Articles de revues : « Screening, Signalling »

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Jeong-Yoo Kim. « Signalling and Screening of Harsh Religious Norms ». Journal of Social Science 41, n^o 3 (décembre 2015) : 103–16. http://dx.doi.org/10.15820/khjss.2015.41.3.005.

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Wolff, Michael, Simone Krede, Dorothea Haasen, Jorg Wiedenmann, G. Nienhaus, Barbara Kistler, Franz Oswald et Ralf Heilker. « High Content Screening of CXCR2-Dependent Signalling Pathways ». Combinatorial Chemistry & ; High Throughput Screening 13, n^o 1 (1 janvier 2010) : 3–15. http://dx.doi.org/10.2174/138620710790218249.

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Chu, Wujin. « Demand Signalling and Screening in Channels of Distribution ». Marketing Science 11, n^o 4 (novembre 1992) : 327–47. http://dx.doi.org/10.1287/mksc.11.4.327.

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Antelo, Manel. « Screening and signalling for technology licensing : a comparison ». R&D Management 42, n^o 4 (27 août 2012) : 289–302. http://dx.doi.org/10.1111/j.1467-9310.2012.00684.x.

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Mori, Takayasu, Eriko Kikuchi, Yuko Watanabe, Shinya Fujii, Mari Ishigami-Yuasa, Hiroyuki Kagechika, Eisei Sohara, Tatemitsu Rai, Sei Sasaki et Shinichi Uchida. « Chemical library screening for WNK signalling inhibitors using fluorescence correlation spectroscopy ». Biochemical Journal 455, n^o 3 (10 octobre 2013) : 339–45. http://dx.doi.org/10.1042/bj20130597.

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To discover WNK–OSR1/SPAK signalling inhibitors, we generated a new high-throughput system using fluorescent correlation spectroscopy capable of screening compounds that disrupt the binding of two molecules. We finally identified two novel and promising compounds for WNK–OSR1/SPAK signalling inhibition.

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Dosis, Anastasios. « On signalling and screening in markets with asymmetric information ». Journal of Mathematical Economics 75 (mars 2018) : 140–49. http://dx.doi.org/10.1016/j.jmateco.2018.01.001.

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Bassi, Vittorio, et Aisha Nansamba. « Screening and Signalling Non-Cognitive Skills : Experimental Evidence from Uganda ». Economic Journal 132, n^o 642 (1 octobre 2021) : 471–511. http://dx.doi.org/10.1093/ej/ueab071.

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Abstract We study how employers and job seekers respond to credible information on skills that are difficult to observe, and how this affects matching in the labour market. We experimentally vary whether certificates on workers’ non-cognitive skills are disclosed to both sides of the market during job interviews between young workers and small firms in Uganda. The certificates cause workers to increase their labour market expectations, while high-ability managers revise their assessments of the workers’ skills upwards. The reaction in terms of beliefs leads to an increase in positive assortative matching and to higher earnings for workers, conditional on employment.

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Fang, Qing, Fleurdeliz Maglangit, Linrui Wu, Rainer Ebel, Kwaku Kyeremeh, Jeanette H. Andersen, Frederick Annang, Guiomar Pérez-Moreno, Fernando Reyes et Hai Deng. « Signalling and Bioactive Metabolites from Streptomyces sp. RK44 ». Molecules 25, n^o 3 (22 janvier 2020) : 460. http://dx.doi.org/10.3390/molecules25030460.

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Streptomyces remains one of the prolific sources of structural diversity, and a reservoir to mine for novel natural products. Continued screening for new Streptomyces strains in our laboratory led to the isolation of Streptomyces sp. RK44 from the underexplored areas of Kintampo waterfalls, Ghana, Africa. Preliminary screening of the metabolites from this strain resulted in the characterization of a new 2-alkyl-4-hydroxymethylfuran carboxamide (AHFA) 1 together with five known compounds, cyclo-(L-Pro-Gly) 2, cyclo-(L-Pro-L-Phe) 3, cyclo-(L-Pro-L-Val) 4, cyclo-(L-Leu-Hyp) 5, and deferoxamine E 6. AHFA 1, a methylenomycin (MMF) homolog, exhibited anti-proliferative activity (EC50 = 89.6 µM) against melanoma A2058 cell lines. This activity, albeit weak is the first report amongst MMFs. Furthermore, the putative biosynthetic gene cluster (ahfa) was identified for the biosynthesis of AHFA 1. DFO-E 6 displayed potent anti-plasmodial activity (IC50 = 1.08 µM) against P. falciparum 3D7. High-resolution electrospray ionization mass spectrometry (HR ESIMS) and molecular network assisted the targeted-isolation process, and tentatively identified six AHFA analogues, 7–12 and six siderophores 13–18.

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Otero-Ramirez, Manuel E., Kyoko Matoba, Emiko Mihara, Toby Passioura, Junichi Takagi et Hiroaki Suga. « Macrocyclic peptides that inhibit Wnt signalling via interaction with Wnt3a ». RSC Chemical Biology 1, n^o 1 (2020) : 26–34. http://dx.doi.org/10.1039/d0cb00016g.

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Discovery and optimization of de novo macrocyclic peptide binders of Wnt3a through RaPID screening against an afamin-stabilized Wnt3a complex, capable of inhibiting Wnt signalling by direct interaction to the Wnt protein.

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Gründling, Angelika, et Vincent T. Lee. « Old concepts, new molecules and current approaches applied to the bacterial nucleotide signalling field ». Philosophical Transactions of the Royal Society B : Biological Sciences 371, n^o 1707 (5 novembre 2016) : 20150503. http://dx.doi.org/10.1098/rstb.2015.0503.

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Signalling nucleotides are key molecules that help bacteria to rapidly coordinate cellular pathways and adapt to changes in their environment. During the past 10 years, the nucleotide signalling field has seen much excitement, as several new signalling nucleotides have been discovered in both eukaryotic and bacterial cells. The fields have since advanced quickly, aided by the development of important tools such as the synthesis of modified nucleotides, which, combined with sensitive mass spectrometry methods, allowed for the rapid identification of specific receptor proteins along with other novel genome-wide screening methods. In this review, we describe the principle concepts of nucleotide signalling networks and summarize the recent work that led to the discovery of the novel signalling nucleotides. We also highlight current approaches applied to the research in the field as well as resources and methodological advances aiding in a rapid identification of nucleotide-specific receptor proteins. This article is part of the themed issue ‘The new bacteriology’.

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Staten, Michael, Otis Gilley et John Umbeck. « SCREENING AND SIGNALLING IN CONSUMER CREDIT : A THEORY OF INDIRECT LENDING ». Financial Review 22, n^o 3 (août 1987) : 114. http://dx.doi.org/10.1111/j.1540-6288.1987.tb01248.x.

