Epigenetic and transcriptional variability contribute to the vast diversity of cellular and organismal phenotypes and are key in human health and disease. In this review, we describe different types, sources, and determinants of epigenetic and transcriptional variability, enabling cells and organisms to adapt and evolve to a changing environment. We highlight the latest research and hypotheses on how chromatin structure and the epigenome influence gene expression variability. Further, we provide an overview of challenges in the analysis of biological variability. An (...) improved understanding of the molecular mechanisms underlying epigenetic and transcriptional variability, at both the intra- and inter-individual level, provides great opportunity for disease prevention, better therapeutic approaches, and personalized medicine. Epigenetic and transcriptional variability mediate phenotypic plasticity, enabling adaptation to changing environments. In this review, we describe the sources of inter- and intra-individual variability and discuss epigenetic regulators of gene expression variability, including DNA methylation and chromatin structure. Understanding these molecular mechanisms will improve therapeutic approaches and personalized medicine. (shrink)

In cancer research, the term epigenetics was used in the 1970s in its modern sense encompassing non‐genetic events modifying the chromatin state, mainly to oppose the emerging oncogene paradigm. However, starting from the establishment of this prominent concept, the importance of these epigenetic phenomena in cancer rarely led to questioning the causal role of genetic alterations. Only in the last 10 years, the accumulation of problematic data, better experimental technologies, and some ambitious models pushed the idea that epigenetics could be (...) at least as important as genetics in early oncogenesis. Until this year, a direct demonstration of epigenetic oncogenesis was still lacking. Now, Parreno, Cavalli and colleagues, using a refined experimental model in the fruit fly Drosophila melanogaster, enforced the initiation of tumors solely by imposing a transient loss of Polycomb repression, leading to a purely epigenetic oncogenesis phenomenon. Despite a few caveats that we discuss, this pioneering work represents a major breakpoint in cancer research. We are led to consider the theoretical and conceptual implications on oncogenesis and to search for links between this artificial experimental model and naturally occurring processes, while revisiting cancer theories that were previously proposed as alternatives to the oncogene‐centered paradigm. (shrink)

ABSTRACT Generality relativism is the view that any domain of quantification can always be expanded. The view promises to resolve a broad range of paradoxes, but, without an explanation of how domains expand, it sounds very mysterious. Proponents of linguistic versions of generality relativism try to demystify the view by likening domain expansions to semantic change. They think that domains expand when we re-interpret certain terms so that, upon re-interpretation, the quantifiers range over more things. This article makes trouble for (...) linguistic approaches. According to the so-called charge of ineffability, generality relativism cannot be asserted in a coherent manner—given that asserting the view requires generalising over absolutely all domains of quantification. Generality relativists typically try to answer the charge with the help of modal operators; but linguistic approaches interpret these operators in semantically and syntactically idiosyncratic ways. I argue that, because of these commitments, linguistic approaches ultimately do not have a good response to the charge of ineffability. (shrink)

This essay traces the changing relationship between horticulture, agriculture, and philosophy across the seventeenth century, as the personae of the philosophical husbandman and the philosophical gardener intertwined and competed. At stake in the dynamics between them was the relationship between abstruse researches and practical applications in evolving experimental philosophy, as well as the aesthetic of experimental practices and rhetoric. Early seventeenth-century promoters of colonial projects, such as Virginian sericulture, situated the metropolitan pleasure garden, a place of whimsy and fantastical reasoning, (...) as a realm of trial that presumed eventual utility and application to large-scale husbandry. Such views informed relationships between fanciful trials, speculative proposals, and presumptions of future utility in the development of the persona of the philosophical gardener and attendant notions of experimental philosophy over the course of the century. (shrink)

We study higher analogues of the classical independence number on $\omega $. For $\kappa $ regular uncountable, we denote by $i(\kappa )$ the minimal size of a maximal $\kappa $ -independent family. We establish ZFC relations between $i(\kappa )$ and the standard higher analogues of some of the classical cardinal characteristics, e.g., $\mathfrak {r}(\kappa )\leq \mathfrak {i}(\kappa )$ and $\mathfrak {d}(\kappa )\leq \mathfrak {i}(\kappa )$. For $\kappa $ measurable, assuming that $2^{\kappa }=\kappa ^{+}$ we construct a maximal $\kappa $ -independent (...) family which remains maximal after the $\kappa $ -support product of $\lambda $ many copies of $\kappa $ -Sacks forcing. Thus, we show the consistency of $\kappa ^{+}=\mathfrak {d}(\kappa )=\mathfrak {i}(\kappa )<2^{\kappa }$. We conclude the paper with interesting open questions and discuss difficulties regarding other natural approaches to higher independence. (shrink)

