Axon regeneration is a conserved process across the animal kingdom. Recent studies using the soil worm Caenorhabditis elegans as a model system revealed that machineries regulating engulfment of dying cells also control axon regeneration and axon debris removal. In this review, the relationships between the engulfment machinery and the biological processes triggered by axon injury and subsequent axon regeneration drawn from divergent views are examined. In one study, it is found that engulfing cells directly promote axon regeneration. In this context, (...) CED‐1 (Drosophila Draper/mouse MEGF10), an engulfment protein expressed on the surface of engulfing cells, functions as a receptor for axon debris removal and as an adhesion molecule for axon regeneration. In other studies, it is shown that those engulfment genes, previously known to function within the engulfing cells for cell corpse removal, can have a cell‐autonomous “non‐engulfing cell” role in axon regeneration. Together, these findings suggest that engulfment genes are repurposed for neuronal regeneration by acting in both engulfing cells and regenerating neurons. (shrink)

Cancers often express hundreds of genes otherwise specific to germ cells, the germline/cancer (GC) genes. Here, we present and discuss the hypothesis that activation of a “germline program” promotes cancer cell malignancy. We do so by proposing four hallmark processes of the germline: meiosis, epigenetic plasticity, migration, and metabolic plasticity. Together, these hallmarks enable replicative immortality of germ cells as well as cancer cells. Especially meiotic genes are frequently expressed in cancer, implying that genes unique to meiosis may play a (...) role in oncogenesis. Because GC genes are not expressed in healthy somatic tissues, they form an appealing source of specific treatment targets with limited side effects besides infertility. Although it is still unclear why germ cell specific genes are so abundantly expressed in cancer, from our hypothesis it follows that the germline's reproductive program is intrinsic to cancer development. (shrink)

The pinnacle of the physician's clinical skills is his ability to develop the autonomy of his patients in the management of their health affairs. To do this requires the forging of a relationship in which patients' attitudes toward their health and illness are products of the doctor-patient relationship rather than unilateral behavior by either one. Modern medicine is beset with problems that make it difficult for physicians to develop and exercise the skills that lead to patient autonomy. An erosion of (...) public confidence in physicians is being caused by several mojar forces that include: (1) the power of science over life; (2) medical technology's dehumanizing effect; (3) legalization of medical ethics; and (4) industrialization and commercialization of medical care. To restore the kind of confidence that makes the physician an effective proponent of his patient's autonomy will require a major emphasis upon all aspects of medical ethics in the medical curriculum and in medical practice. Clinical investigation of this subject is highly appropriate. Clinical faculties should be developed in greater numbers who are authorities in the humanities as well as in science. Our medical schools need also to develop and to utilize models of health care in which relations with patients are personalized, continuous, and comprehensive so that ethical ideals such as patient autonomy can be demonstrated by precept and example, and can also be researched. (shrink)

The apolipoprotein E gene plays an important role in the pathogenesis of Alzheimer's disease, and amyloid plaque comprised mostly of the amyloid-beta peptide ) is one of the major hallmarks of AD. However, the relationship between these two important molecules is poorly understood. We examined how A treatment affects APOE expression in cultured cells and tested the role of the transcription factor NF-B in APOE gene regulation. To delineate NF-B's role, we have characterized a 1098 nucleotide segment containing (...) the 5'-flanking region of the human APOE gene. Sequence analysis of this region suggests the presence of two potential NF-B elements. To demonstrate promoter activity, the region was cloned upstream of a promoterless luciferase gene. This segment was able to drive expression of luciferase in transient transfections of human fetal glial cells. Promoter activity was stimulated twofold by A treatment. Pretreatment with double-stranded DNA decoy oligonucleotides against NF-B reduced A stimulation. Deletion and mutagenetic analyses demonstrated that the distal NF-B element was functional and showed a strong DNA-protein complex band in gel shift analysis, similar to that from control NF-B consensus element. An anti-inflammatory and anti-NF-B drug, sodium salicylate, significantly blocked A-induced APOE promoter function. Our data provide evidence that upregulation of APOE by A in astroglial cells is mediated by an NF-B-element present in the 5'-flanking region of the APOE gene. (shrink)

In the early 1970s, the major industrial states were preparing to shift to nuclear fission as their principal source of electrical power. But that change has not occurred. In part, this is due to a growing public recognition that techniques and institutions for management of spent nuclear fuel, separated plutonium, and long-lived radioactive wastes are not yet fully developed. The consequent pressures for resolution have spurred a series of often ill-defined and sometimes contradictory attempts to promote international cooperation and control (...) of hazardous activities. How are these varied suggestions to be compared and evaluated? By what criteria can plans be selected that are likely to be both effective and negotiable? In this study, Gene I. Rochlin, physicist and social scientist, explores the technical, political, and institutional aspects of international nuclear export and fuel cycle policies. He categorizes existing proposals and suggests way to develop new ones that better promote both national and international goals. Dr. Rochlin argues neither for nor against the use of nuclear power or plutonium fuels. Instead, he addresses the question of how international arrangements could be reached that might jointly satisfy the objective of the several key nations, yet not be too difficult to negotiate. He concludes that a major fault has been the tendency to improvise arrangements for specific technical or industrial operations. As a result, overall social and political goals have become the bargaining points for compromise. Yet attempts to simultaneously resolve all problems are unlikely to prove fruitful. Dr. Rochlin suggests instead the formation of institutions organized around more limited social, political, and technical objectives, even at the expense of excluding some nations or omitting some aspects of the nuclear fuel cycle. Only by so doing, he argues, can immediate agreements be reached that preserve the potential for more comprehensive future arrangements without sacrificing industrial, environmental, or nonproliferation goals. This important book will be of interest to scientists, social scientists, government officials, and others concerned with the problems of plutonium management and nuclear wastes. (shrink)