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Campbell, Michelle, Sophie J. Stephenson, Kevin Whale, Stephen Rapecki, Helene Finney, Gina M. Doody et Reuben M. Tooze. « A screening platform for human plasma cells (PCs) reveals a selective response to SYK inhibition ». Journal of Immunology 202, n^o 1_Supplement (1 mai 2019) : 123.23. http://dx.doi.org/10.4049/jimmunol.202.supp.123.23.

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Abstract Therapeutic targeting of PC populations has potential value in various auto-immune, allergic and neoplastic cell states, but at present few options exist for selective targeting. However, the unique physiology and niche dependence of PCs suggests that such targeting may be achievable. To this end we have developed a sensitive screening platform capable of detecting changes in PC biology. Starting from our published methods for in vitro PC generation we optimised conditions to allow maintenance of PCs in polarised niche environments reflective of homeostatic and inflammatory conditions in microtitre plates. Using this assay format we probed PC biology via small molecule inhibitors (SMIs) targeting BCL2 family members, proteasome, and kinase signalling pathways. We were able to identify SMIs with broad and selective toxicity, as well as SMIs with no effect on PCs. Under all conditions analysed we found consistent divergence in the impact of targeting aspects of B cell receptor (BCR)-associated signalling pathways. Targeting SYK via two distinct SMIs consistently resulted in selective killing of subsets of PCs. By contrast BTK inhibition had no significant effect on PC viability. Whilst the importance of SYK signalling has been well documented at the B cell stage its importance to PCs has to our knowledge not been extensively documented. Retention of functional BCRs has been recently described in BM IgA+ and IgM+ PCs, and examination of expression data indicates selective retention of components of the BCR signalling complex in our assay system. The data presented here demonstrate the potential utility of an in vitro screening platform to evaluate the selective dependency of subsets of PCs on therapeutically targetable pathways.

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Dong, Chuanfu, Franziska Dolke et Stephan H. von Reuss. « Selective MS screening reveals a sex pheromone in Caenorhabditis briggsae and species-specificity in indole ascaroside signalling ». Organic & ; Biomolecular Chemistry 14, n^o 30 (2016) : 7217–25. http://dx.doi.org/10.1039/c6ob01230b.

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Kiss-Toth, E., D. H. Wyllie, K. Holland, L. Marsden, V. Jozsa, K. M. Oxley, T. Polgar, E. E. Qwarnstrom et S. K. Dower. « Functional mapping of Toll/interleukin-1 signalling networks by expression cloning ». Biochemical Society Transactions 33, n^o 6 (26 octobre 2005) : 1405–6. http://dx.doi.org/10.1042/bst0331405.

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Multiple cellular proteins have been identified as participating in Toll/interleukin-1 receptor-mediated inflammatory gene expression. The continuing isolation of novel components, based on sequence similarities, protein–protein interactions and protein purification, suggests that many elements of this signalling network remain to be identified. We report here the development of a high-throughput functional screening platform and its application for the identification of components of inflammatory signalling networks. Our results enable us to estimate that 100–150 gene products are involved in controlling the transcription of the human interleukin 8 gene. The approach, which is simple and robust, constitutes a general method for mapping signal transduction systems and for rapid isolation of a large number of signalling components based on the control of pathways leading to regulation of gene expression.

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Choi, Jeongmin, Kiwamu Tanaka, Yan Liang, Yangrong Cao, Sang Yeol Lee et Gary Stacey. « Extracellular ATP, a danger signal, is recognized by DORN1 in Arabidopsis ». Biochemical Journal 463, n^o 3 (10 octobre 2014) : 429–37. http://dx.doi.org/10.1042/bj20140666.

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ATP, the universal energy currency of all organisms, is released into the extracellular matrix and serves as a signal among cells, where it is referred to as an extracellular ATP. Although a signalling role for extracellular ATP has been well studied in mammals over the last 40 years, investigations of such a role in plants are at an early stage. Recently, the first plant receptor for extracellular ATP, DOes not Respond to Nucleotides (DORN1), was identified in Arabidopsis thaliana by mutant screening. DORN1 encodes a legume-type lectin receptor kinase that is structurally distinct from the mammalian extracellular ATP receptors. In the present review, we highlight the genetic and biochemical evidence for the role of DORN1 in extracellular ATP signalling, placing this within the wider context of extracellular ATP signalling during plant stress responses.

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Dower, S. K., et E. E. Qwarnstrom. « Signalling networks, inflammation and innate immunity ». Biochemical Society Transactions 31, n^o 6 (1 décembre 2003) : 1462–71. http://dx.doi.org/10.1042/bst0311462.

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We have been analysing the signalling systems that couple to receptors of the TIR (Toll/interleukin-1 receptor) family, which signal through a common cytoplasm region; the TIR domain. These systems are of both practical and fundamental biological significance, being central to the pathogenesis of chronic inflammatory diseases such as atherosclerosis, to host defence throughout the biological world, and are ancient in the context of life on earth, having originated more than 1 billion years ago: prior to the divergence of plants and animals. TIR domain receptors couple to at least two sets of well-characterized pathways: those leading to the activation of inhibitory κB kinase complexes/nuclear factor κB, and those leading to the activation of mitogen-activated protein kinase/AP-1/ATF-2 etc. We have been investigating these systems using a combination of expression screening methods to identify new components, and real-time green fluorescent protein-based techniques to observe execution of signalling programmes in real time. Our data reveal that there is a very large level of cell-to-cell variation in signal programme execution even in clonal populations and that at least one mechanism for dealing with this heterogeneity is the assembly of signal transduction components into large multiprotein complexes.

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Kakeya, Hideaki. « Natural products-prompted chemical biology : phenotypic screening and a new platform for target identification ». Natural Product Reports 33, n^o 5 (2016) : 648–54. http://dx.doi.org/10.1039/c5np00120j.

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This highlight focuses on our recent discoveries and chemical genetics approaches for bioactive microbial metabolites that target cancer cells, the cancer microenvironment, and cell membrane signalling. In addition, the development of two new platforms to identify the cellular targets of these molecules is also discussed.

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Liu, Ronghan, Yuehong Chen, Wenyu Fu, Shuya Wang, Yazhou Cui, Xiangli Zhao, Zi-Ning Lei et al. « Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against inflammatory arthritis ». Annals of the Rheumatic Diseases 78, n^o 11 (13 juillet 2019) : 1524–35. http://dx.doi.org/10.1136/annrheumdis-2019-215543.

