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Anti crispr

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https://www.readbyqxmd.com/read/28815045/tumor-derived-exosomes-induce-cd8-t-cell-suppressors
#1
Brian T Maybruck, Lukas W Pfannenstiel, Marcela Diaz-Montero, Brian R Gastman
BACKGROUND: The suppressive nature of immune cells in the tumor microenvironment plays a major role in regulating anti-tumor immune responses. Our previous work demonstrated that a soluble factor from tumor cells is able to induce a suppressor phenotype (SP) in human CD8(+) T cells typified by loss of CD27/CD28 expression and acquisition of a potent suppressor function. The present study hypothesized that the soluble mechanism that is inducing the SP in CD8(+) T cells are tumor-derived exosomes (TDEs)...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28814758/targeted-insertion-of-an-anti-cd2-monoclonal-antibody-transgene-into-the-ggta1-locus-in-pigs-using-foki-dcas9
#2
Mark B Nottle, Evelyn J Salvaris, Nella Fisicaro, Stephen McIlfatrick, Ivan Vassiliev, Wayne J Hawthorne, Philip J O'Connell, Jamie L Brady, Andrew M Lew, Peter J Cowan
Xenotransplantation from pigs has been advocated as a solution to the perennial shortage of donated human organs and tissues. CRISPR/Cas9 has facilitated the silencing of genes in donor pigs that contribute to xenograft rejection. However, the generation of modified pigs using second-generation nucleases with much lower off-target mutation rates than Cas9, such as FokI-dCas9, has not been reported. Furthermore, there have been no reports on the use of CRISPR to knock protective transgenes into detrimental porcine genes...
August 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28813417/cmtm6-maintains-the-expression-of-pd-l1-and-regulates-anti-tumour-immunity
#3
Marian L Burr, Christina E Sparbier, Yih-Chih Chan, James C Williamson, Katherine Woods, Paul A Beavis, Enid Y N Lam, Melissa A Henderson, Charles C Bell, Sabine Stolzenburg, Omer Gilan, Stuart Bloor, Tahereh Noori, David W Morgens, Michael C Bassik, Paul J Neeson, Andreas Behren, Phillip K Darcy, Sarah-Jane Dawson, Ilia Voskoboinik, Joseph A Trapani, Jonathan Cebon, Paul J Lehner, Mark A Dawson
Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) to subvert T-cell-mediated immunosurveillance. The success of therapies that disrupt PD-L1-mediated tumour tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression. Here we identify the uncharacterized protein CMTM6 as a critical regulator of PD-L1 in a broad range of cancer cells, by using a genome-wide CRISPR-Cas9 screen. CMTM6 is a ubiquitously expressed protein that binds PD-L1 and maintains its cell surface expression...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28806909/tumor-derived-exosomes-induce-cd8-t-cell-suppressors
#4
Brian T Maybruck, Lukas W Pfannenstiel, Marcela Diaz-Montero, Brian R Gastman
BACKGROUND: The suppressive nature of immune cells in the tumor microenvironment plays a major role in regulating anti-tumor immune responses. Our previous work demonstrated that a soluble factor from tumor cells is able to induce a suppressor phenotype (SP) in human CD8(+) T cells typified by loss of CD27/CD28 expression and acquisition of a potent suppressor function. The present study hypothesized that the soluble mechanism that is inducing the SP in CD8(+) T cells are tumor-derived exosomes (TDEs)...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28803809/improved-androgen-specificity-of-ar-ecoscreen-by-crispr-based-glucocorticoid-receptor-knockout
#5
Nick Zwart, Dave Andringa, Willem-Jan de Leeuw, Hiroyuki Kojima, Mitsuru Iida, Corine Houtman, Jacob de Boer, Jeroen Kool, Marja Lamoree, Timo Hamers
The AR-EcoScreen is a widely used reporter assay for the detection of androgens and anti-androgens. Endogenous expression of glucocorticoid receptors and their affinity for the androgen responsive element that drives reporter expression, however, makes the reporter cells sensitive to interference by glucocorticoids and less specific for (anti-)androgens. To create a glucocorticoid insensitive derivative of the AR-EcoScreen, CRISPR/Cas9 genome editing was used to develop glucocorticoid receptor knockout mutants by targeting various sites in the glucocorticoid gene...
