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https://www.readbyqxmd.com/read/29148850/atad2-in-cancer-a-pharmacologically-challenging-but-tractable-target
#1
Muzammal Hussain, Yang Zhou, Yu Song, H M Adnan Hameed, Hao Jiang, Yaoquan Tu, Jiancun Zhang
ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have validated it as a compelling drug target for future therapeutic development, recent druggability assessment data suggest that direct targeting of ATAD2's bromodomain (BRD) may be a very challenging task. ATAD2's BRD has been predicted as a "difficult to drug" or "least druggable" target due to the concern that its binding pocket, and the areas around it, seem to be unfeasible for ligand binding...
November 17, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29136190/the-genotype-phenotype-relationships-in-the-light-of-natural-selection
#2
Han Chen, Chung-I Wu, Xionglei He
Although any genotype-phenotype relationships are a result of evolution, little is known about how natural selection and neutral drift, two distinct driving forces of evolution, operate to shape the relationships. By analysing ∼500 yeast quantitative traits we reveal a basic "supervisor-worker" gene architecture underlying a trait. Supervisors are often identified by "perturbational" approaches (such as gene deletion), while workers, which usually show small and statistically insignificant deletion effects, are tracked primarily by "observational" approaches that examine the correlation between gene activity and trait value across a number of conditions...
November 9, 2017: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/29135990/curcumin-affects-gene-expression-and-reactive-oxygen-species-via-a-pka-dependent-mechanism-in-dictyostelium-discoideum
#3
William S Swatson, Mariko Katoh-Kurasawa, Gad Shaulsky, Stephen Alexander
Botanicals are widely used as dietary supplements and for the prevention and treatment of disease. Despite a long history of use, there is generally little evidence supporting the efficacy and safety of these preparations. Curcumin has been used to treat a myriad of human diseases and is widely advertised and marketed for its ability to improve health, but there is no clear understanding how curcumin interacts with cells and affects cell physiology. D. discoideum is a simple eukaryotic lead system that allows both tractable genetic and biochemical studies...
2017: PloS One
https://www.readbyqxmd.com/read/29134959/targeting-ret-driven-cancers-lessons-from-evolving-preclinical-and-clinical-landscapes
#4
REVIEW
Alexander Drilon, Zishuo I Hu, Gillianne G Y Lai, Daniel S W Tan
The gene encoding the receptor-tyrosine kinase RET was first discovered more than three decades ago, and activating RET rearrangements and mutations have since been identified as actionable drivers of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, and confirmed responses to targeted therapy with these agents have been observed in patients with RET-rearranged lung cancers or RET-mutant thyroid cancers. Nevertheless, response rates to RET-directed therapy are modest compared with those achieved using targeted therapies matched to other oncogenic drivers of solid tumours, such as sensitizing EGFR or BRAF(V600E) mutations, or ALK or ROS1 rearrangements...
November 14, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29133621/the-mutational-landscape-of-gastrointestinal-malignancies-as-reflected-by-circulating-tumor-dna
#5
Paul Riviere, Paul T Fanta, Sadakatsu Ikeda, Joel Baumgartner, Gregory M Heestand, Razelle Kurzrock
We aimed to assess the utility of a novel, non-invasive method of detecting genomic alterations in patients with gastrointestinal malignancies i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma (N=55 (26%)), appendiceal adenocarcinoma (N=46 (22%)), hepatocellular carcinoma (N=31 (15%)), and pancreatic ductal adenocarcinoma (N=25 (12%))...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29131817/characterizing-steady-states-of-genome-scale-metabolic-networks-in-continuous-cell-cultures
#6
Jorge Fernandez-de-Cossio-Diaz, Kalet Leon, Roberto Mulet
In the continuous mode of cell culture, a constant flow carrying fresh media replaces culture fluid, cells, nutrients and secreted metabolites. Here we present a model for continuous cell culture coupling intra-cellular metabolism to extracellular variables describing the state of the bioreactor, taking into account the growth capacity of the cell and the impact of toxic byproduct accumulation. We provide a method to determine the steady states of this system that is tractable for metabolic networks of arbitrary complexity...
November 13, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/29131570/identification-and-characterisation-of-dual-inhibitors-of-the-usp25-28-deubiquitinating-enzyme-subfamily
#7
Jonathan D Wrigley, Gerald Gavory, Iain Simpson, Marian Preston, Helen Plant, Jenna Bradley, Anne U Goeppert, Ewelina Rozycka, Gareth Davies, Jarrod Walsh, Andrea Valentine, Keeva McClelland, Krzysztofa Ewa Odrzywol, Jonathan Renshaw, Joanna Boros, Jonathan Tart, Lindsey Leach, Thorsten Nowak, Richard A Ward, Timothy Harrison, David M Andrews
The Ubiquitin Proteasome System is widely postulated to be a new and important field of drug discovery for the future, with the Ubiquitin Specific Proteases (USP) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to target this so far undruggable oncogene. Here we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and whilst displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases...
