The period of highest creativity of the Catholic novels of France, England, and America was that between the two extremes of past isolation and present confluence.

Camus is defined by many as an absurdist philosopher of revolt. The Plague, however, shows him working rigorously through a well-known division between ancient and modern ethics concerning the relation of reason, feeling and happiness. For Aristotle, the virtues are stable dispositions including affective and intellectual elements. For Kant, one’s particular feelings are either that from which we must abstract to judge moral worth, or are a constant hindrance to proper moral activity. Further, Kant claims “habit belongs to the physical (...) nature of the determination of the will,” which seems to imply habit cannot be a moral determination at all. A related disagreement regards virtue and happiness. Aristotle’s happiness is “an activity of the soul in accord with virtue.” For Kant and other moderns, happiness is an ideal of imagination, “a maximum of well-being in my present, and in every future, state,” all the elements of which “are without exception empirical.” Thus happiness seems more the constant counterweight to moral action than its fulfillment. Kant and Aristotle agree, however, in their judgment of many characters and actions, as is illustrated in The Plague. The novel provides realistic insights into a philosophical agreement between these supposed oppositions. In particular, I show how both philosophers would agree in their judgements concerning both the relative goodness and relative happiness of Joseph Grand and Raymond Rambert. The illustration of this agreement proves Camus is valorizing a traditional ethic. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Mimesis: Culture, Art, SocietyGene FendtMimesis: Culture, Art, Society, by Gunter Gebauer and Christoph Wulf; translated by Don Reneau; 400 pp. Berkeley: University of California Press, 1995, $45.00 cloth, $18.00 paper.The purpose of this book is to develop “a historical reconstruction of important phases in the development of mimesis” (p. 1) from a brief discussion of its pre-Platonic Greek significance through contemporary thinkers. It is, then, not strictly a (...) philosophical text, as are most of the texts and authors the book takes up. It is, however, a significant effort in the history of ideas, and as such it is shot through with traces of the traditional tropes, shaping power, ideology, and even social relations of that discipline, particularly as it is practiced in the venerable school of German scholarship. That is, the structure, tone, and argument of the book are shaped mimetically. This book’s problematic is, then, not simply historical, as Republic’s problem with the poets is not simply philosophical. Rather, both books partake of mimesis, even while each one aims to criticize or set forth the concept’s historical development.Let this stand as notice of a deep philosophical problem with the method of historical criticism. In fairness we should note that the authors are not unconscious of their difficulty here: “The fact that mimesis cannot be represented without the use of mimetic processes poses the fundamental problem of theory formation in reference to our object. What is the relation between the representational and the represented world? Is the representation of representation structurally equivalent to simple representation?” (p. 21). The authors hope to moot the power of those questions, if not the questions themselves, by attending “first of all to representations of mimesis found in texts best selected for that purpose and only afterward begin to offer considerations of a more generalizing nature” (p. 21). Their reasoning and choice of texts here is the traditional trope of the discipline: a mimema. Among other things, this methodos requires that the authors treat Girard as developing a “literary critical examination of [mimesis in] nineteenth and twentieth century novels” (p. 359n1) and a “new ordering of nineteenth century social relations” (p. 235), rather than, as he claims, a comprehensive anthropological thesis. At least, this method requires treating the former as essential, and the latter as less justifiable, for if Girard’s anthropological thesis about mimesis were justifiable a history of the idea of mimesis would be merely a heresiology. This problem can be restated mutatis mutandis for such thinkers as Plato and Augustine, whose theses—if they have theses—about mimesis are deeply anthropological.Two further questions arise early on and remain at the end. If, as the authors hold (and show), “the concept of mimesis necessarily loses its intellectual centrality with the rise of rational thought,” so much so that “the field of art, which comes to be regarded in the process as autonomous, undergoes a complete and fundamental restructuring” (p. 3), must we not begin to [End Page 199] suspect—as recent philosophers like Derrida attempt to show—that there is a dialectical relationship between the intentional, truth-functional relations of modern rational thought and the mimetic, unformalizable and “ambivalent” (pp. 2–3) processes of mimesis? Rather than conclude that “the question what is mimesis? is one which demonstratively leads to error” (p. 309), does it not begin to seem that intentional representation, as most visible in science, and mimetic assimilations, as most obviously effective in art, are together the necessary dialectical elements of culture, art and science? While it seems that the rise of rational scientific thought pushes mimesis to the social fringes of the arts, isn’t scientific activity and writing still just as much subject, and just as much a product, of the power of mimesis as art? Similarly art is just as bound as science to “probability” or “the convincing impossibility,” to recall Aristotle. This idea is not entirely foreign to the book; it appears subliminally as a plausible explication of the work of theorists like Benjamin and Adorno (pp. 267–93).The third difficulty is a question about selection. As in Auerbach’s renowned precursor, Wulf... (shrink)

