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https://www.readbyqxmd.com/read/29202466/loss-of-pleckstrin-2-reverts-lethality-and-vascular-occlusions-in-jak2v617f-positive-myeloproliferative-neoplasms
#1
Baobing Zhao, Yang Mei, Lan Cao, Jingxin Zhang, Ronen Sumagin, Jing Yang, Juehua Gao, Matthew J Schipma, Yanfeng Wang, Chelsea Thorsheim, Liang Zhao, Timothy Stalker, Brady Stein, Qiang Jeremy Wen, John D Crispino, Charles S Abrams, Peng Ji
V617F driver mutation of JAK2 is the leading cause of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs). Although thrombosis is a leading cause of mortality and morbidity in MPNs, the mechanisms underlying their pathogenesis are unclear. Here, we identified pleckstrin-2 (Plek2) as a downstream target of the JAK2/STAT5 pathway in erythroid and myeloid cells, and showed that it is upregulated in a JAK2V617F-positive MPN mouse model and in patients with MPNs. Loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes including erythrocytosis, neutrophilia, thrombocytosis, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality in JAK2V617F-knockin mice...
November 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29186692/quiescence-exit-of-tert-stem-cells-by-wnt-%C3%AE-catenin-is-indispensable-for-intestinal-regeneration
#2
Han Na Suh, Moon Jong Kim, Youn-Sang Jung, Esther M Lien, Sohee Jun, Jae-Il Park
Fine control of stem cell maintenance and activation is crucial for tissue homeostasis and regeneration. However, the mechanism of quiescence exit of Tert+ intestinal stem cells (ISCs) remains unknown. Employing a Tert knockin (TertTCE/+) mouse model, we found that Tert+ cells are long-term label-retaining self-renewing cells, which are partially distinguished from the previously identified +4 ISCs. Tert+ cells become mitotic upon irradiation (IR) injury. Conditional ablation of Tert+ cells impairs IR-induced intestinal regeneration but not intestinal homeostasis...
November 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/29183983/precision-genome-editing-using-synthesis-dependent-repair-of-cas9-induced-dna-breaks
#3
Alexandre Paix, Andrew Folkmann, Daniel H Goldman, Heather Kulaga, Michael J Grzelak, Dominique Rasoloson, Supriya Paidemarry, Rachel Green, Randall R Reed, Geraldine Seydoux
The RNA-guided DNA endonuclease Cas9 has emerged as a powerful tool for genome engineering. Cas9 creates targeted double-stranded breaks (DSBs) in the genome. Knockin of specific mutations (precision genome editing) requires homology-directed repair (HDR) of the DSB by synthetic donor DNAs containing the desired edits, but HDR has been reported to be variably efficient. Here, we report that linear DNAs (single and double stranded) engage in a high-efficiency HDR mechanism that requires only ∼35 nucleotides of homology with the targeted locus to introduce edits ranging from 1 to 1,000 nucleotides...
November 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29180645/combinations-of-chromosome-transfer-and-genome-editing-for-the-development-of-cell-animal-models-of-human-disease-and-humanized-animal-models
#4
REVIEW
Narumi Uno, Satoshi Abe, Mitsuo Oshimura, Yasuhiro Kazuki
Chromosome transfer technology, including chromosome modification, enables the introduction of Mb-sized or multiple genes to desired cells or animals. This technology has allowed innovative developments to be made for models of human disease and humanized animals, including Down syndrome model mice and humanized transchromosomic (Tc) immunoglobulin mice. Genome editing techniques are developing rapidly, and permit modifications such as gene knockout and knockin to be performed in various cell lines and animals...
November 27, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/29174564/crispr-cas9-engineered-osteogenesis-imperfecta-type-v-leads-to-severe-skeletal-deformities-and-perinatal-lethality-in-mice
#5
Frank Rauch, Yeqing Geng, Lisa Lamplugh, Bahareh Hekmatnejad, Marie-Hélène Gaumond, Janice Penney, Yojiro Yamanaka, Pierre Moffatt
Osteogenesis imperfecta (OI) type V is caused by an autosomal dominant mutation in the IFITM5 gene, also known as BRIL. The c.-14C>T mutation in the 5'UTR of BRIL creates a novel translational start site adding 5 residues (MALEP) in frame with the natural coding of BRIL. A neomorphic function has been proposed for the MALEP-BRIL but the mechanisms at play are still unknown. In order to further understand the effects of MALEP-BRIL in vivo, we generated a knockin (KI) mouse model having the exact genetic -14C>T replica of patients with OI type V...
