keyword
https://read.qxmd.com/read/38357966/cas-based-bacterial-detection-recent-advances-and-perspectives
#21
REVIEW
Huatao Lan, Weitong Shu, Dan Jiang, Luxin Yu, Guangxian Xu
Persistent bacterial infections pose a formidable threat to global health, contributing to widespread challenges in areas such as food safety, medical hygiene, and animal husbandry. Addressing this peril demands the urgent implementation of swift and highly sensitive detection methodologies suitable for point-of-care testing and large-scale screening. These methodologies play a pivotal role in the identification of pathogenic bacteria, discerning drug-resistant strains, and managing and treating diseases. Fortunately, new technology, the CRISPR/Cas system, has emerged...
February 26, 2024: Analyst
https://read.qxmd.com/read/38354234/uncovering-receptor-ligand-interactions-using-a-high-avidity-crispr-activation-screening-platform
#22
JOURNAL ARTICLE
Liping Yang, Timothy P Sheets, Yang Feng, Guojun Yu, Pradip Bajgain, Kuo-Sheng Hsu, Daeho So, Steven Seaman, Jaewon Lee, Ling Lin, Christine N Evans, Mary R Guest, Raj Chari, Brad St Croix
The majority of clinically approved drugs target proteins that are secreted or cell surface bound. However, further advances in this area have been hindered by the challenging nature of receptor deorphanization, as there are still many secreted and cell-bound proteins with unknown binding partners. Here, we developed an advanced screening platform that combines CRISPR-CAS9 guide-mediated gene activation (CRISPRa) and high-avidity bead-based selection. The CRISPRa platform incorporates serial enrichment and flow cytometry-based monitoring, resulting in substantially improved screening sensitivity for well-known yet weak interactions of the checkpoint inhibitor family...
February 16, 2024: Science Advances
https://read.qxmd.com/read/38334642/advances-in-the-generation-of-constructed-cardiac-tissue-derived-from-induced-pluripotent-stem-cells-for-disease-modeling-and-therapeutic-discovery
#23
REVIEW
Truman J Roland, Kunhua Song
The human heart lacks significant regenerative capacity; thus, the solution to heart failure (HF) remains organ donation, requiring surgery and immunosuppression. The demand for constructed cardiac tissues (CCTs) to model and treat disease continues to grow. Recent advances in induced pluripotent stem cell (iPSC) manipulation, CRISPR gene editing, and 3D tissue culture have enabled a boom in iPSC-derived CCTs (iPSC-CCTs) with diverse cell types and architecture. Compared with 2D-cultured cells, iPSC-CCTs better recapitulate heart biology, demonstrating the potential to advance organ modeling, drug discovery, and regenerative medicine, though iPSC-CCTs could benefit from better methods to faithfully mimic heart physiology and electrophysiology...
January 29, 2024: Cells
https://read.qxmd.com/read/38330097/zeb2-drives-the-formation-of-cd11c%C3%A2-%C3%A2-atypical-b-cells-to-sustain-germinal-centers-that-control-persistent-infection
#24
JOURNAL ARTICLE
Xin Gao, Qian Shen, Jonathan A Roco, Becan Dalton, Katie Frith, C Mee Ling Munier, Fiona D Ballard, Ke Wang, Hannah G Kelly, Maxim Nekrasov, Jin-Shu He, Rebecca Jaeger, Patricia Carreira, Julia I Ellyard, Lynette Beattie, Anselm Enders, Matthew C Cook, John J Zaunders, Ian A Cockburn
CD11c+ atypical B cells (ABCs) are an alternative memory B cell lineage associated with immunization, infection, and autoimmunity. However, the factors that drive the transcriptional program of ABCs have not been identified, and the function of this population remains incompletely understood. Here we identified candidate transcription factors associated with the ABC population based on a human tonsillar B cell single cell dataset. We identified CD11c+ B cells in mice with a similar transcriptomic signature to human ABCs, and using an optimized CRISPR-Cas9 knockdown screen, we observed that loss of zinc finger E-box binding homeobox 2 (Zeb2) impaired ABC formation...
