Principles Of Regulation Research Articles

Abstract PR015: Decoding RNA metabolism by RNA-linked CRISPR screening in human cells

Abstract RNAs undergo a complex choreography of metabolic processes in human cells that are regulated by thousands of RNA-associated proteins. While the effects of individual RNA-associated proteins on RNA metabolism have been extensively characterized, the full complement of regulators for most RNA metabolic events remain unknown. Here we present a massively parallel RNA-linked CRISPR (ReLiC) screening approach to measure the responses of diverse RNA metabolic events to knockout of 2,092 human genes encoding all known RNA-associated proteins. ReLiC screens highlight modular interactions between gene networks regulating splicing, translation, and decay of mRNAs. When combined with biochemical fractionation of polysomes, ReLiC reveals striking pathway-specific coupling between growth fitness and mRNA translation. Perturbing different components of the translation and proteostasis machineries have distinct effects on ribosome occupancy, while perturbing mRNA transcription leaves ribosome occupancy largely intact. Isoform-selective ReLiC screens capture differential regulation of intron retention and exon skipping by SF3b complex subunits. Chemogenomic screens using ReLiC decipher translational regulators upstream of mRNA decay and uncover a role for the ribosome collision sensor GCN1 during treatment with the anti-leukemic drug homoharringtonine. Our work demonstrates ReLiC as a versatile platform for discovering and dissecting regulatory principles of human RNA metabolism. Citation Format: Patrick J Nugent, Heungwon Park, Arvind Rasi Subramaniam. Decoding RNA metabolism by RNA-linked CRISPR screening in human cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR015.

PROBLEMS AND PROSPECTS OF THE DEVELOPMENT OF BANKING REGULATION AND SUPERVISION IN UKRAINE

Effective banking regulation and supervision are key factors for ensuring the stability of the national banking system of Ukraine. The purpose of this article is to analyze the peculiarities of banking regulation and supervision in Ukraine in order to identify problems and possible ways of development, including in the context of world experience. The article examines the theoretical aspects of the essence of the concepts of banking regulation and banking supervision. The main indicators of the banking system of Ukraine for 2020-2024 and the mechanism for identifying risks in the activities of banking institutions are also considered. The global trends in banking regulation at the current stage are its centralization, the concept of risk-oriented supervision, the introduction of new financial technologies, the development of the principles of proportional banking regulation. The main positive and negative methods of supervision in the banking sector are singled out. It has been proven that the conditions of a full-scale military conflict significantly undermined the development of the banking system of Ukraine. The destruction of infrastructure, loss of customer confidence, risks to the bank's loan portfolio and capitalization have become major problems. In addition, the decrease in liquidity and the growth of inflation risks create serious challenges for the banking system. The degree of suitability of world models in terms of the priority tasks of the state regarding the regulation of the banking sector is analyzed. Directions for improving banking supervision through improvement of banking activity licensing procedures are proposed; introduction of permanent monitoring of the activities of domestic commercial banks, in particular their financial condition; implementation of constant monitoring of compliance with banking regulations and current legislation; introduction of permanent inspections of banking activities; implementation by commercial banks of ongoing internal control and external audit control; developing and sending supervisory instructions for banking institutions regarding the implementation of Basel III standards.

The master regulator OxyR orchestrates bacterial oxidative stress response genes in space and time.

Bacteria employ diverse gene regulatory networks to survive stress, but deciphering the underlying logic of these complex networks has proved challenging. Here, we use time-resolved single-cell imaging to explore the functioning of the E.coli regulatory response to oxidative stress. We observe diverse gene expression dynamics within the network. However, by controlling for stress-induced growth-rate changes, we show that these patterns involve just three classes of regulation: downregulated genes, upregulated pulsatile genes, and gradually upregulated genes. The two upregulated classes are distinguished by differences in the binding of the transcription factor, OxyR, and appear to play distinct roles during stress protection. Pulsatile genes activate transiently in a few cells for initial protection of a group of cells, whereas gradually upregulated genes induce evenly, generating a lasting protection involving many cells. Our study shows how bacterial populations use simple regulatory principles to coordinate stress responses in space and time. A record of this paper's transparent peer review process is included in the supplemental information.

