Target binding triggers hierarchical phosphorylation of human Argonaute-2 to promote target release

Argonaute (Ago) proteins play a central role in post-transcriptional gene regulation through RNA interference (RNAi). Agos bind small RNAs (sRNAs) including small interfering RNAs (siRNAs) and microRNAs (miRNAs) to form the functional core of the RNA Induced Silencing Complex (RISC). The sRNA is used as a guide to target mRNAs containing either partially or fully complementary sequences, ultimately leading to down regulation of the corresponding proteins. It was previously shown that the kinase CK1α phosphorylates a cluster of residues in the eukaryotic insertion (EI) of Ago, leading to the alleviation of miRNA-mediated repression through an undetermined mechanism. We show that binding of miRNA-loaded human Ago2 to target RNA with complementarity to the seed and 3′ supplemental regions of the miRNA primes the EI for hierarchical phosphorylation by CK1α. The added negative charges electrostatically promote target release, freeing Ago to seek out additional targets once it is dephosphorylated. The high conservation of potential phosphosites in the EI suggests that such a regulatory strategy may be a shared mechanism for regulating miRNA-mediated repression.

Outsourcing the enforcement of modern slavery: Overcoming the limitations of a market-based disclosure model

Recent legislative efforts to address modern slavery emphasise corporate disclosure as the primary regulatory tool. New modern slavery disclosure laws harden the expectation that business will conduct itself responsibly; however, they are founded on a soft approach to enforcement which is essentially outsourced to the market. This paper questions the effectiveness of this disclosure-based enforcement mechanism, which primarily relies on a narrowly defined concept of ‘the market’ as the basis for its regulatory strategy. Drawing on comparisons with alternative legislative enforcement frameworks to counter foreign bribery and illegal logging, this paper highlights the opportunities and limitations of reliance on market forces for regulation and suggests a path forward for enhancing the modern slavery enforcement approach.

Inner Obstacles and Goal-Directed Behaviors of Elite and Youth Level Cyclists: A Qualitative Analysis From the Perspective of Athletes and Coaches

Top-level performance requires self-regulatory control to overcome different inner obstacles and to apply useful strategies. As for the importance of self-regulation, investigations have been conducted aiming at the efficacy of the self-regulatory strategy of implementation intentions (i.e., if-then plans) on athletic performance, an approach that combines obstacles (if) and goal-directed behaviors (then) to facilitate goal attainment. In this study, we investigated the inner obstacles that athletes face in competitive situations and assessed the goal-directed behaviors they use to deal with these obstacles in order to design effective interventions based on the framework of implementation intention theory. We elucidate inner obstacles and goal-directed behaviors of elite and youth level athletes with a self-designed questionnaire (Study 1). A reworded version of this questionnaire was used for assessing these research questions from a coaches’ perspective (Study 2). Thirty-four elite and youth level athletes (age: M = 23.7 ± 9.9 years) and 42 elite coaches (age: M = 50.2 ± 9.8 years) participated in both studies. Inner obstacles and goal-directed behaviors were analyzed with thematic analyses. The most frequently named inner obstacles were dealing with demanding situations, pressure, and concentration, while the most frequently stated goal-directed behaviors with these obstacles were preparation, self-encouragement, and relaxation (athletes) and concentration (coaches). The results of these studies illustrate the multiple challenges elite and youth level cycling athletes face and provide important insights for sportpsychological research with implementation intentions regarding plan structure and content.

