The cis-regulatory hypothesis is one of the most important claims of evolutionary developmental biology. In this paper I examine the theoretical argument for cis-regulatory evolution and its role within evolutionary theorizing. I show that, although the argument has some weaknesses, it acts as a useful example for the importance of current scientific debates for science education.

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 mechanisms (...) of shadow enhancer function and evolution are discussed. (shrink)

Homology searches between DNA sequences of evolutionary distant species (phylogenetic footprinting) offer a fast detection method for regulatory sequences. Because of the small size of their genomes, tetraodontid species such as the Japanese pufferfish and green spotted pufferfish have become attractive models for comparative genomics. A disadvantage of the tetraodontid species is, however, that they cannot be bred and manipulated routinely under laboratory conditions, so these species are less attractive for developmental and genetic analysis. In contrast, an increasing arsenal (...) of transgene techniques with the developmental model species zebrafish and medaka are being used for functional analysis of cis regulatory sequences. The main disadvantage is the much larger genome. While comparison between many loci proved the suitability of phylogenetic footprinting using fish and mammalian sequences, fast rate of change in enhancer structure and gene duplication within teleosts may obscure detection of homologies. Here we discuss the contribution and potentials provided by different teleost models for the detection and functional analysis of conserved cis‐regulatory elements. BioEssays 24:564–572, 2002. © 2002 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)

DNA with a curved trajectory of its helix axis is called bent DNA, or curved DNA. Interestingly, biologically important DNA regions often contain this structure, irrespective of the origin of DNA. In the last decade, considerable progress has been made in clarifying one role of bent DNA in prokaryotic transcription and its mechanism of action. However, the role of bent DNA in eukaryotic transcription remains unclear. Our recent study raises the possibility that bent DNA is implicated in the “functional packaging” (...) of transcriptional regulatory regions into chromatin. In this article, I review recent progress in bent DNA research in eukaryotic transcription, and summarize the history of bent DNA research and several subjects relevant to this theme. Finally, I propose a hypothesis that bent DNA structures that mimic a negative supercoil, or have a right‐handed superhelical writhe, organize local chromatin infrastructure to help the very first interaction between cis‐acting DNA elements and activators that trigger transcription. BioEssays 23:708–715, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Theories of the genetics underlying punctuated equilibrium (PE) have been vague to date. Here the developmental gene hypothesis is proposed, which states that: 1) developmental regulatory (DevReg) genes are responsible for the orchestration of metazoan morphogenesis and their extreme conservation and mutation intolerance generates the equilibrium or stasis present throughout much of the fossil record and 2) the accumulation of regulatory elements and recombination within these same genes—often derived from transposable elements—drives punctuated bursts of morphological divergence and (...) speciation across metazoa. This two‐part hypothesis helps to explain the features that characterize PE, providing a theoretical genetic basis for the once‐controversial theory. Also see the video abstract here https://youtu.be/C-fu-ks5yDs. (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)

High‐throughput genomic technologies are revolutionizing human genetics. So far the focus has been on the 1.5% of the genome, which is coding, in spite of the fact that the great majority of genomic variants fall outside the coding regions. Recent efforts to annotate the non‐coding sequence show that over 80% of the genome is biochemically active. The genome is divided into regulatory domains consisting of sequence regions that enhance and/or silence the expression of nearby genes and are, in some (...) cases, separated by boundaries with insulator activity. In this paper, we review the recent advances in the identification of variations that influence gene regulation and their consequences for human disease. We hypothesize that structural variations outside of the coding genome can interfere with normal gene regulation by disrupting the regulatory landscape. Therefore, the regulatory landscape of the genome has also to be taken into consideration when investigating the pathology of human disease. (shrink)

Gene regulation involves various cis-regulatory elements that can act at a distance. They may physically interact each other or with their target genes to exert their effects. Such interactions are beginning to be uncovered in the imprinted Igf2/H19 domain.1 The differentially methylated regions (DMRs), containing insulators, silencers and activators, were shown to have physical contacts between them. The interactions were changeable depending on their epigenetic state, presumably enabling Igf2 to move between an active and a silent chromatin domain. The (...) study gives us a novel view on how regulatory elements influence gene expression and how epigenetic modifications modulate their long-range effects. (shrink)

Les professeurs Macey et Miller analysent la relation entre l’assurance des dépôts et l’ inadé quation dans la structure des échéances des actifs et passifs des banques commerciales. Après avoir critiqué l’hypothèse traditionnelle concernant la réglementation, d’après laquelle les banques sont incitées à financer les actifs à long terme par des passifs à court terme parce que l’assurance des dépôts garantie par l’Etat stimule le crédit des banques et subventionne les passifs à court terme, ils utilisent l’analyse économique des décisions (...) publiques pour soutenir qu’une version modifiée de l’hypothèse de la réglementation est la meilleure explication de la déstructuration des échéances des actifs et passifs bancaires.Finalement, ils considèrent que soutenir l’hypothèse de la réglementation n’entraîne pas l’ acceptation du modèle d’assurance des dépôts garantie par l’Etat tel qu’il existe aux Etats-Unis aujourd’hui.Professors Macey and Miller explore the relationship between deposit insurance and the mismatch in the term structure of commercial banks’ assets and liabilities. After criticizing the traditional regulatory hypothesis, which posits that banks have incentives to fund long-term assets with short-term liabilities because government-sponsored deposit insurance enhances bank credit and subsidizes short-term liabilities, they use public choice theory to argue that a modified version of the regulatory hypothesis is the best explanation for the mismatch in the term structure of banks’ assets and liabilities. Finally, they argue that embracing the regulatory hypothesis does not imply acceptance of the government-sponsored deposit insurance scheme as it exists in the U.S. today. (shrink)