November 22, 2017: Bone
https://www.readbyqxmd.com/read/29173896/the-apkc-cbp-pathway-regulates-post-stroke-neurovascular-remodeling-and-functional-recovery
#6
Ayden Gouveia, Matthew Seegobin, Timal S Kannangara, Ling He, Fredric Wondisford, Cesar H Comin, Luciano da F Costa, Jean-Claude Béïque, Diane C Lagace, Baptiste Lacoste, Jing Wang
Epigenetic modifications have emerged as attractive molecular substrates that integrate extrinsic changes into the determination of cell identity. Since stroke-related brain damage releases micro-environmental cues, we examined the role of a signaling-induced epigenetic pathway, an atypical protein kinase C (aPKC)-mediated phosphorylation of CREB-binding protein (CBP), in post-stroke neurovascular remodeling. Using a knockin mouse strain (CbpS436A) where the aPKC-CBP pathway was defective, we show that disruption of the aPKC-CBP pathway in a murine focal ischemic stroke model increases the reprogramming efficiency of ischemia-activated pericytes (i-pericytes) to neural precursors...
November 17, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29158380/anti-sirp%C3%AE-antibody-immunotherapy-enhances-neutrophil-and-macrophage-antitumor-activity
#7
Nan Guo Ring, Dietmar Herndler-Brandstetter, Kipp Weiskopf, Liang Shan, Jens-Peter Volkmer, Benson M George, Melanie Lietzenmayer, Kelly M McKenna, Tejaswitha J Naik, Aaron McCarty, Yunjiang Zheng, Aaron M Ring, Richard A Flavell, Irving L Weissman
Cancer immunotherapy has emerged as a promising therapeutic intervention. However, complete and durable responses are only seen in a fraction of patients who have cancer. A key factor that limits therapeutic success is the infiltration of tumors by cells of the myeloid lineage. The inhibitory receptor signal regulatory protein-α (SIRPα) is a myeloid-specific immune checkpoint that engages the "don't eat me" signal CD47 expressed on tumors and normal tissues. We therefore developed the monoclonal antibody KWAR23, which binds human SIRPα with high affinity and disrupts its binding to CD47...
November 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29157111/hmga2-cooperates-with-either-p27-kip1-deficiency-or-cdk4-r24c-mutation-in-pituitary-tumorigenesis
#8
Monica Fedele, Orlando Paciello, Davide De Biase, Mario Monaco, Gennaro Chiappetta, Michela Vitiello, Antonio Barbieri, Domenica Rea, Antonio Luciano, Serenella Papparella, Claudio Arra, Alfredo Fusco
We have previously reported a critical role of HMGA proteins in pituitary tumorigenesis since either the Hmga1 or Hmga2 gene overexpression/activation induces the development of mixed growth hormone/prolactin cell pituitary adenomas by activating the E2F transcription factor 1, and then enhancing the G1/S transition of the cell cycle. Consistently, amplification and overexpression of the HMGA2 gene was found in human pituitary prolactinomas. Since impairment of the cell cycle control represents a feature of experimental and human pituitary adenomas, we have investigated the possible synergism between the alterations of other cell cycle regulators, such as p27 deficiency or Cdk4(R24C) mutation, with Hmga2 overexpression in pituitary tumorigenesis...
November 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29151587/suppression-of-mapk11-or-hipk3-reduces-mutant-huntingtin-levels-in-huntington-s-disease-models
#9
Meng Yu, Yuhua Fu, Yijiang Liang, Haikun Song, Yao Yao, Peng Wu, Yuwei Yao, Yuyin Pan, Xue Wen, Lixiang Ma, Saiyin Hexige, Yu Ding, Shouqing Luo, Boxun Lu
Most neurodegenerative disorders are associated with accumulation of disease-relevant proteins. Among them, Huntington disease (HD) is of particular interest because of its monogenetic nature. HD is mainly caused by cytotoxicity of the defective protein encoded by the mutant Huntingtin gene (HTT). Thus, lowering mutant HTT protein (mHTT) levels would be a promising treatment strategy for HD. Here we report two kinases HIPK3 and MAPK11 as positive modulators of mHTT levels both in cells and in vivo. Both kinases regulate mHTT via their kinase activities, suggesting that inhibiting these kinases may have therapeutic values...
