Transport of macromolecules from the nucleus to the cytoplasm is essential for nearly all cellular and developmental events, and when mis‐regulated, is associated with diseases, tumor formation/growth, and cancer progression. Nuclear Envelope (NE)‐budding is a newly appreciated nuclear export pathway for large macromolecular machineries, including those assembled to allow co‐regulation of functionally related components, that bypasses canonical nuclear export through nuclear pores. In this pathway, large macromolecular complexes are enveloped by the inner nuclear membrane, transverse the perinuclear space, and then (...) exit through the outer nuclear membrane to release its contents into the cytoplasm. NE‐budding is a conserved process and shares many features with nuclear egress mechanisms used by herpesviruses. Despite its biological importance and clinical relevance, little is yet known about the regulatory and structural machineries that allow NE‐budding to occur in any system. Here we summarize what is currently known or proposed for this intriguing nuclear export process. (shrink)

The logic of genetic discovery has changed little over time, but the focus of biology is shifting from simple genotype–phenotype relationships to complex metabolic, physiological, developmental, and behavioral traits. In light of this, the traditional reductionist view of individual genes as privileged difference‐making causes of phenotypes is re‐examined. The scope and nature of genetic effects in complex regulatory systems, in which dynamics are driven by regulatory feedback and hierarchical interactions across levels of organization are considered. This (...) review argues that it is appropriate to treat genes as specific actual difference‐makers for the molecular regulation of gene expression. However, they are often neither stable, proportional, nor specific as causes of the overall dynamic behavior of regulatory networks. Dynamical models, properly formulated and validated, provide the tools to probe cause‐and‐effect relationships in complex biological systems, allowing to go beyond the limitations of genetic reductionism to gain an integrative understanding of the causal processes underlying complex phenotypes. (shrink)

Various algorithms have been proposed for learning (partial) genetic regulatory networks through systematic measurements of differential expression in wild type versus strains in which expression of specific genes has been suppressed or enhanced, as well as for determining the most informative next experiment in a sequence. While the behavior of these algorithms has been investigated for toy examples, the full computational complexity of the problem has not received sufficient attention. We show that finding the true regulatory network requires (...) (in the worst-case) exponentially many experiments (in the number of genes). Perhaps more importantly, we provide an algorithm for determining the set of regulatory networks consistent with the observed data. We then show that this algorithm is infeasible for realistic data (specifically, nine genes and ten experiments). This infeasibility is not due to an algorithmic flaw, but rather to the fact that there are far too many networks consistent with the data (10 18 in the provided example). We conclude that gene perturbation experiments are useful in confirming regulatory network models discovered by other techniques, but not a feasible search strategy. (shrink)

Growth in CSR-washing claims in recent decades has been dramatic in numerous academic and activist contexts. The discourse, however, has been fragmented, and still lacks an integrated framework of the conditions necessary for successful CSR-washing. Theorizing successful CSR-washing as the joint occurrence of five conditions, this paper undertakes a literature review of the empirical evidence for and against each condition. The literature review finds that many of the conditions are either highly contingent, rendering CSR-washing as a complex and fragile (...) outcome. This finding runs counter to the dominant perception in the general public, among activists, and among a vocal contingent of academics that successful CSR-washing is rampant. (shrink)

Thomas Kuhn described the progress of science as comprising occasional paradigm shifts separated by interludes of ‘normal science’. The paradigm that has held sway since the inception of molecular biology is that genes (mainly) encode proteins. In parallel, theoreticians posited that mutation is random, inferred that most of the genome in complex organisms is non‐functional, and asserted that somatic information is not communicated to the germline. However, many anomalies appeared, particularly in plants and animals: the strange genetic phenomena of (...) paramutation and transvection; introns; repetitive sequences; a complex epigenome; lack of scaling of (protein‐coding) genes and increase in ‘noncoding’ sequences with developmental complexity; genetic loci termed ‘enhancers’ that control spatiotemporal gene expression patterns during development; and a plethora of ‘intergenic’, overlapping, antisense and intronic transcripts. These observations suggest that the original conception of genetic information was deficient and that most genes in complex organisms specify regulatory RNAs, some of which convey intergenerational information. Also see the video abstract here: https://youtu.be/qxeGwahBANw. (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)

Neurons of organisms with complex and flexible behavior, especially humans, must precisely control protein localization and activity to support higher brain functions such as learning and memory. In contrast, simpler organisms generally have simpler individual neurons, less complex nervous systems and display more limited behaviors. Strikingly, however, many key neuronal proteins are conserved between organisms that have very different degrees of behavioral complexity. Here we discuss a possible mechanism by which conserved neuronal proteins acquired new attributes that were (...) crucial in the evolution of complexity of nervous system structure and function. Specifically, we hypothesize that vertebrate‐specific post‐translational palmitoylation sites and PDZ‐binding protein‐protein interaction motifs act as gain‐of‐function mutations, increasing the regulatory potential of conserved proteins without affecting their core functions. We further hypothesize that the additional regulation of neurotransmitter receptors and other membrane proteins made possible by these sites and motifs is critical for the function of complex nervous systems. (shrink)

