The proteins encoded by the ras proto‐oncogenes play critical roles in normal cellular growth, differentiation and development in addition to their potential for malignant transformation. Several proteins that are involved in the control of the activity of p21ras have now been characterised. p120GAP stimulates the GTPase activity of p21ras and hence acts as a negative regulator of ras proteins. It may be controlled by tyrosine phosphorylation or association with tyrosine phosphorylated proteins. The neurofibromatosis type 1 (NF 1) gene also encodes (...) a potential GTPase activating protein which is likely to be subject to a different control mechanism. Guanosine nucleotide exchange factors for p21ras have now been identified: these may be positive regulators of ras protein function. It appears that p21ras is subject to rapid regulation by several distinct mechanisms which are likely to vary in different cell types; the ras proteins are thereby able to act as very sensitive cellular monitors of the extracellular environment. (shrink)

Living systems employ several mechanisms and behaviors to achieve robustness and maintain themselves under changing internal and external conditions. Regulation stands out from them as a specific form of higher-order control, exerted over the basic regime responsible for the production and maintenance of the organism, and provides the system with the capacity to act on its own constitutive dynamics. It consists in the capability to selectively shift between different available regimes of self-production and self-maintenance in response to specific signals (...) and perturbations, due to the action of a dedicated subsystem which is operationally distinct from the regulated ones. The role of regulation, however, is not exhausted by its contribution to maintain a living system’s viability. While enhancing robustness, regulatory mechanisms play a fundamental role in the realization of an autonomous biological organization. Specifically, they are at the basis of the remarkable integration of biological systems, insofar as they coordinate and modulate the activity of distinct functional subsystems. Moreover, by implementing complex and hierarchically organized control architectures, they allow for an increase in structural and organizational complexity while minimizing fragility. Finally, they endow living systems, from their most basic unicellular instances, with the capability to control their own internal dynamics to adaptively respond to specific features of their interaction with the environment, thus providing the basis for the emergence of minimal forms of cognition. (shrink)

Living systems employ several mechanisms and behaviors to achieve robustness and maintain themselves under changing internal and external conditions. Regulation stands out from them as a specific form of higher-order control, exerted over the basic regime responsible for the production and maintenance of the organism, and provides the system with the capacity to act on its own constitutive dynamics. It consists in the capability to selectively shift between different available regimes of self-production and self-maintenance in response to specific signals (...) and perturbations, due to the action of a dedicated subsystem which is operationally distinct from the regulated ones. The role of regulation, however, is not exhausted by its contribution to maintain a living system’s viability. While enhancing robustness, regulatory mechanisms play a fundamental role in the realization of an autonomous biological organization. Specifically, they are at the basis of the remarkable integration of biological systems, insofar as they coordinate and modulate the activity of distinct functional subsystems. Moreover, by implementing complex and hierarchically organized control architectures, they allow for an increase in structural and organizational complexity while minimizing fragility. Finally, they endow living systems, from their most basic unicellular instances, with the capability to control their own internal dynamics to adaptively respond to specific features of their interaction with the environment, thus providing the basis for the emergence of minimal forms of cognition. (shrink)

Ferroptosis, a form of regulated cell death triggered by lipid hydroperoxide accumulation, has an important role in a variety of diseases and pathological conditions, such as cancer. Targeting ferroptosis is emerging as a promising means of therapeutic intervention in cancer treatment. Polyunsaturated fatty acids, reactive oxygen species, and labile iron constitute the major underlying triggers for ferroptosis. Other regulators of ferroptosis have also been discovered recently, among them the mechanistic target of rapamycin complex 1 (mTORC1), a central controller of cell (...) growth and metabolism. Inhibitors of mTORC1 have been used in treating diverse diseases, including cancer. In this review, we discuss recent findings linking mTORC1 to ferroptosis, dissect mechanisms underlying the establishment of mTORC1 as a key ferroptosis modulator, and highlight the potential of co‐targeting mTORC1 and ferroptosis in cancer treatment. This review will provide valuable insights for future investigations of ferroptosis and mTORC1 in fundamental biology and cancer therapy. (shrink)

Hereditary retinal degeneration due to mutations in visual genes may be amenable to therapeutic interventions that modulate, either positively or negatively, the amount of protein product. Some of the proteins involved in phototransduction are rapidly moved by a lightdependent mechanism between the inner segment and the outer segment in rod photoreceptor cells, and this phenomenon is important in phototransduction.