October 13, 2017: Cell Research
https://www.readbyqxmd.com/read/29150006/genome-engineering-using-haploid-embryonic-stem-cells
#10
Takuro Horii, Izuho Hatada
Haploidy is a useful feature for the study of gene function because disruption of one allele in haploid cells, which contain only a single set of chromosomes, can cause loss-of-function phenotypes. Recent success in generating haploid embryonic stem (ES) cells from several mammalian species, including human, provides a new platform for simple genetic manipulation of the mammalian genome. The genome-editing potential of the CRISPR/Cas system is enhanced by the use of haploid ES cells. For example, CRISPR/Cas has been used for high-efficiency generation of multiple knockouts and knockins in haploid ES cells, with potential application in genome-wide screening...
2017: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/29145636/localization-and-functional-characterization-of-the-p-asn965ser-n965s-abca4-variant-in-mice-reveal-pathogenic-mechanisms-underlying-stargardt-macular-degeneration
#11
Laurie L Molday, Daniel Wahl, Marinko Sarunic, Robert S Molday
ABCA4 is a member of the superfamily of ATP-binding cassette (ABC) proteins that transports N-retinylidene-phosphatidylethanolamine (N-Ret-PE) across outer segment disc membranes thereby facilitating the removal of potentially toxic retinoid compounds from photoreceptor cells. Mutations in the gene encoding ABCA4 are responsible for Stargardt disease (STGD1), an autosomal recessive retinal degenerative disease that causes severe vision loss. To define the molecular basis for STGD1 associated with the p.Asn965Ser (N965S) mutation in the Walker A motif of nucleotide binding domain 1 (NBD1), we generated a p...
November 14, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29144234/lrp1-integrates-murine-macrophage-cholesterol-homeostasis-and-inflammatory-responses-in-atherosclerosis
#12
Xunde Xian, Yinyuan Ding, Marco Dieckmann, Li Zhou, Florian Plattner, Mingxia Liu, John S Parks, Robert E Hammer, Philippe Boucher, Shirling Tsai, Joachim Herz
Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor with diverse physiological roles, ranging from cellular uptake of lipoproteins and other cargo by endocytosis to sensor of the extracellular environment and integrator of a wide range of signaling mechanisms. As a chylomicron remnant receptor, LRP1 controls systemic lipid metabolism in concert with the LDL receptor in the liver, whereas in smooth muscle cells (SMC) LRP1 functions as a co-receptor for TGFβ and PDGFRβ in reverse cholesterol transport and the maintenance of vascular wall integrity...
November 16, 2017: ELife
https://www.readbyqxmd.com/read/29130929/tnf-regulates-transcription-of-nlrp3-inflammasome-components-and-inflammatory-molecules-in-cryopyrinopathies
#13
Matthew D McGeough, Alexander Wree, Maria E Inzaugarat, Ariela Haimovich, Casey D Johnson, Carla A Peña, Raphaela Goldbach-Mansky, Lori Broderick, Ariel E Feldstein, Hal M Hoffman
The NLRP3 inflammasome is a protein complex responsible for caspase-1-dependent maturation of the proinflammatory cytokines IL-1β and IL-18. Gain-of-function missense mutations in NLRP3 cause the disease spectrum known as the cryopyrin-associated periodic syndromes (CAPS). In this study, we generated Nlrp3-knockin mice on various KO backgrounds including Il1b/Il18-, caspase-1-, caspase-11- (Casp1/11-), and Tnf-deficient strains. The Nlrp3L351P Il1b-/- Il18-/- mutant mice survived and grew normally until adulthood and, at 6 months of age, exhibited marked splenomegaly and leukophilia...
November 13, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29105654/critical-functions-for-stat5-tetramers-in-the-maturation-and-survival-of-natural-killer-cells
#14
Jian-Xin Lin, Ning Du, Peng Li, Majid Kazemian, Tesfay Gebregiorgis, Rosanne Spolski, Warren J Leonard
Interleukin-15 (IL-15) is essential for the development and maintenance of natural killer (NK) cells. IL-15 activates STAT5 proteins, which can form dimers or tetramers. We previously found that NK cell numbers are decreased in Stat5a-Stat5b tetramer-deficient double knockin (DKI) mice, but the mechanism was not investigated. Here we show that STAT5 dimers are sufficient for NK cell development, whereas STAT5 tetramers mediate NK cell maturation and the expression of maturation-associated genes. Unlike the defective proliferation of Stat5 DKI CD8(+) T cells, Stat5 DKI NK cells have normal proliferation to IL-15 but are susceptible to death upon cytokine withdrawal, with lower Bcl2 and increased active caspases...