COMMUNICATIVE STYLISTICS: LINGUO-COGNITIVE MECHANISMS OF SENSE INTERPRETATION OF THE POETIC TEXT

Введение. Изучение речемыслительной деятельности автора и адресата в процессе сотворчества на основе текста как формы коммуникации относится к числу наиболее актуальных проблем в русистике. Современная когнитивно-дискурсивная парадигма научного знания и развитие коммуникативной теории текста открывают новые перспективы в исследовании текста как объекта восприятия, интерпретации и понимания. Цель – опираясь на теорию регулятивности как одно из направлений коммуникативной стилистики текста, выявить некоторые лингвокогнитивные механизмы формирования гиперконцепта как результата интерпретационной деятельности воспринимающего текст субъекта. Материал и методы. Исследование основано на анализе, сравнении и обобщении научной литературы по теории и истории вопроса, на использовании методологии и понятийно-терминологического аппарата теории регулятивности, разработанной в коммуникативной стилистике текста, применении концептуального, лингвосмыслового, семантико-стилистического анализа. Материалом исследования послужили стихи известных русских поэтов Ф. И. Тютчева, И. А. Бунина, З. Н. Гиппиус, Н. А. Заболоцкого. Результаты и обсуждение. За исходное взято положение о том, что в основе интерпретации текста адресатом лежат лингвокогнитивные механизмы – речемыслительные процессы, формирующие обобщенный смысл текста (гиперконцепт), стимулированные общей системой текста, включающие когнитивные операции анализа, сравнения, синтеза с опорой на ассоциативную деятельность и имеющийся у индивида опыт. В выявлении гиперконцепта важны регулятивная стратегия текста, способы регулятивности, регулятивные средства и структуры, использованные автором в тексте с ориентацией на сотворчество с адресатом, «управление» его познавательной деятельностью. Особенно значима лексическая система текста, стимулирующая его ассоциативно-смысловое развертывание в сознании читателя. Интерпретационная деятельность предполагает взаимосвязь актуализированных в тексте концептов в рамках его общей концептуальной структуры на основе отношений дополнения, усиления, контраста, включения, сопоставления, обобщения. С учетом этого, опираясь на теорию регулятивности, были выявлены лингвокогнитивные механизмы формирования гиперконцепта: 1) сквозной усилительно-конвергентный, связанный с последовательным усилением ключевого концепта различными регулятивными средствами и структурами в рамках индуктивно-дедуктивной лексической макроструктуры текста, с повтором как способом регулятивности и регулятивной стратегией поэтапного усиления семантических признаков ключевого концепта; 2) замкнутый последовательно-дополнительный, проявляющийся в по этапной художественно-образной конкретизации разных признаков гиперконцепта на основе использования сильной регулятивной стратегии однородного эксплицитного типа и повтора как основного способа регулятивности; 3) сопоставительно-парадоксальный, стимулированный регулятивной стратегией парадоксально-контрастивного типа, контрастом как основным способом регулятивности и текстовыми парадигмами антонимического типа как регулятивной доминантой; 4) сопоставительно-синтезирующий, отражающий синтез (обобщение) на основе сопоставительного ассоциативно-смыслового развертывания разных граней (признаков) ключевого концепта, стимулированных ступенчатой лексической макроструктурой индуктивно-дедуктивного типа. Заключение. Использование теории регулятивности и ее понятийно-терминологического аппарата позволяет судить о некоторых заданных в поэтическом тексте автором закономерностях организации интерпретационной деятельности адресата и лингвокогнитивных механизмах формирования общего смысла текста. Полученные наблюдения представляют интерес для дальнейшей разработки проблемы смысловой интерпретации и методики смыслового анализа текста. Introduction. The study of verbal and cognitive activity of an author and an addressee in the process of co-creation based on the text as a form of communication remains an urgent problem. The modern cognitive-discursive paradigm of scientific knowledge and development of communicative theory of text offer the challenge in the study of text as an object of perception, interpretation and understanding. The aim of the article is the detection of some linguo-cognitive mechanisms of hyperconcept forming as a result of interpretative activity by a subject perceiving the text relying on the regulative theory as one of the directions of the communicative stylistics of the text. Material and methods. The research is examined on the analysis, comparison and generalization of scientific literature on the theory and history of the issue, on the use of the methodology and conceptual and terminological apparatus of the regulative theory, on the application of conceptual, linguistic, semantic and stylistic analysis. The material for the study was the poems of famous Russian poets F. I. Tyutchev, I. A. Bunin, Z. N. Gippius, N. A. Zabolotsky. Results and discussion. The starting point is the following: the interpretation of the text by the addressee depends on linguo-cognitive mechanisms – verbal and cognitive processes that form the generalized meaning of the text (hyperconcept), stimulated by the general system of the text, including the cognitive operations of analysis, comparison, synthesis based on associative activity and an experience of a person. In identifying the hyperconcept, the regulatory strategy of the text, the methods of regulation, the regulatory means and structures which the author used in the text with an orientation towards co-creation with the addressee, “control” of his cognitive activity are important. The lexical system of the text stimulating its associative and semantic deployment in the mind of the reader is especially significant. Interpretive activity presupposes the interconnection of the concepts actualized in the text within the limits of its general conceptual structure based on the relations of complement, enhancement, contrast, inclusion, comparison, generalization. Taking this into account, relying on the regulative theory, the following linguocognitive mechanisms of hyperconcept formation were identified: 1) through amplifying-convergent mechanism, associated with the sequential strengthening of the key concept by various regulatory means and structures in the context of the inductive-deductive lexical macrostructure of the text; with repetition as a way of regulation and a regulatory strategy for the stepwise enhancement of the semantic features of the key concept; 2) closed sequentialadditional, manifested in a phased artistic-figurative concretization of various signs of a hyperconcept based on the use of a strong regulatory strategy of a homogeneous explicit type and repetition as the main way of regulation; 3) comparative-paradoxical, stimulated by the regulatory strategy of the paradoxical-contrastive type; contrast as the main method of regulation and textual paradigms of the antonymic type as a regulatory dominant; 4) comparativesynthesizing, reflecting synthesis (generalization) on the basis of parallel comparative associative-semantic deployment of different facets (features) of the key concept, stimulated by a stepped lexical macrostructure of the inductive-deductive type. Conclusion. The use of the regulative theory and its conceptual and terminological apparatus makes it possible to determine some of the patterns organized by the interpretive activity of the addressee and the linguo-cognitive mechanisms of the formation of the general meaning of the text given in the poetic text. Obtained observations are of interest for further development of the problem of notional interpretation and methods of semantic analysis of the text.

Recent drug regulatory affair and CTD module progress review for submission of pharmaceuticals product

Regulatory Affairs (RA), also known as government affairs, is a relatively new profession that arose from governments' desire to protect public health by regulating the safety and efficacy of products such as pharmaceuticals, medical devices, pesticides, veterinary medicines, cosmetics, agrochemicals, and complementary medicines. Pharmaceutical regulatory affairs is concerned with the registration of pharmaceutical goods. All regulatory elements and guidelines connected to product filing are summarized in this evaluation. This study covers the whole CTD and eCTD submission process, as well as the modules that go with it. It also focuses on the key regulatory bodies across the world. Various roles of DRA departments, drug regulatory affairs professionals, the importance of drug affairs in pharmacy curriculum, emerging trends affecting regulatory strategy, regulatory affairs in product management, clinical trials, R&D and the drug approval process in the US, EU, and ROW market trends are discussed.