Lysine methylation has been traditionally associated with histones and epigenetics. Recently, lysine methyltransferases and demethylases – which are involved in methylation of non‐histone substrates – have been frequently found deregulated in human tumours. In this realm, a new discovery has unveiled the methyltransferase SMYD3 as an enhancer of Ras‐driven cancer. SMYD3 is up‐regulated in different types of tumours. SMYD3‐mediated methylation of MAP3K2 increases mutant K‐Ras‐induced activation of ERK1/2. Methylation of MAP3K2 prevents it from binding to the phosphatase PP2A, thereby impeding (...) the impact of this negative regulator on Ras‐ERK1/2 signals, leading to the formation of lung and pancreatic adenocarcinomas. Furthermore, depletion of SMYD3 synergises with a MEK inhibitor, currently in clinical trials, to block Ras‐driven pancreatic neoplasia. These results underscore the importance of lysine methylation in the regulation of signalling pathways relevant for tumourigenesis and endorse the development of drugs targeting unregulated lysine methylation as therapeutic agents in the struggle against cancer. (shrink)

Recent discoveries have suggested the concept that intracellular signals are the sum of multiple, site‐specified subsignals, rather than single, homogeneous entities. In the context of cancer, searching for compounds that selectively block subsignals essential for tumor progression, but not those regulating “house‐keeping” functions, could help in producing drugs with reduced side effects compared to compounds that block signaling completely. The Ras‐ERK pathway has become a paradigm of how space can differentially shape signaling. Today, we know that Ras proteins are found (...) in different plasma membrane microdomains and endomembranes. At these localizations, Ras is subject to site‐specific regulatory mechanisms, distinctively engaging effector pathways and switching‐on diverse genetic programs to generate different biological responses. The Ras effector pathway leading to ERKs activation is also under strict, space‐related regulatory processes. These findings may open a gate for aiming at the Ras‐ERK pathway in a spatially restricted fashion, in our quest for new anti‐tumor therapies. (shrink)

ABSTRACTThis article examines the Trinitarian anthropology inherent in the ‘charism of unity’ that characterizes the Focolare Movement stemming from the mystical experience of Chiara Lubich. After describing the theological cornerstones of this charism―namely the evangelical centrality of the commandment of reciprocal love, the circularity between theology and anthropology and Jesus Forsaken as the Christological key to understanding and achieving unity―the article studies its cultural implications as reflected in the philosophical and theological contribution of Klaus Hemmerle. In dialogue with modern thought, (...) Hemmerle in fact draws from and develops the anthropological meaning of the charism of unity as a feasible way to respond to the most acute challenges of today. (shrink)

El trabajo tiene por objeto reflexionar críticamente sobre el retribucionismo como fin de la pena en el Estado constitucional de Derecho. Tomando como punto de partida el idealismo alemán, se analizan las reformulaciones más recientes de esta corriente de pensamiento aparentemente superada. Se propone una distinción metodológica entre los términos retribución, reprobación y venganza, en orden a la defensa de una teoría de la pena secularizada.

Este artículo aborda el carácter clave del comercio de barrio como espacio para la sociabilidad en contextos locales de migración, centrándose en tres planteamientos que contribuyen a analizar tanto situaciones de convivencia armoniosa como de conflictividad entre vecinos de distintos orígenes etnoculturales: 1) la vinculación entre el comercio como elemento visibilizador de expresiones identitarias y la construcción culturalista del conflicto; 2) cómo se articula el comercio con otros espacios de sociabilidad; y 3) la multiplicidad de espacios de interacción que ofrece (...) la actividad comercial. (shrink)

El objetivo principal del ensayo es intentar entender el significado del silencio del Buddha ante las diez proposiciones sin declarar. Si se consideran como di††hi, las preguntas sin declarar son simplemente un conjunto de proposiciones conceptualmente distorsionadas. El trabajo se ha dividido en cinco secciones. En las dos primeras se presenta la explicación del Buddha de su propio silencio. Tienen un alcance meramente expositivo con el objeto de situar la discusión en los términos en que fue originariamente planteada. La tercera (...) parte explica los mecanismos mentales que intervienen en la generación mental de patrones mentales distorsionados. El papel que desempeña papañca en el desarrollo de las tendencias subyacentes y la aparición de efluvios mentales se ha desarrollado en la cuarta parte. Finalmente, se presenta el silencio del Buddha como la respuesta que es consistente con el conjunto de principios doctrinales que él mismo declaró. (shrink)

El estudio de la motivación de la utilización de los sistemas de control avanzado de música ambiental y el hecho de crear un buen ambiente, una buena experiencia de cara al cliente que entra en un local a realizar una compra debido al atractivo generado por la música es el objetivo de esta investigación. El estudio de las emociones que se derivan de la utilización de la música en locales comerciales y la repercusión que tiene en el comportamiento de compra (...) del consumidor serán analizados con el estudio de varios casos de éxito sobre esta cuestión. (shrink)

(2000). The Evolutionary challenge for the Enterprise. World Futures: Vol. 55, Challenges of Evolution at the Turn of the Millennium: Part III: The Chllenges of Globalization and Sustainability, pp. 159-171.