Although developmental biology is an institutionalized discipline, no unambiguous account of what development is and when it stops has so far been provided. In this article, I focus on two sets of developmental molecular mechanisms, namely those underlying the heterochronic pathway in C. elegans and those involving Hox genes in vertebrates, to suggest a conceptual account of animal development. I point out that, in these animals, the early stages of life exhibit salient mechanistic features, in particular in the way (...) mechanisms of genetic regulation occur in the organism. Indeed, these stages are characterized by sequential and irreversible changes in gene expression taking place throughout the organism. A general definition of animal development based on these distinctive features implies that, at least for some animal species, development does not go on throughout the life of the animal, contrary to what has recently been claimed by some biologists and philosophers. Instead, in such species, development encompasses various events occurring sequentially at the beginning of life. (shrink)

Several suggestions are made for revision of Strategic Pluralism Theory (SPT). One revision requires recognition of the impact of individual differences in cognitive and behavioral competence on optimal mating strategy. In addition, SPT may need to incorporate certain self-regulatory processes such as the impact of widespread valuation of mates with one trait on their availability.

The unfertilized sea urchin egg is a metabolically quiescent cell. Fertilization results in the activation of a variety of metabolic and biosynthetic pathways, including a 20‐ to 40‐fold increase in the rate of protein synthesis by 2 h after fertilization. This increase is regulated at a purely translational level without the need for new transcription. The greatest part of this increase is due to the translation of stored maternal mRNAs which were not translated in the egg. There is also a (...) 2‐to 3‐fold increase in the peptide elongation rate. The molecular and physiological mechanisms responsible for this activation process are beginning to be understood, and turn out to be much more complex than was anticipated. (shrink)

Large protein assemblies are usually the effectors of major cellular processes. The intricate cell homeostasis network is divided into numerous interconnected pathways, each controlled by a set of protein machines. One of these master regulators is the CCR4‐NOT complex, which ultimately controls protein expression levels. This multisubunit complex assembles around a scaffold platform, which enables a wide variety of well‐studied functions from mRNA synthesis to transcript decay, as well as other tasks still being identified. Solving the structure of the entire (...) CCR4‐NOT complex will help to define the distribution of its functions. The recently published three‐dimensional reconstruction of the complex, in combination with the known crystal structures of some of the components, has begun to address this. Methodological improvements in structural biology, especially in cryoelectron microscopy, encourage further structural and protein‐protein interaction studies, which will advance our comprehension of the gene expression machinery. (shrink)

Reproduction and immunity are energy intensive, intimately linked processes in most organisms. In women, pregnancy is associated with widespread immunological adaptations that alter immunity to many diseases, whereas, immune dysfunction has emerged as a major cause for infertility in both men and women. Deciphering the molecular bases of this dynamic association is inherently challenging in mammals. This relationship has been traditionally studied in fast‐living, invertebrate species, often in the context of resource allocation between life history traits. More recently, these studies (...) have advanced our understanding of the mechanistic underpinnings of the immunity‐fertility dialogue. Here, we review the molecular connections between reproduction and immunity from the perspective of human pregnancy to mechanistic discoveries in laboratory organisms. We focus particularly on recent invertebrate studies identifying conserved signaling pathways and transcription factors that regulate resource allocation and shape the balance between reproductive status and immune health. (shrink)

This study's objective is to explore the psychological defense mechanisms of Ukrainian service members as a regulatory system for personality stabilization that influences combat mission effectiveness. The study was carried out during 2019–2020. The respondents were 270 military personnel of the ground forces, who had gained experience in the Anti-Terrorist Operation hostilities in the East of Ukraine in 2017–2020. We used psychodiagnostic methods such as the Lifestyle Index by Plutchik, Kellerman, and Conte; Lazarus’s Coping Test; and Leontiev’s Meaningful (...) Life Orientations Test. Our work confirmed our research hypothesis that psychological defense mechanisms as part of the regulatory system of personality stabilization predetermine the effectiveness of the combat missions performed by military personnel of special branches. Military psychologists can use the results during their official training (psychological training and psycho-corrective measures) in order to acquire among the troops the required effectiveness in combat. Defense mechanisms will also contribute to the observance of military ethics, not least when faced with military immorality on the part of adversaries. (shrink)

Deletions, duplications, insertions, inversions, and translocations, collectively called structural variations (SVs), affect more base pairs of the genome than any other sequence variant. The recent technological advancements in genome sequencing have enabled the discovery of tens of thousands of SVs per human genome. These SVs primarily affect non‐coding DNA sequences, but the difficulties in interpreting their impact limit our understanding of human disease etiology. The functional annotation of non‐coding DNA sequences and methodologies to characterize their three‐dimensional (3D) organization in the (...) nucleus have greatly expanded our understanding of the basic mechanisms underlying gene regulation, thereby improving the interpretation of SVs for their pathogenic impact. Here, we discuss the various mechanisms by which SVs can result in altered gene regulation and how these mechanisms can result in rare genetic disorders. Beyond changing gene expression, SVs can produce novel gene‐intergenic fusion transcripts at the SV breakpoints. (shrink)

It is clear that where a disease affects men and women differently, research on potential therapies or cures should include both men and women and should examine whether the therapy is effective and safe for both sexes. In this paper we consider whether there is an appropriate role for law in regulating to ensure an examination of these sex- and gender-specific aspects in health research. We consider the relative advantages and disadvantages of pursuing a regulatory approach to achieving gender (...) equity in the field of women’s health by exploring first, the meaning of gender equity, and second, the regulatory mechanisms that might be best suited to promoting the goal of gender equity. Within our examination of different regulatory forms and mechanisms, we also interrogate the shift from gender-neutral provisions relating to sex in favor of generalized notions of fairness that remove any specific consideration of sex. (shrink)

Interspecific comparisons reveal remarkable diversity in patterns of gene expression, even among closely related species. Combinatorial regulatory mechanisms could facilitate the evolution of this diversity. However, the high degree of interdependence characteristic of combinatorial networks would represent a major constraint on evolution and might generate many features that have no direct adaptive value.