We study two ideals which are naturally associated to independent families. The first of them, denoted \, is characterized by a diagonalization property which allows along a cofinal sequence of stages along a finite support iteration to adjoin a maximal independent family. The second ideal, denoted \\), originates in Shelah’s proof of \ in Shelah, 433–443, 1992). We show that for every independent family \, \\subseteq \mathcal {J}_\mathcal {A}\) and define a class of maximal independent families, to which we refer (...) as densely maximal, for which the two ideals coincide. Building upon the techniques of Shelah we characterize Sacks indestructibility for such families in terms of properties of \\) and devise a countably closed poset which adjoins a Sacks indestructible densely maximal independent family. (shrink)

One dimension of cognitive success concerns getting it right: having many true beliefs and no false ones. Another dimension of cognitive success concerns using the right concepts. For example, using a concept of a person that systematically excludes people of certain demographics from its extension is a sort of cognitive deficiency. This view, if correct, tasks inquirers with critically examining the concepts they are using and perhaps replacing those concepts with new and better ones. This task is often referred to (...) as “conceptual engineering”. However, so far it is unclear what exactly happens in cases of conceptual engineering. How does language change when we engineer a concept? This article offers an answer. I propose a view on which, when speakers assess the truth of propositions, they often rely on assumptions with regard to what is required for their truth. For example, when speakers assess whether unborn fetuses are people, they rely on assumptions with regard to what is required to be a person. Based on this idea, I develop a model of conceptual engineering according to which speakers “engineer concepts” when they change how they assess the truth of propositions. For example, speakers engineer the concept of a person when they change how they assess the truth of the proposition that unborn fetuses are people. (shrink)

Dieser Text ist bereits in der Zeitschrift Intervalls « Réinventer le rythme / Den Rhythmus neu denken », N° 7, 2015 erschienen. Wir danken Vera Viehöver und Michel Delville, dem Chefredakteur der Zeitschrift, für ihre freundliche Erlaubnis, diesen Text hier wiederzugeben. Vermutlich gehört es in nahezu jeder Kunstform zum Floskelrepertoire der Kritiker, vom „Rhythmus“ eines Werkes zu sprechen : Eine Theaterinszenierung kann ebenso für ihren Rhythmus gepriesen werden wie ein Computerspiel, ein - Poétique et Études littéraires – GALERIE – (...) Nouvel article. (shrink)

In this paper, I discuss whether the results of loop quantum gravity (LQG) constitute a fatal blow to Humeanism. There is at least a prima facie reason for believing so: while Humeanism regards spatiotemporal relations as fundamental, LQG describes the fundamental layer of our reality in terms of spin networks, which are not in spacetime. However, the question should be tackled more carefully. After explaining the importance of the debate on the tenability of Humeanism in light of LQG, and having (...) presented the Humean doctrine, I review two cases which present serious threats to Humeanism, one concerning the fundamentality of vectorial quantities and the other concerning quantum entanglement. In particular, I recall the strategies that are usually employed in these two cases in order to save Humeanism: in the first case, the strategy consists in amending the characterization of the Humean mosaic; in the second case, it consists in adopting a realist or nomological interpretation of the wave function. These solutions will turn out to be helpful in my discussion of LQG where, after describing LQG, I show that Humeans might save their doctrine either by endorsing a realist interpretation of spin networks, or by giving them a nomological status and, at the same time, by revisiting the characterization of the Humean mosaic. However, I conclude that both solutions are wanting. (shrink)

Lists foreground multiplicity: both of objects to be pursued and, for distant objects, of far-flung networks enabling their pursuit. The future-oriented or projective list stretches such networks not only around the world but forward through time. Research agendas are one kind of future-oriented, projective list. Sketching how such lists have functioned over time, from Francis Bacon's “The New World of Sciences, or Desiderata” to today's desiderata lists, suggests how an early modern model of imperial expansion has shaped, in unintended ways, (...) a scientific rhetoric of collaborative advance on shared targets. (shrink)

We study the set of possible sizes of maximal independent families to which we refer as spectrum of independence and denote \\). Here mif abbreviates maximal independent family. We show that:1.whenever \ are finitely many regular uncountable cardinals, it is consistent that \\); 2.whenever \ has uncountable cofinality, it is consistent that \=\{\aleph _1,\kappa =\mathfrak {c}\}\). Assuming large cardinals, in addition to above, we can provide that $$\begin{aligned} \cap \hbox {Spec}=\emptyset \end{aligned}$$for each i, \.

