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https://www.readbyqxmd.com/read/27902356/luciferase-tagged-wild-type-and-tropism-deficient-mouse-cytomegaloviruses-reveal-early-dynamics-of-host-colonization-following-peripheral-challenge
#1
Helen Farrell, Martha Oliveira, Kate Macdonald, Joseph Yunis, Michael Mach, Kimberley Bruce, Philip Stevenson, Rhonda Cardin, Nicholas Davis-Poynter
Cytomegaloviruses (CMVs) establish persistent, systemic infections and cause disease by maternal-fetal transfer, suggesting that their dissemination is a key target for anti-viral intervention. Late clinical presentation has meant that human CMV dissemination is not well understood. Murine CMV provides a tractable model. Whole mouse imaging of virus-expressed luciferase has proved a useful way to track systemic infections. MCMV, in which the abundant lytic gene M78 was luciferase tagged via a self-cleaving peptide (M78-LUC), allowed serial, unbiased imaging of systemic and peripheral infection without significant virus attenuation...
October 26, 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27885283/induced-protein-degradation-an-emerging-drug-discovery-paradigm
#2
Ashton C Lai, Craig M Crews
Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination...
November 25, 2016: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/27881166/using-the-social-amoeba-dictyostelium-to-study-the-functions-of-proteins-linked-to-neuronal-ceroid-lipofuscinosis
#3
REVIEW
Robert J Huber
Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a debilitating neurological disorder that affects both children and adults. Thirteen genetically distinct genes have been identified that when mutated, result in abnormal lysosomal function and an excessive accumulation of ceroid lipofuscin in neurons, as well as other cell types outside of the central nervous system. The NCL family of proteins is comprised of lysosomal enzymes (PPT1/CLN1, TPP1/CLN2, CTSD/CLN10, CTSF/CLN13), proteins that peripherally associate with membranes (DNAJC5/CLN4, KCTD7/CLN14), a soluble lysosomal protein (CLN5), a protein present in the secretory pathway (PGRN/CLN11), and several proteins that display different subcellular localizations (CLN3, CLN6, MFSD8/CLN7, CLN8, ATP13A2/CLN12)...
November 24, 2016: Journal of Biomedical Science
https://www.readbyqxmd.com/read/27873256/cell-based-fluorescent-screen-to-identify-inhibitors-of-bacterial-translation-initiation
#4
Federica Briani
A strategy that can be applied to the research of new molecules with antibacterial activity is to look for inhibitors of essential bacterial processes within large collections of chemically heterogeneous compounds. The implementation of this approach requires the development of proper assays aimed at the identification of molecules interfering with specific cell pathways and potentially applicable to the high throughput analysis of large chemical library. Here, I describe a fluorescence-based whole-cell assay in Escherichia coli devised to find inhibitors of the translation initiation pathway...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27872098/systematic-drug-screening-identifies-tractable-targeted-combination-therapies-in-triple-negative-breast-cancer
#5
Vikram B Wali, Casey G Langdon, Matthew A Held, James T Platt, Gauri A Patwardhan, Anton Safonov, Bilge Aktas, Lajos Pusztai, David F Stern, Christos Hatzis
Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity and validation in low-throughput experiments...
November 21, 2016: Cancer Research
https://www.readbyqxmd.com/read/27824342/systems-level-metabolism-of-the-altered-schaedler-flora-a-complete-gut-microbiota
#6
Matthew B Biggs, Gregory L Medlock, Thomas J Moutinho, Hannah J Lees, Jonathan R Swann, Glynis L Kolling, Jason A Papin
The altered Schaedler flora (ASF) is a model microbial community with both in vivo and in vitro relevance. Here we provide the first characterization of the ASF community in vitro, independent of a murine host. We compared the functional genetic content of the ASF to wild murine metagenomes and found that the ASF functionally represents wild microbiomes better than random consortia of similar taxonomic composition. We developed a chemically defined medium that supported growth of seven of the eight ASF members...