This paper employs Axel Honneth’s recognition theory to interpret ‘quiet quitting’ – the practice of limiting work efforts to contracted requirements – as a strategic response by workers facing misrecognition in their work environment. Honneth argues that misrecognition in any one of three social spheres (the family, political society, and the workplace) constitutes disrespect and causes psychological harm. While Honneth contends that experiences of disrespect tend to motivate collective “struggles for recognition,” we suggest that quiet quitters present an alternative response (...) to disrespect, individually seeking recognition in other social spheres rather than engaging in collective action. Further, we draw on Honneth to suggest that the contemporary “entrepreneurial” work ethic – the widespread expectation that workers invest emotionally in their work role – can in practice undermine workplace recognition, contributing to quiet quitters’ compensatory emphasis on recognitive relations outside of work. This recognition-theoretical approach extends current discussions around quiet quitting and yields valuable insights for management theory and practice regarding the critical role of genuine employee recognition in promoting individual well-being and meaningful work experiences. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Human Rights and the Ethics of Globalization by Daniel E. Lee and Elizabeth J. LeeGuenther "Gene" HaasHuman Rights and the Ethics of Globalization Daniel E. Lee and Elizabeth J. Lee Cambridge: Cambridge University Press, 2010. 264 pp. $27.99While there have been numerous books written on the nature of rights in a world of globalization, this book fills a gap by presenting a thoughtful and balanced discussion that (...) is firmly grounded in ethical theory yet takes into account the concerns of both nongovernmental organizations (NGOs) and the realities of the business world. The authors acknowledge that there can be naive troublemakers in NGOs and greedy people in business as well as socially concerned people in both groups.The book is divided into three parts. Part 1 deals with the philosophical foundations for addressing ethical issues in business within the context of globalization. Here the authors advocate for a limited, carefully defined notion of rights, properly noting that not everything of ethical significance falls under the notion of rights. The important distinction they make is between negative rights (the rights to life and freedom), which oblige us never to harm others, and positive rights (rights of entitlement, such as education, medical care, housing), which depend upon the various types of relationships, voluntary or involuntary, in which people find themselves. The former apply universally to neighbors near and far; the latter, because they are defined by relationships, apply primarily to neighbors near to us. With globalization distant neighbors often become near neighbors—for example, when a company builds a production facility in another country. In view of this, the authors argue that the Enlightenment’s individualistic understanding of rights is incomplete. A fuller version of rights (rooted in Aristotle) situates all humans in social communities where mutual charitable treatment is better suited to promoting human flourishing. With this in mind, the authors use the second form of Kant’s categorical imperative (“Always treat others as ends”) to map out some helpful practical guidelines for multinational corporations that are conducive to human well-being. Such guidelines seek to take into consideration all the constituencies that these organizations are called to serve—including shareholders, customers, employees, suppliers, and communities of location.In part 2 the authors draw on these philosophical foundations and practical guidelines to discuss ethical issues related to business practices in four different [End Page 198] countries: respect for human rights in China given the widespread practice of outsourcing; the condition of workers in Liberia where Firestone is the largest employer; free trade and fair trade issues related to coffee growers in Ethiopia; and the question of whether low-wage factories (maquiladoras) in Mexico exploit workers or provide economic opportunity for them. The authors provide a fair evaluation of each situation rooting their discussion in the nature of each respective business and the conditions over which it has direct control.Part 3 deals with the possibilities and challenges of dealing with multinational corporations that do not respect human rights. Although many argue for sanctions and treaty provisions, the authors argue that these approaches have their limitations. As an alternative, they recommend the Alien Tort Claims Act as the most promising means of enforcing human rights standards among American multinational corporations with overseas operations.This is an insightful and balanced book on human rights and social ethics precisely because it has a positive view of markets and is optimistic about achieving greater social responsibility in the business world. It will be helpful to all committed to promoting ethical business practices in a growing global economy—not only in the church and academy but also in the legal community and business world and in NGOs.Guenther HaasRedeemer University CollegeCopyright © 2013 Society of Christian Ethics... (shrink)

This paper provides a marketing ethics analysis that addresses the practice of selling genetic tests directly to the consumer. It details the complexity of this emergent sector by articulating the panoply of evolving ethical/social questions raised by this development. It advances the conversation about DTC genetic testing by reviewing the business and healthcare literature concerning this topic and by laying out the inherent ethical complications for consumers, marketers, and regulators. It also points to several possible public and company policy adjustments. (...) Because this area is relatively new and incredibly dynamic, its current discussion is necessarily an exercise in the “logic of discovery” rather than the “protocol of validation”. The paper serves as a primer for the types of GT being promoted. It also calls for a public discourse in the academic and general community to uncover and define the ethical guidelines and systemic adjustments necessary to create fairness in the various DTC transactions occurring between genetic test sellers and the buyers/clients of their services. (shrink)

