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https://www.readbyqxmd.com/read/29684399/a-cas9-transgenic-plasmodium-yoelii-parasite-for-efficient-gene-editing
#1
Pengge Qian, Xu Wang, Zhenke Yang, Zhenkui Li, Han Gao, Xin-Zhuan Su, Huiting Cui, Jing Yuan
The RNA-guided endonuclease Cas9 has applied as an efficient gene-editing method in malaria parasite Plasmodium. However, the size (4.2 kb) of the commonly used Cas9 from Streptococcus pyogenes (SpCas9) limits its utility for genome editing in the parasites only introduced with cas9 plasmid. To establish the endogenous and constitutive expression of Cas9 protein in the rodent malaria parasite P. yoelii, we replaced the coding region of an endogenous gene sera1 with the intact SpCas9 coding sequence using the CRISPR/Cas9-mediated genome editing method, generating the cas9-knockin parasite (PyCas9ki) of the rodent malaria parasite P...
April 20, 2018: Molecular and Biochemical Parasitology
https://www.readbyqxmd.com/read/29676940/differential-compensation-of-two-cyclooxygenases-in-renal-homeostasis-is-independent-of-prostaglandin-synthetic-capacity-under-basal-conditions
#2
Xinzhi Li, Liudmila L Mazaleuskaya, Laurel L Ballantyne, Hu Meng, Garret A FitzGerald, Colin D Funk
The distinct functions of each cyclooxygenase (COX) isoform in renal homeostasis have been the subject of intense investigation for many years. We took the novel approach of using 3 characterized mouse lines, where the prostaglandin (PG)-endoperoxide synthase genes 1 and 2 ( Ptgs1 and Ptgs2) substitute for one another to delineate distinct roles and the potential for COX isoform substitution. Flipped Ptgs genes generate a reversed COX-expression pattern in the kidney, where the knockin COX-2 is highly expressed...
April 20, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29672221/glucocorticoid-receptor-isoform-specific-regulation-of-development-circadian-rhythm-and-inflammation-in-mice
#3
Robert H Oakley, Sivapriya Ramamoorthy, Julie F Foley, Jonathan T Busada, Nick Z Lu, John A Cidlowski
Glucocorticoids are primary stress hormones, and their synthetic derivatives are widely used clinically. The therapeutic efficacy of these steroids is limited by side effects and glucocorticoid resistance. Multiple glucocorticoid receptor (GR) isoforms are produced from a single gene by alternative translation initiation; however, the role individual isoforms play in tissue-specific responses to glucocorticoids is unknown. We have generated knockin mice that exclusively express the most active receptor isoform, GR-C3...
April 19, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29669284/manifold-roles-of-ccr7-and-its-ligands-in-the-induction-and-maintenance-of-bronchus-associated-lymphoid-tissue
#4
Henrike Fleige, Berislav Bosnjak, Marc Permanyer, Jasmin Ristenpart, Anja Bubke, Stefanie Willenzon, Gerd Sutter, Sanjiv A Luther, Reinhold Förster
The processes underlying the development and maintenance of tertiary lymphoid organs are incompletely understood. Using a Ccr7 knockout/knockin approach, we show that spontaneous bronchus-associated lymphoid tissue (BALT) formation can be caused by CCR7-mediated migration defects of dendritic cells (DCs) in the lung. Plt/plt mice that lack the CCR7 ligands CCL19 and CCL21-serine do not form BALT spontaneously because lung-expressed CCL21-leucine presumably suffices to maintain steady-state DC egress. However, plt/plt mice are highly susceptible to modified vaccinia virus infection, showing enhanced recruitment of immune cells as well as alterations in CCR7-ligand-mediated lymphocyte egress from the lungs, leading to dramatically enhanced BALT...
April 17, 2018: Cell Reports
https://www.readbyqxmd.com/read/29651330/analysis-of-neuroanatomical-differences-in-mice-with-genetically-modified-serotonin-transporters-assessed-by-structural-magnetic-resonance-imaging
#5
Jacob Ellegood, Yohan Yee, Travis M Kerr, Christopher L Muller, Randy D Blakely, R Mark Henkelman, Jeremy Veenstra-VanderWeele, Jason P Lerch
Background: The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects of brain development, but systematic neuroimaging studies have not previously been reported. In particular, the 5-HT transporter (serotonin transporter, SERT; 5-HTT) gene, Slc6a4 , has been extensively studied...
