Article
Multidisciplinary Sciences
Beate Schwer, Angad Garg, Agata Jacewicz, Stewart Shuman
Summary: The study reveals a mechanism by which Pol2 termination is enhanced through a gain-of-function mutation G476S in the RNA-binding domain, reducing transcriptional interference to derepress specific genes.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Pol Picon-Pages, Monica Bosch-Morato, Laia Subirana, Francisca Rubio-Moscardo, Biuse Guivernau, Hugo Fanlo-Ucar, Melisa Ece Zeylan, Simge Senyuz, Victor Herrera-Fernandez, Ruben Vicente, Jose M. Fernandez-Fernandez, Jordi Garcia-Ojalvo, Attila Gursoy, Ozlem Keskin, Baldomero Oliva, Francesc Posas, Eulalia de Nadal, Francisco J. Munoz
Summary: Alzheimer's disease is caused by misfolded amyloid beta-peptide (Aβ) forming beta-sheets, but there are currently no treatments available to prevent it. Through a genome-wide screen in Saccharomyces cerevisiae, we identified 81 mammalian orthologue genes that enhance Aβ(1-42) toxicity and 157 that provide protection. Further studies revealed that calcium regulation, protein translation, and mitochondrial activity were the main cellular functions affected by Aβ oligomers (oAβ). We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE), and found that it contributes to oAβ(1-42) neurotoxicity by decreasing SOCE activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Jinghui Liu, Yue Zhao, Daheng He, Katelyn M. Jones, Shan Tang, Derek B. Allison, Yanquan Zhang, Jing Chen, Qiongsi Zhang, Xinyi Wang, Chaohao Li, Chi Wang, Lang Li, Xiaoqi Liu
Summary: Enzalutamide (ENZA), a second-generation androgen receptor antagonist, enhances the efficacy of treatment for metastatic prostate cancer (PCa), but resistance remains a challenge. Through a CRISPR-Cas9 knockout screen, casein kinase 1a (CK1a) has been identified as a therapeutic target to overcome ENZA resistance. Inhibition of CK1a stabilizes ATM and restores DNA-damage response signaling, leading to increased cell death and growth arrest.
CELL REPORTS MEDICINE
(2023)
Article
Microbiology
Jamin Liu, Kristeene A. Knopp, Elze Rackaityte, Chung Yu Wang, Matthew T. Laurie, Sara Sunshine, Andreas S. Puschnik, Joseph L. DeRisi
Summary: This study identifies novel host factors associated with Lymphocytic choriomeningitis virus (LCMV) infection of human tissues, highlighting the importance of CD164 in viral entry and suggesting it as a potential therapeutic target for congenital infection.
Article
Multidisciplinary Sciences
Chen Dong, Shuhua Fu, Rowan M. Karvas, Brian Chew, Laura A. Fischer, Xiaoyun Xing, Jessica K. Harrison, Pooja Popli, Ramakrishna Kommagani, Ting Wang, Bo Zhang, Thorold W. Theunissen
Summary: The authors systematically identify and characterize essential and growth-restricting genes in human trophoblast cells through a genome-wide CRISPR-Cas9 knockout screen. They reveal TEAD1 as a key regulator modulating chromatin architecture and gene expression to play a crucial role in the specification, maintenance, and differentiation of the human trophoblast lineage.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Diana G. Calvopina-Chavez, Robyn E. Howarth, Audrey K. Memmott, Oscar H. Pech H. Gonzalez, Caleb B. Hafen, Kyson T. Jensen, Alex B. Benedict, Jessica D. Altman, Brittany S. Burnside, Justin S. Childs, Samuel W. Dallon, Alexa C. DeMarco, Kirsten C. Flindt, Sarah A. Grover, Elizabeth Heninger, Christina S. Iverson, Abigail K. Johnson, Jack B. Lopez, McKay A. Meinzer, Brook A. Moulder, Rebecca I. Moulton, Hyrum S. Russell, Tiana M. Scott, Yuka Shiobara, Mason D. Taylor, Kathryn E. Tippets, Kayla M. Vainerere, Isabella C. Von Wallwitz, Madison Wagley, Megumi S. Wiley, Naomi J. Young, Joel S. Griffitts
Summary: This study investigates the genetic basis of flagellar motility and identifies 37 genes involved in flagellar biosynthesis, including previously unknown functions.
