Opioid receptor signaling, analgesic and side effects induced by a computationally designed pH-dependent agonist

Novel pain killers without adverse effects are urgently needed. Opioids induce central and intestinal side effects such as respiratory depression, sedation, addiction, and constipation. We have recently shown that a newly designed agonist with a reduced acid dissociation constant (pK(a)) abolished pain by selectively activating peripheral mu-opioid receptors (MOR) in inflamed (acidic) tissues without eliciting side effects. Here, we extended this concept in that pK(a) reduction to 7.22 was achieved by placing a fluorine atom at the ethylidene bridge in the parental molecule fentanyl. The new compound (FF3) showed pH-sensitive MOR affinity, [S-35]-GTP gamma S binding, and G protein dissociation by fluorescence resonance energy transfer. It produced injury-restricted analgesia in rat models of inflammatory, postoperative, abdominal, and neuropathic pain. At high dosages, FF3 induced sedation, motor disturbance, reward, constipation, and respiratory depression. These results support our hypothesis that a ligand's pK(a) should be close to the pH of injured tissue to obtain analgesia without side effects

Numerical Analysis of a Dual Polarization Mode-Locked Laser with a Quarter Wave Plate

Dynamical behaviors and frequency characteristics of an active mode-locked laser with a quarter wave plate (QWP) are numerically studied by using a set pf vectorial laser equation. Like a polarization self-modulated laser, a frequency shift of half the cavity mode spacing exists between the eigen-modes in the two neutral axes of QWP. Within the active medium, the symmetric gain and cavity structure maintain the pulse's circular polarization with left-hand and right-hand in turn for each round trip. Once the left-hand or right-hand circularly polarized pulse passes through QWP, its polarization is linear and the polarized direction is in one of the directions of i45o with respect to the neutral axes of QWP. The output components in the directions of i45" from the mirror close to QWP are all linearly polarized with a period of twice the round-trip time

Driven Interface Depinning in a Disordered Medium

The dynamics of a driven interface in a medium with random pinning forces is analyzed. The interface undergoes a depinning transition where the order parameter is the interface velocity $v$, which increases as $v \sim (F-F_c)^\theta$ for driving forces $F$ close to its threshold value $F_c$. We consider a Langevin-type equation which is expected to be valid close to the depinning transition of an interface in a statistically isotropic medium. By a functional renormalization group scheme the critical exponents characterizing the depinning transition are obtained to the first order in $\epsilon=4-D>0$, where $D$ is the interface dimension. The main results were published earlier [T. Nattermann et al., J. Phys. II France {\bf 2} (1992) 1483]. Here, we present details of the perturbative calculation and of the derivation of the functional flow equation for the random-force correlator. The fixed point function of the correlator has a cusp singularity which is related to a finite value of the threshold $F_c$, similar to the mean field theory. We also present extensive numerical simulations and compare them with our analytical results for the critical exponents. For $\epsilon =1$ the numerical and analytical results deviate from each other by only a few percent. The deviations in lower dimensions $\epsilon = 2,3$ are larger and suggest that the roughness exponent is somewhat larger than the value $\zeta = \epsilon / 3$ of an interface in thermal equilibrium.Comment: 32 pages, 14 figures, REVTeX, to be published in Annalen der Physi

Instability Criterion of One-Dimensional Detonation Wave with Three-Step Chain Branching Reaction Model

One-dimensional detonation waves are simulated with the three-step chain branching reaction model, and the instability criterion is studied. The ratio of the induction zone length and the reaction zone length may be used to decide the instability, and the detonation becomes unstable with the high ratio. However, the ratio is not invariable with different heat release values. The critical ratio, corresponding to the transition from the stable detonation to the unstable detonation, has a negative correlation with the heat release. An empirical relation of the Chapman-Jouguet Mach number and the length ratio is proposed as the instability criterion

Set Up of Student Work

All students are welcome to participate in this student exhibition in this 1500 sq. foot finished warehouse space in downtown Buffalo just across from the arena. You must be able to deliver and set up your work between noon and 6pm on Wednesday the 14, and take your work with you at the end of the conference. Work must be ready to hang/install/etc... There will be a reception Wednesday evening

On the possibility of ethical reflection outside of scope of nietzschean critique of morality

