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Michalski, John T. "Network security mechanisms utilising network address translation". International Journal of Critical Infrastructures 2, nr 1 (2006): 10. http://dx.doi.org/10.1504/ijcis.2006.008497.
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Smith, Richard W. P., Ross C. Anderson, Osmany Larralde, Joel W. S. Smith, Barbara Gorgoni, William A. Richardson, Poonam Malik, Sheila V. Graham i Nicola K. Gray. "Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding". Proceedings of the National Academy of Sciences 114, nr 24 (30.05.2017): 6310–15. http://dx.doi.org/10.1073/pnas.1610417114.
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Regulation of mRNA translation is a major control point for gene expression and is critical for life. Of central importance is the complex between cap-bound eukaryotic initiation factor 4E (eIF4E), eIF4G, and poly(A) tail-binding protein (PABP) that circularizes mRNAs, promoting translation and stability. This complex is often targeted to regulate overall translation rates, and also by mRNA-specific translational repressors. However, the mechanisms of mRNA-specific translational activation by RNA-binding proteins remain poorly understood. Here, we address this deficit, focusing on a herpes simplex virus-1 protein, ICP27. We reveal a direct interaction with PABP that is sufficient to promote PABP recruitment and necessary for ICP27-mediated activation. PABP binds several translation factors but is primarily considered to activate translation initiation as part of the PABP–eIF4G–eIF4E complex that stimulates the initial cap-binding step. Importantly, we find that ICP27-PABP forms a complex with, and requires the activity of, eIF4G. Surprisingly, ICP27–PABP–eIF4G complexes act independently of the effects of PABP-eIF4G on cap binding to promote small ribosomal subunit recruitment. Moreover, we find that a cellular mRNA-specific regulator, Deleted in Azoospermia-like (Dazl), also employs the PABP–eIF4G interaction in a similar manner. We propose a mechanism whereby diverse RNA-binding proteins directly recruit PABP, in a non–poly(A) tail-dependent manner, to stimulate the small subunit recruitment step. This strategy may be particularly relevant to biological conditions associated with hypoadenylated mRNAs (e.g., germ cells/neurons) and/or limiting cytoplasmic PABP (e.g., viral infection, cell stress). This mechanism adds significant insight into our knowledge of mRNA-specific translational activation and the function of the PABP–eIF4G complex in translation initiation.
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Papadimitriou, George, Athanasios Chatzidimitriou, Dimitris Gizopoulos i Ronny Morad. "An Agile Post-Silicon Validation Methodology for the Address Translation Mechanisms of Modern Microprocessors". IEEE Transactions on Device and Materials Reliability 17, nr 1 (marzec 2017): 3–11. http://dx.doi.org/10.1109/tdmr.2016.2636880.
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Kornykhin, E. V. "Generation of test data for verification of caching mechanisms and address translation in microprocessors". Programming and Computer Software 36, nr 1 (styczeń 2010): 28–35. http://dx.doi.org/10.1134/s0361768810010056.
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Ostareck-Lederer, Antje, Dirk H. Ostareck, Christophe Cans, Gitte Neubauer, Karol Bomsztyk, Giulio Superti-Furga i Matthias W. Hentze. "c-Src-Mediated Phosphorylation of hnRNP K Drives Translational Activation of Specifically Silenced mRNAs". Molecular and Cellular Biology 22, nr 13 (1.07.2002): 4535–43. http://dx.doi.org/10.1128/mcb.22.13.4535-4543.2002.
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ABSTRACT hnRNPK and hnRNP E1/E2 mediate translational silencing of cellular and viral mRNAs in a differentiation-dependent way by binding to specific regulatory sequences. The translation of 15-lipoxygenase (LOX) mRNA in erythroid precursor cells and of the L2 mRNA of human papilloma virus type 16 (HPV-16) in squamous epithelial cells is silenced when either of these cells is immature and is activated in maturing cells by unknown mechanisms. Here we address the question of how the silenced mRNA can be translationally activated. We show that hnRNP K and the c-Src kinase specifically interact with each other, leading to c-Src activation and tyrosine phosphorylation of hnRNP K in vivo and in vitro. c-Src-mediated phosphorylation reversibly inhibits the binding of hnRNP K to the differentiation control element (DICE) of the LOX mRNA 3′ untranslated region in vitro and specifically derepresses the translation of DICE-bearing mRNAs in vivo. Our results establish a novel role of c-Src kinase in translational gene regulation and reveal a mechanism by which silenced mRNAs can be translationally activated.
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Zhang, Bing. "Unsupervised English Intelligent Machine Translation in Wireless Network Environment". Security and Communication Networks 2022 (21.05.2022): 1–9. http://dx.doi.org/10.1155/2022/8208242.
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Researchers suggest unsupervised English machine translation to address the absence of parallel corpus in English translation. Unsupervised pretraining techniques, denoising autoencoders, back translation, and shared latent representation mechanisms are used to simulate the translation task using just monolingual corpora. This paper uses pseudo-parallel data to construct unsupervised neural machine translation (NMT) and dissimilar language pair analysis. This paper firstly analyzes the low performance of unsupervised translation on dissimilar language pairs from three aspects: bilingual word embedding quality, shared words, and word order. And artificial shared word replacement and preordering strategies are proposed to increase the shared words between dissimilar language pairs and reduce the difference in their syntactic structure, thereby improving the translation performance on dissimilar language pairs. The denoising autoencoder and shared latent representation mechanism in unsupervised English machine translation are only required in the early stage of training, and learning the shared latent representation limits the further improvement of performance in different directions. While training the denoising autoencoder by repeatedly altering the training data slows down the convergence of the model, this is especially true for divergent languages. This paper presents an unsupervised NMT model based on pseudo-parallel data to address this issue. It trains two standard supervised neural machine translation models using the pseudo-parallel corpus generated by the unsupervised neural machine translation system, which enhances translation performance and speeds convergence. Finally, the English intelligent translation model is deployed in the wireless network server, and users can access it through the wireless network.
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Efimova, Nadezhda N., Maria L. Ruzhnikova i Marina I. Violina. "Homophonic Translation as Humpty-Dumpty’s Choice". SHS Web of Conferences 50 (2018): 01049. http://dx.doi.org/10.1051/shsconf/20185001049.
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The article considers mechanisms of sense formation in the course of receptive speech activity and deformation of the source text meaning as a result of intentional receptive distortion in the course of auditory perception. Homophonic translation termed soramimi is discussed as a product of audial perception, as a carnivalized text and as a result of an interpretative strategy of cognitive dissonance alignment. We hereby address the auditory modality from the viewpoint of its inherent potential for misinterpretation, both intentional and unintentional. The perceptional phenomena are viewed through addressee’s strategies of realizing the semantic potential of the target text across several languages.
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Titler, Marita G. "Translation Science and Context". Research and Theory for Nursing Practice 24, nr 1 (luty 2010): 35–55. http://dx.doi.org/10.1891/1541-6577.24.1.35.
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Evidence-based health care practices are available for a number of conditions such as asthma, smoking cessation, heart failure, and management of diabetes. However, these practices are not routinely implemented in care delivery and variations in practices abound. Implementing evidence-based practices (EBPs) is challenging, and difficulties implementing evidence may be largely explained by contextual factors. Thus, strategies are needed that address the complexity and systems of care, individual practitioners, senior leadership, and ultimately changing health care cultures to promote an evidence-based practice environment. To advance knowledge about promoting and sustaining adoption of EBPs in health care, translation science needs more studies that test translating research into practice (TRIP) interventions; studies are needed that investigate what TRIP interventions work, for whom, in what circumstances, in what types of settings, and studies that explain the underlying mechanisms of effective TRIP interventions. According to the Translation Research Model, adoption of innovations, such as EBPs, are influenced by the nature of the innovation (e.g., the type and strength of evidence; the clinical topic), and the manner in which it is communicated (disseminated) to members (e.g., physicians, nurses) of a social system (organization, nursing profession). This article discusses the importance of context in translation using this framework as a guide.
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Jaud, Manon, Céline Philippe, Doriana Di Bella, Weiwei Tang, Stéphane Pyronnet, Henrik Laurell, Laurent Mazzolini, Kevin Rouault-Pierre i Christian Touriol. "Translational Regulations in Response to Endoplasmic Reticulum Stress in Cancers". Cells 9, nr 3 (26.02.2020): 540. http://dx.doi.org/10.3390/cells9030540.