Article
Multidisciplinary Sciences
Lili Zhou, Caitlyn Miller, Loren J. Miraglia, Angelica Romero, Ludovic S. Mure, Satchidananda Panda, Steve A. Kay
Summary: This study identified the miRNA cluster miR-183/96/182 as key regulators of circadian rhythms, with miR-96 directly targeting the core circadian clock gene PER2. Knockout of the miR-183/96/182 cluster in mice showed tissue-specific effects on circadian parameters, highlighting the importance of miRNAs as a genome-wide layer of circadian clock regulation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Cell Biology
Chen Gao, Xiaolan Qi, Xin Gao, Jin Li, Yumin Qin, Yunjun Yin, Fei Gao, Tao Feng, Sen Wu, Xuguang Du
Summary: Screening with a CRISPR library under stringent conditions revealed key regulators of pluripotency exit, including previously reported genes and 17 unreported genes. Zfp771 and Olfr769 were found to be potentially involved in pluripotency exit.
Article
Medicine, Research & Experimental
Kelly Waldeck, Jessica Van Zuylekom, Carleen Cullinane, Twishi Gulati, Kaylene J. Simpson, Richard W. Tothill, Benjamin Blyth, Rodney J. Hicks
Summary: A genome-wide CRISPR/Cas9 screen identified potential gene targets for sensitivity and resistance to LuTate, offering opportunities for novel combination therapies for NET patients. Regulation of DNA damage repair pathways may enhance the efficacy of LuTate treatment.
Article
Hematology
Nam H. K. Nguyen, Roya Rafiee, Abderrahmane Tagmount, Amin Sobh, Alex Loguinov, Angelica K. de Jesus Sosa, Abdelrahman H. Elsayed, Mohammed Gbadamosi, Nathan Seligson, Christopher R. Cogle, Jeffery Rubnitz, Raul Ribeiro, James Downing, Xueyuan Cao, Stanley B. Pounds, Christopher D. Vulpe, Jatinder K. Lamba
Summary: This study utilized CRISPR/Cas9 technology to identify known genes, such as TOP2A and ABCC1, as well as novel genes including RAD54L2, PRKDC, and ZNF451, which may serve as potential therapeutic targets for overcoming treatment resistance.
Article
Cell Biology
Jiequn Li, Chunli Chen, Chenchen Li, Zhiping Hu, Jieqiong Tan, Liuwang Zeng
Summary: This study investigates the molecular mechanisms of ammonia neurotoxicity and potential therapeutic targets for hepatic encephalopathy (HE) through a CRISPR/Cas9 knockout screen. EGLN3 appears to be the most related to ammonia resistance, and its knockdown protects against ammonia-induced apoptosis. The findings suggest that targeting EGLN3 could be a future therapeutic strategy for managing HE.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Liam Gaziano, Claudia Giambartolomei, Alexandre C. Pereira, Anna Gaulton, Daniel C. Posner, Sonja A. Swanson, Yuk-Lam Ho, Sudha K. Iyengar, Nicole M. Kosik, Marijana Vujkovic, David R. Gagnon, A. Patricia Bento, Inigo Barrio-Hernandez, Lars Ronnblom, Niklas Hagberg, Christian Lundtoft, Claudia Langenberg, Maik Pietzner, Dennis Valentine, Stefano Gustincich, Gian Gaetano Tartaglia, Elias Allara, Praveen Surendran, Stephen Burgess, Jing Hua Zhao, James E. Peters, Bram P. Prins, Emanuele Di Angelantonio, Poornima Devineni, Yunling Shi, Kristine E. Lynch, Scott L. DuVall, Helene Garcon, Lauren O. Thomann, Jin J. Zhou, Bryan R. Gorman, Jennifer E. Huffman, Christopher J. O'Donnell, Philip S. Tsao, Jean C. Beckham, Saiju Pyarajan, Sumitra Muralidhar, Grant D. Huang, Rachel Ramoni, Pedro Beltrao, John Danesh, Adriana M. Hung, Kyong-Mi Chang, Yan V. Sun, Jacob Joseph, Andrew R. Leach, Todd L. Edwards, Kelly Cho, J. Michael Gaziano, Adam S. Butterworth, Juan P. Casas
Summary: Large-scale Mendelian randomization and colocalization analyses using gene expression and soluble protein data identified IFNAR2 and ACE2 as promising therapeutic targets for early management of COVID-19. Repurposing drugs offers a rapid solution to address the urgent need for therapeutic interventions against COVID-19.
