Zeitschriftenartikel: „Translational agent“

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Alvstad, Cecilia. „The translation pact“. Language and Literature: International Journal of Stylistics 23, Nr. 3 (31.07.2014): 270–84. http://dx.doi.org/10.1177/0963947014536505.

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In this article I argue that translated texts and translational paratexts invite readers to read translated texts as if they were the originals, a hitherto widely ignored premise of translations. Although translations are produced by many agents in collaboration (authors, publishers, copy-editors and translators), they are generally presented as texts produced predominantly by one agent, the author. I therefore claim that there is a ‘translation pact’ at work in translated literature, a rhetorical construction through which readers are invited to read translated texts as if they were the originals. A narratological implication of the pact is that individual readers who accept the pact will reconstruct only an ‘implied author’ and not an ‘implied translator’. This view differs from earlier works on the implied translator (e.g. Munday, 2008: 11; O’Sullivan, 2003; Schiavi, 1996). The translation pact is most often constructed implicitly, but sometimes translators draw attention to themselves and manifest their agency, for example by discussing translational decisions in prefaces and notes. Against what one would assume from previous claims on the translator’s ‘visibility’ (Venuti, 1995), I demonstrate that the translator’s presence does not necessarily work against the pact but can rather strengthen it. The translation pact explains why readers, including critics, literary scholars and other professional readers, often talk and write about translations as if they were originals composed solely by the author.

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Szczepek, Agnieszka J. „Translational Research in Audiology“. Audiology Research 13, Nr. 5 (25.09.2023): 721–23. http://dx.doi.org/10.3390/audiolres13050063.

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The importance of translational research in the medical sciences is growing logarithmically, as this type of research provides the translation of basic research into a clinical product (a drug, therapeutic agent or means of monitoring a disease), as well as the inverse translation of clinical findings into basic research models [...]

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An, Gary, Qi Mi, Joyeeta Dutta‐Moscato und Yoram Vodovotz. „Agent‐based models in translational systems biology“. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 1, Nr. 2 (September 2009): 159–71. http://dx.doi.org/10.1002/wsbm.45.

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Mayfield, Stephen. „Double agent: translational regulation by a transcription factor“. Chemistry & Biology 3, Nr. 6 (Juni 1996): 415–18. http://dx.doi.org/10.1016/s1074-5521(96)90088-5.

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Dowling, Ryan J. O., Saroj Niraula, Vuk Stambolic und Pamela J. Goodwin. „Metformin in cancer: translational challenges“. Journal of Molecular Endocrinology 48, Nr. 3 (20.02.2012): R31—R43. http://dx.doi.org/10.1530/jme-12-0007.

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The anti-diabetic drug metformin is rapidly emerging as a potential anti-cancer agent. Metformin, effective in treating type 2 diabetes and the insulin resistance syndromes, improves insulin resistance by reducing hepatic gluconeogenesis and by enhancing glucose uptake by skeletal muscle. Epidemiological studies have consistently associated metformin use with decreased cancer incidence and cancer-related mortality. Furthermore, numerous preclinical and clinical studies have demonstrated anti-cancer effects of metformin, leading to an explosion of interest in evaluating this agent in human cancer. The effects of metformin on circulating insulin levels indicate a potential efficacy towards cancers associated with hyperinsulinaemia; however, metformin may also directly inhibit tumour growth. In this review, we describe the mechanism of action of metformin and summarise the epidemiological, clinical and preclinical evidence supporting a role for metformin in the treatment of cancer. In addition, the challenges associated with translating preclinical results into therapeutic benefit in the clinical setting will be discussed.

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Alfer, Alexa. „The translaborative case for a translational hermeneutics“. Target. International Journal of Translation Studies 32, Nr. 2 (08.07.2020): 261–81. http://dx.doi.org/10.1075/target.20105.alf.

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Abstract This paper takes the notion of translaboration as a stepping stone for an exploration of some of the recent debates about translational hermeneutics. In doing so, it aims to expand translaboration’s focus beyond concrete collaborations between multiple translators, or authors and translators, and to think about, and theorise, translaboration as a possible means of framing textual agents reading and writing each other within texts. The argument presented draws on both Hans-Georg Gadamer’s and Paul Ricoeur’s conceptions of the individual subject as interpretative agent, and of translation as an object of philosophical enquiry, and adopts the concept of a “hermeneutics of decipherment” (Maitland 2017, 38) as an alternative to dialogic models of understanding and translating. Similarly, the relationship between philosophical and translational hermeneutics is interrogated and recast as a translaborative endeavour rather than as an immediately reciprocal dialogue. Translaboration, this paper argues, thus also actively furthers the move away from what Blumczynski (2016, 29) calls “an arborescent epistemological paradigm” of interdisciplinarity and contributes to animating a transdisciplinarity that is fundamentally “rhizomatic” (ibid.; see Deleuze and Guattari 2004) in nature.

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Mohammed, Altaf, Roderick H. Dashwood, Sally Dickinson, Mary L. Disis, Elizabeth M. Jaffee, Bryon D. Johnson, Samir N. Khleif et al. „Translational Advances in Cancer Prevention Agent Development (TACPAD) Virtual Workshop on Immunomodulatory Agents: Report“. Journal of Cancer Prevention 26, Nr. 4 (30.12.2021): 309–17. http://dx.doi.org/10.15430/jcp.2021.26.4.309.

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A. Sheikh Al-Shabab, Omar. „Linguistic Experience and Identity: Contextualizing the Mental Lexicon In English-Arabic Poetry Translation“. International Journal of Applied Linguistics and English Literature 10, Nr. 6 (30.11.2021): 38. http://dx.doi.org/10.7575/aiac.ijalel.v.10n.6p.38.

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Monolingual Language behavior rests on three components: human agent, code and message. Translation processing requires three more constructs: translator, two codes, and a message in two texts. Equivalence theories attempted to supersede faithfulness and sameness of meaning in translation, but equivalence is a “convenience”, and is “always relative” (Baker 1992). Translational commensurability and semantic transportation thwart obtaining equivalence; therefore, the Interpretive Frame includes experience and identity among the elements necessary for any translation (Author, 2008). To explore poetic aesthetics, experience is related to personality observed in the Mental lexicon, while identity is related to phonic appeal observed in euphony. These relations are investigated in Arabic translations of English poems by Coleridge, Keats, Tennyson, Wordsworth, and Auden. Preliminary results show that: 1) the Mental Lexicon and euphony vary according to experience and identity, 2) contextualizing lexical appropriateness, euphony and metaphors contributes to poetic aesthetics.

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Han, J., P. Thompson und B. Beutler. „Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway.“ Journal of Experimental Medicine 172, Nr. 1 (01.07.1990): 391–94. http://dx.doi.org/10.1084/jem.172.1.391.

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The induction of cachectin/tumor necrosis factor (TNF) synthesis by bacterial endotoxins is a process that entails activation at several levels. Cachectin/TNF gene transcription is accelerated, leading to rapid accumulation of mRNA within the macrophage cytosol. In addition, translational derepression occurs, leading to far more efficient message utilization. Through the use of posttranscriptional reporter constructs, we now demonstrate that certain agents capable of inhibiting cachectin/TNF biosynthesis operate through different mechanisms. In RAW 264.7 macrophages, pentoxifylline blocks cachectin/TNF mRNA accumulation but has no effect upon the efficiency of reporter mRNA translation. Dexamethasone, on the other hand, has only a modest effect on cachectin/TNF mRNA accumulation, but strongly impedes translational derepression. Combined application of dexamethasone and pentoxifylline to macrophages causes a greater suppression of cachectin/TNF biosynthesis that can be achieved by either agent alone. These findings suggest that the signaling pathway activated by endotoxin is branched, and that selective inhibition of different parts of the pathway may be achieved through the use of distinct agents.