November 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/29099045/gene-editing-in-human-lymphoid-cells-role-for-donor-dna-type-of-genomic-nuclease-and-cell-selection-method
#15
Anastasia Zotova, Elena Lopatukhina, Alexander Filatov, Musa Khaitov, Dmitriy Mazurov
Programmable endonucleases introduce DNA breaks at specific sites, which are repaired by non-homologous end joining (NHEJ) or homology recombination (HDR). Genome editing in human lymphoid cells is challenging as these difficult-to-transfect cells may also inefficiently repair DNA by HDR. Here, we estimated efficiencies and dynamics of knockout (KO) and knockin (KI) generation in human T and B cell lines depending on repair template, target loci and types of genomic endonucleases. Using zinc finger nuclease (ZFN), we have engineered Jurkat and CEM cells with the 8...
November 2, 2017: Viruses
https://www.readbyqxmd.com/read/29082720/-advances-in-targeted-replacement-genome-editing-in-plants
#16
Honglin Wang, Congsheng Zhang, Changlin Liu, Chuanxiao Xie
Targeted replacement genome editing refers to DNA modification and engineering technology that could induce and achieve mutations of targeted gene replacement or knockin at a target gene or DNA region. In this review, the principles, implementation methods, factors that influence efficiency and accuracy, and applications of gene replacement editing were summarized and discussed. It provides the reference for gene functional characterization and genetic improvements through gene replacement strategies in higher plant especially crops...
October 25, 2017: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
https://www.readbyqxmd.com/read/29074838/-genome-editing-principle-and-possibility-of-a-novel-genetic-engineering-technology-basic-principles-of-genome-editing
#17
Takashi Yamamoto
Programmable site-specific nuclease mediated-genome editing is an emerging biotechnology for precise manipulation of target genes. In genome editing, gene-knockout as well as gene-knockin are possible in various organisms and cultured cells. CRISPR-Cas9, which was developed in 2012, is a convenient and efficient programmable site-specific nuclease and the use spreads around the world rapidly. For this, it is important for the progress of life science research to introduce the genome editing technology.
2017: Clinical Calcium
https://www.readbyqxmd.com/read/29073101/utx-guided-neural-crest-function-underlies-craniofacial-features-of-kabuki-syndrome
#18
Karl B Shpargel, Joshua Starmer, Chaochen Wang, Kai Ge, Terry Magnuson
Kabuki syndrome, a congenital craniofacial disorder, manifests from mutations in an X-linked histone H3 lysine 27 demethylase (UTX/KDM6A) or a H3 lysine 4 methylase (KMT2D). However, the cellular and molecular etiology of histone-modifying enzymes in craniofacial disorders is unknown. We now establish Kabuki syndrome as a neurocristopathy, whereby the majority of clinical features are modeled in mice carrying neural crest (NC) deletion of UTX, including craniofacial dysmorphism, cardiac defects, and postnatal growth retardation...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29072702/a-novel-lnc-pcf-promotes-the-proliferation-of-tgf-%C3%AE-1-activated-epithelial-cells-by-targeting-mir-344a-5p-to-regulate-map3k11-in-pulmonary-fibrosis
#19
Huizhu Liu, Bingsi Wang, Jinjin Zhang, Songzi Zhang, Youlei Wang, Jie Zhang, Changjun Lv, Xiaodong Song
Emerging evidence suggests that microRNA (miRNA) and long noncoding RNA (lncRNA) play important roles in disease development. However, the mechanism underlying mRNA interaction with miRNA and lncRNA in idiopathic pulmonary fibrosis (IPF) remains unknown. This study presents a novel lnc-PCF that promotes the proliferation of TGF-β1-activated epithelial cells through the regulation of map3k11 by directly targeting miR-344a-5p during pulmonary fibrogenesis. Bioinformatics and in vitro translation assay were performed to confirm whether or not lnc-PCF is an actual lncRNA...
October 26, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29069598/brain-wide-mapping-of-endogenous-serotonergic-transmission-via-chemogenetic-fmri
#20
Andrea Giorgi, Sara Migliarini, Alberto Galbusera, Giacomo Maddaloni, Maddalena Mereu, Giulia Margiani, Marta Gritti, Silvia Landi, Francesco Trovato, Sine Mandrup Bertozzi, Andrea Armirotti, Gian Michele Ratto, Maria Antonietta De Luca, Raffaella Tonini, Alessandro Gozzi, Massimo Pasqualetti
Serotonin-producing neurons profusely innervate brain regions via long-range projections. However, it remains unclear whether and how endogenous serotonergic transmission specifically influences regional or global functional activity. We combined designed receptors exclusively activated by designed drugs (DREADD)-based chemogenetics and functional magnetic resonance imaging (fMRI), an approach we term "chemo-fMRI," to causally probe the brain-wide substrates modulated by endogenous serotonergic activity...
October 24, 2017: Cell Reports
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