Complex cognitive processes like concept learning involve a mixture of redundant explicit and implicit processes that are active simultaneously. This aspect of cognitive architecture creates difficulties in determining the influence of consciousness on processing. We propose that the interaction between an individual's regulatory focus and the reward structure of the current task influences the degree to which explicit processing is active. Thus, by manipulating people's motivational state and the nature of the task they perform, we can vary the (...) influence of conscious processing in cognitive performance. We demonstrate the utility of this view by focusing on studies in which people acquire new perceptual concepts by learning to classify them. This technique will allow us to better tease apart the roles of explicit and implicit processing in a variety of cognitive tasks. (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)

Clp ATPase chaperone proteins are found in procaryotes and eucaryotes. Recently, ClpC of Bacillus subtilis was found to be part of a regulatory switch(1). ClpC, in combination with the MecA and ComS proteins, regulates the activity of a transcription factor, ComK, which is necessary for the development of genetic competence (the ability to bind and take up exogenous DNA). The complex of ClpC:MecA:ComK renders ComK inactive. Interaction between ComS and the ternary complex releases active ComK. This (...) class='Hi'>regulatory switch controls ComK activity in response to cell density signals that affect production of ComS. Regulated interaction between Clp ATPases and target proteins might prove to be widespread. (shrink)

When cells are starved of their substrate, many nutrient transporters are induced. These undergo rapid endocytosis and redirection of their intracellular trafficking when their substrate becomes available again. The discovery that some of these transporters also act as receptors, or transceptors, suggests that at least part of the sophisticated controls governing the trafficking of these proteins has to do with their signaling function rather than with control of transport. In yeast, the general amino acid permease Gap1 mediates signaling to the (...) protein kinase A pathway. Its endocytic internalization and intracellular trafficking are subject to amino acid control. Other nutrient transceptors controlling this signal transduction pathway appear to be subject to similar trafficking regulation. Transporters with complex regulatory control have also been suggested to function as transceptors in other organisms. Hence, precise regulation of intracellular trafficking in nutrient transporters may be related to the need for tight control of nutrient‐induced signaling. (shrink)

Singapore, a highly affluent island city-state located in Southeast Asia, has increasingly leveraged new assisted reproductive technologies (ART) to overcome its dismal fertility rates in recent years. A new frontier in ART is preimplantation genetic testing (PGT) for polygenic risk scores (PRS) to predict complex multifactorial traits in IVF (in vitro fertilisation) embryos, such as type 2 diabetes, cardiovascular diseases and various other characteristics like height, intelligence quotient (IQ), hair and eye colour. Unlike well-known safety risks with human genome (...) editing, there are negligible risks with PGT-P, because there are no man-made genetic modifications that can be transmitted to future generations. Nevertheless, the current efficacy of using PGT-P to select IVF embryos for either increased or decreased probability of developing specific polygenic traits is still far from certain. Hence, the regulatory safeguards proposed here will be based on the assumption that the efficacy of this new technology platform has already been validated. These include: (1) restricting the application of PGT-P only for prevention of clinically relevant polygenic disease traits, (2) securely blocking patients’ access to the raw genomic DNA sequencing data of their IVF embryos, (3) validating diagnosis of polygenic disease traits in the prospective parents/grandparents of IVF embryos, and restricting PGT-P only for preventing specifically diagnosed polygenic disease traits and (4) mandating rigorous and comprehensive genetic counselling for IVF patients considering PGT-P. There is an urgent and dire need to prevent abuse of the PGT-P technique, as well as protect the interests and welfare of patients if its clinical application is to be permitted in the country. (shrink)

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)

It is argued that fundamental to Piaget's life works is a biologically based naturalism in which the living world is a nested complex of self-regulating, self-organising (constructing) adaptive systems. A structuralist-rationalist overlay on this core position is distinguished and it is shown how it may be excised without significant loss of content or insight. A new and richer conception of the nature of Piaget's genetic epistemology emerges, one which enjoys rich interrelationships with evolutionary epistemology. These are explored and it (...) is shown how a regulatory systems evolutionary epistemology may be embedded within genetic epistemology. (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)

The marketing of unproven direct-to-consumer stem cell interventions is becoming widespread in Canada. There is little evidence supporting their use and they have been associated with a range of harms. Canada has been slower to act against clinics offering these interventions than other jurisdictions, including the United States. Here, we outline the regulatory and policy tools available in Canada to address this growing problem. Health Canada’s regulations governing cell therapies are complex, but recent statements make it clear that (...) Health Canada believes it has jurisdiction over many of the currently marketed stem cell interventions. Still, further regulatory clarity is needed from Health Canada, as are increased directed enforcement efforts on interventions that fall within their scope. The Competition Bureau, via the Competition Act, prohibits advertisers from making materially false or misleading promotional representations. The Competition Bureau could collaborate with the scientific community to analyze the claims of existing clinics in Canada, and impose sanctions upon those who breach the established standard. Professional regulators, including provincial colleges of physicians and surgeons, have considerable power over what products and services their members can offer. Every college of physicians in Canada requires, via policy and codes of ethics, that doctors maintain evidence-based practices. This requirement is incompatible with offering many unproven stem cell interventions. Litigation may be another tool, including the use of fraud, misrepresentation and/or negligence claims for failing to meet the required standard of care. Finally, political pressure on federal and provincial lawmakers could encourage changes to marketing, cell therapy and professional regulations that would allow a more comprehensive response. In sum, there are many existing tools that can be used to protect the public from unproven stem cell interventions. Increased bureaucratic will and grassroots efforts are needed in order to effect a positive policy response. (shrink)

