Recent results confirm that long‐term expression of therapeutic transgenes can be achieved by using a transposon‐based system in primary stem cells and in vivo. Transposable elements are natural DNA transfer vehicles that are capable of efficient genomic insertion. The latest generation, Sleeping Beauty transposon‐based hyperactive vector (SB100X), is able to address the basic problem of non‐viral approaches – that is, low efficiency of stable gene transfer. The combination of transposon‐based non‐viral gene transfer with the latest improvements of non‐viral delivery techniques (...) could provide a long‐term therapeutic effect without compromising biosafety. The new challenges of pre‐clinical research will focus on further refinement of the technology in large animal models and improving the safety profile of SB vectors by target‐selected transgene integration into genomic “safe harbors.” The first clinical application of the SB system will help to validate the safety of this approach. (shrink)

Peter Abelard (1079–1142 ce) was the most wide‐ranging philosopher of the twelfth century. He quickly established himself as a leading teacher of logic in and near Paris shortly after 1100. After his affair with Heloise, and his subsequent castration, Abelard became a monk, but he returned to teaching in the Paris schools until 1140, when his work was condemned by a Church Council at Sens. His logical writings were based around discussion of the “Old Logic”: Porphyry's Isagoge, aristotle'S Categories and (...) On Interpretation and boethius'S textbook on topical inference. They comprise a freestanding Dialectica (“Logic”; probably c.1116), a set of commentaries (known as the Logica [Ingredientibus], c. 1119) and a later (c. 1125) commentary on the Isagoge (Logica Nostrorum Petititoni Sociorum or Glossulae). In a work Abelard called his Theologia, issued in three main versions (between 1120 and c.1134), he attempted a logical analysis of trinitarian relations and explored the philosophical problems surrounding God's claims to omnipotence and omniscience. The Collationes (“Debates,” also known as “Dialogue between a Christian, a Philosopher and a Jew”; probably c.1130) present a rational investigation into the nature of the highest good, in which the Christian and the Philosopher (who seems to be modeled on a philosopher of pagan antiquity) are remarkably in agreement. The unfinished Scito teipsum (“Know thyself,” also known as the “Ethics”; c.1138) analyses moral action. (shrink)

Descartes' place in history, by L. J. Lafleur.--A central ambiguity in Descartes, by S. Rosen.--Doubt, common sense and affirmation in Descartes and Hume, by H. J. Allen.--Some remarks on logic and the cogito, by R. N. Beck.--The cogito, an ambiguous performance, by J. B. Wilbur.--The modalities of Descartes' proofs for the existence of God, by B. Magnus.--Descartes and the phenomenological problem of the embodiment of consciousness, by J. M. Edie.--The person and his body: critique of existentialist responses to Descartes, by (...) P. A. Bertocci. (shrink)

Burning fossil fuel in the North American continent contributes more to the CO2 global warming problem than in any other continent. The resulting climate changes are expected to alter food production. The overall changes in temperature, moisture, carbon dioxide, insect pests, plant pathogens, and weeds associated with global warming are projected to reduce food production in North America. However, in Africa, the projected slight rise in rainfall is encouraging, especially since Africa already suffers from severe shortages of rainfall. For all (...) regions, a reduction in fossil fuel burning is vital. Adoption of sound ecological resource management, especially soil and water conservation and the prevention of deforestation, is important. Together, these steps will benefit agriculture, the environment, farmers, and society as a whole. (shrink)

This book is a collection of secondary essays on America's most important philosophic thinkers—statesmen, judges, writers, educators, and activists—from the colonial period to the present. Each essay is a comprehensive introduction to the thought of a noted American on the fundamental meaning of the American regime.

The US neutrino community gathered at the Workshop on the Intermediate Neutrino Program at Brookhaven National Laboratory February 4-6, 2015 to explore opportunities in neutrino physics over the next five to ten years. Scientists from particle, astroparticle and nuclear physics participated in the workshop. The workshop examined promising opportunities for neutrino physics in the intermediate term, including possible new small to mid-scale experiments, US contributions to large experiments, upgrades to existing experiments, R&D plans and theory. The workshop was organized into (...) two sets of parallel working group sessions, divided by physics topics and technology. Physics working groups covered topics on Sterile Neutrinos, Neutrino Mixing, Neutrino Interactions, Neutrino Properties and Astrophysical Neutrinos. Technology sessions were organized into Theory, Short-Baseline Accelerator Neutrinos, Reactor Neutrinos, Detector R&D and Source, Cyclotron and Meson Decay at Rest sessions.This report summarizes discussion and conclusions from the workshop. (shrink)

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls. Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents. Probands were more likely to carry an additional large copy-number variant when compared to matched controls. The clinical (...) features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease. © 2010 Nature America, Inc. All rights reserved. (shrink)

This paper presents an axiomatic characterization of the Owen set of transportation games. In the characterization we use six properties including consistency (CONS2) and splitting and merging (SM) which are firstly proposed and defined for this setup in the present paper.