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Gibson, Jason, Tristan Schuler, Loy McGuire, Daniel M. Lofaro und Donald Sofge. „Swarm and Multi-agent Time-based A* Path Planning for Lighter-Than-Air Systems“. Unmanned Systems 08, Nr. 03 (Juli 2020): 253–60. http://dx.doi.org/10.1142/s2301385020500181.

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This work develops and implements a multi-agent time-based path-planning method using A*. The purpose of this work is to create methods in which multi-agent systems can coordinate actions and complete them at the same time. We utilized A* with constraints defined by a dynamic model of each agent. The model for each agent is updated during each time step and the resulting control is determined. This results in a translational path that each of the agents is physically capable of completing in synchrony. The resulting path is given to the agents as a sequence of waypoints. Periodic updates of the path are calculated, utilizing real-world position and velocity information, as the agents complete the task to account for external disturbances. Our methodology is tested in a dynamic simulation environment as well as on real-world lighter-than-air robotic agents.

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Hidalgo, M., B. Rubio-Viqueira, C. Weekes, D. Song, P. Shah, W. Messersmith, W. Messersmith et al. „In vivo platform for translational drug development and biomarker discovery in pancreatic cancer“. Journal of Clinical Oncology 24, Nr. 18_suppl (20.06.2006): 4000. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4000.

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4000 While there are many new agents entering clinical development, there is very little data to prioritize which agents should be explored in pancreas cancer. Furthermore, often there is no information on biomarkers that may predict the activity of these drugs in pancreas cancer. In this project, we have generated a cohort of 30 pancreatic cancer xenografts by implanting in nude mice tumor materials from surgical specimens. Molecular studies show that a) these tumors maintain the genetic features of the originator cancer such as KRAS, p53 and DPC4 gene status; b) tumors represent the heterogeneity of pancreatic cancer well (there is not selection of any genotype in the xenograft ) and c) features do not changed over time. We have used this platform to explore the activity of a battery with a total of 10 new anticancer agents including inhibitors of MAPK, EGFR, mTOR, src kinase, Ras oncogene, mitosis regulators, angiogenesis, heat shock protein and hedgehog pathway inhibitors using a methodology similar to a two stage phase II clinical trial. All agents are tested against 10 xenografts. Those inactive are not explored anymore. Active agents are tested against the full set of tumors. Thus far we have shown that inhibitors of mTOR and MAPK have substantial activity in this model while Ras interacting agents and EGFR targeted drugs have no single agent activity. For active agents, we have characterized the tumors for potential strategies and biormarkers that may predict activity using both a target-focus approach as well as general profiling approach. Signaling inhibitors are more active in tumors with evidence of activation of the targeted pathway. In addition, ex vivo assays indicate that the ability to inhibit the targeted pathway is associated with agent activity. This information may help to prioritize agents for clinical development in pancreatic cancer. [Table: see text]

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Çelik, Bilal. „Translation in the Kurdish magazine Hawar“. Translation and/in Periodical Publications 14, Nr. 2 (26.06.2019): 283–305. http://dx.doi.org/10.1075/tis.00042.cel.

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Abstract This article explores the role of translation in forming and legitimizing a Kurdish cultural identity through diverse renderings in the Kurdish magazine Hawar launched by Celadet Alî Bedirxan between 1932 and 1943 in Damascus. It also sheds light on the tense relationship between Kurdish and Turkish cultures, which also impacted the translational and cultural aspects of the periodical. This relation has relatively improved from the late twentieth century onwards. My argument is that the composition of Hawar as a whole and translations in the periodical aimed to form a Kurdish cultural identity and legitimize it both for the Kurds and worldwide audience in the historical conditions of the 1930s and 1940s. This article will point out the pivotal position of translation in the composition of Hawar and the role played by Celadet Alî Bedirxan as an agent in this undertaking.

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Miller, Mark Steven, Peter J. Allen, Powel H. Brown, Andrew T. Chan, Margie L. Clapper, Roderick H. Dashwood, Shadmehr Demehri et al. „Meeting Report: Translational Advances in Cancer Prevention Agent Development Meeting“. Journal of Cancer Prevention 26, Nr. 1 (30.03.2021): 71–82. http://dx.doi.org/10.15430/jcp.2021.26.1.71.

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Üstün Külünk, Sema. „The novel Mütercim as a site of transfiction: A case of translation in life and the translation of life in the transformational republican era in Turkey“. International Journal of Translation and Interpreting Research 15, Nr. 1 (28.02.2023): 236–52. http://dx.doi.org/10.12807/ti.115201.2023.a12.

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Translation has a rich history in Ottoman and Turkish literature, and a study of transmesis in a transfiction has great potentials for analyzing the praxis and pragmatics of translation in Turkey. This study focuses on the translational action in the mirror of fiction with a case study on the Turkish novel Mütercim (2013) [Translator] by Alper Gürkan. Investigating translation both as a performance (i.e., text) and an experience (i.e., agency), the analysis is constructed upon four categories: 1) actual translation in its technical sense; (2) the agency of the translator as a subject and object of the translation; (3) figurative/metaphoric use of translation; and (4) the potentials of mistranslation vis-a-vis pseudotranslation. The multi-layered translational baggage of the novel serves as a site par excellence to delimit the definition of translation, which begins as a faithful translation and ends up as an almost genuine writing, a mistranslation in the novel. Skillfully imposed attributions to change, transformation, fragmentation, and dislocation under a translational context determine the fate of both the text and the agent in Mütercim: corrupted and originally lost. This elegy for origins resonates in the discourse of the author as neo- Ottoman fantasy where we witness the emergence of translation as the lieu of historical criticism under the guise of a transfiction.

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Fowkes, Milan M., Patricia Das Neves Borges, Fernando Cacho-Nerin, Paul E. Brennan, Tonia L. Vincent und Ngee H. Lim. „Imaging articular cartilage in osteoarthritis using targeted peptide radiocontrast agents“. PLOS ONE 17, Nr. 5 (10.05.2022): e0268223. http://dx.doi.org/10.1371/journal.pone.0268223.

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Background Established MRI and emerging X-ray contrast agents for non-invasive imaging of articular cartilage rely on non-selective electrostatic interactions with negatively charged proteoglycans. These contrast agents have limited prognostic utility in diseases such as osteoarthritis (OA) due to the characteristic high turnover of proteoglycans. To overcome this limitation, we developed a radiocontrast agent that targets the type II collagen macromolecule in cartilage and used it to monitor disease progression in a murine model of OA. Methods To confer radiopacity to cartilage contrast agents, the naturally occurring tyrosine derivative 3,5-diiodo-L-tyrosine (DIT) was introduced into a selective peptide for type II collagen. Synthetic DIT peptide derivatives were synthesised by Fmoc-based solid-phase peptide synthesis and binding to ex vivo mouse tibial cartilage evaluated by high-resolution micro-CT. Di-Iodotyrosinated Peptide Imaging of Cartilage (DIPIC) was performed ex vivo and in vivo 4, 8 and 12 weeks in mice after induction of OA by destabilisation of the medial meniscus (DMM). Finally, human osteochondral plugs were imaged ex vivo using DIPIC. Results Fifteen DIT peptides were synthesised and tested, yielding seven leads with varying cartilage binding strengths. DIPIC visualised ex vivo murine articular cartilage comparably to the ex vivo contrast agent phosphotungstic acid. Intra-articular injection of contrast agent followed by in vivo DIPIC enabled delineation of damaged murine articular cartilage. Finally, the translational potential of the contrast agent was confirmed by visualisation of ex vivo human cartilage explants. Conclusion DIPIC has reduction and refinement implications in OA animal research and potential clinical translation to imaging human disease.

