (ΔN/ΔN)), we aimed to investigate the cardioprotective mechanism of AC6 in the heart...
September 4, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28864281/interaction-of-brain-derived-neurotrophic-factor-val66met-genotype-and-history-of-stress-in-regulation-of-prepulse-inhibition-in-mice
#17
Maarten van den Buuse, John Juan Wen Lee, Emily J Jaehne
The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism results in reduced activity-dependent BDNF release and has been implicated in schizophrenia. However, effects of the polymorphism on functional dopaminergic and N-methyl-d-aspartate (NMDA) receptor-associated activity remain unclear. We used prepulse inhibition, a measure of sensorimotor gating which is disrupted in schizophrenia, and assessed the effects of acute treatment with the dopamine receptor agonist, apomorphine (APO), and the NMDA receptor antagonist, MK-801...
August 29, 2017: Schizophrenia Research
https://www.readbyqxmd.com/read/28864076/the-role-of-fibroblast-growth-factor-binding-protein-1-in-skin-carcinogenesis-and-inflammation
#18
Marcel Oliver Schmidt, Khalid Ammar Garman, Yong Gu Lee, Chong Zuo, Patrick James Beck, Mingjun Tan, Juan Antonio Aguilar-Pimentel, Markus Ollert, Carsten Schmidt-Weber, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Elena Tassi, Anna Tate Riegel, Anton Wellstein
Fibroblast growth factor-binding protein 1 (FGFBP1, FGF-BP) is a secreted chaperone that mobilizes paracrine-acting FGFs, stored in the extracellular matrix, and presents them to their cognate receptors. FGFBP1 enhances FGF signaling including angiogenesis during cancer progression, and is upregulated in various cancers. Here we evaluated the contribution of endogenous FGFBP1 to development and homeostasis as well as to skin pathologies utilizing Fgfbp1-knockout (KO) mice. Relative to wild-type (WT) littermates KO mice showed no gross pathologies...
August 29, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28827327/sensitized-mutagenesis-screen-in-factor-v-leiden-mice-identifies-thrombosis-suppressor-loci
#19
Randal J Westrick, Kärt Tomberg, Amy E Siebert, Guojing Zhu, Mary E Winn, Sarah L Dobies, Sara L Manning, Marisa A Brake, Audrey C Cleuren, Linzi M Hobbs, Lena M Mishack, Alexander J Johnston, Emilee Kotnik, David R Siemieniak, Jishu Xu, Jun Z Li, Thomas L Saunders, David Ginsburg
Factor V Leiden (F5(L) ) is a common genetic risk factor for venous thromboembolism in humans. We conducted a sensitized N-ethyl-N-nitrosourea (ENU) mutagenesis screen for dominant thrombosuppressor genes based on perinatal lethal thrombosis in mice homozygous for F5(L) (F5(L/L) ) and haploinsufficient for tissue factor pathway inhibitor (Tfpi(+/-) ). F8 deficiency enhanced the survival of F5(L/L)Tfpi(+/-) mice, demonstrating that F5(L/L)Tfpi(+/-) lethality is genetically suppressible. ENU-mutagenized F5(L/L) males and F5(L/+)Tfpi(+/-) females were crossed to generate 6,729 progeny, with 98 F5(L/L)Tfpi(+/-) offspring surviving until weaning...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28819283/the-c-terminal-multimerization-domain-is-essential-for-leukemia-development-by-cbf%C3%AE-smmhc-in-a-mouse-knockin-model
#20
L Zhao, H Alkadi, E M Kwon, T Zhen, J Lichtenberg, L Alemu, J Cheng, A D Friedman, P P Liu
Leukemia accepted article preview online, 18 August 2017. doi:10.1038/leu.2017.262.
August 18, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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