2018: Molecular Autism
https://www.readbyqxmd.com/read/29622782/multiple-sgrnas-with-overlapping-sequences-enhance-crispr-cas9-mediated-knock-in-efficiency
#6
Da Eun Jang, Jae Young Lee, Jae Hoon Lee, Ok Jae Koo, Hee Sook Bae, Min Hee Jung, Ji Hyun Bae, Woo Sung Hwang, Yoo Jin Chang, Yoon Hoo Lee, Han Woong Lee, Su Cheong Yeom
The CRISPR/Cas9 system is widely applied in genome engineering due to its simplicity and versatility. Although this has revolutionized genome-editing technology, knockin animal generation via homology directed repair (HDR) is not as efficient as nonhomologous end-joining DNA-repair-dependent knockout. Although its double-strand break activity may vary, Cas9 derived from Streptococcus pyogenens allows robust design of single-guide RNAs (sgRNAs) within the target sequence; However, prescreening for different sgRNA activities delays the process of transgenic animal generation...
April 6, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29610531/small-molecules-promote-crispr-cpf1-mediated-genome-editing-in-human-pluripotent-stem-cells
#7
Xiaojie Ma, Xi Chen, Yan Jin, Wenyan Ge, Weiyun Wang, Linghao Kong, Junfang Ji, Xing Guo, Jun Huang, Xin-Hua Feng, Junfen Fu, Saiyong Zhu
Human pluripotent stem cells (hPSCs) have potential applications in biological studies and regenerative medicine. However, precise genome editing in hPSCs remains time-consuming and labor-intensive. Here we demonstrate that the recently identified CRISPR-Cpf1 can be used to efficiently generate knockout and knockin hPSC lines. The unique properties of CRISPR-Cpf1, including shorter crRNA length and low off-target activity, are very attractive for many applications. In particular, we develop an unbiased drug-selection-based platform feasible for high-throughput screening in hPSCs and this screening system enables us to identify small molecules VE-822 and AZD-7762 that can promote CRISPR-Cpf1-mediated precise genome editing...
April 3, 2018: Nature Communications
https://www.readbyqxmd.com/read/29606503/a-blood-brain-barrier-penetrating-anti-human-transferrin-receptor-antibody-fusion-protein-for-neuronopathic-mucopolysaccharidosis-ii
#8
Hiroyuki Sonoda, Hideto Morimoto, Eiji Yoden, Yuri Koshimura, Masafumi Kinoshita, Galina Golovina, Haruna Takagi, Ryuji Yamamoto, Kohtaro Minami, Akira Mizoguchi, Katsuhiko Tachibana, Tohru Hirato, Kenichi Takahashi
Mucopolysaccharidosis II (MPS II) is an X-linked recessive lysosomal storage disease caused by mutations in the iduronate-2-sulfatase (IDS) gene. Since IDS catalyzes the degradation of glycosaminoglycans (GAGs), deficiency in this enzyme leads to accumulation of GAGs in most cells in all tissues and organs, resulting in severe somatic and neurological disorders. Although enzyme replacement therapy with human IDS (hIDS) has been used for the treatment of MPS II, this therapy is not effective for defects in the CNS mainly because the enzyme cannot cross the blood-brain barrier (BBB)...
March 6, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29606351/a-huntingtin-knockin-pig-model-recapitulates-features-of-selective-neurodegeneration-in-huntington-s-disease
#9
Sen Yan, Zhuchi Tu, Zhaoming Liu, Nana Fan, Huiming Yang, Su Yang, Weili Yang, Yu Zhao, Zhen Ouyang, Chengdan Lai, Huaqiang Yang, Li Li, Qishuai Liu, Hui Shi, Guangqing Xu, Heng Zhao, Hongjiang Wei, Zhong Pei, Shihua Li, Liangxue Lai, Xiao-Jiang Li
Huntington's disease (HD) is characterized by preferential loss of the medium spiny neurons in the striatum. Using CRISPR/Cas9 and somatic nuclear transfer technology, we established a knockin (KI) pig model of HD that endogenously expresses full-length mutant huntingtin (HTT). By breeding this HD pig model, we have successfully obtained F1 and F2 generation KI pigs. Characterization of founder and F1 KI pigs shows consistent movement, behavioral abnormalities, and early death, which are germline transmittable...