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ObjectiveTumour necrosis factor alpha (TNF-α) signalling plays a central role in the pathogenesis of various autoimmune diseases, particularly inflammatory arthritis. This study aimed to repurpose clinically approved drugs as potential inhibitors of TNF-α signalling in treatment of inflammatory arthritis.MethodsIn vitro and in vivo screening of an Food and Drug Administration (FDA)-approved drug library; in vitro and in vivo assays for examining the blockade of TNF actions by fexofenadine: assays for defining the anti-inflammatory activity of fexofenadine using TNF-α transgenic (TNF-tg) mice and collagen-induced arthritis in DBA/1 mice. Identification and characterisation of the binding of fexofenadine to cytosolic phospholipase A2 (cPLA2) using drug affinity responsive target stability assay, proteomics, cellular thermal shift assay, information field dynamics and molecular dynamics; various assays for examining fexofenadine inhibition of cPLA2 as well as the dependence of fexofenadine’s anti-TNF activity on cPLA2.ResultsSerial screenings of a library composed of FDA-approved drugs led to the identification of fexofenadine as an inhibitor of TNF-α signalling. Fexofenadine potently inhibited TNF/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) signalling in vitro and in vivo, and ameliorated disease symptoms in inflammatory arthritis models. cPLA2 was isolated as a novel target of fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished fexofenadine’s anti-TNF activity.ConclusionCollectively, these findings not only provide new insights into the understanding of fexofenadine action and underlying mechanisms but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly inflammatory rheumatic diseases.

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Cheng, Lin, Yun Zhao et Hong Ke. « Screening for Immune-Related RNA Biomarkers of Aneurysmal Subarachnoid Hemorrhage ». Clinical and Investigative Medicine 45, n^o 2 (26 juin 2022) : E28–38. http://dx.doi.org/10.25011/cim.v45i2.38449.

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Purpose: Through comprehensive bioinformatics analysis based on the immune microenvironment, this study aimed to identify immune-related RNA biomarkers that indicate aneurysmal subarachnoid hemorrhage (aSAH). Methods: The GSE73378 dataset was downloaded from the National Center for Biotechnology Information GEO database, providing blood from 107 normal controls and 103 patients with aSAH. The immune infiltration types in the aSAH blood samples were assessed and RNAs that were differentially expressed (DE) between 1) the aSAH and control groups and 2) the immune infiltration groups (high and low) were identified. The intersecting genes were subjected to weighted gene co-expression network analysis followed by co-expression network construction. The aSAH-related genes and pathways were identified from the Comparative Toxicogenomics Database: update 2019. Results: A total of three DE long non-coding RNAs (lncRNAs) and 301 DE mRNAs were identified. Of the 301 mRNAs, 91 were significantly enriched in three modules. Based on the 91 mRNAs and three lncRNAs, a co-expression network related to the disease pathway was constructed. This pathway consisted of 16 factors, including the 13 mRNAs (e.g., TNFSF13B, TNFSF10, MYD88, GNA12 and NSMAF) and three lncRNAs (FAM66A, LINC00954 and CELF2-AS2), as well as six pathways, including the NF-κB, toll-like receptor, and sphingolipid signalling pathways. Conclusion: TNFSF13B, MYD88, GNA12, NSMAF, FAM66A, LINC00954 and CELF2-AS2 may serve as biomarkers for aSAH. The NF-κB, toll-like receptor and sphingolipid signalling pathways may play critical roles in the progression of aSAH.

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Pietrzak, Michał. « Information Asymmetry, Signalling and Screening vs. Audit Culture – Selected Challenges for Academic Governance ». Problemy Zarzadzania 4/2018, n^o 77 (9 janvier 2019) : 134–52. http://dx.doi.org/10.7172/1644-9584.77.8.

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Foulkes, Daniel M., Dominic P. Byrne, Fiona P. Bailey et Patrick A. Eyers. « Tribbles pseudokinases : novel targets for chemical biology and drug discovery ? » Biochemical Society Transactions 43, n^o 5 (1 octobre 2015) : 1095–103. http://dx.doi.org/10.1042/bst20150109.

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Tribbles (TRIB) proteins are pseudokinase mediators of eukaryotic signalling that have evolved important roles in lipoprotein metabolism, immune function and cellular differentiation and proliferation. In addition, an evolutionary-conserved modulation of PI3K/AKT signalling pathways highlights them as novel and rather unusual pharmaceutical targets. The three human TRIB family members are uniquely defined by an acidic pseudokinase domain containing a ‘broken’ α C-helix and a MEK (MAPK/ERK)-binding site at the end of the putative C-lobe and a distinct C-terminal peptide motif that interacts directly with a small subset of cellular E3 ubiquitin ligases. This latter interaction drives proteasomal-dependent degradation of networks of transcription factors, whose rate of turnover determines the biological attributes of individual TRIB family members. Defining the function of individual Tribs has been made possible through evaluation of individual TRIB knockout mice, siRNA/overexpression approaches and genetic screening in flies, where the single TRIB gene was originally described 15 years ago. The rapidly maturing TRIB field is primed to exploit chemical biology approaches to evaluate endogenous TRIB signalling events in intact cells. This will help define how TRIB-driven protein–protein interactions and the atypical TRIB ATP-binding site, fit into cellular signalling modules in experimental scenarios where TRIB-signalling complexes remain unperturbed. In this mini-review, we discuss how small molecules can reveal rate-limiting signalling outputs and functions of Tribs in cells and intact organisms, perhaps serving as guides for the development of new drugs. We predict that appropriate small molecule TRIB ligands will further accelerate the transition of TRIB pseudokinase analysis into the mainstream of cell signalling.

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Vijayakrishnan, N., et K. Broadie. « Temperature-sensitive paralytic mutants : insights into the synaptic vesicle cycle ». Biochemical Society Transactions 34, n^o 1 (20 janvier 2006) : 81–87. http://dx.doi.org/10.1042/bst0340081.

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Forward genetic screens have identified numerous proteins with critical roles in neurotransmission. One particularly fruitful screening target in Drosophila has been TS (temperature-sensitive) paralytic mutants, which have revealed proteins acutely required in neuronal signalling. In the present paper, we review recent insights and current questions from one recently cloned TS paralytic mutant, rbo (rolling blackout). The rbo mutant identifies a putative integral lipase of the pre-synaptic plasma membrane that is required for the SV (synaptic vesicle) cycle. Identification of this mutant adds to a growing body of evidence that lipid-modifying enzymes locally control specialized lipid microenvironments and lipid signalling pathways with key functions regulating neurotransmission strength. The RBO protein is absolutely required for phospholipase C signalling in phototransduction. We posit that RBO might be required to regulate the availability of fusogenic lipids such as phosphatidylinositol 4,5-bisphosphate and diacylglycerol that may directly modify membrane properties and/or activate lipid-binding fusogenic proteins mediating SV exocytosis.

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Marconi, Guya Diletta, Cristina Porcheri, Oriana Trubiani et Thimios A. Mitsiadis. « Three-Dimensional Culture Systems for Dissecting Notch Signalling in Health and Disease ». International Journal of Molecular Sciences 22, n^o 22 (19 novembre 2021) : 12473. http://dx.doi.org/10.3390/ijms222212473.

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Three-dimensional (3D) culture systems opened up new horizons in studying the biology of tissues and organs, modelling various diseases, and screening drugs. Producing accurate in vitro models increases the possibilities for studying molecular control of cell–cell and cell–microenvironment interactions in detail. The Notch signalling is linked to cell fate determination, tissue definition, and maintenance in both physiological and pathological conditions. Hence, 3D cultures provide new accessible platforms for studying activation and modulation of the Notch pathway. In this review, we provide an overview of the recent advances in different 3D culture systems, including spheroids, organoids, and “organ-on-a-chip” models, and their use in analysing the crucial role of Notch signalling in the maintenance of tissue homeostasis, pathology, and regeneration.