Enhancers are short segments of regulatory DNA that control when and in which cell‐type genes should be turned on in response to a variety of extrinsic and intrinsic signals. At the molecular level, enhancers serve as a genomic scaffold that recruits sequence‐specific transcription factors and co‐activators to facilitate transcription from linked promoters. However, it remains largely unclear how enhancers communicate with appropriate target promoters in the context of higher‐order genome topology. In this review, we discuss recent progress in (...) our understanding of the functional interplay between enhancers, genome topology, and the molecular properties of transcription machineries in gene regulation. We suggest that the activities of transcription hubs are highly regulated through the dynamic rearrangement of enhancer‐promoter and promoter‐promoter connectivity during animal development. (shrink)

The nuclear envelope shapes the functional organization of the nucleus. Increasing evidence indicates that one of its main components, the nuclear lamina, dynamically interacts with the genome, including the promoter region of specific genes. This seems to occur in a manner that accords developmental significance to these interactions. This essay addresses key issues raised by recent data on the association of nuclear lamins with the genome. We discuss how lamins interact with large chromatin domains and with spatially restricted regions on (...) gene promoters. We address the relationship between these interactions, chromatin modifications and gene expression outcomes. Lamin‐genome contacts are redistributed after cell division and during stem cell differentiation, with evidence of lineage specificity. Thus, we also speculate on a developmental role of lamin interactions with specific genes. Finally, we highlight how concepts arising from this recent work lay the foundations of future challenges and investigations. (shrink)

Emerging evidence suggests that DNA topology plays an instructive role in cell fate control through regulation of gene expression. Transcription produces torsional stress, and the resultant supercoiling of the DNA molecule generates an array of secondary structures. In turn, local DNA architecture is harnessed by the cell, acting within sensory feedback mechanisms to mediate transcriptional output. MYC is a potent oncogene, which is upregulated in the majority of cancers; thus numerous studies have focused on detailed understanding of its regulation. (...) Dissection of regulatory regions within the MYC promoter provided the first hint that intimate feedback between DNA topology and associated DNA remodeling proteins is critical for moderating transcription. As evidence of such regulation is also found in the context of many other genes, here we expand on the prototypical example of the MYC promoter, and also explore DNA architecture in a genome-wide context as a global mechanism of transcriptional control. Torsional stress, and supercoiling generated by transcription, shape the topology of DNA. Furthermore, the resultant secondary DNA structures and their interacting partners provide feedback to regulate gene expression. Emerging evidence suggests these mechanisms, identified through analysis of the MYC promoter, are applicable genome-wide. (shrink)

SummaryGene transcription is strictly controlled by the interplay of regulatory events at gene promoters and gene‐distal regulatory elements called enhancers. Despite extensive studies of enhancers, we still have a very limited understanding of their mechanisms of action and their restricted spatio‐temporal activities. A better understanding would ultimately lead to fundamental insights into the control of gene transcription and the action of regulatory genetic variants involved in disease. Here, I review and discuss pros and cons of state‐of‐the‐art (...) genomics methods to localize and infer the activity of enhancers. Among the different approaches, profiling of enhancer RNAs yields the highest specificity and may be superior in detecting in vivo activity. I discuss their apparent similarities to promoters, which challenge the established view of enhancers and promoters as distinct entities, and present a unifying model of regulatory elements in transcriptional regulation, in which activity, transcriptional output and regulatory function is context specific. (shrink)

Throughout the biological and biomedical sciences there is a growing need for, prescriptive ‘minimum information’ (MI) checklists specifying the key information to include when reporting experimental results are beginning to find favor with experimentalists, analysts, publishers and funders alike. Such checklists aim to ensure that methods, data, analyses and results are described to a level sufficient to support the unambiguous interpretation, sophisticated search, reanalysis and experimental corroboration and reuse of data sets, facilitating the extraction of maximum value from data sets (...) them. However, such ‘minimum information’ MI checklists are usually developed independently by groups working within representatives of particular biologically- or technologically-delineated domains. Consequently, an overview of the full range of checklists can be difficult to establish without intensive searching, and even tracking thetheir individual evolution of single checklists may be a non-trivial exercise. Checklists are also inevitably partially redundant when measured one against another, and where they overlap is far from straightforward. Furthermore, conflicts in scope and arbitrary decisions on wording and sub-structuring make integration difficult. This presents inhibit their use in combination. Overall, these issues present significant difficulties for the users of checklists, especially those in areas such as systems biology, who routinely combine information from multiple biological domains and technology platforms. To address all of the above, we present MIBBI (Minimum Information for Biological and Biomedical Investigations); a web-based communal resource for such checklists, designed to act as a ‘one-stop shop’ for those exploring the range of extant checklist projects, and to foster collaborative, integrative development and ultimately promote gradual integration of checklists. (shrink)

Cell interdivision periods (IDP) in homogenous cell populations vary stochastically. Another aspect of probabilistic cell behavior is randomness in cell differentiation. These features are suggested to result from competing stochastic events of assembly/disassembly of the transcription pre‐initiation complex (PIC) at gene promoters. The time needed to assemble a proper PIC from different proteins, which must be numerous enough to make their combination gene specific, may be comparable to the IDP. Nascent mRNA visualization at defined genes and inferences (...) from protein level fluctuations in single cells suggest that some genes do operate in this way. The onset of mRNA production by such genes may miss the time windows provided by the cell cycle, resulting in cells differentiating into those in which the respective mRNAs are either present or absent. This creates a way to generate cell phenotype diversity in multicellular organisms. (shrink)