March 23, 2018: Cell
https://www.readbyqxmd.com/read/29605859/functional-insulator-scanning-of-cpg-islands-to-identify-regulatory-regions-of-promoters-using-crispr
#10
Alice Grob, Masue Marbiah, Mark Isalan
The ability to mutate a promoter in situ is potentially a very useful approach for gaining insights into endogenous gene regulation mechanisms. The advent of CRISPR/Cas systems has provided simple, efficient, and targeted genetic manipulation in eukaryotes, which can be applied to studying genome structure and function.The basic CRISPR toolkit comprises an endonuclease, Cas9, and a short DNA-targeting sequence, made up of a single guide RNA (sgRNA). The catalytic domains of Cas9 are rendered active upon dimerization of Cas9 with sgRNA, resulting in targeted double stranded DNA breaks...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29600961/targeting-of-nonlipidated-aggregated-apoe-with-antibodies-inhibits-amyloid-accumulation
#11
Fan Liao, Aimin Li, Monica Xiong, Nga Bien-Ly, Hong Jiang, Yin Zhang, Mary Beth Finn, Rosa Hoyle, Jennifer Keyser, Katheryn B Lefton, Grace O Robinson, Javier Remolina Serrano, Adam P Silverman, Jing L Guo, Jennifer Getz, Kirk Henne, Cheryl Eg Leyns, Gilbert Gallardo, Jason D Ulrich, Patrick M Sullivan, Eli Paul Lerner, Eloise Hudry, Zachary K Sweeney, Mark S Dennis, Bradley T Hyman, Ryan J Watts, David M Holtzman
The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid β (Aβ) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease Aβ pathology in mice producing both human Aβ and apoE4, and investigated the mechanism underlying these effects...
March 30, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29593216/klf4-glutamylation-is-required-for-cell-reprogramming-and-early-embryonic-development-in-mice
#12
Buqing Ye, Benyu Liu, Lu Hao, Xiaoxiao Zhu, Liuliu Yang, Shuo Wang, Pengyan Xia, Ying Du, Shu Meng, Guanling Huang, Xiwen Qin, Yanying Wang, Xinlong Yan, Chong Li, Junfeng Hao, Pingping Zhu, Luyun He, Yong Tian, Zusen Fan
Temporal and spatial-specific regulation of pluripotency networks is largely dependent on the precise modifications of core transcription factors. Misregulation of glutamylation is implicated in severe physiological abnormalities. However, how glutamylation regulates cell reprogramming and pluripotency networks remains elusive. Here we show that cytosolic carboxypeptidases 1 (CCP1) or CCP6 deficiency substantially promotes induced pluripotent cell (iPSC) induction and pluripotency of embryonic stem cells (ESCs)...
March 28, 2018: Nature Communications
https://www.readbyqxmd.com/read/29581356/icos-signaling-controls-induction-and-maintenance-of-collagen-induced-arthritis
#13
Vincent Panneton, Sahar Bagherzadeh Yazdchi, Mariko Witalis, Jinsam Chang, Woong-Kyung Suh
ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS+ T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis...
March 26, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29581299/mdmx-acidic-domain-inhibits-p53-dna-binding-in-vivo-and-regulates-tumorigenesis
#14
Qingling Huang, Lihong Chen, Leixiang Yang, Xiaoling Xie, Lin Gan, John L Cleveland, Jiandong Chen
The MDM2 homolog MDMX oncoprotein is indispensable for inhibition of p53 during normal embryonic development and malignant transformation, yet how MDMX harnesses p53 functions is unclear. In addition to a canonical N-terminal p53-binding domain, recent work suggests the central acidic domain of MDMX regulates p53 interaction through intramolecular mimicry and engages in second-site interaction with the p53 core domain in vitro. To test the physiological relevance of these interactions, we generated an MDMX knockin mouse having substitutions in a conserved WW motif necessary for these functions (W201S/W202G)...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29566795/gamma-oscillation-dysfunction-in-mpfc-leads-to-social-deficits-in-neuroligin-3-r451c-knockin-mice
#15
Wei Cao, Shen Lin, Qiang-Qiang Xia, Yong-Lan Du, Qian Yang, Meng-Ying Zhang, Yi-Qing Lu, Jing Xu, Shu-Min Duan, Jun Xia, Guoping Feng, Junyu Xu, Jian-Hong Luo
No abstract text is available yet for this article.