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di Martino, Erica, Darren C. Tomlinson et Margaret A. Knowles. « A Decade of FGF Receptor Research in Bladder Cancer : Past, Present, and Future Challenges ». Advances in Urology 2012 (2012) : 1–10. http://dx.doi.org/10.1155/2012/429213.

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Fibroblast growth factors (FGFs) orchestrate a variety of cellular functions by binding to their transmembrane tyrosine-kinase receptors (FGFRs) and activating downstream signalling pathways, including RAS/MAPK, PLCγ1, PI3K, and STATs. In the last ten years, it has become clear that FGF signalling is altered in a high proportion of bladder tumours. Activating mutations and/or overexpression ofFGFR3are common in urothelial tumours with low malignant potential and low-stage and -grade urothelial carcinomas (UCs) and are associated with a lower risk of progression and better survival in some subgroups.FGFR1is not mutated in UC, but overexpression is frequent in all grades and stages and recent data indicate a role in urothelial epithelial-mesenchymal transition.In vitroandin vivostudies have shown that FGFR inhibition has cytotoxic and/or cytostatic effects in FGFR-dependent bladder cancer cells and FGFR-targeted agents are currently being investigated in clinical studies for the treatment of UC. Urine-based tests detecting commonFGFR3mutations are also under development for surveillance of low-grade and -stage tumours and for general population screening. Overall, FGFRs hold promise as therapeutic targets, diagnostic and prognostic markers, and screening tools for early detection and clinical management of UC.

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Sharma, Sumana, et Evangelia Petsalaki. « Application of CRISPR-Cas9 Based Genome-Wide Screening Approaches to Study Cellular Signalling Mechanisms ». International Journal of Molecular Sciences 19, n^o 4 (21 mars 2018) : 933. http://dx.doi.org/10.3390/ijms19040933.

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Garcia, Mar Arias, Miguel Sanchez Alvarez, Heba Sailem, Vicky Bousgouni, Julia Sero et Chris Bakal. « Differential RNAi screening provides insights into the rewiring of signalling networks during oxidative stress ». Molecular BioSystems 8, n^o 10 (2012) : 2605. http://dx.doi.org/10.1039/c2mb25092f.

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Chong, Irene Yu-Shing, Sean D. Hooper, David Cunningham, Richard Elliott, Lina Chen, James Campbell, Ilirjana Bajrami et al. « Association of high-throughput RNAi and drug screening with candidate novel therapeutic targets in esophageal carcinoma. » Journal of Clinical Oncology 31, n^o 4_suppl (1 février 2013) : 31. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.31.

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31 Background: Oesophageal cancer is the sixth most commonly diagnosed cancer worldwide and carries a poor prognosis. Targeted therapeutic strategies have relied on the identification of genes which are amplified and overexpressed but the discrimination between genes which drive cancer and those that are coincidental has not yet been fully achieved. Methods: We carried out a functional genetic screen of 714 kinases in 18 tumour cell line models of oesophageal adenocarcinoma (EAC) and squamous cell carcinoma (SCC) to identify genes critical to the survival of specific oesophageal subtypes. High throughput drug screening of 80 compounds, largely comprising those used in clinical trials or in routine clinical practice, was undertaken in parallel to reveal druggable targets and to validate functional screening results. Results: We show proof of principle that the integration of functional and drug profiling results with molecular profiling data is a valid approach for identifying druggable targets by correlating the effects of ERBB2, EGFR and CDK6 gene knockdown with sensitivity to drugs targeting their respective proteins. We have characterised new genetic dependencies for EAC involving TGF beta signalling and the JAK/STAT pathway. Decreased cell viability associated with silencing of ACVR2 and ACVR1C (activin receptors involved in TGF beta signalling) was consistent with sensitivity to nilotinib, a cABL inhibitor that modulates TGF beta signalling. Furthermore, decreased cell viability in EAC models was observed with silencing of JAK2. This strongly correlated with sensitivity to PF-04691502 and BEZ 235, both potent inhibitors of PI3K/mTOR which signal downstream of JAK2. We have validated novel sensitivity to small molecule tankyrase inhibitors in a subgroup of oesophageal models, suggesting that a subset of Wnt dependent oesophageal cancers could be targeted with these agents. Conclusions: The molecular and functional genetics of oesophageal cancer is poorly understood. By generating functional viability and drug sensitivity data for a panel of oesophageal tumour cell lines, we have identified new genetic dependencies and candidate drug targets for this aggressive disease.

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Bisserier, Malik, Jean-Paul Blondeau et Frank Lezoualc’h. « Epac proteins : specific ligands and role in cardiac remodelling ». Biochemical Society Transactions 42, n^o 2 (20 mars 2014) : 257–64. http://dx.doi.org/10.1042/bst20140033.

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Epacs (exchange proteins directly activated by cAMP) act as guanine-nucleotide-exchange factors for the Ras-like small G-proteins Rap1 and Rap2, and are now recognized as incontrovertible factors leading to complex and diversified cAMP signalling pathways. Given the critical role of cAMP in the regulation of cardiac function, several studies have investigated the functional role of Epacs in the heart, providing evidence that Epacs modulate intracellular Ca2+ and are involved in several cardiac pathologies such as cardiac hypertrophy and arrhythmia. The present review summarizes recent data on the Epac signalling pathway and its role in cardiac pathophysiology. We also discuss recent advances in the discovery of novel pharmacological modulators of Epacs that were identified by high-throughput screening and their therapeutic potential for the treatment of cardiac disorders.

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Agrawal, Neha, Katherine Lawler, Catherine M. Davidson, Julia M. Keogh, Robert Legg, Inês Barroso, I. Sadaf Farooqi et Andrea H. Brand. « Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila ». PLOS Biology 19, n^o 11 (8 novembre 2021) : e3001255. http://dx.doi.org/10.1371/journal.pbio.3001255.

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The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.

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Zhang, Siqi, Qiaoling Song, Xueting Wang, Zhiqiang Wei, Rilei Yu, Xin Wang et Tao Jiang. « Virtual Screening Guided Design, Synthesis and Bioactivity Study of Benzisoselenazolones (BISAs) on Inhibition of c-Met and Its Downstream Signalling Pathways ». International Journal of Molecular Sciences 20, n^o 10 (20 mai 2019) : 2489. http://dx.doi.org/10.3390/ijms20102489.

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c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including 7a, 7b, 8a, 8b and 12c (with IC50 values of less than 20 μM in MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design.

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Hayes, Sheri, Beatrice Malacrida, Maeve Kiely et Patrick A. Kiely. « Studying protein–protein interactions : progress, pitfalls and solutions ». Biochemical Society Transactions 44, n^o 4 (15 août 2016) : 994–1004. http://dx.doi.org/10.1042/bst20160092.

