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Gene targeting

Rag da Silva, C P Churchward, A V Karlyshev, O Eleftheriadou, A K Snabaitis, M R Longman, A Ryan, R Griffin
BACKGROUND AND PURPOSE: The level of cell surface expression of the meningococcal vaccine antigen, Factor H binding protein (FHbp) varies between and within strains and this limits the breadth of strains that can be targeted by FHbp-based vaccines. The molecular pathway dictating expression of FHbp at the cell surface, including its lipidation, sorting to the outer membrane and export, and the potential regulation of this pathway have not been investigated until now. This knowledge will aid our evaluation of FHbp vaccines...
October 26, 2016: British Journal of Pharmacology
Musaffe Tuna, Christopher I Amos
Approximately 18% of all human cancers have a viral etiology, and human papillomavirus (HPV) has been identified as one of the most prevalent viruses that plays causative role in nearly all cervical cancers and, in addition, in subset of head and neck, anal, penile and vulvar cancers. The recent introduction of next generation sequencing (NGS) and other 'omics' approaches have resulted in comprehensive knowledge on the pathogenesis of HPV-driven tumors. Specifically, these approaches have provided detailed information on genomic HPV integration sites, disrupted genes and pathways, and common and distinct genetic and epigenetic alterations in different human HPV-associated cancers...
October 23, 2016: Oncotarget
Bo Yang, Shiming Zhang, Zhihao Wang, Chunxu Yang, Wen Ouyang, Fuxiang Zhou, Yunfeng Zhou, Conghua Xie
β-catenin is a crucial signal transduction molecule in the Wnt/β-catenin signal pathway, and increased β-catenin expression has consistently been found in high grade gliomas. However, the mechanisms responsible for β-catenin overexpression have remained elusive. Here we show that the deubiquitinase USP9X stabilizes β-catenin and thereby promotes high grade glioma cell growth. USP9X binds β-catenin and removes the Lys 48-linked polyubiquitin chains that normally mark β-catenin for proteasomal degradation...
October 22, 2016: Oncotarget
Judd F Hultquist, Kathrin Schumann, Jonathan M Woo, Lara Manganaro, Michael J McGregor, Jennifer Doudna, Viviana Simon, Nevan J Krogan, Alexander Marson
New genetic tools are needed to understand the functional interactions between HIV and human host factors in primary cells. We recently developed a method to edit the genome of primary CD4(+) T cells by electroporation of CRISPR/Cas9 ribonucleoproteins (RNPs). Here, we adapted this methodology to a high-throughput platform for the efficient, arrayed editing of candidate host factors. CXCR4 or CCR5 knockout cells generated with this method are resistant to HIV infection in a tropism-dependent manner, whereas knockout of LEDGF or TNPO3 results in a tropism-independent reduction in infection...
October 25, 2016: Cell Reports
Eloi R Verrier, Che C Colpitts, Charlotte Bach, Laura Heydmann, Laetitia Zona, Fei Xiao, Christine Thumann, Emilie Crouchet, Raphaël Gaudin, Camille Sureau, François-Loïc Cosset, Jane A McKeating, Patrick Pessaux, Yujin Hoshida, Catherine Schuster, Mirjam B Zeisel, Thomas F Baumert
Chronic hepatitis B, C, and D virus (HBV, HCV, and HDV) infections are the leading causes of liver disease and cancer worldwide. Recently, the solute carrier and sodium taurocholate co-transporter NTCP has been identified as a receptor for HBV and HDV. Here, we uncover NTCP as a host factor regulating HCV infection. Using gain- and loss-of-function studies, we show that NTCP mediates HCV infection of hepatocytes and is relevant for cell-to-cell transmission. NTCP regulates HCV infection by augmenting the bile-acid-mediated repression of interferon-stimulated genes (ISGs), including IFITM3...
October 25, 2016: Cell Reports
Michael A White, Jamie C Kwasnieski, Connie A Myers, Susan Q Shen, Joseph C Corbo, Barak A Cohen
Transcription factors often activate and repress different target genes in the same cell. How activation and repression are encoded by different arrangements of transcription factor binding sites in cis-regulatory elements is poorly understood. We investigated how sites for the transcription factor CRX encode both activation and repression in photoreceptors by assaying thousands of genomic and synthetic cis-regulatory elements in wild-type and Crx(-/-) retinas. We found that sequences with high affinity for CRX repress transcription, whereas sequences with lower affinity activate...