ANNOTATION Sardak S.E. Global Regulatory System of Human Resources Development. – Manuscript. Thesis for the Doctor of Economic Science academic degree with major in 08.00.02 – World Economy and international economic relations. – SHEE «Kyiv National Economic University named after Vadym Hetman», Kyiv, 2014. The preconditions and factors of the global economic system with the identified relevant subjects areas and mechanisms of regulation instruments have been investigated. The crucial role of humans in the global economic system as a (...) key factor of production, the main resource, the producer and the consumer of economic and social benefits that are exposed to global threats, problems, challenges, trends and subjects has been confirmed. There have been revealed the causes and consequences of the public institutions transformation under the influence of globalization, which formed a qualitatively new conditions for social and economic development that determine the need for further changes in the areas of conceptual guideline for the management of human resources development, optimization of tasks, state and international institutions activity forms, integration of efforts as for monitoring, planning and forecasting. The modern major instruments and spheres of international cooperation to ensure human development have been determined. The integrated characteristic of human resources and their role in social development both from the standpoint of their use in labour processes and as a medium of civilization and social utility with the help of the categorical classification system organizing and expanding which enables to design and apply the appropriate approaches at all managerial levels have been defined. The necessity and the concept of human resources development in the context of the content of managerial influence identifying (self-development, self-management and external control of development) at different administrative levels that ensures the growth of human capital to the limits of its potential have been analysed. The survey of human activity system aspects in the global world, taking into account the parametrization of the global environment, its structure, management and development have been realized. The formed methodology principles of managerial influence on the development of human resources with scientific schools, hardness degrees, available models, research and providing theoretical and practical implementation peculiarities for groups of countries and territories of the world taken into consideration have been examined. There have been noted civilization and national differences in the forms of managerial influence on the development of human resources, which lead to the formation of human resources development national control systems conditioned by different value public strategic guidelines, especially in relation to social security, education, national management and state migration policy. The current and future requirements for global human resources development which are proposed to be achieved by the development and formalization of global civilizational paradigm of social development due to social coordination interaction have been given. The influence of the institute of state on the human resources development has been evaluated and it has been proved that in the beginning of the XXI century in the global environment the institute of state is the ultimate guarantor of its citizens’ labour ability and vital activity renewal, that makes it the main instrument of managerial influence on human development. The methodology of countries and territories matrix positioning by human development qualitative criteria and population size quantitative parameters which allows to design unified managerial measures as for human resources for similar national economies in the context of global regulatory trends has been proposed. The strategic trends of improvement of human resources development in the national economy, taking into account the differences in the development of human resources in different countries and areas which vary and differ in their focus, content and ways of implementation for such groups. The varying criteria for evaluating the effectiveness of the global impact on human resources development, taking into account the natural, biological, technological, economic, social and management dimensions and the results of human resources development management in social and economic systems at various levels have been revealed. The periodization and the forecast of the global dynamics of human resources development by analyzing and modeling the values of the absolute and relative terms correlation character have been carried out, which enables to make their retrospective and prospective comparison and to find chronological boundaries of qualitatively different periods. The configuration of the human resource development global coordinate system as a set of interrelated principles, components, fields, tools, frameworks, management levels and forms of managerial influence that allows with the help of institutional means to adapt the state of human resources development to a globally varying environment. (shrink)

The article is devoted to the study of the phenomenon of ideology in the context of its normative and regulatory function. The author's contribution to the further knowledge of the ideology was the following main conclusions. The emergence of ideology as a regulatory mechanism was primarily due to the transition from a traditional society to a modern one. Ideology is an attribute of modern society, since it acts as an intermediary between a person and social reality, determining and (...) regulating the activities of all people and relations between them in any sphere of society. In the XIX – first half of the XX centuries political ideology in its theoretical form dominated. As a regulatory mechanism, it functioned alongside religion, morality, and law, complementing them. In the second half of the XX – XXI centuries, as a result of the third STR, ideology in an ordinary and practical form became widespread. It began to replace the traditional regulatory mechanisms, surpassing them in the degree of influence on public consciousness and becoming the main mechanism of social regulation. (shrink)