Features of Credit Institutions Carrying out Activities in the Field of AML/CFT/PWF in the Context of the Application of Sanctions and Counter-Sanctions

The article analyzes the impact of sanctions and counter-sanctions on the procedure and standards of banking services, including on the implementation of credit organizations activities in the field of AML/CFT/PWF. Based on the study of relevant legal acts adopted by authorized Russian bodies and domestic legal doctrine, the author shows that in the current situation of inconsistency between applied models of legal regulation and the established principles of regulation of banking relations, credit organizations are forced to revise their previously successfully tested standards and ethical models of customer service. Therefore, the optimal procedure for the normative consolidation of anti-money laundering procedures in the context of the implementation of counter-sanctions have been determined. The trends in sanction (counter-sanction) compliance and aspects of its interaction with financial monitoring in credit organizations are considered, and a form of formalization of the sanctions (counter-sanction) compliance policy in credit organizations is proposed.

Explainable machine learning models for predicting the acute toxicity of pesticides to sheepshead minnow (Cyprinodon variegatus).

A quantitative structure-activity relationship (QSAR) study was conducted on 313 pesticides to predict their acute toxicity to Sheepshead minnow (Cyprinodon variegatus) by using DRAGON descriptors. Essentials accounting for a reliable model were all considered carefully, giving full consideration to the OECD (Organization for Economic Co-operation and Development) principles for QSAR acceptability in regulation during the model construction and assessment process. Nine variables were selected through the forward stepwise regression method and used as inputs to construct both linear and nonlinear models. The obtained models were validated internally and externally. Generally, machine learning-based methods, namely support vector machine (SVM), random forest (RF), and projection pursuit regression (PPR), perform better than the multiple linear regression (MLR) model. The statistical results (R2 = 0.682-0.933, Q2LOO = 0.604-0.659, Q2F1 = 0.740-0.796, CCC = 0.861-0.882) of the developed models show that they are robust, reliable, reproducible, accurate and predictive. Comparatively, the RF model performs best, giving predictive correlation coefficient Q2 of 0.814, root mean squared error (RMSE) of 0.658 and mean absolute error (MAE) of 0.534 for the test set, respectively. The RF model (as well as SVM and PPR models) was visualized and explained by using the SHapley Additive explanation (SHAP) analysis to enhance its transparency and credibility. In addition, the applicability domain (AD) range of the RF model was characterized by the Williams plot and the tree manifold approximation and projection (TMAP) technology was utilized to illustrate similarity and diversity of the entire data space, to assist in the analysis of the outliers. Activity cliff detection was investigated by using Arithmetic Residuals in K-groups Analysis (ARKA) descriptors. It was found that none of the pesticides was identified as an activity cliff in the training set or a potential prediction cliff in the test set. Therefore, the RF model fulfills each OECD principle in regulation for QSAR models. The research in this work will aid in the in silico QSAR prediction of the acute toxicity to Sheepshead minnow (Cyprinodon variegatus) for untested and new toxic pesticides and can also be extended to other studies.

Re-aerobic treatment and dissolved oxygen regulation in full-scale aerobic-hydrolysis and denitrification-aerobic process for achieving simultaneous detoxification and nitrification of coking wastewater

The biological treatment of coking wastewater is a challenge. The application of prepositioned aerobic process has rarely been systematically reported, among which the detoxification and nitrification performance of the prepositioned aerobic unit (O1) is worthy of investigation. Results indicate that O1 achieves stable simultaneous detoxification and nitrification by regulating the dissolved oxygen, effectively maintaining ammonification, nitrosation, and complete nitrification phases. Microbial community structure, metabolic pathways and functional genes showed different preferences at different phases. High dissolved oxygen concentrations (2.20–3.00 mg/L) benefited the enrichment of carbon and nitrogen related major metabolic pathways and functional genes. BOD5/CODCr ratio, dissolved oxygen and toxic pollutants together shaped microbial community structure and nitrogen transformation processes. Based on the principle of DO regulation, it could assemble a biotransformation compartment for nitrogen removal from complex wastewaters through a pollutant detoxification mechanism of rapid microbial proliferation，and provides a promising approach for toxic industrial wastewater.

