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https://www.readbyqxmd.com/read/28346812/identification-of-a-novel-benzimidazole-pyrazolone-scaffold-that-inhibits-kdm4-lysine-demethylases-and-reduces-proliferation-of-prostate-cancer-cells
#1
David M Carter, Edgar Specker, Jessica Przygodda, Martin Neuenschwander, Jens Peter von Kries, Udo Heinemann, Marc Nazaré, Ulrich Gohlke
Human lysine demethylase (KDM) enzymes (KDM1-7) constitute an emerging class of therapeutic targets, with activities that support growth and development of metastatic disease. By interacting with and co-activating the androgen receptor, the KDM4 subfamily (KDM4A-E) promotes aggressive phenotypes of prostate cancer (PCa). Knockdown of KDM4 expression or inhibition of KDM4 enzyme activity reduces the proliferation of PCa cell lines and highlights inhibition of lysine demethylation as a possible therapeutic method for PCa treatment...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346092/screening-for-protein-protein-interaction-inhibitors-using-a-bioluminescence-resonance-energy-transfer-bret-based-assay-in-yeast
#2
Caroline Corbel, Sara Sartini, Elisabetta Levati, Pierre Colas, Laurent Maillet, Cyril Couturier, Barbara Montanini, Stéphane Bach
The bioluminescence resonance energy transfer (BRET) technology is a widely used live cell-based method for monitoring protein-protein interactions as well as conformational changes within proteins or molecular complexes. Considering the emergence of protein-protein interactions as a new promising class of therapeutic targets, we have adapted the BRET method in budding yeast. In this technical note, we describe the advantages of using this simple eukaryotic model rather than mammalian cells to perform high-throughput screening of chemical compound collections: genetic tractability, tolerance to solvent, rapidity, and no need of expensive robotic systems...
January 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28340538/development-of-high-throughput-screening-assay-for-antihantaviral-therapeutics
#3
Anuradha Roy, Mohammad A Mir
Humans acquire hantavirus infection by the inhalation of aerosolized excreta of infected rodent hosts. There is no treatment for hantavirus diseases at present. Therapeutic intervention during early stages of viral infection can improve the outcome of this zoonotic viral illness. The interaction between an evolutionary conserved sequence at the 5' terminus of hantaviral genomic RNA and hantavirus nucleocapsid protein plays a critical role in the hantavirus replication cycle. This unique interaction is a novel target for therapeutic intervention of hantavirus disease...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28327571/insights-from-early-experience-of-a-rare-disease-genomic-medicine-multidisciplinary-team-a-qualitative-study
#4
Elizabeth Ormondroyd, Michael P Mackley, Edward Blair, Jude Craft, Julian C Knight, John Taylor, Jenny C Taylor, Andrew Om Wilkie, Hugh Watkins
Whole-exome/whole-genome sequencing (WES/WGS) has the potential to enhance genetic diagnosis of rare disease, and is increasingly becoming part of routine clinical care in mainstream medicine. Effective translation will require ongoing efforts in a number of areas including: selection of appropriate patients, provision of effective consent, pre- and post-test genetic counselling, improving variant interpretation algorithms and practices, and management of secondary findings including those found incidentally and those actively sought...
March 22, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28299743/computational-approaches-to-matrix-metalloprotease-drug-design
#5
Tanya Singh, B Jayaram, Olayiwola Adedotun Adekoya
Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes required for homeostasis. These enzymes are an important class of drug targets as their over expression is associated with many disease states. Most of the inhibitors reported against this class of proteins have failed in clinical trials due to lack of specificity. In order to assist in drug design endeavors for MMP targets, a computationally tractable pathway is presented, comprising, (1) docking of small molecule inhibitors against the target MMPs, (2) derivation of quantum mechanical charges on the zinc ion in the active site and the amino acids coordinating with zinc including the inhibitor molecule, (3) molecular dynamics simulations on the docked ligand-MMP complexes, and (4) evaluation of binding affinities of the ligand-MMP complexes via an accurate scoring function for zinc containing metalloprotein-ligand complexes...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28288121/a-genetic-system-to-study-plasmodium-falciparum-protein-function
#6
Jakob Birnbaum, Sven Flemming, Nick Reichard, Alexandra Blancke Soares, Paolo Mesén-Ramírez, Ernst Jonscher, Bärbel Bergmann, Tobias Spielmann
Current systems to study essential genes in the human malaria parasite Plasmodium falciparum are often inefficient and time intensive, and they depend on the genetic modification of the target locus, a process hindered by the low frequency of integration of episomal DNA into the genome. Here, we introduce a method, termed selection-linked integration (SLI), to rapidly select for genomic integration. SLI allowed us to functionally analyze targets at the gene and protein levels, thus permitting mislocalization of native proteins, a strategy known as knock sideways, floxing to induce diCre-based excision of genes and knocking in altered gene copies...