November 8, 2016: ISME Journal
https://www.readbyqxmd.com/read/27820905/covering-ground-movement-patterns-and-random-walk-behavior-in-aquilonastra-anomala-sea-stars
#7
Amanda C Lohmann, Dennis Evangelista, Lindsay D Waldrop, Christopher L Mah, Tyson L Hedrick
The paths animals take while moving through their environments affect their likelihood of encountering food and other resources; thus, models of foraging behavior abound. To collect movement data appropriate for comparison with these models, we used time-lapse photography to track movements of a small, hardy, and easy-to-obtain organism, Aquilonastra anomala sea stars. We recorded the sea stars in a tank over many hours, with and without a food cue. With food present, they covered less distance, as predicted by theory; this strategy would allow them to remain near food...
October 2016: Biological Bulletin
https://www.readbyqxmd.com/read/27814964/changing-global-policy-to-deliver-safe-equitable-and-affordable-care-for-women-s-cancers
#8
REVIEW
Ophira Ginsburg, Rajan Badwe, Peter Boyle, Gemma Derricks, Anna Dare, Tim Evans, Alexandru Eniu, Jorge Jimenez, Tezer Kutluk, Gilberto Lopes, Sulma I Mohammed, You-Lin Qiao, Sabina Faiz Rashid, Diane Summers, Diana Sarfati, Marleen Temmerman, Edward L Trimble, Aasim I Padela, Ajay Aggarwal, Richard Sullivan
Breast and cervical cancer are major threats to the health of women globally, particularly in low-income and middle-income countries. Radical progress to close the global cancer divide for women requires not only evidence-based policy making, but also broad multisectoral collaboration that capitalises on recent progress in the associated domains of women's health and innovative public health approaches to cancer care and control. Such multisectoral collaboration can serve to build health systems for cancer, and more broadly for primary care, surgery, and pathology...
November 1, 2016: Lancet
https://www.readbyqxmd.com/read/27807368/expression-of-the-fetal-hematopoiesis-regulator-fev-indicates-leukemias-of-prenatal-origin
#9
T-H Liu, Y-J Tang, Y Huang, L Wang, X-L Guo, J-Q Mi, L-G Liu, H Zhu, Y Zhang, L Chen, X Liu, L-H Zhang, Q-J Ye, B-S Li, J-Y Tang, A Ford, T Enver, F Liu, G-Q Chen, D-L Hong
The origin of cancers is associated with etiology as well as therapeutics. Several studies reveal that malignancies in children can originate in utero. However a diagnostic approach to distinguish between cancers initiated pre- or postnatally is absent. Here we identified a transcriptional factor FEV that was expressed in fetal hematopoietic cells and became silent after birth. We characterized that FEV was essential for the self-renewal of hematopoietic stem cells (HSCs). We next found FEV was expressed in most infant leukemia samples, but not in adult samples, in accord with the known pre-natal origins of the former...
November 3, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27798629/a-viral-strategy-for-targeting-and-manipulating-interneurons-across-vertebrate-species
#10
Jordane Dimidschstein, Qian Chen, Robin Tremblay, Stephanie L Rogers, Giuseppe-Antonio Saldi, Lihua Guo, Qing Xu, Runpeng Liu, Congyi Lu, Jianhua Chu, Michael C Avery, Mohammad S Rashid, Myungin Baek, Amanda L Jacob, Gordon B Smith, Daniel E Wilson, Georg Kosche, Illya Kruglikov, Tomasz Rusielewicz, Vibhakar C Kotak, Todd M Mowery, Stewart A Anderson, Edward M Callaway, Jeremy S Dasen, David Fitzpatrick, Valentina Fossati, Michael A Long, Scott Noggle, John H Reynolds, Dan H Sanes, Bernardo Rudy, Guoping Feng, Gord Fishell
A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations. The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types. In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans...
