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https://www.readbyqxmd.com/read/29208474/caenorhabditis-elegans-as-a-model-system-for-target-identification-and-drug-screening-against-neurodegenerative-diseases
#1
REVIEW
Liang Ma, Yudan Zhao, Yuchen Chen, Biao Cheng, Anlin Peng, Kun Huang
Over the past decades, C. elegans has been widely used as a model system because of its small size, transparent body, short generation time and lifespan (~3 days and 3 weeks, respectively), completely sequenced genome and tractability to genetic manipulation. Protein misfolding and aggregation are key pathological features in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Animal models, including Caenorhabditis elegans (C...
December 2, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29200206/discovery-and-characterization-of-highly-potent-and-selective-allosteric-usp7-inhibitors
#2
Gerald Gavory, Colin R O'Dowd, Matthew D Helm, Jakub Flasz, Elias Arkoudis, Anthony Dossang, Caroline Hughes, Eamon Cassidy, Keeva McClelland, Ewa Odrzywol, Natalie Page, Oliver Barker, Hugues Miel, Timothy Harrison
Given the importance of ubiquitin-specific protease 7 (USP7) in oncogenic pathways, identification of USP7 inhibitors has attracted considerable interest. Despite substantial efforts, however, the development of validated deubiquitinase (DUB) inhibitors that exhibit drug-like properties and a well-defined mechanism of action has proven particularly challenging. In this article, we describe the identification, optimization and detailed characterization of highly potent (IC50 < 10 nM), selective USP7 inhibitors together with their less active, enantiomeric counterparts...
December 4, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29192287/next-generation-antibody-drugs-pursuit-of-the-high-hanging-fruit
#3
REVIEW
Paul J Carter, Greg A Lazar
Antibodies are the most rapidly growing drug class and have a major impact on human health, particularly in oncology, autoimmunity and chronic inflammatory diseases. Many of the best understood and most tractable cell surface and secreted targets with known roles in human diseases have been extensively exploited for antibody drug development. In this Review, we focus on emerging and novel mechanisms of action of antibodies and innovative targeting strategies that could extend their therapeutic applications, including antibody-drug conjugates, bispecific antibodies and antibody engineering to facilitate more effective delivery...
December 1, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29190638/linking-gene-dynamics-to-vascular-hyperplasia-toward-a-predictive-model-of-vein-graft-adaptation
#4
Stefano Casarin, Scott A Berceli, Marc Garbey
Reductionist approaches, where individual pieces of a process are examined in isolation, have been the mainstay of biomedical research. While these methods are effective in highly compartmentalized systems, they fail to account for the inherent plasticity and non-linearity within the signaling structure. In the current manuscript, we present the computational architecture for tracking an acute perturbation in a biologic system through a multiscale model that links gene dynamics to cell kinetics, with the overall goal of predicting tissue adaptation...
2017: PloS One
https://www.readbyqxmd.com/read/29186850/optimal-power-allocation-strategy-in-a-joint-bistatic-radar-and-communication-system-based-on-low-probability-of-intercept
#5
Chenguang Shi, Fei Wang, Sana Salous, Jianjiang Zhou
In this paper, we investigate a low probability of intercept (LPI)-based optimal power allocation strategy for a joint bistatic radar and communication system, which is composed of a dedicated transmitter, a radar receiver, and a communication receiver. The joint system is capable of fulfilling the requirements of both radar and communications simultaneously. First, assuming that the signal-to-noise ratio (SNR) corresponding to the target surveillance path is much weaker than that corresponding to the line of sight path at radar receiver, the analytically closed-form expression for the probability of false alarm is calculated, whereas the closed-form expression for the probability of detection is not analytically tractable and is approximated due to the fact that the received signals are not zero-mean Gaussian under target presence hypothesis...
November 25, 2017: Sensors
https://www.readbyqxmd.com/read/29177500/cerebrovascular-abnormalities-in-alzheimer-s-dementia-a-more-tractable-treatment-target
#6
Hugh S Markus
No abstract text is available yet for this article.
July 1, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29167338/inhibition-of-cytosolic-phospholipase-a2%C3%AE-impairs-an-early-step-of-coronavirus-replication-in-cell-culture
#7
Christin Müller, Martin Hardt, Dominik Schwudke, Benjamin W Neuman, Stephan Pleschka, John Ziebuhr
Coronavirus replication is associated with intracellular membrane rearrangements in infected cells, resulting in the formation of double membrane vesicles (DMV) and other membranous structures that are referred to as replicative organelles (RO). The latter provide a structural scaffold for viral replication/transcription complexes (RTC) and help to sequester RTC components from recognition by cellular factors involved in antiviral host responses. There is increasing evidence that plus-strand (+) RNA virus replication, including RO formation and virion morphogenesis, affects cellular lipid metabolism and critically depends on enzymes involved in lipid synthesis and processing...
