Entendimento poético como entrada inicial de ser-no-mundo

Comprehension of modern poetic phenomena is based on Heidegger’s fundamental ontology and Gadamer's hermeneutics. The rhythm of poetry cuts through the inner space of a thing, as agitated movements cut through the air, and almost every poetic line exists in its own special inclination, which makes the poems become voluminous. The composition of words in poetry is shifted and relabeled as if over tightened by a single rhythmic impulse, which also changes the state of literature. The initial occurrence of being-in-the-world through poetic understanding – these are the word-whistlers and word-spells from which verses are created, can be formed (and are added) into meaningful phrases, but their nature remains the same: mental and impulsive, in fact, pre-speech. According to Heidegger, Poetry is regarded as the initial mode of realization of the language. The essence of language – speech – permeates all existentials (being-preunderstanding, mood), in its original mode, speech is revealed in the self-pronunciation of being-in-the-world, that is, in finding the word-in-being-in-the-world. Since the pronunciation of meaning in words occurs simultaneously with understanding, poetic pronunciation is the place for the most complete manifestation of meaning in language.La comprensión de los fenómenos poéticos modernos se basa en la ontología fundamental de Heidegger y la hermenéutica de Gadamer. El ritmo de la poesía atraviesa el espacio interior de una cosa, como movimientos agitados cortan el aire, y casi todas las líneas poéticas existen en su propia inclinación especial, lo que hace que los poemas se vuelvan voluminosos. La composición de las palabras en la poesía se desplaza y se vuelve a etiquetar como si estuviera más apretada por un solo impulso rítmico, que también cambia el estado de la literatura. La aparición inicial del ser en el mundo a través de la comprensión poética: estos son los silbadores de palabras y los hechizos de palabras a partir de los cuales se crean los versos, se pueden formar (y agregar) en frases significativas, pero su naturaleza sigue siendo la misma: Mental e impulsivo, de hecho, pre-discurso. Según Heidegger, la poesía es considerada como el modo inicial de realización del lenguaje. La esencia del lenguaje, el habla, impregna todos los existenciales (ser un pre-entendimiento, estado de ánimo), en su modo original, el habla se revela en la auto-pronunciación de ser-en-el-mundo, es decir, en encontrar la palabra-in estar en el mundo Dado que la pronunciación del significado en palabras ocurre simultáneamente con la comprensión, la pronunciación poética es el lugar para la manifestación más completa del significado en el lenguaje.A compreensão dos fenómenos poéticos modernos baseia-se na ontologia fundamental de Heidegger e na hermenêutica de Gadamer. O ritmo da poesia corta o espaço interior de uma coisa, enquanto movimentos agitados atravessam o ar, e quase todas as linhas poéticas existem em sua própria inclinação especial, o que faz com que os poemas se tornem volumosos. A composição das palavras na poesia é deslocada e rotulada como se fosse apertada por um único impulso rítmico, que também muda o estado da literatura. A ocorrência inicial do ser-no-mundo através da compreensão poética - estes são os assobiadores de palavras e os feitiços de palavras dos quais os versos são criados, podem ser formados (e adicionados) em frases significativas, mas sua natureza permanece a mesma: mental e impulsivo, de fato, pré-fala. Segundo Heidegger, a Poesia é considerada o modo inicial de realização da linguagem. A essência da linguagem - fala - permeia todos os existenciais (estar-pre-entendimento, humor), em seu modo original, a fala é revelada na auto-pronúncia do ser-no-mundo, ou seja, em encontrar a palavra-in-the-word. estar-no-mundo. Como a pronúncia do significado em palavras ocorre simultaneamente à compreensão, a pronúncia poética é o lugar para a mais completa manifestação de significado na linguagem

Novel RET agonist for the treatment of experimental neuropathies

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) alleviate symptoms of experimental neuropathy, protect and stimulate regeneration of sensory neurons in animal models of neuropathic pain, and restore their functional activity. However, clinical development of GFL proteins is complicated by their poor pharmacokinetic properties and multiple effects mediated by several receptors. Previously, we have identified a small molecule that selectively activates the major signal transduction unit of the GFL receptor complex, receptor tyrosine kinase RET, as an alternative to GFLs, for the treatment of neuropathic pain. We then introduced a series of chemical changes to improve the biological activity of these compounds and tested an optimized compound named BT44 in a panel of biological assays. BT44 efficiently and selectively stimulated the GFL receptor RET and activated the intracellular mitogene-activated protein kinase/extracellular signal-regulated kinase pathway in immortalized cells. In cultured sensory neurons, BT44 stimulated neurite outgrowth with an efficacy comparable to that of GFLs. BT44 alleviated mechanical hypersensitivity in surgery- and diabetes-induced rat models of neuropathic pain. In addition, BT44 normalized, to a certain degree, the expression of nociception-related neuronal markers which were altered by spinal nerve ligation, the neuropathy model used in this study. Our results suggest that the GFL mimetic BT44 is a promising new lead for the development of novel disease-modifying agents for the treatment of neuropathy and neuropathic pain.Peer reviewe