We investigate the regulatory sanctions imposed on independent directors for their firms’ financial frauds in China. These regulatory sanctions are prima-facie evidence of significant lapses in business ethics. During the period 2003–2010, 302-person-time independent directors were penalized by the regulator, and the two stock exchanges. We find that the independent directors with accounting experiences are more likely to be penalized by the CSRC, though they do not suffer more severe penalties than do the other sanctioned independent directors. We (...) also find that independent directors suffer less severe penalties than do the insider directors. These results are consistent with the hypothesis that the sanctions on independent directors are tied to their assumed ethical and legal responsibilities. Following a regulatory sanction, penalized independent directors experience a significant decline in the number of other board seats held. However, they can gain board seats in better quality firms. We find that interlocked firms that share penalized independent directors with the fraud firm do not suffer from a valuation decline. Overall, our results suggest that regulatory sanctions have not triggered further sanctions on the penalized directors in the labor market but they have, instead, created a disincentive for these directors to serve on the company boards of high-risk firms. (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)

Prevention focus is a self-regulatory orientation that serves the need for security, and promotion focus is a self-regulatory orientation that serves the need for growth. From mid-March to early April 2020, did people judge prevention focus to be more useful than promotion focus for responding to COVID-19? Our study tested and showed support for this hypothesis with 401 American and Canadian participants, who we sampled in 100-person waves on the first four Thursdays of the pandemic. For this (...) study, we developed a new measure of the judged usefulness of promotion and prevention focus. Additionally, results showed that the judged usefulness of promotion and prevention focus related positively to support of the psychological needs for autonomy and relatedness, respectively, in responding to COVID-19. Exploratory analyses showed that day-to-day differences in autonomy, competence, and relatedness support and in promotion and prevention focus tended to be small, which is notable given the large-scale changes to social distancing, employment, and media coverage of the virus during this time. Our research could be useful for crafting persuasive advocacy and narrative communications that encourage social distancing to protect others about whom people care most. (shrink)

Computational imagination (CI) conceives imagination as an agent’s simulated sensorimotor interaction with the environment in the absence of sensory feedback, predicting consequences based on this interaction (Marques and Holland in Neurocomputing 72:743–759, 2009). Its bedrock is the simulation hypothesis whereby imagination resembles seeing or doing something in reality as both involve similar neural structures in the brain (Hesslow in Trends Cogn Sci 6(6):242–247, 2002). This paper raises two-forked doubts: (1) neural-level equivalence is escalated to make phenomenological equivalence. Even at (...) an abstract level, many imagined and real actions turn out to be dissimilar. More so, some imagined actions have no corresponding real actions and vice versa, even though neural regions involved in imaginings and real action-perception are the same (Sect. 1). (2) At the implementation level, the hypothesis presents a mutually exclusive view of imagination and perception whereby imagination functions in the absence of the sensory feedback and is action based. Both these issues are contested here: Neither imagination functions in the absence of perception nor all forms of imaginings are action based; it is, rather, about conceiving possibilities which emerge during the perceptual stage itself (Sect. 2). For the modal aspect to arise, it is submitted that an integrative framework is required which Kant can provide for whom imagination is an indispensable part of perception. Kant’s views on concept-formation are presented here to illustrate this aspect (Sect. 3). The Paper is concluded with emphasizing the relevance of Kant’s views to the problems identified in the two sections. (shrink)

The eukaryotic genome is organized into different domains by cis‐acting elements, such as boundaries/insulators and matrix attachment regions, and is packaged with different degrees of condensation. In the M phase, the chromatin becomes further highly condensed into chromosomes. The first step for transcriptional activation of a given gene, at a particular time during development, in any locus, is the opening of its chromatin domain. This locus needs to be kept in this state in each early G1 phase during every cell (...) cycle. Certain distal enhance elements, including locus control regions (LCRs) and enhancers, are believed to perform this target chromatin domain opening process and several models have been proposed to explain distal enhance action. But they did not explain precisely how a given chromatin domain is opened. Based on various studies, we propose a hypothesis for the mechanism of opening chromatin on a large scale. One important mechanism may involved breaking one or two DNA strands and reducing the linking numbers within chromatin domain. The topological changes can overpass some complexes formed on DNA strands and can be transmitted from specific localized points over a broad region, until boundary elements or insulators are reached. These may initiate downstream events such as propagation of histone acetylation and the binding of transcription factors to proximal promoters and may further augment the action mediated by distal enhancer elements. BioEssays 25:507–514, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Precise spatiotemporal control of gene expression during normal development and cell differentiation is achieved by the combined action of proximal (promoters) and distal (enhancers) cis‐regulatory elements. Recent studies have reported that a subset of promoters, termed Epromoters, works also as enhancers to regulate distal genes. This new paradigm opened novel questions regarding the complexity of our genome and raises the possibility that genetic variation within Epromoters has pleiotropic effects on various physiological and pathological traits by differentially impacting multiple proximal (...) and distal genes. Here, we discuss the different observations pointing to an important role of Epromoters in the regulatory landscape and summarize the evidence supporting a pleiotropic impact of these elements in disease. We further hypothesize that Epromoter might represent a major contributor to phenotypic variation and disease. (shrink)