October 25, 2016: Cell Reports
Karla A Mark, Kathleen J Dumas, Dipa Bhaumik, Birgit Schilling, Sonnet Davis, Tal Ronnen Oron, Dylan J Sorensen, Mark Lucanic, Rachel B Brem, Simon Melov, Arvind Ramanathan, Bradford W Gibson, Gordon J Lithgow
Vitamin D has multiple roles, including the regulation of bone and calcium homeostasis. Deficiency of 25-hydroxyvitamin D, the major circulating form of vitamin D, is associated with an increased risk of age-related chronic diseases, including Alzheimer's disease, Parkinson's disease, cognitive impairment, and cancer. In this study, we utilized Caenorhabditis elegans to examine the mechanism by which vitamin D influences aging. We found that vitamin-D3-induced lifespan extension requires the stress response pathway genes skn-1, ire-1, and xbp-1...
October 25, 2016: Cell Reports
Rene Daer, Josh P Cutts, David A Brafman, Karmella A Haynes
In order to efficiently edit eukaryotic genomes, it is critical to test the impact of chromatin dynamics on CRISPR/Cas9 function and develop strategies to adapt the system to eukaryotic contexts. So far, research has extensively characterized the relationship between the CRISPR endonuclease Cas9 and the composition of the RNA-DNA duplex that mediates the system's precision. Evidence suggests that chromatin modifications and DNA packaging can block eukaryotic genome editing by custom-built DNA endonucleases like Cas9; however, the underlying mechanism of Cas9 inhibition is unclear...
October 26, 2016: ACS Synthetic Biology
Patrick T Walsh, Padraic G Fallon
The recently discovered interleukin (IL)-36 family of cytokines form part of the broader IL-1 family and are emerging as important mediators of inflammatory disease. The IL-36 subfamily consists of three ligands-IL-36α, IL-36β, and IL-36γ-and the natural antagonist IL-36Ra. The cytokines exert their effects through a specific IL-36 receptor consisting of IL-36R and IL-1RAcP chains. IL-36 cytokines can direct both innate and adaptive immune responses by acting on parenchymal, stromal, and specific immune cell subsets...
October 26, 2016: Annals of the New York Academy of Sciences
Georgios N Panagopoulos, Panayiotis D Megaloikonomos, Andreas F Mavrogenis
Peripheral nerve injury can have a potentially devastating impact on a patient's quality of life, resulting in severe disability with substantial social and personal cost. Refined microsurgical techniques, advances in peripheral nerve topography, and a better understanding of the pathophysiology and molecular basis of nerve injury have all led to a decisive leap forward in the field of translational neurophysiology. Nerve repair, nerve grafting, and nerve transfers have improved significantly with consistently better functional outcomes...
October 25, 2016: Orthopedics
Rahul Agrawal, Tina P Dale, Mohammed A Al-Zubaidi, Prit Benny Malgulwar, Nicholas R Forsyth, Ritu Kulshreshtha
MicroRNAs are reported to have a crucial role in the regulation of self-renewal and differentiation of stem cells. Hypoxia has been identified as a key biophysical element of the stem cell culture milieu however, the link between hypoxia and miRNA expression in stem cells remains poorly understood. We therefore explored miRNA expression in hypoxic human embryonic and mesenchymal stem cells (hESCs and hMSCs). A total of 50 and 76 miRNAs were differentially regulated by hypoxia (2% O2) in hESCs and hMSCs, respectively, with a negligible overlap of only three miRNAs...
2016: PloS One
Yonghe Qi, Zhenchao Gao, Guangwei Xu, Bo Peng, Chenxuan Liu, Huan Yan, Qiyan Yao, Guoliang Sun, Yang Liu, Dingbin Tang, Zilin Song, Wenhui He, Yinyan Sun, Ju-Tao Guo, Wenhui Li
Hepatitis B virus (HBV) infection of hepatocytes begins by binding to its cellular receptor sodium taurocholate cotransporting polypeptide (NTCP), followed by the internalization of viral nucleocapsid into the cytoplasm. The viral relaxed circular (rc) DNA genome in nucleocapsid is transported into the nucleus and converted into covalently closed circular (ccc) DNA to serve as a viral persistence reservoir that is refractory to current antiviral therapies. Host DNA repair enzymes have been speculated to catalyze the conversion of rcDNA to cccDNA, however, the DNA polymerase(s) that fills the gap in the plus strand of rcDNA remains to be determined...
October 2016: PLoS Pathogens
Asghar Ghasemi, Soudabeh Fallah, Mohammad Ansari
Aberrant DNA methylation has been shown to inactivate tumor suppressor genes during carcinogenesis. MicroRNA-149 (miR-149) was recently demonstrated to function as a tumor suppressor gene in glioblastoma multiforme (GBM). However, the potential linkage of miR-149 levels and the underlying epigenetic regulatory mechanism in human GBM has not been studied. We used quantitative real-time polymerase chain reaction to investigate the levels of miR-149 in GBM tissues, their matched adjacent normal tissues, and glioblastoma U87MG cell line...