Moral disengagement is a process whereby the self-regulatory mechanisms that would otherwise sanction unethical conduct can be selectively disabled. The present research proposed that moral disengagement might be adopted in the endorsement of asylum seeker policies in Australia, and in order to test this, a scale was developed and was validated in two studies. Factor analysis demonstrated that a 2-factor, 16-item structure had the best fit, and the construct validity of the scale was supported. Results provide evidence for (...) the use of moral disengagement in the context of asylum seekers as a means of rationalizing conduct that may otherwise be sanctioned. (shrink)

The literature has suggested that to understand the diffusion of unethical conduct in the workplace, it is important to investigate the underlying processes sustaining engagement in misbehaviour and to study what occurs during vocational education. Drawing on social-cognitive theory, in this study, we longitudinally examined the role of two opposite dimensions of the self-regulatory moral system, regulatory self-efficacy and moral disengagement, in influencing academic cheating behaviour. In addition, in line with the theories highlighting the bidirectional relationship between cognitive (...) processes and behaviour, we aimed to also examine the reciprocal influence of behaviour on these dimensions over time. Overall, no previous studies have examined the longitudinal interplay between these variables. The sample included 866 nursing students who were assessed three times annually from the beginning of their vocational education. The findings from a cross-lagged model confirmed that regulatory self-efficacy and moral disengagement have opposite influences on cheating behaviour, that regulatory self-efficacy negatively influences not only the engagement in misconduct but also the justification mechanisms that allow the divorce between moral standards and action, and that moral disengagement and cheating behaviour reciprocally support each other over time. Specifically, not only did moral disengagement influence cheating behaviour even when controlling for its prior levels, but also cheating behaviour affected moral disengagement one year later, controlling for its prior levels. These findings suggest that recourse to wrongdoing could gradually lead to further normalising this kind of behaviour and morally desensitising individuals to misconduct. (shrink)

Glucocorticoid hormones are effective in controlling inflammation, but the mechanisms that confer this action are largely unknown. Recent advances in this field have shown that both positive and negative regulation of gene expression are necessary for this process. The genes whose activity are modulated in the anti‐inflammatory process code for several cytokines, adhesion molecules and enzymes. Most of them do not carry a classical binding site for regulation by a glucocorticoid receptor, but have instead regulatory sequences for transcription (...) factors such as AP‐1 or NF‐κ. This makes them unusual targets for glucocorticoid action and emphasizes the need for novel regulatory mechanisms. Recent studies describe an important contribution by protein‐protein interactions, in which several domains of the receptor participate; these studies provide a better understanding of the action of the receptor and offer opportunities for the design of steroidal compounds that could function more effectively as anti‐inflammatory drugs. (shrink)

Although much has been learned about hereditary mechanisms since Gregor Mendel’s famous experiments, gene concepts have always remained vague, notwithstanding their central role in biology. During over hundred years of genetic research, gene concepts have often and dynamically changed to accommodate novel experimental findings, without ever providing a generally accepted definition of the ‘gene.’ Yet, the distinction between ‘regulatory genes’ and ‘structural genes’ has remained a common theme in modern gene concepts since the definition of the operon-model. This (...) distinction is now challenged by recent findings which suggest that, at least in eukaryotes, structural genes may in many situations have a regulatory function that is independent of the function of the gene product (protein or non-coding RNA molecule). This brief paper discusses these new findings and some possible implications for the notion of the ‘regulatory gene.’. (shrink)

This paper, in the form of a frequently asked questions page (FAQ), addresses outstanding questions about “shadow enhancers”, quasi‐redundant cis‐regulatory elements, and their proposed roles in transcriptional control. Questions include: What exactly are shadow enhancers? How many genes have shadow/redundant/distributed enhancers? How redundant are these elements? What is the function of distributed enhancers? How modular are enhancers? Is it useful to study a single enhancer in isolation? In addition, a revised definition of “shadow enhancers” is proposed, and possible (...) class='Hi'>mechanisms of shadow enhancer function and evolution are discussed. (shrink)

The goal of this paper is to examine the impact of leadership and promotion regulatory focus on employees’ willingness to engage in unethical pro-organizational behavior . Building from a person–situation interactionist perspective, we investigate the interaction of leadership style and how leaders frame messages, as well as test a three-way interaction with promotion focus. Using an experimental design, we found that inspirational and charismatic transformational leaders elicited higher levels of UPB than transactional leaders when the leaders used loss framing, (...) but not gain framing. Furthermore, followers’ promotion regulatory focus moderated this relationship such that the effect held for followers with low promotion focus, but not for individuals with high promotion focus. Our findings extend the understanding of UPB, offer theoretical mechanisms to explain when this behavior occurs, and contribute to leadership theory and research on ethical decision making. (shrink)

Computational approaches in systems biology have become a powerful tool for understanding the fundamental mechanisms of cellular metabolism and regulation. However, the interplay between the regulatory and the metabolic system is still poorly understood. In particular, there is a need for formal mathematical frameworks that allow analyzing metabolism together with dynamic enzyme resources and regulatory events. Here, we introduce a metabolic-regulatory network model that allows integrating metabolism with transcriptional regulation, macromolecule production and enzyme resources. Using this (...) model, we show that the dynamic interplay between these different cellular processes can be formalized by a hybrid automaton, combining continuous dynamics and discrete control. (shrink)