O artigo reconstrói duas tentativas de delimitação da abrangência da crítica nietszchiana à moralidade: a primeira atribui a Nietzsche uma rejeição radical da moral, associando-o a uma perspectiva imoralista; a segunda defende que a crítica do filósofo se dirige a uma moralidade específica, oriunda da tradição platônica/cristã. Após reconstruir as duas abordagens, apresenta-se uma interpretação alternativa que mostra que, embora a crítica nietszchiana vise toda moral centrada na noção de obrigação, nem por isso ela esgota o domínio da valoração prática.The paper reconstructs two attempts at outlining the scope of Nietzsche’s criticism of morality: the first attributes to Nietzsche a radical rejection of morality and associates him to an imoralist perspective; the second claims that his criticism aims at a particular morality, rooted on the Platonic/Christian tradition. The paper presents an alternative interpretation, arguing that, although Nietzsche’s criticism aims at any morality centred on the notion of obligation, this does not mean that it exhausts all the practical value domain.The paper reconstructs two attempts at outlining the scope of Nietzsche’s criticism of morality: the first attributes to Nietzsche a radical rejection of morality and associates him to an imoralist perspective; the second claims that his criticism aims at a particular morality, rooted on the Platonic/Christian tradition. The paper presents an alternative interpretation, arguing that, although Nietzsche’s criticism aims at any morality centred on the notion of obligation, this does not mean that it exhausts all the practical value domain

Um relato intempestivo

The present text represents the revised version of the report that I presented at the end of the supervised practice in philosophy. The detail is that the completion of the supervised practice dates back to 2014 — that is, at least seven years have passed, many things have changed, starting with the organization of High School: I thought, therefore, that it would be more accurate to qualify my report as an untimely report. But despite this extemporaneousness — or precisely because of it — it may be that the text still retains an interest for today's reader: for the text deals, first of all, with a problem that is itself extemporaneous, notably, the setbacks with which is confronted a trainee-teachertrying to put into practice everything he has planned.O presente texto é uma versão revista do relatório que apresentei ao final do estágio supervisionado em filosofia. O detalhe é que a realização do estágio remonta aos idos de 2014 — ou seja, lá se vão pelo menos sete anos, muitas coisas não são mais as mesmas, a começar pelas políticas educacionais que estruturam o Ensino Médio: julguei, pois, que seria mais apurado qualificar meu relato como um relato intempestivo. Mas apesar dessa extemporaneidade — ou justamente por causa dela — pode ser que o texto ainda conserve algum interesse para o leitor de hoje: pois embora remonte a um contexto em que as políticas educacionais do ensino médio eram outras, muito diferentes das de agora, o presente relato trata, sobretudo, de um problema ele próprio extemporâneo, a saber, as contrariedades com que se depara um professor-aprendiz ao tentar pôr em prática tudo o que planejou

O elemento estranho da experiência: a crítica como doutrina do conceito de incondicionado

O artigo busca expor as linhas fundamentais do argumento formulado por Afrikan Spir (Denken und Wirklichkeit) para sustentar a principal reivindicação de sua releitura da fi- losofia crítica, notadamente, a reivindicação de que a realidade (das Real) é um elemento estranho à experiência (das Wirkliche)

A reconstrução da linguagem: alguns poréns

O fato de que se pode elaborar artificialmente uma linguagem manipulável pelo cálculo lógico a partir das estruturas da linguagem natural dá provas de que a linguagem pode ser reescrita por inteiro formalmente? Ou melhor: até que ponto a linguagem natural pode ser reescrita apropriadamente e sem prejuízos quanto ao significado através de sistemas formais de simbolização? A partir do livre desenvolvimento de algumas intuições da filosofia tardia de Wittgenstein, o presente texto aponta algumas dificuldades para quem pensa poder dar uma resposta otimista a essas indagações.Does the fact that a language can be artificially constructed using logical calculus from the structures of natural language provide evidence that language can be entirety rewritten formally? Or rather: to what extent can natural language be rewritten appropriately and without to prejudice its meaning through systems of formal symbolization? Based on the free consideration of some intuitions from Wittgenstein's late philosophy, this text points out some difficulties for those who think they can give an optimistic answer to these questions

"alma é apenas uma palavra para um algo no corpo": a propósito de uma sentença de Zaratustra repetidas vezes mencionada nos manuscritos de Wittgenstein

In this article I discuss an excerpt from Wittgenstein’s manuscripts in which a sentence from Zarathustra is mentioned. Adopting the excerpt as an exemplary case, I intend to show that the criticism of the illusory aspect of much of what is said in the language of psychological concepts, contrary to what it may seems at first, does not give reason to adopt a materialist posture such as that expressed in sentence of Zarathustra. In the sequence, I then try to show that the very reasoning that proceeds from the linguistic criticism of psychological concepts to the affirmation of the inexistence of such phenomena stands on a grammatical illusion