© 2015, Springer-Verlag Berlin Heidelberg.Genetic studies have identified single nucleotide polymorphisms associated with the risk of prostate cancer. It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score and aggressiveness. Statistical analyses were used to compare the frequency (...) of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 was significantly and inversely associated with aggressive and high-grade disease in European men. Similar associations with aggressive and high-grade disease were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness. (shrink)

Background If trials of therapeutic interventions are to serve society's interests, they must be of high methodological quality and must satisfy moral commitments to human subjects. The authors set out to develop a clinical - trials compendium in which standards for the ethical treatment of human subjects are integrated with standards for research methods. Methods The authors rank-ordered the world's nations and chose the 31 with >700 active trials as of 24 July 2008. Governmental and other authoritative entities of the (...) 31 countries were searched, and 1004 English-language documents containing ethical and/or methodological standards for clinical trials were identified. The authors extracted standards from 144 of those: 50 designated as ‘core’, 39 addressing trials of invasive procedures and a 5% sample of the remainder. As the integrating framework for the standards we developed a coherent taxonomy encompassing all elements of a trial's stages. Findings Review of the 144 documents yielded nearly 15 000 discrete standards. After duplicates were removed, 5903 substantive standards remained, distributed in the taxonomy as follows: initiation, 1401 standards, 8 divisions; design, 1869 standards, 16 divisions; conduct, 1473 standards, 8 divisions; analysing and reporting results, 997 standards, four divisions; and post-trial standards, 168 standards, 5 divisions. Conclusions The overwhelming number of source documents and standards uncovered in this study was not anticipated beforehand and confirms the extraordinary complexity of the clinical trials enterprise. This taxonomy of multinational ethical and methodological standards may help trialists and overseers improve the quality of clinical trials, particularly given the globalisation of clinical research. (shrink)

Mitochondrial function is achieved through the cooperative interaction of two genomes: one nuclear (nuDNA) and the other mitochondrial (mtDNA). The unusual transmission of mtDNA, predominantly maternal without recombination is predicted to affect the fitness of male offspring. Recent research suggests the strong sexual dimorphism in aging is one such fitness consequence. The uniparental inheritance of mtDNA results in a selection asymmetry; mutations that affect only males will not respond to natural selection, imposing a male‐specific mitochondrial mutation load. Prior work has (...) implicated this male‐specific mutation load in disease and infertility, but new data from fruit flies suggests a prominent role for mtDNA in aging; across many taxa males almost invariably live shorter lives than females. Here we discuss this new work and identify some areas of future research that might now be encouraged to explore what may be the underpinning cause of the strong sexual dimorphism in aging.Editor's suggested further reading in BioEssays: Mitonuclear match: Optimizing fitness and fertility over generations drives ageing within generations AbstractMitochondrial manoeuvres: Latest insights and hypotheses on mitochondrial partitioning during mitosis in Saccharomyces cerevisiae AbstractMitochondria and the culture of the Borg Abstract. (shrink)

The development of gene expression profiling and next-generation sequencing technologies have steered oncogenomics to the forefront of precision medicine. This created a need for harmonious cooperation between clinicians and researchers to increase access to precision oncology, despite multiple implementation challenges being encountered. The aim is to apply personalised treatment strategies early in cancer management, targeting tumour subtypes and actionable gene variants within the individual’s broader clinical risk profile and wellbeing. A knowledge-generating database linked to the South African Medical Research Council’s (...) Genomic Centre has been created for the application of personalised medicine, using an integrated service and research approach. Insights gained from patient experiences related to tumour heterogeneity, access to targeted therapies and incidental findings of pathogenic germline variants in tumour DNA, provided practice-changing evidence for the implementation of a cost-minimisation pathology-supported genetic testing strategy. Integrating clinical care with genomic research through data sharing advances personalised medicine and maximises precision oncology benefits. (shrink)

