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https://www.readbyqxmd.com/read/28510727/alternative-splicing-in-the-c-terminal-tail-of-cav2-1-is-essential-for-preventing-a-neurological-disease-in-mice
#1
Tomonori Aikawa, Takaki Watanabe, Taisuke Miyazaki, Takayasu Mikuni, Minoru Wakamori, Miyano Sakurai, Hidenori Aizawa, Nobutaka Ishizu, Masahiko Watanabe, Masanobu Kano, Hidehiro Mizusawa, Kei Watase
Alternative splicing (AS) that occurs at the final coding exon (exon 47) of the Cav2.1 voltage-gated calcium channel (VGCC) gene produces two major isoforms in the brain, MPI and MPc. These isoforms differ in their splice acceptor sites; human MPI is translated into a polyglutamine tract associated with spinocerebellar ataxia type 6 (SCA6), whereas MPc splices to an immediate stop codon, resulting in a shorter cytoplasmic tail.To gain insight into the functional role of the AS in vivo and whether modulating the splice patterns at this locus can be a potential therapeutic strategy for SCA6, here we created knockin mice that exclusively express MPc by inserting the splice-site mutation...
May 16, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28507102/foxo3-pgc-1%C3%AE-signaling-axis-is-essential-for-cancer-stem-cell-properties-of-pancreatic-ductal-adenocarcinoma
#2
Motofumi Kumazoe, Mika Takai, Shun Hiroi, Chieri Takeuchi, Mai Kadomatsu, Takashi Nojiri, Hiroaki Onda, Jaehoon Bae, Yuhui Huang, Kanako Takamatsu, Shuya Yamashita, Kenji Kangawa, Hirofumi Tachibana
In 95% of patients with pancreatic ductal adenocarcinoma (PDAC), recurrence is observed following chemotherapy. Findings from several studies have indicated that cancer stem cells (CSCs) are resistant to anti-cancer agents and may be involved in cancer recurrence and metastasis. The CD44 protein is a major CSC marker, and CD44 also plays an indispensable role in the CSC properties in several cancers, including pancreatic cancer; however, no clinical approach exists to inhibit CD44 activity. Here, we have performed knockin/knock down experiments and we demonstrate that the forkhead box O3 (FOXO3)/liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/PPAR-γ co-activator-1β (PGC- 1β)/pyruvate dehydrogenase -A1 (PDHA1) pathway is essential for CD44 expression and CSC properties...
May 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28505490/heat-induced-temperature-dysregulation-and-seizures-in-dravet-syndrome-gefs-gabrg2-q390x-mice
#3
Timothy A Warner, Zhong Liu, Robert L Macdonald, Jing-Qiong Kang
It has been established that febrile seizures and its extended syndromes like generalized epilepsy with febrile seizures (FS) plus (GEFS+) and Dravet syndrome have been associated with mutations especially in SCN1A and GABRG2 genes. In patients, the onset of FS is likely due to the combined effect of temperature and inflammation in genetically vulnerable individuals because fever is often associated with infection. Much effort has been spent to understand the mechanisms underlying fever induction of seizures...
April 30, 2017: Epilepsy Research
https://www.readbyqxmd.com/read/28464208/knock-knock-knockin-on-bile-duct-s-door-the-tip-of-the-biopsy-forceps-technique-probing-the-route-during-freehand-intubated-direct-cholangioscopy
#4
https://www.readbyqxmd.com/read/28461508/conditional-knockin-of-dnmt3a-r878h-initiates-acute-myeloid-leukemia-with-mtor-pathway-involvement
#5
Yu-Jun Dai, Yue-Ying Wang, Jin-Yan Huang, Li Xia, Xiao-Dong Shi, Jie Xu, Jing Lu, Xian-Bin Su, Ying Yang, Wei-Na Zhang, Pan-Pan Wang, Song-Fang Wu, Ting Huang, Jian-Qing Mi, Ze-Guang Han, Zhu Chen, Sai-Juan Chen
DNMT3A is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot DNMT3A R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin(-)Sca1(+)cKit(+) cell compartments. The transcriptome and DNA methylation profiling of bulk leukemic cells and the single-cell RNA sequencing of leukemic stem/progenitor cells revealed significant changes in gene expression and epigenetic regulatory patterns that cause differentiation arrest and growth advantage...