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Signalling proteins are intrinsic to all biological processes and interact with each other in tightly regulated and orchestrated signalling complexes and pathways. Characterization of protein binding can help to elucidate protein function within signalling pathways. This information is vital for researchers to gain a more comprehensive knowledge of cellular networks which can then be used to develop new therapeutic strategies for disease. However, studying protein–protein interactions (PPIs) can be challenging as the interactions can be extremely transient downstream of specific environmental cues. There are many powerful techniques currently available to identify and confirm PPIs. Choosing the most appropriate range of techniques merits serious consideration. The aim of this review is to provide a starting point for researchers embarking on a PPI study. We provide an overview and point of reference for some of the many methods available to identify interactions from in silico analysis and large scale screening tools through to the methods used to validate potential PPIs. We discuss the advantages and disadvantages of each method and we also provide a workflow chart to highlight the main experimental questions to consider when planning cell lysis to maximize experimental success.

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Menon, Manoj B., et Matthias Gaestel. « TPL2 meets p38MAPK : emergence of a novel positive feedback loop in inflammation ». Biochemical Journal 473, n^o 19 (27 septembre 2016) : 2995–99. http://dx.doi.org/10.1042/bcj20160672c.

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The activation of p38MAPK by Toll-like receptor signalling is essential for the inflammatory response of innate immunity due to its role in post-transcriptional regulation of TNFα and cytokine biosynthesis. p38MAPK activation proceeds by the upstream MAP2Ks, MAPK kinase (MKK)3/6 as well as MKK4, which in turn are substrates for MAP3Ks, such as TGFβ-activated protein kinase-1 (TAK1). In contrast, TPL2 has been described as an exclusive MAP3K of MKK1/2-triggering activation of the classical ERKs, ERK1/2. In the recent issue of the Biochemical Journal, Pattison et al. report their screening for TPL2 substrates in LPS-stimulated macrophages and the identification of MKK3/6. Using catalytic-dead TPL2 (Map3k8D270A/D270A) knockin macrophages, they demonstrated that activation of MKK3/6 by TPL2 significantly contributes to LPS-dependent TNFα biosynthesis and is also essential for TNF-receptor 1 signalling. Hence, a new signalling pathway from TAK1 via IκB kinase, p105 NFκB and TPL2 to MKK3/6 and p38MAPK is established in macrophages. Taking into account that some isoforms of p38MAPK are necessary for maintaining functional steady-state levels of TPL2, a positive feedback loop in inflammation emerges.

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Toenjes, Kurt A., Benjamin C. Stark, Krista M. Brooks et Douglas I. Johnson. « Inhibitors of cellular signalling are cytotoxic or block the budded-to-hyphal transition in the pathogenic yeast Candida albicans ». Journal of Medical Microbiology 58, n^o 6 (1 juin 2009) : 779–90. http://dx.doi.org/10.1099/jmm.0.006841-0.

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The pathogenic yeast Candida albicans can grow in multiple morphological states including budded, pseudohyphal and true hyphal forms. The ability to interconvert between budded and hyphal forms, herein termed the budded-to-hyphal transition (BHT), is important for C. albicans virulence, and is regulated by multiple environmental and cellular signals. To identify small-molecule inhibitors of known cellular processes that can also block the BHT, a microplate-based morphological assay was used to screen the BIOMOL–Institute of Chemistry and Cell Biology (ICCB) Known Bioactives collection from the ICCB-Longwood Screening Facility (Harvard Medical School, Boston, MA, USA). Of 480 molecules tested, 53 were cytotoxic to C. albicans and 16 were able to block the BHT without inhibiting budded growth. These 16 BHT inhibitors affected protein kinases, protein phosphatases, Ras signalling pathways, G protein-coupled receptors, calcium homeostasis, nitric oxide and guanylate cyclase signalling, and apoptosis in mammalian cells. Several of these molecules were also able to inhibit filamentous growth in other Candida species, as well as the pathogenic filamentous fungus Aspergillus fumigatus, suggesting a broad fungal host range for these inhibitory molecules. Results from secondary assays, including hyphal-specific transcription and septin localization analysis, were consistent with the inhibitors affecting known BHT signalling pathways in C. albicans. Therefore, these molecules will not only be invaluable in deciphering the signalling pathways regulating the BHT, but also may serve as starting points for potential new antifungal therapeutics.

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Fontana, Roberto, Aldo Geuna et Mireille Matt. « Factors affecting university–industry R&D projects : The importance of searching, screening and signalling ». Research Policy 35, n^o 2 (mars 2006) : 309–23. http://dx.doi.org/10.1016/j.respol.2005.12.001.

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Aina, Carmen, et Francesco Pastore. « Delayed Graduation and Overeducation in Italy : A Test of the Human Capital Model Versus the Screening Hypothesis ». Social Indicators Research 152, n^o 2 (28 juillet 2020) : 533–53. http://dx.doi.org/10.1007/s11205-020-02446-0.

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Abstract Exploiting the human capital versus screening hypothesis frameworks, this paper studies the link between delayed graduation and overeducation, and their effect on wages, by using the ISFOL-Plus data. The evidence lines towards predictions based on the signalling model. However, as to the determinants of overeducation the coefficient of delayed graduation is significant only for delays of 3 years or more and also controlling for the entire set of covariates. This suggests that delay conveys a signal of low skill.

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Mosienko, Valentina, Seyed Rasooli-Nejad, Kasumi Kishi, Matt De Both, David Jane, Matt Huentelman, Sergey Kasparov et Anja Teschemacher. « Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus ». Neuroglia 1, n^o 2 (16 novembre 2018) : 365–80. http://dx.doi.org/10.3390/neuroglia1020025.

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The importance of astrocytic l-lactate (LL) for normal functioning of neural circuits such as those regulating learning/memory, sleep/wake state, autonomic homeostasis, or emotional behaviour is being increasingly recognised. l-Lactate can act on neurones as a metabolic or redox substrate, but transmembrane receptor targets are also emerging. A comparative review of the hydroxy-carboxylic acid receptor (HCA1, formerly known as GPR81), Olfactory Receptor Family 51 Subfamily E Member 2 (OR51E2), and orphan receptor GPR4 highlights differences in their LL sensitivity, pharmacology, intracellular coupling, and localisation in the brain. In addition, a putative Gs-coupled receptor on noradrenergic neurones, LLRx, which we previously postulated, remains to be identified. Next-generation sequencing revealed several orphan receptors expressed in locus coeruleus neurones. Screening of a selection of these suggests additional LL-sensitive receptors: GPR180 which inhibits and GPR137 which activates intracellular cyclic AMP signalling in response to LL in a heterologous expression system. To further characterise binding of LL at LLRx, we carried out a structure–activity relationship study which demonstrates that carboxyl and 2-hydroxyl moieties of LL are essential for triggering d-lactate-sensitive noradrenaline release in locus coeruleus, and that the size of the LL binding pocket is limited towards the methyl group position. The evidence accumulating to date suggests that LL acts via multiple receptor targets to modulate distinct brain functions.