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During carcinogenesis, almost all the biological processes are modified in one way or another. Among these biological processes affected, anomalies in protein synthesis are common in cancers. Indeed, cancer cells are subjected to a wide range of stresses, which include physical injuries, hypoxia, nutrient starvation, as well as mitotic, oxidative or genotoxic stresses. All of these stresses will cause the accumulation of unfolded proteins in the Endoplasmic Reticulum (ER), which is a major organelle that is involved in protein synthesis, preservation of cellular homeostasis, and adaptation to unfavourable environment. The accumulation of unfolded proteins in the endoplasmic reticulum causes stress triggering an unfolded protein response in order to promote cell survival or to induce apoptosis in case of chronic stress. Transcription and also translational reprogramming are tightly controlled during the unfolded protein response to ensure selective gene expression. The majority of stresses, including ER stress, induce firstly a decrease in global protein synthesis accompanied by the induction of alternative mechanisms for initiating the translation of mRNA, later followed by a translational recovery. After a presentation of ER stress and the UPR response, we will briefly present the different modes of translation initiation, then address the specific translational regulatory mechanisms acting during reticulum stress in cancers and highlight the importance of translational control by ER stress in tumours.
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Kamkin, A., A. Protsenko i A. Tatarnikov. "An Approach to Test Program Generation Based on Formal Specifications of Caching and Address Translation Mechanisms". Proceedings of the Institute for System Programming of the RAS, nr 3 (2015): 125–38. http://dx.doi.org/10.15514/ispras-2015-27(3)-9.
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Isobell, Deborah, Sandy Lazarus, Shahnaaz Suffla i Mohamed Seedat. "Research translation through participatory research: The case of two community-based projects in low-income African settings". Action Research 14, nr 4 (24.07.2016): 393–411. http://dx.doi.org/10.1177/1476750315626779.
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In the context of a call for public health research to address social challenges and transform communities and society, research translation has increasingly become an imperative in South Africa. Research translation seeks to improve real-world settings and enhance quality of life by applying research-generated knowledge. These goals are shared by proponents of participatory action research (PAR). However, the way in which research is pursued constitutes a major focus for PAR, where the paradigmatic position influences how we relate to knowledge and people, and whether and how we achieve the goals concerned. This article contrasts the meta-theoretical positioning of PAR with that of research translation as it is pursued within public health circles, and then argues how PAR both challenge and optimise the espoused goals of research translation through its accent on co-learning, knowledge co-construction, social action and the dialectic between research and action. We offer two African-centred examples of community-engaged research focusing on violence prevention, and safety and peace promotion to illustrate how the participatory mechanisms of empowerment and agency, knowledge co-construction and knowledge sharing foster research translation. Attention to power dynamics, exemplified through researcher reflexivity is emphasised as a key challenge for researchers wishing to address public health challenges.
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Lang, Charles H., Robert A. Frost i Thomas C. Vary. "Thermal injury impairs cardiac protein synthesis and is associated with alterations in translation initiation". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 286, nr 4 (kwiecień 2004): R740—R750. http://dx.doi.org/10.1152/ajpregu.00661.2003.
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The purpose of the present study was to determine whether burn injury decreases myocardial protein synthesis and potential contributing mechanisms for this impairment. To address this aim, thermal injury was produced by a 40% total body surface area full-thickness scald burn in anesthetized rats, and the animals were studied 24 h later. Burn decreased the in vivo-determined rate of myocardial protein synthesis and translation efficiency by 25% but did not alter the protein synthetic rate in skeletal muscle. To identify potential mechanisms responsible for regulating mRNA translation in cardiac muscle, we examined several eukaryotic initiation factors (eIFs) and elongation factors (eEFs). Burn failed to alter eIF2B activity or the total amount or phosphorylation status of either eIF2α or eIF2Bϵ in heart. In contrast, hearts from burned rats demonstrated 1) an increased binding of the translational repressor 4E-BP1 with eIF4E, 2) a decreased amount of eIF4E associated with eIF4G, and 3) a decreased amount of the hyperphosphorylated γ-form of 4E-BP1. These changes in eIF4E availability were not seen in gastrocnemius muscle where burn injury did not decrease protein synthesis. Furthermore, constitutive phosphorylation of mTOR, S6K1, the ribosomal protein S6, and eIF4G were also decreased in hearts from burned rats. Burn did not appear to adversely affect elongation because there was no significant difference in the myocardial content of eEF1α or eEF2 or the phosphorylation state of eEF2. The above-mentioned burn-induced changes in mRNA translation were associated with an impairment of in vitro myocardial performance. Finally, 24 h postburn, the cardiac mRNA content of IL-1β, IL-6, and high-mobility group protein B1 (but not TNF-α) was increased. In summary, these data suggest that thermal injury specifically decreases cardiac protein synthesis in part by decreasing mRNA translation efficiency resulting from an impairment in translation initiation associated with alterations in eIF4E availability and S6K1 activity.
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Flamerie de Lachapelle, Guillaume. "“Libre à de plus audacieux de pousser plus loin la fidélité”: Traduire les passages obscènes dans la “Collection des Universités de France” entre 1920 et 1945". Philologus 162, nr 1 (1.06.2018): 137–56. http://dx.doi.org/10.1515/phil-2018-0006.
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SummaryThis article aims to show how the translators of the Latin series of the “Collection des Universités de France” treated the obscene passages between 1920 and 1945. Some address the issue in their preface; many deliberately avoid a literal translation, either by quite simply refraining from translating the passages concerned, or by relying on a form of euphemisation. Each of these two strategies itself drew on various mechanisms. In the end, the “Collection des Universités de France” is shown to be more precise than older or contemporary bilingual collections, whether in France or in the English-speaking world. Nontheless, from the 1930 s onward Jules Marouzeau criticised the translators for their prudery; progressively, the new translators became more explicit.
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Alzaid, Wael, i Biju Issac. "Analysis of IPv6 through Implementation of Transition Technologies and Security Attacks". International Journal of Business Data Communications and Networking 12, nr 1 (styczeń 2016): 36–62. http://dx.doi.org/10.4018/ijbdcn.2016010103.
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IPv6 provides more address space, improved address design, and greater security than IPv4. Different transition mechanisms can be used to migrate from IPv4 to IPv6 which includes dual stack networks, tunnels and translation technologies. Within all of this, network security is an essential element and therefore requires special attention. This paper analyses two transition technologies which are dual stack and tunnel. Both technologies are implemented using Cisco Packet Tracer and GNS3. This work will also analyse the security issues of IPv6 to outline the most common vulnerabilities and security issues during the transition. Finally, the authors will design and implement the dual stack, automatic and manual tunnelling transition mechanisms using Riverbed Modeler simulation tool to analyse the performance and compare with the native IPv4 and IPv6 networks.
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Chotewutmontri, Prakitchai, Rosalind Williams-Carrier i Alice Barkan. "Exploring the Link between Photosystem II Assembly and Translation of the Chloroplast psbA mRNA". Plants 9, nr 2 (25.01.2020): 152. http://dx.doi.org/10.3390/plants9020152.
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Photosystem II (PSII) in chloroplasts and cyanobacteria contains approximately fifteen core proteins, which organize numerous pigments and prosthetic groups that mediate the light-driven water-splitting activity that drives oxygenic photosynthesis. The PSII reaction center protein D1 is subject to photodamage, whose repair requires degradation of damaged D1 and its replacement with nascent D1. Mechanisms that couple D1 synthesis with PSII assembly and repair are poorly understood. We address this question by using ribosome profiling to analyze the translation of chloroplast mRNAs in maize and Arabidopsis mutants with defects in PSII assembly. We found that OHP1, OHP2, and HCF244, which comprise a recently elucidated complex involved in PSII assembly and repair, are each required for the recruitment of ribosomes to psbA mRNA, which encodes D1. By contrast, HCF136, which acts upstream of the OHP1/OHP2/HCF244 complex during PSII assembly, does not have this effect. The fact that the OHP1/OHP2/HCF244 complex brings D1 into proximity with three proteins with dual roles in PSII assembly and psbA ribosome recruitment suggests that this complex is the hub of a translational autoregulatory mechanism that coordinates D1 synthesis with need for nascent D1 during PSII biogenesis and repair.
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Cao, Jie, Hairong Liu, Shuya Tan i Zhonghai Li. "Transcription Factors-Regulated Leaf Senescence: Current Knowledge, Challenges and Approaches". International Journal of Molecular Sciences 24, nr 11 (25.05.2023): 9245. http://dx.doi.org/10.3390/ijms24119245.
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Leaf senescence is a complex biological process regulated at multiple levels, including chromatin remodeling, transcription, post-transcription, translation, and post-translational modifications. Transcription factors (TFs) are crucial regulators of leaf senescence, with NAC and WRKY families being the most studied. This review summarizes the progress made in understanding the regulatory roles of these families in leaf senescence in Arabidopsis and various crops such as wheat, maize, sorghum, and rice. Additionally, we review the regulatory functions of other families, such as ERF, bHLH, bZIP, and MYB. Unraveling the mechanisms of leaf senescence regulated by TFs has the potential to improve crop yield and quality through molecular breeding. While significant progress has been made in leaf senescence research in recent years, our understanding of the molecular regulatory mechanisms underlying this process is still incomplete. This review also discusses the challenges and opportunities in leaf senescence research, with suggestions for possible strategies to address them.