Ample research links mothers’ postpartum depression (PPD) to adverse interactions with their infants. However, most studies relied on general population samples, whereas a substantial number of women are at elevated depression risk. The purpose of this study was to describe mothers’ interactions with their 6- and 12-month-old infants among women at elevated risk, although with a range of symptom severity. We also identified higher-order factors that best characterized the interactions and tested longitudinal consistency of these factors from 6 to 12 (...) months of infant age. We leveraged data from eight projects across the United States (n = 647), using standardized depression measures and an adaptation of the NICHD Mother-Infant Interaction Scales. Overall, these depression-vulnerable mothers showed high levels of sensitivity and positive regard and low levels of intrusiveness, detachment, and negative regard with their infants. Factor analyses of maternal behaviors identified two overarching factors—“positive engagement” and “negative intrusiveness” that were comparable at 6 and 12 months of infant age. Mothers’ ability to regulate depressed mood was a key behavior that defined “positive engagement” in factor loadings. An exceptionally strong loading of intrusiveness on the second factor suggested its central importance for women at elevated depression risk. Mothers with severe depressive symptoms had significantly more “negative intrusiveness” and less “positive engagement” with their 6-month-old infants than women with moderate or fewer depressive symptoms, suggesting a potential tipping point at which symptoms may interfere with the quality of care. Results provide the foundation for further research into predictors and moderators of women’s interactions with their infant among women at elevated risk for PPD. They also indicate a need for evidence-based interventions that can support more severely depressed women in providing optimal care. (shrink)

Letting is a common practice in mathematics. For example, we let x be the sum of the first n integers and, after a short proof, conclude that x = n(n+1)/2; we let J be the point where the bisectors of two of the angles of a triangle intersect and prove that this coincides with H, the point at which another pair of bisectors of the angles of that triangle intersect. Karl Weierstrass's colleagues, in an attempt to solve optimization problems, stipulated (...) that the minimum area for a triangle with a given perimeter be a straight line segment conceived as a triangle with zero altitude. (Weierstrass complained that this obscured the insight that some problems have no solutions.) In mathematics applied to physics, we let x be the temperature in Fahrenheit corresponding to 30° Centigrade; we let v be the velocity of the Earth through the luminiferous ether. Before the error was spotted, the official rules for Little League Baseball made an inconsistent stipulation about the dimensions of home plate (Bradley 1996). (shrink)

Kin relations have a strong theoretical and empirical basis for explaining cooperative behavior. Nevertheless, there is growing recognition that context—the cooperative environment of an individual—also shapes the willingness of individuals to cooperate. For nomadic pastoralists in Norway, cooperation among both kin and non-kin is an essential predictor for success. The northern parts of the country are characterized by a history of herder-herder competition exacerbating between-herder conflict, lack of trust, and subsequent coordination problems. In contrast, because of a history of herder-farmer (...) competition, southern Norway is characterized by high levels of between-herder coordination and trust. This comparative study investigates the relative importance of “cooperative context” and kinship in structuring cooperative behavior using an experimental gift game. The main findings from this study were that in the South, a high level of cooperation around an individual pushes gifts to be distributed evenly among other herders. Nevertheless, kinship matters, since close kin give and receive larger gifts. In contrast, kinship seems to be the main factor affecting gift distribution in the North. Herders in the North are also concerned with distributing gifts equally, albeit limiting them to close kin: the level of intragroup cooperation drives gifts to be distributed evenly among other closely related herders. The observed regional contrasts in cooperative decisions fit with the different historical levels of conflict and trust in the two regions: whereas herders in the South are affected by both cooperative context and kinship, kinship seems to be the main determinant of cooperation in the North. (shrink)

Les inscriptions présentées dans cet article proviennent du second théâtre de Larissa qui a été construit au ier s. av. J.‑C. avec des blocs de remploi provenant d’un bâtiment arrondi, appartenant à un sanctuaire. Certains de ces blocs portent des dédicaces faites par des affranchis à une divinité qui n’est jamais nommée ; la nature de l’objet consacré n’est jamais précisée (peut‑être s’agit‑il de la pierre elle‑même?). Ces inscriptions, qui datent de la fin du iiie s.-début du iie s. av. (...) J.‑C, sont toutes en dialecte thessalien. Les noms des affranchis sont généralement accompagnés d’un adjectif patronymique, toujours différent du nom de leur manumissor, dont on ne peut dire s’il correspond au nom de leur père ou à celui de leur ancien maître. Certains des affranchissements mentionnés dans ces dédicaces apparaissent comme consécutifs à un héritage et il se pourrait que ce soit le cas de l’ensemble de ces inscriptions. Ces dédicaces constituent vraisemblablement une première forme de la taxe d’affranchissement. (shrink)

