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https://www.readbyqxmd.com/read/29342275/hot-spot-kif5a-mutations-cause-familial-als
#1
David Brenner, Rüstem Yilmaz, Kathrin Müller, Torsten Grehl, Susanne Petri, Thomas Meyer, Julian Grosskreutz, Patrick Weydt, Wolfgang Ruf, Christoph Neuwirth, Markus Weber, Susana Pinto, Kristl G Claeys, Berthold Schrank, Berit Jordan, Antje Knehr, Kornelia Günther, Annemarie Hübers, Daniel Zeller, Christian Kubisch, Sibylle Jablonka, Michael Sendtner, Thomas Klopstock, Mamede de Carvalho, Anne Sperfeld, Guntram Borck, Alexander E Volk, Johannes Dorst, Joachim Weis, Markus Otto, Joachim Schuster, Kelly Del Tredici, Heiko Braak, Karin M Danzer, Axel Freischmidt, Thomas Meitinger, Tim M Strom, Albert C Ludolph, Peter M Andersen, Jochen H Weishaupt
Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis...
January 12, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29340026/evaluating-the-bias-of-circrna-predictions-from-total-rna-seq-data
#2
Jinzeng Wang, Kang Liu, Ya Liu, Qi Lv, Fan Zhang, Haiyun Wang
CircRNAs are a group of endogenous noncoding RNAs. The quickly developing high throughput RNA sequencing technologies along with novel bioinformatics approaches have enabled researchers to systematically identify circRNAs and their biological functions in cells. Deep sequencing of rRNA-depleted RNAs treated with RNase R, which digests linear RNAs and leaves circRNAs enriched, is an efficient way to identify circRNAs. However, very few of RNase R treated data are at hand but a large amount of total RNA-Seq data with no sequencing costs is available, for circRNA predictions...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339801/cardiac-glycoside-aglycones-inhibit-hiv-1-gene-expression-by-a-mechanism-requiring-mek1-2-erk1-2-signaling
#3
Raymond W Wong, Clifford A Lingwood, Mario A Ostrowski, Tyler Cabral, Alan Cochrane
The capacity of HIV-1 to develop resistance to current drugs calls for innovative strategies to control this infection. We aimed at developing novel inhibitors of HIV-1 replication by targeting viral RNA processing-a stage dependent on conserved host processes. We previously reported that digoxin is a potent inhibitor of this stage. Herein, we identify 12 other cardiac glycoside/aglycones or cardiotonic steroids (CSs) that impede HIV growth in HIV-infected T cells from clinical patients at IC50s (1.1-1.3 nM) that are 2-26 times below concentrations used in patients with heart conditions...
January 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29339440/repurposing-tin-mesoporphyrin-as-an-immune-checkpoint-inhibitor-shows-therapeutic-efficacy-in-preclinical-models-of-cancer
#4
Tamara Muliaditan, James W Opzoomer, Jonathan Caron, Mary Okesola, Paris Kosti, Sharanpreet Lall, Mieke Van Hemelrijck, Francesco Dazzi, Andrew Tutt, Anita Grigoriadis, Cheryl Gillett, Stephen F Madden, Joy M Burchell, Shahram Kordasti, Sandra S Diebold, James Spicer, James N Arnold
PURPOSE: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immune suppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited anti-tumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinaemia, as an immune checkpoint blockade therapy for the treatment of cancer...
January 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29339148/biochemical-characterization-of-campylobacter-jejuni-pnpase-an-exoribonuclease-important-for-bacterial-pathogenicity
#5
Jorge Casinhas, Rute G Matos, Nabila Haddad, Cecília M Arraiano
Bacteria need to promptly respond to environmental changes. Ribonucleases (RNases) are key factors in the adaptation to new environments by enabling a rapid adjustment in RNA levels. The exoribonuclease polynucleotide phosphorylase (PNPase) is essential for low-temperature cell survival, affects the synthesis of proteins involved in virulence and has an important role in swimming, cell adhesion/invasion ability, and chick colonization in C. jejuni. However, the mechanism of action of this ribonuclease is not yet known...
January 12, 2018: Biochimie
https://www.readbyqxmd.com/read/29337374/pooled-lentiviral-delivery-genetic-screens
#6
Federica Piccioni, Scott T Younger, David E Root
Pooled cell-based screens of mammalian genetic perturbations enable systematic large-scale, even genome-scale, evaluation of gene function. Pooled screens introduce genetic perturbations into a cell population through viral transduction such that each cell integrates into its DNA a single or small number of library perturbations with barcodes identifying the perturbations. One then selects and physically isolates the subset of cells that exhibit the phenotype of interest. Sequencing the barcodes in the hit cells reveals which genes favored or inhibited the hit phenotype...