March 13, 2017: Nature Methods
https://www.readbyqxmd.com/read/28257444/mechanisms-of-fast-and-stringent-search-in-homologous-pairing-of-double-stranded-dna
#7
Amir Bitran, Wei-Yin Chiang, Erel Levine, Mara Prentiss
Self-organization in the cell relies on the rapid and specific binding of molecules to their cognate targets. Correct bindings must be stable enough to promote the desired function even in the crowded and fluctuating cellular environment. In systems with many nearly matched targets, rapid and stringent formation of stable products is challenging. Mechanisms that overcome this challenge have been previously proposed, including separating the process into multiple stages; however, how particular in vivo systems overcome the challenge remains unclear...
March 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28252202/a-mouse-model-for-ocular-surface-staphylococcus-aureus-infection
#8
Zhiyong Zhang, Osama Abdel-Razek, Guirong Wang
Creation of an appropriate animal model that accurately reflects the disease and host immune response to bacterial infection in humans is a major challenge in ocular-surface infection research. For decades, mice have been the ideal small animal model for ocular-surface infection research because of the availability and relatively low cost of various genetic backgrounds, targeted defects, and immunologic reagents. By employing different combinations of mouse and bacterial strains, murine infection models can be used to explore a complete picture of bacterial infection and innate immunity of the ocular surface...
March 2, 2017: Current Protocols in Mouse Biology
https://www.readbyqxmd.com/read/28212080/improving-registration-robustness-for-image-guided-liver-surgery-in-a-novel-human-to-phantom-data-framework
#9
Jarrod Collins, Jared Weis, Jon Heiselman, Logan Clements, Amber Simpson, Willam Jarnagin, Michael Miga
In open image-guided liver surgery (IGLS), a sparse representation of the intraoperative organ surface can be acquired to drive image-to-physical registration. We hypothesize that uncharacterized error induced by variation in the collection patterns of organ surface data limits the accuracy and robustness of IGLS registration. Clinical validation of such registration methods is challenged due to the difficulty in obtaining data representative of the true state of organ deformation. We propose a novel human-to-phantom validation framework that transforms surface collection patterns from in vivo IGLS procedures (n=13) onto a well-characterized hepatic deformation phantom for the purpose of validating surface-driven, volumetric nonrigid registration methods...
February 13, 2017: IEEE Transactions on Medical Imaging
https://www.readbyqxmd.com/read/28202661/targeting-pak1
#10
REVIEW
Galina Semenova, Jonathan Chernoff
p21-Activated kinase 1 (PAK1) has attracted much attention as a potential therapeutic target due to its central role in many oncogenic signaling pathways, its frequent dysregulation in cancers and neurological disorders, and its tractability as a target for small-molecule inhibition. To date, several PAK1-targeting compounds have been developed as preclinical agents, including one that has been evaluated in a clinical trial. A series of ATP-competitive inhibitors, allosteric inhibitors and peptide inhibitors with distinct biochemical and pharmacokinetic properties represent useful laboratory tools for studies on the role of PAK1 in biology and in disease contexts, and could lead to promising therapeutic agents...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28186211/controlling-the-network-type-in-self-assembled-dipeptide-hydrogels
#11
Catherine Colquhoun, Emily R Draper, Ralf Schweins, Marco Marcello, Devkee Vadukul, Louise C Serpell, Dave J Adams
We show that the same low molecular weight gelator can form gels using three different methods. Gels were formed from a high pH solution either by adding a salt or by adding an acid; gels were also formed by adding water to a solution of the gelator in an organic solvent. The mechanical properties for the gels formed by the different methods are different from one another. We link this to the network type that is formed, as well as the fibrous structures that are formed. The salt-triggered gels show a significant number of fibres that tend to align...