This chapter notes the complex and unsatisfying efforts to distinguish between punishment and regulation, and reframes the discussion of punishment and regulation by labeling the former law and the latter police. Doing so relocates this classification in a particular historical genealogy. Reconceptualizing the terms of the discussion suggests that while law operates on the individual, the object of police regulation tends to be collective. One of the distinctions frequently invoked as crucial to the difference between punishment and regulation is (...) the difference between private and public. However, the notion of private law and public regulation relies on an overly simplistic model and history of law. Comparing punishment and regulation is like comparing apples and oranges, because they are two fundamentally different things. Regulation is an empty label unless it is combined with a mode of governance. That mode of governance, which parallels and complements law, is the concept of police. Police and law are contemporary manifestations of the ancient Greek distinction between household governance and public governance. (shrink)

Prior researchers have studied individual components of a theoretical decision-making model. This paper presents the results of a more complete study of the model components and presents limited support of theory. The study examines the relative importance of regulatory, organizational, and personal constructs on an individual''s ethical sensitivity. Auditors from the major international accounting firms, located in two southeastern cities, are surveyed. Structural equation modeling is used to allow for the simultaneous evaluation of the three constructs of interest. The (...) results indicate that the regulatory and organizational constructs are negatively correlated with the personal experience construct. The three constructs are not significant causal factors on ethical sensitivity. This result may be due to the manner in which ethical sensitivity is typically measured or may indicate that the complexity of the ethical decision-making process is not fully captured in the theoretical models. Thus, the models suggested in the prior literature and the results presented in prior studies of the individual components may need to be reconsidered. (shrink)

Metazoan genomes contain thousands of protein‐coding and non‐coding RNA genes, most of which are differentially expressed, i.e., at different locations, at different times during development, or in response to environmental signals. Differential gene expression is achieved through complex regulatory networks that are controlled in part by two types of trans‐regulators: transcription factors (TFs) and microRNAs (miRNAs). TFs bind to cis‐regulatory DNA elements that are often located in or near their target genes, while miRNAs hybridize to cis‐regulatory (...) RNA elements mostly located in the 3′ untranslated region of their target mRNAs. Here, we describe how these trans‐regulators interact with each other in the context of gene regulatory networks to coordinate gene expression at the genome‐scale level, and discuss future challenges of integrating these networks with other types of functional networks. (shrink)

Feet play a crucial role in migration, and experiences of death and hopes for new life are etched into migrants’ soles. In the face of complex and fraught ethical debates that have largely been deontological and teleological in tone, this article employs feet and footwashing as heuristic devices to suggest the need for receiving communities to develop a multi-textured virtue-based response alongside these. Cultivation of a habitus rooted in attention to bodies, service, power subversion, mutuality and confession could lead (...) to new life both for those in migration and those long settled. (shrink)

This collection of essays explores the different ways the insights from complexity theory can be applied to law. Complexity theory - a variant of systems theory - views law as an emergent, complex, self-organising system comprised of an interactive network of actors and systems that operate with no overall guiding hand, giving rise to complex, collective behaviour in law communications and actions. Addressing such issues as the unpredictability of legal systems, the ability of legal systems to adapt to (...) changes in society, the importance of context, and the nature of law, the essays look to the implications of a complexity theory analysis for the study of public policy and administrative law, international law and human rights, regulatory practices in business and finance, and the practice of law and legal ethics. These are areas where law, which craves certainty, encounters unending, irresolvable complexity. This collection shows the many ways complexity theory thinking can reshape and clarify our understanding of the various problems relating to the theory and practice of law. (shrink)

The notion of validity fulfils a crucial role in legal theory. In the emerging Web 3.0, Semantic Web languages, legal ontologies, and normative multi-agent systems are designed to cover new regulatory needs. Conceptual models for complex regulatory systems shape the characteristic features of rules, norms, and principles in different ways. This article outlines one of such multilayered governance models, designed for the CAPER platform, and offers a definition of Semantic Web Regulatory Models . It distinguishes between (...) normative-SWRM and institutional-SWRM. It also compares existing principles in privacy by design, linked open data , legal information institutes , and online dispute resolution . The article concludes by proposing the notion of Relational Law to summarize the ethical dimension of SWRM. Ethics are the only regulatory way to constitute a global space, out of the jurisdictional public domain set by national, international, or transnational law, and opposed to the private one. (shrink)

Developmental processes in complex animals are directed by a hardwired genomic regulatory code, the ultimate function of which is to set up a progression of transcriptional regulatory states in space and time. The code specifies the gene regulatory networks (GRNs) that underlie all major developmental events. Models of GRNs are required for analysis, for experimental manipulation and, most fundamentally, for comprehension of how GRNs work. To model GRNs requires knowledge of both their overall structure, which depends (...) upon linkage amongst regulatory genes, and the modular building blocks of which GRNs are heirarchically constructed. The building blocks consist of basic transcriptional control processes executed by one or a few functionally linked genes. We show how the functions of several such building blocks can be considered in mathematical terms, and discuss resolution of GRNs by both “top down” and “bottom up” approaches. BioEssays 24:1118–1129, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