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Tator, Charles H., Robin Hashimoto, Annie Raich, Daniel Norvell, Michael G. Fehlings, James S. Harrop, James Guest, Bizhan Aarabi und Robert G. Grossman. „Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury“. Journal of Neurosurgery: Spine 17, Suppl1 (September 2012): 157–229. http://dx.doi.org/10.3171/2012.5.aospine12116.

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There is a need to enhance the pipeline of discovery and evaluation of neuroprotective pharmacological agents for patients with spinal cord injury (SCI). Although much effort and money has been expended on discovering effective agents for acute and subacute SCI, no agents that produce major benefit have been proven to date. The deficiencies of all aspects of the pipeline, including the basic science input and the clinical testing output, require examination to determine remedial strategies. Where has the neuroprotective/pharmacotherapy preclinical process failed and what needs to be done to achieve success? These are the questions raised in the present review, which has 2 objectives: 1) identification of articles that address issues related to the translational readiness of preclinical SCI pharmacological therapies; and 2) examination of the preclinical studies of 5 selected agents evaluated in animal models of SCI (including blunt force trauma, penetrating trauma, or ischemia). The 5 agents were riluzole, glyburide, magnesium sulfate, nimodipine, and minocycline, and these were selected because of their promise of translational readiness as determined by the North American Clinical Trials Network Consortium. The authors found that there are major deficiencies in the effort that has been extended to coordinate and conduct preclinical neuroprotection/pharmacotherapy trials in the SCI field. Apart from a few notable exceptions such as the NIH effort to replicate promising strategies, this field has been poorly coordinated. Only a small number of articles have even attempted an overall evaluation of the neuroprotective/pharmacotherapy agents used in preclinical SCI trials. There is no consensus about how to select the agents for translation to humans on the basis of their preclinical performance and according to agreed-upon preclinical performance criteria. In the absence of such a system and to select the next agent for translation, the Consortium has developed a Treatment Strategy Selection Committee, and this committee selected the most promising 5 agents for potential translation. The results show that the preclinical work on these 5 agents has left numerous gaps in knowledge about their preclinical performance and confirm the need for significant changes in preclinical neuroprotection/pharmacotherapy trials in SCI. A recommendation is made for the development and validation of a preclinical scoring system involving worldwide experts in preclinical and clinical SCI.

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Li, Yinghui, Laurel E. Schappell, Claire Polizu, James DiPersio, Stella E. Tsirka, Marc W. Halterman und Neil A. Nadkarni. „Evolving Clinical–Translational Investigations of Cerebroprotection in Ischemic Stroke“. Journal of Clinical Medicine 12, Nr. 21 (24.10.2023): 6715. http://dx.doi.org/10.3390/jcm12216715.

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Ischemic stroke is a highly morbid disease, with over 50% of large vessel stroke (middle cerebral artery or internal carotid artery terminus occlusion) patients suffering disability despite maximal acute reperfusion therapy with thrombolysis and thrombectomy. The discovery of the ischemic penumbra in the 1980s laid the foundation for a salvageable territory in ischemic stroke. Since then, the concept of neuroprotection has been a focus of post-stroke care to (1) minimize the conversion from penumbra to core irreversible infarct, (2) limit secondary damage from ischemia-reperfusion injury, inflammation, and excitotoxicity and (3) to encourage tissue repair. However, despite multiple studies, the preclinical–clinical research enterprise has not yet created an agent that mitigates post-stroke outcomes beyond thrombolysis and mechanical clot retrieval. These translational gaps have not deterred the scientific community as agents are under continuous investigation. The NIH has recently promoted the concept of cerebroprotection to consider the whole brain post-stroke rather than just the neurons. This review will briefly outline the translational science of past, current, and emerging breakthroughs in cerebroprotection and use of these foundational ideas to develop a novel paradigm for optimizing stroke outcomes.

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Miller, Mark Stevn, Brian Cholewa, John Clifford, Vignesh Gunasekharan, Altaf Mohammed, Shanker Gupta, Robert Shoemaker und Shizuko Sei. „Abstract IA007: PREVENT agent development pipeline“. Cancer Prevention Research 15, Nr. 12_Supplement_2 (01.12.2022): IA007. http://dx.doi.org/10.1158/1940-6215.tacpad22-ia007.

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Abstract The NCI’s PREVENT Cancer Preclinical Drug Development Program is a peer-reviewed program designed to support the preclinical development of promising agents and biomarkers for cancer interception/prevention towards clinical applications. PREVENT is not a grant program but allocates NCI contract resources to advance approved projects in a milestone-driven manner. Results obtained through NCI contract resources are returned to the applicant PIs and used to support further development by the applicants or in partnership with NCI. Resources available to PREVENT Program applicants include preclinical efficacy testing, CGMP manufacturing, GLP pharmacokinetic and IND-enabling toxicology studies, and IND filings. The PREVENT Program is focused on preventive agent development in the areas of Immunoprevention (cancer vaccines and immunomodulatory agents), Chemoprevention (novel mechanisms, anti-inflammatory agents, drug repurposing, toxicity reduction via alternative dosing regimens and agent combinations) and clinically translatable mechanistic biomarkers (pharmacodynamics, immune correlates, and tumor preventive efficacy). Submission deadlines for PREVENT Concept Applications occur twice per year on the second Monday in January and July. Further information can be obtained at the PREVENT Program website: https://prevention.cancer.gov/major-programs/prevent-cancer-preclinical Citation Format: Mark Stevn Miller, Brian Cholewa, John Clifford, Vignesh Gunasekharan, Altaf Mohammed, Shanker Gupta, Robert Shoemaker, Shizuko Sei. PREVENT agent development pipeline [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA007.

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Hu, Jie-li, Ge Xu, Ling Lei, Wen-lu Zhang, Ai-long Huang und Xue-fei Cai. „Etoposide Phosphate Enhances the Acetylation Level of Translation Elongation Factor 1A in PLC5 Cells“. Zeitschrift für Naturforschung C 67, Nr. 5-6 (01.06.2012): 327–30. http://dx.doi.org/10.1515/znc-2012-5-613.

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Translation elongation factor 1A (eEF1A) is a factor critically involved in the process of protein synthesis. The activity of eEF1A has been shown by several studies to be regulated by post-translational modifi cations such as phosphorylation and dephosphorylation. However, until now less research has focused on other post-translational modifi cations of eEF1A, especially acetylation. In this report, we provide new evidence for the existence of eEF1A acetylation in PLC5 cells by immunoprecipitation and Western blotting. Using the histone deacetylase (HDAC) inhibitor trichostatin A (TSA), we found that the deacetylation of eEF1A is mainly attributable to classes I and II HDAC rather than class III HDAC, and, furthermore, that the antitumour agent etoposide phosphate (VP 16) enhances the acetylation of eEF1A in a synergistic way with TSA. Our data suggest the possibility that the increased acetylation of eEF1A could be a new mechanism for the antitumour effect of etoposide

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Scavuzzo, C. J., M. J. LeBlancq, F. Nargang, H. Lemieux, T. J. Hamilton und C. T. Dickson. „The amnestic agent anisomycin disrupts intrinsic membrane properties of hippocampal neurons via a loss of cellular energetics“. Journal of Neurophysiology 122, Nr. 3 (01.09.2019): 1123–35. http://dx.doi.org/10.1152/jn.00370.2019.