February 8, 2024: Science Immunology
https://read.qxmd.com/read/38329124/gene-coexpression-networks-reveal-a-broad-role-for-lncrnas-in-inflammatory-bowel-disease
#25
JOURNAL ARTICLE
John L Johnson, Davit Sargsyan, Eric M Neiman, Amy Hart, Aleksandar Stojmirovic, Roman Kosoy, Haritz Irizar, Mayte Suárez-Fariñas, Won-Min Song, Carmen Argmann, Stefan Avey, Liraz Shmuel-Galia, Tim Vierbuchen, Gerold Bongers, Yu Sun, Leonard Edelstein, Jacqueline Perrigoue, Jennifer E Towne, Aisling O'Hara Hall, Katherine A Fitzgerald, Kasper Hoebe
The role of long noncoding RNAs (lncRNAs) in disease is incompletely understood, but their regulation of inflammation is increasingly appreciated. We addressed the extent of lncRNA involvement in inflammatory bowel disease (IBD) using biopsy-derived RNA-sequencing data from a large cohort of deeply phenotyped patients with IBD. Weighted gene correlation network analysis revealed gene modules of lncRNAs coexpressed with protein-coding genes enriched for biological pathways, correlated with epithelial and immune cell signatures, or correlated with distal colon expression...
February 8, 2024: JCI Insight
https://read.qxmd.com/read/38328043/targetable-leukemia-dependency-on-noncanonical-pi3k%C3%AE-signaling
#26
Qingyu Luo, Evangeline G Raulston, Miguel A Prado, Xiaowei Wu, Kira Gritsman, Kezhi Yan, Christopher A G Booth, Ran Xu, Peter van Galen, John G Doench, Shai Shimony, Henry W Long, Donna S Neuberg, Joao A Paulo, Andrew A Lane
Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and activation of phosphoinositide 3-kinase regulatory subunit 5 ( PIK3R5 ), which encodes a regulatory subunit of PI3Kγ and stabilizes the active enzymatic complex...
December 15, 2023: bioRxiv
https://read.qxmd.com/read/38324452/crispr-cas9-screening-identifies-an-irf1-socs1-mediated-negative-feedback-loop-that-limits-cxcl9-expression-and-antitumor-immunity
#27
Imran G House, Emily B Derrick, Kevin Sek, Amanda X Y Chen, Jasmine Li, Junyun Lai, Kirsten L Todd, Isabelle Munoz, Jessica Michie, Cheok Weng Chan, Yu-Kuan Huang, Jack D Chan, Emma V Petley, Junming Tong, DatMinh Nguyen, Sven Engel, Peter Savas, Simon J Hogg, Stephin J Vervoort, Conor J Kearney, Marian L Burr, Enid Y N Lam, Omer Gilan, Sammy Bedoui, Ricky W Johnstone, Mark A Dawson, Sherene Loi, Phillip K Darcy, Paul A Beavis
No abstract text is available yet for this article.
February 5, 2024: Cell Reports
https://read.qxmd.com/read/38319732/pi3k-mtor-is-a-therapeutically-targetable-genetic-dependency-in-diffuse-intrinsic-pontine-glioma
#28
JOURNAL ARTICLE
Ryan J Duchatel, Evangeline R Jackson, Sarah G Parackal, Dylan Kiltschewskij, Izac J Findlay, Abdul Mannan, Dilana E Staudt, Bryce C Thomas, Zacary P Germon, Sandra Laternser, Padraic S Kearney, M Fairuz B Jamaluddin, Alicia M Douglas, Tyrone S Beitaki, Holly P McEwen, Mika L Persson, Emily A Hocke, Vaibhav Jain, Michael Aksu, Elizabeth E Manning, Heather C Murray, Nicole M Verrills, Claire Xin Sun, Paul Daniel, Ricardo E Vilain, David A Skerrett-Byrne, Brett Nixon, Susan Hua, Charles E de Bock, Yolanda Colino-Sanguino, Fatima Valdes-Mora, Maria Tsoli, David S Ziegler, Murray J Cairns, Eric H Raabe, Nicholas A Vitanza, Esther Hulleman, Timothy N Phoenix, Carl Koschmann, Frank Alvaro, Christopher V Dayas, Christopher L Tinkle, Helen Wheeler, James R Whittle, David D Eisenstat, Ron Firestein, Sabine Mueller, Santosh Valvi, Jordan R Hansford, David M Ashley, Simon G Gregory, Lindsay B Kilburn, Javad Nazarian, Jason E Cain, Matthew D Dun
Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma - DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR-Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across DIPG patient models, highlighting the therapeutic potential of the blood-brain barrier penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors...