August 10, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28781236/structural-variation-of-type-i-f-crispr-rna-guided-dna-surveillance
#6
Patrick Pausch, Hanna Müller-Esparza, Daniel Gleditzsch, Florian Altegoer, Lennart Randau, Gert Bange
CRISPR-Cas systems are prokaryotic immune systems against invading nucleic acids. Type I CRISPR-Cas systems employ highly diverse, multi-subunit surveillance Cascade complexes that facilitate duplex formation between crRNA and complementary target DNA for R-loop formation, retention, and DNA degradation by the subsequently recruited nuclease Cas3. Typically, the large subunit recognizes bona fide targets through the PAM (protospacer adjacent motif), and the small subunit guides the non-target DNA strand. Here, we present the Apo- and target-DNA-bound structures of the I-Fv (type I-F variant) Cascade lacking the small and large subunits...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28768188/blockage-of-core-fucosylation-reduces-cell-surface-expression-of-pd-1-and-promotes-anti-tumor-immune-responses-of-t-cells
#7
Masahiro Okada, Shunsuke Chikuma, Taisuke Kondo, Sana Hibino, Hiroaki Machiyama, Tadashi Yokosuka, Miyako Nakano, Akihiko Yoshimura
Programmed cell death 1 (PD-1) is highly expressed on exhausted T cells and inhibits T cell activation. Antibodies that block the interaction between PD-1 and its ligand prevent this inhibitory signal and reverse T cell dysfunction, providing beneficial anti-tumor responses in a substantial number of patients. Mechanisms for the induction and maintenance of high PD-1 expression on exhausted T cells have not been fully understood. Utilizing a genome-wide loss-of-function screening method based on the CRISPR-Cas9 system, we identified genes involved in the core fucosylation pathway as positive regulators of cell-surface PD-1 expression...
August 1, 2017: Cell Reports
https://www.readbyqxmd.com/read/28752109/conjugation-assay-for-testing-crispr-cas-anti-plasmid-immunity-in-staphylococci
#8
Forrest C Walker, Asma Hatoum-Aslan
CRISPR-Cas is a prokaryotic adaptive immune system that prevents uptake of mobile genetic elements such as bacteriophages and plasmids. Plasmid transfer between bacteria is of particular clinical concern due to increasing amounts of antibiotic resistant pathogens found in humans as a result of transfer of resistance plasmids within and between species. Testing the ability of CRISPR-Cas systems to block plasmid transfer in various conditions or with CRISPR-Cas mutants provides key insights into the functionality and mechanisms of CRISPR-Cas as well as how antibiotic resistance spreads within bacterial communities...
May 5, 2017: Bio-protocol
https://www.readbyqxmd.com/read/28749735/the-discovery-mechanisms-and-evolutionary-impact-of-anti-crisprs
#9
Adair L Borges, Alan R Davidson, Joseph Bondy-Denomy
Bacteria and archaea use CRISPR-Cas adaptive immune systems to defend themselves from infection by bacteriophages (phages). These RNA-guided nucleases are powerful weapons in the fight against foreign DNA, such as phages and plasmids, as well as a revolutionary gene editing tool. Phages are not passive bystanders in their interactions with CRISPR-Cas systems, however; recent discoveries have described phage genes that inhibit CRISPRCas function. More than 20 protein families, previously of unknown function, have been ascribed anti-CRISPR function...
July 27, 2017: Annual Review of Virology
https://www.readbyqxmd.com/read/28738256/p53-and-mitf-bcl-2-identified-as-key-pathways-in-the-acquired-resistance-of-nras-mutant-melanoma-to-mek-inhibition
#10
Ahmad Najem, Mohammad Krayem, François Salès, Nader Hussein, Bassam Badran, Caroline Robert, Ahmad Awada, Fabrice Journe, Ghanem E Ghanem
Activating mutations in Neuroblastoma RAS viral oncogene homolog (NRAS) are found in 15-30% of melanomas and are associated with a poor prognosis. Although MAP kinase kinase (MEK) inhibitors used as single agents showed a limited clinical benefit in patients with NRAS-mutant melanoma due to their rather cytostatic effect and high toxicity, their combination with other inhibitors of pathways known to cooperate with MEK inhibition may maximise their antitumour activity. Similarly, in a context where p53 is largely inactivated in melanoma, hyperexpression of Microphthalmia associated transcription factor (MITF) and its downstream anti-apoptotic targets may be the cause of the restraint cytotoxic effects of MEK inhibitors...