Liquid crystal phase behavior of oxalated cellulose nanocrystal and optical films with controllable structural color induced by centripetal force

Cellulose nanocrystal (CNC) is a sustainable bio-nanomaterial. The distinctive left-handed polarization properties render cellulose nanocrystal a promising candidate for optical film. Due to eco-friendliness, reliability, mildness and simplicity, the oxalate hydrolysis method stands out among various preparation methods for CNC. This study delved into the liquid crystal phase behavior of oxalated cellulose nanocrystal derived from pulp, and discovered the influences of CNC concentration and pH on suspension stability and phase transition, and evaluated its optical properties. The results demonstrated that oxalated CNC presented two different liquid crystal phases, the nematic phase and the cholesteric phase. The stability mechanism of CNC suspension and the regulatory principle of the liquid crystal phase transition were revealed. A novel CNC film-forming technology, the multilayer spin-coating technique, was developed for cellulose nanocrystal optical films. Driven by centrifugal force, cellulose nanocrystals were induced to self-assembly and formed the optical film with circular dichroism and structural color. This simple and efficient film-forming technology promised rapid processing (1 h) and controllable film structure and optical properties compared to traditional technologies. This work provided a theoretical understanding and practical prospects for integrating oxalated cellulose nanocrystal into sustainable advanced optical film materials.

Genetic and Epigenetic Dysregulation of Transcriptional Enhancers in Cancer

Enhancers are noncoding DNA sequences responsible for orchestrating gene expression programs by interacting with transcription factors and chromatin regulators within complex genome structures. However, their fundamental functions can be disrupted by genetic and epigenetic alterations, leading to aberrant enhancer activation or rewiring that contributes to oncogenesis. Analyzing dysregulated enhancer landscapes reveals new subtype-defining genomic features, such as enhancer hijacking, and identifies disease-relevant transcriptional regulators as potential targets for developing enhancer-targeting therapeutic strategies. Here, we delve into evolving concepts and technologies for studying enhancers; discuss how genetic, epigenetic, and topological alterations disrupt enhancer regulation to promote oncogenic gene expression; and underscore the importance of understanding the regulatory principles governing enhancer function to guide therapeutic strategies. Furthermore, we highlight key challenges and emerging opportunities in targeting enhancers and their regulators to improve cancer classification, prognosis, and treatment.

Global coupling of R-loopdynamics with RNA polymerase II modulates gene expression and early development of Drosophila.

R-loops are involved in many biological processes in cells, yet the regulatory principles for R-loops in vivo and their impact on development remain to be explored. Here, we modified the CUT&Tag strategy to profile R-loops in Drosophila at multiple developmental stages. While high GC content promotes R-loop formation in mammalian cells, it is not required in Drosophila. In contrast, RNAPII abundance appears to be a universal inducing factor for R-loop formation, including active promoters and enhancers, and H3K27me3 decorated repressive regions and intergenic repeat sequences. Importantly, such a regulatory relationship is dynamically maintained throughout development, and development-related transcription factors may regulate RNAPII activation and R-loop dynamics. By ablating Spt6, we further showed the global R-loop induction coupled with RNAPII pausing. Importantly, depending on the gene length, genes underwent up- or down-regulation, both of which were largely reversed by rnh1 overexpression, suggesting that R-loops play a significant role in the divergent regulation of transcription by Spt6 ablation. DNA damage, defects in survival, and cuticle development were similarly alleviated by rnh1 overexpression. Altogether, our findings indicate that dynamic R-loop regulation is dictated by RNAPII pausing and transcription activity, and plays a feedback role in gene regulation, genome stability maintenance, and Drosophila development.