The concept of “public participation” is currently one of great interest to researchers and policy makers. In response to a perceived need for greater public involvement in decision making and policy formation processes on the part of both policymakers and the general public, a variety of novel mechanisms have been developed, such as the consensus conference and citizens jury, to complement traditional mechanisms, such as the public meeting. However, the relative effectiveness of the various mechanisms is unclear, as efforts (...) at evaluation have been sparse. In this article, the authors describe an evaluation of a two-day “deliberative conference” on the topic of radiation dose assessment. The authors detail the evaluation framework that they adopt and describe the instruments that they have developed to determine the attainment of the evaluationcriteria stipulated in that framework. They then describe the participation exercise that they have evaluated. Finally, they apply the instruments to assess the effectiveness of the exercise, and discuss the results and their implications for the conduct of evaluations and the use of this particular participation mechanism. (shrink)

Patient portals are poised to transform health communication by empowering patients with rapid access to their own health data. The 21st Century Cures Act is a US federal law that, among other provisions, prevents health entities from engaging in practices that disrupt the exchange of electronic health information—a measure that may increase the usage of patient health portals. Caregiver access to patient portals, however, may lead to breaches in patient privacy and confidentiality if not managed properly through proxy accounts. We (...) present an ethical framework that guides policy and clinical workflow development for healthcare institutions to support the best use of patient portals. Caregivers are vital members of the care team and should be supported through novel forms of health information technology (IT). Patients, however, may not want all information to be shared with their proxies so healthcare institutions must support the development and use of separate proxy accounts as opposed to using the patient’s own account as well provide controls for limiting the scope of information displayed in the proxy accounts. Lastly, as socioeconomic barriers to adoption of health IT persist, healthcare providers must work to ensure multiple streams of patient communication, to prevent further propagating health inequities. (shrink)

Gene retrocopies are generated by reverse transcription and genomic integration of mRNA. As such, retrocopies present an important exception to the central dogma of molecular biology, and have substantially impacted the functional landscape of the metazoan genome. While an estimated 8,000–17,000 retrocopies exist in the human genome reference sequence, the extent of variation between individuals in terms of retrocopy content has remained largely unexplored. Three recent studies by Abyzov et al., Ewing et al. and Schrider et al. have exploited (...) 1,000 Genomes Project Consortium data, as well as other sources of whole‐genome sequencing data, to uncover novel gene retrocopies. Here, we compare the methods and results of these three studies, highlight the impact of retrocopies in human diversity and genome evolution, and speculate on the potential for somatic gene retrocopies to impact cancer etiology and genetic diversity among individual neurons in the mammalian brain. (shrink)

Co‐option of the eye developmental gene regulatory network may have led to the appearance of novel functional traits on the wings of flies and butterflies. The first trait is a recently described wing organ in a species of extinct midge resembling the outer layers of the midge's own compound eye. The second trait is red pigment patches on Heliconius butterfly wings connected to the expression of an eye selector gene, optix. These examples, as well as others, are (...) discussed regarding the type of empirical evidence and burden of proof that have been used to infer gene network co‐option underlying the origin of novel traits. A conceptual framework describing increasing confidence in inference of network co‐option is proposed. Novel research directions to facilitate inference of network co‐option are also highlighted, especially in cases where the pre‐existent and novel traits do not resemble each other. (shrink)

Co‐option of the eye developmental gene regulatory network may have led to the appearance of novel functional traits on the wings of flies and butterflies. The first trait is a recently described wing organ in a species of extinct midge resembling the outer layers of the midge's own compound eye. The second trait is red pigment patches on Heliconius butterfly wings connected to the expression of an eye selector gene, optix. These examples, as well as others, are (...) discussed regarding the type of empirical evidence and burden of proof that have been used to infer gene network co‐option underlying the origin of novel traits. A conceptual framework describing increasing confidence in inference of network co‐option is proposed. Novel research directions to facilitate inference of network co‐option are also highlighted, especially in cases where the pre‐existent and novel traits do not resemble each other. (shrink)

There are an increasing number of cell therapy approaches being studied and employed world‐wide. An emerging area in this field is the use of human pluripotent stem cell (hPSC) products for the treatment of injuries/diseases that cannot be effectively managed through current approaches. However, as with any cell therapy, vast numbers of functional and safe cells are required. Bioreactors provide an attractive avenue to generate clinically relevant cell numbers with decreased labour and decreased batch to batch variation. Yet, current methods (...) of performing quality control are not readily scalable to the cell densities produced during bioreactor scale‐up. One potential solution is the application of inducible/controllable suicide genes that can trigger cell death in unwanted cell types. These types of approaches have been demonstrated to increase the quality and safety of the resultant cell products. In this review, we will provide background on these approaches and how they could be used together with bioreactor technology to create effective bioprocesses for the generation of high quality and safe hPSCs for use in regenerative medicine approaches. (shrink)