May 1, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28422748/therapeutic-inhibition-of-soluble-brain-tnf-promotes-remyelination-by-increasing-myelin-phagocytosis-by-microglia
#6
Maria Karamita, Christopher Barnum, Wiebke Möbius, Malú G Tansey, David E Szymkowski, Hans Lassmann, Lesley Probert
Multiple sclerosis (MS) is an inflammatory CNS demyelinating disease in which remyelination largely fails. Transmembrane TNF (tmTNF) and TNF receptor 2 are important for remyelination in experimental MS models, but it is unknown whether soluble TNF (solTNF), a major proinflammatory factor, is involved in regeneration processes. Here, we investigated the specific contribution of solTNF to demyelination and remyelination in the cuprizone model. Treatment with XPro1595, a selective inhibitor of solTNF that crosses the intact blood-brain barrier (BBB), in cuprizone-fed mice did not prevent toxin-induced oligodendrocyte loss and demyelination, but it permitted profound early remyelination due to improved phagocytosis of myelin debris by CNS macrophages and prevented disease-associated decline in motor performance...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28407484/autoreactive-t-cells-and-chronic-fungal-infection-drive-esophageal-carcinogenesis
#7
Feng Zhu, Jami Willette-Brown, Na-Young Song, Dakshayani Lomada, Yongmei Song, Liyan Xue, Zane Gray, Zitong Zhao, Sean R Davis, Zhonghe Sun, Peilin Zhang, Xiaolin Wu, Qimin Zhan, Ellen R Richie, Yinling Hu
Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a T cell-driven autoimmune disease caused by impaired central tolerance, are susceptible to chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However, the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikkα knockin mice develop APECED-like phenotypes, including impaired central tolerance, autoreactive T cells, chronic fungal infection, and ESCCs expressing specific human ESCC markers...
April 12, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28404732/roles-of-the-traf6-and-pellino-e3-ligases-in-myd88-and-rankl-signaling
#8
Sam Strickson, Christoph H Emmerich, Eddy T H Goh, Jiazhen Zhang, Ian R Kelsall, Thomas Macartney, C James Hastie, Axel Knebel, Mark Peggie, Francesco Marchesi, J Simon C Arthur, Philip Cohen
It is widely accepted that the essential role of TRAF6 in vivo is to generate the Lys63-linked ubiquitin (K63-Ub) chains needed to activate the "master" protein kinase TAK1. Here, we report that TRAF6 E3 ligase activity contributes to but is not essential for the IL-1-dependent formation of K63-Ub chains, TAK1 activation, or IL-8 production in human cells, because Pellino1 and Pellino2 generate the K63-Ub chains required for signaling in cells expressing E3 ligase-inactive TRAF6 mutants. The IL-1-induced formation of K63-Ub chains and ubiquitylation of IRAK1, IRAK4, and MyD88 was abolished in TRAF6/Pellino1/Pellino2 triple-knockout (KO) cells, but not in TRAF6 KO or Pellino1/2 double-KO cells...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28402860/idh1-mutation-promotes-tumorigenesis-by-inhibiting-jnk-activation-and-apoptosis-induced-by-serum-starvation
#9
Bin Jiang, Jia Zhang, Jinmei Xia, Wentao Zhao, Yanan Wu, Minggang Shi, Lianzhong Luo, Huamin Zhou, Ai Chen, Huanhuan Ma, Qingwen Zhao, Muhammad Suleman, Furong Lin, Lin Zhou, Jinyang Wang, Yan Zhang, Ying He, Xiaotong Li, Li-Man Hung, Tak Wah Mak, Qinxi Li
Two hallmarks of cancer cells are their resistance to apoptosis and ability to thrive despite reduced levels of vital serum components. c-jun N-terminal kinase (JNK) activation is crucial for apoptosis triggered by serum starvation (SS), and isocitrate dehydrogenase 1 (IDH1) mutations are tumorigenic, in part, because they produce the abnormal metabolite 2-hydroxyglutarate (2-HG). However, it is unknown whether 2-HG-induced tumorigenesis is partially due to JNK inhibition and thus defective SS-induced apoptosis...