Genome organization and stability in mammalian pre-implantation development

A largely stable genome is required for normal development, even as genetic change is an integral aspect of reproduction, genetic adaptation and evolution. Recent studies highlight a critical window of mammalian development with intrinsic DNA replication stress and genome instability in the first cell divisions after fertilization. Patterns of DNA replication and genome stability are established very early in mammals, alongside patterns of nuclear organization, and before the emergence of gene expression patterns, and prior to cell specification and germline formation. The study of DNA replication and genome stability in the mammalian embryo provides a unique cellular system due to the resetting of the epigenome to a totipotent state, and the de novo establishment of the patterns of nuclear organization, gene expression, DNA methylation, histone modifications and DNA replication. Studies on DNA replication and genome stability in the early mammalian embryo is relevant for understanding both normal and disease-causing genetic variation, and to uncover basic principles of genome regulation.

Aligning Greece’s Regulatory Governance With International Transformative Principles and Objectives: The Case of the UN 2030 Agenda for Sustainable Development

Abstract The article highlights the importance that the international dimension of the regulatory context of draft legislation acquires for the drafting of effective regulation. It attempts to demonstrate the added value that the integrated incorporation of fundamental regulatory principles and objectives derived from influential global regulatory texts enjoying full acceptance, like the UN Resolution on the 2030 Agenda for Sustainable Development, brings to a country’s regulatory governance. From an empirical perspective, the article focuses on a thorough analysis of the degree to which Greece’s law-making process is interconnected and aligned with core regulatory principles of the 2030 Agenda, such as the principle of policy coherence, the evidence-based principle, and the principle of inclusion. It examines the key instruments, procedures, and ways in which these principles are appropriately mainstreamed into the Greek legislative process and the institutional and policy framework of the Government on which its legislative interventions are founded. As a case study, the alignment and coherence of the provisions of a specific law pertaining to tourism development with the overarching regulatory principles of the UN 2030 Agenda are examined. Τhe concluding part presents some proposals that could contribute to improving the way the SDGs are effectively mainstreamed into Greece’s legislative process.

A lineage-specific nascent RNA assay unveils principles of gene regulation in tissue biology.

Gene regulatory mechanisms that modulate RNA Polymerase II activity are difficult to access in mammalian tissues composed of multiple cell lineages. Here, we develop a nascent RNA assay (PReCIS-seq) that measures lineage-specific transcriptionally-engaged Pol II on genes and DNA enhancer elements in intact mouse tissue. By employing keratinocytes as a prototype lineage, we unearth Pol II promoter-recruitment versus pause-release mechanisms operating in adult skin homeostasis. Moreover, we relate active enhancer proximity and transcription factor binding motifs on promoters to Pol II activity and promoter-proximal pausing level. Finally, we find Pol II firing rapidly into elongation on lineage identity genes and highly paused on cellular safeguarding genes in a context-dependent manner. Our work provides a basic platform to investigate mechanistic principles of gene regulation in individual lineages of complex mammalian tissues.

Regulatory and legal principles of management of sports schools for children and youth

The activities of sports schools for children and youth play a key role in shaping the physical culture of young people, promoting a healthy lifestyle, and preparing future professional athletes. The successful functioning of these schools relies on appropriate legal frameworks that outline the operational rules, requirements for educational processes, funding, and management of facilities. there is a pressing need to analyze the current legal framework governing the management of sports school for children and youth. Considering the constant changes in the legislation and the growing requirements for the quality of sports institutions, there is a pressing need to analyze the current legal framework governing the management of sports schools for children and youth. The purpose of this article is to analyze the regulatory and legal principles of managing the activities of sports schools for children and youth in Ukraine. The key legislative acts regulating the organizational, financial, and legal aspects of the functioning of sports schools for children and youth have been analyzed, including the Constitution of Ukraine, the Law ‘On Physical Culture and Sports,’ and the orders of the Ministry of Education and Science and the Ministry of Youth and Sports. This resolution provides a comprehensive framework for the operation of sports schools for children and youth as well as defines the forms of ownership, legal foundations of their activities, funding procedures, and requirements for athlete training. Particular attention is given to the state social standard in physical culture and sports, which sets requirements for the quality of services, infrastructure, and athlete training. The mechanisms of management that contribute to increasing the efficiency of sports schools for children and youth are highlighted.