The larval arms of echinoid plutei are used for locomotion and feeding. They are composed of internal calcite skeletal rods covered by an ectoderm layer bearing a ciliary band. Skeletogenesis includes an autonomous molecular differentiation program in primary mesenchyme cells (PMCs), initiated when PMCs leave the vegetal plate for the blastocoel, and a patterning of the differentiated skeletal units that requires molecular cues from the overlaying ectoderm. The arms represent a larval feature that arose in the echinoid lineage during the (...) Paleozoic and offers a subject for the study of gene co-option in the evolution of novel larval features. We isolated new molecular markers in two closely related but differently developing species, Heliocidaris tuberculata and Heliocidaris erythrogramma. We report the expression of a larval arm-associated ectoderm gene tetraspanin, as well as two new PMC markers, advillin and carbonic anhydrase. Tetraspanin localizes to the animal half of blastula stage H. tuberculata and then undergoes a restriction into the putative oral ectoderm and future location of the postoral arms, where it continues to be expressed at the leading edge of both the postoral and anterolateral arms. In H. erythrogramma, its expression initiates in the animal half of blastulae and expands over the entire ectoderm from gastrulation onward. Advillin and carbonic anhydrase are upregulated in the PMCs postgastrulation and localized to the leading edge of the growing larval arms of H. tuberculata but do not exhibit coordinated expression in H. erythrogramma larvae. The tight spatiotemporal regulation of these genes in H. tuberculata along with other ontogenetic and phylogenetic evidence suggest that pluteus arms are novel larval organs, distinguishable from the processes of skeletogenesis per se. The dissociation of expression control in H. erythrogramma suggest that coordinate gene expression in H. tuberculata evolved as part of the evolution of pluteus arms, and is not required for larval or adult development. (shrink)

Within academic circles, the “deficit” model of public understanding of science has been subject to increasing critical scrutiny by those who favor more constructivist approaches. These suggest that “the public” can articulate sophisticated ideas about the social and ethical implications of science regardless of their level of technical knowledge. The seminal studies following constructivist approaches have generally involved small-scale qualitative investigations, which have minimized the pre-framing of issues to a greater or lesser extent. This article describes the Gene Week (...) Project, sponsored by the Wellcome Trust, which attempted to extend this work to a large-scale consultation on genetics and health through the medium of a local daily newspaper. Readers were invited to respond to a set of open-ended questions that accompanied stimulus material published each day for five consecutive weekdays. The articles were written with the intention of extending the limited range of discourses around genetics and biotechnology that are usually presented by the popular media. Responses raised overarching issues about the place of emerging health technologies in society reminiscent of previous open-ended consultations in this field. The paper ends with a critical discussion about the potential of this method to contribute to the further development of open-ended public consultations. (shrink)

Amyloid-beta peptide plaque in the brain is the primary diagnostic criterion of Alzheimer's disease . The physiological role of Abeta are poorly understood. We have previously determined an Abeta interacting domain in the promoters of AD-associated genes . This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma cells treated with FITC conjugated (...) Abeta1-40 localized Abeta to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Abeta peptides and/or H2O2. Abeta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Abeta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. (shrink)

Novel regulatory elements that enabled expression of pre‐existing immune genes in reproductive tissues and novel immune genes with pregnancy‐specific roles in eutherians have shaped the evolution of mammalian pregnancy by facilitating the emergence of novel mechanisms for immune regulation over its course. Trade‐offs arising from conflicting fitness effects on reproduction and host defenses have further influenced the patterns of genetic variation of these genes. These three mechanisms (novel regulatory elements, novel immune genes, and trade‐offs) played (...) a pivotal role in refining the regulation of maternal immune systems during pregnancy in eutherians, likely facilitating the establishment of prolonged direct maternal–fetal contact in eutherians without causing immunological rejection of the genetically distinct fetus. (shrink)

A far-reaching and influential view in evolutionary biology claims that species are cohesive units held together by gene flow. Biologists have recognized empirical problems facing this view; after sharpening the expression of the view, we present novel conceptual problems for it. At the heart of these problems is a distinction between two importantly different concepts of cohesion, what we call integrative and response cohesion. Acknowledging the distinction problematizes both the explanandum of species cohesion and the explanans of (...) class='Hi'>gene flow that are central to the view we discuss. We conclude by tracing four broader implications for the study and conceptualization of species. (shrink)

The precautionary principle aims to influence decision‐making in contexts where some activity poses uncertain but potentially grave threats. This perfectly describes the controversy surrounding germline gene editing. This article considers whether the precautionary principle should influence how we weigh the risks and benefits of human germline interventions, focusing especially on the possible threats to the health of future generations. We distinguish between several existing forms of the precautionary principle, assess their plausibility and consider their implications for the ethics of (...) germline modification. We also offer a novel form of the precautionary principle: the sufficientarian precautionary principle. Some plausible versions of the precautionary principle recommend placing somewhat greater weight on avoiding threats to future generations than on achieving short‐term benefits. However, no plausible versions of the precautionary principle entail that we should outright reject the use germline gene editing in human reproduction and some, such as the sufficientarian version, might endorse its use. (shrink)