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Nesterova, Olga A., i Elena N. Sokolova. "Linguocultureme as a Marker of Identity (Based on English Translation of the Novel Zuleikha by G. Yakhina)". NSU Vestnik. Series: Linguistics and Intercultural Communication 19, nr 1 (2021): 127–41. http://dx.doi.org/10.25205/1818-7935-2021-19-1-127-141.
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The article reveals the decoding mechanisms of linguoculturemes occurring in the translation of the novel “Zuleikha opens her eyes” by G. Yakhina into the English language. In the original text of the novel linguoculturemes express ethnical and socio-cultural identity of the main character Zuleikha. Working on the translation of the novel Lisa Hayden, the translator, uses different types of adaptive transcoding for interlanguage and intercultural communication. The translation is characterized by double transcoding that is based on three languages: Tatar, Russian and English. Tatar words and expressions with explicit national cultural elements form a cultural background in the novel and often have no equivalents or definitions in the English language. The comparative analysis of the original text and its translations highlight a number of different groups of linguoculturemes, such as terms for members of ethno-cultural community and types of address, names of mythical and religious characters, names of objects, elements of interior design of a peasant’s home, pieces of furniture, and clothes. Linguoculturemes also help to recreate the historical atmosphere in Russia in the 1920-1930s, as well as the relationships in a traditional patriarchal family, conventional values of a local ethno-cultural community and socio-political realia depicted in the novel. A complex hierarchy of contextual image levels of the novel in the process of translation of the novel. The outer level of the story (the plot) is being transformed and many story lines are translated into English without any significant semantic change. Universal human problems represented via archetypes are well received by the English-language readers regardless of their language and socio-cultural background. The inner levels of the story expressing specific social relationships and interactions, ethnocultural, religious, and ethnopsychological stands with the help of linguoculturemes appear to be “encoded” for readers with different language backgrounds, but open in their complete semantic value to the bearers of the given social, religious and ethnical cultures. The authors’ message is that the English translation of the text does not lack in national cultural identity or ethnocultural values, it is just that these values become secondary and, as a result, harm the intimacy of the unique world perception of the main character.
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Nixon, J. Sebastian, i Megersa Amenu. "Investigating Security Issues and Preventive Mechanisms in Ipv6 Deployment". International Journal of Advanced Engineering and Nano Technology 9, nr 2 (28.02.2022): 1–20. http://dx.doi.org/10.35940/ijaent.b0466.029222.
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Internet Protocols are utilized to empower the communication between the computing devices in the computer networks. IPv6 offers additional address space and more noteworthy security than IPv4. The progress from IPv4 to IPv6 has been finished through three primary change systems: dual-stack, tunneling, and translation. The IPv6 progress relies upon the similarity with the enormous introduced base of IPv4 nodes and routers just as keeping up with the security of the network from possible threats and vulnerabilities of both Internet protocols. This research identifies potential security issues in the transition mechanisms and proposing prevention mechanisms to the problems identified. Dual-Stack & Tunneling mechanisms were completely implemented in this research work and the security test was based on dual-stack network. A simulation has been designed by using GNS3 and the penetration test by the THC-IPv6 toolkit. After the implementation of simulation, IPv6 in the dual-stack mechanism was identified as vulnerable to DoS via RA flooding and IPv6 fragmentation attacks that shown the IPv6 security problems. Therefore, IPv6 ACLs and RA guards were proposed in order to protect from flooding attacks and VFR should be configured to prevent IPv6 fragmentation.
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Sturla, Lisa, Bassil Dekky, Xuemei Zhang, Katherine S. Bowdish i Chris VanDeusen. "Abstract 2562: eIF4E modulators to address breast cancer resistance". Cancer Research 82, nr 12_Supplement (15.06.2022): 2562. http://dx.doi.org/10.1158/1538-7445.am2022-2562.
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Abstract ER+/HER2- advanced or metastatic breast cancers represents a large patient population served by CDK4/6 inhibitors combined with hormonal therapy as standard of care. As acquired resistance emerges, molecular profiling indicates about > 100 different mutations render resistance, creating challenges for treating physicians, patients, and the healthcare system broadly. The aim of our work is to maintain consolidation of this large patient population by developing targeted therapies to a key fundamental mechanism at the convergence of many oncogenic signaling pathways through which resistance arises. The regulation of CAP dependent protein translation is a central element in oncogenesis. One of a family of CAP binding proteins, eIF4E serves to anchor the m7GTP CAP of RNA into several protein complexes and regulates multiple aspects of mRNA processing such as nuclear export and ribosomal translation. Our efforts focused on simultaneously developing potent small molecule modulators of eIF4E and patient hypotheses through which to direct their initial clinical use. By aligning medicinal chemistry tools with patient directed pharmacology, we optimized our inhibitors to identify orally bioavailable, nM modulators of eIF4E. Biochemical assays demonstrated direct binding and allosteric modulation of eIF4E activity by PICRN941, along with Proximity Ligation Assays (PLA) demonstrating reduced eIF4E and 4G association in cells. Western analysis demonstrated that PICRN941 induced simultaneous and significant modulation of a number of key oncogenes that have been postulated to drive intrinsic or acquired resistance in response to standard of care including anti-estrogen treatment, CDK4/6 inhibitors or PI3K inhibitors combined with hormonal therapy, including MYC, CDK2, CDK4, CCND1 and eIF4E itself. Treatment of ER+ breast cancer cell lines including ZR-75-1, T47D, and ZR-75-30 with PICRN941 induced a dose dependent reduction in the levels of hyper-phosphorylated 4E-BP1 commensurate to increases in unphosphorylated 4E-BP1, and dose-dependent reduction in protein expression of Cyclin D1, CDK4, ER alpha, phosphorylated Rb and eIF4E. Reduced protein expression correlated with subsequent cell cycle arrest and apoptosis. We further studied our inhibitors in primary patient derived organoids in collaboration with the Hubrecht Institute, where we observed potent and complete responses in breast cancer organoids that represent patient populations where unmet needs remain high including PTEN and RB null organoid models. Markers of target engagement correlated well with organoid model sensitivity, including Cyclin D1 responses. Our findings suggest that our allosteric eIF4E modulators may provide a unique and efficient therapeutic approach to address multiple resistance mechanisms across cancer patient populations, toward fulfilling the promise of this elusive target. Citation Format: Lisa Sturla, Bassil Dekky, Xuemei Zhang, Katherine S. Bowdish, Chris VanDeusen. eIF4E modulators to address breast cancer resistance [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 2562.
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Roelfsema, Pieter R., i Victor A. F. Lamme. "Which brain mechanism cannot count beyond four?" Behavioral and Brain Sciences 24, nr 1 (luty 2001): 142–43. http://dx.doi.org/10.1017/s0140525x01493927.
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Cowan makes an intriguing case for a fundamental limit in the number of chunks that can be stored in short term memory (STM). Chunks are collections of concepts that have strong associations to one another and much weaker associations to other chunks. A translation of this definition for the visual domain would be that a visual chunk is a collection of features that belong to the same perceptual group (see also Mahoney & Ullman 1988). Here, we will first address the neuronal mechanisms that may demarcate visual chunks. Then we critically evaluate to what extent these mechanisms might be responsible for the limit on the number of chunks that can be held in STM. We conclude that the clarity with which the psychophysical data point to the number four is not matched by a similarly clear limit imposed by physiological mechanisms.
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Beemon, Karen L. "Retroviral RNA Processing". Viruses 14, nr 5 (23.05.2022): 1113. http://dx.doi.org/10.3390/v14051113.
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This review is an accompaniment to a Special Issue on “Retroviral RNA Processing”. It discusses post-transcriptional regulation of retroviruses, ranging from the ancient foamy viruses to more modern viruses, such as HIV-1, HTLV-1, Rous sarcoma virus, murine leukemia virus, mouse mammary tumor virus, and Mason-Pfizer monkey virus. This review is not comprehensive. However, it tries to address some of the major questions in the field with examples of how different retroviruses express their genes. It is amazing that a single primary RNA transcript can have so many possible fates: genomic RNA, unspliced mRNA, and up to 50 different alternatively spliced mRNAs. This review will discuss the sorting of RNAs for packaging or translation, RNA nuclear export mechanisms, splicing, translation, RNA modifications, and avoidance of nonsense-mediated RNA decay.
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Raza, Farheen, Joseph Alexander Waldron i John Le Quesne. "Translational dysregulation in cancer: eIF4A isoforms and sequence determinants of eIF4A dependence". Biochemical Society Transactions 43, nr 6 (27.11.2015): 1227–33. http://dx.doi.org/10.1042/bst20150163.