The placenta invades the adjacent uterus and controls the maternal immune system, like a cancer invades surrounding organs and suppresses the local immune response. Intriguingly, placental and cancer cells are globally hypomethylated and share an epigenetic phenomenon that is not well understood – they fail to silence repetitive DNA sequences that are silenced in healthy somatic cells. In the placenta, hypomethylation of retrotransposons has facilitated the evolution of new genes essential for placental function. In cancer, hypomethylation is thought to contribute (...) to activation of oncogenes, genomic instability, and retrotransposon unsilencing; the latter, we postulate, is possibly the most important consequence. Activation of placental retrotransposon-derived genes in cancer underpins our hypothesis that hypomethylation of these genes drives cancer cell invasion. This alludes to an interesting paradox, that while placental retrotransposon-derived genes are essential for promoting early hominid life, the same genes promote disease-susceptibility and death through cancer. Placental and cancer cells fail to silence retrotransposons that are normally silenced in healthy tissues. This has created new genes that are essential for placental function, yet they are also expressed in cancer. We hypothesize that active retrotransposons are a double-edged sword, contributing both adaptive and deleterious functions to biology. (shrink)

Professor Bartha Maria Knoppers stepped down from the Canada Research Chair in Law and Medicine at McGill University in April 2024, a post she held for more than 20 years. Professor Knoppers consistently prioritized "humanity" in her academic work and in policymaking. As such, she forged a strong intellectual legacy, notably through her work on the human right to science, genomic and health-related data sharing, genome editing, human reproductive technologies, stem cell research, the rights of children, and population health. This (...) collection of essays honours her extraordinary academic contributions to law, policy, and medicine. (shrink)

The pituitary hormone prolactin (PRL) is best known for its role in the regulation of lactation. Recent evidence furthermore indicates PRL is required for normal reproduction in rodents. Here, we report on the insertion of two transposon-like DNA sequences in the human prolactin gene, which together function as an alternative promoter directing extrapituitary PRL expression. Indeed, the transposable elements contain transcription factor binding sites that have been shown to mediate PRL transcription in human uterine decidualised endometrial cells and lymphocytes. (...) We hypothesize that the transposon insertion event has resulted in divergent (pituitary versus extrapituitary) expression of prolactin in primates, and in differential actions of pituitary versus extrapituitary prolactin in lactation versus pregnancy respectively. Importantly, the TE insertion might provide a context for some of the conflicting results obtained in studies of PRL function in mice and man. (shrink)

New emerging biotechnologies, such as gene editing, vastly extend our ability to alter the human being. This comes together with strong aspirations to improve humans not only physically, but also mentally, morally, and socially. These conjoined ambitions aggregate to what can be labelled “the gene editing of super-ego.” This article investigates a general way used to argue for new biotechnologies, such as gene-editing: if it is safe and efficacious to implement technology X for the purpose of a (...) common good Y, why should we not do so? This is a rhetorical question with a conditional, and may be dismissed as such. Moreover, investigating the question transformed into a formal argument reveals that the argument does not hold either. Nonetheless, the compelling force of the question calls for closer scrutiny, revealing that this way of arguing for biotechnology is based on five assumptions. Analysis of these assumptions shows their significant axiological, empirical, and philosophical challenges. This makes it reasonable to claim that these kinds of question based promotions of specific biotechnologies fail. Hence, the aspirations to make a super-man with a super-ego appear fundamentally flawed. As these types of moral bioenhancement arguments become more prevalent, a revealing hype test is suggested: What is special with this technology, compared to existing methods, that makes it successful in improving human social characteristics in order to make the world a better place for all? Valid answers to this question will provide good reasons to pursue such technologies. Hence, the aim is not to bar the development of modern biotechnology, but rather to ensure good developments and applications of highly potent technologies. So far, we still have a long way to go to make persons with goodness gene. (shrink)

Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream (...) from the +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (shrink)

The computational genomics community has come increasingly to rely on the methodology of creating annotations of scientific literature using terms from controlled structured vocabularies such as the Gene Ontology (GO). We here address the question of what such annotations signify and of how they are created by working biologists. Our goal is to promote a better understanding of how the results of experiments are captured in annotations in the hope that this will lead to better representations of biological reality (...) through both the annotation process and ontology development, and in more informed use of the GO resources by experimental scientists. (shrink)