American policymakers delegate the administration of many welfare programs to states, where officials implement them in increasingly diverse ways. Welfare state scholarship has little to say about this subnational policy divergence, and it portrays the complexity of delegated governance as a barrier to nonelite legislative influence. Drawing on an ethnographic study of one state’s Medicaid program, this article shows that delegated governance offers ample opportunity for nonelite influence and policy divergence, but through regulatory governance rather than legislative advocacy. Medicaid (...) is opaque to politicians, whose inability to monitor program details creates conditions of bureaucratic autonomy and even activism: health-care agency personnel sequence regulatory tweaks to protect and expand entitlements. But budget cuts, outsourcing, and fraught provider relations also deprive bureaucrats of street-level know-how, and bureaucrats depend on beneficiaries’ advocates who selectively illuminate a path to reform. A full rendering of subnational divergence in American federalism requires attention to underexamined factors such as bureaucratic activism, agency advocacy, and regulatory governance. (shrink)

Recent experimental evidence suggests that most of the genome is transcribed into non‐coding RNAs. The initial transcripts undergo further processing generating shorter, metabolically stable RNAs with diverse functions. Small nucleolar RNAs (snoRNAs) are non‐coding RNAs that modify rRNAs, tRNAs, and snRNAs that were considered stable. We review evidence that snoRNAs undergo further processing. High‐throughput sequencing and RNase protection experiments showed widespread expression of snoRNA fragments, known as snoRNA‐derived RNAs (sdRNAs). Some sdRNAs resemble miRNAs, these can associate with argonaute proteins and (...) influence translation. Other sdRNAs are longer, form complexes with hnRNPs and influence gene expression. C/D box snoRNA fragmentation patterns are conserved across multiple cell types, suggesting a processing event, rather than degradation. The loss of expression from genetic loci that generate canonical snoRNAs and processed snoRNAs results in diseases, such as Prader‐Willi Syndrome, indicating possible physiological roles for processed snoRNAs. We propose that processed snoRNAs acquire new roles in gene expression and represent a new class of regulatory RNAs distinct from canonical snoRNAs.Also watch the Video Abstract. (shrink)

Regulatory offences are a complex phenomenon, presenting problematic aspects both at the level of criminalisation and at the level of enforcement. The literature abounds in works that study the phenomenon. There is, however, an aspect that has remained largely unexplored. It concerns the relationship between the regulatory framework within which the crime occurs and the procedural safeguards that defendants normally enjoy at trial or at the pre-trial stage: defendants tried for regulatory offences are often denied safeguards (...) that are generally considered as important constituents of trial fairness. Relying on a new conceptualisation of regulatory offences, this paper advances a theory that justifies these exceptional rulings. (shrink)

This article introduces a framework which aims at capturing the complexity of economic organizations. The analysis of most legitimate conventions of coordination results in a new approach to the firm as a compromising device between several modes of coordination which engage different repertoires of evaluation. This contribution to the Économie des conventions offers an analytical tool to operate comparative research on firms, intermediate regulatory committees or public policies.

Many European planning schools recently celebrated their 50th anniversary: a sign that planning education became a distinct and established discipline in Europe. Simultaneously, political regimes, paradigms, cultures, and economies continue fueling mixed connotations within the planning sector. Additionally, growing wicked problems in built areas emphasize an even greater need for well-trained planners. These challenges span climate crises, wars, authoritarian regimes, socio-political instability, and constantly changing global geopolitics. The increasingly complex demands on planners are highly pertinent for Young Academics (YA). (...) They require political, regulatory, and technical knowledge to navigate the profession. To support them and represent their voices in planning debates, the YA network (YAN) of AESOP was established in 2003. We, the current Coordination Team, use this paper to voice our take on the question of what planning challenges dominate and what can be done to prepare YAs better for the future. Building on plenty discussions within the YAN, literature, and AESOP’s activities at large, we propose: A challenge compilation for the profession, a list of core capacities, and a framework for future education. This shall aid in enabling YAs and educators today to set the foundation for planning sustainable and people-centered settlements tomorrow. (shrink)

Models of gene regulatory networks have proven useful for understanding many aspects of the highly complex behavior of biological control networks. Randomly generated non-Boolean networks were used in experimental simulations to generate data on dynamic phenotypes as a function of several genotypic parameters. We found that predictive relationships between some phenotypes and quantitative genotypic parameters such as number of network genes, interaction density, and initial condition could be derived depending on the strength of the topological genotype on specific (...) phenotypes. We quantitated the strength of the topological genotype effect on a number of phenotypes in multi-gene networks. For phenotypes with a low influence of topological genotype, derived and empirical relationships using quantitative genotype parameters were accurate in phenotypic outcomes. We found a number of dynamic network properties, including oscillation behaviors, that were largely dependent on genotype topology, and for which no such general quantitative relationships were determinable. It remains to be determined if these results are applicable to biological gene regulatory networks. (shrink)