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The malignant phenotype is largely the consequence of dysregulated gene expression. Transformed cells depend upon not just a global increase in protein synthesis but an altered translational landscape in which pro-oncogenic mRNAs are translationally up-regulated. Such mRNAs have been shown to possess longer and more structured 5′-UTRs requiring high levels of eukaryotic initiation factor 4A (eIF4A) helicase activity for efficient translation. As such there is a developing focus on targeting eIF4A as a cancer therapy. In order for such treatments to be successful, we must develop a detailed understanding of the mechanisms which make specific mRNAs more dependent on eIF4A activity than others. It is also crucial to fully characterize the potentially distinct roles of eIF4A1 and eIF4A2, which until recently were thought to be functionally interchangeable. This review will highlight the recent advances made in this field that address these issues.
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Grieshaber, Nicole A., Travis J. Chiarelli, Cody R. Appa, Grace Neiswanger, Kristina Peretti i Scott S. Grieshaber. "Translational gene expression control in Chlamydia trachomatis". PLOS ONE 17, nr 1 (27.01.2022): e0257259. http://dx.doi.org/10.1371/journal.pone.0257259.
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The human pathogen Chlamydia trachomatis proceeds through a multi phenotypic developmental cycle with each cell form specialized for different roles in pathogenesis. Understanding the mechanisms regulating this complex cycle has historically been hampered by limited genetic tools. In an effort to address this issue, we developed a translational control system to regulate gene expression in Chlamydia using a synthetic riboswitch. Here we demonstrate that translational control via a riboswitch can be used in combination with a wide range of promoters in C. trachomatis. The synthetic riboswitch E, inducible with theophylline, was used to replace the ribosome binding site of the synthetic promoter T5-lac, the native chlamydial promoter of the pgp4 plasmid gene and an anhydrotetracycline responsive promoter. In all cases the riboswitch inhibited translation, and high levels of protein expression was induced with theophylline. Combining the Tet transcriptional inducible promoter with the translational control of the riboswitch resulted in strong repression and allowed for the cloning and expression of the potent chlamydial regulatory protein, HctB. The ability to control the timing and strength of gene expression independently from promoter specificity is a new and important tool for studying chlamydial regulatory and virulence genes.
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Ali, Zeeshan, P. Charukeshi Chandrasekera i John J. Pippin. "Animal Research for Type 2 Diabetes Mellitus, Its Limited Translation for Clinical Benefit, and the Way Forward". Alternatives to Laboratory Animals 46, nr 1 (marzec 2018): 13–22. http://dx.doi.org/10.1177/026119291804600101.
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Obesity and type 2 diabetes mellitus (T2DM) have reached pandemic proportions worldwide, and considerable research efforts have been dedicated to investigating disease pathology and therapeutic options. The two hallmark features of T2DM, insulin resistance and pancreatic dysfunction, have been studied extensively by using various animal models. Despite the knowledge acquired from such models, particularly mechanistic discoveries that sometimes mimic human T2DM mechanisms or pathways, many details of human T2DM pathogenesis remain unknown, therapeutic options remain limited, and a cure has eluded research. Emerging human data have raised concern regarding inter-species differences at many levels (e.g. in gene regulation, pancreatic cytoarchitecture, glucose transport, and insulin secretion regulation), and the subsequent impact of these differences on the clinical translation of animal research findings. Therefore, it is important to recognise and address the translational gap between basic animal-based research and the clinical advances needed to prevent and treat T2DM. The purpose of this report is to identify some limitations of T2DM animal research, and to propose how greater human relevance and applicability of hypothesis-driven basic T2DM research could be achieved through the use of human-based data acquisition at various biological levels. This report addresses how in vitro, in vivo and in silico technologies could be used to investigate particular aspects of human glucose regulation. We do not propose that T2DM animal research has been without value in the identification of mechanisms, pathways, or potential targets for therapies, nor do we claim that human-based methods can provide all the answers. We recognise that the ultimate goal of T2DM animal research is to identify ways to advance the prevention, recognition and treatment of T2DM in humans, but postulate that this is where the use of animal models falls short, despite decades of effort. The best way to achieve this goal is by prioritising human-centred research.
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Lim, Yan Yik, Ahmad Mujahid Ahmad Zaidi i Azizi Miskon. "Composing On-Program Triggers and On-Demand Stimuli into Biosensor Drug Carriers in Drug Delivery Systems for Programmable Arthritis Therapy". Pharmaceuticals 15, nr 11 (27.10.2022): 1330. http://dx.doi.org/10.3390/ph15111330.
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Medication in arthritis therapies is complex because the inflammatory progression of rheumatoid arthritis (RA) and osteoarthritis (OA) is intertwined and influenced by one another. To address this problem, drug delivery systems (DDS) are composed of four independent exogenous triggers and four dependent endogenous stimuli that are controlled on program and induced on demand, respectively. However, the relationships between the mechanisms of endogenous stimuli and exogenous triggers with pathological alterations remain unclear, which results in a major obstacle in terms of clinical translation. Thus, the rationale for designing a guidance system for these mechanisms via their key irritant biosensors is in high demand. Many approaches have been applied, although successful clinical translations are still rare. Through this review, the status quo in historical development is highlighted in order to discuss the unsolved clinical difficulties such as infiltration, efficacy, drug clearance, and target localisation. Herein, we summarise and discuss the rational compositions of exogenous triggers and endogenous stimuli for programmable therapy. This advanced active pharmaceutical ingredient (API) implanted dose allows for several releases by remote controls for endogenous stimuli during lesion infections. This solves the multiple implantation and local toxic accumulation problems by using these flexible desired releases at the specified sites for arthritis therapies.
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Minami, Daisuke. "Lost in translation: Problematizing the localization of transnational activism". European Journal of International Relations 25, nr 2 (23.10.2018): 511–37. http://dx.doi.org/10.1177/1354066118794836.
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Existing studies on human rights change posit that activists use transnational networks to organize global and local movements against governments. However, this explanation assumes that international rights claims gain local support and underestimates how difficult it could be for activists to translate global movements into local movements. I address this issue by proposing three mechanisms through which activists face such difficulties and fail to pressure governments. First, misrepresentation occurs when international organizations accept and support activists who do not represent local voices and cannot get local support for their rights claims. Second, misperception happens when activists introduce global norms into local debates but local audiences, unfamiliar with these “foreign” concepts, misperceive them and thus do not support international rights claims. Third, mismatch occurs when pre-existing local movements mistakenly use international rights claims for their own goals, lead local discussions, and overshadow transnational activism. Due to these problems of misrepresentation, misperception, and mismatch, activists may fail to localize their transnational activism. This, in turn, makes it difficult to realize their claims at home. I demonstrate my argument by analyzing the indigenous peoples’ movements in Japan, tracing the success and failure of Ainu and Okinawan activists to domesticate the global indigenous peoples’ movement.
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Mosedale, Abby, Elizabeth Geelhoed, Yvonne Zurynski, Suzanne Robinson, Kevin Chai i Delia Hendrie. "An impact review of a Western Australian research translation program". PLOS ONE 17, nr 3 (31.03.2022): e0265394. http://dx.doi.org/10.1371/journal.pone.0265394.
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The translation gap between knowledge production and implementation into clinical practice and policy is an ongoing challenge facing researchers, funders, clinicians and policy makers globally. Research generated close to practice and in collaboration with end users is an approach that is recognised as an effective strategy to facilitate an improvement in the relevance and use of health research as well as building research capacity amongst end users. The Research Translation Projects (RTP) program funded by the Western Australian (WA) Department of Health facilitates clinical and academic collaboration through competitive funding of short-term research projects. Its aim is to improve healthcare practice while also finding efficiencies that can be delivered to the WA health system. A mixed methods approach was adopted to evaluate the research impact of the RTP program, at completion of the two-year funding period, across a range of impact domains through the adaptation and application of the Canadian Academy of Health Sciences’ (CAHS) framework for research impact. In addition, further analysis was undertaken to address specific objectives of the RTP program more closely, in particular research capacity building and collaboration and health system Inefficiencies targeted by the program. Social network analysis was applied to assess the extent and growth of collaboration across WA health organisations over time. Results indicated that the ‘bottom up’ approach to research translation has triggered modest, yet positive outcomes across impact domains including advancing knowledge, collaboration and capacity building as well as contributing to changes in policy and practice. Additionally, the projects identified opportunities by which inefficiencies in the health system can be addressed. Further work is required to better understand the pathways by which short-term outcomes can be translated into more long-term impacts and the mechanisms that trigger this process.
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Alcántara-Ayala, Irasema, i Anthony Oliver-Smith. "Early Warning Systems: Lost in Translation or Late by Definition? A FORIN Approach". International Journal of Disaster Risk Science 10, nr 3 (wrzesień 2019): 317–31. http://dx.doi.org/10.1007/s13753-019-00231-3.