Histone acetylation is an important regulatory mechanism that controls transcription and diverse nuclear processes. While great progress has been made in understanding how localized acetylation and deacetylation control promoter activity, virtually nothing is known about the consequences of acetylation throughout entire chromosomal regions. An increasing number of genes have been found to reside in large chromatin domains that are controlled by regulatory elements many kilobases away. Recent studies have shown that broad histone acetylation patterns are hallmarks of chromatin domains. The (...) purpose of this review is to discuss how such patterns are established and their implications for regulating gene expression. BioEssays 23:820–830, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Renin is the rate‐limiting enzyme in a cascade that leads to production of angiotensin II, which is perhaps our most important regulator of salt and water balance and blood pressure. In this personal perspective, I describe how I entered the renin field 33 years ago by discovering that proteases increased the level of renin activity in biological fluids, so revealing the existence of a ‘pro’ form of the molecule. This led me on a journey that encapsulated all of the major (...) milestones in molecular discovery for renin. These included (1) the elucidation of the steps in renin biosynthesis, (2) the cloning of renin cDNA and its gene, (3) demonstration of the structure of the renin protein, (4) using the renin gene in the first genetic studies in hypertension, (5) finding the mechanism by which the major controller, cyclic AMP, regulates the promoter, (6) showing that a strong enhancer and its weak promoter control this physiologically regulatable gene in accord with the variegation (on/off switching) model, and (7) being the first to identify molecules involved in posttranscriptional control. The renin molecule, its gene and molecular control are now very well understood, but more fine details on the topic of renin continue to emerge to delight ‘reninologists’ and others. BioEssays 25:520–527, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Scholars have long speculated about what a future affected by gene editing technologies might hold. This article enters current debates over the future of gene editing and the place of disability within it. Specifically, I evaluate contemporary utopian thinking about gene editing found in two different schools of thought: transhumanism and critical disability studies, ultimately judging the latter to be richer and more politically promising than the former. If we take it as our goal to protect and (...) promote future people’s autonomy interests, I argue that current political efforts should be directed toward modifying ableist environments rather than employing genetic technologies to avoid disability or enhance capacity. The article concludes by drawing from disability justice scholarship to make the case that the “right to an open future” should be understood as the “right to an accessible future,” one wherein society is “open” to people with diverse genetic traits and capacities. (shrink)

Advances in genetic technology, including new methods for gene editing, promise to provide parents and prospective parents with more information about and more control over the genetic make-up of their children. Information and control are both highly prized in our culture, and both could offer substantial benefits to parents and children. Yet offers of information and control that promise to benefit children can quickly generate new parental responsibilities, morphing from opportunities to obligations and raising the question whether refusing to (...) use the technologies might one day be considered inconsistent with being a “good parent.” This chapter explores the idea of the good parent and argues that understandings of the good parent must evolve to take parents’ own flourishing into account. Only with this richer understanding of the nature and responsibilities of parenting can we adopt technologies such as gene editing in ways that benefit both parents and children. (shrink)

The rapid development of CRISPR-based gene editing has been accompanied by a polarized governance debate about the status of CRISPR-edited crops as genetically modified organisms. This article argues that the polarization around the governance of gene editing partly reflects a failure of public engagement with the current state of research in genomics and postgenomics. CRISPR-based gene-editing technology has become embedded in a narrow narrative about the ease and precision of the technique that presents the gene as (...) a stable object under technological control. By tracing the considerably destabilized scientific understanding of the gene in genomics and postgenomics, this article highlights that this publicly mediated ontology strategically avoids positioning the “ease of CRISPR-based editing” in the wider context of the “complexity of the gene.” While this strategic narrowness of CRISPR narratives aims to create public support for gene-editing technologies, we argue that it stands in the way of socially desirable anticipatory governance and open public dialogue about societal promises and the unintended consequences of gene editing. In addressing the polarization surrounding CRISPR-based editing technology, the article emphasizes the need for engagement with the complex state of postgenomic science that avoids strategic simplifications of the scientific literature in promoting or opposing the commercial use of the gene-editing technology. (shrink)

The rapid development of CRISPR-based gene editing has been accompanied by a polarized governance debate about the status of CRISPR-edited crops as genetically modified organisms. This article argues that the polarization around the governance of gene editing partly reflects a failure of public engagement with the current state of research in genomics and postgenomics. CRISPR-based gene-editing technology has become embedded in a narrow narrative about the ease and precision of the technique that presents the gene as (...) a stable object under technological control. By tracing the considerably destabilized scientific understanding of the gene in genomics and postgenomics, this article highlights that this publicly mediated ontology strategically avoids positioning the “ease of CRISPR-based editing” in the wider context of the “complexity of the gene.” While this strategic narrowness of CRISPR narratives aims to create public support for gene-editing technologies, we argue that it stands in the way of socially desirable anticipatory governance and open public dialogue about societal promises and the unintended consequences of gene editing. In addressing the polarization surrounding CRISPR-based editing technology, the article emphasizes the need for engagement with the complex state of postgenomic science that avoids strategic simplifications of the scientific literature in promoting or opposing the commercial use of the gene-editing technology. (shrink)

Mutational robustness facilitates evolutionary innovations. Gene duplications are unique kinds of mutations, in that they generally increase such robustness. The frequent association of gene duplications in regulatory networks with evolutionary innovation is thus a special case of a general mechanism linking innovation to robustness. The potential power of this mechanism to promote evolutionary innovations on large time scales is illustrated here with several examples. These include the role of gene duplications in the vertebrate radiation, flowering plant evolution (...) and heart development, which encompass some of the most striking innovations in the evolution of life. BioEssays 30:367–373, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Comparative mapping and sequencing show that turnover of sex determining genes and chromosomes, and sex chromosome rearrangements, accompany speciation in many vertebrates. Here I review the evidence and propose that the evolution of therian mammals was precipitated by evolution of the male‐determining SRY gene, defining a novel XY sex chromosome pair, and interposing a reproductive barrier with the ancestral population of synapsid reptiles 190 million years ago (MYA). Divergence was reinforced by multiple translocations in monotreme sex chromosomes, the first (...) of which supplied a novel sex determining gene. A sex chromosome‐autosome fusion may have separated eutherians (placental mammals) from marsupials 160 MYA. Another burst of sex chromosome change and speciation is occurring in rodents, precipitated by the degradation of the Y. And although primates have a more stable Y chromosome, it may be just a matter of time before the same fate overtakes our own lineage. (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)