The use of socially learned information (culture) is central to human adaptations. We investigate the hypothesis that the process of cultural evolution has played an active, leading role in the evolution of genes. Culture normally evolves more rapidly than genes, creating novel environments that expose genes to new selective pressures. Many human genes that have been shown to be under recent or current selection are changing as a result of new environments created by cultural innovations. Some changed in response (...) to the development of agricultural subsistence systems in the Early and Middle Holocene. Alleles coding for adaptations to diets rich in plant starch (e.g., amylase copy number) and to epidemic diseases evolved as human populations expanded (e.g., sickle cell and G6PD defi- ciency alleles that provide protection against malaria). Large-scale scans using patterns of linkage disequilibrium to detect recent selection suggest that many more genes evolved in response to agriculture. Genetic change in response to the novel social environment of contemporary modern societies is also likely to be occurring. The functional effects of most of the alleles under selection during the last 10,000 years are currently unknown. Also unknown is the role of paleoenvironmental change in regulating the tempo of hominin evolution. Although the full extent of culture-driven gene-culture coevolution is thus far unknown for the deeper history of the human lineage, theory and some evidence suggest that such effects were profound. Genomic methods promise to have a major impact on our understanding of gene-culture coevolution over the span of hominin evolutionary history. (shrink)

Novel technological developments mean that gene editing – making deliberately targeted alterations in specific genes – is now a clinical reality. The inherited metabolic disorders, a group of clinically significant, monogenic disorders, provide a useful paradigm to explore some of the many ethical issues that arise from this technological capability. Fundamental questions about the significance of the genome, and of manipulating it by selection or editing, are reviewed, and a particular focus on the legislative process that has permitted (...) the development of mitochondrial donation techniques is considered. Ultimately, decisions about what we should do with gene editing must be determined by reference to other non-genomic texts that determine what it is to be human – rather than simply to undertake gene editing because it can be done. (shrink)

Ocular gene transfer clinical trials are raising hopes for blindness treatments and attracting media attention. News media provide an accessible health information source for patients and the public, but are often criticized for overemphasizing benefits and underplaying risks of novel biomedical interventions. Overly optimistic portrayals of unproven interventions may influence public and patient expectations; the latter may cause patients to downplay risks and over-emphasize benefits, with implications for informed consent for clinical trials. We analyze the news media communications (...) landscape about ocular gene transfer and make recommendations for improving communications between clinicians and potential trial participants in light of media coverage. (shrink)

The human major histocompatibility complex (MHC), on the short arm of chromosome 6, represents one of the most extensively characterised regions of the human genome. This ∼4 Mb segment of DNA contains genes encoding the polymorphic MHC class I and class II molecules which are involved in antigen presentation during an immune response. Recently the whole of the MHC has been cloned in cosmids and/or yeast artificial chromosomes (YACs) and large portions have been characterised for the presence of novel (...) genes. Many unrelated genes, both housekeeping and tissue specific, have been identified and the gene density in some regions is now approaching one gene every few kilobases. Some of the novel genes encode proteins involved in the intracellular processing and transport of antigens that are presented by MHC class I molecules. Others, however, have no obvious role in the immune response. The MHC is located in the chromosome band 6p21.3 which is a Giemsa (G)‐light band. The detection of such a large number of functional genes (at least 70) in this region is compatible with the idea that both housekeeping and tissue‐specific genes are localised predominantly in G‐light bands. (shrink)

Gene editing techniques, such as CRISPR, are being heralded as powerful new tools for delivering agricultural products and foods with a variety of beneficial traits quickly, easily, and cheaply. Proponents are concerned, however, about whether the public will accept the new technology and that excessive regulatory oversight could limit the technology’s potential. In this paper, we draw on the sociotechnical imaginaries literature to examine how proponents are imagining the potential benefits and risks of gene editing technologies within agriculture. (...) We derive our data from a content analysis of public comments submitted to the Food and Drug Administration’s 2017 docket titled “Genome Editing in New Plant Varieties Used for Food.” Our sample frame consists of 26 comments representing 30 agriculture and biotech companies, organizations, and trade associations. Our findings reveal three key sociotechnical imaginaries, including that gene editing technologies in agriculture: are not GMO but instead equivalent to traditional plant breeding; have the potential to usher in a new Green Revolution; and could facilitate the democratization of agricultural biotechnologies. We argue that forming and projecting these collective interpretations of the potential of gene editing technologies for crops and foods plays an important role in efforts by proponents to influence regulatory oversight, modes of governance, and build public acceptance. This research contributes to calls by science and technology studies scholars to investigate emergent concerns and imaginaries for novel technoscientific advances to help inform upstream models of public engagement and governance decisions. (shrink)

Polyphenic differences between individuals arise not through differences at the genome level but as a result of specific cues received during development. Polyphenisms often involve entire suites of characters, as shown dramatically by the polyphenic castes found in many social insect colonies. An understanding of the genetic architecture behind polyphenisms provides a novel means of studying the interplay between genomes, gene expression and phenotypes. Here we discuss polyphenisms and molecular genetic tools now available to unravel their developmental bases (...) in insects. We focus on several recent studies that have tracked gene-expression patterns during social insect caste determination. BioEssays 23:62–68, 2001. Published 2001 John Wiley & Sons, Inc. (shrink)