July 21, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28706995/disabling-cas9-by-an-anti-crispr-dna-mimic
#11
Jiyung Shin, Fuguo Jiang, Jun-Jie Liu, Nicolas L Bray, Benjamin J Rauch, Seung Hyun Baik, Eva Nogales, Joseph Bondy-Denomy, Jacob E Corn, Jennifer A Doudna
CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 gene editing technology is derived from a microbial adaptive immune system, where bacteriophages are often the intended target. Natural inhibitors of CRISPR-Cas9 enable phages to evade immunity and show promise in controlling Cas9-mediated gene editing in human cells. However, the mechanism of CRISPR-Cas9 inhibition is not known, and the potential applications for Cas9 inhibitor proteins in mammalian cells have not been fully established...
July 2017: Science Advances
https://www.readbyqxmd.com/read/28705213/the-therapeutic-landscape-of-hiv-1-via-genome-editing
#12
REVIEW
Alexander Kwarteng, Samuel Terkper Ahuno, Godwin Kwakye-Nuako
Current treatment for HIV-1 largely relies on chemotherapy through the administration of antiretroviral drugs. While the search for anti-HIV-1 vaccine remain elusive, the use of highly active antiretroviral therapies (HAART) have been far-reaching and has changed HIV-1 into a manageable chronic infection. There is compelling evidence, including several side-effects of ARTs, suggesting that eradication of HIV-1 cannot depend solely on antiretrovirals. Gene therapy, an expanding treatment strategy, using RNA interference (RNAi) and programmable nucleases such as meganuclease, zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins (CRISPR-Cas9) are transforming the therapeutic landscape of HIV-1...
July 14, 2017: AIDS Research and Therapy
https://www.readbyqxmd.com/read/28668720/inhibition-of-crispr-cas-systems-by-mobile-genetic-elements
#13
REVIEW
Erik J Sontheimer, Alan R Davidson
Clustered, regularly interspaced, short, palindromic repeats (CRISPR) loci, together with their CRISPR-associated (Cas) proteins, provide bacteria and archaea with adaptive immunity against invasion by bacteriophages, plasmids, and other mobile genetic elements. These host defenses impart selective pressure on phages and mobile elements to evolve countermeasures against CRISPR immunity. As a consequence of this pressure, phages and mobile elements have evolved 'anti-CRISPR' proteins that function as direct inhibitors of diverse CRISPR-Cas effector complexes...
June 29, 2017: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/28667332/viperin-is-an-important-host-restriction-factor-in-control-of-zika-virus-infection
#14
Kylie H Van der Hoek, Nicholas S Eyre, Byron Shue, Onruedee Khantisitthiporn, Kittirat Glab-Ampi, Jillian M Carr, Matthew J Gartner, Lachlan A Jolly, Paul Q Thomas, Fatwa Adikusuma, Tanja Jankovic-Karasoulos, Claire T Roberts, Karla J Helbig, Michael R Beard
Zika virus (ZIKV) infection has emerged as a global health threat and infection of pregnant women causes intrauterine growth restriction, spontaneous abortion and microcephaly in newborns. Here we show using biologically relevant cells of neural and placental origin that following ZIKV infection, there is attenuation of the cellular innate response characterised by reduced expression of IFN-β and associated interferon stimulated genes (ISGs). One such ISG is viperin that has well documented antiviral activity against a wide range of viruses...
June 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28663543/nr3c1-null-mutant-zebrafish-are-viable-and-reveal-dna-binding-independent-activities-of-the-glucocorticoid-receptor
#15
N Facchinello, T Skobo, G Meneghetti, E Colletti, A Dinarello, N Tiso, R Costa, G Gioacchini, O Carnevali, F Argenton, L Colombo, L Dalla Valle
Glucocorticoids (GCs) play important roles in developmental and physiological processes through the transcriptional activity of their cognate receptor (Gr). Using CRISPR/Cas9 technology, we established a zebrafish null Gr mutant line and compared its phenotypes with wild type and a zebrafish line with partially silenced gr (gr (s357/s357) ). Homozygous gr (-/-) larvae are morphologically inconspicuous and, in contrast to GR (-/-) knockout mice, viable through adulthood, although with reduced fitness and early life survival...