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The nearly axiomatic idea that de novo protein synthesis is necessary for long-term memory consolidation is based heavily on behavioral studies using translational inhibitors such as anisomycin. Although inhibiting protein synthesis has been shown to disrupt the expression of memory, translational inhibitors also have been found to profoundly disrupt basic neurobiological functions, including the suppression of ongoing neural activity in vivo. In the present study, using transverse hippocampal brain slices, we monitored the passive and active membrane properties of hippocampal CA1 pyramidal neurons using intracellular whole cell recordings during a brief ~30-min exposure to fast-bath-perfused anisomycin. Anisomycin suppressed protein synthesis to 46% of control levels as measured using incorporation of radiolabeled amino acids and autoradiography. During its application, anisomycin caused a significant depolarization of the membrane potential, without any changes in apparent input resistance or membrane time constant. Anisomycin-treated neurons also showed significant decreases in firing frequencies and spike amplitudes, and showed increases in spike width across spike trains, without changes in spike threshold. Because these changes indicated a loss of cellular energetics contributing to maintenance of ionic gradients across the membrane, we confirmed that anisomycin impaired mitochondrial function by reduced staining with 2,3,5-triphenyltetrazolium chloride and also impaired cytochrome c oxidase (complex IV) activity as indicated through high-resolution respirometry. These findings emphasize that anisomycin-induced alterations in neural activity and metabolism are a likely consequence of cell-wide translational inhibition. Critical reevaluation of studies using translational inhibitors to promote the protein synthesis dependent idea of long-term memory is absolutely necessary. NEW & NOTEWORTHY Memory consolidation is thought to be dependent on the synthesis of new proteins because translational inhibitors produce amnesia when administered just after learning. However, these agents also disrupt basic neurobiological functions. We show that blocking protein synthesis disrupts basic membrane properties of hippocampal neurons that correspond to induced disruptions of mitochondrial function. It is likely that translational inhibitors cause amnesia through their disruption of neural activity as a result of dysfunction of intracellular energetics.

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An, Gary, und Scott Christley. „Addressing the Translational Dilemma: Dynamic Knowledge Representation of Inflammation Using Agent-Based Modeling“. Critical Reviews in Biomedical Engineering 40, Nr. 4 (2012): 323–40. http://dx.doi.org/10.1615/critrevbiomedeng.v40.i4.70.

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Li, Xiao, Yi-Ying Lin, Jia-Yi Tan, Kang-Lun Liu, Xiao-Ling Shen, Ying-Jie Hu und Rui-Yi Yang. „Lappaol F, an anticancer agent, inhibits YAP via transcriptional and post-translational regulation“. Pharmaceutical Biology 59, Nr. 1 (01.01.2021): 619–28. http://dx.doi.org/10.1080/13880209.2021.1923759.

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An, Gary. „QS448. From Molecule to Man: Multi-Scale Translational Agent Based Modeling of Inflammation“. Journal of Surgical Research 144, Nr. 2 (Februar 2008): 445–46. http://dx.doi.org/10.1016/j.jss.2007.12.706.

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Hoogstins, C. E. S., Q. R. J. G. Tummers, A. F. Cohen, C. J. H. van de Velde, A. L. Vahrmeijer und J. Burggraaf. „A novel tumor-specific imaging agent for fluorescence guided surgery: a translational study“. Clinical Therapeutics 37, Nr. 8 (August 2015): e70. http://dx.doi.org/10.1016/j.clinthera.2015.05.211.

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Hoenig, Wolfgang, T. K. Kumar, Liron Cohen, Hang Ma, Hong Xu, Nora Ayanian und Sven Koenig. „Multi-Agent Path Finding with Kinematic Constraints“. Proceedings of the International Conference on Automated Planning and Scheduling 26 (30.03.2016): 477–85. http://dx.doi.org/10.1609/icaps.v26i1.13796.

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Multi-Agent Path Finding (MAPF) is well studied in both AI and robotics. Given a discretized environment and agents with assigned start and goal locations, MAPF solvers from AI find collision-free paths for hundreds of agents with user-provided sub-optimality guarantees. However, they ignore that actual robots are subject to kinematic constraints (such as finite maximum velocity limits) and suffer from imperfect plan-execution capabilities. We therefore introduce MAPF-POST, a novel approach that makes use of a simple temporal network to postprocess the output of a MAPF solver in polynomial time to create a plan-execution schedule that can be executed on robots. This schedule works on non-holonomic robots, takes their maximum translational and rotational velocities into account, provides a guaranteed safety distance between them, and exploits slack to absorb imperfect plan executions and avoid time-intensive replanning in many cases. We evaluate MAPF-POST in simulation and on differential-drive robots, showcasing the practicality of our approach.

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Karas, Hilla. „Illustrated translations longing for the Middle Ages, exemplified by modern french versions of Aucassin et Nicolette“. Punctum. International Journal of Semiotics 06, Nr. 01 (16.10.2020): 161–83. http://dx.doi.org/10.18680/hss.2020.0008.

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The relations between the verbal component, the visual component, and the translational aspect of a given text have been discussed and described by translation scholars and semioticians in a diversity of manners. A significant graphic element may be introduced during the translation production, usually in dialogue with the verbal one, thus creating a new intersemiotic text. Medieval manuscripts are known for offering their readers illustrations, miniatures, rubrics, decorated initials, colored and gilded details, and other visual ingredients. As a result, the codex functions as an essential interpretive agent rather than a passive container for verbal texts. This model of the intricate illuminated manuscript was imported into modern culture systems through transfer. However, in reality, most manuscripts exhibit simple decorative schemes or are plain and unadorned, which means that ornaments in their current versions most likely derive from the model mentioned above. The paper looks at the productivity of this medieval model by examining various visual components inserted into the printed modern French translations based on the unmistakably plain manuscript of the thirteenth-century work Aucassin et Nicolette. The analysis will focus on the illustrated translations, addressing the added elements and their characteristics, their relation to the model, the increased determinacy they create, and the resulting reading they seem to encourage. We will suggest that even the narration levels and the performative aspect of the text may be affected by the new, intersemiotic nature bestowed upon this ancient text through the integration of other modalities into its translations.

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Meiyanto, Edy, Adam Hermawan und Anindyajati Anindyajati. „Translational Research in Cancer Drug Development“. Indonesian Journal of Cancer Chemoprevention 2, Nr. 2 (28.06.2011): 198. http://dx.doi.org/10.14499/indonesianjcanchemoprev2iss2pp198-211.

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The development of cancer treatment were initiated by the existence of human’s effort to treat by applying certain materials which is mostly part(s) or extracts of plants, which are now adapted as traditional herbal medicine. The discovery of new drugs was based on intuition and empirical evidence. Thus, high luck factor was involved in a successful treatment with unguaranteed reproducibility. One example of drug being developed through conventional drug development is Taxol. Taxol is an extremely complex natural product and requires a bunch of hard work with high level of serendipity to be discovered as antitumor agent. Recently, rapid development in human biology and technology allow a change in drug discovery strategy by minimizing the luck factor. Targeted therapy has been a very promising strategy of drug development research, especially in cancer treatment. Although cancer has been known as a disease with very complex cellular and histo-pathophysiology, the abundance of studies on proteins, such as receptors and hormones, as the hallmarks of cancer allows us to explore carcinogenesis suppression further based on molecular targeted therapy. Kinases, one type of protein involved in signal transduction regulating cell growth and differentiation, could be the proteins that are proposed to be inhibited in suppressing tumor growth. An interesting example of the drug being discovered based on molecular modeling is the discovery of lapatinib as anti- cancer with specific target on HER-2 and EGFR to overcome the resistance of cancer to Herceptin caused by elevated level of EGFR expression.Keywords : targeted therapy, cancer, translational drug development

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Callahan, Kevin P., Cheryl Corbett, Steven Jacob, Mohammad Minhajuddin, Eleni D. Lagadinou, Randall M. Rossi, Valerie Gross et al. „Rocaglamide Selectively Eradicates Human Leukemia Stem Cells and Synergizes with Multiple Agents to Target AML Cells“. Blood 120, Nr. 21 (16.11.2012): 1338. http://dx.doi.org/10.1182/blood.v120.21.1338.1338.