October 31, 2016: Nature Neuroscience
https://www.readbyqxmd.com/read/27737879/cxcr2-dependent-accumulation-of-tumor-associated-neutrophils-regulates-t-cell-immunity-in-pancreatic-ductal-adenocarcinoma
#11
Timothy Chao, Emma E Furth, Robert H Vonderheide
Tumor-associated neutrophils are increasingly recognized for their ability to promote tumor progression, mediate resistance to therapy, and regulate immunosuppression. Evidence from various murine models has shown that the chemokine receptor CXCR2 attracts neutrophil into tumors and, therefore, represents a tractable therapeutic target. Here, we report prominent expression of a neutrophil gene signature in a subset of human pancreatic adenocarcinoma (PDA). CXCL5 was the most prominently expressed CXCR2 ligand in human PDA, and its expression was higher in PDA than in any other common tumor represented in The Cancer Genome Atlas...
November 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27710242/metabolic-fingerprints-of-circulating-igf-i-and-the-igf-i-igfbp-3-ratio-a-multi-fluid-metabolomics-study
#12
Henrike Knacke, Maik Pietzner, Kieu Trinh Do, Werner Römisch-Margl, Gabi Kastenmüller, Uwe Völker, Henry Völzke, Jan Krumsiek, Anna Artati, Henri Wallaschofski, Matthias Nauck, Karsten Suhre, Jerzy Adamski, Nele Friedrich
OBJECTIVE: Insulin-like Growth Factor (IGF-I) is known for its various physiological and severe pathophysiological effects on human metabolism, however underlying molecular mechanisms still remain unsolved. To reveal possible molecular mechanisms mediating these effects, for the first time we associated serum IGF-I levels with multi-fluid untargeted metabolomics data. METHODS: Plasma/urine samples of 995 non-diabetic participants of the Study of Health in Pomerania (SHIP-TREND) were characterized by mass spectrometry...
October 6, 2016: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27687311/mutant-kit-as-imatinib-sensitive-target-in-metastatic-sinonasal-carcinoma
#13
S M Dieter, C Heining, A Agaimy, D Huebschmann, D Bonekamp, B Hutter, K R Ehrenberg, M Fröhlich, M Schlesner, C Scholl, H-P Schlemmer, S Wolf, A Mavratzas, C S Jung, S Gröschel, C V Kalle, R Eils, B Brors, R Penzel, M Kriegsmann, D E Reuss, P Schirmacher, A Stenzinger, P A Federspil, W Weichert, H Glimm, S Fröhling
BACKGROUND: Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. We here aimed to identify actionable genetic alterations in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27671169/evaluating-targeted-interventions-via-meta-population-models-with-multi-level-mixing
#14
Zhilan Feng, Andrew N Hill, Aaron T Curns, John W Glasser
Among the several means by which heterogeneity can be modeled, Levins' (1969) meta-population approach preserves the most analytical tractability, a virtue to the extent that generality is desirable. When model populations are stratified, contacts among their respective sub-populations must be described. Using a simple meta-population model, Feng et al. (2015) showed that mixing among sub-populations, as well as heterogeneity in characteristics affecting sub-population reproduction numbers, must be considered when evaluating public health interventions to prevent or control infectious disease outbreaks...