November 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29155208/inflammatory-renin-angiotensin-system-disruption-attenuates-sensory-hyperinnervation-and-mechanical-hypersensitivity-in-a-rat-model-of-provoked-vestibulodynia
#8
Anuradha Chakrabarty, Zhaohui Liao, Ying Mu, Peter G Smith
Vestibulodynia is characterized by peri-vaginal mechanical hypersensitivity, hyperinnervation, and abundant inflammatory cells expressing renin-angiotensin system proteins. We developed a tractable rat model of vestibulodynia to further assess the contributions of the renin-angiotensin system. Complete Freund's adjuvant (CFA) injected into the posterior vestibule induced marked vestibular hypersensitivity throughout a 7-day test period. Numbers of axons immunoreactive for PGP9.5, calcitonin gene-related peptide, and GFRα2 were increased...
November 15, 2017: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/29155068/a-noncanonical-poly-a-rna-polymerase-gene-affects-morphology-in-phoma-medicaginis
#9
Kihyuck Choi, Stephen M Marek
Phoma medicaginis (syn. Ascochyta medicaginicola Qchen &L. Cai) causes spring black stem and leaf spot, an important disease of alfalfa and annual medics. P. medicaginis forms uninucleate conidia in melanized pycnidia and is genetically tractable using Agrobacterium mediated transformation (ATMT), resulting in random integration of T-DNA that occasionally generates pycnidial mutants. The T-DNA tagged mutant, P265 displayed smaller pycnidia and more aerial hyphae than the wild type. A single T-DNA disrupted a putative noncanonical poly(A) RNA polymerase gene, Pmncpap1, which in yeast interacts with ribonucleotide reductase (RNR)...
November 15, 2017: Fungal Genetics and Biology: FG & B
https://www.readbyqxmd.com/read/29152050/consequences-of-depsipeptide-substitution-on-the-clpp-activation-activity-of-antibacterial-acyldepsipeptides
#10
Yangxiong Li, Nathan P Lavey, Jesse A Coker, Jessica E Knobbe, Dat C Truong, Hongtao Yu, Yu-Shan Lin, Susan L Nimmo, Adam S Duerfeldt
The acyldepsipeptide (ADEP) antibiotics operate through a clinically unexploited mechanism of action and thus have attracted attention from several antibacterial development groups. The ADEP scaffold is synthetically tractable, and deep-seated modifications have produced extremely potent antibacterial leads against Gram-positive pathogens. Although newly identified ADEP analogs demonstrate remarkable antibacterial activity against bacterial isolates and in mouse models of bacterial infections, stability issues pertaining to the depsipeptide core remain...
November 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29148850/atad2-in-cancer-a-pharmacologically-challenging-but-tractable-target
#11
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/29134959/targeting-ret-driven-cancers-lessons-from-evolving-preclinical-and-clinical-landscapes
#12
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/29131570/identification-and-characterisation-of-dual-inhibitors-of-the-usp25-28-deubiquitinating-enzyme-subfamily
#13
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
#14
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
#15
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/29118093/current-perspectives-in-fragment-based-lead-discovery-fbld
#16
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
#17
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/29109267/protein-engineering-of-the-chemokine-ccl20-prevents-psoriasiform-dermatitis-in-an-il-23-dependent-murine-model
#18
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/29107557/boundary-formation-through-a-direct-threshold-based-readout-of-mobile-small-rna-gradients
#19
Damianos S Skopelitis, Anna H Benkovics, Aman Y Husbands, Marja C P Timmermans
Small RNAs have emerged as a new class of mobile signals. Here, we investigate their mechanism of action and show that mobile small RNAs generate sharply defined domains of target gene expression through an intrinsic and direct threshold-based readout of their mobility gradients. This readout is highly sensitive to small RNA levels at the source, allowing plasticity in the positioning of a target gene expression boundary. Besides patterning their immediate targets, the readouts of opposing small RNA gradients enable specification of robust, uniformly positioned developmental boundaries...
November 6, 2017: Developmental Cell
https://www.readbyqxmd.com/read/29107183/therapeutic-targeting-of-pp2a
#20
REVIEW
Caitlin M O'Connor, Abbey Perl, Daniel Leonard, Jaya Sangodkar, Goutham Narla
Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that regulates many cellular processes. Given the central role of PP2A in regulating diverse biological functions and its dysregulation in many diseases, including cancer, PP2A directed therapeutics have become of great interest. The main approaches leveraged thus far can be categorized as follows: 1) inhibiting endogenous inhibitors of PP2A, 2) targeted disruption of post translational modifications on PP2A subunits, or 3) direct targeting of PP2A...
October 26, 2017: International Journal of Biochemistry & Cell Biology
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