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Abstract Early warning systems (EWSs) are widely considered to be one of the most important mechanisms to prevent disasters around the globe. But as disasters continue to affect countries where EWSs have already been implemented, the striking disaster consequences have led us to reflect on the focus, architecture, and function of the warning systems. Since the 2004 Indian Ocean tsunami there has been a rapid rise in the promotion and use of EWSs to minimize disaster losses and damage. However, few researchers have addressed the question of their acceptability as an adaptive measure to the existing exposure conditions. EWSs are far more linked to emergency response and humanitarian crises and accepted technological interventions as solutions than they are to explicitly advance integrated analysis, disaster risk reduction, and policy making. A major flaw of EWSs is that the term “early” has been essentially used in reference to the speed of hazard onset, founded on a physicalist perspective that has encouraged a considerable dependence on technology. In this article we address the need for a clear understanding of the root causes and risk drivers of disaster risk creation, as advanced in the FORIN (forensic investigation of disasters) approach, as a prerequisite for the development of more articulated EWSs that could contribute to disaster risk reduction through policy making and practice, based on integrated and transdisciplinary management, in the interest of sustainable development, and human welfare and well-being.
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Sun, Boyang, Yupeng Mei, Ni Yan i Yingyi Chen. "UMGAN: Underwater Image Enhancement Network for Unpaired Image-to-Image Translation". Journal of Marine Science and Engineering 11, nr 2 (17.02.2023): 447. http://dx.doi.org/10.3390/jmse11020447.
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Due to light absorption and scattering underwater images suffer from low contrast, color distortion, blurred details, and uneven illumination, which affect underwater vision tasks and research. Therefore, underwater image enhancement is of great significance in vision applications. In contrast to existing methods for specific underwater environments or reliance on paired datasets, this study proposes an underwater multiscene generative adversarial network (UMGAN) to enhance underwater images. The network implements unpaired image-to-image translation between the underwater turbid domain and the underwater clear domain. It has a great enhancement impact on several underwater image types. Feedback mechanisms and a noise reduction network are designed to optimize the generator and address the issue of noise and artifacts in GAN-produced images. Furthermore, a global–local discriminator is employed to improve the overall image while adaptively modifying the local region image effect. It resolves the issue of over- and underenhancement in local regions. The reliance on paired training data is eliminated through a cycle consistency network structure. UMGAN performs satisfactorily on various types of data when compared quantitatively and qualitatively to other state-of-the-art algorithms. It has strong robustness and can be applied to various enhancement tasks in different scenes.
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Park, Ye Lin, Kiwon Park i Jae Min Cha. "3D-Bioprinting Strategies Based on In Situ Bone-Healing Mechanism for Vascularized Bone Tissue Engineering". Micromachines 12, nr 3 (8.03.2021): 287. http://dx.doi.org/10.3390/mi12030287.
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Over the past decades, a number of bone tissue engineering (BTE) approaches have been developed to address substantial challenges in the management of critical size bone defects. Although the majority of BTE strategies developed in the laboratory have been limited due to lack of clinical relevance in translation, primary prerequisites for the construction of vascularized functional bone grafts have gained confidence owing to the accumulated knowledge of the osteogenic, osteoinductive, and osteoconductive properties of mesenchymal stem cells and bone-relevant biomaterials that reflect bone-healing mechanisms. In this review, we summarize the current knowledge of bone-healing mechanisms focusing on the details that should be embodied in the development of vascularized BTE, and discuss promising strategies based on 3D-bioprinting technologies that efficiently coalesce the abovementioned main features in bone-healing systems, which comprehensively interact during the bone regeneration processes.
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Burwick, Nicholas, Jeffrey J. Delrow i Akiko Shimamura. "Translational Profiling Reveals The eIF2 Kinase Pathway As a Mediator Of Dexamethasone Induced Apoptosis In Multiple Myeloma". Blood 122, nr 21 (15.11.2013): 3104. http://dx.doi.org/10.1182/blood.v122.21.3104.3104.
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Abstract Dexamethasone has been used to treat Multiple Myeloma (MM), a plasma cell cancer, for over forty years. Nonetheless, dexamethasone toxicity is a source of morbidity for many patients and drug resistance invariably develops. A better understanding of the mechanisms of dexamethasone activity could provide novel avenues for drug development. To gain new insights into dex activity in MM, we started with the clinical observation that dex is an effective treatment for both MM and the ribosomal disorder Diamond Blackfan anemia (DBA). Interestingly, dex has opposite effects in these two disorders, promoting apoptosis in MM and inducing an erythroid response in DBA. Given these opposing responses to dex, we hypothesized that dex disrupts ribosomal profiles in MM, altering the translation of specific mRNAs to promote apoptosis. To address this hypothesis, we performed an unbiased assessment of mRNA translation in MM +/- dex, using translational (polysome) profiling. We show that dex disrupts ribosomal profiles in sensitive (MM1.S), but not resistant (MM1.R) myeloma cell lines as early as 4 hours, well-preceding dex-induced apoptosis. These effects are dose and time dependent. We next treated the MM1.S and MM1.R cell lines with 1μM dex or control for 4 hours. Cells were lysed and separated by ultracentrifugation. Polysome gradients were obtained, and the gradients were fractionated into two pools: (A) non-polysome associated RNA and (B) polysome associated RNA. Pool B is enriched for actively translated mRNA. A translation coefficient for each condition was defined as the amount of mRNA in polysome/non-polysome pools. Unfractionated total cellular RNA was used to assess transcriptional changes. RNA was analyzed using human gene arrays. The results demonstrate that dex alters a group of translational networks that are distinct from its effect on transcriptional networks. The top translational network modulated by dex was eIF2 signaling (p-value 1.4 E-09). The eIF2 kinase pathway regulates protein translation, and repression of this pathway paradoxically increases the translation of the transcription factor ATF4. We show that dex increases ATF4 translation. In addition dex up-regulates transcription of the ATF4 target gene DDIT4 (REDD1). Dex also represses the translation of ribosomal protein genes downstream of REDD1, including RPS6, RPS19 and RPS24. The large ribosomal protein genes RPL3 and RPL10 were unchanged, suggesting that dex represses the translation of a subset of ribosomal protein genes. Changes in protein expression were validated by immunoblot. Finally, we tested whether specific inhibition of the eIF2 kinase pathway could overcome dex resistance. Using an MTS assay we demonstrate that BTdCPU, a specific eIF2 kinase inhibitor, induces cytotoxicity in dex sensitive (MM1.S, RPMI8266) and dex resistant (MM1.R, U266) cell lines. Using flow cytometry, BTdCPU also induces apoptosis in both dex sensitive and resistant cell lines. Furthermore, BTdCPU and dex have additive cytotoxicity/apoptosis in the MM1.S cell line. Lastly, we show that BTdCPU specifically up-regulates the ATF4 target genes REDD1 and CHOP. Up-regulation of the pro-apoptotic gene CHOP by BTdCPU may explain the additive cytotoxicity in conjunction with dex. In summary, 1) The eIF2 kinase pathway is modulated by dexamethasone at the level of mRNA translation in multiple myeloma. 2) Direct targeting of the eIF2 kinase pathway with BTdCPU overcomes dex resistance. We show that dexamethasone alters the translation of specific pathways in MM (independent of transcription), including eIF2, revealing potential new avenues for drug development. Disclosures: No relevant conflicts of interest to declare.
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Murphy, Joanne, Sara McDowell, Maire Braniff i David Denyer. "Managing contested spaces: Public managers, obscured mechanisms and the legacy of the past in Northern Ireland". Environment and Planning C: Politics and Space 36, nr 3 (15.06.2017): 443–59. http://dx.doi.org/10.1177/2399654417714800.
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Societies emerging from ethno-political and inter-communal conflict face a range of complex problems that stem directly from the recent lived experience of bloodshed and injury, militarisation, securitisation and segregation. As institutional agents in such an environment, public managers perform the dual role of both interpreting public policy and implementing it within a politically contested space and place. In this article, we address how managers cope with the outworking of ethno-nationalist conflict and peace building within government processes and policy implementation and contend this is a subject of emerging concern within the wider public administration, urban studies and conflict literature. Using data from a witness seminar initiative on the Northern Ireland conflict transformation experience, we explain how public sector managers make sense of their role in post-agreement public management and highlight the importance of three identified mechanisms; ‘bricolage’, ‘diffusion’ and ‘translation’ in the management of public sector organisations and urban spaces in a context of entrenched conflict and an uncertain path to peace.
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Chi, Mai Nguyen, Jacques Auriol, Bernard Jégou, Dimitris L. Kontoyiannis, James M. A. Turner, Dirk G. de Rooij i Dominique Morello. "The RNA-binding protein ELAVL1/HuR is essential for mouse spermatogenesis, acting both at meiotic and postmeiotic stages". Molecular Biology of the Cell 22, nr 16 (15.08.2011): 2875–85. http://dx.doi.org/10.1091/mbc.e11-03-0212.