The effects that artificial intelligence (AI) technologies will have on society in the short- and long-term are inherently uncertain. For this reason, many governments are avoiding strict command and control regulations for this technology and instead rely on softer ethics-based approaches. The Russian approach to regulating AI is characterized by the prevalence of unenforceable ethical principles implemented via industry self-regulation. We analyze the emergence of the regulatory regime for AI in Russia to illustrate the limitations of this approach. The (...) article is based on 50 interviews with policymakers, representatives of AI companies, and academics in the country. The findings show that this regulatory regime was formed under the strong influence of Russian big tech companies, which saw an opportunity to avoid regulatory oversight by washing out concrete regulatory measures from the policy. This approach is part of a broader protectionist sanction-proofing strategy for the local IT sector designed by the government, which can be characterized by lifting regulatory barriers for local companies. Unenforceable ethics-based self-regulation is a _regulatory gift_ from the Russian government to the industry. This _gift_ was intentionally designed because the government thought that prioritizing local innovation over consumer protection would benefit the public. However, the _gift_ can also unintentionally undermine the public interest by providing an opportunity for _ethics washing_. (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 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 major challenge in complex disease genetics is to understand the fundamental features of this complexity and why functional alterations at multiple independent genes conspire to lead to an abnormal phenotype. We hypothesize that the various genes involved are all functionally united through gene regulatory networks (GRN), and that mutant phenotypes arise from the consequent perturbation of one or more rate‐limiting steps that affect the function of the entire GRN. Understanding a complex phenotype thus entails unraveling the (...) details of each GRN, namely, the transcription factors that bind to cis regulatory elements affected by sequence variants altering transcription of specific genes, and their mutual feedback relationships. These GRNs can be identified through their rate‐limiting steps and are best uncovered by genomic analyses of rare, extreme phenotype families, thus providing a coherent molecular basis to complex traits and disorders. (shrink)

The evolution of the human brain has resulted in the emergence of higher-order cognitive abilities, such as reasoning, planning and social awareness. Although there has been a concomitant increase in brain size and complexity, and component diversification, we argue that RNA regulation of epigenetic processes, RNA editing, and the controlled mobilization of transposable elements have provided the major substrates for cognitive advance. We also suggest that these expanded capacities and flexibilities have led to the collateral emergence of psychiatric fragilities and (...) conditions. (shrink)

Glycosylation refers to the co‐ and post‐translational modification of protein and lipids by monosaccharides or oligosaccharide chains. The surface of mammalian cells is decorated by a heterogeneous and highly complex array of protein and lipid linked glycan structures that vary significantly between different cell types, raising questions about their roles in development and disease pathogenesis. This review will begin by focusing on recent findings that define roles for cell surface protein and lipid glycosylation in pluripotent stem cells and their (...) functional impact during normal development. Then, we will describe how patient derived induced pluripotent stem cells are being used to model human diseases such as congenital disorders of glycosylation. Collectively, these studies indicate that cell surface glycans perform critical roles in human development and disease. (shrink)

Metabolic systems are complicated and contain very large numbers of interacting reactions and many internal regulatory mechanisms. This does not prevent the genetic composition of an organism from influencing its behavior, however, nor does it preclude the possibility that some aspects of its behavior may be amenable to simple explanations.

Universal Basic Income (UBI) has been proposed as a potential way in which welfare states could be made more responsive to the ever-shifting evolutionary challenges of institutional adaptation in a dynamic environment. It has been proposed as a tool of “real freedom” (Van Parijs) and as a tool of making the welfare state more efficient. (Friedman) From the point of view of complexity theory and evolutionary economics, I argue that only a welfare state model that is “polycentrically” (Polanyi, Hayek) organized (...) as an evolving network of distributed decision-making can respond to the challenges of complexity in an adaptively efficient manner. UBI has the theoretical possibility to facilitate flexible, bottom-up innovation, since a) it embodies the “rule of law” principles of generality, nondiscrimination, simplicity, and transparency, and b) it grants people widespread freedom to experiment, innovate, and deviate from established practices and norms; but whether it can be made to work as intended depends on a number of variables in its design. I situate my research in the contemporary UBI debate around automation and technological development, which I interpret creatively through the lens of contemporary evolutionary political economy. I advance a syncretic model of institutional design based upon the shared insights of the Santa Fe, Neo-Hayekian, and Neo-Schumpeterian schools of evolutionary economics that, following Adam Thierer and Michael Munger, I call the framework of Permissionless Innovation (PI). Under the PI framework, which is a development of the tradition of evolutionary liberalism (Hume, Smith, Mandeville, Mill, Hayek, Polanyi, Schumpeter, Hodgson), individuals are granted the default right to innovate without having to ask for permission, and the right to basic income, which they can use to support their right to innovate, mutate, and experiment. This framework is a liberal framework to the extent it relies on widespread human freedom as a means of fostering innovation and social learning. And it is an evolutionary framework to the extent that it seeks to facilitate evolutionary socioeconomic processes for the sake of social progress and welfare advancement. I proceed to show, through an analysis of how innovation operates in both the economy and the cultural domain, that UBI can be used as an important cornerstone of an evolutionary liberal model of “ecostructural” governance that treats the socioeconomic order as an ecological garden of spontaneous growths, adaptations, and innovations. I call this the Permissionless Innovation Universal Basic Income (PIUBI) framework. In it, the right to innovate, deviate, and mutate is upheld as the “gold standard” of institutional design whereby individuals are granted widespread freedoms combined with the provision of UBI and other innovation-fostering (carefully bound) services and regulations. In the coming decades, UBI may even enable poor people to take better advantage of Human Enhancement Technologies (HETs) and other experimental innovations. Such a framework is compatible with a fast pace of evolutionary development, but the regulatory model accompanying such a framework must be capable of responding to evolutionary lock-ins, maladaptive innovations, self-destructive behaviour on the part of UBI recipients, and the management of catastrophic and existential risks. In the end, I will have shown that the PIUBI framework can be justified as a plausible default institutional mechanism for responding to radical uncertainty, but it needs to be experimentally adapted to changing circumstances with the help of various situation-specific, polycentric, multi-level, approaches. (shrink)