Knowledge on regulatory relations, in for example regulatory pathways in biology, is used widely in experiment design by biomedical researchers and in systems biology. The knowledge has typically either been represented through simple graphs or through very expressive differential equation simulations of smaller sections of a pathway. As an alternative, in this work we suggest a knowledge representation of the most basic relations in regulatory processes regulates, positively regulates and negatively regulates in logics based on a semantic (...) analysis. We discuss the usage of these relations in biology and in artificial intelligence for hypothesis development in drug discovery. (shrink)

The ontogeny of the vertebrate retina has been a topic of interest to developmental biologists and human geneticists for many decades. Understanding the unfolding of the genetic program that transforms a field of progenitors cells into a functionally complex and multi‐layered sensory organ is a formidable challenge. Although classical genetic studies succeeded in identifying the key regulators of retina specification, understanding the architecture of their gene network and predicting their behavior are still a distant hope. The emergence of next‐generation sequencing (...) platforms revolutionized the field unlocking the access to genome‐wide datasets. Emerging techniques such as RNA‐seq, ChIP‐seq, ATAC‐seq, or single cell RNA‐seq are used to characterize eye developmental programs. These studies provide valuable information on the transcriptional and cis‐regulatory profiles of precursors and differentiated cells, outlining the trajectories that connect each intermediate state. Here, recent systems biology efforts are reviewed to understand the genetic programs shaping the vertebrate retina. (shrink)

Werner syndrome (WS) is an inherited disorder that produces somatic stunting, premature ageing and early onset of degenerative and neoplastic diseases. Cultured fibroblasts derived from subjects with WS are found to undergo premature replicative senescence and thus provide a cellular model system to study the disorder. Recently, several overexpressed gene sequences isolated from a WS fibroblast cDNA library have been shown to possess the capacity to inhibit DNA synthesis and disrupt many normal biochemical processes. Because a similar constellation of genes (...) is overexpressed in WS and senescent normal fibroblasts, these data suggest the existence of a common molecular genetic pathway for replicative senescence in both types of cell. We propose that the primary defect in WS is a mutation in a gene for a trans‐acting repressor protein that reduces its binding affinity for shared regulatory regions of several genes, including those that encode inhibitors of DNA synthesis (IDS). The mutant WS repressor triggers a sequence of premature expression of IDS and other genes, with resulting inhibition of DNA synthesis and early cellular senescence, events which occur much later in normal cells. (shrink)

Protein synthesis inhibitors prolong the half‐lives of most mRNAs at least fourfold in the somatic cells of higher eukaryotes and in yeast cells. Some mRNAs are stabilized because the inhibitors affect mRNA‐specific regulatory factors; however, hundreds or thousands of other mRNAs are probably stabilized by a common mechanism. We propose that mRNA stabilization in cells treated with a translation inhibitor reflects a physiological process that occurs during each mitosis and is important for cell survival. Transcription and translation rates decline (...) drastically during a 1–2 hour interval of mitosis. We hypothesize that translational repression during this interval somehow inactivates a critical component of the mRNA degradation machinery. As a result, mRNA half‐lives are prolonged during the interval when transcription is repressed. If labile mRNAs were not stabilized during mitosis they, and perhaps also the labile proteins they encode, would be depleted as the cell entered G1 phase, with deleterious consequences. Stabilization during mitosis, or in response to translation inhibitors, thus preserves the capacity of the cell to synthesize essential proteins as it enters G1 or recovers from inhibitor treatment. mRNA stabilization might serve a similar purpose during starvation or any stress negatively affecting translation. (shrink)

Alpha‐fetoprotein (AFP)AFP, alpha‐fetoprotein; T3R, thyroid hormone (triiodothyronine) receptor; RAR, retionic acid receptor; erbA, putative thyroid hormone receptor proto‐oncogene products; VDR, vitamin D receptor; MR, mineralocorticoid receptor; GR, glucocorticoid receptor; PR, progesterone receptor; AR, androgen receptor; HRE, hormone response element on DNA; RXR, retionic‐X‐receptor; RAP, receptor auxiliary (accessory) proteins; E, estrogen. is a tumor‐associated fetal marker, associated both with tumor growth and with birth defects. AFP, whose precise function is unknown, has been classified as belonging to a protein superfamily together with (...) albumin and vitamin D‐binding (Gc) protein. AFP has been shown to bind various ligands in vitro including fatty acids, estrogens, thyroid hormones and retinoic acids. The steroid/thyroid nuclear receptor superfamily of proteins has recently become a major focus of biomedical investigation regarding regulation of gene expression. These receptors are thought to bind to DNA‐hormone response elements (HRE) that affect growth, development, differentiation, reproduction and homeostasis. The HREs are known to share DNA sequences with the various members of the nuclear receptor superfamily. In the present report, the possibility of a leucine‐zipper dimerization (heptad) motif in the carboxy‐terminal third domain of both rodent and human AFP is postulated. The presence of nine such hydrophobic repeats in the third domain of the AFP molecule mimics the heptad dimerization repeats found in the retinoic acid, thyroid, e‐erbA and other members of the nuclear receptor superfamily. Computer analysis revealed that the most conservative matching occurred between AFP and the retinoic acid class of receptors. However, other superfamily members displayed 40–60% homology with 5 of 9 AFP heptads. These findings could provide a possible mechanism for explaining the growth‐regulatory properties (both inhibition and enhancement) that have been ascribed to AFP in the last decade. (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)