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Abstract Abstract 1338 Recent evidence suggests that myeloid leukemia is initiated and maintained by Leukemia Stem Cells (LSCs). Standard chemotherapy however, does not efficiently ablate LSCs. Consequently, even for leukemia patients who attain a clinical remission, LSCs are generally not destroyed and are thought to be responsible for subsequent relapse of the disease. Therefore, new treatment regimens are necessary to improve therapeutic outcomes. Nearly half of the agents used in cancer therapy today are either natural products or derivatives of natural products. The present studies demonstrate that rocaglamide, a compound derived from the traditional Chinese medicinal plants Aglaia induces robust apoptosis in primary human AML cells while sparing normal hematopoietic cells. Further analysis of progenitor cells using in vitro colony assays, as well as stem cells using the NOD Scid Gamma (NSG) xenograft model, show that rocaglamide also preferentially targets AML progenitor and stem cell populations. Methionine metabolic labeling experiments show that rocaglamide inhibits the translation of nascent protein synthesis within twenty-four hours and this inhibition results in the rapid loss of short-lived survival proteins such as c-myc, Mcl-1, and Bcl-xl. These results are consistent with previous work showing rocaglamide, and members of the rocaglamide family of compounds, inhibit translation. To investigate further the molecular mechanism of LSC-specific cell death induced by rocaglamide we performed next generation sequencing on 5 AML specimens treated with rocaglamide. Bioinformatic analysis and subsequent experiments showed that rocagalmide leads to P53 activation, NFkB inhibition, cell cycle inhibition as well as defects in mitochondrial integrity and energy metabolism. In addition to efficacy as a single agent, pre-treatment of leukemia cells with rocaglamide significantly sensitizes the cells to several anti-cancer compounds, including cytarabine and daunorubicin two of the front-line chemotherapuetic drugs for AML patients. Importantly, we show that many of the mechanistic features of rocaglamide as a single agent play a role in its ability to synergize. In comparison with translational inhibitors that are used clinically to treat AML patients, temsirolimus and ribovarin, rocaglamide is significantly more toxic to leukemia cells. Interestingly, this increased cytotoxicity does not directly correlate with ability of the compounds to inhibit translational inhibition. Temsirolimus, inhibits translation at levels equal to or greater than rocaglamide however it has a cytostatic effect on leukemia cells in contrast to the cytotoxic effects of rocaglamide. Temsirolimus also does not synergize with anti-cancer compounds to the same degree as rocaglamide. These results suggest that rocaglamide's ability to modulate several key pathways in addition to inhibiting translation are critical to the activity of rocagalmaide and may suggest ways to improve the efficacy of translational inhibitors currently used in the clinic. These studies along with preliminary in vivo pharmacodynamic and pharmacokinetic experiments indicate that rocaglamide may be a promising candidate for the development of a new class of compounds for the treatment of leukemia and for increasing the efficacy of treatments designed to specifically target AML cells. Disclosures: No relevant conflicts of interest to declare.

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Howard, Alex, und William Hope. „Assessment of Antifungal Pharmacodynamics“. Journal of Fungi 9, Nr. 2 (01.02.2023): 192. http://dx.doi.org/10.3390/jof9020192.

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Pharmacokinetic-pharmacodynamic (PK-PD) analysis is of central importance to the progress of an antifungal agent into clinical use. It is crucial to ensure that preclinical studies give the best possible prediction of the way drugs are likely to behave in a clinical setting. This review details the last 30 years of progress in terms of disease model design, efficacy outcome selection and translational modelling in antifungal PK-PD studies. The principles of how PK-PD parameters inform current clinical practice are also discussed, including a review of how these apply to existing and novel agents.

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Mellor, Kimberley M., Margaret A. Brimble und Lea M. D. Delbridge. „Glucose as an agent of post-translational modification in diabetes — New cardiac epigenetic insights“. Life Sciences 129 (Mai 2015): 48–53. http://dx.doi.org/10.1016/j.lfs.2014.03.020.

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Dalasanur Nagaprashantha, Lokesh, Ramesh Adhikari, Jyotsana Singhal, Shireen Chikara, Sanjay Awasthi, David Horne und Sharad S. Singhal. „Translational opportunities for broad-spectrum natural phytochemicals and targeted agent combinations in breast cancer“. International Journal of Cancer 142, Nr. 4 (28.11.2017): 658–70. http://dx.doi.org/10.1002/ijc.31085.

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Simeonov, Anton. „Abstract IA010: NCATS Collaborative Translational Research/Drug Development Resources“. Cancer Prevention Research 15, Nr. 12_Supplement_2 (01.12.2022): IA010. http://dx.doi.org/10.1158/1940-6215.tacpad22-ia010.

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Abstract The mission of the National Center for Advancing Translational Sciences (NCATS) is to catalyze the generation of innovative methods and technologies that will enhance the development, testing, and implementation of interventions across a wide range of human diseases and conditions. NCATS is directly addressing this problem by discovering new technologies and other approaches that could greatly accelerate the process of developing and deploying therapeutic solutions. An introduction of the Center’s internal research operations will be presented, focusing on the use of advanced assay and chemistry technologies to address the wide range of needs associated with early discovery space. Further, an overview of collaborative opportunities for joint projects will be provided. Citation Format: Anton Simeonov. NCATS Collaborative Translational Research/Drug Development Resources [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA010.

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Hsu, Jack Chun-Chieh, Maudry Laurent-Rolle, Joanna B. Pawlak, Craig B. Wilen und Peter Cresswell. „Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein“. Proceedings of the National Academy of Sciences 118, Nr. 24 (27.05.2021): e2101161118. http://dx.doi.org/10.1073/pnas.2101161118.

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The ongoing COVID-19 pandemic has caused an unprecedented global health crisis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19. Subversion of host protein synthesis is a common strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to shut down host protein synthesis and that SARS-CoV-2 nonstructural protein NSP14 exerts this activity. We show that the translation inhibition activity of NSP14 is conserved in human coronaviruses. NSP14 is required for virus replication through contribution of its exoribonuclease (ExoN) and N7-methyltransferase (N7-MTase) activities. Mutations in the ExoN or N7-MTase active sites of SARS-CoV-2 NSP14 abolish its translation inhibition activity. In addition, we show that the formation of NSP14−NSP10 complex enhances translation inhibition executed by NSP14. Consequently, the translational shutdown by NSP14 abolishes the type I interferon (IFN-I)-dependent induction of interferon-stimulated genes (ISGs). Together, we find that SARS-CoV-2 shuts down host innate immune responses via a translation inhibitor, providing insights into the pathogenesis of SARS-CoV-2.

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Yoon, Hyung Joon. „Toward Agentic HRD: A Translational Model of Albert Bandura’s Human Agency Theory“. Advances in Developing Human Resources 21, Nr. 3 (15.07.2019): 335–51. http://dx.doi.org/10.1177/1523422319851437.

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The Problem Albert Bandura has refined a theory of human agency with three modes and four core properties within social cognitive theory. Human agency plays a critical role in one’s adaptation, self-development, and self-renewal. Despite its relevance to human resource development (HRD), human agency theory has not been explored or effectively utilized in HRD research and practice. The Solution Following Bandura’s human agency theory, a translational and implementational model for HRD was proposed. First, the model integrated the four core properties of human agency (intentionality, forethought, self-reactiveness, and self-reflectiveness) into a model by altering the sequence to align with major HRD processes. Second, it synthesized triadic reciprocal determinism with the four core properties of human agency by placing the agent at the center of the model. Third, it is an open systems model that describes reciprocal determinism between the agent and the environment at micro, meso, and macro levels, indicating the dynamics of personal, proxy, and collective agency. The Stakeholders The model will be useful for career practitioners, coaches, organization development consultants, and other HRD professionals who deliver interventions. HRD researchers and theorists may find it worthwhile to test and validate the model. In addition, regardless of disciplines, researchers, and practitioners who follow social cognitive theory may find some insights from the translational model.