Polyphenic differences between individuals arise not through differences at the genome level but as a result of specific cues received during development. Polyphenisms often involve entire suites of characters, as shown dramatically by the polyphenic castes found in many social insect colonies. An understanding of the genetic architecture behind polyphenisms provides a novel means of studying the interplay between genomes, gene expression and phenotypes. Here we discuss polyphenisms and molecular genetic tools now available to unravel their developmental bases (...) in insects. We focus on several recent studies that have tracked gene‐expression patterns during social insect caste determination. BioEssays 23:62–68, 2001. Published 2001 John Wiley & Sons, Inc. (shrink)

While the definition of the ‘genotype’ has undergone dramatic changes in the transition from classical to molecular genetics, the definition of the ‘phenotype’ has remained for a long time within the classical framework. In addition, while the notion of the genotype has received significant attention from philosophers of biology, the notion of the phenotype has not. Recent developments in the technology of measuring gene-expression levels have made it possible to conceive of phenotypic traits in terms of levels of (...) class='Hi'>gene expression. We demonstrate that not only has this become possible but it has also become an actual practice. This suggests a significant change in our conception of the phenotype: as in the case of the ‘genotype’, phenotypes can now be conceived in quantitative and measurable terms on a comprehensive molecular level. We discuss in what sense gene expression profiles can be regarded as phenotypic traits and whether these traits are better described as a novel concept of phenotype or as an extension of the classical concept. We argue for an extension of the classical concept and call for an examination of the type of extension involved. (shrink)

We focus here on high-risk pediatric research with the prospect of direct benefit and point out some aspects that have raised significant debate. In particular, we call attention to disagreements related to two essential aspects of this type of research: (i) determining what constitutes a “prospect of direct benefit” in phase I trials that involve gene transfer technologies and (ii) assessing when in these trials the risk is justified by the anticipated benefit to the participant children. Although much of (...) our discussion is applicable to other types of high-risk pediatric trials, as an example of the dilemma this type of research poses we use pediatric trials that involve gene transfer technologies. We focus on clinical trials for late infantile neuronal ceroid lipofuscinosis (LINCL). Exploring the ethical implications of some of these disagreements might identify resources for determining how best to deal with the ethical concerns at stake in high-risk pediatric research. We thus offer some recommendations for responding to these concerns. (shrink)

Mendelian Inheritance in Man, a computerized catalogue of human genetic disorders authored and maintained by cardiologist and medical genetics pioneer Victor A. McKusick, played a major part in demarcating between a novel biomedical science and the eugenic projects of racial betterment which existed prior to its emergence. Nonetheless, it built upon prior efforts to systematize genetic knowledge tied to individuals and institutions invested in eugenics. By unpacking the process of digitizing a homespun cataloguing project and charting its development into (...) an online database, this article aims to illuminate how the institution-building efforts of one individual created an ‘information order’ for accessing genetic information that tacitly shaped the norms and priorities of the field toward the pursuit of specific genes associated with discernible genetic disorders. This was not by design, but rather arose through negotiation with the catalogue's users; it accommodated further changes as biomedical research displaced the Mendelian paradigm. While great effort was expended toward making sequence data available to investigators during the Human Genome Project, MIM was largely taken for granted as a ‘legacy system’, McKusick's own labour of love. Drawing on recent histories of biomedical data, the article suggests that the bibliographical work of curation and translation is a central feature of value production in the life sciences meriting attention in its own right. (shrink)

Serial analysis of gene expression (SAGE) is a powerful technique that can be used for global analysis of gene expression. Its chief advantage over other methods is that it does not require prior knowledge of the genes of interest and provides qualitative and quantitative data of potentially every transcribed sequence in a particular cell or tissue type. This is a technique of expression profiling, which permits simultaneous, comparative and quantitative analysis of gene‐specific, 9‐ to 13‐basepair sequences. These (...) short sequences, called SAGE tags, are linked together for efficient sequencing. The sequencing data are then analyzed to identify each gene expressed in the cell and the levels at which each gene is expressed. The main benefit of SAGE includes the digital output and the identification of novel genes. In this review, we present an outline of the method, various bioinformatics methods for data analysis and general applications of this important technology. BioEssays 26:916–922, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