November 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29130360/autophagy-and-innate-immunity-insights-from-invertebrate-model-organisms
#8
Cheng-Ju Kuo, Malene Hansen, Emily Troemel
Macroautophagy/autophagy is a fundamental intracellular degradation process with multiple roles in immunity, including direct elimination of intracellular microorganisms via 'xenophagy.' In this review, we summarize studies from the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans that highlight the roles of autophagy in innate immune responses to viral, bacterial, and fungal pathogens. Research from these genetically tractable invertebrates has uncovered several conserved immunological paradigms, such as direct targeting of intracellular pathogens by xenophagy and regulation of autophagy by pattern recognition receptors in D...
November 13, 2017: Autophagy
https://www.readbyqxmd.com/read/29127686/the-challenge-of-modeling-protein-assemblies-the-casp12-capri-experiment
#9
Marc F Lensink, Sameer Velankar, Minkyung Baek, Lim Heo, Chaok Seok, Shoshana J Wodak
We present the quality assessment of 5613 models submitted by predictor groups from both CAPRI and CASP for the total of 15 most tractable targets from the second joint CASP-CAPRI protein assembly prediction experiment. These targets comprised 12 homo-oligomers and 3 hetero-complexes. The bulk of the analysis focuses on 10 targets (of CAPRI Round 37), which included all 3 hetero-complexes, and whose protein chains or the full assembly could be readily modeled from structural templates in the PDB. On average, 28 CAPRI groups and 10 CASP groups (including automatic servers), submitted models for each of these 10 targets...
November 10, 2017: Proteins
https://www.readbyqxmd.com/read/29127664/larvalign-aligning-gene-expression-patterns-from-the-larval-brain-of-drosophila-melanogaster
#10
Sascha E A Muenzing, Martin Strauch, James W Truman, Katja Bühler, Andreas S Thum, Dorit Merhof
The larval brain of the fruit fly Drosophila melanogaster is a small, tractable model system for neuroscience. Genes for fluorescent marker proteins can be expressed in defined, spatially restricted neuron populations. Here, we introduce the methods for 1) generating a standard template of the larval central nervous system (CNS), 2) spatial mapping of expression patterns from different larvae into a reference space defined by the standard template. We provide a manually annotated gold standard that serves for evaluation of the registration framework involved in template generation and mapping...
November 10, 2017: Neuroinformatics
https://www.readbyqxmd.com/read/29126246/bringing-numerous-methods-for-expression-and-promoter-analysis-to-a-public-cloud-computing-service
#11
Krzysztof Polanski, Bo Gao, Sam A Mason, Paul Brown, Sascha Ott, Katherine J Denby, David L Wild
Summary: Every year, a large number of novel algorithms are introduced to the scientific community for a myriad of applications, but using these across different research groups is often troublesome, due to suboptimal implementations and specific dependency requirements. This does not have to be the case, as public cloud computing services can easily house tractable implementations within self-contained dependency environments, making the methods easily accessible to a wider public. We have taken 14 popular methods, the majority related to expression data or promoter analysis, developed these up to a good implementation standard and housed the tools in isolated Docker containers which we integrated into the CyVerse Discovery Environment, making these easily usable for a wide community as part of the CyVerse UK project...
November 6, 2017: Bioinformatics
https://www.readbyqxmd.com/read/29122032/a-sentimental-education-the-place-of-sentiments-in-personality-and-social-psychology
#12
Nick Haslam
"Sentiment" is a potentially appealing concept for social and personality psychologists. It can render some complex affective phenomena theoretically tractable, help refine accounts of social perception, and illuminate some personality dispositions. The success of a future sentimental psychology depends on whether "sentiment" can be delimited as a distinct domain, and whether a credible classification of sentiments can be developed.
January 2017: Behavioral and Brain Sciences
https://www.readbyqxmd.com/read/29120516/carbon-cycle-confidence-and-uncertainty-exploring-variation-among-soil-biogeochemical-models
#13
William R Wieder, Melannie D Hartman, Benjamin Sulman, Ying-Ping Wang, Charles D Koven, Gordon B Bonan
Emerging insights into factors responsible for soil organic matter stabilization and decomposition are being applied in a variety of contexts, but new tools are needed to facilitate the understanding, evaluation and improvement of soil biogeochemical theory and models at regional to global scales. To isolate the effects of model structural uncertainty on the global distribution of soil carbon stocks and turnover times we developed a soil biogeochemical testbed that forces three different soil models with consistent climate and plant productivity inputs...
November 9, 2017: Global Change Biology
https://www.readbyqxmd.com/read/29118348/frontal-theta-activation-during-motor-synchronization-in-autism
#14
Masahiro Kawasaki, Keiichi Kitajo, Kenjiro Fukao, Toshiya Murai, Yoko Yamaguchi, Yasuko Funabiki
Autism is characterized by two primary characteristics: deficits in social interaction and repetitive behavioral patterns. Because interpersonal communication is extremely complicated, its underlying brain mechanisms remain unclear. Here we showed that both characteristics can be explained by a unifying underlying mechanism related to difficulties with irregularities. To address the issues, we measured electroencephalographm during a cooperative tapping task, which required participants to tap a key alternately and synchronously with constant rhythmic a PC program, a variable rhythmic PC program, or a human partner...