Terminology within the biological sciences gets its import not just from semantic meaning, but also from the way it functions within the rhetorics of the various disciplinary practices. The ‘sociobiology’ of human behavior inherits three distinct rhetorics from the genetic disciplines. Sociobiologists use population genetic, biometrical genetic, and molecular genetic rhetorics, without acknowledging the conceptual and experimental constraints that are assumed by geneticists. The eclectic blending of these three rhetorics obscures important differences of context and meaning. Sociobiologists use foundational terms (...) in genetics, such as ‘gene’, ‘fitness’, ‘evolution’, ‘heritability’, ‘trait’ and ‘polygenic inheritance’, in starkly different ways from geneticists, while basing their analysis of human behavior on the implied authority of genetics. As a free‐floating ‘gene talk’ moves across different disciplinary contexts, and before different audiences, it takes the form of an over‐simplified and misleading arch‐determinism. The result is widespread application of vague, incomplete, and distorted biological theory. If most sociobiologists, do not deliberately promote biological determinism, still less a political agenda, there is ample evidence that they misconstrue the implications of the genetic language that they borrow. (shrink)

BACKGROUND: Serotonin transporter promoter genotype appears to increase risk for depression in the context of stressful life events. However, the effects of this genotype on measures of stress sensitivity are poorly understood. Therefore, this study examined whether 5-HTTLPR genotype was associated with negative information processing biases in early childhood. METHOD: Thirty-nine unselected seven-year-old children completed a negative mood induction procedure and a Self-Referent Encoding Task designed to measure positive and negative schematic processing. Children were also genotyped for the 5-HTTLPR (...) class='Hi'>gene. RESULTS: Children who were homozygous for the short allele of the 5-HTTLPR gene showed greater negative schematic processing following a negative mood prime than those with other genotypes. 5-HTTLPR genotype was not significantly associated with positive schematic processing. LIMITATIONS: The sample size for this study was small. We did not analyze more recently reported variants of the 5-HTTLPR long alleles. CONCLUSIONS: 5-HTTLPR genotype is associated with negative information processing styles following a negative mood prime in a non-clinical sample of young children. Such cognitive styles are thought to be activated in response to stressful life events, leading to depressive symptoms; thus, cognitive styles may index the "stress-sensitivity" conferred by this genotype. (shrink)

The term functional domain is often used to describe the region containing the cis acting sequences that regulate a gene locus. “Strong” domain models propose that the domain is a spatially isolated entity consisting of a region of extended accessible chromatin bordered by insulators that have evolved to act as functional boundaries. However, the observation that independently regulated loci can overlap partially or completely raises questions about functional requirements for physically isolated domain structures. An alternative model, the “weak” domain (...) model, proposes that domain structure is determined by the distribution of binding sites for positively acting factors, without a requirement for functional boundaries. The domain would effectively be the region that contains these factor-binding sites. Specificity of promoter-enhancer interactions would play a major role in maintaining the functional autonomy of adjacent genes. Sequences that interfere with these interactions (frequently characterised as insulators) would be selected against if they occurred within the domain but not at the edges, or in the interdomain regions. As a result, insulators would often be found near the borders of domains without necessarily being selected to act as boundaries. BioEssays 22:657–665, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Numerous genes contain regulatory elements located many tens of kilobases away from the promoter they control. Specific mechanisms must be required to ensure that such distant elements can find and interact with their proper targets but not with extraneous genes. This review explores the connections between transvection phenomena, the activation of domains of homeotic gene expression, position effect variegation and silencers. These various examples of long‐distance effects suggest that, in all cases, related forms of chromatin packaging may be involved.

It is tempting to invoke organismal selection as perpetually optimizing the function of any given gene. However, natural selection can drive genic functional change without improvement of biochemical activity, even to the extinction of gene activity. Detrimental mutations can creep in owing to linkage with other selectively favored loci. Selection can promote functional degradation, irrespective of genetic drift, when adaptation occurs by loss of gene function. Even stabilizing selection on a trait can lead to divergence of the (...) underlying molecular constituents. Selfish genetic elements can also proliferate independent of any functional benefits to the host genome. Here we review the logic and evidence for these diverse processes acting in genome evolution. This collection of distinct evolutionary phenomena – while operating through easily understandable mechanisms – all contribute to the seemingly counterintuitive notion that maintenance or improvement of a gene's biochemical function sometimes do not determine its evolutionary fate. (shrink)

After yeast cells commit to the cell cycle in a process called START, genes required for DNA synthesis are expressed in late G1. Periodicity is mediated by a hexameric sequence, known as a MCB element, present in all DNA synthesis gene promoters. A complex that specifically binds MCBs has been identified. One polypeptide in the MCB complex is Swi6, a transcription factor that together with Swi4 also binds G1 cyclin promoters and participates in a positive feedback loop (...) at START. The finding that Swi6 is directly involved in both START and DNA synthesis gene control suggest a model in which Swi6, activated through its participation in START, serves as the central transcription factor in coordinating late G1 gene expression. The mechanism may be conserved in all eukaryotic cells. (shrink)

Approach–avoidance generally describes appetitive motivation and fear of punishment. In a social context approach motivation is, however, also expressed as social aggression and dominance. We therefore link approach–avoidance to dominance–submissiveness, and provide a neural framework that describes how the steroid hormone testosterone shifts reflexive as well as deliberate behaviors towards dominance and promotion of social status. Testosterone inhibits acute fear at the level of the basolateral amygdala and hypothalamus and promotes reactive dominance through upregulation of vasopressin gene expression in (...) the central-medial amygdala. Finally, the hormone can, depending on social context and prenatal hormone exposure, promote both pro- and antisocial behaviors and decisions through its effects on prefrontal–amygdala interactions. All these effects of testosterone, however, serve to increase and maintain social status. (shrink)