This paper examines the culture, the dynamics and the financial underpinnings that determine how medical research is being conducted on children in the United States. Children have increasingly become the subject of experiments that offer them no potential direct benefit but expose them to risks of harm and pain. A wide range of such experiments will be examined, including a lethal heartburn drug test, the experimental insertion of a pacemaker, an invasive insulin infusion experiment, and a fenfluramine "violence prediction" experiment. (...) Emphasis, however, is given to psychoactive drug tests because of the inherent ethical and diagnostic problems involved in the absence of any objective, verifiable diagnostic tool. Effort is made to provide readers comprehensive reference sources to evidence-based reports about the serious risks these drugs pose for adults and children so that the reader may judge whether the benefits (if any) outweigh the risks for children. The first ethical issue raised by these experiments is: did the severity of illness in these children justify their exposure to short and long-term risks? The ethics of the experiments will be evaluated by referring to existing codes of medical research ethics-the Nuremberg Code, the Declaration of Helsinki, and the federal Code of Regulations. The thirteen cases presented will demonstrate that children are being used in ever more speculative experiments, often in the absence of a therapeutic intent, but a significant chance for causing harm and / or discomfort. Some of the experiments were designed to explore the mechanisms of pathology and pharmacological interventions, or the response of neurological brain receptors to chemical provocation ("challenge"). Others were designed to test the safety or efficacy of new drugs, even to test these drugs on healthy children who were hypothesized to be "at risk." Children and adolescents have been subjected to "forced dose titration" experiments that induced a spectrum of severe adverse effects, including insomnia, extreme restlessness, agitation, (akathisia) and self-injurious behavior. FDA reports show that suicide is a significant issue in psychotropic drug trials-in pediatric trials the problem is even greater. The paper aims to demonstrate how the enactment of the Better Pharmaceuticals for Children Act (incorporated into the Food and Drug Administration Modernization Act, FDAMA), set in motion a radical shift in public policy by providing huge financial incentives to pharmaceutical companies to test new or patented drugs in children. Federal policy shifted from one aimed at protecting children by setting limits on permissible research risks, to a policy aimed at broadening the inclusion of children as test subjects. It will be shown how the FDA and the Department of Health and Human Services lifted regulatory restrictions to permit research involving greater than minimal risk to be conducted on healthy children, claiming that all children are potentially "at risk" of a future condition. Children were in this way deprived of regulatory protections. An argument will be made that the approval of nontherapeutic, harmful experiments-such as exposure of toddlers to lead poison-under the current gate keeping system raises serious doubts about the sustainability of institutional review boards (IRBs) as protectors of human research subjects. Children, who are precluded from exercising the adult human's right to informed consent, are being exploited as commodities for commercial ends. It is the position of the author that nothing less than the enactment of a federal law mandating a radical overhaul of the current research review system, with independent checks and balances, will provide children the legal protections they need. Ten specific recommendations are offered to protect children from harmful experiments. (shrink)

Let V be a finite relational vocabulary in which no symbol has arity greater than 2. Let be countable V‐structure which is homogeneous, simple and 1‐based. The first main result says that if is, in addition, primitive, then it is strongly interpretable in a random structure. The second main result, which generalizes the first, implies (without the assumption on primitivity) that if is “coordinatized” by a set with SU‐rank 1 and there is no definable (without parameters) nontrivial equivalence relation on (...) M with only finite classes, then is strongly interpretable in a random structure. (shrink)

PROGRAMA DE AGRESSORES COMO PARTE DA RESPOSTA COORDENADA DA COMUNIDADE – A EXPERIÊNCIA DO GRUPO REFLEXIVO DE HOMENS NO MINISTÉRIO PÚBLICO DO RIO GRANDE DO NORTE.