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Wongtrakoongate, Patompon, Sittiruk Roytrakul, Sukkid Yasothornsrikul und Sumalee Tungpradabkul. „A Proteome Reference Map of the Causative Agent of MelioidosisBurkholderia pseudomallei“. Journal of Biomedicine and Biotechnology 2011 (2011): 1–5. http://dx.doi.org/10.1155/2011/530926.

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Burkholderia pseudomalleiis the etiologic agent of melioidosis. Using 2DE and MALDI-TOF MS, we report here a proteome reference map constructed from early stationary phase, a bacterial adaptation process. We identified 282 protein spots representing 220 ORFs; many of them have been implicated in bacterial pathogenesis. Up to 20% of identified ORFs belong to post-translational modification and stress responses. The proteome reference map will support future analysis of the bacterial gene and environmental regulation and facilitate comparative proteomics with its sibling species.

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Swenson, Steve, Radu Minea, Cao Tuan, Thu-Zan Thein, Thomas Chen und Francis Markland. „A Novel Venom-Derived Peptide for Brachytherapy of Glioblastoma: Preclinical Studies in Mice“. Molecules 23, Nr. 11 (08.11.2018): 2918. http://dx.doi.org/10.3390/molecules23112918.

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We developed a bacterial expression system to produce a recombinant disintegrin, vicrostatin (VCN), whose structure is based on a natural disintegrin isolated from southern copperhead snake venom. Our goal is to develop VCN for potential clinical translation as an anti-cancer agent. VCN is a peptide of 69 amino acids with a single tyrosine residue. We have employed VCN as integrin-targeted radionuclide therapy (brachytherapy) for treatment of glioblastoma (GBM, glioma). GBM is a deadly brain cancer that doesn’t discriminate between sexes and knows no age limit. We established that the tyrosine residue in VCN can be radioiodinated with full retention of bioactivity. 131I-VCN was utilized for integrin-targeted radionuclide therapy using mouse models of glioma. The combination of radioiodinated VCN plus temozolomide (a DNA alkylating agent) significantly prolonged survival of glioma-bearing mice. We also obtained similar results using an immunocompetent mouse model and a murine glioma cell line. In summary, as demonstrated in studies reported here we have shown that VCN as targeted radionuclide therapy for GBM has significant translational potential for therapy of this deadly disease.

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Słomka, Artur, Miroslaw Kornek und William C. Cho. „Small Extracellular Vesicles and Their Involvement in Cancer Resistance: An Up-to-Date Review“. Cells 11, Nr. 18 (17.09.2022): 2913. http://dx.doi.org/10.3390/cells11182913.

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In recent years, tremendous progress has been made in understanding the roles of extracellular vesicles (EVs) in cancer. Thanks to advancements in molecular biology, it has been found that the fraction of EVs called exosomes or small EVs (sEVs) modulates the sensitivity of cancer cells to chemotherapeutic agents by delivering molecularly active non-coding RNAs (ncRNAs). An in-depth analysis shows that two main molecular mechanisms are involved in exosomal modified chemoresistance: (1) translational repression of anti-oncogenes by exosomal microRNAs (miRs) and (2) lack of translational repression of oncogenes by sponging of miRs through long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). At the cellular level, these processes increase the proliferation and survival of cancer cells and improve their ability to metastasize and resist apoptosis. In addition, studies in animal models have shown enhancing tumor size under the influence of exosomal ncRNAs. Ultimately, exosomal ncRNAs are responsible for clinically significant chemotherapy failures in patients with different types of cancer. Preliminary data have also revealed that exosomal ncRNAs can overcome chemotherapeutic agent resistance, but the results are thoroughly fragmented. This review presents how exosomes modulate the response of cancer cells to chemotherapeutic agents. Understanding how exosomes interfere with chemoresistance may become a milestone in developing new therapeutic options, but more data are still required.

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Nakazato, Hitoshi, Hisashi Oku, Shoji Yamane, Yuji Tsuruta und Ryuji Suzuki. „A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-α at the translational level“. European Journal of Pharmacology 446, Nr. 1-3 (Juni 2002): 177–85. http://dx.doi.org/10.1016/s0014-2999(02)01758-2.

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PURRO, Silvia A., C. Gastón BISIG, María A. CONTIN, Héctor S. BARRA und Carlos A. ARCE. „Post-translational incorporation of the antiproliferative agent azatyrosine into the C-terminus of α-tubulin“. Biochemical Journal 375, Nr. 1 (01.10.2003): 121–29. http://dx.doi.org/10.1042/bj20030776.

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Detyrosination/tyrosination of tubulin is a post-translational modification that occurs at the C-terminus of the α-subunit, giving rise to microtubules rich in either tyrosinated or detyrosinated tubulin which coexist in the cell. We hereby report that the tyrosine analogue, azatyrosine, can be incorporated into the C-terminus of α-tubulin instead of tyrosine. Azatyrosine is structurally identical to tyrosine except that a nitrogen atom replaces carbon-2 of the phenolic group. Azatyrosine competitively excluded incorporation of [14C]tyrosine into tubulin of soluble brain extract. A newly developed rabbit antibody specific to C-terminal azatyrosine was used to study incorporation of azatyrosine in cultured cells. When added to the culture medium (Ham's F12K), azatyrosine was incorporated into tubulin of glioma-derived C6 cells. This incorporation was reversible, i.e. after withdrawal of azatyrosine, tubulin lost azatyrosine and reincorporated tyrosine. Azatyrosinated tubulin self-assembled into microtubules to a similar degree as total tubulin both in vitro and in vivo. Studies by other groups have shown that treatment of certain types of cultured cancer cells with azatyrosine leads to reversion of phenotype to normal, and that administration of azatyrosine into animals harbouring human proto-oncogenic c-Ha-ras prevents tumour formation. These interesting observations led us to study this phenomenon in relation to tubulin status. Under conditions in which tubulin was mostly azatyrosinated, C6 cells remained viable but did not proliferate. After 7–10 days under these conditions, morphology changed from a fused, elongated shape to a rounded soma with thin processes. Incorporation of azatyrosine into the C-terminus of α-tubulin is proposed as one possible cause of reversion of the malignant phenotype.

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Saylor, Timothy C., Timothy Casselli, Kathryn G. Lethbridge, Jessamyn P. Moore, Katie M. Owens, Catherine A. Brissette, Wolfram R. Zückert und Brian Stevenson. „Borrelia burgdorferi, the Lyme disease spirochete, possesses genetically-encoded responses to doxycycline, but not to amoxicillin“. PLOS ONE 17, Nr. 9 (30.09.2022): e0274125. http://dx.doi.org/10.1371/journal.pone.0274125.

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Some species of bacteria respond to antibiotic stresses by altering their transcription profiles, in order to produce proteins that provide protection against the antibiotic. Understanding these compensatory mechanisms allows for informed treatment strategies, and could lead to the development of improved therapeutics. To this end, studies were performed to determine whether Borrelia burgdorferi, the spirochetal agent of Lyme disease, also exhibits genetically-encoded responses to the commonly prescribed antibiotics doxycycline and amoxicillin. After culturing for 24 h in a sublethal concentration of doxycycline, there were significant increases in a substantial number of transcripts for proteins that are involved with translation. In contrast, incubation with a sublethal concentration of amoxicillin did not lead to significant changes in levels of any bacterial transcript. We conclude that B. burgdorferi has a mechanism(s) that detects translational inhibition by doxycycline, and increases production of mRNAs for proteins involved with translation machinery in an attempt to compensate for that stress.

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Kopitz, J., B. Rist und P. Bohley. „Post-translational arginylation of ornithine decarboxylase from rat hepatocytes“. Biochemical Journal 267, Nr. 2 (15.04.1990): 343–48. http://dx.doi.org/10.1042/bj2670343.