The contribution of microlensing surveys to the distance scale

In the early nineties several teams started large scale systematic surveys of the Magellanic Clouds and the Galactic Bulge to search for microlensing effects. As a by product, these groups have created enormous time-series databases of photometric measurements of stars with a temporal sampling duration and accuracy which are unprecedented. They provide the opportunity to test the accuracy of primary distance indicators, such as Cepheids, RRLyrae stars, the detached eclipsing binaries, or the luminosity of the red clump. We will review the contribution of the microlensing surveys to the understanding of the physics of the primary distance indicators, recent differential studies and direct distance determinations to the Magellanic Clouds and the Galactic Bulge.Comment: Invited review article to appear in: `Post-Hipparcos Cosmic Candles', A. Heck & F. Caputo (Eds), Kluwer Academic Publ., Dordrecht, in press. 21 pages; uses Kluwer's crckapb.sty LaTeX style file, enclose

Genetic variation in P2RX7 and pain tolerance

P2X7 is a nonselective cation channel activated by extracellular ATP. P2X7 activation contributes to the proinflammatory response to injury or bacterial invasion and mediates apoptosis. Recently, P2X7 function has been linked to chronic inflammatory and neuropathic pain. P2X7 may contribute to pain modulation both by effects on peripheral tissue injury underlying clinical pain states, and through alterations in central nervous system processing, as suggested by animal models. To further test its role in pain sensitivity, we examined whether variation within the P2RX7 gene, which encodes the P2X7 receptor, was associated with experimentally induced pain in human patients. Experimental pain was assessed in Tromso 6, a longitudinal and cross-sectional population-based study (N = 3016), and the BrePainGen cohort, consisting of patients who underwent breast cancer surgery (N = 831). For both cohorts, experimental pain intensity and tolerance were assessed with the cold-pressor test. In addition, multisite chronic pain was assessed in Tromso 6 and pain intensity 1 week after surgery was assessed in BrePainGen. We tested whether the single-nucleotide polymorphism rs7958311, previously implicated in clinical pain, was associated with experimental and clinical pain phenotypes. In addition, we examined effects of single-nucleotide polymorphisms rs208294 and rs208296, for which previous results have been equivocal. Rs7958311 was associated with experimental pain intensity in the meta-analysis of both cohorts. Significant associations were also found for multisite pain and postoperative pain. Our results strengthen the existing evidence and suggest that P2X7 and genetic variation in the P2RX7-gene may be involved in the modulation of human pain sensitivity.Peer reviewe

An Optical Frequency Domain Reflectometer’s (OFDR) Performance Improvement via Empirical Mode Decomposition (EMD) and Frequency Filtration for Smart Sensing

We describe a method for reducing the cost of optical frequency domain reflectometer (OFDR) hardware by replacing two reference channels, including an auxiliary interferometer and a gas cell, with a single channel. To extract useful information, digital signal processing methods were used: digital frequency filtering, as well as empirical mode decomposition. It is shown that the presented method helps to avoid the use of an unnecessary analog-to-digital converter and photodetector, while the OFDR trace is restored by the equal frequency resampling (EFR) algorithm without loss of high resolution and with good measurement repeatability

A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons in Vitro and Attenuates Experimental Neuropathy in the Rat

Neuropathic pain caused by nerve damage is a common and severe class of chronic pain. Disease-modifying clinical therapies are needed as current treatments typically provide only symptomatic relief; show varying clinical efficacy; and most have significant adverse effects. One approach is targeting either neurotrophic factors or their receptors that normalize sensory neuron function and stimulate regeneration after nerve damage. Two candidate targets are glial cell line-derived neurotrophic factor (GDNF) and artemin (ARTN), as these GDNF family ligands (GFLs) show efficacy in animal models of neuropathic pain (Boucher et al., 2000; Gardell et al., 2003: Wang et al., 2008, 2014). As these protein ligands have poor drug-like properties and are expensive to produce for clinical use, we screened 18,400 drug-like compounds to develop small molecules that act similarly to GFLs (GDNF mimetics). This screening identified BT13 as a compound that selectively targeted GFL receptor RET to activate downstream signaling cascades. BT13 was similar to NGF and ARTN in selectively promoting neurite outgrowth from the peptidergic class of adult sensory neurons in culture, but was opposite to ARTN in causing neurite elongation without affecting initiation. When administered after spinal nerve ligation in a rat model of neuropathic pain, 20 and 25 mg/kg of BT13 decreased mechanical hypersensitivity and normalized expression of sensory neuron markers in dorsal root ganglia. In control rats, BT13 had no effect on baseline mechanical or thermal sensitivity, motor coordination, or weight gain. Thus, small molecule BT13 selectively activates RET and offers opportunities for developing novel disease-modifying medications to treat neuropathic pain.Peer reviewe