“Pilgrims Speaking Angry Words: Change and Anger in Chaucer’s Canterbury Tales”

Medieval literature presents emotions such as anger as negative and destructive for the development of the medieval subject and society and defines anger not as a positive constructive affect but as an emotive reaction that should be suppressed, controlled or avoided. Chaucer’s Canterbury Tales, written against a background of tremendous change generated by political and religious conflict, the Black Death and the Peasants’ Revolt, acknowledges anger as an essential element of medieval culture although it does not give much space to the causes of it. The Canterbury pilgrims experience and perform anger as a result of the unstructured and fast change taking place in the traditional stabilities. Indeed, the changing society represented by the pilgrims in the Canterbury Tales appears to have anger issues and accordingly is characterised by situations of conflict and emotional crises. The pilgrims are presented as failing in terms of conformity and obedience to the regulatory principles of the feudal structure also because they foster anger and have angry responses when they are expected to suppress, avoid and control their anger. Anger in this context is presented as an essential element of the new culture that produces it. This paper reads Chaucer’s representation of anger as an affect/emotion in the Canterbury Tales and argues that as an emotive/affective agent, anger performed by the defiant pilgrims represents and forms the cultural response to the pervasive change and its results in the medieval feudal social structure represented in the Canterbury Tales.

A guide to studying 3D genome structure and dynamics in the kidney.

The human genome is tightly packed into the 3D environment of the cell nucleus. Rapidly evolving and sophisticated methods of mapping 3D genome architecture have shed light on fundamental principles of genome organization and gene regulation. The genome is physically organized on different scales, from individual genes to entire chromosomes. Nuclear landmarks such as the nuclear envelope and nucleoli have important roles in compartmentalizing the genome within the nucleus. Genome activity (for example, gene transcription) is also functionally partitioned within this 3D organization. Rather than being static, the 3D organization of the genome is tightly regulated over various time scales. These dynamic changes in genome structure over time represent the fourth dimension of the genome. Innovative methods have been used to map the dynamic regulation of genome structure during important cellular processes including organism development, responses to stimuli, cell division and senescence. Furthermore, disruptions to the 4D genome have been linked to various diseases, including of the kidney. As tools and approaches to studying the 4D genome become more readily available, future studies that apply these methods to study kidney biology will provide insights into kidney function in health and disease.

Digital RMB: Regulation of Central Bank Digital Currency (CBDC) in China

Introduction. “Digital RMB” is the digital currency of the People's Bank of China that has attracted the attention of researchers around the world. This project is not the first to be put into circulation, but it is the largest in terms of the volume of issued currency and the number of people using the CBDC as a means of payment.Materials and methods. The analysis of the practice of putting into effect, as well as the basics of regulating the CBDC of the PRC, can become a source of information that allows, when making a comparison, to develop a policy of action for the regulator in relation to the digital currencies of other countries.This article considers only the CBDC of the PRC, its features, technological and non-technological components. The main source of analysis is the Program Document or the Whitepaper of the CBDC of the PRC, which is currently the only official source of information on how the currency regulation is structured. This document is one of those establishing regulatory principles and is an example of a generally accepted method of regulating innovative financial technologies at the pilot stage.Results of the study. Based on the analysis, the article offers conclusions, current and final, about what the PRC CBDC is, what its structure is, what are the features and of the PRC CBDC.Discussion and conclusion. Areas of application of the PRC CBDC are being considered, the legal effect of its implementation.