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)

Regulation of microtubule (MT) dynamics is essential for many cellular processes, but the machinery that controls MT dynamics remains poorly understood. MT plus‐end tracking proteins (+TIPs) are a set of MT‐associated proteins that dynamically track growing MT ends and are uniquely positioned to govern MT dynamics. +TIPs associate with each other in a complex array of inter‐ and intra‐molecular interactions known as the “+TIP network.” Why do so many +TIPs bind to other +TIPs? Typical answers include the ideas that these (...) interactions localize proteins where they are needed, deliver proteins to the cortex, and/or create regulatory pathways. We propose an additional and more mechanistic hypothesis: that +TIPs bind each other to create a superstructure that promotes MT assembly by constraining the structural fluctuations of the MT tip, thus acting as a polymerization chaperone. (shrink)

In 2013, controversy sparked student protests, campus debates, and national attention when Smith College denied admittance to Calliope Wong—a trans woman. Since then, eight women’s colleges have revised their admissions policies to include different gender identities such as trans women and genderqueer people. Given the recency of such policies, we interrogate the ways the category “woman” is determined through certain alignments of biology-, legal-, and identity-based criteria. Through an inductive analysis of administrative scripts appearing both in student newspapers and in (...) trans admittance policies, we highlight two areas U.S. women’s colleges straddle while creating these policies: inclusion/exclusion scripts of self-identification and legal documentation, and tradition-/activism-speak. Through these tensions, women’s college admittance policies not only construct “womanhood” but also serve as regulatory norms that redo gender as a structuring agent within the gendered organization. (shrink)

An individual’s accountability to oneself leads to self-regulatory behaviour. A field experiment afforded an opportunity to test this relation, given that external accountability conditions were absent. A single group pre-test/post-test design was used to test the hypothesis. A group of full-time resident management students, n ≈ 550, take four meals during the day in the institute mess. As a part of the experiment, food wastage in the form of leftovers on the plates of subjects was measured. As a (...) pre-test, the measurement occurred at two levels. Subjects could see how much they are adding to the total waste by looking at a weighing scale placed under a waste basket, and they could also see the total waste data for each of the four meals for the day and a day earlier displayed at a prominent place. After 105 days, the weighing scale under the basket was removed, and as a post-test measurement, the total waste data for the four meals were noted down for another 72 days. A manipulation test indicated that the experiment has had the desired effect of invoking self-accountability in subjects during the pre-test phase, and diluting it during the post-test phase. Time series analysis of pre-test and post-test data indicated that the wastage data decreased in the pre-test phase. However, the post-test waste data showed an increase over a period of time. The results indicate that accountability conditions like social norms invoke self-accountability cognition leading to self-regulatory behaviours in individuals. (shrink)

The amdS gene of A. nidulans has proved extremely favourable for the isolation of mutations affecting gene regulation. Trans‐acting regulatory genes involved in amdS induction by small molecular weight effectors have been identified – amdR (ω‐amino acids) facB (acetate) and amdA (acetate). Another gene, the areA gene, has properties expected of a major activator gene involved in nitrogen metabolite repression of amdS. All of these regulatory genes are also involved in the control of various other functions encoded by (...) structural genes unlinked to amdS. Mutations in the 5′‐region adjacent to amdS have been isolated and allow the identification of independent cis‐acting sequences which are the target sites for the regulatory genes. The involvement of these sequences in regulatory product binding has been deduced from titration studies using transformants containing multiple copies of the 5′ sequences. A combination of genetics and molecular analysis is allowing a detailed characterization of this system. (shrink)

The ability to transfer genes from one species to another provides a powerful method to study genetic regulatory differences between species in a homogeneous genetic background. A survey of several transgenic animal experiments indicates that the vast majority of regulatory differences observed between species are due to differences in the cis‐acting elements associated with the genes under study. A corollary is that in almost all cases the host species provides the necessary regulatory proteins for expression of the (...) transgenes in specific tissues in which the endogenous homolog is not expressed. Although the details of the cis‐acting differences are unknown for most cases, it appears that these differences may consist of the acquisition or loss of unique elements or subtle variation of conserved elements. It is unknown whether much of this variation is directly related to adaptive evolution. The identification of the promoter enhancer elements responsible for these differences is an important first step in examining the functional significance of this variation. (shrink)

Mucoidy and cytotoxicity arise from two independent modifications of the phenotype of the bacterium Pseudomonas aeruginosa that contribute to the mortality and morbidity of cystic fibrosis. We show that, even though the transcriptional regulatory networks controlling both processes are quite different from a molecular or mechanistic point of view, they may be identical from a dynamic point of view: epigenesis may in both cases be the cause of the acquisition of these new phenotypes. This was highlighted by the identity (...) of formal graphs modelling these networks. A mathematical framework based on formal methods from computer science was defined and implemented with a software environment. It allows an easy and rigorous validation and certification of these models and of the experimental methods that can be proposed to falsify or validate the underlying hypothesis. (shrink)