My main concern in this paper is to develop some ideas within the Kantian ethical tradition. More precisely, my aim is to develop an ethical perspective that is grounded upon the Kantian ideas of autonomy and ideal of the person (Kant’s notion of humanity) as fundamental starting points for a coherent account of Kant’s ethics in contrast to the deontological duty-based interpretation of his moral philosophy, then sketch, subsequently, some suggestions to show why this reading has more philosophical import than (...) what a deontological reading may provide. I take no issue for the time being however, as to whether or not the perspective I have in mind leads to either a Kantian orthodoxy or a revisionist direction in Kant scholarships. (shrink)

In a time marked by the development of innovative treatments in healthcare and the need for health professionals to deal with resulting ethical dilemmas in clinical practice, this study was developed to determine the influence of the bioethics teaching on the moral competence of medical and nursing students. The authors conduct a longitudinal study using the Moral Competence Test extended version before and after attending the ethics curricular unit, in three nursing schools and three medical schools of Portugal. In this (...) questionnaire the participant is confronted with three ethical dilemmas and asked to evaluate arguments for and against the attitude of the main character. For both nursing and medical students, C-score was lower after the attendance of the ethics curricular units, with a statistically significant decrease in the total score for nursing students and a decrease not statistically significant for medical students. A multivariate analysis did not find any association between this decrease and gender, course, or age. The phenomenon of moral segmentation was observed, with better performance in the worker and judge dilemma, than in the doctor dilemma. These results highlight the need to reflect on the curricular strategies that can be implemented for health professionals to better develop moral competence and decision-making, allowing for the provision of humanized health care. (shrink)

In this article, I want to ponder one particular aspect of Michel Serres as a writer: the peculiar impression that his texts are written as if “in many tongues.” Serres’s ambition with writing was to “travel light,” and indeed “lightning fast.” His style, I will argue, is characterized by a chiastic crossing of light and time whose proportioning is cosmic and architectonic, and figures canons of how embodied knowledges can cohabit in a domain of wisdom and ethical respect.

In this article, I try to go beyond the traditional objections to strict liability public welfare offenses and confront other possible justifications for punishing non-culpable conduct. Specifically, I consider the following arguments:Penalties for public welfare offenses are punishment by name only, thus traditional justifications for punishment are not needed;Even if those penalties are punishment, punishing those who produce or threaten significant harm to others is not necessarily unjust; andEven if such punishment is not entirely just, it is consistent with other (...) widely accepted criminal law doctrines. (shrink)

Definition of the problemThe article addresses the relationship between reproduction, time and the good life. Services offered by reproductive medicine and conceptions of the good life in time influence each other reciprocally. This interaction is characterised by implicit and explicit normative settings and expectations of appropriate temporality.ArgumentsWe first discuss the significance of time for the life course and for parenthood from a sociological and social psychological perspective. Reproductive medicine can increase the options for becoming a parent and thus for life-time (...) autonomy. However, in the context of societal imperatives for optimisation and efficiency, it can also have opposite effects and increase heteronomy. Overall, this leads to changed forms of adaptation and self-determination, new dilemmas and ambivalences in the temporal optimisation of parenthood.ConclusionsAgainst this background, we explain how the ethics of reproductive medicine could benefit from interdisciplinary research that focuses on life in its temporal course. (shrink)

Most courts around the world have been refusing wrongful life actions. The main argument invoked is that the supposed compensable injury cannot be classified as such, since life is always a blessing no matter how hard and painful it is.In opposition to mainstream scholars and the dominant case law, this article sustains that life must be distinguished from living conditions, the former being the real injury at stake, since some living conditions are so intolerable that in themselves they justify a (...) compensation within wrongful life actions. (shrink)

Motivated by recent results and questions of Raghavan and Shelah, we present ZFC theorems on the bounding and various almost disjointness numbers, as well as on reaping and dominating families on uncountable, regular cardinals. We show that if $\kappa =\lambda ^+$ for some $\lambda \geq \omega $ and $\mathfrak {b}=\kappa ^+$ then $\mathfrak {a}_e=\mathfrak {a}_p=\kappa ^+$. If, additionally, $2^{<\lambda }=\lambda $ then $\mathfrak {a}_g=\kappa ^+$ as well. Furthermore, we prove a variety of new bounds for $\mathfrak {d}$ in terms of (...) $\mathfrak {r}$, including $\mathfrak {d}\leq \mathfrak {r}_\sigma \leq \operatorname {\mathrm {cf}}]^\omega )$, and $\mathfrak {d}\leq \mathfrak {r}$ whenever $\mathfrak {r}<\mathfrak {b}^{+\kappa }$ or $\operatorname {\mathrm {cf}})\leq \kappa $ holds. (shrink)

We show that Hechler’s forcings for adding a tower and for adding a mad family can be represented as finite support iterations of Mathias forcings with respect to filters and that these filters are $${\mathcal {B}}$$ B -Canjar for any countably directed unbounded family $${\mathcal {B}}$$ B of the ground model. In particular, they preserve the unboundedness of any unbounded scale of the ground model. Moreover, we show that $${\mathfrak {b}}=\omega _1$$ b = ω 1 in every extension by the (...) above forcing notions. (shrink)