A network of gene regulation organized in a hierarchical and combinatorial manner is crucially involved in the development of the neural network, and has to be considered one of the main substrates of genetic change in its evolution. Though qualitative features may emerge by way of the accumulation of rather unspecific quantitative changes, it is reasonable to assume that at least in some cases specific combinations of regulatory parts of the genome initiated new directions of evolution, leading to (...) class='Hi'>novel capabilities of the brain. These notions are applied, in this paper, to the evolution of the capability of cognition-based human empa­thy. It is suggested that it has evolved as a secondary effect of the evolution of strategic thought. Development of strategies depends on abstract representations of one’s own pos­sible future states in one’s own brain to allow assessment of their emotional desirability, but also on the representation and emotional evaluation of possible states of others, allowing anticipation of their behaviour. This is best achieved if representations of others are con­nected to one’s own emotional centres in a manner similar to self-representations. For this reason, the evolution of the human brain is assumed to have established representations with such linkages. No group selection is involved, because the quality of strategic thought affects the fitness of the individual. A secondary effect of this linkage is that both the actual states and the future perspectives of others elicit vicarious emotions, which may contribute to the motivations of altruistic behaviour. (shrink)

Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain‐of‐function mutations, in general, has been productive. However, (...) it has been a major challenge to use standard pharmacologic approaches to target loss‐of‐function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics. (shrink)

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

A novel algebraic structure of the genetic code is proposed. Here, the principal partitions of the genetic code table were obtained as equivalent classes of quotient spaces of the genetic code vector space over the Galois field of the four DNA bases. The new algebraic structure shows strong connections among algebraic relationships, codon assignment and physicochemical properties of amino acids. Moreover, a distance function defined between the codon binary representations in the vector space was demonstrated to have a linear (...) behavior respect to physical variables such as the mean of amino acids interaction energies in proteins. It was also noticed that the distance between wild type and mutant codons approach to smaller values in mutational variants of four genes, i.e., human phenylalanine hydroxylase, human β-globin, HIV-1 protease and HIV-1 reverse transcriptase. These results strongly suggest that deterministic rules must be involved in the genetic code origin. (shrink)

Histone variant exchange is a novel epigenetic regulator of cognition. We speculate that H2A.Z, a variant of canonical histone H2A, exerts unique effects on transcription during distinct stages of memory formation, ultimately acting to maintain memory of previous transcriptional states and poise genes for re‐activation. Hippocampus‐dependent memory formation is initiated by transient expression of memory‐related genes, which support the storage of recently acquired memories. Soon after, memories undergo systems consolidation, which transfers memories from the hippocampus to the cortex for (...) long‐term storage, and requires ongoing re‐activation of memory‐related genes. We speculate that learning‐induced H2A.Z eviction from nucleosomes initially contributes to stimulus‐induced transcriptional induction needed for the initial process of memory consolidation. During systems consolidation, we speculate that delayed incorporation of H2A.Z into nucleosomes of memory‐related genes in the cortex is needed to poise genes for rapid re‐activation, thus supporting the long‐term process of memory stabilization.Also watch the Video Abstract. (shrink)

CRISPR (clustered regularly interspaced short palindromic repeats) activation (CRISPRa) in bacteria is an attractive method for programmable gene activation. Recently, a eukaryote‐like, σ54‐dependent CRISPRa system has been reported. It exhibits high dynamic ranges and permits flexible target site selection. Here, an overview of the existing strategies of CRISPRa in bacteria is presented, and the characteristics and design principles of the CRISPRa system are introduced. Possible scenarios for applying the eukaryote‐like CRISPRa system is discussed with corresponding suggestions for performance optimization (...) and future functional expansion. The authors envision the new eukaryote‐like CRISPRa system enabling novel designs in multiplexed gene regulation and promoting research in the σ54‐dependent gene regulatory networks among a variety of biotechnology relevant or disease‐associated bacterial species. (shrink)

The presence of gene–environment statistical interaction and correlation in biological development has led both practitioners and philosophers of science to question the legitimacy of heritability estimates. The paper offers a novel approach to assess the impact of GxE and rGE on the way genetic and environmental causation can be partitioned. A probabilistic framework is developed, based on a quantitative genetic model that incorporates GxE and rGE, offering a rigorous way of interpreting heritability estimates. Specifically, given an estimate of (...) heritability and the variance components associated with estimates of GxE and rGE, I arrive at a probabilistic account of the relative effect of genes and environment. (shrink)

In the mouse, at least 16 genes regulate vesicle trafficking to specialized lysosome‐related organelles, including platelet dense granules and melanosomes. Fourteen of these genes have been identified by positional cloning. All 16 mouse mutants are models for the genetically heterogeneous human disease, Hermansky–Pudlak Syndrome (HPS). Five HPS genes encode known vesicle trafficking proteins. Nine genes are novel, are found only in higher eukaryotes and encode members of three protein complexes termed BLOCs (Biogenesis of Lysosome‐related Organelles Complexes). Mutations in murine (...) HPS genes, which encode protein co‐members of BLOCs, produce essentially identical phenotypes. In addition to their well‐known effects on pigmentation, platelet function and lysosome secretion, HPS genes control a wide range of physiological processes including immune recognition, neuronal functions and lung surfactant trafficking. Studies of the molecular functions of HPS proteins will reveal important details of vesicle trafficking and may lead to therapies for HPS. BioEssays 26:616–628, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

