In this essay, I propose that DNA‐binding anti‐cancer drugs work more via chromatin disruption than DNA damage. Success of long‐awaited drugs targeting cancer‐specific drivers is limited by the heterogeneity of tumors. Therefore, chemotherapy acting via universal targets (e.g., DNA) is still the mainstream treatment for cancer. Nevertheless, the problem with targeting DNA is insufficient efficacy due to high toxicity. I propose that this problem stems from the presumption that DNA damage is critical for the anti‐cancer activity of these drugs. DNA (...) in cells exists as chromatin, and many DNA‐targeting drugs alter chromatin structure by destabilizing nucleosomes and inducing histone eviction from chromatin. This effect has been largely ignored because DNA damage is seen as the major reason for anti‐cancer activity. I discuss how DNA‐binding molecules destabilize chromatin, why this effect is more toxic to tumoral than normal cells, and why cells die as a result of chromatin destabilization. (shrink)

Phenotypic plasticity is a crucial feature of aggressive cancer, providing the means for cancer progression. Stochastic changes in tumor cell transcriptional programs increase the chances of survival under any condition. I hypothesize that unstable chromatin permits stochastic transitions between transcriptional programs in aggressive cancers and supports non‐genetic heterogeneity of tumor cells as a basis for their adaptability. I present a mechanistic model for unstable chromatin which includes destabilized nucleosomes, mobile chromatin fibers and random enhancer‐promoter contacts, resulting in stochastic transcription. I (...) suggest potential markers for “unsettled” chromatin in tumors associated with poor prognosis. Although many of the characteristics of unstable chromatin have been described, they were mostly used to explain changes in the transcription of individual genes. I discuss approaches to evaluate the role of unstable chromatin in non‐genetic tumor cell heterogeneity and suggest using the degree of chromatin instability and transcriptional noise in tumor cells to predict cancer aggressiveness. (shrink)

We are drowning in information, while starving for wisdom.Are the smartest people also the wisest? Not necessarily. While traditional intellectual reasoning and procedural knowledge have helped build the communities we live in, there is a growing scientific understanding that we need emotionally balanced and better-fitting prosocial frameworks for coping with the uncertainties and complexities of life and addressing new challenges of the modern world. We are now poised on the edge of a new science of wisdom.The concept of wisdom, long (...) considered the “pinnacle of insight into the human condition”, has been that of an intangible, subjective, culturally specific entity—an unscientific... (shrink)

This study deals with a controversy between Leibniz and Clarke concerning the relativity of space. Although substantivalism, i.e. an approach treating space as a substance, is to be indicated as the main target of Leibniz’s attack, it has usually been replaced by Newtonian absolutism instead, as a proper opposition to Leibniz’s relationalism. However, such absolutism has not been defined ontologically, but dynamically, as if the difference between their conceptions consisted of a different approach to the inertiallity of motion. However, this (...) would mean that while Leibniz intended to reduce all motion to an inertial one, Newton reduced it to a noninertial one instead, or that only one of them acknowledged the existence of noninertial motion at all. Nevertheless, none of them actually denied the existence of noninertial motion, and although all motion indeed seemed noninertial to Newton, Leibniz never responded to such a challenge in the course of their correspondence. (shrink)

Studie se věnuje otázce po ontologickém statusu ideálního, potažmo fenomenálního prostoru v pojetí Gottfrieda Wilhelma Leibnize. Nejprve bude ujasněno, v jakém smyslu lze podle Leibnize za prostor v pravém slova smyslu považovat primárně pouze prostor ideální, sekundárně však rovněž prostor fenomenální. Posléze se vymezím zejména vůči takovým interpretacím leibnizovského ideálního prostoru, které v něm spatřují předzvěst prostoru kantovského. Leibnizův ideální, matematický prostor zde totiž bude přirovnán spíše k prostoru suárezovskému, případně hobbesovskému, nikoli však kantovskému.

Studie se věnuje otázce po ontologickém statusu ideálního, potažmo fenomenálního prostoru v pojetí Gottfrieda Wilhelma Leibnize. Nejprve bude ujasněno, v jakém smyslu lze podle Leibnize za prostor v pravém slova smyslu považovat primárně pouze prostor ideální, sekundárně však rovněž prostor fenomenální. Posléze se vymezím zejména vůči takovým interpretacím leibnizovského ideálního prostoru, které v něm spatřují předzvěst prostoru kantovského. Leibnizův ideální, matematický prostor zde totiž bude přirovnán spíše k prostoru suárezovskému, případně hobbesovskému, nikoli však kantovskému.