La présente contribution propose une étude de la périphérie gauche au sein d’un corpus oral multigenres, représentant douze activités de communication orale, annoté syntaxiquement et prosodiquement. La segmentation discursive du corpus en unités de base du discours (BDU) résulte d’une coïncidence entre unités syntaxiques et prosodiques, correspondant à des encodages linguistiques distincts mais complémentaires. Partant du postulat selon lequel ces unités discursives remplissent une fonction cognitive dans la planification et l’interprétation du discours, nous nous intéressons à l’étude de leur périphérie (...) gauche. Ce lieu, qui constitue le point d’ancrage du message, joue en effet un rôle important dans la négociation de la structure discursive. Dans l’objectif d’étudier les stratégies discursives à l’œuvre dans les différents genres du corpus, nous faisons l’inventaire des types formels observés et étudions finalement les fonctions discursives que ces éléments périphériques peuvent revêtir. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Decolonizing MemoryLaurence J. Kirmayer*, MD (bio)In this far-reaching essay, Emily Walsh explores the significance of memory for coming to grips with the enduring legacy of colonialism in psychiatry. She argues that "for reasons of self-preservation, racialized individuals should reject collective memories underwritten by colonialism." Psychiatry can enable this process or collude with the structures of domination to silence and disable those who bear the brunt of the colonialist history (...) of violence and its current global incarnations. In this brief commentary, I want to underscore the importance of Walsh's argument, link it to contemporary work in cognitive and social science on the dynamics of memory, and point to some resources for implementing these insights in health services and clinical practice.Memory as Psychological Process, Social Practice and Cultural InstitutionMemory is not simply an individual psychological process of accessing images, stories, and knowledge of the past, but a reconstructive process of building a narrative (Kirmayer, 1996). This narrative is profoundly shaped by available templates, metaphors and models that are provided by the tacit, normative and official histories of society (Hirst, Yamashiro & Coman, 2018). But memory is also shaped by cultural affordances that guide attention and by narrative practices, which depend on other people (Ramstead, Veissière, & Kirmayer, 2017). In effect, remembering is not a matter of reaching down into one's memory archive or sedimented experience, but an embodied and enactive process of thinking with and through others (Laanes & Meretoja, 2021; Veissière, Constant, Ramstead, Friston, & Kirmayer, 2020). Memory then depends on community and on a shared understanding of history and of possible futures through which one can anchor and elaborate one's individual story.A direct consequence is that disconnecting a person from others, disembedding them from their social milieu, will lead to disruptions in memory and in the continuity of self. When the environment is toxic, this severance may sometimes be (partly) beneficial—but it always comes at a cost. Figuring out those costs, making them explicit, and ensuring that those whose history is being suppressed or overwritten by others have a chance to reclaim and write their own, is an ethical and pragmatic imperative.The denial of vital memories (recent or remote, personal or collective) causes fractures in the self that may disorganize the individual, install false consciousness, and cement the exclusionary and disvalued position of colonized, racialized, and [End Page 243] marginalized subjects. This process is not only—or even primarily—about memory. It is part of the structure of everyday life, inscribed in institutions and practices where colonial histories, racism, and economic exploitation are deeply entangled. Representations of the past are part of the way we construe the present and anticipate the future—but not every interpretive frame is a memory; there are structures in and of the moment that condition how we think about ourselves in health and illness and these too convey interests and biases disguised as "just the way things are."Fanon's Politics of Postcolonial Memory and IdentityWalsh offers a reading of aspects of Fanon's philosophy to reveal the workings of colonialism in and through memory. She is concerned with specific subsets of collective memories that are affectively charged and related to the identity of a group (Wertsch & Roediger, 2008). These memories are collective not simply they are shared by or distributed among the members of a group but because they define or constitute the collective itself.History is written largely by the powerful who create dominant or 'master' narratives that serve their own projects of legitimation and self-mystification (Trouillot, 2015; Lindqvist, 2021). But the creation of dominant narratives is not solely the province of those in power. There are many kinds of self-serving collective memory (Baumeister & Hastings, 2013)—from those related to the creation of nation states, which may ignore not only colonized peoples, but all ethnicities, religions or linguistic groups subordinated to the ideals of the dominant group (Anderson, 2006; Gunew, 2013; van Alphen & Carretero, 2015), to other forms of collective identity, even to those created by liberatory movements. These are maintained by institutionalization, ceremonial repetition and reenactment... (shrink)