February 6, 2024: Journal of Clinical Investigation
https://read.qxmd.com/read/38309267/phlda2-mediated-phosphatidic-acid-peroxidation-triggers-a-distinct-ferroptotic-response-during-tumor-suppression
#29
JOURNAL ARTICLE
Xin Yang, Zhe Wang, Svetlana N Samovich, Alexander A Kapralov, Andrew A Amoscato, Vladimir A Tyurin, Haider H Dar, Zhiming Li, Shoufu Duan, Ning Kon, Delin Chen, Benjamin Tycko, Zhiguo Zhang, Xuejun Jiang, Hülya Bayir, Brent R Stockwell, Valerian E Kagan, Wei Gu
Although the role of ferroptosis in killing tumor cells is well established, recent studies indicate that ferroptosis inducers also sabotage anti-tumor immunity by killing neutrophils and thus unexpectedly stimulate tumor growth, raising a serious issue about whether ferroptosis effectively suppresses tumor development in vivo. Through genome-wide CRISPR-Cas9 screenings, we discover a pleckstrin homology-like domain family A member 2 (PHLDA2)-mediated ferroptosis pathway that is neither ACSL4-dependent nor requires common ferroptosis inducers...
January 29, 2024: Cell Metabolism
https://read.qxmd.com/read/38308274/mapping-the-functional-impact-of-non-coding-regulatory-elements-in-primary-t-cells-through-single-cell-crispr-screens
#30
JOURNAL ARTICLE
Celia Alda-Catalinas, Ximena Ibarra-Soria, Christina Flouri, Jorge Esparza Gordillo, Diana Cousminer, Anna Hutchinson, Bin Sun, William Pembroke, Sebastian Ullrich, Adam Krejci, Adrian Cortes, Alison Acevedo, Sunir Malla, Carl Fishwick, Gerard Drewes, Radu Rapiteanu
BACKGROUND: Drug targets with genetic evidence are expected to increase clinical success by at least twofold. Yet, translating disease-associated genetic variants into functional knowledge remains a fundamental challenge of drug discovery. A key issue is that the vast majority of complex disease associations cannot be cleanly mapped to a gene. Immune disease-associated variants are enriched within regulatory elements found in T-cell-specific open chromatin regions. RESULTS: To identify genes and molecular programs modulated by these regulatory elements, we develop a CRISPRi-based single-cell functional screening approach in primary human T cells...
February 2, 2024: Genome Biology
https://read.qxmd.com/read/38302097/targeted-macrophage-crispr-cas13-mrna-editing-in-immunotherapy-for-tendon-injury
#31
JOURNAL ARTICLE
Shuo Wang, Yao Xiao, Jian Tian, Bo Dai, Zaijin Tao, Jingwen Liu, Zhenyu Sun, Xuanzhe Liu, Yanhao Li, Gang Zhao, Yong Cui, Fei Wang, Shen Liu
CRISPR-Cas13 holds substantial promise for tissue repair through its RNA editing capabilities and swift catabolism. However, conventional delivery methods fall short in addressing the heightened inflammatory response orchestrated by macrophages during the acute stages of tendon injury. In this investigation, macrophage-targeting cationic polymers are systematically screened to facilitate the entry of Cas13 ribonucleic-protein complex (Cas13 RNP) into macrophages. Notably, SPP1 (OPN encoding)-producing macrophages are recognized as a profibrotic subtype that emerges during the inflammatory stage...