It is not yet clear which response behavior requires self-regulatory effort in the moral dilemma task. Previous research has proposed that utilitarian responses require cognitive control, but subsequent studies have found inconsistencies with the empirical predictions of that hypothesis. In this paper we treat participants’ sensitivity to utilitarian gradients as a measure of performance. We confronted participants (N = 82) with a set of five dilemmas evoking a gradient of mean utilitarian responses in a 4-point scale and collected (...) data on heart rate variability and on utilitarian responses. We found positive correlations between tonic and phasic HRV and sensitivity to the utilitarian gradient in the high tonic group, but not in the low tonic group. Moreover, the low tonic group misplaced a scenario with a selfish incentive at the high end of the gradient. Results suggest that performance is represented by sensitivity correlated with HRV and accompanied with a reasonable placement of individual scenarios within the gradient. (shrink)

Osteopathy is a person-centred healthcare discipline that emphasizes the body’s structure-function interrelationship—and its self-regulatory mechanisms—to inform a whole-person approach to health and wellbeing. This paper aims to provide a theoretical framework for developing an integrative hypothesis in osteopathy, which is based on the enactivist and active inference accounts. We propose that osteopathic care can be reconceptualised under active inference as a unifying framework. Active inference suggests that action-perception cycles operate to minimize uncertainty and optimize an individual’s internal model (...) of the lived world and, crucially, the consequences of their behaviour. We argue that active inference offers an integrative framework for osteopathy, which can evince the mechanisms underlying dyadic and triadic exchanges and osteopathic care outcomes. We propose that this theoretical framework can underpin osteopathic care across the lifespan, from preterm infants to the elderly and those with persistent pain and other physical symptoms. In situations of chronicity, as an ecological niche, the patient-practitioner dyad provides the osteopath and the patient with a set of affordances, i.e., possibilities for action provided by the environment, that through shared intentionally, can promote adaptations and restoration of productive agency. Through a dyadic therapeutic relationship, as they engage with their ecological niche’s affordances—a structured set of affordances shared by agents—osteopath and patient actively construct a shared sense-making narrative and realise a shared generative model of their relation to the niche. In general, touch plays a critical role in developing a robust therapeutic alliance, mental state alignment, and biobehavioural synchrony between patient and practitioner. However, its role is particularly crucial in the fields of neonatology and paediatrics, where it becomes central in regulating allostasis and restoring homeostasis. We argue that from an active inference standpoint, the dyadic shared ecological niche underwrites a robust therapeutic alliance, which is crucial to the effectiveness of osteopathic care. Considerations and implications of this model—to clinical practice and research, both within- and outside osteopathy—are critically discussed. (shrink)

Recent findings indicate that frontal brain asymmetry may be a marker of for depression. However, the psychological predispositions that account linkage between frontal brain asymmetry and depression are unclear. approach-withdrawal hypothesis is the primary framework that has been to account for the linkages between frontal brain asymmetry and or emotional disorders. We review evidence consistent with this and suggest several directions for its extension. One such direction is to constrain the approach-withdrawal hypothesis by linking frontal asymmetry to the (...) known functions of the prefrontal cortex. On this we propose that frontal brain asymmetry may be preferentially linked processes that promote the temporal continuity and shifting of or emotional priorities and the suppression of interference by sources of motivation or emotion. We review evidence from and neurobiological studies of depression that is broadly consistent with these predictions. We emphasise the need for future studies testing our hypotheses. (shrink)

Merleau-Ponty, la passivité et la scienceJe soutiens qu’il y a plus en jeu dans l’intérêt de Merleau-Ponty pour la science qu’une simple dialectique entre disciplines. C’est parce que son évolutionméthodologique le conduit à trouver dans la science un moyen spécifique d’approfondir ses recherches ontologiques, que celle-ci hante de plus en plus sa philosophie. En effet, dans le chapitre « champ phénoménal » de la Phénoménologie de la perception, il est possible de rapprocher certains aspects de son défi méthodologique et l’idée (...) selon laquelle la philosophie tient son origine d’une conscience réflexive, active et autonome dans son ensemble. Je lie cela aux problèmes de la passivité de telle sorte que la science apparaisse comme une façon de saisir la réflexion non pas comme autonome, mais comme une opération du champ phénomenal, comme réflexion radicale. Grâce à l’analyse critique des recherches récentes sur le génome, je montre ensuite commentl’embryologie peut nous aider à conceptualiser la vie comme un champ phénoménal, c’est-à-dire comme un champ qui engendre ce même genre d’opérations qui caractérisent aussi la phénoménalité. Cela nous conduit à voir la phénomenologie non plus comme une réflexion de survol sur les phénomènes, mais plutôt comme une réflexion radicale qui se realise à travers un phénoménalité plus « ancienne », qui appartient à la vie ellemême. Cela ouvre également des perspectives sur quelques problèmes difficiles de la dernière philosophie de Merleau-Ponty; ceux-ci sont abordés d’une manière nouvelle, grâce au rapprochement de sa première philosophie et de la science actuelle.Merleau-Ponty, la passività e la scienzaRitengo che, nell’interesse che Merleau-Ponty rivolge alla scienza, vi sia in gioco qualcosa di più del semplice confronto dialettico con un’altra disciplina. Il motivo è che il suo impegno metodologico finisce per individuare nella scienza una speciale risorsa per l’indagine di quelle profonde questioni ontologiche che investono in modo crescente la sua filosofia. Intendo argomentare tale ipotesi, connettendo dei passi del capitolo di Fenomenologia della percezione “Il campo fenomenico” con la sua sfida metodologica all’idea che la filosofia abbia inizio da una coscienza riflessiva autonoma e interamente attiva. Collego questo alle questioni della passività in un modo che rivela la scienza come una potenziale risorsa per comprendere la riflessione non come autonoma, bensì in quanto operazione di e nel campo fenomenico – come riflessione radicale. Poi, attraverso un’analisi critica dei risultati recenti riguardanti il DNA regolatore, mostrocome l’attuale embriologia può aiutarci a concettualizzare la vita come un campo fenomenico che implicitamente produce i tipi di operazioni rivelatrici distintive della fenomenalità. Questo ci permette di collocare la fenomenologia non semplicemente come una riflessione dall’alto sui fenomeni, ma come una riflessione radicale che opera grazie ad una “più antica” fenomenalità della vita. Questo ci fornisce degli spunti su alcune difficili questioni nella filosofia dell’ultimo Merleau-Ponty, suggerendo un nuovo percorso che giunga a queste combinando il primo periodo della sua filosofia con la scienza recente. (shrink)