All recent memory theories of hippocampal function have incorporated the idea that the hippocampus is required to process items only of some qualitatively specifiahle kind, and is not required to process items of some complementary set. In contrast, it is now proposed that the hippocampus is needed to process stimuli of all kinds, but only when there is a need to associate those stimuli with other events that are temporally discontiguous. In order to form or use temporally discontiguous associations, it (...) is essential to maintain some memory of the first component until the second component has occurred. When the temporal gap to he spanned is small, and the number of items to be temporarily retained is low, a limited-capacity, short-term store is sufficient to allow associations to be formed. Such a store is presumed to operate in parallel with the hippocampus in normal animals. Hippocampal damage disrupts a much higher-capacity store that has a slower decay rate, and so leaves animals with only a very limited ability to form temporally discontiguous associations. Hippocampal damage, however, is not held to affect the long-term storage of associations of any kind, if they can be formed. Analyses of both new and existing data are presented to show that by classifying tasks in terms of the need to use a temporary memory store to retain temporally discontiguous information one can cut right across existing classifications as well as achieve a better fit to the data. The hippocampus thus seems best described as a high-capacity, intermediate-term memory store. (shrink)

This book collects some of the most exciting pioneering work in perceptual and cognitive psychology. The authors' quantitative approach to the study of mental images and their representation is clearly depicted in this invaluable volume of research which presents, interprets, evaluates, and extends their work. The selections are preceded by a thorough review of the history of their experiments, and all of the articles have been updated with reviews of the current literature. The book's first part focuses on mental rotation; (...) the second includes other, more complex transformations and sequences of transformations. A third part describes work on rotational transformations in the context of the perceptual illusion of &"apparent motion.&" Roger N. Shepard is Professor of Psychology, Stanford University. Lynn A. Cooper is Professor of Psychology, University of Arizona. A Bradford Book. (shrink)

Mohanty, J.N. Understanding Husserl's transcendental phenomenology.--Fink, E. The problem of the phenomenology of Edmund Husserl. Operative concepts in Husserl's phenomenology.--Funke, G. A transcendental-phenomenological investigation concerning universal idealism, intentional analysis, and the genesis of habitus: archē, phansis, hexis, logos.--Pentzopoulou-Valalas, T. Reflections on the foundation of the relation between the a priori and the eidos in the phenomenology of Husserl.--Landgrebe, L. Regions of being and regional ontologies in Husserl's phenomenology. The problem posed by the transcendental science of the a priori of the (...) life world.--Wahl, J. Notes on the first part of Experience and judgment by Husserl.--Landgrebe, L. A letter from Ludwig Landgrebe to Jean Wahl.-- Wahl, J. A note on some empiricist aspects of the thought of Husserl.--Toulemont, R. The specific character of the social according to Husserl. (shrink)

Speculations of this last type have existed from a much earlier period in the Eastern civilizations, particularly in those areas affected by Hindu philosophy. For example, in the Sánkhya or Yoga-Sútras by Patánjali, we find a very radical distinction between the external world and the individual soul or self. But for Sánkhya, the "external world" includes everything that could possibly be an object of consciousness--physical objects and their relationships, sensations and imaginations, dreams, memories, expectations, etc. In other words, for Sánkhya, (...) our thoughts or desires, far from being the "cause" of the external world as in some forms of Western idealism, are simply other aspects of the external world itself, that is, merely particular items in the totality of our consciousness. On the other hand, the individual soul or self is only the spectator of this consciousness and not ordinarily conscious of itself. If the self were to become conscious of "itself" in the same way that it was conscious of all other objects, all that it would really be aware of would be another object of consciousness---the mere idea of itself, while it would remain the unknown knower. Nevertheless, realizing that a completely "unconscious self" would be simply a postulate of thought and therefore part of the external world, the Sánkhya-Sútras emphasize that the self can become aware of itself by another and more intuitive means. (shrink)

Psychopathology can render people strange and difficult to understand. Communication can lead to empathic understanding, which in turn can guide compassionate action. But communication depends on a shared conceptual world. How can language convey meanings that are not shared, that mark a divide between human beings or whole communities? A consideration of the poetics of Paul Celan sheds light on the power of language to bridge disparate worlds and on the ethical stance needed when empathy fails. Celan’s poetics of alterity (...) has implications for our efforts to understand individuals’ illness experience as a grounding for the ethics of the clinical encounter. (shrink)

In a provocative essay, Sarah Kamens recommends the literature of postcolonial theory as a remedy for some of the limitations of current psychiatric theory and practice. Her provocation lies not advocating engagement with this literature, which certainly has much to offer psychiatry, but in the way she chooses to energize her argument by contrasting two very different phenomena: the experience of hearing voices and the use of ghost-writing in the psychiatric literature. Although Ka-mens acknowledges these phenomena come from “distant teleological (...) and experiential realms,” in both cases, she suggests, there are hidden authors who may be experienced or understood as hauntings. In this brief commentary, I will... (shrink)