BackgroundGene drive technologies (GDTs) promote the rapid spread of a particular genetic element within a population of non-human organisms. Potential applications of GDTs include the control of insect vectors, invasive species and agricultural pests. Whether, and if so, under what conditions, GDTs should be deployed is hotly debated. Although broad stances in this debate have been described, the convictions that inform the moral views of the experts shaping these technologies and related policies have not been examined in depth in the (...) academic literature.MethodsIn this qualitative study, we interviewed GDT experts (n = 33) from different disciplines to identify and better understand their moral views regarding these technologies. The pseudonymized transcripts were analyzed thematically.ResultsThe respondents’ moral views were principally influenced by their attitudes towards (1) the uncertainty related to GDTs; (2) the alternatives to which they should be compared; and (3) the role humans should have in nature. Respondents agreed there is epistemic uncertainty related to GDTs, identified similar knowledge gaps, and stressed the importance of realistic expectations in discussions on GDTs. They disagreed about whether uncertainty provides a rationale to refrain from field trials (‘risks of intervention’ stance) or to proceed with phased testing to obtain more knowledge given the harms of the status quo (‘risks of non-intervention’ stance). With regards to alternatives to tackle vector-borne diseases, invasive species and agricultural pests, respondents disagreed about which alternatives should be considered (un)feasible and (in)sufficiently explored: conventional strategies (‘downstream solutions’ stance) or systematic changes to health care, political and agricultural systems (‘upstream solutions’ stance). Finally, respondents held different views on nature and whether the use of GDTs is compatible with humans’ role in nature (‘interference’ stance) or not (‘non-interference stance’).ConclusionsThis interview study helps to disentangle the debate on GDTs by providing a better understanding of the moral views of GDT experts. The obtained insights provide valuable stepping-stones for a constructive debate about underlying value conflicts and call attention to topics that deserve further (normative) reflection. Further evaluation of these issues can facilitate the debate on and responsible development of GDTs. (shrink)

Nerve processes elongate, branch and form synaptic contacts in a highly regulated and specific manner. Long‐distance axon elongation is restricted to the main phase of axon formation during development, but can be reinduced upon lesions in the adult (regeneration). It correlates with the expression of defined genes, including proteins involved in signalling (e.g. src, NCAM, integrins), transcription factors (e.g. c‐jun) and structural proteins (e.g. actin and tubulin isoforms). Activation of an axon elongation program may require bcl‐2. The formation and growth (...) of local branches (sprouting) is controlled by mechanisms in the target region. In addition, the expression of growth‐associated proteins such as GAP‐43 and CAP‐23 in neurons lowers the threshold for nerve sprouting and potentiates its vigour. Recent studies suggest that nerve sprouting and long‐distance elongation depend on the expression of different intrinsic components in neurons. One implication of these findings is that the differential expression of genes facilitating local branching may affect structural plasticity in the intact adult nervous system. (shrink)

: In the past five years, China has experienced increased efforts to regulate activities in biomedical research and practice. Background is provided on some of the key developments in Chinese bioethics especially in relation to genetics, stem cells, cloning, and reproductive medicine. This background sets the stage for a document entitled "Ethical Guidelines for Human Embryo Stem Cell Research," proposed by the Bioethics Committee of the Southern China National Human Gene Research Center, Shanghai, which is reprinted in this volume (...) of the Kennedy Institute of Ethics Journal. (shrink)

Transcription is a fundamental cellular process and the first step in gene regulation. Although RNA polymerase (RNAP) is highly processive, in growing cells the progression of transcription can be hindered by obstacles on the DNA template, such as damaged DNA. The authors recent findings highlight a trade‐off between transcription fidelity and DNA break repair. While a lot of work has focused on the interaction between transcription and nucleotide excision repair, less is known about how transcription influences the repair of (...) DNA breaks. The authors suggest that when the cell experiences stress from DNA breaks, the control of RNAP processivity affects the balance between preserving transcription integrity and DNA repair. Here, how the conflict between transcription and DNA double‐strand break (DSB) repair threatens the integrity of both RNA and DNA are discussed. In reviewing this field, the authors speculate on cellular paradigms where this equilibrium is well sustained, and instances where the maintenance of transcription fidelity is favored over genome stability. (shrink)

The metabolic requirements of differentiated neurons are significantly different from that of neuronal precursor and neural stem cells. While a re‐programming of metabolism is tightly coupled to the neuronal differentiation process, whether shifts in mitochondrial mass, glycolysis, and oxidative phosphorylation are required (or merely consequential) in differentiation is not yet certain. In addition to providing more energy, enhanced metabolism facilitates differentiation by supporting increased neurotransmitter signaling and underpinning epigenetic regulation of gene expression. Both epidemiological and animal studies demonstrate that (...) micronutrients (MNs) significantly influence many aspects of neonatal brain development, particularly neural migration and survival, neurite outgrowth, and process maturation. Here we review recent insights into the importance of metabolic reprogramming in neuronal differentiation, before considering evidence that micronutrient signaling may be key to regulating these processes. (shrink)