X‐chromosome inactivation refers to the coordinate regulation of almost all genes on the mammalian × chromosome. Most models for × chromosome inactivation suppose a role for methylation of × chromosome DNA sequences and/or the heterochromatinization of large «domains» of the × chromosome containing many genes.1 Some recent work concerning the expression of X‐linked transgenes, and parallels between regulated expression of sex‐linked genes in invertebrates and mammals, suggest that × chromosome inactivation may be a gene‐by‐gene event mediated by the interaction between (...) regulatory sequences common to all X‐linked genes and soluble activators and repressors. (shrink)

Merleau-Ponty, la passivité et la scienceJe soutiens qu’il y a plus en jeu dans l’intérêt de Merleau-Ponty pour la science qu’une simple dialectique entre disciplines. C’est parce que son évolutionméthodologique le conduit à trouver dans la science un moyen spécifique d’approfondir ses recherches ontologiques, que celle-ci hante de plus en plus sa philosophie. En effet, dans le chapitre « champ phénoménal » de la Phénoménologie de la perception, il est possible de rapprocher certains aspects de son défi méthodologique et l’idée (...) selon laquelle la philosophie tient son origine d’une conscience réflexive, active et autonome dans son ensemble. Je lie cela aux problèmes de la passivité de telle sorte que la science apparaisse comme une façon de saisir la réflexion non pas comme autonome, mais comme une opération du champ phénomenal, comme réflexion radicale. Grâce à l’analyse critique des recherches récentes sur le génome, je montre ensuite commentl’embryologie peut nous aider à conceptualiser la vie comme un champ phénoménal, c’est-à-dire comme un champ qui engendre ce même genre d’opérations qui caractérisent aussi la phénoménalité. Cela nous conduit à voir la phénomenologie non plus comme une réflexion de survol sur les phénomènes, mais plutôt comme une réflexion radicale qui se realise à travers un phénoménalité plus « ancienne », qui appartient à la vie ellemême. Cela ouvre également des perspectives sur quelques problèmes difficiles de la dernière philosophie de Merleau-Ponty; ceux-ci sont abordés d’une manière nouvelle, grâce au rapprochement de sa première philosophie et de la science actuelle.Merleau-Ponty, la passività e la scienzaRitengo che, nell’interesse che Merleau-Ponty rivolge alla scienza, vi sia in gioco qualcosa di più del semplice confronto dialettico con un’altra disciplina. Il motivo è che il suo impegno metodologico finisce per individuare nella scienza una speciale risorsa per l’indagine di quelle profonde questioni ontologiche che investono in modo crescente la sua filosofia. Intendo argomentare tale ipotesi, connettendo dei passi del capitolo di Fenomenologia della percezione “Il campo fenomenico” con la sua sfida metodologica all’idea che la filosofia abbia inizio da una coscienza riflessiva autonoma e interamente attiva. Collego questo alle questioni della passività in un modo che rivela la scienza come una potenziale risorsa per comprendere la riflessione non come autonoma, bensì in quanto operazione di e nel campo fenomenico – come riflessione radicale. Poi, attraverso un’analisi critica dei risultati recenti riguardanti il DNA regolatore, mostrocome l’attuale embriologia può aiutarci a concettualizzare la vita come un campo fenomenico che implicitamente produce i tipi di operazioni rivelatrici distintive della fenomenalità. Questo ci permette di collocare la fenomenologia non semplicemente come una riflessione dall’alto sui fenomeni, ma come una riflessione radicale che opera grazie ad una “più antica” fenomenalità della vita. Questo ci fornisce degli spunti su alcune difficili questioni nella filosofia dell’ultimo Merleau-Ponty, suggerendo un nuovo percorso che giunga a queste combinando il primo periodo della sua filosofia con la scienza recente. (shrink)