February 10, 2017: Soft Matter
https://www.readbyqxmd.com/read/28163917/mitochondrial-mutations-and-metabolic-adaptation-in-pancreatic-cancer
#12
Rae-Anne Hardie, Ellen van Dam, Mark Cowley, Ting-Li Han, Seher Balaban, Marina Pajic, Mark Pinese, Mary Iconomou, Robert F Shearer, Jessie McKenna, David Miller, Nicola Waddell, John V Pearson, Sean M Grimmond, Leonid Sazanov, Andrew V Biankin, Silas Villas-Boas, Andrew J Hoy, Nigel Turner, Darren N Saunders
BACKGROUND: Pancreatic cancer has a five-year survival rate of ~8%, with characteristic molecular heterogeneity and restricted treatment options. Targeting metabolism has emerged as a potentially effective therapeutic strategy for cancers such as pancreatic cancer, which are driven by genetic alterations that are not tractable drug targets. Although somatic mitochondrial genome (mtDNA) mutations have been observed in various tumors types, understanding of metabolic genotype-phenotype relationships is limited...
2017: Cancer & Metabolism
https://www.readbyqxmd.com/read/28135089/the-emergence-of-small-molecule-non-rgd-mimetic-inhibitors-for-rgd-integrins
#13
Lisa M Miller, John M Pritchard, Simon J F Macdonald, Craig Jamieson, Allan J B Watson
The RGD integrins are recognized therapeutic targets for thrombosis, fibrosis, and cancer, amongst others. Current inhibitors are designed to mimic the tripeptide sequence (arginine-glycine-aspartic acid) of the natural ligands; however, the RGD-mimetic antagonists for αIIbβ3 have been shown to cause partial agonism, leading to the opposite pharmacological effect. The challenge of obtaining oral activity and synthetic tractability with RGD-mimetic molecules, along with the issues relating to pharmacology, has left integrin-therapeutics in need of a new strategy...
January 30, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28130450/rab8a-recruited-pi3k%C3%AE-regulates-signaling-and-cytokine-outputs-from-endosomal-toll-like-receptors
#14
Adam A Wall, Lin Luo, Yu Hung, Samuel J Tong, Nicholas D Condon, Antje Blumenthal, Matthew J Sweet, Jennifer L Stow
Lipopolysaccharide (LPS)-mediated activation of Toll-like receptor 4 (TLR4) in macrophages results in the coordinated release of proinflammatory cytokines, followed by regulatory mediators, to ensure that this potentially destructive pathway is tightly regulated. We previously showed that Rab8a recruits PI3Kγ for Akt-dependent signaling during TLR4 activation to limit the production of the pro-inflammatory cytokines IL-6 and IL-12p40, while enhancing the release of the regulatory/anti-inflammatory cytokine IL-10...
January 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28128944/design-and-elaboration-of-a-tractable-tricyclic-scaffold-to-synthesize-druglike-inhibitors-of-dipeptidyl-peptidase-4-dpp-4-antagonists-of-the-c-c-chemokine-receptor-type-5-ccr5-and-highly-potent-and-selective-phosphoinositol-3-kinase-%C3%AE-pi3k%C3%AE-inhibitors
#15
Carolin Schwehm, Barrie Kellam, Aimie E Garces, Stephen J Hill, Nicholas D Kindon, Tracey D Bradshaw, Jin Li, Simon J F Macdonald, James E Rowedder, Leigh A Stoddart, Michael J Stocks
A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs...