Popper’s ‘Situational Analysis’ (SA) constitutes his methodological proposal for the social sciences. We claim that the two hallmarks of SA are: (i) that scientists assume they possess a ‘wider’ view of the problem-situation than actors do, and (ii) use the model as an ideal ‘benchmark’ scenario to identify thedeviationof actors’ actual behaviour from the former. We argue that SA is not a generalization of the neoclassical theory of individual behaviour but captures instead the methodology adopted by modern behavioural economists. Last, (...) we argue that SA highlights a way of acquiring knowledge that has gone unnoticed in the literature. (shrink)

MARK LOŠONC, PREDRAG KRSTIĆ, HOLOKAUST I FILOZOFIJA, INSTITUT ZA FILOZOFIJU I DRUŠTVENU TEORIJU, BEOGRAD, 2018.Vera Mevorah.

Dieser Text ist bereits in der Zeitschrift Intervalls « Réinventer le rythme / Den Rhythmus neu denken », N° 7, 2015, erschienen. Wir danken Vera Viehöver und Michel Delville, dem Chefredakteur der Zeitschrift, für ihre freundliche Erlaubnis, diesen Text hier wiederzugeben. Résumé : Vera Viehöver étudie dans cet article la signification de la pensée rythmique de Henri Meschonnic pour son concept de la lecture. L'étroite association du rythme et du sujet – qui fait premièrement penser au sujet de (...) - Poétique et Études littéraires – GALERIE – Nouvel article. (shrink)

Ontological expressivism is the view that ontological existence claims express non-cognitive mental states. I develop a version of ontological expressivism that is modeled after Gibbard’s (2003) norm-expressivism. I argue that, when speakers assess whether, say, composite objects exist, they rely on assumptions with regard to what is required for composition to occur. These assumptions guide their assessment, similar to how norms may guide the assessment of normative propositions. Against this backdrop, I argue that “some objects have parts”, uttered in the (...) context of an ontological disagreement, expresses a noncognitive disposition to assess the truth of propositions by using only rules of assessment according to which the proposition that some objects have parts is to be evaluated as true. (shrink)

What parameters determine brain size? This question is of particular interest for humans because our large brains confer outstanding cognitive abilities. The answer has long been sought in comparative analyses of brain size relative to body size (herein termed ‘brain size’) in our fellow homeothermic vertebrates – namely other mammals and birds. Unfortunately, brain size is an idiosyncratic trait corresponding to a seemingly miscellaneous collection of traits ranging from gestation length to deception behaviour. Some order can be established by attributing (...) brain size correlates to categories of constraint (‘what traits permit or limit increased brain sizes?’) and selection (‘what traits select for increased brain sizes?. Even so, the vast number of potential correlates has lead to a plethora of (frequently mutually exclusive) hypotheses regarding avian and mammalian brain size evolution. This confusion has recently prompted calls for better integration of brain size correlates. In this article we argue that the latest advances in the field of brain size constraints, combined with modern techniques for tracing brain development, put an integrated framework of brain size evolution within our reach. (shrink)

We study \(\kappa \) -maximal cofinitary groups for \(\kappa \) regular uncountable, \(\kappa = \kappa ^{. Revisiting earlier work of Kastermans and building upon a recently obtained higher analogue of Bell’s theorem, we show that: Any \(\kappa \) -maximal cofinitary group has \({ many orbits under the natural group action of \(S(\kappa )\) on \(\kappa \). If \(\mathfrak {p}(\kappa ) = 2^\kappa \) then any partition of \(\kappa \) into less than \(\kappa \) many sets can be realized as the (...) orbits of a \(\kappa \) -maximal cofinitary group. For any regular \(\lambda > \kappa \) it is consistent that there is a \(\kappa \) -maximal cofinitary group which is universal for groups of size \({. If we only require the group to be universal for groups of size \(\kappa \) then this follows from \(\mathfrak {p}(\kappa ) = 2^\kappa \). (shrink)

A collection of essays by an international team of scholars, _Archival Afterlives_ explores the posthumous fortunes of scientific and medical archives in early modern Britain. It demonstrates the sustaining importance of archival institutions in the growth of the “New Sciences.”.

This article examines Boris N. Chicherin’s ideas about property. It shows that the thinker interprets property as a material form of the objectification of human freedom, the most important and nec...