September 23, 2016: Mathematical Biosciences
https://www.readbyqxmd.com/read/27613054/high-throughput-sirna-screening-applied-to-the-ubiquitin-proteasome-system
#15
Esben G Poulsen, Sofie V Nielsen, Elin J Pietras, Jens V Johansen, Cornelia Steinhauer, Rasmus Hartmann-Petersen
The ubiquitin-proteasome system is the major pathway for intracellular protein degradation in eukaryotic cells. Due to the large number of genes dedicated to the ubiquitin-proteasome system, mapping degradation pathways for short lived proteins is a daunting task, in particular in mammalian cells that are not genetically tractable as, for instance, a yeast model system. Here, we describe a method relying on high-throughput cellular imaging of cells transfected with a targeted siRNA library to screen for components involved in degradation of a protein of interest...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27601656/in-b-cells-phosphatidylinositol-5-phosphate-4-kinase-%C3%AE-synthesizes-pi-4-5-p2-to-impact-mtorc2-and-akt-signaling
#16
Simon J Bulley, Alaa Droubi, Jonathan H Clarke, Karen E Anderson, Len R Stephens, Phillip T Hawkins, Robin F Irvine
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are enigmatic lipid kinases with physiological functions that are incompletely understood, not the least because genetic deletion and cell transfection have led to contradictory data. Here, we used the genetic tractability of DT40 cells to create cell lines in which endogenous PI5P4Kα was removed, either stably by genetic deletion or transiently (within 1 h) by tagging the endogenous protein genomically with the auxin degron. In both cases, removal impacted Akt phosphorylation, and by leaving one PI5P4Kα allele present but mutating it to be kinase-dead or have PI4P 5-kinase activity, we show that all of the effects on Akt phosphorylation were dependent on the ability of PI5P4Kα to synthesize phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] rather than to remove PI5P...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27599694/transcript-signatures-that-predict-outcome-and-identify-targetable-pathways-in-mycn-amplified-neuroblastoma
#17
Robin M Hallett, Alex B K Seong, David R Kaplan, Meredith S Irwin
BACKGROUND: In the pediatric cancer neuroblastoma (NB), patients are stratified into low, intermediate or high-risk subsets based in part on MYCN amplification status. While MYCN amplification in general predicts unfavorable outcome, no clinical or genomic factors have been identified that predict outcome within these cohorts of high-risk patients. In particular, it is currently not possible at diagnosis to determine which high-risk neuroblastoma patients will ultimately fail upfront therapy...
November 2016: Molecular Oncology
https://www.readbyqxmd.com/read/27597858/advances-in-faba-bean-genetics-and-genomics
#18
REVIEW
Donal M O'Sullivan, Deepti Angra
Vicia faba L, is a globally important grain legume whose main centers of diversity are the Fertile Crescent and Mediterranean basin. Because of its small number (six) of exceptionally large and easily observed chromosomes it became a model species for plant cytogenetics the 70s and 80s. It is somewhat ironic therefore, that the emergence of more genomically tractable model plant species such as Arabidopsis and Medicago coincided with a marked decline in genome research on the formerly favored plant cytogenetic model...
2016: Frontiers in Genetics
https://www.readbyqxmd.com/read/27597652/treatment-of-inflammatory-arthritis-via-targeting-of-tristetraprolin-a-master-regulator-of-pro-inflammatory-gene-expression
#19
E A Ross, A J Naylor, J D O'Neil, T Crowley, M L Ridley, J Crowe, T Smallie, T J Tang, J D Turner, L V Norling, S Dominguez, H Perlman, N M Verrills, G Kollias, M P Vitek, A Filer, C D Buckley, J L Dean, A R Clark
OBJECTIVES: Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP...
September 5, 2016: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/27580202/improving-the-efficiency-of-molecular-replacement-by-utilizing-a-new-iterative-transform-phasing-algorithm
#20
Hongxing He, Hengrui Fang, Mitchell D Miller, George N Phillips, Wu Pei Su
An iterative transform method proposed previously for direct phasing of high-solvent-content protein crystals is employed for enhancing the molecular-replacement (MR) algorithm in protein crystallography. Target structures that are resistant to conventional MR due to insufficient similarity between the template and target structures might be tractable with this modified phasing method. Trial calculations involving three different structures are described to test and illustrate the methodology. The relationship of the approach to PHENIX Phaser-MR and MR-Rosetta is discussed...
September 1, 2016: Acta Crystallographica. Section A, Foundations and Advances
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