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https://www.readbyqxmd.com/read/28213819/conditional-knockout-of-activin-like-kinase-1-alk-1-leads-to-heart-failure-without-maladaptive-remodeling
#1
Kevin J Morine, Xiaoying Qiao, Vikram Paruchuri, Mark J Aronovitz, Emily E Mackey, Lyanne Buiten, Jonathan Levine, Keshan Ughreja, Prerna Nepali, Robert M Blanton, Richard H Karas, S Paul Oh, Navin K Kapur
Activin like kinase-1 (AlK-1) mediates signaling via the transforming growth factor beta (TGFβ) family of ligands. AlK-1 activity promotes endothelial proliferation and migration. Reduced AlK-1 activity is associated with arteriovenous malformations. No studies have examined the effect of global AlK-1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of AlK-1 promote maladaptive cardiac remodeling. To test this hypothesis, we employed AlK-1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele, whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre recombinase-mediated excision of floxed AlK-1 alleles...
February 17, 2017: Heart and Vessels
https://www.readbyqxmd.com/read/28213473/central-role-of-t-helper-17-cells-in-chronic-hypoxia-induced-pulmonary-hypertension
#2
Levi D Maston, David T Jones, Wieslawa Giermakowska, Tamara A Howard, Judy L Cannon, Wei Wang, Yongyi Wei, Weimin Xuan, Thomas C Resta, Laura V Gonzalez Bosc
RATIONALE: Inflammation is a prominent pathologic feature in pulmonary arterial hypertension as demonstrated by pulmonary vascular infiltration of inflammatory cells, including T and B lymphocytes. However, the contribution of the adaptive immune system is not well characterized in pulmonary hypertension caused by chronic hypoxia. CD4(+) T cells are required for initiating and maintaining inflammation, suggesting these cells could play an important role in the pathogenesis of hypoxic pulmonary hypertension...
February 17, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28213441/secreted-metalloproteinase-adamts-3-inactivates-reelin
#3
Himari Ogino, Arisa Hisanaga, Takao Kohno, Yuta Kondo, Kyoko Okumura, Takana Kamei, Tempei Sato, Hiroshi Asahara, Hitomi Tsuiji, Masaki Fukata, Mitsuharu Hattori
The secreted glycoprotein Reelin regulates embryonic brain development and adult brain functions. It has been suggested that reduced Reelin activity contributes to the pathogenesis of several neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer's disease; however, non-invasive methods that can upregulate Reelin activity in vivo have yet to be developed. We previously found that the proteolytic cleavage of Reelin within Reelin repeat 3 (N-t site) abolishes Reelin activity in vitro, but it remains controversial as to whether this effect occurs in vivo Here we partially purified the enzyme that mediates the N-t cleavage of Reelin from the culture supernatant of cerebral cortical neurons...
February 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28213154/density-and-neurochemical-profiles-of-neuronal-nitric-oxide-synthase-expressing-interneuron-in-the-mouse-basolateral-amygdala
#4
Xiaona Wang, Chunhua Liu, Xiaochen Wang, Fei Gao, Ren-Zhi Zhan
Neuronal nitric oxide synthase (nNOS)-expressing interneurons reside in the basolateral nucleus of the amygdala (BLA) of rodents. In the present study, we immunohistochemically analyzed nNOS-positive cells in the mouse BLA by focusing on their density, γ-Aminobutyric acid (GABA)ergicity, and co-localization with calcium-binding proteins and neuropeptides. The density of nNOS-containing neurons was analyzed with unbiased stereology. Experiments were conducted in both adult wild-type C57BL/6 and glutamic acid decarboxylase-green fluorescence protein (GAD67-GFP) knock-in mice, in which GFP is expressed in GABAergic neurons under the control of the endogenous GAD67 gene promoter...
February 14, 2017: Brain Research
https://www.readbyqxmd.com/read/28211815/generation-and-characterization-of-knock-in-mouse-models-expressing-versions-of-huntingtin-with-either-an-n17-or-a-combined-polyq-and-proline-rich-region-deletion
#5
Emily A André, Elise M Braatz, Jeh-Ping Liu, Scott O Zeitlin
BACKGROUND: The polyglutamine (polyQ) stretch of the Huntingtin protein (HTT) in mammals is flanked by a highly conserved 17 amino acid N-terminal domain (N17), and a proline-rich region (PRR). The PRR is a binding site for many HTT-interacting proteins, and the N17 domain regulates several normal HTT functions, including HTT's ability to associate with membranes and organelles. OBJECTIVE: This study investigates the consequence of deleting mouse Huntingtin's (Htt's) N17 domain or a combination of its polyQ stretch and PRR (QP) on normal Htt function in mice...