June 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28656178/gene-knockout-shows-that-pml-trim19-does-not-restrict-the-early-stages-of-hiv-1-infection-in-human-cell-lines
#16
Nasser Masroori, Pearl Cherry, Natacha Merindol, Jia-Xin Li, Caroline Dufour, Lina Poulain, Mélodie B Plourde, Lionel Berthoux
The PML (promyelocytic leukemia) protein is a member of the TRIM family, a large group of proteins that show high diversity in functions but possess a common tripartite motif giving the family its name. We and others recently reported that both murine PML (mPML) and human PML (hPML) strongly restrict the early stages of infection by HIV-1 and other lentiviruses when expressed in mouse embryonic fibroblasts (MEFs). This restriction activity was found to contribute to the type I interferon (IFN-I)-mediated inhibition of HIV-1 in MEFs...
May 2017: MSphere
https://www.readbyqxmd.com/read/28628795/knockout-of-the-nogo-b-gene-attenuates-tumor-growth-and-metastasis-in-hepatocellular-carcinoma
#17
Bo Zhu, Shaobo Chen, Xiaoding Hu, Xiaofeng Jin, Yichen Le, Lihuan Cao, Zhonghua Yuan, Zhen Lin, Songmin Jiang, Lichun Sun, Long Yu
Human hepatocellular carcinoma (HCC) is a malignant cancer. It is a challenge to develop anti-HCC drugs due to HCC's extreme aggressiveness and with the sensitivity of the liver to show severe adverse effects. More importantly, the precise mechanisms causing HCC pathogenicity are not known. Our previous study disclosed Nogo-B as a reticulon 4 (Rtn4) family member. In the present study, we first identified that Nogo-B played a critical role in HCC progression. We found, via in vitro and in vivo assays, that Nogo-B was expressed aberrantly in primary HCC tumor tissues and immortal HCC cells but was relatively scarce in the normal liver tissues or cells...
July 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28621109/comparative-genomic-analysis-of-lactobacillus-plantarum-gb-lp1-isolated-from-traditional-korean-fermented-food
#18
Jihyun Yu, Sojin Ahn, Kwondo Kim, Kelsey Caetano-Anolles, Chanho Lee, Jungsun Kang, Kyungjin Cho, SookHee Yoon, Dae-Kyung Kang, Heebal Kim
As probiotics play an important role in maintaining a healthy gut flora environment through antitoxin activity and inhibition of pathogen colonization, they have been of interest to the medical research community for quite some time now. Probiotic bacteria such as Lactobacillus plantarum, which can be found in fermented food, are of particular interest given their easy accessibility. We performed whole genome sequencing and genomic analysis on a GB-LP1 strain of L. plantarum isolated from Korean traditional fermented food; this strain is well known for its functions in immune response, suppression of pathogen growth and anti-toxin effects...
June 16, 2017: Journal of Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28619709/loss-of-fam46c-promotes-cell-survival-in-myeloma
#19
Yuan Xiao Zhu, Chang-Xin Shi, Laura A Bruins, Patrick Jedlowski, Xuewei Wang, K Martin Kortüm, Moulun Luo, Jonathan M Ahmann, Esteban Braggio, A Keith Stewart
FAM46C is one of the most recurrently mutated genes in multiple myeloma; however its role in disease pathogenesis has not been determined. Here we demonstrate that wild-type (WT) FAM46C overexpression induces substantial cytotoxicity in multiple myeloma cells. In contrast, FAM46C mutations found in multiple myeloma patients abrogate this cytotoxicity, indicating a survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, and MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP Furthermore, pathway analysis suggests that enforced FAM46C expression activated the unfolded protein response pathway and induced mitochondrial dysfunction...
August 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28602637/inhibition-mechanism-of-an-anti-crispr-suppressor-acriia4-targeting-spycas9
#20
Hui Yang, Dinshaw J Patel
Prokaryotic CRISPR-Cas adaptive immune systems utilize sequence-specific RNA-guided endonucleases to defend against infection by viruses, bacteriophages, and mobile elements, while these foreign genetic elements evolve diverse anti-CRISPR proteins to overcome the CRISPR-Cas-mediated defense of the host. Recently, AcrIIA2 and AcrIIA4, encoded by Listeria monocytogene prophages, were shown to block the endonuclease activity of type II-A Streptococcus pyogene Cas9 (SpyCas9). We now report the crystal structure of AcrIIA4 in complex with single-guide RNA-bound SpyCas9, thereby establishing that AcrIIA4 preferentially targets critical residues essential for PAM duplex recognition, as well as blocks target DNA access to key catalytic residues lining the RuvC pocket...
July 6, 2017: Molecular Cell
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