In this paper, I shall set out the pros and cons of assigning legal personhood on artificial intelligence systems under civil law. More specifically, I will provide arguments supporting a functionalist justification for conferring personhood on AIs, and I will try to identify what content this legal status might have from a regulatory perspective. Being a person in law implies the entitlement to one or more legal positions. I will mainly focus on liability as it is one of the (...) main grounds for the attribution of legal personhood, like for collective legal entities. A better distribution of responsibilities resulting from unpredictably illegal and/or harmful behaviour may be one of the main reasons to justify the attribution of personhood also for AI systems. This means an efficient allocation of the risks and social costs associated with the use of AIs, ensuring the protection of victims, incentives for production, and technological innovation. However, the paper also considers other legal positions triggered by personhood in addition to responsibility: specific competencies and powers such as, for example, financial autonomy, the ability to hold property, make contracts, sue. (shrink)

Cis‐regulatory elements govern gene expression programs to determine cell identity during development. Recently, the possibility that multiple enhancers are orchestrated in clusters of enhancers has been suggested. How these elements are arranged in the 3D space to control the activation of a specific promoter remains unclear. Our recent work revealed that the TGFβ pathway drives the assembly of enhancer clusters and precise gene activation during neurogenesis. We discovered that the TGFβ pathway coactivator JMJD3 was essential in maintaining these structures (...) in the 3D space. To do that, JMJD3 required an intrinsically disordered region involved in forming phase‐separated biomolecular condensates found in the enhancer clusters. Our data support the existence of a relationship between 3D‐conformation of the chromatin, biomolecular condensates, and TGFβ‐driven response during mammalian neurogenesis. In this review, we discuss how signaling (TGFβ), epigenetics (JMJD3), and biochemical properties (biomolecular condensates nucleation) are coordinated to modulate the genome structure to guarantee proper neural development. Moreover, we comment on the potential underlying mechanisms and implications of the enhancer‐mediated regulation. Finally, we point out the knowledge gaps that still need to be addressed. (shrink)

Kevin Gray,Kafumu Kalyalya | : In this paper we challenge the role of consent in the global order by discussing current modes of international law making in the global order. We contend that the features of state consent in international law depart substantially from those assumed by theorists of the liberal order, who subscribe, in most cases, to the realist conception of state action. We argue, against those theorists, that state consents to coercive measures, and the state’s role in carrying (...) them out, has ceased to be central to an account of global law. We conclude that international law—often thought of as law beyond the state—now has expanded its scope to reach individuals and corporations, and that this change has important ramifications for theories of global justice. | : Dans cet article, nous interrogeons le rôle de l’accord dans l’ordre global en discutant les modes courants de constitution des lois internationales au sein de cet ordre. Nous prétendons que les fonctions de l’accord étatique en loi internationale s’écartent substantiellement de celles assumées par les théoriciens de l’ordre libéral, qui souscrivent, dans la plupart des cas, à la conception réaliste de l’action étatique. Contre ces théoriciens, nos posons que l’État consent à des mesures coercitives, et que le rôle de l’État d’effectuer celles-ci a cessé d’être central dans l’explication de la loi globale. Nous concluons que la loi internationale – souvent pensée comme une loi hors de l’État – a maintenant étendu son spectre jusqu’aux individus et corporations, et que ce changement a d’importantes ramifications que les théories globales de la justice devraient considérer. (shrink)

The study explores the challenges UK-based institutional investors face when trying to monitor investee companies and influence their social, environmental, and governance practices. Consistent with previous research, I find that misalignment of interests within the investment chain and dispersed ownership are factors which inhibit investor activism. However, other underexplored challenges include lack of investee company transparency and investor experience in activism, as well as low client demand for engagement and internal conflicts of interest. The results contribute to the literature on (...) institutional investor activism by using direct empirical evidence to systematically discuss the challenges to stewardship. Given the intensification of media and regulatory attention on shareholders in the post-global financial crisis era, coupled with investors’ growing awareness and practice of stewardship, the research opens new avenues for enquiry which go beyond the on-going debate about the monitoring versus short-termism roles of institutional investors. (shrink)

In human languages, a palindrome reads the same forward as backward (e.g., ‘madam’). In regulatory DNA, a palindrome is an inverted sequence repeat that allows a transcription factor to bind as a homodimer or as a heterodimer with another type of transcription factor. Regulatory palindromes are typically imperfect, that is, the repeated sequences differ in at least one base pair, but the functional significance of this asymmetry remains poorly understood. Here, we review the use of imperfect palindromes in (...) Drosophila photoreceptor differentiation and mammalian steroid receptor signaling. Moreover, we discuss mechanistic explanations for the predominance of imperfect palindromes over perfect palindromes in these two gene regulatory contexts. Lastly, we propose to elucidate whether specific imperfectly palindromic variants have specific regulatory functions in steroid receptor signaling and whether such variants can help predict transcriptional outcomes as well as the response of individual patients to drug treatments. (shrink)