The ability to memorize changes in the environment is present at all biological levels, from social groups and individuals, down to single cells. Trans‐generational memory is embedded subcellularly through genetic and epigenetic mechanisms. Evidence that cells process and remember features of the immediate environment using protein sensors is reviewed. It is argued that this mnemonic ability is encapsulated within the protein conformational space and lasts throughout its lifetime, which can overlap with the lifespan of the organism. Means to determine (...) diachronic changes in protein activity are presented. (shrink)

The molecular cloning of new neuroactive growth factors and their receptors has greatly enhanced our understanding of important interactions among receptors and singnaling molecules. These studies have begun to illuminate some of the mechanisms that allow for specificity in neuronal signaling. Model cell systems, such as the PC‐12 pheochromocytoma cell line, express receptors for these different neurotirophic factors, leading to comparisons of signaling pathways for these factors. Upon binding their ligands, these receptors undergo phosphorylation on tyrosine residues, which directs (...) their interaction with signaling proteins containing src homology (SH2) domains, sequences that mediate associations with tyrosine‐phosphorylated proteins. These SH2 proteins translate the tyrosine kinase activity of receptors into downstream events that result in the specific cellular response. Investigations such as these have revealed that molecular specificity in signaling pathways may arise from combinatorial diversity in interactions between receptors and key regulatory proteins. (shrink)

The nonreductionistic theory of the multiple aspects of reality offered by the Dutch philosopher Herman Dooyeweerd is employed to illuminate the status of bodies and biological entities in relation to attached and incorporated technological devices. I first present a review of the interpretations of the mechanization of biology and then argue from a Dooyeweerdian viewpoint that this mechanization also amounts to a reduction of the biotic aspect to previous aspects, such as the physical and the regulatory or cybernetic aspect. (...) Next, the irreducible meaning of the biotic aspect is defined as the vital life cycle and generational continuity that delineate the form of a species. Finally, I show how this definition helps us identify a normativity and a respect for living things, and I discuss its implications for bioengineering practices. (shrink)

This research is conducted by the Intellectual Property and Policy Research Group at the W. Maurice Young Centre for Applied Ethics at the University of British Columbia. It is part of the GE3LS component of the Genome Canada Project "Dissecting Gene Expression Networks in Mammalian Organogenesis," MORGEN, which is located principally at the British Columbia Cancer Agency, Vancouver, British Columbia, Canada. The project is involved in upstream, basic genomic research. Part of this work includes the characterization of gene regulatory (...) mechanisms governing organogenesis with a special focus on the heart, liver and pancreas. This paper serves as an introduction to both the MORGEN case study and the role of alternative mechanisms, such as open source. We discuss interim research results as they relate to our broader study of the relationship between open science, commercialization and technology transfer offices. The role of technology transfer offices is central to our analysis and is viewed as a key factor in implementing Genome Canada policies and principles associated with IP and commercialization. (shrink)

This study extends regulatory capture theory to investigate how and to what extent a firm’s political and nonpolitical ties jointly influence corporate regulatory participation. In the context of regulatory standards setting, although firms with political ties are better able to promote firm standards into industry regulations, it remains unclear whether the coexistence of firms’ nonpolitical ties (i.e., university ties and interlocked firms in our study) is more or less likely to reduce the effect of political ties. Although (...) corporate leaders with political and nonpolitical ties may provide complementary resources, they may follow different mechanisms to drive firm actions. We, thus, argue that nonpolitical ties likely reduce the effect of political ties on regulatory standards setting. Using a sample of public manufacturing firms in China, we find evidence that supports our predictions. Our study contributes to the regulatory capture literature by redirecting attention to the dynamics of political versus nonpolitical ties. (shrink)

This article examines the impact of the prevailing state ownership in the Chinese stock market on corporate governance and the financial regulatory system, respectively, as the internal and external monitoring mechanisms to deter corporate fraud and protect investors. In line with the literature that state ownership exaggerates the agency problem, we find that the retained state ownership in privatised firms increases the incidence of regulatory enforcements against fraud. For the state-owned enterprises (SOEs), however, larger state ownership is (...) associated with a lower incidence of enforcement actions. This is attributed to the mutual political affiliation of the fraudulent SOEs and the regulatory commission. A new regulation "Solutions for Listed Firm Checks" promulgated in March 2001 has mitigated this effect by empowering the regulatory commission to increase the severity of regulatory conditions. Our evidence confirms the improvement in the regulatory environment and investor protection in the Chinese stock market brought about by the regulatory reform and development. (shrink)

This paper analyses Richard Bader’s ‘operational’ view of quantum mechanics and the role it plays in the the explanation of chemistry. I argue that QTAIM can partially be reconstructed as an ‘austere’ form of quantum mechanics, which is in turn committed to an eliminative concept of reduction that stems from Kemeny and Oppenheim. As a reductive theory in this sense, the theory fails. I conclude that QTAIM has both a regulatory and constructive function in the theories of chemistry.