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Ornithine decarboxylase (ODC) was purified 6500-fold from NMRI mouse kidneys under conditions designed to inhibit degradation by proteinases. The enzyme was homogeneous by SDS/polyacrylamide-gel electrophoresis, and the specific activity was among the highest reported. The yield was 70%. A monoclonal antibody against this preparation was generated and used in studies to investigate the half-life of ODC in cultured rat hepatocytes labelled with [35S]methionine. This value was 39 +/- 4 min and was unchanged when either NH4Cl (as a lysosomotropic agent) or leupeptin (as a lysosomal proteinase inhibitor) was added to the culture medium. Thus the intracellular turnover of ODC in cultured hepatocytes occurs mainly in extra-lysosomal compartments. Arginylation of rat ODC was investigated in vitro by incubation with L-[3H]arginyl-tRNA, and the incorporation of the label was compared with that of total cytosolic proteins. Arginylated ODC had a specific radioactivity 8600 times that of the bulk of cytosolic protein. Edman degradation of this ODC showed that the post-translational arginylation occurred only at the alpha-amino end of the enzyme. The inhibitor of arginyl-tRNA:protein arginyltransferase (EC 2.3.2.8), L-glutamyl-L-valyl-L-phenylalanine, increased the half-life of ODC in cultured hepatocytes from 39 min to more than 90 min. The possible significance of the preferential post-translational arginylation of ornithine decarboxylase to its rapid turnover is discussed.

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Attwood, Kathleen, Aaron Robichaud, Jae Ho Han, Gabriel Wajnberg, Jeremy Roy und Adrienne Weeks. „DDDR-06. THE SMOKING CESSATION AGENT LOBELINE DELAYS HYPOXIC STRESS RECOVERY RESULTING IN GLIOBLASTOMA CELL DEATH“. Neuro-Oncology 25, Supplement_5 (01.11.2023): v106. http://dx.doi.org/10.1093/neuonc/noad179.0400.

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Abstract Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumour with a universally fatal prognosis. GBM is characterized by extensive regions of hypoxia which adversely impacts clinical outcomes, as hypoxia promotes chemoresistance. Tumour cells can adapt to and survive hypoxic stress by inducing rapid changes in the translational landscape, facilitated in part by the formation of stress granules (SGs). SGs are cytoplasmic aggregates of untranslated mRNAs and RNA binding proteins formed in response to a variety of cellular stressors, that allow cells to temporarily prioritize translation of stress-related proteins. Previous work in our laboratory has shown that GBM cells form SGs in vitro and in vivo, and that pharmacologically altering SG dynamics to prevent their dissolution (effectively locking cells in a stressed state) increases GBM cell death. Here we have identified another compound that delays the dissolution of hypoxia-induced SGs in GBM cells, the smoking cessation agent lobeline. SG dissolution typically occurs within 15 minutes post-hypoxia, however pre-treatment of immortalized GBM cells with lobeline delays SG dissolution for up to 2 hours. This delay in SG dissolution is dose dependent, as higher lobeline concentrations resulted in corresponding increases in the percentage of cells containing SGs and the average number of SGs per cell post-hypoxia. Lobeline also led to sustained phosphorylation of eIF2a (a key regulator of translation initiation) with an accompanying decrease in global protein translation levels post-hypoxia. Importantly, the combination of lobeline and hypoxia led to synergistic cell death in both immortalized and primary GBM cells, specifically through increased necrosis. Lobeline acts as a VMAT2 ligand and can stimulate dopamine release. Interestingly, we have found miRNA related to dopamine metabolism pathways overrepresented in extracellular vesicles isolated from GBM patient plasma. We postulate that disrupting the balance of stress pathways may have therapeutic potential in the future.

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Langdon, Grant, John D. Davis, Lynn M. McFadyen, Mark Dewhurst, Neil S. Brunton, Jaiessh K. Rawal, Piet H. Van der Graaf und Neil Benson. „Translational pharmacokinetic-pharmacodynamic modelling; application to cardiovascular safety data for PF-00821385, a novel HIV agent“. British Journal of Clinical Pharmacology 69, Nr. 4 (April 2010): 336–45. http://dx.doi.org/10.1111/j.1365-2125.2009.03594.x.

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Verdura, Sara, Elisabet Cuyàs, Verónica Ruiz-Torres, Vicente Micol, Jorge Joven, Joaquim Bosch-Barrera und Javier A. Menendez. „Lung Cancer Management with Silibinin: A Historical and Translational Perspective“. Pharmaceuticals 14, Nr. 6 (11.06.2021): 559. http://dx.doi.org/10.3390/ph14060559.

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The flavonolignan silibinin, the major bioactive component of the silymarin extract of Silybum marianum (milk thistle) seeds, is gaining traction as a novel anti-cancer therapeutic. Here, we review the historical developments that have laid the groundwork for the evaluation of silibinin as a chemopreventive and therapeutic agent in human lung cancer, including translational insights into its mechanism of action to control the aggressive behavior of lung carcinoma subtypes prone to metastasis. First, we summarize the evidence from chemically induced primary lung tumors supporting a role for silibinin in lung cancer prevention. Second, we reassess the preclinical and clinical evidence on the effectiveness of silibinin against drug resistance and brain metastasis traits of lung carcinomas. Third, we revisit the transcription factor STAT3 as a central tumor-cell intrinsic and microenvironmental target of silibinin in primary lung tumors and brain metastasis. Finally, by unraveling the selective vulnerability of silibinin-treated tumor cells to drugs using CRISPR-based chemosensitivity screenings (e.g., the hexosamine biosynthesis pathway inhibitor azaserine), we illustrate how the therapeutic use of silibinin against targetable weaknesses might be capitalized in specific lung cancer subtypes (e.g., KRAS/STK11 co-mutant tumors). Forthcoming studies should take up the challenge of developing silibinin and/or next-generation silibinin derivatives as novel lung cancer-preventive and therapeutic biomolecules.

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Wu, San-Yuan, Jui-Lung Shen, Kee-Ming Man, Yuan-Ju Lee, Huey-Yi Chen, Yung-Hsiang Chen, Kao-Sung Tsai, Fuu-Jen Tsai, Wei-Yong Lin und Wen-Chi Chen. „An Emerging Translational Model to Screen Potential Medicinal Plants for Nephrolithiasis, an Independent Risk Factor for Chronic Kidney Disease“. Evidence-Based Complementary and Alternative Medicine 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/972958.

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Pharmacological therapy for urolithiasis using medicinal plants has been increasingly adopted for the prevention of its recurrence. ADrosophila melanogastermodel developed for translational research of urolithiasis was applied to evaluate agents with potential antilithic effects and calcium oxalate (CaOx) formation. Potential antilithic herbs were prepared in a mixture of food in a diluted concentration of 5,000 from the original extract with 0.5% ethylene glycol (EG) as the lithogenic agent. The control group was fed with food only. After 3 weeks, flies (n≥150for each group) were killed using CO2narcotization, and the Malpighian tubules were dissected, removed, and processed for polarized light microscopy examination of the crystals. The crystal formation rate in the EG group was 100.0%. In the study, 16 tested herbal drugs reached the crystal formation rate of 0.0%, includingSalviae miltiorrhizae,Paeonia lactiflora, andCarthami flos.Scutellaria baicalensisenhanced CaOx crystal formation. Two herbal drugsCommiphora molmolandNatrii sulfascaused the death of all flies. Our rapid screening methods provided evidence that some medicinal plants have potential antilithic effects. These useful medicinal plants can be further studied using other animal or human models to verify their effects.Corrigendum to “An Emerging Translational Model to Screen Potential Medicinal Plants for Nephrolithiasis, an Independent Risk Factor for Chronic Kidney Disease”

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Kang, C., W. P. Jepson und M. Gopal. „Effect of Drag-Reducing Agent on Slug Characteristics in Multiphase Flow in Inclined Pipes“. Journal of Energy Resources Technology 121, Nr. 2 (01.06.1999): 86–90. http://dx.doi.org/10.1115/1.2795073.