Article
Biochemistry & Molecular Biology
Ying Hu, Xin Li, Jing Zhang, Dengfeng Liu, Renbin Lu, Jia-Da Li
Summary: This study identifies deubiquitinase USP1 as a previously unknown regulator of the mammalian circadian clock and highlights the potential of genome-wide CRISPR screens in the identification of regulators for the circadian clock.
Article
Virology
Jinhe Jiang, Yumei Sun, Yunlong Wang, Ahmed Sabek, Aishao Shangguan, Kai Wang, Shuhong Zhao, Guoliang Li, Ao Zhou, Shujun Zhang
Summary: Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) is a viral infection that leads to severe reproductive failure and respiratory disease in pigs, resulting in significant economic losses to the global swine industry. This study used CRISPR/Cas9 knockout screen to identify genes associated with PRRSV replication in pig kidney cells, and found several genes that were highly enriched after PRRSV selection.
Article
Biology
Olga T. Schubert, Joshua S. Bloom, Meru J. Sadhu, Leonid Kruglyak, Kevin J. Verstrepen
Summary: This article describes a genetic screening method for studying the encoding of protein abundance regulation in the genome. The researchers identified numerous regulatory relationships and revealed the different roles of specific regulators and broad regulators in protein translation.
Article
Virology
Emma S. Winkler, Rita E. Chen, Fahmida Alam, Soner Yildiz, James Brett Case, Melissa B. Uccellini, Michael J. Holtzman, Adolfo Garcia-Sastre, Michael Schotsaert, Michael S. Diamond
Summary: The study developed a mouse model for SARS-CoV-2 infection by introducing the human ACE2 gene into the mouse genome, providing insights into viral replication and pathology in mice. Additionally, the study identified the impact of the N501Y mutation in mice on viral replication and pathogenesis.
JOURNAL OF VIROLOGY
(2022)
Article
Biochemistry & Molecular Biology
Guangning Zong, Stephen B. Shears, Huanchen Wang
Summary: In this study, the biochemical and structural analysis of ITPKs from maize and soybeans were conducted, providing insights into the inositol phosphate kinases family in plants. By introducing a new enzyme activity assay and determining the crystal complex structure, the catalytic mechanism of these kinases was elucidated. The study discovered a signaling molecule related to phosphate homeostasis and revealed functional differences between different isoforms.
Article
Chemistry, Medicinal
Yubai Zhou, Sandip Mukherjee, Daowei Huang, Molee Chakraborty, Chunfang Gu, Guangning Zong, Michael A. Stashko, Kenneth H. Pearce, Stephen B. Shears, Anutosh Chakraborty, Huanchen Wang, Xiaodong Wang
Summary: This article investigates the therapeutic potential of IP6K inhibitor20 for obesity and related diseases, and demonstrates its treatment effects in mice through experiments.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Huanchen Wang, Lalith Perera, Nikolaus Jork, Guangning Zong, Andrew M. Riley, Barry V. L. Potter, Henning J. Jessen, Stephen B. Shears
Summary: This study provides the analysis of ligand/enzyme crystal complexes for Arabidopsis thaliana Plant and Fungi Atypical Dual Specificity Phosphatase 1 (AtPFA-DSP1), uncovering its regioselective and efficient phosphatase activity towards inositol pyrophosphate (PP-InsP) signaling molecules. Despite lacking the traditional tripeptide motif, the WPD loop structural element still contributes to catalysis by assisting with the delivery of PP-InsP into the catalytic pocket. Functionally, it is proposed that the substrate PP-InsP substitutes for the absent aspartate/glutamate general-acid through intramolecular proton donation.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Danye Qiu, Chunfang Gu, Guizhen Liu, Kevin Ritter, Verena B. Eisenbeis, Tamara Bittner, Artiom Gruzdev, Lea Seidel, Bertram Bengsch, Stephen B. Shears, Henning J. Jessen
Summary: This study used capillary electrophoresis mass spectrometry to investigate the levels of InsPs and PP-InsPs in mouse tissues. The results showed unusually high levels of InsPs and PP-InsPs in the mouse colon, and the PP-InsP profile was more complex than previously reported. Additionally, the study found that these molecules were not only present in the colon, but also in the heart and blood cells.