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Posttranscriptional mechanisms are crucial to regulate spermatogenesis. Accurate protein synthesis during germ cell development relies on RNA binding proteins that control the storage, stability, and translation of mRNAs in a tightly and temporally regulated manner. Here, we focused on the RNA binding protein Embryonic Lethal Abnormal Vision (ELAV) L1/Human antigen R (HuR) known to be a key regulator of posttranscriptional regulation in somatic cells but the function of which during gametogenesis has never been investigated. In this study, we have used conditional loss- and gain-of-function approaches to address this issue in mice. We show that targeted deletion of HuR specifically in germ cells leads to male but not female sterility. Mutant males are azoospermic because of the extensive death of spermatocytes at meiotic divisions and failure of spermatid elongation. The latter defect is also observed upon HuR overexpression. To elucidate further the molecular mechanisms underlying spermatogenesis defects in HuR-deleted and -overexpressing testes, we undertook a target gene approach and discovered that heat shock protein (HSP)A2/HSP70-2, a crucial regulator of spermatogenesis, was down-regulated in both situations. HuR specifically binds hspa2 mRNA and controls its expression at the translational level in germ cells. Our study provides the first genetic evidence of HuR involvement during spermatogenesis and reveals Hspa2 as a target for HuR.
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Wood, Ian C., Nicola K. Gray i Lesley Jones. "Gene Expression in Neuronal Disease". Biochemical Society Transactions 37, nr 6 (19.11.2009): 1261–62. http://dx.doi.org/10.1042/bst0371261.
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The brain is the most complex organ of the body and it contains the greatest diversity of cell types. Collectively, the cells within the brain express the greatest number of genes encoded within our genome. Inappropriate gene expression within these cells plays a fundamental role in many neuronal diseases. Illuminating the mechanisms responsible for gene expression is key to understanding these diseases. Because of the complexity, however, there is still much to understand about the mechanisms responsible for gene expression in the brain. There are many steps required for a protein to be generated from a gene, and groups who focus on gene expression normally study a single step such as regulation of transcription, mechanisms of RNA processing or control of translation. To address this, experts were brought together at the Gene Expression in Neuronal Disease meeting in Cardiff. This forum provided the latest insights into specific stages of gene expression in the brain and encompassed the complete pathway from DNA to protein. The present article summarizes the meeting talks and related papers in this issue of Biochemical Society Transactions.
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Senges, Christoph H. R., Jennifer J. Stepanek, Michaela Wenzel, Nadja Raatschen, Ümran Ay, Yvonne Märtens, Pascal Prochnow i in. "Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation". Antimicrobial Agents and Chemotherapy 65, nr 1 (12.10.2020): e01373-20. http://dx.doi.org/10.1128/aac.01373-20.
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ABSTRACTNew antibiotics are urgently needed to address the mounting resistance challenge. In early drug discovery, one of the bottlenecks is the elucidation of targets and mechanisms. To accelerate antibiotic research, we provide a proteomic approach for the rapid classification of compounds into those with precedented and unprecedented modes of action. We established a proteomic response library of Bacillus subtilis covering 91 antibiotics and comparator compounds, and a mathematical approach was developed to aid data analysis. Comparison of proteomic responses (CoPR) allows the rapid identification of antibiotics with dual mechanisms of action as shown for atypical tetracyclines. It also aids in generating hypotheses on mechanisms of action as presented for salvarsan (arsphenamine) and the antirheumatic agent auranofin, which is under consideration for repurposing. Proteomic profiling also provides insights into the impact of antibiotics on bacterial physiology through analysis of marker proteins indicative of the impairment of cellular processes and structures. As demonstrated for trans-translation, a promising target not yet exploited clinically, proteomic profiling supports chemical biology approaches to investigating bacterial physiology.
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Zhang, Laining, Qidong Si, Kejie Yang, Wenwei Zhang, Thomas W. Okita i Li Tian. "mRNA Localization to the Endoplasmic Reticulum in Plant Endosperm Cells". International Journal of Molecular Sciences 23, nr 21 (4.11.2022): 13511. http://dx.doi.org/10.3390/ijms232113511.
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Subcellular mRNA localization is an evolutionarily conserved mechanism to spatially and temporally drive local translation and, in turn, protein targeting. Hence, this mechanism achieves precise control of gene expression and establishes functional and structural networks during cell growth and development as well as during stimuli response. Since its discovery in ascidian eggs, mRNA localization has been extensively studied in animal and yeast cells. Although our knowledge of subcellular mRNA localization in plant cells lags considerably behind other biological systems, mRNA localization to the endoplasmic reticulum (ER) has also been well established since its discovery in cereal endosperm cells in the early 1990s. Storage protein mRNA targeting to distinct subdomains of the ER determines efficient accumulation of the corresponding proteins in different endosomal storage sites and, in turn, underlies storage organelle biogenesis in cereal grains. The targeting process requires the presence of RNA localization elements, also called zipcodes, and specific RNA-binding proteins that recognize and bind these zipcodes and recruit other factors to mediate active transport. Here, we review the current knowledge of the mechanisms and functions of mRNA localization to the ER in plant cells and address directions for future research.
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COPP, ANDREW J., i ELIZABETH M. C. FISHER. "Abstracts of papers presented at the fifteenth Genetics Society's Mammalian Genetics and Development Workshop held at the Institute of Child Health, University College London on 22 and 23 November 2004". Genetical Research 86, nr 3 (grudzień 2005): 233–41. http://dx.doi.org/10.1017/s0016672305007895.
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The Transforming growth factor-β (TGF-β) family control diverse cellular processes and specify cell-fate/differentiation during embryogenesis in vertebrates and invertebrates. Mutations disrupting TGF-β signalling lead to developmental abnormalities and a range of diseases such as cancer. Nodal is a major TGF-β signal, responsible for gastrulation in embryogenesis. Arkadia (Akd) was discovered by mouse gene-trap mutagenesis and encodes a nuclear E3 ubiquitin ligase. Akd allows the Nodal signal to reach its maximum level and Akd-null mice lack mammalian organiser (MO) and mesendodermal tissues. Although Akd RNA is ubiquitously expressed, Akd-null mice lose a subset of Nodal-dependent functions. The specificity of Akd function is therefore most likely to be regulated post-transcriptionally or by co-factors. Akd possesses differentially spliced 5′ untranslated regions (UTRs) and large 3′ UTR. We have employed bioinformatics and developed a reporter system to address Akd post-transcriptional regulation. Akd RNA may initiate from different promoters and 5′ UTR differential splicing, upstream AUGs (uAUGs) and open-reading frames upstream (uORFs) may regulate protein translation. 5′ and 3′ UTRs can interact to either destabilise or decrease translational efficiency of RNA. The nature of this interaction is cell-type and signal level dependent. These data may represent mechanisms by which translational control of Arkadia is achieved and ultimately how TGF-β/Nodal signalling is regulated during embryogenesis.
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Carbonara, Katrina, Martin Andonovski i Jens R. Coorssen. "Proteomes Are of Proteoforms: Embracing the Complexity". Proteomes 9, nr 3 (31.08.2021): 38. http://dx.doi.org/10.3390/proteomes9030038.
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Proteomes are complex—much more so than genomes or transcriptomes. Thus, simplifying their analysis does not simplify the issue. Proteomes are of proteoforms, not canonical proteins. While having a catalogue of amino acid sequences provides invaluable information, this is the Proteome-lite. To dissect biological mechanisms and identify critical biomarkers/drug targets, we must assess the myriad of proteoforms that arise at any point before, after, and between translation and transcription (e.g., isoforms, splice variants, and post-translational modifications [PTM]), as well as newly defined species. There are numerous analytical methods currently used to address proteome depth and here we critically evaluate these in terms of the current ‘state-of-the-field’. We thus discuss both pros and cons of available approaches and where improvements or refinements are needed to quantitatively characterize proteomes. To enable a next-generation approach, we suggest that advances lie in transdisciplinarity via integration of current proteomic methods to yield a unified discipline that capitalizes on the strongest qualities of each. Such a necessary (if not revolutionary) shift cannot be accomplished by a continued primary focus on proteo-genomics/-transcriptomics. We must embrace the complexity. Yes, these are the hard questions, and this will not be easy…but where is the fun in easy?
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Hofmann, Riikka, i Sonia Ilie. "A Theory-Led Evaluation of a Scalable Intervention to Promote Evidence-Based, Research-Informed Practice in Schools to Address Attainment Gaps". Education Sciences 12, nr 5 (18.05.2022): 353. http://dx.doi.org/10.3390/educsci12050353.
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Evidence-based practice is a salient solution that has been presented to address the persistent educational attainment gap linked to economic disadvantage. However, most schools do not engage with research, and we know little about facilitating school-led research use at scale. Linking different approaches to studying educational effectiveness, equity and change, and drawing on cultural-historical activity theory, this study develops intermediate theory about the mechanisms influencing institutions’ success in using research. In the context of the Opportunity Area Programme, supporting place-based interventions in the UK’s most socio-economically disadvantaged regions, we conducted a theory-led evaluation of the Evidence-Based Practice Fund (EBPF), aimed at supporting school-led research engagement to improve learning outcomes. We analysed the documentation of 83 EBPF projects, 8 focus groups, and a school survey. We demonstrate that enabling schools to address locally identified needs motivates research engagement but formulating these as stimulus for change requires scaffolding. Schools were keen but needed re-translation to use research to address those challenges. Low-key school-to-school support was found adequate. Leadership support and collaboration were significant but require relational expertise and professional learning to be effective. This study demonstrates that the use of research by schools at scale is possible and can transform a school’s agency in developing their own practice to improve equity.