February 16, 2017: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/28209967/optimization-of-the-production-of-knock-in-alleles-by-crispr-cas9-microinjection-into-the-mouse-zygote
#6
Aurélien Raveux, Sandrine Vandormael-Pournin, Michel Cohen-Tannoudji
Microinjection of the CRISPR/Cas9 system in zygotes is an efficient and comparatively fast method to generate genetically modified mice. So far, only few knock-in mice have been generated using this approach, and because no systematic study has been performed, parameters controlling the efficacy of CRISPR/Cas9-mediated targeted insertion are not fully established. Here, we evaluated the effect of several parameters on knock-in efficiency changing only one variable at a time. We found that knock-in efficiency was dependent on injected Cas9 mRNA and single-guide RNA concentrations and that cytoplasmic injection resulted in more genotypic complexity compared to pronuclear injection...
February 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28209720/acquired-expression-of-cbl-q367p-in-mice-induces-dysplastic-myelopoiesis-mimicking-chronic-myelomonocytic-leukemia
#7
Yuichiro Nakata, Takeshi Ueda, Akiko Nagamachi, Norimasa Yamasaki, Ken-Ichiro Ikeda, Yasuyuki Sera, Keiyo Takubo, Akinori Kanai, Hideaki Oda, Masashi Sanada, Seishi Ogawa, Kohichiro Tsuji, Yasuhiro Ebihara, Linda Wolff, Zen-Ichiro Honda, Toshio Suda, Toshiya Inaba, Hiroaki Honda
Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by uncontrolled proliferation of dysplastic myelomonocytes and frequent progression to acute myeloid leukemia (AML). We identified mutations in the Cbl gene, which encodes a negative regulator of cytokine signaling, in a subset of CMML patients. To investigate the contribution of mutant Cbl in CMML pathogenesis, we generated conditional knock-in mice for Cbl that express wild-type Cbl in a steady state and inducibly express Cbl(Q367P) , a CMML-associated Cbl mutant...
February 16, 2017: Blood
https://www.readbyqxmd.com/read/28209530/slc39a6-promotes-aggressiveness-of-esophageal-carcinoma-cells-by-increasing-intracellular-levels-of-zinc-activating-phosphatidylinositol-3-kinase-signaling-and-upregulating-genes-that-regulate-metastasis
#8
Xinxin Cheng, Lixuan Wei, Xudong Huang, Jian Zheng, Mingming Shao, Ting Feng, Jun Li, Yaling Han, Wenle Tan, Wen Tan, Dongxin Lin, Chen Wu
BACKGROUND & AIMS: A common variant in the solute carrier family 39 member 6 gene (SLC39A6) has been associated with survival times of patients with esophageal squamous-cell carcinoma (ESCC). We investigated the function of SLC39A6 and ways in which this variant affects tumor progression by studying ESCC samples and cell lines. METHODS: SLC39A6 was expressed, or knocked down by expression of small hairpin RNAs, in ESCC cells (KYSE30 and KYSE450) and HeLa cells using lentiviral vectors; we analyzed effects on proliferation, colony formation, migration, and invasion in vitro...
February 13, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28207852/tetraspanin-6-a-novel-regulator-of-hippocampal-synaptic-transmission-and-long-term-plasticity
#9
Isabel H Salas, Zsuzsanna Callaerts-Vegh, Amaia M Arranz, Francesc X Guix, Rudi D'Hooge, José A Esteban, Bart De Strooper, Carlos G Dotti
Tetraspanins (Tspan) are transmembrane proteins with important scaffold and signalling functions. Deletions of Tetraspanin 6 (Tspan6) gene, a member of the tetraspanin family, have been reported in patients with Epilepsy Female-restricted with Mental Retardation (EFMR). Interestingly, mutations in Tspan7, highly homologous to Tspan6, are associated with X-linked intellectual disability, suggesting that these two proteins are important for cognition. Considering recent evidences showing that Tspan7 plays a key role in synapse development and AMPAR trafficking, we initiated the study of Tspan6 in synaptic function using a Tspan6 knock out mouse model...