March 21, 2018: Neuron
https://www.readbyqxmd.com/read/29559584/gain-of-function-mutations-in-the-gene-encoding-the-tyrosine-phosphatase-shp2-induce-hydrocephalus-in-a-catalytically-dependent-manner
#16
Hong Zheng, Wen-Mei Yu, Ronald R Waclaw, Maria I Kontaridis, Benjamin G Neel, Cheng-Kui Qu
Catalytically activating mutations in Ptpn11 , which encodes the protein tyrosine phosphatase SHP2, cause 50% of Noonan syndrome (NS) cases, whereas inactivating mutations in Ptpn11 are responsible for nearly all cases of the similar, but distinct, developmental disorder Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome). However, both types of disease mutations are gain-of-function mutations because they cause SHP2 to constitutively adopt an open conformation. We found that the catalytic activity of SHP2 was required for the pathogenic effects of gain-of-function, disease-associated mutations on the development of hydrocephalus in the mouse...
March 20, 2018: Science Signaling
https://www.readbyqxmd.com/read/29532590/generation-of-elf5-cre-knockin-mouse-strain-for-trophoblast-specific-gene-manipulation
#17
Shuangbo Kong, Guixian Liang, Zhaowei Tu, Dunjin Chen, Haibin Wang, Jinhua Lu
Placental development is a complex and highly controlled process during which trophoblast stem cells differentiate to various trophoblast subtypes. The early embryonic death of systemic gene knockout models hampers the investigation of these genes that might play important roles during placentation. A trophoblast specific Cre mouse model would be of great help for dissecting out the potential roles of these genes during placental development. For this purpose, we generate a transgenic mouse with the Cre recombinase inserted into the endogenous locus of Elf5 gene that is expressed specifically in placental trophoblast cells...
March 13, 2018: Genesis: the Journal of Genetics and Development
https://www.readbyqxmd.com/read/29511098/murine-knockin-model-for-progranulin-deficient-frontotemporal-dementia-with-nonsense-mediated-mrna-decay
#18
Andrew D Nguyen, Thi A Nguyen, Jiasheng Zhang, Swathi Devireddy, Ping Zhou, Anna M Karydas, Xialian Xu, Bruce L Miller, Frank Rigo, Shawn M Ferguson, Eric J Huang, Tobias C Walther, Robert V Farese
Frontotemporal dementia (FTD) is the most common neurodegenerative disorder in individuals under age 60 and has no treatment or cure. Because many cases of FTD result from GRN nonsense mutations, an animal model for this type of mutation is highly desirable for understanding pathogenesis and testing therapies. Here, we generated and characterized Grn R493X knockin mice, which model the most common human GRN mutation, a premature stop codon at arginine 493 (R493X). Homozygous Grn R493X mice have markedly reduced Grn mRNA levels, lack detectable progranulin protein, and phenocopy Grn knockout mice, with CNS microgliosis, cytoplasmic TDP-43 accumulation, reduced synaptic density, lipofuscinosis, hyperinflammatory macrophages, excessive grooming behavior, and reduced survival...
March 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29509513/crispr-cas9-mediated-2-sgrna-cleavage-facilitates-pseudorabies-virus-editing
#19
Yan-Dong Tang, Jin-Chao Guo, Tong-Yun Wang, Kuan Zhao, Ji-Ting Liu, Jia-Cong Gao, Zhi-Jun Tian, Tong-Qing An, Xue-Hui Cai
Several groups have used CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) for DNA virus editing. In most cases, one single-guide RNA (sgRNA) is used, which produces inconsistencies in gene editing. In this study, we used a swine herpesvirus, pseudorabies virus, as a model to systematically explore the application of CRISPR/Cas9 in DNA virus editing. In our current report, we demonstrated that cotransfection of 2 sgRNAs and a viral genome resulted in significantly better knockout efficiency than the transfection-infection-based approach...
March 6, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29503190/gamma-oscillation-dysfunction-in-mpfc-leads-to-social-deficits-in-neuroligin-3-r451c-knockin-mice
#20
Wei Cao, Shen Lin, Qiang-Qiang Xia, Yong-Lan Du, Qian Yang, Meng-Ying Zhang, Yi-Qing Lu, Jing Xu, Shu-Min Duan, Xia Jun, Guoping Feng, Junyu Xu, Jian-Hong Luo
Neuroligins (NLs) are critical for synapse formation and function. NL3 R451C is an autism-associated mutation. NL3 R451C knockin (KI) mice exhibit autistic behavioral abnormalities, including social novelty deficits. However, neither the brain regions involved in social novelty nor the underlying mechanisms are clearly understood. Here, we found decreased excitability of fast-spiking interneurons and dysfunction of gamma oscillation in the medial prefrontal cortex (mPFC), which contributed to the social novelty deficit in the KI mice...
February 22, 2018: Neuron
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