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He, Zuping, Maria Kokkinaki, Disha Pant, G. Ian Gallicano i Martin Dym. "Small RNA molecules in the regulation of spermatogenesis". REPRODUCTION 137, nr 6 (czerwiec 2009): 901–11. http://dx.doi.org/10.1530/rep-08-0494.
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Small RNA molecules (small RNAs), including small interfering RNAs (siRNAs), microRNAs (miRNAs), and piwi-interacting RNAs (piRNAs), have recently emerged as important regulators of gene expression at the post-transcriptional or translation level. Significant progress has recently been made utilizing small RNAs in elucidating the molecular mechanisms regulating spermatogenesis. Spermatogenesis is a complex process that involves the division and eventual differentiation of spermatogonial stem cells into mature spermatozoa. The process of spermatogenesis is composed of several phases: mitotic proliferation of spermatogonia to produce spermatocytes; two meiotic divisions of spermatocytes to generate haploid round spermatids; and spermiogenesis, the final phase that involves the maturation of early-round spermatids into elongated mature spermatids. A number of miRNAs are expressed abundantly in male germ cells throughout spermatogenesis, while piRNAs are only present in pachytene spermatocytes and round spermatids. In this review, we first address the synthesis, mechanisms of action, and functions of siRNA, miRNA, and piRNA, and then we focus on the recent advancements in defining the small RNAs in the regulation of spermatogenesis. Concerns pertaining to the use of siRNAs in exploring spermatogenesis mechanisms and open questions in miRNAs and piRNAs in this field are highlighted. The potential applications of small RNAs to male contraception and treatment for male infertility and testicular cancer are also discussed.
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Mativenga, Ronnie, Prince Hamandawana, Tae-Sun Chung i Jongik Kim. "FTRM: A Cache-Based Fault Tolerant Recovery Mechanism for Multi-Channel Flash Devices". Electronics 9, nr 10 (27.09.2020): 1581. http://dx.doi.org/10.3390/electronics9101581.
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Flash memory prevalence has reached greater extents with its performance and compactness capabilities. This enables it to be easily adopted as storage media in various portable devices which includes smart watches, cell-phones, drones, and in-vehicle infotainment systems to mention but a few. To support large flash storage in such portable devices, existing flash translation layers (FTLs) employ a cache mapping table (CMT), which contains a small portion of logical page number to physical page number (LPN-PPN) mappings. For robustness, it is of importance to consider the CMT reconstruction mechanisms during system recovery. Currently, existing approaches cannot overcome the performance penalty after experiencing unexpected power failure. This is due to the disregard of the delay caused by inconsistencies between the cached page-mapping entries in RAM and their corresponding mapping pages in flash storage. Furthermore, how to select proper pages for reconstructing the CMT when rebooting a device needs to be revisited. In this study we address these problems and propose a fault tolerant power-failure recovery mechanism (FTRM) for flash memory storage systems. Our empirical study shows that FTRM is an efficient recovery and robust protocol.
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Jenvey, C. J., D. Alenizi, F. Almasi, C. Cairns, A. Holmes, S. Sloan i M. J. Stear. "Bioinformatic analysis of eosinophil activity and its implications for model and target species". Parasitology 147, nr 4 (16.12.2019): 393–400. http://dx.doi.org/10.1017/s0031182019001768.
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AbstractEosinophils are important immune cells that have been implicated in resistance to gastrointestinal nematode (GIN) infections in both naturally and experimentally infected sheep. Proteins of particular importance appear to be IgA-Fc alpha receptor (FcαRI), C-C chemokine receptor type 3 (CCR3), proteoglycan 3 (PRG3, major basic protein 2) and EPX (eosinophil peroxidase). We used known human nucleotide sequences to search the ruminant genomes, followed by translation to protein and sequence alignments to visualize differences between sequences and species. Where a sequence was retrieved for cow, but not for sheep and goat, this was used additionally as a reference sequence. In this review, we show that eosinophil function varies among host species. Consequently, investigations into the mechanisms of ruminant immune responses to GIN should be conducted using the natural host. Specifically, we address differences in protein sequence and structure for eosinophil proteins.
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Dikiy, Igor, Uthama R. Edupuganti, Rinat R. Abzalimov, Peter P. Borbat, Madhur Srivastava, Jack H. Freed i Kevin H. Gardner. "Insights into histidine kinase activation mechanisms from the monomeric blue light sensor EL346". Proceedings of the National Academy of Sciences 116, nr 11 (26.02.2019): 4963–72. http://dx.doi.org/10.1073/pnas.1813586116.
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Translation of environmental cues into cellular behavior is a necessary process in all forms of life. In bacteria, this process frequently involves two-component systems in which a sensor histidine kinase (HK) autophosphorylates in response to a stimulus before subsequently transferring the phosphoryl group to a response regulator that controls downstream effectors. Many details of the molecular mechanisms of HK activation are still unclear due to complications associated with the multiple signaling states of these large, multidomain proteins. To address these challenges, we combined complementary solution biophysical approaches to examine the conformational changes upon activation of a minimal, blue-light–sensing histidine kinase from Erythrobacter litoralis HTCC2594, EL346. Our data show that multiple conformations coexist in the dark state of EL346 in solution, which may explain the enzyme’s residual dark-state activity. We also observe that activation involves destabilization of the helices in the dimerization and histidine phosphotransfer-like domain, where the phosphoacceptor histidine resides, and their interactions with the catalytic domain. Similar light-induced changes occur to some extent even in constitutively active or inactive mutants, showing that light sensing can be decoupled from activation of kinase activity. These structural changes mirror those inferred by comparing X-ray crystal structures of inactive and active HK fragments, suggesting that they are at the core of conformational changes leading to HK activation. More broadly, our findings uncover surprising complexity in this simple system and allow us to outline a mechanism of the multiple steps of HK activation.
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De Freitas Lacerda, Rogério, Abigail Gonçalves da Silva i Isabela Cristina Sena Romano. "NEURODEGENERATION PROCESSES GO FAR BEYOND NECROSIS AND APOPTOSIS!" Multidisciplinary Sciences Reports 1, nr 1 (20.08.2021): 1–19. http://dx.doi.org/10.54038/ms.v1i1.2.
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Neural plasticity is a consequence of a delicate balance between the processes of neurodegeneration and neurogenesis. When neurodegeneration overcomes neurogenesis, neurodegenerative diseases occur, which affect cognitive functions such as memory, language, and executive functions. Neurodegeneration, the process of neuronal cell death, presents several aspects that were categorized according to their macroscopic and/or morphological characteristics. The concept of apoptosis, autophagy, and necrosis is still widely used today. On the other hand, more in-depth forms emerge in the clinical and academia, describing the cascade of cell death events through biochemical approaches, and the essential (causal) and accessory (correlative) aspects of the cell death process. New concepts were introduced, addressed in the modules of signal translation involving issues such as the initiation, execution, and propagation of cell death, as well as the pathophysiological relevance of each of the main types. Currently, twelve types of cell death are already defined, not only apoptosis, necrosis, and autophagy. In this review, we will address the main mechanisms of cell death, with special emphasis on the participation of caspases and other proteins in these mechanisms. We will discuss some types of cell death such as extrinsic and intrinsic apoptosis, necrosis, necroptosis, and autophagy-dependent cell death. We hope to elucidate key points in molecular systems, including the receptors involved in cell death and their role in neurodegeneration, and showing that neurodegeneration has characteristics beyond morphological (apoptosis and necrosis).
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Attieh, Randa, Marie-Pierre Gagnon, Geneviève Roch i Sarah L. Krein. "Translating Technology in Professional Practices to Optimize Infection Prevention and Control". International Journal of Actor-Network Theory and Technological Innovation 8, nr 3 (lipiec 2016): 26–47. http://dx.doi.org/10.4018/ijantti.2016070103.
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The aim of this study was to explain how the Polymerase Chain Reaction (PCR) technology was translated into professional practices to prevent and control vancomycin-resistant enterococci outbreaks via an actor-network, based on the integrated framework TRIP-ANT. A single case study was conducted in three purposefully selected sites implementing the PCR-VRE assay. The complete dataset comprised semi-structured interviews with 28 participants and a review of hospital and external documents. A content analysis was conducted. The authors' findings indicate the emergence of four main themes, including illustration of who was involved in the adoption process, attribution of roles and responsibilities, interaction/communication/ collaboration mechanisms, and changes in professional practices. Their findings also address five challenges that arose from each theme. The translation of PCR technology into professional practices relies on the enrolment of an organisational, clinical, managerial and financial support network, and on the evolution of practices, communications, and roles and responsibilities.