November 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29118093/current-perspectives-in-fragment-based-lead-discovery-fbld
#15
REVIEW
Bas Lamoree, Roderick E Hubbard
It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most 'conventional' targets in drug discovery such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, such as disruption of protein-protein interactions. The main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. In this essay, we overview current practice in the methods and discuss how they have had an impact in lead discovery - generating a large number of fragment-derived compounds that are in clinical trials and two medicines treating patients...
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29111116/coevolution-takes-the-sting-out-of-it-evolutionary-biology-and-mechanisms-of-toxin-resistance-in-animals
#16
REVIEW
Kevin Arbuckle, Ricardo C Rodríguez de la Vega, Nicholas R Casewell
Understanding how biotic interactions shape the genomes of the interacting species is a long-sought goal of evolutionary biology that has been hampered by the scarcity of tractable systems in which specific genomic features can be linked to complex phenotypes involved in interspecific interactions. In this review we present the compelling case of evolved resistance to the toxic challenge of venomous or poisonous animals as one such system. Animal venoms and poisons can be comprised of few or of many individual toxins...
October 27, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/29109478/a-bacterial-pioneer-produces-cellulase-complexes-that-persist-through-community-succession
#17
Sebastian Kolinko, Yu-Wei Wu, Firehiwot Tachea, Evelyn Denzel, Jennifer Hiras, Raphael Gabriel, Nora Bäcker, Leanne Jade G Chan, Stephanie A Eichorst, Dario Frey, Qiushi Chen, Parastoo Azadi, Paul D Adams, Todd R Pray, Deepti Tanjore, Christopher J Petzold, John M Gladden, Blake A Simmons, Steven W Singer
Cultivation of microbial consortia provides low-complexity communities that can serve as tractable models to understand community dynamics. Time-resolved metagenomics demonstrated that an aerobic cellulolytic consortium cultivated from compost exhibited community dynamics consistent with the definition of an endogenous heterotrophic succession. The genome of the proposed pioneer population, 'Candidatus Reconcilibacillus cellulovorans', possessed a gene cluster containing multidomain glycoside hydrolases (GHs)...
November 6, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/29109294/key-amino-acid-residues-conferring-enhanced-enzyme-activity-at-cold-temperatures-in-an-antarctic-polyextremophilic-%C3%AE-galactosidase
#18
Victoria J Laye, Ram Karan, Jong-Myoung Kim, Wolf T Pecher, Priya DasSarma, Shiladitya DasSarma
The Antarctic microorganism Halorubrum lacusprofundi harbors a model polyextremophilic β-galactosidase that functions in cold, hypersaline conditions. Six amino acid residues potentially important for cold activity were identified by comparative genomics and substituted with evolutionarily conserved residues (N251D, A263S, I299L, F387L, I476V, and V482L) in closely related homologs from mesophilic haloarchaea. Using a homology model, four residues (N251, A263, I299, and F387) were located in the TIM barrel around the active site in domain A, and two residues (I476 and V482) were within coiled or β-sheet regions in domain B distant to the active site...
November 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29109267/protein-engineering-of-the-chemokine-ccl20-prevents-psoriasiform-dermatitis-in-an-il-23-dependent-murine-model
#19
A E Getschman, Y Imai, O Larsen, F C Peterson, X Wu, M M Rosenkilde, S T Hwang, B F Volkman
Psoriasis is a chronic inflammatory skin disease characterized by the infiltration of T cell and other immune cells to the skin in response to injury or autoantigens. Conventional, as well as unconventional, γδ T cells are recruited to the dermis and epidermis by CCL20 and other chemokines. Together with its receptor CCR6, CCL20 plays a critical role in the development of psoriasiform dermatitis in mouse models. We screened a panel of CCL20 variants designed to form dimers stabilized by intermolecular disulfide bonds...
November 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29108019/stochastic-loss-and-gain-of-symmetric-divisions-in-the-c-elegans-epidermis-perturbs-robustness-of-stem-cell-number
#20
Dimitris Katsanos, Sneha L Koneru, Lamia Mestek Boukhibar, Nicola Gritti, Ritobrata Ghose, Peter J Appleford, Maria Doitsidou, Alison Woollard, Jeroen S van Zon, Richard J Poole, Michalis Barkoulas
Biological systems are subject to inherent stochasticity. Nevertheless, development is remarkably robust, ensuring the consistency of key phenotypic traits such as correct cell numbers in a certain tissue. It is currently unclear which genes modulate phenotypic variability, what their relationship is to core components of developmental gene networks, and what is the developmental basis of variable phenotypes. Here, we start addressing these questions using the robust number of Caenorhabditis elegans epidermal stem cells, known as seam cells, as a readout...
November 2017: PLoS Biology
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