The generation of patterns and the diversity of cell types in a multicellular organism require differential gene regulation. At the heart of this process are enhancers or cis‐regulatory modules (CRMs), genomic regions that are bound by transcription factors (TFs) that control spatio‐temporal gene expression in developmental networks. To date, only a few CRMs have been studied in detail and the underlying cis‐regulatory code is not well understood. Here, we review recent progress on the genome‐wide identification of CRMs with (...) chromatin immunoprecipitation of TF‐DNA complexes followed by microarrays (ChIP‐on‐chip). We focus on two computational approaches that have succeeded in predicting the expression pattern driven by a CRM either based on TF binding site preferences and their expression levels, or quantitative analysis of CRM occupancy by key TFs. We also discuss the current limits of these methods and highlight some of the key problems that have to be solved to gain a more complete understanding of the structure and function of CRMs. (shrink)

International regulation of autonomous weapon systems (AWS) is increasingly conceived as an exercise in risk management. This requires a shared approach for assessing the risks of AWS. This paper presents a structured approach to risk assessment and regulation for AWS, adapting a qualitative framework inspired by the Intergovernmental Panel on Climate Change (IPCC). It examines the interactions among key risk factors—determinants, drivers, and types—to evaluate the risk magnitude of AWS and establish risk tolerance thresholds through a risk matrix informed by (...) background knowledge of event likelihood and severity. Further, it proposes a methodology to assess community risk appetite, emphasizing that such assessments and resulting tolerance levels should be determined through deliberation in a multistakeholder forum. The paper highlights the complexities of applying risk-based regulations to AWS internationally, particularly the challenge of defining a global community for risk assessment and regulatory legitimization. (shrink)

This paper deals with the problem of reconstruction of the intergenic interaction graph from the raw data of genetic co-expression coming with new technologies of bio-arrays (DMA-arrays, protein-arrays, etc.). These new imaging devices in general only give information about the asymptotical part (fixed configurations of co-expression or limit cycles of such configurations) of the dynamical evolution of the regulatory networks (genetic and/or proteic) underlying the functioning of living systems. Extracting the casual structure and interaction coefficients of a gene interaction (...) network from the observed configurations is a complex problem. But if all the fixed configurations are supposedly observed and if they are factorizable into two or more subsets of values, then the interaction graph possesses as many connected components as the number of factors and the solution is obtained in polynomial time. This new result allows us for example to partly solve the topology of the genetic regulatory network ruling the flowering in Arabidopsis thaliana. (shrink)

The sizeable theoretical and empirical literature on corporate social responsibility and business ethics in Western, developed economies indicates that the topic has attracted significant interest from academics and practitioners. There is, however, less evidence of the practice of CSR and business ethics in non-Western, transition economies, as insufficient attention is paid to the contextual specifications and underlying processes that may lead to different versions of CSR. Therefore, this paper examines the practice and sense-making of CSR and business ethics from the (...) perspective of the fertile and under researched post-communist context of Central and Eastern Europe, to join the growing academic debate about the impact of cultural and historical traditions on the practice and sense-making of CSR and business ethics in non-Western contexts. The study adopts a particular focus on the post-communist and under researched context of Bulgaria where CSR is still a relatively new phenomenon. By following an exploratory research design and by collecting qualitative data from 34 executives employed by public and private sector organisations in Bulgaria, the study finds that the local business environment is composed of a complex mix of various institutionalised pressures and challenges that predispose organisations to adopt a particular approach to CSR, ethical misconduct and CSR-washing. Apart from the significant contributions related to the practice, understanding and contextualisation of CSR in non-Western countries, the study also identifies challenges of business ethics in transition economies and adds depth to the emerging literature on CSR-washing by proposing a model for neo-communist CSR-washing. The study also offers contributions for practitioners and policy-makers. (shrink)