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Nabil, Muhammad, Azman Seeni, Wan Ismahanisa Ismail et Nurhidayah Ab Rahim. « Proteomic Analysis of Anti-Cancer Effects of Streblus Asper Extract on HeLa Cancer Cells ». Biomedical & ; Pharmacology Journal 12, n^o 3 (18 septembre 2019) : 1263–77. http://dx.doi.org/10.13005/bpj/1755.

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Cervical cancer is the third most common cancer affecting women worldwide. This occurs despite having precancerous screening and HPV vaccination implemented vigorously as a definitive intervention. Natural plant like Streblus asper has been discovered to offer great hope in treating and preventing cancers. In this study, we explored the potential of S.asper to inhibit the growth of cervical cancer cell line by using liquid chromatography mass spectrometry (LCMS). Upon analysis, seventy-six proteins that are common to both untreated and treated groups were identified. Of this, 14 proteins are found differentially expressed more than 2-fold changes. Based on past literature, we selected 7 proteins that are closely associated with treatment effects. These include Dermcidin, Keratin, type I cytoskeletal 9, Tropomyosin alpha-4 chain, Myristoylated alanine-rich C-kinase (MARCKS), Tumour protein D52, Folate receptor alpha, and Parathymosin. Pathway enrichment analysis by Reactome revealed 9 related pathways which include metabolism of protein, post-translational protein modification, signalling by Rho GTPases, signalling by NOTCH, cell cycle, cellular senescence, signalling by WNT, transcriptional regulation by TP53, and cellular responses to stress. These findings may improve our understanding on the related significant mechanism involving anti-cancer effects of S.asper on the cervical cancer cell line.

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Kostyrko, Andrzej, Joanna Hauser, Janusz K. Rybakowski et Wiesław H. Trzeciak. « Screening of chromosomal region 21q22.3 for mutations in genes associated with neuronal Ca2+ signalling in bipolar affective disorder. » Acta Biochimica Polonica 53, n^o 2 (29 mai 2006) : 317–20. http://dx.doi.org/10.18388/abp.2006_3345.

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The therapeutic effect of lithium in bipolar affective disorder may be connected with decreasing intracellular Ca(2+) concentrations. Several linkage studies have identified a potential bipolar affective disorder susceptibility locus within chromosomal region 21q22.3. This locus contains two genes expressed in the brain - ADARB1 and TRPM2 - involved in regulating intracellular Ca(2+) concentrations. The aim of this study was an identification of mutations in the coding sequences of ADARB1 and TRPM2 and their association with bipolar affective disorder. For that purpose we screened 60 patients with bipolar affective disorder and a control group of 66 subjects using single strand conformation polymorphism and sequence analysis. For rapid screening we performed restriction fragment length polymorphism analysis. Screening of bipolar affective disorder patients for mutations in TRPM2 led to identification of three novel and four known transitions. Two transitions resulted in the substitutions: R755C and A890V. Screening of the coding sequence of ADARB1 did not reveal any mutations except one already known transition. A comparison of the transition frequency in patients and controls does not support association of the detected mutations with bipolar affective disorder. According to our results, bipolar affective disorder may not be caused by mutations in ADARB1. However, this study does not exclude TRPM2 as a candidate gene since we have screened only about 30 per cent of the entire coding sequence of this large gene.

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NIU, Jiaxin, Astrid SCHESCHONKA, Kirk M. DRUEY, Amanda DAVIS, Eleanor REED, Vladimir KOLENKO, Richard BODNAR et al. « RGS3 interacts with 14-3-3 via the N-terminal region distinct from the RGS (regulator of G-protein signalling) domain ». Biochemical Journal 365, n^o 3 (1 août 2002) : 677–84. http://dx.doi.org/10.1042/bj20020390.

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RGS3 belongs to a family of the regulators of G-protein signalling (RGS), which bind and inhibit the Gα subunits of heterotrimeric G-proteins via a homologous RGS domain. Increasing evidence suggests that RGS proteins can also interact with targets other than G-proteins. Employing yeast two-hybrid screening of a cDNA library, we identified an interaction between RGS3 and the phosphoserine-binding protein 14-3-3. This interaction was confirmed by in vitro binding and co-immunoprecipitation experiments. RGS3-deletion analysis revealed the presence of a single 14-3-3-binding site located outside of the RGS domain. Ser264 was then identified as the 14-3-3-binding site of RGS3. The S264A mutation resulted in the loss of RGS3 binding to 14-3-3, without affecting its ability to bind Gαq. Signalling studies showed that the S264A mutant was more potent than the wild-type RGS3 in inhibition of G-protein-mediated signalling. Binding experiments revealed that RGS3 exists in two separate pools, either 14-3-3-bound or G-protein-bound, and that the 14-3-3-bound RGS3 is unable to interact with G-proteins. These data are consistent with the model wherein 14-3-3 serves as a scavenger of RGS3, regulating the amounts of RGS3 available for binding G-proteins. This study describes a new level in the regulation of G-protein signalling, in which the inhibitors of G-proteins, RGS proteins, can themselves be regulated by phosphorylation and binding 14-3-3.

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Shkhyan, Ruzanna, Ben Van Handel, Jacob Bogdanov, Siyoung Lee, Yifan Yu, Mila Scheinberg, Nicholas W. Banks et al. « Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair ». Annals of the Rheumatic Diseases 77, n^o 5 (7 février 2018) : 760–69. http://dx.doi.org/10.1136/annrheumdis-2017-212037.

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ObjectiveHuman adult articular cartilage (AC) has little capacity for repair, and joint surface injuries often result in osteoarthritis (OA), characterised by loss of matrix, hypertrophy and chondrocyte apoptosis. Inflammation mediated by interleukin (IL)-6 family cytokines has been identified as a critical driver of proarthritic changes in mouse and human joints, resulting in a feed-forward process driving expression of matrix degrading enzymes and IL-6 itself. Here we show that signalling through glycoprotein 130 (gp130), the common receptor for IL-6 family cytokines, can have both context-specific and cytokine-specific effects on articular chondrocytes and that a small molecule gp130 modulator can bias signalling towards anti-inflammatory and antidegenerative outputs.MethodsHigh throughput screening of 170 000 compounds identified a small molecule gp130 modulator termed regulator of cartilage growth and differentiation (RCGD 423) that promotes atypical homodimeric signalling in the absence of cytokine ligands, driving transient increases in MYC and pSTAT3 while suppressing oncostatin M- and IL-6-mediated activation of ERK and NF-κB via direct competition for gp130 occupancy.ResultsThis small molecule increased proliferation while reducing apoptosis and hypertrophic responses in adult chondrocytes in vitro. In a rat partial meniscectomy model, RCGD 423 greatly reduced chondrocyte hypertrophy, loss and degeneration while increasing chondrocyte proliferation beyond that observed in response to injury. Moreover, RCGD 423 improved cartilage healing in a rat full-thickness osteochondral defect model, increasing proliferation of mesenchymal cells in the defect and also inhibiting breakdown of cartilage matrix in de novo generated cartilage.ConclusionThese results identify a novel strategy for AC remediation via small molecule-mediated modulation of gp130 signalling.