April 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28394263/elevating-expression-of-mecp2-t158m-rescues-dna-binding-and-rett-syndrome-like-phenotypes
#10
Janine M Lamonica, Deborah Y Kwon, Darren Goffin, Polina Fenik, Brian S Johnson, Yue Cui, Hengyi Guo, Sigrid Veasey, Zhaolan Zhou
Mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT), a neurological disorder affecting cognitive development, respiration, and motor function. Genetic restoration of MeCP2 expression reverses RTT-like phenotypes in mice, highlighting the need to search for therapeutic approaches. Here, we have developed knockin mice recapitulating the most common RTT-associated missense mutation, MeCP2 T158M. We found that the T158M mutation impaired MECP2 binding to methylated DNA and destabilized MeCP2 protein in an age-dependent manner, leading to the development of RTT-like phenotypes in these mice...
May 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28389619/differential-expression-of-oatp1b3-mediates-unconjugated-testosterone-influx
#11
Tristan M Sissung, Ariel M Ley, Jonathan D Strope, Edel M McCrea, Shaunna L Beedie, Cody J Peer, Suneet Shukla, Jennifer C van Velkinburgh, Kelie Reece, Sarah Troutman, Tessa Campbell, Elena Fernandez, Phoebe Huang, Jordan Smith, Nilay Thakkar, David Venzon, Steffan Brenner, Wooin Lee, Maria J Merino, Ji Luo, Walter Jager, Cindy H Chau, Douglas K Price, William D Figg
Castration resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. The present study was undertaken to ascertain the androgen uptake kinetics, functional, and clinical relevance of de novo expression of the steroid hormone transporter OATP1B3 (SLCO1B3). Experiments testing the cellular uptake of androgens suggest that testosterone is an excellent substrate of OATP1B3 (KM=23.2µM; VMAX=321...
April 7, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28374116/designing-an-escherichia-coli-strain-for-phenylalanine-overproduction-by-metabolic-engineering
#12
Neetu Tyagi, Deepti Saini, Richa Guleria, Krishna Jyoti Mukherjee
The phenylalanine pathway flux is controlled by two types of regulators, those that are specific to the pathway, as well as by global regulators. In order to demonstrate the importance of these global regulators, we first removed the pathway-specific regulators using all possible combinations of gene knockouts and knockins. We found that genes like aroG (fbr) performed best individually as well as in combination with other genes, while other genes like tyrA and tyrR worked only in combination with other modifications...
April 3, 2017: Molecular Biotechnology
https://www.readbyqxmd.com/read/28363697/polymorphisms-and-mutations-in-the-melanocortin-3-receptor-and-their-relation-to-human-obesity
#13
REVIEW
Andrew P Demidowich, Joo Yun Jun, Jack A Yanovski
Inactivating mutations in the melanocortin 3 receptor (Mc3r) have been described as causing obesity in mice, but the physiologic effects of MC3R mutations in humans have been less clear. Here we review the MC3R polymorphisms and mutations identified in humans, and the in vitro, murine, and human cohort studies examining their putative effects. Some, but not all, studies suggest that the common human MC3R variant T6K+V81I, as well as several other rare, function-altering mutations, are associated with greater adiposity and hyperleptinemia with altered energy partitioning...
March 28, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28348219/mouse-adapted-mers-coronavirus-causes-lethal-lung-disease-in-human-dpp4-knockin-mice
#14
Kun Li, Christine L Wohlford-Lenane, Rudragouda Channappanavar, Jung-Eun Park, James T Earnest, Thomas B Bair, Amber M Bates, Kim A Brogden, Heather A Flaherty, Tom Gallagher, David K Meyerholz, Stanley Perlman, Paul B McCray
The Middle East respiratory syndrome (MERS) emerged in Saudi Arabia in 2012, caused by a zoonotically transmitted coronavirus (CoV). Over 1,900 cases have been reported to date, with ∼36% fatality rate. Lack of autopsies from MERS cases has hindered understanding of MERS-CoV pathogenesis. A small animal model that develops progressive pulmonary manifestations when infected with MERS-CoV would advance the field. As mice are restricted to infection at the level of DPP4, the MERS-CoV receptor, we generated mice with humanized exons 10-12 of the mouse Dpp4 locus...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28346224/mutant-%C3%AE-2-chimaerin-signals-via-bidirectional-ephrin-pathways-in-duane-retraction-syndrome
#15
Alicia A Nugent, Jong G Park, Yan Wei, Alan P Tenney, Nicole M Gilette, Michelle M DeLisle, Wai-Man Chan, Long Cheng, Elizabeth C Engle
Duane retraction syndrome (DRS) is the most common form of congenital paralytic strabismus in humans and can result from α2-chimaerin (CHN1) missense mutations. We report a knockin α2-chimaerin mouse (Chn1KI/KI) that models DRS. Whole embryo imaging of Chn1KI/KI mice revealed stalled abducens nerve growth and selective trochlear and first cervical spinal nerve guidance abnormalities. Stalled abducens nerve bundles did not reach the orbit, resulting in secondary aberrant misinnervation of the lateral rectus muscle by the oculomotor nerve...