Introduction -- The form of happiness -- Affirmation -- Beauty is everywhere -- Love of life -- Fundamental OK -- The uniqueness of each moment -- Taste -- Spontaneity -- The reality of reality -- Healing -- Beauty cures -- Creative expression -- Nature and music -- The invisible ally -- The heart of beauty -- Sharing -- The beauty of the soul -- Good and beautiful -- Aesthetics and biology -- Knowledge -- Mind and beauty -- Revelation -- Hidden (...) resonance -- Trascendence -- Self, nature, and society -- Abuse vs. awe -- Beauty is the opposite of war. (shrink)

These proceedings collect the selected contributions of participants of the First Karl Schwarzschild Meeting on Gravitational Physics, held in Frankfurt, Germany to celebrate the 140th anniversary of Schwarzschild's birth. They are grouped into 4 main themes: I. The Life and Work of Karl Schwarzschild; II. Black Holes in Classical General Relativity, Numerical Relativity, Astrophysics, Cosmology, and Alternative Theories of Gravity; III. Black Holes in Quantum Gravity and String Theory; IV. Other Topics in Contemporary Gravitation. Inspired by the foundational principle ``By (...) acknowledging the past, we open a route to the future", the week-long meeting, envisioned as a forum for exchange between scientists from all locations and levels of education, drew participants from 15 countries across 4 continents. In addition to plenary talks from leading researchers, a special focus on young talent was provided, a feature underlined by the Springer Prize for the best student and junior presentations. (shrink)

Saggio straordinariamente felice, analizza l'uomo e la donna da prima della nascita a dopo la morte. Ecco i titoli dei venti capitoli: Incontro - Nessuno nasce solo - Metamorfosi - Dramma del vagito - Novecento giorni - Magie della parola - Abbaco e abbiccì - Efebo ingrato - Rischi di Ebe - Scelta del personaggio - Diritti del cuore - La coppia umana - Homo familiaris - Ognuno fra la gente - Desti nel sonno - Madre o suocera - Mezzo (...) secolo - La vetta longeva - La gran Madre antica - Elogio dell'uomo. Questa edizione definitiva è stata riveduta dall'autore nel 1983 con l'aggiunta di importanti accrescimenti e di significative modifiche. (shrink)

Jason Brennan has argued that democracy is intrinsically unjust, for it grants voting power to politically incompetent individuals, thus exposing people to an undue risk of harm. He claims democracy should be replaced by epistocracy, i.e., the rule of the knowers. In this paper, I show that his argument fails. First, Brennan mistakes voters’ competence for voters’ trustworthiness. Second, despite Brennan's claim to the contrary, an epistocracy may not reduce people’s exposure to an undue risk of harm. Third, Brennan overlooks (...) the fact that citizens are not equally affected by ‘bad voting.’ Fourth, far from being a defence of libertarian ideals, Brennan's argument supports paternalism. (shrink)

Many believe that a citizen who engages in civil disobedience is not exempt from the sanctions that apply to standard law-breaking conduct. Since he is responsible for a deliberate breach of the law, he is also liable to punishment. Focusing on a conception of responsibility as answerability, I argue that a civil disobedient is responsible (i.e. answerable) to his fellows for the charges of wrongdoing, yet he is not liable to punishment merely for breaching the law. To support this claim, (...) I defend an account of political obligation framed in terms of respect for (rather than mere obedience to) the law, and argue that the mere illegality of civil disobedience does not suffice to establish wrongdoing. I then discuss and reject three objections to my argument. (shrink)

Alzheimer's disease remains the most common form of dementia. Dementia symptoms vary depending on individual personality, life experience, and social and cultural influences. As dementia progresses, involvement of multi-disciplinary health care professionals is needed to manage the disease. Alzheimer research is progressing rapidly. While 5% of all Alzheimer's disease may be genetically determined, the majority is not. Susceptibility genes can reveal the risk of contracting Alzheimer's disease. Early life risk factors such as education, nutrition, and vascular disease may increase the (...) likelihood of dementia in later life. In the United States, two acetylcholinesterase inhibitors have been approved as cognitive enhancers. Possible prevention and symptomatic treatment interventions have focused on estrogen replacement therapy, antioxidants, and anti-inflammatory medications. Research advances have improved the clinical management of dementia. Ethical implications to the patient, family, and society are multiple and remain challenging. (shrink)