One of the central but yet unresolved problems in evolutionary biology concerns the origin of novel complex traits. One hypothesis is that complex traits derive from pre‐existing gene regulatory networks (GRNs) reused and modified to specify a novel trait somewhere else in the body. This simple explanation encounters problems when the novel trait that emerges in a body is in a region that is known to harbor a latent or repressed trait that has been silent for (...) millions of years. Is the novel trait merely a re‐emerged de‐repressed trait or a truly novel trait that emerged via a novel deployment of an old GRN? A couple of new studies sided on opposite sides of this question when investigating the origin of horns in dung beetles and helmets in treehoppers that develop in the first thoracic segment (T1) of their bodies, a segment known to harbor a pair of repressed/modified wings in close relatives. Here, I point to some key limitations of the experimental approaches used and highlight additional experiments that could be done in future to resolve the developmental origin of these and other traits. (shrink)

Significant associations have been found between specific human leukocyte antigen (HLA) alleles and organ transplant rejection, autoimmune disease development, and the response to infection. Traditional searches for disease associations have conventionally measured risk associated with the presence of individual HLA alleles. However, given the high level of HLA polymorphism, the pattern of amino acid variability, and the fact that most of the HLA variation occurs at functionally important sites, it may be that a combination of variable amino acid sites shared (...) by several alleles (shared epitopes) are better descriptors of the actual causative genetic variants. Here we describe a novel approach to genetic association analysis in which genes/proteins are broken down into smaller sequence features and then variant types defined for each feature, allowing for independent analysis of disease association with each sequence feature variant type. We have used this approach to analyze a cohort of systemic sclerosis patients and show that a sequence feature composed of specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk for systemic sclerosis. (shrink)

Graphical AbstractOn the Black Swans of conventional sex determination theory: There aren't many, but when an exception to the standard model of sex determination (evolutionary turnover of genes playing the role of “master sex determiner”) arises, it certainly screams out for an explanation. In this issue, a novel one is put forward. It now awaits testing, particularly at the population level.

CRISPR-Cas9 genome editing can and has altered human genomes, bringing bioethical debates about this capability to the forefront of philosophical and policy considerations. Here, I consider the underexplored implications of CRISPR-Cas9 gene drives for heritable human genome editing. Modification gene drives applied to heritable human genome editing would introduce a novel form of involuntary eugenic practice that I term guerrilla eugenics. Once introduced into a genome, stealth genetic editing by a gene drive genetic element would occur (...) each subsequent generation irrespective of whether reproductive partners consent to it and irrespective of whether the genetic change confers any benefit. By overriding the ability to ‘opt in’ to genome editing, gene drives compromise the autonomy of carrier individuals and their reproductive partners to choose to use or avoid genome editing and impose additional burdens on those who hope to ‘opt out’ of further genome editing. High incidence of an initially rare gene drive in small human communities could occur within 200 years, with evolutionary fixation globally in a timeframe that is thousands of times sooner than achievable by non-drive germline editing. Following any introduction of heritable gene drives into human genomes, practices intended for surveillance or reversal also create fundamental ethical problems. Current policy guidelines do not comment explicitly on gene drives in humans. These considerations motivate an explicit moratorium as being warranted on gene drive development in heritable human genome editing. (shrink)

Over the last decades, it has become evident that highly complex networks of regulators govern post‐transcriptional regulation of gene expression. A novel class of Argonaute (Ago)‐associated RNA molecules, the agotrons, was recently shown to function in a Drosha‐ and Dicer‐independent manner, hence bypassing the maturation steps required for canonical microRNA (miRNA) biogenesis. Agotrons are found in most mammals and associate with Ago as ∼100 nucleotide (nt) long RNA species. Here, we speculate on the functional and biological relevance of (...) agotrons: (i) agotrons could serve as non‐promiscuous miRNA‐like regulators with reduced off‐targeting or (ii) agotrons could encompass other putative functions, such as protecting Ago proteins from taking up aberrant short RNAs or by rescuing and stabilizing otherwise unloaded Ago‐proteins from degradation. Collectively, agotrons have emerged as a novel class of interesting non‐coding RNA molecules, but their full functional potential and biological impact still remain to be disclosed. (shrink)

Analysing cylindromatosis and the associated defects in the CYLD gene is providing novel insights into the molecular principles of epithelial growth control and carcinogenesis in, and beyond, the skin. In this review, we summarize the histopathology and histogenesis of cylindromas, and the available genetic information on patients with these skin appendage tumors. Focusing on recent data concerning the normal functions and signaling interactions of the CYLD gene product, we explain how CYLD interferes with TNF‐α or TLR‐mediated signaling (...) as well as with JNK or NF‐κB‐dependent p65/50 signaling to limit inflammation. In addition, we delineate how CYLD interferes with activation of the proto‐oncogene Bcl3 and with cyclin D1 expression to limit tumorigenesis, and chart how tumor growth‐promoting agents or UV light and inflammatory mediators can activate CYLD. We argue that these recent insights into CYLD function and cylindroma pathogenesis may lead to the development of novel molecular strategies for cancer prevention and treatment. BioEssays 29:1203–1214, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