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Massoumi, Hamed, Sohil Amin, Mohammad Soleimani, Bita Momenaei, Mohammad Javad Ashraf, Victor H. Guaiquil, Peiman Hematti, Mark I. Rosenblatt, Ali R. Djalilian i Elmira Jalilian. "Extracellular-Vesicle-Based Therapeutics in Neuro-Ophthalmic Disorders". International Journal of Molecular Sciences 24, nr 10 (19.05.2023): 9006. http://dx.doi.org/10.3390/ijms24109006.
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Extracellular vesicles (EVs) have been recognized as promising candidates for developing novel therapeutics for a wide range of pathologies, including ocular disorders, due to their ability to deliver a diverse array of bioactive molecules, including proteins, lipids, and nucleic acids, to recipient cells. Recent studies have shown that EVs derived from various cell types, including mesenchymal stromal cells (MSCs), retinal pigment epithelium cells, and endothelial cells, have therapeutic potential in ocular disorders, such as corneal injury and diabetic retinopathy. EVs exert their effects through various mechanisms, including promoting cell survival, reducing inflammation, and inducing tissue regeneration. Furthermore, EVs have shown promise in promoting nerve regeneration in ocular diseases. In particular, EVs derived from MSCs have been demonstrated to promote axonal regeneration and functional recovery in various animal models of optic nerve injury and glaucoma. EVs contain various neurotrophic factors and cytokines that can enhance neuronal survival and regeneration, promote angiogenesis, and modulate inflammation in the retina and optic nerve. Additionally, in experimental models, the application of EVs as a delivery platform for therapeutic molecules has revealed great promise in the treatment of ocular disorders. However, the clinical translation of EV-based therapies faces several challenges, and further preclinical and clinical studies are needed to fully explore the therapeutic potential of EVs in ocular disorders and to address the challenges for their successful clinical translation. In this review, we will provide an overview of different types of EVs and their cargo, as well as the techniques used for their isolation and characterization. We will then review the preclinical and clinical studies that have explored the role of EVs in the treatment of ocular disorders, highlighting their therapeutic potential and the challenges that need to be addressed for their clinical translation. Finally, we will discuss the future directions of EV-based therapeutics in ocular disorders. Overall, this review aims to provide a comprehensive overview of the current state of the art of EV-based therapeutics in ophthalmic disorders, with a focus on their potential for nerve regeneration in ocular diseases.
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Alharbi, Khulud, Thomas Blakeman, Harm van Marwijk, David Reeves i Jung Yin Tsang. "Understanding the implementation of interventions to improve the management of frailty in primary care: a rapid realist review". BMJ Open 12, nr 6 (czerwiec 2022): e054780. http://dx.doi.org/10.1136/bmjopen-2021-054780.
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ObjectiveIdentifying and managing the needs of frail people in the community is an increasing priority for policy makers. We sought to identify factors that enable or constrain the implementation of interventions for frail older persons in primary care.DesignA rapid realist review.Data sourcesCochrane Library, SCOPUS and EMBASE, and grey literature. The search was conducted in September 2019 and rerun on 8 January 2022.Eligibility criteria for selecting studiesWe considered all types of empirical studies describing interventions targeting frailty in primary care.AnalysisWe followed the Realist and Meta-narrative Evidence Syntheses: Evolving Standards quality and publication criteria for our synthesis to systematically analyse and synthesise the existing literature and to identify (intervention-context-mechanism-outcome) configurations. We used normalisation processes theory to illuminate mechanisms surrounding implementation.ResultsOur primary research returned 1755 articles, narrowed down to 29 relevant frailty intervention studies conducted in primary care. Our review identified two families of interventions. They comprised: (1) interventions aimed at the comprehensive assessment and management of frailty needs; and (2) interventions targeting specific frailty needs. Key factors that facilitate or inhibit the translation of frailty interventions into practice related to the distribution of resources; patient engagement and professional skill sets to address identified need.ConclusionThere remain challenges to achieving successful implementation of frailty interventions in primary care. There were a key learning points under each family. First, targeted allocation of resources to address specific needs allows a greater alignment of skill sets and reduces overassessment of frail individuals. Second, earlier patient involvement may also improve intervention implementation and adherence.PROSPERO registration numberThe published protocol for the review is registered with PROSPERO (CRD42019161193).
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Wissler, Josef. "Functional non-coding ncRNA in immunity and tolerance: what can be learned from structures and functions of transfer factors of delayed-type[-IV] hypersensititvity on genetics, epigenetics and recognition repertoires (62.12)". Journal of Immunology 186, nr 1_Supplement (1.04.2011): 62.12. http://dx.doi.org/10.4049/jimmunol.186.supp.62.12.
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Abstract AIM: Immunity and [self-]tolerance are usually considered orchestrated by protein repertoires upon genetic [Mendelian] and epigenetic [non-Mendelian] variation mechanisms. All is still not fully understood, as evident from transfer factor and LeDouarin phenomena, environmental influences, peptidome complexity and diversity [Adv.Immunol.11,195-266,1969; Int.J.Dev.Biol.49,131-136,2005]. Endogenous ncRNA incl. microRNA mostly escaped consideration. METHODS: Ann.N.Y.Acad.Sci.1137,316-342,2008. RESULTS: Landsteiner-Chase-Lawrence transfer factors showed up as paradigmatic guides in some terra incognita of adaptive immune memory. Original crude preparations were found as paucidisperse solute systems of numerous functional small ncRNA [<200n] in interaction with proteins. Some environment-modified redox- and metalloregulated small hairpin shRNA [<200 bases] were sequenced. By 5'-CUG-3’-hairpin loops, they may address conserved homologous helix-nucleating domains shared in self and foreign proteofactors of tolerated growth, metabolism, vascularization, cancer and epigenome indexing. CONCLUSIONS: Immune cells are not restricted to known protein recognition systems. They have further repertoires of environment-adapted ncRNA as earliest outputs in transcription and translation. These are superior in diversity/specificity [≥10E17] to immune proteins repertoires [~10E13]. All attributes make them competent to integrate information flow on possible molecular shapes into genomic mechanisms.
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Browne, Katrina, Sudip Chakraborty, Renxun Chen, Mark DP Willcox, David StClair Black, William R. Walsh i Naresh Kumar. "A New Era of Antibiotics: The Clinical Potential of Antimicrobial Peptides". International Journal of Molecular Sciences 21, nr 19 (24.09.2020): 7047. http://dx.doi.org/10.3390/ijms21197047.
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Antimicrobial resistance is a multifaceted crisis, imposing a serious threat to global health. The traditional antibiotic pipeline has been exhausted, prompting research into alternate antimicrobial strategies. Inspired by nature, antimicrobial peptides are rapidly gaining attention for their clinical potential as they present distinct advantages over traditional antibiotics. Antimicrobial peptides are found in all forms of life and demonstrate a pivotal role in the innate immune system. Many antimicrobial peptides are evolutionarily conserved, with limited propensity for resistance. Additionally, chemical modifications to the peptide backbone can be used to improve biological activity and stability and reduce toxicity. This review details the therapeutic potential of peptide-based antimicrobials, as well as the challenges needed to overcome in order for clinical translation. We explore the proposed mechanisms of activity, design of synthetic biomimics, and how this novel class of antimicrobial compound may address the need for effective antibiotics. Finally, we discuss commercially available peptide-based antimicrobials and antimicrobial peptides in clinical trials.
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Razak, Nur Izah Ab, Nor Eliani Ezani i Norzian Ismail. "Particulate Matter-Induced Acute Coronary Syndrome: MicroRNAs as Microregulators for Inflammatory Factors". Mediators of Inflammation 2021 (11.12.2021): 1–13. http://dx.doi.org/10.1155/2021/6609143.
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The most prevalent cause of mortality and morbidity worldwide is acute coronary syndrome (ACS) and its consequences. Exposure to particulate matter (PM) from air pollution has been shown to impair both. Various plausible pathogenic mechanisms have been identified, including microRNAs (miRNAs), an epigenetic regulator for gene expression. Endogenous miRNAs, average 22-nucleotide RNAs (ribonucleic acid), regulate gene expression through mRNA cleavage or translation repression and can influence proinflammatory gene expression posttranscriptionally. However, little is known about miRNA responses to fine PM (PM2.5, PM10, ultrafine particles, black carbon, and polycyclic aromatic hydrocarbon) from air pollution and their potential contribution to cardiovascular consequences, including systemic inflammation regulation. For the past decades, microRNAs (miRNAs) have emerged as novel, prospective diagnostic and prognostic biomarkers in various illnesses, including ACS. We wanted to outline some of the most important studies in the field and address the possible utility of miRNAs in regulating particulate matter-induced ACS (PMIA) on inflammatory factors in this review.