The basic premise of the host‐defense theory is that genomic imprinting, the parent‐of‐origin expression of a subset of mammalian genes, derives from mechanisms originally dedicated to silencing repeated and retroviral‐like sequences that deeply colonized mammalian genomes. We propose that large clusters of tandemly‐repeated C/D‐box small nucleolar RNAs (snoRNAs) or microRNAs represent a novel category of sequences recognized as “genomic parasites”, contributing to the emergence of genomic imprinting in a subset of chromosomal regions that contain them. Such a view is (...) supported by evidence derived from studies of the imprinted snoRNA‐ and/or miRNA‐encoding Dlk1‐Dio3, Snurf‐Snrpn, Sfbmt2, and C19MC domains. While adding a new piece to the challenging puzzle of mammalian genome history, this hypothesis also reinforces the notion that dissecting the features and molecular mechanisms that discriminate between “foreign” and “endogenous” sequences is of crucial importance in the field of mammalian epigenetics. (shrink)

Transcriptional networks regulate cell fate decisions, which occur at the level of individual cells. However, much of what we know about their structure and function comes from studies averaging measurements over large populations of cells, many of which are functionally heterogeneous. Such studies conceal the variability between cells and so prevent us from determining the nature of heterogeneity at the molecular level. In recent years, many protocols and platforms have been developed that allow the high throughput analysis of gene expression (...) in single cells, opening the door to a new era of biology. Here, we discuss the need for single cell gene expression analysis to gain deeper insights into the transcriptional control of cell fate decisions, and consider the insights it has provided so far into transcriptional regulatory networks in development. (shrink)

Different countries worldwide have issues with adapting legal terminology in a multilingual society. Such issues are still prevalent in Kazakhstan, where it is particularly difficult to guarantee the quality of laws written in the state language. This study aims to answer the question of what scientific, methodological, and legal mechanisms can be used to enhance legislative drafting practises in countries with two or more official languages by using Kazakhstan as an example. The Kazakh legal terminology reflects the societal communication (...) requirements for the control of public relations. According to the findings, the current challenges of establishing a legal conceptual framework in Kazakhstan are closely connected to trends in expanding the terminological lexicon. This trend stems from neologisation, optimisation of borrowings of legal terms, and internationalisation of legal discourse. The ways to improve the legislative drafting technique are suggested based on a generalised analysis of texts in the state language of some legislative instruments of the Republic of Kazakhstan. The article offers several recommendations for specialists-translators of legal texts practising in rule-making and lawyers-specialists in legislative drafting and review. (shrink)

Recent work has shown that segmentation underlies the patterning of the vertebrate hindbrain and its neural crest derivatives. Several genes have been identified with segment‐restricted expression, and evidence is now emerging regarding their function and regulatory relationships. The expression patterns of Hox genes and the phenotype of null mutants indicate roles in specifying segment identity. A zinc finger gene Krox‐20 is a segment‐specific regulator of Hox expression, and it seems probable that retinoic acid receptors also regulate Hox genes in (...) the hindbrain. The receptor tyrosine kinase gene Sek may mediate cell‐cell interactions that lead to segmentation. These studies provide a starting point for understanding the molecular basis of segmental patterning in the hindbrain. (shrink)

Hawe et al. raise concerns about Human Research Ethics Committees (HRECs) taking a risk-averse and litigation-sensitive approach to ethical review of research proposals. HRECs are tasked with reviewing proposals for compliance with the National Statement on Ethical Conduct in Human Research for the purpose of promoting the welfare of participants. While these guidelines intentionally include a significant degree of discretion in HREC decision making, there is also evidence that HRECs sometimes request changes that go beyond the guidance provided by the (...) National Statement. When HRECs request changes outside their remit, inconsistencies between individual HRECs become more common, contributing to delays in ethical review and reducing the quality of HREC decision making. Improvements to the HREC regulatory system are needed to promote transparency and accountability. (shrink)

It is widely accepted that stressful conditions can facilitate evolutionary change. The mechanisms elucidated thus far accomplish this with a generic increase in heritable variation that facilitates more rapid adaptive evolution, often via plastic modifications of existing characters. Through scrutiny of different meanings of stress in biological research, and an explicit recognition that stressors must be characterized relative to their effect on capacities for maintaining functional integrity, we distinguish between: (1) previously identified stress-responsive mechanisms that facilitate evolution by (...) maintaining an adaptive fit with the environment, and (2) the co-option of stress-responsive mechanisms that are specific to stressors leading to the origin of novelties via compensation. Unlike standard accounts of gene co-option that identify component sources of evolutionary change, our model documents the cost-benefit trade-offs and thereby explains how one mechanism—an immediate response to acute stress—is transformed evolutionarily into another—routine protection from recurring stressors. We illustrate our argument with examples from cell type origination as well as processes and structures at higher levels of organization. These examples suggest a general principle of evolutionary origination based on the capacity to switch between regulatory states related to reproduction and proliferation versus survival and differentiation. (shrink)