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

ESTs or ‘expressed sequence tags’ are DNA sequences read from both ends of expressed gene fragments. The Merck‐WashU EST Project and several other public EST projects are being performed to rapidly discover the complement of human genes, and make them easily accessible. These ESTs are widely used to discover novel members of gene families, to map genes to chromosomes as ‘sequence‐tagged sites’ (STSs), and to identify mutations leading to heritable diseases. Informatic strategies for querying the EST databases (...) are discussed, as well as the strengths and weaknesses of the EST data. There is a compelling need to build on the informatic synthesis of human gene data, and to devise facile methods for determining gene functions. (shrink)

In the yeast Saccharomyces cerevisiae, the regulation of expression of many of the enzymes for amino acid biosynthesis involves an interlinked general control system. Molecular and genetic analyses of this system reveal an underlying set of hierarchical transcriptional controls and a novel translational regulatory mechanism for governing expression of a key activator gene.

In the big data era, sequencing technology has produced a large number of biological sequencing data. Different views of the cancer genome data provide sufficient complementary information to explore genetic activity. The identification of differentially expressed genes from multiview cancer gene data is of great importance in cancer diagnosis and treatment. In this paper, we propose a novel method for identifying differentially expressed genes based on tensor robust principal component analysis, which extends the matrix method to the processing (...) of multiway data. To identify differentially expressed genes, the plan is carried out as follows. First, multiview data containing cancer gene expression data from different sources are prepared. Second, the original tensor is decomposed into a sum of a low-rank tensor and a sparse tensor using TRPCA. Third, the differentially expressed genes are considered to be sparse perturbed signals and then identified based on the sparse tensor. Fourth, the differentially expressed genes are evaluated using Gene Ontology and Gene Cards tools. The validity of the TRPCA method was tested using two sets of multiview data. The experimental results showed that our method is superior to the representative methods in efficiency and accuracy aspects. (shrink)

The identity and the existence of genes has been challenged by postgenomic discoveries. Specifically, the consideration of molecular and cellular phenomena in which genes are embedded has proved relevant for their understanding. In response to these challenges, I will argue that the complexity of genetic phenomena supports the weak emergence of genes from the DNA. In Section 2, I will expose what genes are taken to be in the postgenomic world. In Section 3, I will present the relevant account of (...) emergence. I consider weak emergence as in Franklin and Knox, for which a phenomenon is emergent when it displays novelty and robustness. In Section 4, I will argue that genes are weakly emergent since they are novel, improving explanations, and robust in respect to some perturbations. Then, I will conclude in Section 5 that genes’ emergence is a way to allow genes’ flexibility and context dependency, without compromising their existence. (shrink)

New possibilities to modify function and direct repair in the central nervous system (CNS) have been established by the merger of gene transfer technology with neural transplantation. Rapid advances in viral‐mediated DNA‐delivery procedures permit the study of novel gene expression in neurons and glial cells. Foreign genes, transferred by a virus vector, can be used to generate new cell lines, identify transplanted cells, and express growth factors or enzymes for neurotransmitter synthesis. In addition to CNS cell types, (...) non‐neural cells are also being studied with transgene technology in the nervous system. Functional effects have been obtained with grafts of genetically modified cells in animal models of several nervous system disorders, and the recent results set the stage for potential application of these techniques to human CNS gene therapy. (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)

Genetic studies have revealed that the antagonistic interplay between PcG and TrxG/MLL complexes is essential for the proper maintenance of vertebrate Hox gene expression in time and space. Hox genes must be silenced in totipotent embryonic stem cells and, in contrast, rapidly activated during embryogenesis. Here we discuss some recently published articles1-4 that propose a novel mechanism for the induction of Hox gene transcription. These studies report a new family of histone demethylases that remove H3K27me3/me2 repressive marks (...) at Hox promoters during differentiation of stem cells. Though the overall importance of these enzymes for proper embryogenesis was demonstrated, their precise role in Hox gene epigenetic regulation during development still remains to be firmly established. BioEssays 30:199–202, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Recent work on the evolution of signaling systems provides a novel way of thinking about genetic information, where information is passed between genes in a regulatory network. I use examples from evolutionary developmental biology to show how information can be created in these networks and how it can be reused to produce rapid phenotypic change.

The present response elaborates and defends the main theses advanced in the target article: namely, that in order to provide an evolutionary account of brain lateralization, we should consider advantages and disadvantages associated both with the individual possession of an asymmetrical brain and with the alignment of the direction of lateralization at the population level. We explain why we believe that the hypothesis that directional lateralization evolved as an evolutionarily stable strategy may provide a better account than alternative hypotheses. We (...) also further our discussion of the influence of stimulation and experience in early life on lateralization, and thereby show that our hypothesis is not deterministic. We also consider some novel data and ideas in support of our main thesis. (shrink)