May 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28344083/cholesterol-modification-of-smoothened-is-required-for-hedgehog-signaling
#16
Xu Xiao, Jing-Jie Tang, Chao Peng, Yan Wang, Lin Fu, Zhi-Ping Qiu, Yue Xiong, Lian-Fang Yang, Hai-Wei Cui, Xiao-Long He, Lei Yin, Wei Qi, Catherine C L Wong, Yun Zhao, Bo-Liang Li, Wen-Wei Qiu, Bao-Liang Song
Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling...
April 6, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28300840/ganetespib-synergizes-with-cyclophosphamide-to-improve-survival-of-mice-with-autochthonous-tumors-in-a-mutant-p53-dependent-manner
#17
Evguenia M Alexandrova, Sulan Xu, Ute M Moll
The DNA-alkylating cytotoxic agent cyclophosphamide (CTX) is commonly used in the clinic to treat hematological malignancies like lymphomas and leukemias as well as solid tumors, but shows dose-dependent potentially life-threatening toxicities and can induce secondary malignancies. Thus, the clinical utility of CTX would be improved if a companion drug could be identified that allows lowering the CTX dose, while maintaining or even increasing its antineoplastic therapeutic efficacy. In mouse models, high-dose CTX (300 mg/kg) is effective in treating T-lymphomas, while low dose (defined here as 100 mg/kg) is ineffective...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28273465/a-knockin-reporter-allows-purification-and-characterization-of-mda-neurons-from-heterogeneous-populations
#18
Ninuo Xia, Fang Fang, Pengbo Zhang, Jun Cui, Chhavy Tep-Cullison, Tim Hamerley, Hyun Joo Lee, Theo Palmer, Brian Bothner, Jin Hyung Lee, Renee Reijo Pera
Generation of midbrain dopaminergic (mDA) neurons from human pluripotent stem cells provides a platform for inquiry into basic and translational studies of Parkinson's disease (PD). However, heterogeneity in differentiation in vitro makes it difficult to identify mDA neurons in culture or in vivo following transplantation. Here, we report the generation of a human embryonic stem cell (hESC) line with a tyrosine hydroxylase (TH)-RFP (red fluorescent protein) reporter. We validated that RFP faithfully mimicked TH expression during differentiation...
March 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28263886/gene-editing-in-mouse-zygotes-using-the-crispr-cas9-system
#19
Benedikt Wefers, Sanum Bashir, Jana Rossius, Ralf Kühn
The generation of targeted mouse mutants is a key technology for biomedical research. Using the CRISPR/Cas9 system for induction of targeted double-strand breaks, gene editing can be performed in a single step directly in mouse zygotes. This article covers the design of knockout and knockin alleles, preparation of reagents, microinjection or electroporation of zygotes and the genotyping of pups derived from gene editing projects. In addition we include a section for the control of experimental settings by targeting the Rosa26 locus and PCR based genotyping of blastocysts...
March 2, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28247345/isolation-culture-and-immunostaining-of-skeletal-muscle-myofibers-from-wildtype-and-nestin-gfp-mice-as-a-means-to-analyze-satellite-cell
#20
Pascal Stuelsatz, Paul Keire, Zipora Yablonka-Reuveni
Multinucleated myofibers, the functional contractile units of adult skeletal muscle, harbor mononuclear Pax7(+) myogenic progenitors on their surface between the myofiber basal lamina and plasmalemma. These progenitors, known as satellite cells, are the primary myogenic stem cells in adult muscle. This chapter describes our laboratory protocols for isolating, culturing, and immunostaining intact myofibers from mouse skeletal muscle as a means for studying satellite cell dynamics. The first protocol discusses myofiber isolation from the flexor digitorum brevis (FDB) muscle...
2017: Methods in Molecular Biology
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