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The effect of drag-reducing agent (DRA) on multiphase flow in upward and downward inclined pipes has been studied. The effect of DRA on pressure drop and slug characteristics such as slug translational velocity, the height of the liquid film, slug frequency, and Froude number have been determined. Experiments were performed in 10-cm i.d., 18-m long plexiglass pipes at inclinations of 2 and 15 deg for 50 percent oil-50 percent water-gas. The DRA effect was examined for concentrations ranging from 0 to 50 ppm. Studies were done for superficial liquid velocities between 0.5 and 3 m/s and superficial gas velocities between 2 and 10 m/s. The results indicate that the DRA was effective in reducing the pressure drop for both upflow and downflow in inclined pipes. Pressure gradient reduction of up to 92 percent for stratified flow with a concentration of 50 ppm DRA was achieved in ±2 deg downward inclined flow. The effectiveness of DRA for slug flow was 67 percent at a superficial liquid velocity of 0.5 m/s and superficial gas velocity of 2 m/s in 15 deg upward inclined pipes. Slug translational velocity does not change with DRA concentrations. The slug frequency decreases from 68 to 54 slugs/min at superficial liquid velocity of 1 m/s and superficial gas velocity of 4 m/s in 15 deg upward inclined pipes as the concentration of 50 ppm was added. The height of the liquid film decreased with the addition of DRA, which leads to an increase in Froude number.

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Pal, Jagannath, Masood Shammas, Subodh Kumar, Maria Gkotzamanidou, Puru Nanjappa, Leutz Buon und Nikhil C. Munshi. „Telomerase-Mediated Repair of Induced DNA Breaks Leads to Increased Genomic Instability in Multiple Myeloma Cells: Possible Mechanism and Translational Significance“. Blood 124, Nr. 21 (06.12.2014): 5170. http://dx.doi.org/10.1182/blood.v124.21.5170.5170.

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Abstract Telomerase has multiple functions. We here reported that besides telomere maintenance, telomerase is also involved in the repair of DNA breaks in myeloma (MM) cells. By sequence analyses of “TTAGGG” enriched genomic fragments, we also mapped the interstitial telomeric repeat sequences (ITS) and demonstrate that telomerase mediated repair involves the insertion of ITS within cancer genome. More importantly, we show that such insertions which occur at higher frequency in cancer vs. normal cells, are reduced in the presence of telomerase inhibitor (TI). We hypothesized that if the ITS if inserted in large numbers following massive DNA breaks, induced by a genotoxic agent, could become substrates for recombination (which is elevated in myeloma) leading to increased genomic instability. To investigate if repair of induced DNA breaks by telomerase would contribute to genomic instability, DNA breaks in RPMI cells were induced by UV, cells cultured in the presence of TI or control oligo for four 4 days, drug was then withdrawn and cells continued in culture for 30 days. Cells were harvested at days 10, 20 and 30 and their genomic DNA evaluated for copy number changes using SNP6.0 arrays. Genome of day 10 for each sample was used as baseline to identify genomic changes in corresponding day 20 and day 30 samples. We observed a gradual increase in deletion events in UV treated control cells from 14-fold at day 20 to 147-fold at day 30, relative to corresponding changes in UV-TI samples at respective time points. Likewise, the amplifications were massively increased (by 500-fold) at day 30, relative to changes in UV-TI cells at the respective time points. When we compared the fold changes in copy number in these samples relative to UV unexposed baseline control cells, changes in TI-treated cells remained close to the baseline till day 30. However, there was a sharp rise in copy number changes in UV treated control cells at corresponding time point. These data indicate that a brief telomerase inhibition during induced DNA damage may prevent late genomic instability. We have further evaluated the translational significance of these findings. We investigated if inhibition of telomerase mediated repair could sensitize cancer cells to DNA damaging chemotherapeutic agents. RPMI MM cells, pretreated with TI or control oligo for 60 hours, were incubated with melphalan at various concentrations for 48 hrs and cell viability assessed. Cell death in cells pretreated with TI was significantly higher than control cells at each dose level suggesting that TI pretreatment sensitizes cells to DNA damaging agents. Telomerase mediated repair involving insertion of telomeric repeats at interstitial break sites prevents immediate genomic loss, and inhibition of this repair sensitizes MM calls to DNA damaging agent. We conclude that presence of a TI during treatment with a DNA damaging agent would not only enhance the efficacy of treatment but may also protect cancer cells against therapy induced late genomic instability and evolution of aggressive malignant clones. Disclosures No relevant conflicts of interest to declare.

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LIM, LILY SIOK HOON, und BRIAN M. FELDMAN. „The Risky Business of Studying Prognosis“. Journal of Rheumatology 40, Nr. 1 (01.12.2012): 9–15. http://dx.doi.org/10.3899/jrheum.121360.

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Prognosis studies provide important healthcare information. Clinicians use prognostic factors to predict disease progress, thus allowing individualization of disease management. Prognosis is the issue in many translational studies that aim to identify biomarkers to predict outcomes. In a clinical trial, researchers may use prognostic factors to sort patients into risk groups, to clarify the effects of a new therapeutic agent. Prognosis studies can have significant effects on clinical practice.

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Rothwell, Stephen W., und Valerie S. Calvert. „Activation of Human Platelets Causes Post-translational Modifications to Cytoplasmic Dynein“. Thrombosis and Haemostasis 78, Nr. 02 (1997): 910–18. http://dx.doi.org/10.1055/s-0038-1657651.

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SummaryIn our studies of human platelets we have detected the presence of the molecular motors kinesin and dynein. Dynein is present at a concentration (0.8 μg/g tissue) that is approximately 1/3 the concentration reported for neuronal tissue. Immunofluorescence microscopy of resting platelets shows that, while platelet microtubules are arranged in coiled hoops forming the marginal band in the cortical region of the platelet, dynein is distributed in a pattern of punctate staining throughout the cytoplasm of the platelets. Fractionation of unactivated platelets shows that dynein partitions to the soluble fraction. Stimulation of platelets with thrombin, ADP or epinephrine causes a partial translocation of dynein from the soluble fraction to the particulate fraction with thrombin being the most efficient agent at promoting this shift. Dynein intermediate chain recovered in the soluble fraction of disrupted platelets following activation displays a transient, time-dependent phosphorylation. In contrast, dynein intermediate chain recovered in the particulate fraction shows decreased phosphorylation. These results indicate that human platelets contain a complex microtubule-based system of motor proteins that is an integral part of the physiological changes occurring during platelet activation.

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Lindquist, Susan, Sylvia Krobitsch, Liming Li und Neal Sondheimer. „Investigating protein conformation–based inheritance and disease in yeast“. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 356, Nr. 1406 (28.02.2001): 169–76. http://dx.doi.org/10.1098/rstb.2000.0762.

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Our work supports the hypothesis that a protein can serve as an element of genetic inheritance. This protein–only mechanism of inheritance is propagated in much the same way as hypothesized for the transmission of the protein–only infectious agent in the spongiform encephalopathies; hence these protein factors have been called yeast prions. Our work has focused on [ PSI + ], a dominant cytoplasmically inherited factor that alters translational fidelity.This change in translation is produced by a self–perpetuating change in the conformation of the translation–termination factor, Sup35. Most recently, we have determined that new elements of genetic inheritance can be created by deliberate genetic engineering, opening prospects for new methods of manipulating heredity. We have also uncovered evidence that other previously unknown elements of protein–based inheritance are encoded in the yeast genome. Finally, we have begun to use yeast as a model system for studying human protein folding diseases, such as Huntington's disease. Proteins responsible for some of these diseases have properties uncannily similar to those that produce protein–based mechanisms of inheritance.

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