Article
Biochemistry & Molecular Biology
Soumyadip Sahu, Jacob Gordon, Chunfang Gu, Mack Sobhany, Dorothea Fiedler, Robin E. Stanley, Stephen B. Shears
Summary: 5-InsP(7) regulates the binding of nucleolar proteins, and altering its levels can affect the volume of the nucleolar granular region in cells.
Article
Biochemistry & Molecular Biology
Hayley L. Whitfield, Sining He, Yinghong Gu, Colleen Sprigg, Hui -Fen Kuo, Tzyy-Jen Chiou, Andrew M. Riley, Barry V. L. Potter, Andrew M. Hemmings, Charles A. Brearley
Summary: This study describes the differences in substrate specificity between two isoforms of ITPK enzymes (ITPK1 and ITPK4) in Arabidopsis, and provides a molecular explanation for the diverse phosphotransferase activity of ITPK4 by analyzing its ATP-coordinated structure. Furthermore, the study reveals a previously unreported N-terminal haloacid dehalogenase-like fold in ITPK4 and its homologues in other plants.
BIOCHEMICAL JOURNAL
(2023)
Article
Medicine, Research & Experimental
Ji Qi, Weiwei Cheng, Zhe Gao, Yuanyuan Chen, Megan L. Shipton, David Furkert, Alfred C. Chin, Andrew M. Riley, Dorothea Fiedler, Barry V. L. Potter, Chenglai Fu
Summary: The antifungal drug itraconazole has been found to disrupt focal adhesion dynamics and actin cytoskeleton remodeling by displacing IP6K1/5-InsP7, thus inhibiting cell motility. The study reveals the critical roles of IP6K1-generated 5-InsP7 in regulating these cellular processes and provides functional mechanisms by which itraconazole inhibits angiogenesis.
BIOMEDICINE & PHARMACOTHERAPY
(2023)
Article
Immunology
Sadaf Aslam, Madhusudan Rajendran, Divya Kriti, Andrew Kurland, Jeffrey Johnson, Harm van Bakel, Florian Krammer, Adolfo Garcia-Sastre, Juan Ayllon
Summary: To improve the production yield of seasonal influenza vaccines, we have identified optimal vaccine seed virus backbones for influenza B virus through research and evaluation in embryonated eggs. This study includes 71 strains of influenza B virus from 1940 to the present, representing the known temporal and genetic variability. By assessing the growth profiles and effectiveness of these strains, we selected three strains with the best performance as vaccine seed virus backbones to increase the production yield of influenza B virus seasonal vaccines.
Article
Immunology
Maria M. Lorenzo, Alejandro Marin-Lopez, Kevin Chiem, Luis Jimenez-Cabello, Irfan Ullah, Sergio Utrilla-Trigo, Eva Calvo-Pinilla, Gema Lorenzo, Sandra Moreno, Chengjin Ye, Jun-Gyu Park, Alejandro Matia, Alejandro Brun, Juana M. Sanchez-Puig, Aitor Nogales, Walther Mothes, Pradeep D. Uchil, Priti Kumar, Javier Ortego, Erol Fikrig, Luis Martinez-Sobrido, Rafael Blasco
Summary: The COVID-19 pandemic highlights the need for fast responses and reliable technologies for vaccine development. This study reports on the construction and preclinical testing of a recombinant MVA vaccine, with the MVA-Spf vaccine candidate showing higher levels of antibodies, a stronger T cell response, and a higher degree of protection.