V tomto článku analyzuji virální video Přemluv bábu, které mělo ambice zasáhnout do voleb do Poslanecké sněmovny Parlamentu České republiky v roce 2010. Ke klipu přistupuji z pozice kritické diskurzivní analýzy (CDA), pracuji především s předpoklady, koncepty a analytickými nástroji Normana Fairclougha, který pomáhal CDA rozvíjet a v akademickém poli prosadit. Tvrdím, že klip Přemluv bábu těží z pružnosti, respektive uhýbavosti postmoderního diskurzu, což mohlo smysl jeho výpovědi i její naléhavost spíše oslabit a znečitelnit než podepřít. Demonstruji na příkladech a (...) snažím se identifikovaným ambivalencím porozumět s ohledem na kontext intertextový, interdiskurzivní, situační a socio-politický. (shrink)

V rámci tohoto příspěvku se pokusím zpochybnit dosavadní mainstreamovou interpretaci Leibnizovy metafyziky prostoru, jak ji představil v dopisech anglickému učenci Samuelu Clarkovi. Přestože bývá Leibnizova metafyzika prostoru právě na základě jeho korespondence s Clarkem obvykle považována za ostrý protipól metafyziky Clarkovy, respektive Newtonovy, v rámci tohoto příspěvku poukážu na to, že při zvážení Leibnizovy geometrie zvané „analysis situs“ se taková interpretace stává neudržitelnou. Leibnize nelze považovat za zastánce typicky relačního pojetí prostoru.

Is it possible to invoke the use of moral responsibility as part of the selection criteria in the allocation of livers for transplant? Criticism has been applied to the difficulties inherent in including such a criterion and also the effect that employing such a judgement might have upon the relationship between the physician and patient. However, these criticisms rely on speculation and conjecture and do not relate to all the arguments put forward in favour of applying moral responsibility. None of (...) the present arguments against using moral responsibility in the allocation of livers for transplant are good enough to warrant its dismissal. (shrink)

Purpose. The article is aimed to substantiate the view on the phenomenon of laughter as a subject of semiotic analysis, which leads to the following tasks: to reveal the possibilities of semiotics application in the study of laughter nature; to analyze the phenomenon of laughter as a cultural and natural phenomenon, as a sign and as an attribute; to consider the place of laughter in culture, which is understood as a sign system. Theoretical basis. The semiotic approach proceeds from the (...) fact that human lives in the world of signs, all the surrounding reality can be interpreted as a sign system. The basic concept of semiotics is the concept of a sign. The theoretical basis of the article is understanding the culture as a sign-symbolic system. Laughter is considered as a phenomenon ontologically rooted in human culture. At the same time, laughter is on the edge of culture. The research is based on the work of semiotic authors, cultural researchers, and the researchers of laughter. Originality. The originality lies in the application of the semiotic method to the research of laughter phenomenon, consideration of the dialectics of natural and cultural, signedness and non-signedness, manifested in the phenomenon of laughter. Conclusions. Laughter is considered as a psychophysiological phenomenon and as a cultural phenomenon. Laughter acts as an emotional manifestation, a physiological reaction, but socially and culturally mediated. In any case, laughter indicates an emotional or cognitive state of a human. Laughter acts as a process and result of the interpretation of a sign, a reaction to a sign. Laughter is a form and a means of communication. Being a natural phenomenon, in the process of social evolution, laughter acquires signedness, is integrated by culture as a sign system, and, at the same time, maintains a connection with nature. Thus, laughter occupies an ambivalent position between nature and culture. In the phenomenon of laughter, the dual state of human is revealed. In laughter, boundaries are blurred, the unity and opposition of natural and cultural, biological and social, soul and body, thought and feeling, sign and attribute are manifested. (shrink)

My dear Aleksandr!I have finally found some quiet time for a slow and attentive read of your article “The Beginning of the Black Notebooks.”1 I very much liked the article, especially for your trul...