Horizontal gene transfer advances bacterial evolution. To benefit from horizontally acquired genes, enteric bacteria must overcome silencing caused when the widespread heat‐stable nucleoid structuring (H‐NS) protein binds to AT‐rich horizontally acquired genes. This ability had previously been ascribed to both anti‐silencing proteins outcompeting H‐NS for binding to AT‐rich DNA and RNA polymerase initiating transcription from alternative promoters. However, we now know that pathogenic Salmonella enterica serovar Typhimurium and commensal Escherichia coli break down H‐NS when this silencer is not (...) bound to DNA. Curiously, both species use the same protease – Lon – to destroy H‐NS in distinct environments. Anti‐silencing proteins promote the expression of horizontally acquired genes without binding to them by displacing H‐NS from AT‐rich DNA, thus leaving H‐NS susceptible to proteolysis and decreasing H‐NS amounts overall. Conserved amino acid sequences in the Lon protease and H‐NS cleavage site suggest that diverse bacteria degrade H‐NS to exploit horizontally acquired genes. (shrink)

The gene regulation function (GRF) provides an operational description of a promoter behavior as a function of the concentration of one of its transcriptional regulators. Behind this apparently trivial definition lies a central concept in biological control: the GRF provides the input/output relationship of each edge in a transcriptional network, independently from the molecular interactions involved. Here we discuss how existing methods allow direct measurement of the GRF, and how several trade‐offs between scalability and accuracy have hindered its application (...) to relatively large networks. We discuss the theoretical and technical requirements for obtaining the GRF. Based on these requirements, we introduce a simplified and easily scalable method that is able to capture the significant parameters of the GRF. The GRF is able to predict the behavior of a simple genetic circuit, illustrating how addressing the quantitative nature of gene regulation substantially increases our comprehension on the mechanisms of gene control. (shrink)

Horizontal gene transfer (HGT) is a major mechanism responsible for the spread of antibiotic resistance. Conversely, it is often assumed that antibiotics promote HGT. Careful dissection of the literature, however, suggests a lack of conclusive evidence supporting this notion in general. This is largely due to the lack of well‐defined quantitative experiments to address this question in an unambiguous manner. In this review, we discuss the extent to which HGT is responsible for the spread of antibiotic resistance and examine (...) what is known about the effect of antibiotics on the HGT dynamics. We focus on conjugation, which is the dominant mode of HGT responsible for spreading antibiotic resistance on the global scale. Our analysis reveals a need to design experiments to quantify HGT in such a way to facilitate rigorous data interpretation. Such measurements are critical for developing novel strategies to combat resistance spread through HGT. -/- . (shrink)

The fine‐structure analyses of the nopaline synthase (nos) promoter which is active constitutively in a wide range of plant tissues reveal that a portion of the upstream essential region for maximal transcription is a potential Z‐DNA‐forming element. Z‐DNA sequences are found in almost all plant‐promoter regions, suggesting that these structural elements may play important roles in plant gene expression.

One facet of the control of gene expression is long‐range promoter regulation by distant enhancers. It is an important component of the regulation of genes that control metazoan development and has been appreciated for some time but the molecular mechanisms underlying this regulation have remained poorly understood. A recent study by Cleard and colleagues1 reports the first in vivo evidence of chromatin looping and boundary element promoter interaction. Specifically, they studied the function of a boundary element within the cis‐regulatory (...) region of the Abdominal‐B (Abd‐B) gene of Drosophila melanogaster. BioEssays 29: 7–10, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

Epidemiological evidence supports a health‐promoting effect of the Mediterranean Diet (MedDiet), especially in the prevention of cardiovascular diseases. These cardiovascular benefits have been attributed to a number of components of the MedDiet such as monounsaturated fatty acids, antioxidant vitamins and phytochemicals. However, the underlying mechanisms remain unknown. Likewise, little is known about the genes that define inter‐individual variation in response to the MedDiet, although the TCF7L2 gene is emerging as an illustrative candidate for determining relative risk of cardiovascular events (...) in response to the MedDiet. Moreover, omics technologies are providing evidence supporting potential mechanisms, some of them implicating epigenetics (i.e. microRNAs, methylation), and certain data suggest that some traditional foods could contribute via microRNAs possibly acting as exogenous regulators of gene expression. Future research should aim at increasing and consolidating the nutrigenetic and nutrigenomic knowledge of the MedDiet in order to provide sound, personalized and optimized nutritional recommendations. (shrink)

OBJECTIVES: Early-emerging, temperamental differences in fear-related traits may be a heritable vulnerability factor for anxiety disorders. Previous research indicates that the serotonin transporter promoter region polymorphism is a candidate gene for such traits. METHODS: Associations between 5-HTTLPR genotype and indices of fearful child temperament, derived from maternal report and standardized laboratory observations, were examined in a community sample of 95 preschool-aged children. RESULTS: Children with one or more long alleles of the 5-HTTLPR gene were rated as significantly more (...) nervous during standardized laboratory tasks than children who were homozygous for the short alleles. Children homozygous for the short alleles were also rated as significantly shyer, by maternal report, than those with at least one copy of the long allele of the 5-HTTLPR gene. CONCLUSIONS: This study extends the literature linking the short alleles of the serotonin transporter promoter region polymorphism to fear and anxiety-related traits in early childhood and adulthood, and is one of very few studies to examine the molecular genetics of preschoolers' temperament using multiple measures of traits in a normative sample. (shrink)