January 16, 2018: Current Protocols in Molecular Biology
https://www.readbyqxmd.com/read/29337370/modulating-gene-expression-in-epstein-barr-virus-ebv-positive-b-cell-lines-with-crispra-and-crispri
#7
Liang Wei Wang, Stephen J Trudeau, Chong Wang, Catherine Gerdt, Sizun Jiang, Bo Zhao, Benjamin E Gewurz
Epstein-Barr virus (EBV) transforms small resting primary B cells into large lymphoblastoid cells which are able to grow and survive in vitro indefinitely. These cells represent a model for oncogenesis. In this unit, variants of conventional clustered regularly interspaced short palindromic repeats (CRISPR), namely the CRISPR activation (CRISPRa) and CRISPR interference (CRISPRi) methods, are discussed in the context of gene regulation at genomic DNA promoter and enhancer elements. Lymphoblastoid B cell lines (LCLs) stably expressing nuclease-deficient Cas9 (dCas9)-VP64 (Cas9 associated with CRISPRa) or dCas9-KRAB (Cas9 associated with CRISPRi) are transduced with lentivirus that encodes a single guide RNA (sgRNA) that targets a specific gene locus...
January 16, 2018: Current Protocols in Molecular Biology
https://www.readbyqxmd.com/read/29335794/effect-of-a-calcitonin-gene-related-peptide-binding-l-rna-aptamer-on-neuronal-activity-in-the-rat-spinal-trigeminal-nucleus
#8
Michael J M Fischer, Jakob Schmidt, Stanislav Koulchitsky, Sven Klussmann, Axel Vater, Karl Messlinger
BACKGROUND: Calcitonin gene-related peptide (CGRP) plays a major role in the pathogenesis of migraine and other primary headaches. Spinal trigeminal neurons integrate nociceptive afferent input from trigeminal tissues including intracranial afferents, and their activity is thought to reflect facial pain and headache in man. CGRP receptor inhibitors and anti-CGRP antibodies have been demonstrated to be therapeutically effective in migraine. In parallel, CGRP receptor inhibition has been shown to lower spinal trigeminal neuron activity in animal models of meningeal nociception...
January 15, 2018: Journal of Headache and Pain
https://www.readbyqxmd.com/read/29335606/conserved-properties-of-dentate-gyrus-neurogenesis-across-postnatal-development-revealed-by-single-cell-rna-sequencing
#9
Hannah Hochgerner, Amit Zeisel, Peter Lönnerberg, Sten Linnarsson
The dentate gyrus of the hippocampus is a brain region in which neurogenesis persists into adulthood; however, the relationship between developmental and adult dentate gyrus neurogenesis has not been examined in detail. Here we used single-cell RNA sequencing to reveal the molecular dynamics and diversity of dentate gyrus cell types in perinatal, juvenile, and adult mice. We found distinct quiescent and proliferating progenitor cell types, linked by transient intermediate states to neuroblast stages and fully mature granule cells...
January 15, 2018: Nature Neuroscience
https://www.readbyqxmd.com/read/29335281/high-throughput-identification-of-rna-nuclear-enrichment-sequences
#10
Chinmay J Shukla, Alexandra L McCorkindale, Chiara Gerhardinger, Keegan D Korthauer, Moran N Cabili, David M Shechner, Rafael A Irizarry, Philipp G Maass, John L Rinn
In the post-genomic era, thousands of putative noncoding regulatory regions have been identified, such as enhancers, promoters, long noncoding RNAs (lncRNAs), and a cadre of small peptides. These ever-growing catalogs require high-throughput assays to test their functionality at scale. Massively parallel reporter assays have greatly enhanced the understanding of noncoding DNA elements en masse Here, we present a massively parallel RNA assay (MPRNA) that can assay 10,000 or more RNA segments for RNA-based functionality...