This article presents the findings of a study on homeschooling in Czechia. It focuses on the gender aspects of this uncommon educational decision. Based on forty-three individual interviews with homeschooling parents, the article’s unifying thread is interest in understanding how mothers are involved in the decision to homeschool, and how the practice is embedded in gendered relationships within the society. We explore the results from two perspectives. First, we consider how the choice to homeschool lies simultaneously in embracing and opposing (...) cultural imperatives of good mothering. Second, we explore the precarious status of homeschooling mothers in relation to economic independence. By shedding light on individual choice within social structures, we situate the practice of homeschooling within the gender inequalities of today’s society. (shrink)

In early 1864, disappointed by the response to his previous work, the young Manchester academic W. Stanley Jevons announced that he was undertaking a study of the so-called coal question: ‘A good publication on the subject would draw a good deal of attention … it is necessary for the present at any rate to write on popular subjects’. When Jevons's The Coal Question was published in April 1865, however, it received comparatively little attention and sales were slow. Jevons and his (...) publisher, Alexander Macmillan, then began sending complimentary copies to luminaries such as Sir John Herschel and Alfred Tennyson. In February 1866 the marketing campaign produced its first substantial return. Macmillan had sent CQ to William Gladstone who responded with letters to both Macmillan and Jevons, noting that the book had strengthened his ‘conviction’ on the necessity for reducing the National Debt. In April, John Stuart Mill praised CQ in the House of Commons, calling for action on the Debt and, three weeks later, as Chancellor of the Exchequer, Gladstone introduced the budget using half his speech to examine the Debt situation and referring to CQ in support for a proposed measure of Debt reduction. With the extensive publicity given to CQ following Mill's speech and the budget, Jevons had achieved his objective in writing the text which went into a second edition in 1866. On the face of it, CQ 's success was due to its effect of introducing a change in budget policy and this is the impression given by some accounts of the episode. (shrink)

Epithelia are the first organized tissues that appear during development. In many animal embryos, early divisions give rise to a polarized monolayer, the primary epithelium, rather than a random aggregate of cells. Here, we review the mechanisms by which cells organize into primary epithelia in various developmental contexts. We discuss how cells acquire polarity while undergoing early divisions. We describe cases where oriented divisions constrain cell arrangement to monolayers including organization on top of yolk surfaces. We finally discuss how epithelia (...) emerge in embryos from animals that branched early during evolution and provide examples of epithelia‐like arrangements encountered in single‐celled eukaryotes. Although divergent and context‐dependent mechanisms give rise to primary epithelia, here we trace the unifying principles underlying their formation. (shrink)

In an article which appeared a few years ago, entitled ‘God's Death’ , A.D. Smith launched one of the most interesting of recent attacks on the traditional doctrine of the Incarnation. Focusing on the death of Christ, he claimed to demonstrate the logical impossibility of Jesus having been both human and divine. Each of the premises of his argument was said to be a commitment of orthodox theology. He thus presented his reasoning as displaying an internal incoherence in that way (...) of thinking about divinity, humanity, and the person of Christ. The argument was basically quite simple: According to Christian theology and in concurrence with general thought on the matter, we must hold that human death involves the possibility of annihilation. As a man, Jesus of Nazareth faced and underwent a human death. He thus faced the possibility of annihilation. But orthodox theologians hold God to be of such an ontological status that no divine being could even possibly be annihilated. So no divine person could die a human death. From this follows the impossibility of the traditional claim that the Second Person of the divine Trinity became a man, lived a human life, and died a human death for us and our salvation. The qualitative difference between God and man is such as to render incarnational christology an incoherent theological stance. (shrink)

ICTs, personal data, digital rights, the GDPR, data privacy, online security… these terms, and the concepts behind them, are increasingly common in our lives. Some of us may be familiar with them, but others are less aware of the growing role of ICTs and data in our lives - and the potential risks this creates. These risks are even more pronounced for vulnerable groups in society. People can be vulnerable in different, often overlapping, ways, which place them at a disadvantage (...) to the majority of citizens; Table 3 in this guide presents some of the many forms and causes of vulnerability. As a result, vulnerable people need greater support to navigate the digital world, and to ensure that they are able to exercise their rights. This guide explains where such support can be found, and also answers the following questions: - What are the main ethical and legal issues around ICTs for vulnerable citizens? - Who is vulnerable in Europe? - How do issues around ICTs affect vulnerable people in particular? This guide is a resource for members of vulnerable groups, people who work with vulnerable groups, and citizens more broadly. It is also useful for data controllers1 who collect data about vulnerable citizens. While focused on citizens in Europe, it may be of interest to people in other parts of the world. It forms part of the Citizens’ Information Pack produced by the PANELFIT project, and is available in English, French, German, Italian and Spanish. You are welcome to translate this guide into other languages. Please send us a link to online versions in other languages, so that we can add them to the project website. (shrink)