The early discovery of cis‐regulatory elements able to promote transcription of genes over large distances led to the postulate that elements, termed insulators, should also exist that would limit the action of enhancers, LCRs and silencers to defined domains. Such insulators were indeed found during the past fifteen years in a wide range of organisms, from yeast to humans. Recent advances point to an important role of transcription factors in insulator activity and demonstrate that the operational observation of an (...) insulator effect relies on a delicate balance between the “efficiency” of the insulator and that of the element to be counteracted. In addition, genuine insulator elements now appear less common than initially envisaged, and they are only found at loci displaying a high density of coding or regulatory information. Where this is not the case, chromatin domains of opposing properties are thought to confront each other at “fuzzy” boundaries. In this article, we propose models for both fixed and fuzzy boundaries that incorporate probabilistic and dynamic parameters. BioEssays 26:523–532, 2004. © 2004 Wiley Periodicals, Inc. (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 study of evolutionary developmental biology (“evo‐devo”) has recently experienced a dramatic surge in popularity among researchers and theorists concerned with evolution. However, some biologists and philosophers remain skeptical of the claims of evo‐devo. This paper discusses and responds to the recent high profile criticisms of evo‐devo presented by biologists Hopi E. Hoekstra and Jerry A. Coyne. I argue that their objections are unconvincing. Indeed, empirical research supports the main tenets of evo‐devo, including the claim that morphological evolution is the (...) result of cis ‐regulatory change and the distinction that evo‐devo draws between morphological and physiological traits. *Received January 2008; revised March 2009. †To contact the author, please write to: Department of Philosophy, University of Cincinnati, Cincinnati, OH 45221; e‐mail: [email protected]. (shrink)

Homeotic genes are subject to transcriptional silencing, which prevents their expression in inappropriate body regions. Here, we shall focus on Drosophila, as little is known about this process in other organisms. Evidence is accumulating that silencing of Drosophila homeotic genes is conferred by two types of cis‐regulatory sequences: initiation (SIL‐I) and maintenance (SIL‐M) elements. The former contain target sites for transient repressors with a highly localised distribution in the early embryo and the latter for constitutive repressors that are likely (...) to be present in all cells. We discuss how SIL‐I elements may cooperate with SIL‐M elements to promote formation of a silencing complex. We propose that this complex consists of specific non‐histone proteins, the so‐called Polycomb group proteins, and that it is anchored at SIL‐M elements and at the promoter. (shrink)

The transcription of rat prolactin and growth hormone genes in vitro requires a pituitary transcription factor, specific to certain cell types in the pituitary, which currently appears to be the PUF‐I/Pit‐1/GHF‐1 protein. This factor binds to cis‐regulatory elements in the 5′ region of both genes and exerts a positive influence on transcription initiation presumably by interacting with general transcription factors. The PUF‐I/Pit‐1/GHF‐1 transcriptional regulatory protein probably has an important role in not only the differentiation of the pituitary lactotroph/somatotroph (...) cell lineage; it is also expressed in the early development of the nervous system but its function there is less well documented. It appears to be one member of a family of trans‐activator proteins involved in differential gene expression in several cell types. (shrink)

Hidden among the myriad nucleotide variants that constitute each species' gene pool are a few variants that contribute to phenotypic variation. Many of these differences that make a difference are non‐coding cis‐regulatory variants, which, unlike coding variants, can only be identified through laborious experimental analysis. Recently, Cowles et al.1 described a screening method that does an end‐run around this problem by searching for genes whose cis regulation varies without having to find the polymorphic nucleotides that influence transcription. While we (...) will continue to require a diverse arsenal of experimental methods, this versatile method will speed the identification of functional genetic variation. BioEssays 25:421–424, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

One of the earliest and most‐fundamental pattern‐ formation events in embryonic development is endoderm and mesoderm specification. In sea urchin embryos, this process begins with blimp1 and wnt8 gene expression at the vegetal pole as soon as embryonic transcription begins. Shortly afterwards, wnt8/blimp1 expression spreads to the adjacent ring of mesoderm progenitor cells and is extinguished in the vegetal‐most cells. A little later, the ring of wnt8/blimp1 activity moves out of the mesoderm progenitors and into the neighboring endoderm cells. Remarkably, (...) this moving ring of gene expression has now been shown to be controlled entirely by transcriptional cis‐regulatory logic.1. BioEssays 30:412–417, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

It is often overlooked that, in addition to the integrity of protein‐coding sequences (PCSs), human health is crucially linked to the normal expression of genes by cis‐regulatory sequences (CRSs). These CRSs often lie at some considerable distance from the PCSs whose expression they control and often within other genes. The resulting gene interdigitation can make long‐range CRS identification and characterisation difficult. We propose that the need to conserve long‐range CRSs in cis with their target PCSs through evolution, in combination (...) with gene interdigitation and co‐regulation of many genes by individual CRSs, has contributed to the persistence of conserved synteny blocks between diverse species. We further hypothesise that examination of the varying extents of synteny blocks between multiple species in combination with phylogenetic footprinting to find CRSs might provide important clues to the existence of crucial functional CRS–PCS linkages. Identifying CRS–PCS linkages crucial to human health will lead to a better understanding of how their disruption by CRS mutation or chromosome translocation might contribute to many distressing human diseases. BioEssays 26:1217–1224, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The genomes of vertebrates, flies, and nematodes contain highly conserved noncoding elements (CNEs). CNEs cluster around genes that regulate development, and where tested, they can act as transcriptional enhancers. Within an animal group CNEs are the most conserved sequences but between groups they are normally diverged beyond recognition. Alternative CNEs are, however, associated with an overlapping set of genes that control development in all animals. Here, we discuss the evidence that CNEs are part of the core gene regulatory networks (...) (GRNs) that specify alternative animal body plans. The major animal groups arose >550 million years ago. We propose that the cis‐regulatory inputs identified by CNEs arose during the “re‐wiring” of regulatory interactions that occurred during early animal evolution. Consequently, different animal groups, with different core GRNs, contain alternative sets of CNEs. Due to the subsequent stability of animal body plans, these core regulatory sequences have been evolving in parallel under strong purifying selection in different animal groups. (shrink)