Specifics of the Constitutional Right to Establish and Operate the Trade Unions

Introduction. In the framework of the legal regulation of the trade union activities in Russia, a number of regulations cause certain contradictions with regard to establishment of the social and labour relations. Difficulties in interaction of the trade unions with the employers and the state, supplemented by the competition with the private labour, arise the problem of preserving the institution under study as the one aimed at the formation of a system of social partnership, development of the labour environment, national economy and social equality. Therefore, the research strives to investigate the constitutional requirements for establishment and operation of the trade unions to enable harmonization of the social and labour relations. By finding the legislative gaps in the process of implementing the rights of citizens to establish and operate the trade unions, it is possible to modernize the regulatory legal institutions in this field. The aim of the research is to study the specifics of the constitutional right to establish and operate the trade unions.Materials and Methods. The methodological framework was organised based on the selection, analysis and systematisation of the relevant regulatory and legal data and research works in the subject area. The use of a set of general scientific (dialectical, logical, systemic) and specific scientific methods of cognition (comparative legal, dogmatic legal, sociolegal) made it possible to study the principles of state regulation of the trade union activities, identify the gaps in their work and shortcomings due to be eliminated, as well as to summarise the factors of applicability of the constitutional operational procedure to the activities of the trade union organisations in Russia.Results. The constitutional right to establish and operate the trade unions has been analysed. It has been acknowledged that determination of the legal advantages of the trade union members does not correlate with the process of declining the popularity of this institution in the Russian Federation. It has been revealed that this trend is caused by the several problems, i.e.: the multiplicity of the legislative requirements creates a number of contradictions in the relations between the trade unions and employers preventing the full freedom of organisations’ activities; the process of establishing the trade unions is complicated by the need to incorporate the legal entity, the legislative predetermination and formality do not give freedom to the organisations in compiling the charter and making changes to it without permission of the state; the principles of the internal relations regulation must comply with the standard provisions of the Labour Code of the Russian Federation, which also limits the trade union activity; the court defence of the rights of the trade union members needs to be revised and modernized to eliminate the ambiguous provisions and reduce the bureaucratic processes. The use of the variable collective agreements and principles of social partnership aimed at harmonisation of the social and labour relations have been proposed as the solutions to the identified problems.Discussion and Conclusion. The study has identified the key issues and underdeveloped aspects of the constitutional regulation of the trade union activities in the Russian Federation, which could be solved through the optimisation of the excessive legislative requirements, issuing the updated provisions on court defence of the trade union members, establishing the full independence and autonomy of such organisations in the matters of internal regulation, as well as through the development of the system of social partnership. The theoretical and practical conclusions drawn in the paper could be used for further research in the field of improving the legal literacy of the trade union members.

Principles of regulation of business activities in modern conditions

The article examines and analyzes the basic principles of regulation of business activities. The characteristics of such principles as the principle of social justice, the principle of state control (supervision) and municipal control, the principle of stimulating conscientious compliance with mandatory requirements, the principle of mutual assistance and protection of interests, the principles of tax regulation of business activities are given. Attention is drawn to the need to transform the approach to maintaining fairness and balance of these principles.

Нормирование труда: некоторые теоретические и практические проблемы

This paper examines some theoretical and practical problems of labor rationing, which is of crucial importance for regulating labor and other directly related relations. The interrelation of labor rationing with the task of labor legislation in the form of optimal coordination of the interests of the parties to labor relations and the interests of the state is presented, the inclusion of labor rationing relations in which the employer is in a relationship with employees and (or) their representatives in the content of labor organization and labor management relations is justified. The author presents the relationship between labor rationing and the principles of legal regulation of labor relations. It is noted that it is necessary to consolidate the obligation of the employer to carry out rationing in the organization.

Conserved mechanism of Xrn1 regulation by glycolytic flux and protein aggregation

The regulation of gene expression in eukaryotes relies largely on the action of exoribonucleases, evolutionarily conserved enzymes that digest decapped messenger RNAs in the 5’-3’ direction. The activity of Xrn1, the major yeast exoribonuclease, is regulated by targeted changes in its cellular localisation in direct response to the cell’s metabolic state. When fermentable carbon sources are available, active Xrn1 is diffusely localised in the cytosol. Upon depletion of these sources, Xrn1 is sequestered at the plasma membrane-associated protein complex, the eisosome, and becomes inactive. Although this phenomenon has been described previously, the molecular mechanisms underlying these changes remain unknown. We report that the binding of Xrn1 to the plasma membrane is subject to glycolytic flux, rather than the availability of a fermentable carbon source, is independent of TORC1 activity and requires the core eisosomal proteins Pil1 and Lsp1. We identify the SH3-like domain of the Xrn1 protein as a putative interaction domain. In addition, we show that when expressed in Saccharomyces cerevisiae, the human orthologue of Xrn1 mirrors its yeast counterpart, i.e., it segregates to the eisosome under conditions of halted glycolysis. Our results not only advance our understanding of Xrn1 regulation but also indicate that this regulatory principle is conserved from yeast to humans.