January 15, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29334988/epidermal-wnt-signalling-regulates-transcriptome-heterogeneity-and-proliferative-fate-in-neighbouring-cells
#11
Arsham Ghahramani, Giacomo Donati, Nicholas M Luscombe, Fiona M Watt
BACKGROUND: Canonical Wnt/beta-catenin signalling regulates self-renewal and lineage selection within the mammalian epidermis. Although the transcriptional response of keratinocytes that receive a Wnt signal is well characterized, little is known about the mechanism by which keratinocytes in proximity to the Wnt-receiving cell are co-opted to undergo a change in cell fate. RESULTS: To address this, we perform single-cell RNA-sequencing on mouse keratinocytes co-cultured with and without beta-catenin-activated neighbouring cells...
January 15, 2018: Genome Biology
https://www.readbyqxmd.com/read/29334771/development-of-anti-human-mesothelin-targeted-chimeric-antigen-receptor-car-messenger-rna-mrna-transfected-peripheral-blood-lymphocytes-carma-hmeso-for-ovarian-cancer-therapy
#12
Chien-Fu Hung, Xuequn Xu, Linhong Li, Ying Ma, Qiu Jin, Angelia Viley, Cornell Allen, Pachai Natarajan, Rama Shivakumar, Madhusudan V Peshwa, Leisha A Emens
CD19-targeted chimeric antigen receptor (CAR) engineered T/natural kill (NK)-cell therapies can result in durable clinical responses in B-cell malignancies. However, CAR-based immunotherapies have been much less successful in solid cancers, in part due to 'on-target off-tumor' toxicity related to expression of target tumor antigens on normal tissue. Based on preliminary observations of safety and clinical activity in proof-of-concept clinical trials, tumor antigen-specific messenger RNA (mRNA) CAR transfection into selected, activated, and expanded T/NK-cells may permit prospective control of 'on-target off-tumor toxicity'...
January 15, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29333573/simultaneous-site-directed-mutagenesis-of-duplicated-loci-in-soybean-using-a-single-guide-rna
#13
Yuhei Kanazashi, Aya Hirose, Ippei Takahashi, Masafumi Mikami, Masaki Endo, Sakiko Hirose, Seiichi Toki, Akito Kaga, Ken Naito, Masao Ishimoto, Jun Abe, Tetsuya Yamada
Using a gRNA and Agrobacterium-mediated transformation, we performed simultaneous site-directed mutagenesis of two GmPPD loci in soybean. Mutations in GmPPD loci were confirmed in at least 33% of T2 seeds. The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated endonuclease 9 (Cas9) system is a powerful tool for site-directed mutagenesis in crops. Using a single guide RNA (gRNA) and Agrobacterium-mediated transformation, we performed simultaneous site-directed mutagenesis of two homoeologous loci in soybean (Glycine max), GmPPD1 and GmPPD2, which encode the orthologs of Arabidopsis thaliana PEAPOD (PPD)...
January 15, 2018: Plant Cell Reports
https://www.readbyqxmd.com/read/29332168/efficient-crispr-cas9-based-genome-editing-in-carrot-cells
#14
Magdalena Klimek-Chodacka, Tomasz Oleszkiewicz, Levi G Lowder, Yiping Qi, Rafal Baranski
The first report presenting successful and efficient carrot genome editing using CRISPR/Cas9 system. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas9) is a powerful genome editing tool that has been widely adopted in model organisms recently, but has not been used in carrot-a model species for in vitro culture studies and an important health-promoting crop grown worldwide. In this study, for the first time, we report application of the CRISPR/Cas9 system for efficient targeted mutagenesis of the carrot genome...
January 13, 2018: Plant Cell Reports
https://www.readbyqxmd.com/read/29330484/single-cell-rna-sequencing-resolves-self-antigen-expression-during-mtec-development
#15
Ricardo J Miragaia, Xiuwei Zhang, Tomás Gomes, Valentine Svensson, Tomislav Ilicic, Johan Henriksson, Gozde Kar, Tapio Lönnberg
The crucial capability of T cells for discrimination between self and non-self peptides is based on negative selection of developing thymocytes by medullary thymic epithelial cells (mTECs). The mTECs purge autoreactive T cells by expression of cell-type specific genes referred to as tissue-restricted antigens (TRAs). Although the autoimmune regulator (AIRE) protein is known to promote the expression of a subset of TRAs, its mechanism of action is still not fully understood. The expression of TRAs that are not under the control of AIRE also needs further characterization...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29326266/the-epigenetic-control-of-stemness-in-cd8-t-cell-fate-commitment
#16
Luigia Pace, Christel Goudot, Elina Zueva, Paul Gueguen, Nina Burgdorf, Joshua J Waterfall, Jean-Pierre Quivy, Geneviève Almouzni, Sebastian Amigorena
After priming, naïve CD8+ T lymphocytes establish specific heritable transcription programs that define progression to long-lasting memory cells or to short-lived effector cells. Although lineage specification is critical for protection, it remains unclear how chromatin dynamics contributes to the control of gene expression programs. We explored the role of gene silencing by the histone methyltransferase Suv39h1. In murine CD8+ T cells activated after Listeria monocytogenes infection, Suv39h1-dependent trimethylation of histone H3 lysine 9 controls the expression of a set of stem cell-related memory genes...