February 1, 2024: Advanced Materials
https://read.qxmd.com/read/38301646/smarcal1-is-a-dual-regulator-of-innate-immune-signaling-and-pd-l1-expression-that-promotes-tumor-immune-evasion
#32
JOURNAL ARTICLE
Giuseppe Leuzzi, Alessandro Vasciaveo, Angelo Taglialatela, Xiao Chen, Tessa M Firestone, Allison R Hickman, Wendy Mao, Tanay Thakar, Alina Vaitsiankova, Jen-Wei Huang, Raquel Cuella-Martin, Samuel B Hayward, Jordan S Kesner, Ali Ghasemzadeh, Tarun S Nambiar, Patricia Ho, Alexander Rialdi, Maxime Hebrard, Yinglu Li, Jinmei Gao, Saarang Gopinath, Oluwatobi A Adeleke, Bryan J Venters, Charles G Drake, Richard Baer, Benjamin Izar, Ernesto Guccione, Michael-Christopher Keogh, Raphael Guerois, Lu Sun, Chao Lu, Andrea Califano, Alberto Ciccia
Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 limits endogenous DNA damage, thereby suppressing cGAS-STING-dependent signaling during cancer cell growth...
February 15, 2024: Cell
https://read.qxmd.com/read/38294344/the-extracellular-niche-and-tumor-microenvironment-enhance-kras-inhibitor-efficacy-in-pancreatic-cancer
#33
JOURNAL ARTICLE
Vishnu Kumarasamy, Jianxin Wang, Costakis Frangou, Yin Wan, Andrew Dynka, Hanna Rosenheck, Prasenjit Dey, Ethan V Abel, Erik S Knudsen, Agnieszka K Witkiewicz
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective treatment options, highlighting the need for developing new therapeutic interventions. Here, we assessed the response to pharmacological inhibition of KRAS, the central oncogenic driver of PDAC. In a panel of PDAC cell lines, inhibition of KRASG12D with MRTX1133 yielded variable efficacy in suppressing cell growth and downstream gene expression programs in 2D cultures. Based on CRISPR-Cas9 loss-of-function screens, ITGB1 was identified as a target to enhance the therapeutic response to MRTX1133 by regulating mechanotransduction signaling and YAP/TAZ expression, which was confirmed by gene specific knockdown and combinatorial drug synergy...
January 31, 2024: Cancer Research
https://read.qxmd.com/read/38293095/genome-scale-crispr-screens-identify-actin-capping-proteins-as-key-modulators-of-therapeutic-responses-to-radiation-and-immunotherapy
#34
Nipun Verma, Paul A Renauer, Chuanpeng Dong, Shan Xin, Qianqian Lin, Feifei Zhang, Peter M Glazer, Sidi Chen
Radiotherapy (RT), is a fundamental treatment for malignant tumors and is used in over half of cancer patients. As radiation can promote anti-tumor immune effects, a promising therapeutic strategy is to combine radiation with immune checkpoint inhibitors (ICIs). However, the genetic determinants that impact therapeutic response in the context of combination therapy with radiation and ICI have not been systematically investigated. To unbiasedly identify the tumor intrinsic genetic factors governing such responses, we perform a set of genome-scale CRISPR screens in melanoma cells for cancer survival in response to low-dose genotoxic radiation treatment, in the context of CD8 T cell co-culture and with anti-PD1 checkpoint blockade antibody...
January 15, 2024: bioRxiv
https://read.qxmd.com/read/38267541/bcl2-inhibition-stimulates-dendritic-cell-function-for-improved-anticancer-immunotherapy
#35
JOURNAL ARTICLE
Peng Liu, Liwei Zhao, Guido Kroemer, Oliver Kepp
Recently we developed a dendritic cell (DC) genotype-phenotype screening platform that is based on CRISPR/Cas9-mediated gene editing of immortalized DC precursors. Whole genome screening for gain-of-function phenotypes led to the identification of BCL2 as a DC-specific immune checkpoint. Genetic or pharmacological inhibition of BCL2 similarly enhanced the antigen presentation capacity of conventional type-1 dendritic cells (cDC1) and mediated T cell-dependent anticancer immunity. The therapeutic anticancer efficacy of the BCL2 inhibitor venetoclax in mice was further increased when combined with a PD-1-targeted immune checkpoint inhibitor...
January 24, 2024: Genes and Immunity
https://read.qxmd.com/read/38260508/a-genome-wide-crispr-screen-identifies-sortilin-as-the-receptor-responsible-for-galectin-1-lysosomal-trafficking
#36
Justin Donnelly, Roarke A Kamber, Simon Wisnovsky, David S Roberts, Egan L Peltan, Michael C Bassik, Carolyn R Bertozzi
Galectins are a family of mammalian glycan-binding proteins that have been implicated as regulators of myriad cellular processes including cell migration, apoptosis, and immune modulation. Several members of this family, such as galectin-1, exhibit both cell-surface and intracellular functions. Interestingly, galectin-1 can be found in the endomembrane system, nucleus, or cytosol, as well as on the cell surface. The mechanisms by which galectin-1 traffics between cellular compartments, including its unconventional secretion and internalization processes, are poorly understood...