October 26, 2016: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Thierry Lioux, Marc-Antoine Mauny, Alain Lamoureux, Nicolas Bascoul, Mathieu Hays, Fabienne Vernejoul, Anne-Sophie Baudru, Cédric Boularan, Justine Lopes-Vicente, Gregory Qushair, Gérard Tiraby
We describe novel STING-activating cyclic dinucleotides whose constituent nucleosides are adenosine and inosine, and that vary by ribose substitution, internucleotide linkage position and phosphate modification. In mammalian cells in vitro, some of these cAIMP analogs induce greater STING-dependent IRF and NF-κB pathway signaling than do the reference agonists for murine (DMXAA) or human (2',3'-cGAMP) STING. In human blood ex vivo, they induce type I interferons (IFNs) and pro-inflammatory cytokines: for the former, 3',3'-cAIMP (9; EC50: 6...
October 26, 2016: Journal of Medicinal Chemistry
Qing Liu, Dinghong Wu, Ling Han, Jingwen Deng, Li Zhou, Rui He, Chuanjian Lu, Qing-Sheng Mi
MicroRNAs (miRNAs) are small non-coding RNA molecules, which function in RNA silencing and post-transcriptional regulation of gene expression. Psoriasis is an inflammatory skin disease characterized by the dysfunction of keratinocytes, with the immune dysregulation. We reviewed the recent studies on the roles of miRNAs in psoriasis, and showed that miRNAs play key roles in psoriasis, including the regulation of hyperproliferation, cytokine and chemokine production in keratinocyte, as well as mediating immune dysfunction in psoriasis...
October 26, 2016: Experimental Dermatology
Michele P Calos
Fueled by advances in the field of genetics, the methods available to edit DNA sequences in living cells have continued to develop steadily. These technologies directly impact the fields of gene and cell therapy, where changes in the DNA sequence of target cells offer a route to correct genetic diseases and manipulate disorders like cancer. We review here the expanding menu of genome editing techniques and how they are being applied to therapeutic targets. The methods encompass a myriad of approaches to modify the covalent structure of DNA, including the targeted creation of double-strand breaks that can catalyze genomic changes, as well as the use of retroviruses and transposons to mediate gene addition, recombinases for sequence-specific gene addition and deletion, and base repair for direct sequence changes...
October 26, 2016: Clinical Pharmacology and Therapeutics
Kit Man Wong, Lindsey N Micel, Heather M Selby, Aik Choon Tan, Todd M Pitts, Stacey M Bagby, Anna Spreafico, Peter J Klauck, Stephen J Blakemore, Peter F Smith, Alice McDonald, Allison Berger, John J Tentler, S Gail Eckhardt
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models...
October 25, 2016: Investigational New Drugs
Feng Q He, Markus Ollert
Identification of key genes for a given physiological or pathological process is an essential but still very challenging task for the entire biomedical research community. Statistics-based approaches, such as genome-wide association study (GWAS)- or quantitative trait locus (QTL)-related analysis have already made enormous contributions to identifying key genes associated with a given disease or phenotype, the success of which is however very much dependent on a huge number of samples. Recent advances in network biology, especially network inference directly from genome-scale data and the following-up network analysis, opens up new avenues to predict key genes driving a given biological process or cellular function...
October 26, 2016: Advances in Biochemical Engineering/biotechnology
Yong Huang, Jinxiu Huang, Renli Qi, Qi Wang, Yongjiang Wu, Jing Wang
MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate growth, development, and programmed death of cells. A newly-published study has shown that miRNA-23a could regulate 3T3-L1 adipocyte differentiation. Here, we identified miRNA-23a as a negative regulator of 3T3-L1 adipocyte differentiation again. Over-expression of miRNA-23a inhibited differentiation and decreased lipogenesis as well as down-regulated mRNA and protein expression of both peroxisome proliferator-activated receptor (PPAR) γ and fatty acid binding protein (FABP) 4, whereas knock down of miRNA-23a showed the opposite effects on differentiation as well as increasing the number of apoptotic cells...
October 24, 2016: Genes
Tobias Cohen, Toni M Schwarz, Frederic Vigant, Thomas J Gardner, Rosmel E Hernandez, Benhur Lee, Domenico Tortorella
Human cytomegalovirus is a ubiquitous β-herpesvirus that infects many different cell types through an initial binding to cell surface receptors followed by a fusion event at the cell membrane or endocytic vesicle. A recent high-throughput screen to identify compounds that block a step prior to viral gene expression identified podofilox as a potent and nontoxic inhibitor. Time-of-addition studies in combination with quantitative-PCR analysis demonstrated that podofilox limits an early step of virus entry at the cell surface...
October 24, 2016: Viruses
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