January 12, 2018: Science
https://www.readbyqxmd.com/read/29326162/structural-basis-for-p-ppgpp-synthesis-by-the-staphylococcus-aureus-small-alarmone-synthetase-relp
#17
Melek Cemre Manav, Jelena Beljantseva, Martin Saxtorph Bojer, Tanel Tenson, Hanne Ingmer, Vasili Hauryliuk, Ditlev Egeskov Brodersen
The stringent response is a global reprogramming of bacterial physiology that renders cells more tolerant to antibiotics and induces virulence gene expression in pathogens in response to stress. This process is driven by accumulation of the intracellular alarmone guanosine-5'-di(tri)phosphate-3'-diphosphate ([p]ppGpp), which is produced by enzymes of the RelA SpoT homologue (RSH) family. The Gram-positive Firmicute pathogen, Staphylococcus aureus, encodes three RSH enzymes: a multi-domain RSH (Rel) that senses amino acid starvation on the ribosome and two small alarmone synthetase (SAS) enzymes, RelQ (SAS1) and RelP (SAS2)...
January 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29325021/oligonucleotides-targeting-tcf4-triplet-repeat-expansion-inhibit-rna-foci-and-mis-splicing-in-fuchs-dystrophy
#18
Jiaxin Hu, Ziye Rong, Xin Gong, Zhengyang Zhou, Vivek K Sharma, Chao Xing, Jonathan K Watts, David R Corey, V Vinod Mootha
Fuchs' endothelial corneal dystrophy (FECD) is the most common repeat expansion disorder. FECD impacts 4% of United States population and is the leading indication for corneal transplantation. Most cases are caused by an expanded intronic CUG tract in the TCF4 gene that forms nuclear foci, sequesters splicing factors, and impairs splicing. We investigated the sense and antisense RNA landscape at the FECD gene and find that the sense expanded repeat transcript is the predominant species in patient corneas. In patient tissue, sense foci number were negatively correlated with age and showed no correlation with sex...
January 8, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29323290/clonal-analysis-of-lineage-fate-in-native-haematopoiesis
#19
Alejo E Rodriguez-Fraticelli, Samuel L Wolock, Caleb S Weinreb, Riccardo Panero, Sachin H Patel, Maja Jankovic, Jianlong Sun, Raffaele A Calogero, Allon M Klein, Fernando D Camargo
Haematopoiesis, the process of mature blood and immune cell production, is functionally organized as a hierarchy, with self-renewing haematopoietic stem cells and multipotent progenitor cells sitting at the very top. Multiple models have been proposed as to what the earliest lineage choices are in these primitive haematopoietic compartments, the cellular intermediates, and the resulting lineage trees that emerge from them. Given that the bulk of studies addressing lineage outcomes have been performed in the context of haematopoietic transplantation, current models of lineage branching are more likely to represent roadmaps of lineage potential than native fate...
January 11, 2018: Nature
https://www.readbyqxmd.com/read/29322913/cell-type-discovery-and-representation-in-the-era-of-high-content-single-cell-phenotyping
#20
Trygve Bakken, Lindsay Cowell, Brian D Aevermann, Mark Novotny, Rebecca Hodge, Jeremy A Miller, Alexandra Lee, Ivan Chang, Jamison McCorrison, Bali Pulendran, Yu Qian, Nicholas J Schork, Roger S Lasken, Ed S Lein, Richard H Scheuermann
BACKGROUND: A fundamental characteristic of multicellular organisms is the specialization of functional cell types through the process of differentiation. These specialized cell types not only characterize the normal functioning of different organs and tissues, they can also be used as cellular biomarkers of a variety of different disease states and therapeutic/vaccine responses. In order to serve as a reference for cell type representation, the Cell Ontology has been developed to provide a standard nomenclature of defined cell types for comparative analysis and biomarker discovery...
December 21, 2017: BMC Bioinformatics
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