January 3, 2024: bioRxiv
https://read.qxmd.com/read/38258394/crispr-activation-as-a-platform-to-identify-interferon-stimulated-genes-with-anti-viral-function
#37
JOURNAL ARTICLE
Emily N Kirby, Xavier B Montin, Timothy P Allen, Jaslan Densumite, Brooke N Trowbridge, Michael R Beard
Interferon Stimulated Gene (ISG) expression plays a key role in the control of viral replication and development of a robust adaptive response. Understanding this dynamic relationship between the pathogen and host is critical to our understanding of viral life-cycles and development of potential novel anti-viral strategies. Traditionally, plasmid based exogenous prompter driven expression of ISGs has been used to investigate anti-viral ISG function, however there are deficiencies in this approach. To overcome this, we investigated the utility of CRISPR activation (CRISPRa), which allows for targeted transcriptional activation of a gene from its endogenous promoter...
January 23, 2024: Innate Immunity
https://read.qxmd.com/read/38254179/pd-1-signaling-uncovers-a-pathogenic-subset-of-t-cells-in-inflammatory-arthritis
#38
JOURNAL ARTICLE
Johanna Straube, Shoiab Bukhari, Shalom Lerrer, Robert J Winchester, Yevgeniya Gartshteyn, Brian S Henick, Matthew A Dragovich, Adam Mor
BACKGROUND: PD-1 is an immune checkpoint on T cells, and interventions to block this receptor result in T cell activation and enhanced immune response to tumors and pathogens. Reciprocally, despite a decade of research, approaches to treat autoimmunity with PD-1 agonists have only had limited successful. To resolve this, new methods must be developed to augment PD-1 function beyond engaging the receptor. METHODS: We conducted a flow cytometry analysis of T cells isolated from the peripheral blood and synovial fluid of patients with rheumatoid arthritis...
January 22, 2024: Arthritis Research & Therapy
https://read.qxmd.com/read/38245560/structure-guided-discovery-of-anti-crispr-and-anti-phage-defense-proteins
#39
JOURNAL ARTICLE
Ning Duan, Emily Hand, Mannuku Pheko, Shikha Sharma, Akintunde Emiola
Bacteria use a variety of defense systems to protect themselves from phage infection. In turn, phages have evolved diverse counter-defense measures to overcome host defenses. Here, we use protein structural similarity and gene co-occurrence analyses to screen >66 million viral protein sequences and >330,000 metagenome-assembled genomes for the identification of anti-phage and counter-defense systems. We predict structures for ~300,000 proteins and perform large-scale, pairwise comparison to known anti-CRISPR (Acr) and anti-phage proteins to identify structural homologs that otherwise may not be uncovered using primary sequence search...
January 20, 2024: Nature Communications
https://read.qxmd.com/read/38242867/the-cul5-e3-ligase-complex-negatively-regulates-central-signaling-pathways-in-cd8-t-cells
#40
JOURNAL ARTICLE
Xiaofeng Liao, Wenxue Li, Hongyue Zhou, Barani Kumar Rajendran, Ao Li, Jingjing Ren, Yi Luan, David A Calderwood, Benjamin Turk, Wenwen Tang, Yansheng Liu, Dianqing Wu
CD8+ T cells play an important role in anti-tumor immunity. Better understanding of their regulation could advance cancer immunotherapies. Here we identify, via stepwise CRISPR-based screening, that CUL5 is a negative regulator of the core signaling pathways of CD8+ T cells. Knocking out CUL5 in mouse CD8+ T cells significantly improves their tumor growth inhibiting ability, with significant proteomic alterations that broadly enhance TCR and cytokine signaling and their effector functions. Chemical inhibition of neddylation required by CUL5 activation, also enhances CD8 effector activities with CUL5 validated as a major target...
January 19, 2024: Nature Communications
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