Thanks to genetic and biochemical advances on the molecular mechanism of circadian rhythms in Drosophila, theoretical models closely related to experimental observations can be considered for the regulatory mechanism of the circadian clock in this organism. Modeling is based on the autoregulatory negative feedback exerted by a complex between PER and TIM proteins on the expression of per and tim genes. The model predicts the occurrence of sustained circadian oscillations in continuous darkness. When incorporating light‐induced TIM degradation, the (...) model accounts for damping of oscillations in constant light, entrainment of the rhythm by light‐dark cycles of varying period or photoperiod, and phase shifting by light pulses. The model further provides a molecular dynamical explanation for the permanent or transient suppression of circadian rhythmicity triggered in a variety of organisms by a critical pulse of light. Finally, the model shows that to produce a robust rhythm the various clock genes must be expressed at the appropriate levels since sustained oscillations only occur in a precise range of parameter values. BioEssays 22:84–93, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

The purpose of this review is to draw attention to the mechanism of dosage compensation in Drosophila as a model for the study of the regulation of gene activity through the modulation of transcription. Dosage compensation resembles some mechanisms of transcriptional regulation, found in widely divergent organisms, that do not play a role in the activation of silent genes but determine the level of activity of genes that have been induced through the action of specific activators. It differs from other (...) known regulatory mechanisms in that its effect is to achieve, on average, a twofold change in gene activity levels. This review introduces the notion that, in order to yield such a defined level of regulation, the mechanism of dosage compensation in Drosophila, and perhaps in Caenorhabditis as well, incorporates elements that govern both transcriptional enhancement and repression within the same multi‐protein regulatory complex. (shrink)

DREAM complexes are transcriptional regulators that control the expression of hundreds to thousands of target genes involved in the cell cycle, quiescence, differentiation, and apoptosis. These complexes contain many subunits that can vary according to the considered target genes. Depending on their composition and the nature of the partners they recruit, DREAM complexes control gene expression through diverse mechanisms, including chromatin remodeling, transcription cofactor and factor recruitment at various genomic binding sites. This complexity is particularly high in mammals. Since the (...) discovery of the first dREAM complex (drosophila Rb, E2F, and Myb) in Drosophila melanogaster, model organisms such as Caenorhabditis elegans, and plants allowed a deeper understanding of the processes regulated by DREAM‐like complexes. Here, we review the conservation of these complexes. We discuss the contribution of model organisms to the study of DREAM‐mediated transcriptional regulatory mechanisms and their relevance in characterizing novel activities of DREAM complexes. (shrink)

We apply molecular code theory to a rule-based model of the human inner kinetochore and study how complex formation in general can give rise to molecular codes. We analyze 105 reaction networks generated from the rule-based inner kinetochore model in two variants: with and without dissociation of complexes. Interestingly, we found codes only when some but not all complexes are allowed to dissociate. We show that this is due to the fact that in the kinetochore model proteins can only (...) bind at kinetochores by attaching to already attached proteins and cannot form complexes in free solution. Using a generalized linear mixed model we study which centromere protein can take which role in a molecular code . By this, associations between CENPs and code roles are found. We observed that CenpA is a major risk factor while CenpQ is a major protection factor . Finally we show, using an abstract model of copolymer formation, that molecular codes can also be realized solely by the formation of stable complexes, which do not dissociate. For example, with particular dimers as context a molecular code mapping from two different monomers to two particular trimers can be realized just by non-selective complex formation. We conclude that the formation of protein complexes can be utilized by the cell to implement molecular codes. Living cells thus facilitate a subsystem allowing for an enormous flexibility in the realization of mappings, which can be used for specific regulatory processes, e.g. via the context of a mapping. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Garrison on Beauty in Artworks as a Response to Regulatory PowerA Focus on Butler and KantKelly Coble (bio)As Garrison concedes, critical theory and Confucian philosophy will strike many of his readers as unlikely interlocutors. One would be hard-pressed to find two intellectual traditions more historically and culturally remote, and at least at first glance, more antithetical in their stances on authority and cultural power. In Reconsidering the Life (...) of Power Garrison prosecutes a brilliant case against these appearances, bringing these traditions into sustained and productive conversation. He is able to do so successfully by steadfastly refraining from a style of intercultural philosophy that would force these traditions into abrupt conversation—an errand that would involve stripping each tradition of the cultural and historical circumstances that give it life (p. 31). Instead, Garrison delineates a vast, rhizomatic network in which these traditions can be observed interacting and intersecting, displaying "intriguing similarities as well as informative divergences" (p. 50). Tracing such a network is a daunting task, demanding one bring to bear (i) an elegant, accessible rhetorical style; (ii) redoubtable scholarly erudition: the book features close readings of texts by European philosophers from Kant to Foucault and Butler, Confucius and major figures in the classical Confucian tradition, and leading contemporary scholars of (and in) Confucian philosophy; and not least (iii) an original argument breathing fresh life into the many texts, old and new, under examination.In what follows I offer a summary of a large part of that argument and offer critical comment on a small part of it. As Garrison's title indicates, the book can profitably be read as a sympathetic development of, and critical response to, Butler's account of the psychodynamics of power as developed, [End Page 821] above all, in their 1997 The Psychic Life of Power. Of course, what sets Garrison's endeavor apart from the standard commentary is the use he makes of Confucian insights. One impetus for his doing so is recognition of fertile common ground. The poststructuralist, psychoanalytic, queer-theoretical tradition of which Butler is a major contributor shares with the Confucian tradition a "particular insight into how the relational self arises discursively through naming, ritual, and performance" (p. 49).On what grounds, then, does Butler's account of power merit a critical response, according to Garrison, and how do Confucian insights help shape that response? The point de départ of Butler's 1997 book is Foucault's affiliated notions of assujettissement ("subjection" or "subjugation") and subjectivation (in English as in French). "Subjectivation" is Foucault's coinage for the complex process responsible at once for the formation and maintenance of subjects and their subjection and subordination, a para-doxical achievement that is a hallmark of panoptic regulatory power. As Butler observes, subjection signifies "the way regulatory power maintains subjects in subordination by producing and exploiting the demand for continuity, visibility, and place."1 (We note that Butler's influential account of the performativity of gender also draws heavily on this concept of subjectivation.) In their 1997 book Butler gives systematic attention to the following dynamic: subjects depend on the subordinating effects of regulatory power for their existence, giving them an existential stake in, and concomitant desire for, their own subordination. Building on the Foucauldian thesis that the "psychic operation of the norm offers a more insidious route for regulatory power than explicit coercion," Butler proceeds through Hegel's "unhappy consciousness" and Nietzsche's "bad conscience" to an original reading of Freud's melancholia.2 As in Hegel and Nietzsche, so also in Freud, Butler observes, the ego is said to "turn back upon itself," taking itself "not only as an object of love, but of aggression and hate as well."3 And as in Hegel and Nietzsche, so also in Freud, this idea of a turn from the object to the ego that produces the ego, Butler observes, both defies intelligibility and describes a scene of failure. In Butler's words, "The turn from the object to the ego can never quite be accomplished," and as a result the subject "is haunted by an inassimilable remainder, a melancholia that marks the limits of subjectivation."4So far, Garrison... (shrink)