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Van der Merwe, Alex. « Does Human Capital Theory Explain The Value Of Higher Education ? A South African Case Study ». American Journal of Business Education (AJBE) 3, n^o 1 (1 janvier 2010) : 107–18. http://dx.doi.org/10.19030/ajbe.v3i1.378.

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A perennial debate in the economics of education is whether human capital or screening/signalling theories best explain the value of schooling and hence the private demand for, in particular, higher education. Human capital theory proposes that formal training such as that offered by higher education institutions improves the productive capacity of individuals. Screening theory, on the other hand, posits that the value of higher education credentials flows primarily from their value as signals to potential employers of the abilities of the holders of such qualifications. Following the application of Wiles’ (1974) test and regression analysis this case study finds that it is probable that both human capital and screening theories account for the economic value of higher education in the perceptions and experiences of a local cohort of recent Durban University of Technology graduates. This finding, in spite of its empirical support, relies on a certain amount of intuition necessitated by technical and analytical constraints that are discussed in the paper.

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Xing, Yanjiang, Shuang Zhao, Qingxia Wei, Shiqiang Gong, Xin Zhao, Fang Zhou, Rafia AI-Lamki et al. « A novel piperidine identified by stem cell-based screening attenuates pulmonary arterial hypertension by regulating BMP2 and PTGS2 levels ». European Respiratory Journal 51, n^o 4 (15 février 2018) : 1702229. http://dx.doi.org/10.1183/13993003.02229-2017.

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Genetic defects in bone morphogenetic protein type II receptor (BMPRII) signalling and inflammation contribute to the pathogenesis of pulmonary arterial hypertension (PAH). The receptor is activated by bone morphogenetic protein (BMP) ligands, which also enhance BMPR2 transcription. A small-molecule BMP upregulator with selectivity on vascular endothelium would be a desirable therapeutic intervention for PAH.We assayed compounds identified in the screening of BMP2 upregulators for their ability to increase the expression of inhibitor of DNA binding 1 (Id1), using a dual reporter driven specifically in human embryonic stem cell-derived endothelial cells. These assays identified a novel piperidine, BMP upregulator 1 (BUR1), that increased endothelial Id1 expression with a half-maximal effective concentration of 0.098 μmol·L−1. Microarray analyses and immunoblotting showed that BUR1 induced BMP2 and prostaglandin-endoperoxide synthase 2 (PTGS2) expression. BUR1 effectively rescued deficient angiogenesis in autologous BMPR2+/R899X endothelial cells generated by CRISPR/Cas9 and patient cells.BUR1 prevented and reversed PAH in monocrotaline rats, and restored BMPRII downstream signalling and modulated the arachidonic acid pathway in the pulmonary arterial endothelium in the Sugen 5416/hypoxia PAH mouse model.In conclusion, using stem cell technology we have provided a novel small-molecule compound which regulates BMP2 and PTGS2 levels that might be useful for the treatment of PAH.

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Jensen, Adina R. D., Edward R. Horton, Lene H. Blicher, Elin J. Pietras, Cornelia Steinhauer, Raphael Reuten, Erwin M. Schoof et Janine T. Erler. « Organ-Specific, Fibroblast-Derived Matrix as a Tool for Studying Breast Cancer Metastasis ». Cancers 13, n^o 13 (2 juillet 2021) : 3331. http://dx.doi.org/10.3390/cancers13133331.

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During the metastatic process, breast cancer cells must come into contact with the extra-cellular matrix (ECM) at every step. The ECM provides both structural support and biochemical cues, and cell–ECM interactions can lead to changes in drug response. Here, we used fibroblast-derived ECM (FDM) to perform high throughput drug screening of 4T1 breast cancer cells on metastatic organ ECM (lung), and we see that drug response differs from treatment on plastic. The FDMs that we can produce from different organs are abundant in and contains a complex mixture of ECM proteins. We also show differences in ECM composition between the primary site and secondary organ sites. Furthermore, we show that global kinase signalling of 4T1 cells on the ECM is relatively unchanged between organs, while changes in signalling compared to plastic are significant. Our study highlights the importance of context when testing drug response in vitro, showing that consideration of the ECM is critically important.

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ZHONG, JIM, et BARRY YEDVOBNICK. « Targeted gain-of-function screening inDrosophilausingGAL4-UASand random transposon insertions ». Genetics Research 91, n^o 4 (30 juillet 2009) : 243–58. http://dx.doi.org/10.1017/s0016672309990152.

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SummaryAlterations in the activity level or temporal expression of key signalling genes elicit profound patterning effects during development. Consequently, gain-of-function genetic schemes that overexpress or misexpress such loci can identify novel candidates for functions essential for a developmental process.GAL4-Upstream Activating Sequence(UAS)-targeted regulation of gene expression inDrosophilahas allowed rapid analyses of coding sequences for potential roles in specific tissues at particular developmental stages.GAL4has also been combined with randomly mobilized transposons capable ofUAS-directed misexpression or overexpression of flanking sequences. This combination has produced a genetic screening system that can uncover novel loci refractory to standard loss of function genetic approaches, such as redundant genes. Available libraries of strains with sequenced insertion sites can allow direct correlation of phenotypes to genetic function. These techniques have also been applied to genetic interaction screening, where aGAL4driver andUAS-regulated insertion collection are combined with an extant mutant genotype. In this article, we summarize studies that have utilizedGAL4-UASoverexpression or misexpression of random loci to screen for candidates involved in specific developmental processes.

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Denny, William A. « Inhibitors and Activators of the p38 Mitogen-activated MAP Kinase (MAPK) Family as Drugs to Treat Cancer and Inflammation ». Current Cancer Drug Targets 22, n^o 3 (mars 2022) : 209–20. http://dx.doi.org/10.2174/1568009622666220215142837.

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Abstract: The p38 MAP kinases are a sub-family of the broad group of mitogen-activated serinethreonine protein kinases. The best-characterised, most widely expressed, and most targeted by drugs is p38α MAP kinase. This review briefly summarises the place of p38α MAP kinase in cellular signalling and discusses the structures and activity profiles of representative examples of the major classes of inhibitors and activators (both synthetic compounds and natural products) of this enzyme. Primary screening was direct in vitro inhibition of isolated p38α enzyme.

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Tai, G., P. Hohenstein et J. A. Davies. « FAK-Src signalling is important to renal collecting duct morphogenesis : discovery using a hierarchical screening technique ». Biology Open 2, n^o 4 (28 février 2013) : 416–23. http://dx.doi.org/10.1242/bio.20133780.