This book is a translation of W.V. Quine's Kant Lectures, given as a series at Stanford University in 1980. It provide a short and useful summary of Quine's philosophy. There are four lectures altogether: I. Prolegomena: Mind and its Place in Nature; II. Endolegomena: From Ostension to Quantification; III. Endolegomena loipa: The forked animal; and IV. Epilegomena: What's It all About? The Kant Lectures have been published to date only in Italian and German translation. The present book is filled out (...) with the translator's critical Introduction, "The esoteric Quine?" a bibliography based on Quine's sources, and an Index for the volume. (shrink)

Modern applied mathematics is focused on global problems of civilization. Its ultimate aim is to provide human socio-cultural activity with tool and project. That is why applied mathematics nowadays usually gives scientific explanation typical to sociological knowledge - an intentional explanation. In the article, a question is discussed about the abilities of mathematics to explain. This question was put by J. Brown in the article published in the journal ‘Epistemology and Philosophy of Science‘. The philosophy of mathematics, as well as (...) the philosophy of science, cannot do without consideration of philosophical problems related to the development of modern applied mathematics as a vast area of modern science. In the past half century, the interest in the philosophical interpretation of the application of the process of mathematics has intensified. In the domestic literature, interest in this problem has blossomed in 70-80 years. As a result, ‘the application of mathematics‘ was interpreted in two ways: as the mathematization of science and mathematics as a way to participate in solving the problems of life. In today’s context, the theme of the effectiveness of mathematics sounded once again. However, it has a new aspect: the effectiveness of mathematics as a tool to be used in human activities. The term ‘applied mathematics‘ obtained three meanings: 1) the usefulness of mathematics to human life and society; 2) mathematization - the application of mathematics in other fields of knowledge; 3) modern applied mathematics - branch of mathematics, the core of which is the computational mathematics and computer systems. The author analyzed the cognitive situation corresponding to these three meanings. In the third case, i.e. in modern applied mathematics, the study consists of two phases: the nomination of a mathematical model and the study of the mathematical model. It is appropriate to call the explanation given by the step as the intentional explanation. Because the first of the two stages of the research in applied mathematics - the creation of the model and the study the model - is the basis of the second, the reasonable explanation of the possible actions of the actor given in applied mathematics is called intentional. (shrink)

This paper is devoted to Leonardo da Vinci’s ‘The Arno Valley Landscape‘. The historical aspect of the subject under study has been considered, as well as the methodological issues in learning the professional drawing techniques in the framework of Leonardo’s ten attributes of sight and the Thinking through Drawing methodology. Our approach allows formulating the figurative and artistic component of the masterpiece and find out Leonardo’s hidden messages, full of mystics and symbolism.

Издание представляет результаты исследования малоизученной темы социально-экономических доктрин консерватизма. Оно отражает их развитие от времени выражения их в виде утопий, погруженных в более общие социально-философские и политические учения.

The rhetoric studies art of well-reasoned and convincing speech since antique times. In the article, a rhetoric phenomenon is viewed as certain method in Cicero’s philosophy of education. He considered a semantic component as a basis of the speaker speech. From the point of view of a rhetoric demand in teaching mathematics of various levels, modern interpretation of rhetorical skill does not come down to eloquence only. The rhetoric is still methodological means for strengthening the convincing influence of mathematical arguments (...) at a statement of difficult mathematical terminology or at proving theorem. Article underlines a role of the good speaker’s rhetoric of the live speech. Rhetoric gives the required words and ‘colors‘ that are essential for the live speech. From the point of teaching mathematics, the convincing speech art is especially demanded for understanding of mathematics at various justification levels. The rhetoric studies art of the convincing and reasoned eloquence. Sometimes, addressing to non-mathematician audience, mathematicians allow themselves to substitute arguments by unreasoned rhetorical means, but it is necessary to amplify the pragmatical aspect of rhetoric at lectures on mathematics. It provides the means for communication with the student audience of any level of mathematical knowledge. (shrink)

The article is devoted to aesthetic nature of the philosophy of dance as a rapidly developing area of studying. The aesthetic issues of choreographies in the cognitive context have not been properly studied. The mathematical component of the classical ballet, which is shown through the internal patterns of the expressiveness of the different types of dance movements in the system of artistic thinking, is analyzed in a wide range of the philosophical problems of art of dancing. The substantial triad of (...) structure of dance is considered at the level of philosophical research. In it, along with static and dynamic forms of dance, the third component, which reflects physicality, related to the ‘sense of movement‘ or the perception of information through body movements is added to the binary structure of dance. (shrink)