Synthesizing self‐regulatory theories, we provide new insights into the antecedents of abusive supervision. We, from the perspective of supervisor's self‐regulatory resources depletion or impairment, introduce supervisor hindrance stress as an underlying mechanism of the subordinate deviance–abusive supervision relationship: this mediated relationship will be intensified at the level of high subordinate job performance. In addition, we develop a complex contingency model and propose a three‐way interaction (i.e., subordinate deviance, job performance, supervisor outcome dependence) to obtain the complete understanding (...) of the subordinate deviance–abusive supervision relationship facilitated through the supervisors’ hindrance stress. To test our moderated moderated mediation model, we gathered time‐lagged and multisource data from a large food service company located in southern China. We collected data at two different points (i.e., Time 1 and Time 2) from supervisors and their direct reports (N = 298 responses from 68 supervisors and 298 direct reports), and findings provide support for the hypothesized moderated moderated mediation model of our study. We highlight the implications of our study for theory, research, and practice. (shrink)

Egg freezing has led to heated debates in healthcare policy and bioethics. A crucial issue in this context concerns the distinction between “medical” and “social” egg freezing —contrasting objections to bio-medicalization with claims for oversimplification. Yet such categorization remains a criterion for regulation. This paper aims to explore the “regulatory boundary-work” around the “medical”–”social” distinction in different egg freezing regulations. Based on systematic documents’ analysis we present a cross-national comparison of the way the “medical”–”social” differentiation finds expression in (...) class='Hi'>regulatory frameworks in Austria, Germany, Israel, and the Netherlands. Findings are organized along two emerging themes: the definition of MEF and its distinctiveness—highlighting regulatory differences in the clarity of the definition and in the medical indications used for creating it ; and hierarchy of medical over social motivations reflected in usage and funding regulations. Blurred demarcation lines between “medical” and “social” are further discussed as representing a paradoxical inclusion of SEF while offering new insights into the complexity and normativity of this distinction. Finally, we draw conclusions for policymaking and the bioethical debate, also concerning the related cryopolitical aspects. (shrink)

Genetic regulatory networks are complex, involving tens or hundreds of genes and scores of proteins with varying dependencies and organizations. This invites the application of artificial techniques in coming to understand natural complexity. I describe two attempts to deploy artificial models in understanding natural complexity. The first abstracts from empirically established patterns, favoring random architectures and very general constraints, in an attempt to model developmental phenomena. The second incorporates detailed information concerning the genetic structure, organization, and dependencies in (...) actual systems in an attempt to explain developmental differences. The results offered by these models, pitched at these different levels of abstraction, are different. The more detailed models are more continuous with classical developmental approaches. (shrink)

The interactions between genetic and environmental risk factors contribute to the aetiology of complex human diseases. Genome‐wide association studies (GWAS) have revealed that most of the genetic variants associated with complex diseases are located in the non‐coding part of the genome, preferentially within enhancers. Enhancers are distal cis‐regulatory elements composed of clusters of transcription factors binding sites that positively regulate the expression of their target genes. The generation of genome‐wide maps for histone marks (e.g., H3K27ac), chromatin accessibility (...) and transcription factor and coactivator (e.g., p300) binding profiles have enabled the identification of enhancers across many human cell types and tissues. Nonetheless, the functional and pathological consequences of the majority of disease‐associated genetic variants located within enhancers seem to be rather minor under normal conditions, thus questioning their medical relevance. Here we propose that, due to the prevalence of enhancer redundancy, the pathological effects of many disease‐associated non‐coding genetic variants might be preferentially (or even only) manifested under environmental stress. (shrink)