The stable differentiation of cells into other cell types typically involves dramatic reorganization of cellular structures and functions. This often includes remodeling of the cell cycle and the apparatus that controls it. Here we review our understanding of the role and regulation of cell cycle control elements during cell differentiation in the yeast, Saccharomyces cerevisiae. Although the process of differentiation may be more overtly obvious in metazoan organisms, those systems are by nature more difficult to study at a mechanistic level. (...) We consider the relatively well‐understood mechanisms by which mating‐type switching and the pheromone‐induced differentiation of gametes are coupled to the cell cycle as well as the more obscure mechanisms that govern the remodeling of the cell cycle during meiosis and filamentous growth. In some cases, the cell cycle is a primary stimulus for differentiation whereas, in other cases, the signals that promote differentiation alter the cell cycle. Thus, despite relative simplicity of these processes in yeast, the nature of the interplay between the cell cycle and differentiation is diverse. BioEssays 25:856–867, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Insulators play a central role in subdividing the chromosome into a series of discrete topologically independent domains and in ensuring that enhancers and silencers contact their appropriate target genes. In this review we first discuss the general characteristics of insulator elements and their associated protein factors. A growing collection of insulator proteins have been identified including a family of proteins whose expression is developmentally regulated. We next consider several unexpected discoveries that require us to completely rethink how insulators function (and (...) how they can best be assayed). These discoveries also require a reevaluation of how insulators might restrict or orchestrate (by preventing or promoting) interactions between regulatory elements and their target genes. We conclude by connecting these new insights into the mechanisms of insulator action to dynamic changes in the three‐dimensional topology of the chromatin fiber and the generation of specific patterns of gene activity during development and differentiation. (shrink)

The autophagy initiation complex is brought about via a highly ordered and stepwise assembly process. Two crucial signaling molecules, mTORC1 and AMPK, orchestrate this assembly by phosphorylating/dephosphorylating autophagy‐related proteins. Activation of Atg1 followed by recruitment of both Atg9 vesicles and the PI3K complex I to the PAS (phagophore assembly site) are particularly crucial steps in its formation. Ypt1, a small Rab GTPase in yeast cells, also plays an essential role in the formation of the autophagy initiation complex through multiple (...) class='Hi'>regulatory pathways. In this review, our primary focus is to discuss how signaling molecules initiate the assembly of the autophagy initiation complex, and highlight the significant roles of Ypt1 in this process. We end by addressing issues that need future clarification. (shrink)

The new wave of ‘foundation models’—general-purpose generative AI models, for production of text (e.g., ChatGPT) or images (e.g., MidJourney)—represent a dramatic advance in the state of the art for AI. But their use also introduces a range of new risks, which has prompted an ongoing conversation about possible regulatory mechanisms. Here we propose a specific principle that should be incorporated into legislation: that any organization developing a foundation model intended for public use must demonstrate a reliable detection mechanism (...) for the content it generates, as a condition of its public release. The detection mechanism should be made publicly available in a tool that allows users to query, for an arbitrary item of content, whether the item was generated (wholly or partly) by the model. In this paper, we argue that this requirement is technically feasible and would play an important role in reducing certain risks from new AI models in many domains. We also outline a number of options for the tool’s design, and summarize a number of points where further input from policymakers and researchers would be required. (shrink)

Personalised medicine has been discussed as a medical paradigm shift that will improve health while reducing inefficiency and waste. At the same time, it raises new practical, regulatory, and ethical challenges. In this paper, we examine PM strategies epistemologically in order to develop capacities to address these challenges, focusing on a recently proposed strategy for developing patient-specific models from induced pluripotent stem cells so as to make individualised treatment predictions. We compare this strategy to two main PM strategies—stratified medicine (...) and computational models. Drawing on epistemological work in the philosophy of medicine, we explain why these two methods, while powerful, are neither truly personalised nor, epistemologically speaking, novel strategies. Both are forms of correlational black box. We then argue that the iPSC models would count as a new kind of black box. They would not rely entirely on mechanistic knowledge, and they would utilise correlational evidence in a different way from other strategies—a way that would enable personalised predictions. In arguing that the iPSC models would present a novel method of gaining evidence for clinical practice, we provide an epistemic analysis that can help to inform the practical, regulatory, and ethical challenges of developing an iPSC system. (shrink)

We argue that the concepts of mechanism and autonomy appear to be antagonistic when autonomy is conflated with agency. Once these concepts are disentangled, it becomes clearer how autonomy emerges from complex forms of control. Subsequently, current biomimetic strategies tend to focus on homeostatic regulatory systems; we propose that research in AI and robotics would do well to incorporate biomimetic strategies that instead invoke models of allostatic mechanisms as a way of understanding how to enhance autonomy in artificial (...) systems. (shrink)