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YAJIMA, Masashi, Masatoshi TAKADA, Nahoko TAKAHASHI, Haruhisa KIKUCHI, Shunji NATORI, Yoshiteru OSHIMA et Shoichiro KURATA. « A newly established in vitro culture using transgenic Drosophila reveals functional coupling between the phospholipase A2-generated fatty acid cascade and lipopolysaccharide-dependent activation of the immune deficiency (imd) pathway in insect immunity ». Biochemical Journal 371, n^o 1 (1 avril 2003) : 205–10. http://dx.doi.org/10.1042/bj20021603.

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Innate immunity is the first line of defence against infectious micro-organisms, and the basic mechanisms of pathogen recognition and response activation are evolutionarily conserved. In mammals, the innate immune response in combination with antigen-specific recognition is required for the activation of adaptive immunity. Therefore, innate immunity is a pharmaceutical target for the development of immune regulators. Here, for the purpose of pharmaceutical screening, we established an in vitro culture based on the innate immune response of Drosophila. The in vitro system is capable of measuring lipopolysaccharide (LPS)-dependent activation of the immune deficiency (imd) pathway, which is similar to the tumour necrosis factor signalling pathway in mammals. Screening revealed that well-known inhibitors of phospholipase A2 (PLA2), dexamethasone (Dex) and p-bromophenacyl bromide (BPB) inhibit LPS-dependent activation of the imd pathway. The inhibitory effects of Dex and BPB were suppressed by the addition of an excess of three (arachidonic acid, eicosapentaenoic acid and γ-linolenic acid) of the fatty acids so far tested. Arachidonic acid, however, did not activate the imd pathway when used as the sole agonist. These findings indicate that PLA2 participates in LPS-dependent activation of the imd pathway via the generation of arachidonic acid and other mediators, but requires additional signalling from LPS stimulation. Moreover, PLA2 was activated in response to bacterial infection in Sarcophaga. These results suggest a functional link between the PLA2-generated fatty acid cascade and the LPS-stimulated imd pathway in insect immunity.

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Boumelha, Jesse, Pablo Romero-Clavijo, Sophie de Carné, Miriam Molina-Arcas et Julian Downward. « Abstract 1352 : In vivo CRISPR screening identifies mediators of immune evasion in KRAS-mutant lung cancer ». Cancer Research 82, n^o 12_Supplement (15 juin 2022) : 1352. http://dx.doi.org/10.1158/1538-7445.am2022-1352.

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Abstract Oncogenic KRAS mutations drive tumourigenesis in 30% of non-small cell lung cancer (NSCLC). Despite much effort, targeted therapies that aim to directly inhibit signalling pathways downstream of KRAS have limited clinical benefits for NSCLC patients, but the recent approval of PD-1/PD-L1 antibodies has led to striking durable responses. However, only a fraction of patients respond and therefore a deeper understanding of the mechanisms that drive immune evasion are required in order to broaden the clinical efficacy of immunotherapy. Increasing evidence suggests that oncogenic signalling pathways greatly influence the tumour immune landscape to impair anti-tumour immune responses. We therefore aim to understand the mechanisms by which KRAS signalling mediates immune evasion in lung cancer. Current mouse models of KRAS-mutant lung cancer are poorly immunogenic, limiting investigations into tumour-immune interactions. To overcome this, we generated a novel transplantable KRAS-mutant lung cancer model, KPAR1.3, which triggers spontaneous anti-tumour immune responses and is sensitive to immune checkpoint blockade. To identify mechanisms of immune evasion we carried out an in vivo pooled CRISPR-Cas9 screen targeting 240 KRAS-regulated genes using this novel immunogenic model. This identified the prostaglandin synthase COX-2 as a mediator of immune evasion and its expression was driven by KRAS in multiple models of mouse and human lung cancer. Loss of COX-2 promoted a pro-inflammatory tumour microenvironment and sensitised tumours to both innate and adaptive anti-tumour immune responses. Furthermore, therapeutic COX inhibition extended the survival of tumour-bearing mice and synergised with PD-1 blockade. Together these data suggest that targeting KRAS-driven mechanisms of immune evasion could broaden the clinical efficacy of immunotherapy in KRAS-mutant NSCLC. Since the approval of immunotherapy, a novel class of mutant-specific KRAS-G12C inhibitors have recently been approved for the treatment of KRAS-mutant NSCLC, however acquired drug resistance is common. We are therefore also currently investigating whether the inhibition of the COX-2/PGE2 axis enhances the therapeutic benefit of KRAS-G12C inhibitors. Citation Format: Jesse Boumelha, Pablo Romero-Clavijo, Sophie de Carné, Miriam Molina-Arcas, Julian Downward. In vivo CRISPR screening identifies mediators of immune evasion in KRAS-mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1352.

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Ademuwagun, Ibitayo Abigail, Gbolahan Oladipupo Oduselu, Solomon Oladapo Rotimi et Ezekiel Adebiyi. « Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders ». Bioinformatics and Biology Insights 17 (janvier 2023) : 117793222311582. http://dx.doi.org/10.1177/11779322231158254.

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Therapeutic intervention in cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs) has remained a concern over the years. Recent advances into the mechanistic interplay of signalling pathways has revealed the role of deficient tropomyosin receptor kinase B (TrkB)/phospholipase C γ1 signalling cascade in CDD. Novel findings showed that in vivo administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), resulted in a remarkable reversal in the molecular pathologic mechanisms underlying CDD. Owing to this discovery, this study aimed to identify more potent TrkB agonists than 7,8-DHF that could serve as alternatives or combinatorial drugs towards effective management of CDD. Using pharmacophore modelling and multiple database screening, we identified 691 compounds with identical pharmacophore features with 7,8-DHF. Virtual screening of these ligands resulted in identification of at least 6 compounds with better binding affinities than 7,8-DHF. The in silico pharmacokinetic and ADMET studies of the compounds also indicated better drug-like qualities than those of 7,8-DHF. Postdocking analyses and molecular dynamics simulations of the best hits, 6-hydroxy-10-(2-oxo-1-azatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem: 91637738) and 6-hydroxy-10-(8-methyl-2-oxo-1H-quinolin-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem ID: 91641310), revealed unique ligand interactions, validating the docking findings. We hereby recommend experimental validation of the best hits in CDKL5 knock out models before consideration as drugs in CDD management.

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Ishii, J., T. Tanaka, S. Matsumura, K. Tatematsu, S. Kuroda, C. Ogino, H. Fukuda et A. Kondo. « Yeast-Based Fluorescence Reporter Assay of G Protein-coupled Receptor Signalling for Flow Cytometric Screening : FAR1-Disruption Recovers Loss of Episomal Plasmid Caused by Signalling in Yeast ». Journal of Biochemistry 143, n^o 5 (23 janvier 2008) : 667–74. http://dx.doi.org/10.1093/jb/mvn018.

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Articles de revues sur le sujet « Screening, Signalling »

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