2017: PloS One
https://www.readbyqxmd.com/read/28206686/nte-pnpla6-is-expressed-in-mature-schwann-cells-and-is-required-for-glial-ensheathment-of-remak-fibers
#10
Janis McFerrin, Bruce L Patton, Elizabeth R Sunderhaus, Doris Kretzschmar
Neuropathy target esterase (NTE) or patatin-like phospholipase domain containing 6 (PNPLA6) was first linked with a neuropathy occurring after organophosphate poisoning and was later also found to cause complex syndromes when mutated, which can include mental retardation, spastic paraplegia, ataxia, and blindness. NTE/PNPLA6 is widely expressed in neurons but experiments with its Drosophila orthologue Swiss-cheese (SWS) suggested that it may also have glial functions. Investigating whether NTE/PNPLA6 is expressed in glia, we found that NTE/PNPLA6 is expressed by Schwann cells in the sciatic nerve of adult mice with the most prominent expression in nonmyelinating Schwann cells...
February 16, 2017: Glia
https://www.readbyqxmd.com/read/28202908/silencing-c-rel-in-macrophages-dampens-th1-and-th17-immune-responses-and-alleviates-experimental-autoimmune-encephalomyelitis-in-mice
#11
Hongling Zhang, Jiacheng Bi, Huqiang Yi, Tingting Fan, Qingguo Ruan, Lintao Cai, Youhai H Chen, Xiaochun Wan
Autoimmune Th1 and Th17 responses are critical for the development of central nervous system (CNS) pathology in experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. Although macrophages play important roles in the development of Th1 and Th17 responses, whether modulating macrophage gene transcription can diminish Th1- and Th17 cell-induced CNS pathology is unclear. In this study, we successfully silenced the expression of the transcription factor c-Rel in macrophages of mice with EAE (including those infiltrating the CNS) using chemically modified c-Rel-specific siRNAs delivered by nanoparticles...
February 16, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28202907/calpain-1-deletion-impairs-mglur-dependent-ltd-and-fear-memory-extinction
#12
Guoqi Zhu, Victor Briz, Jeff Seinfeld, Yan Liu, Xiaoning Bi, Michel Baudry
Recent studies indicate that calpain-1 is required for the induction of long-term potentiation (LTP) elicited by theta-burst stimulation in field CA1 of hippocampus. Here we determined the contribution of calpain-1 in another type of synaptic plasticity, the long-term depression (LTD) elicited by activation of type-I metabotropic glutamate receptors (mGluR-LTD). mGluR-LTD was associated with calpain-1 activation following T-type calcium channel opening, and resulted in the truncation of a regulatory subunit of PP2A, B56α...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28202618/the-inflammatory-bowel-disease-associated-autophagy-gene-atg16l1t300a-acts-as-a-dominant-negative-variant-in-mice
#13
Ping Gao, Hongtao Liu, Huarong Huang, Qi Zhang, Warren Strober, Fuping Zhang
The basis of the increased risk for Crohn's disease conferred by the Atg16L1T300A polymorphism is incompletely understood. An important step forward came from the recent demonstration that the murine equivalent of Atg16L1T300A (Atg16L1T316A) exhibits increased susceptibility to caspase 3-mediated cleavage and resulting decreased levels of full-length Atg16L1 in macrophages. However, although this finding showed that this polymorphism is a loss-of-function abnormality, it did not address the possibility that this polymorphism also affects the function of a normal Atg16L1 allele in heterozygous mice...
February 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28202616/dna-repair-interacts-with-autophagy-to-regulate-inflammatory-responses-to-pulmonary-hyperoxia
#14
Yan Ye, Ping Lin, Weidong Zhang, Shirui Tan, Xikun Zhou, Rongpeng Li, Qinqin Pu, Jonathan L Koff, Archana Dhasarathy, Feng Ma, Xin Deng, Jianxin Jiang, Min Wu
Oxygen is supplied as a supportive treatment for patients suffering from acute respiratory distress syndrome. Unfortunately, high oxygen concentration increases reactive oxygen species generation, which causes DNA damage and ultimately cell death in the lung. Although 8-oxoguanine-DNA glycosylase (OGG-1) is involved in repairing hyperoxia-mediated DNA damage, the underlying molecular mechanism remains elusive. In this study, we report that ogg-1-deficient mice exhibited a significant increase of proinflammatory cytokines (TNF-α, IL-6, and IFN-γ) in the lung after being exposed to 95% oxygen...