The sequencing of the human genome has opened the way for using bioinformatics to identify sets of genes controlled by specific regulatory signals. Here, we review the unexpected diversity of DNA response elements mediating transcriptional regulation by estrogen receptors (ERs), which control the broad physiological effects of estrogens. Consensus palindromic estrogen response elements are found in only a few known estrogen target genes, whereas most responsive genes contain only low‐affinity half palindromes, which may also control regulation by other nuclear (...) receptors. ERs can also regulate gene expression in the absence of direct interaction with DNA, via protein–protein interactions with other transcription factors or by modulating the activity of upstream signaling components, thereby significantly expanding the repertoire of estrogen‐responsive genes. These diverse mechanisms of action must be taken into account in screening for potential estrogen‐responsive sequences in the genome or in regulatory regions of target genes identified by expression profiling. BioEssays 24:244–254, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10066. (shrink)

The One Health approach to antimicrobial resistance (AMR) requires stakeholders to contribute to cross-sectoral efforts to improve antimicrobial stewardship (AMS). One Health AMR policy implementation is challenging in livestock farming because of the infrastructural role of antibiotics in production systems. Mitigating AMR may require the development of more stringent stewardship obligations and the future limitation of established entitlements. Drawing on Amatai Etzioni’s compliance theory, regulatory analyses and qualitative studies with stakeholder groups we examine the structural and socio-cultural dimension of (...) antibiotic use and AMS compliance in Australian beef and dairy production. We found a disconnect between how antibiotic use is conceptualised by farmers and the way in which AMS policies construe agricultural AMR risks. Under the umbrella of food safety standards and national-level prescribing restrictions, farmers and veterinarians interact around antibiotic use with different operating logics and compliance mechanisms. These parallel regimes service distinct and sometimes competing common goods of food security and antibiotic preservation. Further reforms to mitigate AMR need to account for the value orientations of different groups and the embeddedness of the constraints imposed by existing systems. Advocacy for greater AMR precaution in agriculture should acknowledge and compensate for erosions in competing common goods and the cost of proposed interventions. (shrink)

The cerebral cortex controls our most distinguishing higher cognitive functions. Human‐specific gene expression differences are abundant in the cerebral cortex, yet we have only begun to understand how these variations impact brain function. This review discusses the current evidence linking non‐coding regulatory DNA changes, including enhancers, with neocortical evolution. Functional interrogation using animal models reveals converging roles for our genome in key aspects of cortical development including progenitor cell cycle and neuronal signaling. New technologies, including iPS cells and organoids, (...) offer potential alternatives to modeling evolutionary modifications in a relevant species context. Several diseases rooted in the cerebral cortex uniquely manifest in humans compared to other primates, thus highlighting the importance of understanding human brain differences. Future studies of regulatory loci, including those implicated in disease, will collectively help elucidate key cellular and genetic mechanisms underlying our distinguishing cognitive traits. (shrink)

In recent years, membrane contact sites (MCS), which mediate interactions between virtually all subcellular organelles, have been extensively characterized and shown to be essential for intracellular communication. In this review essay, we focus on an emerging topic: the regulation of MCS. Focusing on the tether proteins themselves, we discuss some of the known mechanisms which can control organelle tethering events and identify apparent common regulatory hubs, such as the VAP interface at the endoplasmic reticulum (ER). We also highlight (...) several currently hypothetical concepts, including the idea of tether oligomerization and redox regulation playing a role in MCS formation. We identify gaps in our current understanding, such as the identity of the majority of kinases/phosphatases involved in tether modification and conclude that a holistic approach—incorporating the formation of multiple MCS, regulated by interconnected regulatory modulators—may be required to fully appreciate the true complexity of these fascinating intracellular communication systems. (shrink)

This paper demonstrates how the UK’s Advertising Standards Authority governs advertising ethics with and on behalf of its members and stakeholders. Drawing on an archive of 310 non-commercial adjudication reports, we highlight the substantive norms and procedural mechanisms through which the ASA governs advertising complaints alleging offence and/or harm. Substantively, the ASA precludes potential normative transgressions by publishing, disseminating, consulting upon, and updating detailed codes of advertising conduct. Procedurally, the ASA adjudicates between allegations and justifications of offence and harm (...) on a received complaint-by-complaint basis, often upon consequentialist grounds. Such consequentialism, we claim, has the effect of normalizing power imbalances between the ASA’s members, on the one hand, and wider stakeholders, on the other hand. The paper argues that, in the context of UK advertising, what Michel Foucault called the right ‘to be or not to be governed like that’ is enjoyed by relatively few subjects. Having demonstrated how UK advertising practices are governed, the paper closes with suggestions as to how they might be governed otherwise. (shrink)