Article
Multidisciplinary Sciences
Dijin Xu, Weiqian Jiang, Lizhen Wu, Ryan G. Gaudet, Eui-Soon Park, Maohan Su, Sudheer Kumar Cheppali, Nagarjuna R. Cheemarla, Pradeep Kumar, Pradeep D. Uchil, Jonathan R. Grover, Ellen F. Foxman, Chelsea M. Brown, Phillip J. Stansfeld, Joerg Bewersdorf, Walther Mothes, Erdem Karatekin, Craig B. Wilen, John D. MacMicking
Summary: Understanding protective immunity to COVID-19 facilitates preparedness for future pandemics and combats new SARS-CoV-2 variants. PLSCR1 is identified as a potent cell-autonomous restriction factor against SARS-CoV-2 infection and other highly pathogenic coronaviruses. It interferes with viral entry and fusion, providing a potential target for antiviral strategies.
Article
Immunology
Sonia Jangra, Jeffrey J. Landers, Gabriel Laghlali, Raveen Rathnasinghe, Prajakta Warang, Seok-Chan Park, Jessica. J. O'Konek, Gagandeep Singh, Katarzyna W. Janczak, Adolfo Garcia-Sastre, Nandini Arya, Dilara Karadag, Jr James R. Baker, Michael Schotsaert, Pamela T. Wong
Summary: Multiple FDA-approved vaccines provide good protection against severe disease caused by SARS-CoV-2. However, immunity can decline quickly, especially in the elderly, and new viral variants are emerging that can evade the immune response induced by infection or vaccination. Intranasal vaccination is more effective in inducing mucosal immune responses than injectable vaccines, which can improve protection and reduce viral transmission.
Review
Immunology
Vicent Tur-Planells, Adolfo Garcia-Sastre, Sara Cuadrado-Castano, Estanislao Nistal-Villan
Summary: This review provides an overview of non-human-adapted RNA viruses used in cancer therapy and the diverse strategies employed to optimize their therapeutic capabilities. Through this article, we gain insights into the promising advancements in virotherapy and its potential to revolutionize cancer treatment.
Article
Immunology
Alberto Grandi, Michele Tomasi, Irfan Ullah, Cinzia Bertelli, Teresa Vanzo, Silvia Accordini, Assunta Gagliardi, Ilaria Zanella, Mattia Benedet, Riccardo Corbellari, Gabriele Di Lascio, Silvia Tamburini, Elena Caproni, Lorenzo Croia, Micol Rava, Valeria Fumagalli, Pietro Di Lucia, Davide Marotta, Eleonora Sala, Matteo Iannacone, Priti Kumar, Walther Mothes, Pradeep D. Uchil, Peter Cherepanov, Martino Bolognesi, Massimo Pizzato, Guido Grandi
Summary: The study demonstrates that engineered OMVs vaccines can induce effective immune responses, producing neutralizing antibodies and protecting animals from SARS-CoV-2 infection. Furthermore, the vaccine can also elicit immune responses against the Omicron BA.1 and BA.5 variants. OMV-based SARS-CoV-2 vaccines, with the convenience of engineering, production, and distribution, can be a crucial addition to the currently available vaccines.
Article
Chemistry, Multidisciplinary
Megan L. Shipton, Fathima A. Jamion, Simon Wheeler, Andrew M. Riley, Felix Plasser, Barry V. L. Potter, Stephen J. Butler
Summary: We report the first molecular probe for the selective and sensitive detection of the most abundant cellular inositol pyrophosphate 5-PP-InsP(5), as well as an efficient new synthesis. Our probe offers a potential screening methodology to identify drug-like compounds that modulate the activity of enzymes of inositol pyrophosphate metabolism.