February 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28202532/cd40-signaling-drives-potent-cellular-immune-responses-in-heterologous-cancer-vaccinations
#15
Supot Nimanong, Dmitrij Ostroumov, Jessica Wingerath, Sarah Knocke, Norman Woller, Engin Guerlevik, Christine Falk, Michael P Manns, Florian Kuehnel, Thomas C Wirth
Antagonistic antibodies targeting co-inhibitory receptors have revolutionized the treatment of cancer by inducing durable immune responses and clinical remissions in patients. In contrast, success of agonistic costimulatory antibodies has thus far been limited due to insufficient induction of adaptive immune responses. Here we describe a novel vaccination method consisting of a primary dendritic cell immunization followed by a composite vaccination including an agonistic CD40 antibody, soluble antigen and a TLR3 agonist, referred to as CoAT...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28199901/cd44-deficiency-enhanced-streptococcus-equi-ssp-zooepidemicus-dissemination-and-inflammation-response-in-a-mouse-model
#16
Qiang Fu, Pingping Xiao, Yaosheng Chen, Zigong Wei, Xiaohong Liu
Streptococcus equi ssp. zooepidemicus (S. zooepidemicus) is responsible for peritonitis, septicemia, meningitis, arthritis and several other serious diseases in various species. Recent studies have demonstrated that CD44 is implicated in the process of host defense against pathogenic microorganisms. In the present study, the role of CD44 in the host response to S. zooepidemicus infection was investigated in a mouse model. Upon intraperitoneal infection with S. zooepidemicus, the expression of CD44 on the peritoneal exudate cells from wild-type (WT) mice was increased...
February 9, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28199486/gsg1-trnp1-and-tmem215-mark-subpopulations-of-bipolar-interneurons-in-the-mouse-retina
#17
Ko Uoon Park, Grace Randazzo, Kenneth L Jones, Joseph A Brzezinski
Purpose: How retinal bipolar cell interneurons are specified and assigned to specialized subtypes is only partially understood. In part, this is due to a lack of early pan- and subtype-specific bipolar cell markers. To discover these factors, we identified genes that were upregulated in Blimp1 (Prdm1) mutant retinas, which exhibit precocious bipolar cell development. Methods: Postnatal day (P)2 retinas from Blimp1 conditional knock-out (CKO) mice and controls were processed for RNA sequencing...
February 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28199320/the-use-of-urinary-proteomics-in-the-assessment-of-suitability-of-mouse-models-for-ageing
#18
Esther Nkuipou-Kenfack, Joost P Schanstra, Seerat Bajwa, Martin Pejchinovski, Claire Vinel, Cédric Dray, Philippe Valet, Jean-Loup Bascands, Antonia Vlahou, Thomas Koeck, Melanie Borries, Hauke Busch, Wibke Bechtel-Walz, Tobias B Huber, Karl L Rudolph, Andreas Pich, Harald Mischak, Petra Zürbig
Ageing is a complex process characterised by a systemic and progressive deterioration of biological functions. As ageing is associated with an increased prevalence of age-related chronic disorders, understanding its underlying molecular mechanisms can pave the way for therapeutic interventions and managing complications. Animal models such as mice are commonly used in ageing research as they have a shorter lifespan in comparison to humans and are also genetically close to humans. To assess the translatability of mouse ageing to human ageing, the urinary proteome in 89 wild-type (C57BL/6) mice aged between 8-96 weeks was investigated using capillary electrophoresis coupled to mass spectrometry (CE-MS)...
2017: PloS One
https://www.readbyqxmd.com/read/28198698/a-role-for-cerebellum-in-the-hereditary-dystonia-dyt1
#19
Rachel Fremont, Ambika Tewari, Chantal Angueyra, Kamran Khodakhah
DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential development compensation between rodents and humans. To address this issue, torsinA was acutely knocked down in select brain regions of adult mice using shRNAs. TorsinA knockdown in the cerebellum, but not in the basal ganglia, was sufficient to induce dystonia...
February 15, 2017: ELife
https://www.readbyqxmd.com/read/28198409/electrical-stimulation-using-conductive-polymer-polypyrrole-counters-reduced-neurite-outgrowth-of-primary-prefrontal-cortical-neurons-from-nrg1-ko-and-disc1-li-mice
#20
Qingsheng Zhang, Dorna Esrafilzadeh, Jeremy M Crook, Robert Kapsa, Elise M Stewart, Eva Tomaskovic-Crook, Gordon G Wallace, Xu-Feng Huang
Deficits in neurite outgrowth, possibly involving dysregulation of risk genes neuregulin-1 (NRG1) and disrupted in schizophrenia 1 (DISC1) have been implicated in psychiatric disorders including schizophrenia. Electrical stimulation using conductive polymers has been shown to stimulate neurite outgrowth of differentiating human neural stem cells. This study investigated the use of the electroactive conductive polymer polypyrrole (Ppy) to counter impaired neurite outgrowth of primary pre-frontal cortical (PFC) neurons from NRG1-knock out (NRG1-KO) and DISC1-locus impairment (DISC1-LI) mice...
February 15, 2017: Scientific Reports
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