February 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28107502/rnai-based-functional-genomics-identifies-new-virulence-determinants-in-mucormycosis
#16
Trung Anh Trieu, María Isabel Navarro-Mendoza, Carlos Pérez-Arques, Marta Sanchis, Javier Capilla, Patricia Navarro-Rodriguez, Loida Lopez-Fernandez, Santiago Torres-Martínez, Victoriano Garre, Rosa María Ruiz-Vázquez, Francisco E Nicolás
Mucorales are an emerging group of human pathogens that are responsible for the lethal disease mucormycosis. Unfortunately, functional studies on the genetic factors behind the virulence of these organisms are hampered by their limited genetic tractability, since they are reluctant to classical genetic tools like transposable elements or gene mapping. Here, we describe an RNAi-based functional genomic platform that allows the identification of new virulence factors through a forward genetic approach firstly described in Mucorales...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28106166/rapid-generation-of-hypomorphic-mutations
#17
Laura L Arthur, Joyce J Chung, Preetam Jankirama, Kathryn M Keefer, Igor Kolotilin, Slavica Pavlovic-Djuranovic, Douglas L Chalker, Vojislava Grbic, Rachel Green, Rima Menassa, Heather L True, James B Skeath, Sergej Djuranovic
Hypomorphic mutations are a valuable tool for both genetic analysis of gene function and for synthetic biology applications. However, current methods to generate hypomorphic mutations are limited to a specific organism, change gene expression unpredictably, or depend on changes in spatial-temporal expression of the targeted gene. Here we present a simple and predictable method to generate hypomorphic mutations in model organisms by targeting translation elongation. Adding consecutive adenosine nucleotides, so-called polyA tracks, to the gene coding sequence of interest will decrease translation elongation efficiency, and in all tested cell cultures and model organisms, this decreases mRNA stability and protein expression...
January 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/28096221/efficient-crispr-cas9-assisted-gene-targeting-enables-rapid-and-precise-genetic-manipulation-of-mammalian-neural-stem-cells
#18
Raul Bardini Bressan, Pooran Singh Dewari, Maria Kalantzaki, Ester Gangoso, Mantas Matjusaitis, Claudia Garcia-Diaz, Carla Blin, Vivien Grant, Harry Bulstrode, Sabine Gogolok, William C Skarnes, Steven M Pollard
Mammalian neural stem cell (NSC) lines provide a tractable model for discovery across stem cell and developmental biology, regenerative medicine and neuroscience. They can be derived from foetal or adult germinal tissues and continuously propagated in vitro as adherent monolayers. NSCs are clonally expandable, genetically stable, and easily transfectable - experimental attributes compatible with targeted genetic manipulations. However, gene targeting, which is crucial for functional studies of embryonic stem cells, has not been exploited to date in NSC lines...
February 15, 2017: Development
https://www.readbyqxmd.com/read/28087712/pdx1-dynamically-regulates-pancreatic-ductal-adenocarcinoma-initiation-and-maintenance
#19
Nilotpal Roy, Kenneth K Takeuchi, Jeanine M Ruggeri, Peter Bailey, David Chang, Joey Li, Laura Leonhardt, Sapna Puri, Megan T Hoffman, Shan Gao, Christopher J Halbrook, Yan Song, Mats Ljungman, Shivani Malik, Christopher V E Wright, David W Dawson, Andrew V Biankin, Matthias Hebrok, Howard C Crawford
Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA...
December 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/28087534/mechanisms-of-horizontal-cell-to-cell-transfer-of-wolbachia-spp-in-drosophila-melanogaster
#20
Pamela M White, Jose E Pietri, Alain Debec, Shelbi Russell, Bhavin Patel, William Sullivan
Wolbachia is an intracellular endosymbiont present in most arthropod and filarial nematode species. Transmission between hosts is primarily vertical, taking place exclusively through the female germline, though horizontal transmission has also been documented. Several studies indicate that Wolbachia is capable of transfer between somatic and germline cells during nematode development and in adult flies. However, the mechanisms underlying horizontal cell-to-cell transfer remain largely unexplored. Here, we establish a tractable system for probing horizontal transfer of Wolbachia between Drosophila cells in culture using fluorescence in situ hybridization (FISH)...
January 13, 2017: Applied and Environmental Microbiology
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