Protease-activated receptor 2 (PAR2) protein and transient receptor potential vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling

G protein-coupled receptors of nociceptive neurons can sensitize transient receptor potential (TRP) ion channels, which amplify neurogenic inflammation and pain. Protease-activated receptor 2 (PAR(2)), a receptor for inflammatory proteases, is a major mediator of neurogenic inflammation and pain. We investigated the signaling mechanisms by which PAR(2) regulates TRPV4 and determined the importance of tyrosine phosphorylation in this process. Human TRPV4 was expressed in HEK293 cells under control of a tetracycline-inducible promoter, allowing controlled and graded channel expression. In cells lacking TRPV4, the PAR(2) agonist stimulated a transient increase in [Ca(2+)](i). TRPV4 expression led to a markedly sustained increase in [Ca(2+)](i). Removal of extracellular Ca(2+) and treatment with the TRPV4 antagonists Ruthenium Red or HC067047 prevented the sustained response. Inhibitors of phospholipase A(2) and cytochrome P450 epoxygenase attenuated the sustained response, suggesting that PAR(2) generates arachidonic acid-derived lipid mediators, such as 5',6'-EET, that activate TRPV4. Src inhibitor 1 suppressed PAR(2)-induced activation of TRPV4, indicating the importance of tyrosine phosphorylation. The TRPV4 tyrosine mutants Y110F, Y805F, and Y110F/Y805F were expressed normally at the cell surface. However, PAR(2) was unable to activate TRPV4 with the Y110F mutation. TRPV4 antagonism suppressed PAR(2) signaling to primary nociceptive neurons, and TRPV4 deletion attenuated PAR(2)-stimulated neurogenic inflammation. Thus, PAR(2) activation generates a signal that induces sustained activation of TRPV4, which requires a key tyrosine residue (TRPV4-Tyr-110). This mechanism partly mediates the proinflammatory actions of PAR(2).

Neurogenic responses mediated by vanilloid receptor-1 (TRPV1) are blocked by the high affinity antagonist, iodo-resiniferatoxin

(1) Stimulation of the vanilloid receptor-1 (TRPV1) results in the activation of nociceptive and neurogenic inflammatory responses. Poor specificity and potency of TRPV1 antagonists has, however, limited the clarification of the physiological role of TRPV1. (2) Recently, iodo-resiniferatoxin (I-RTX) has been reported to bind as a high affinity antagonist at the native and heterologously expressed rat TRPV1. Here we have studied the ability of I-RTX to block a series of TRPV1 mediated nociceptive and neurogenic inflammatory responses in different species (including transfected human TRPV1). (3) We have demonstrated that I-RTX inhibited capsaicin-induced mobilization of intracellular Ca(2+) in rat trigeminal neurons (IC(50) 0.87 nM) and in HEK293 cells transfected with the human TRPV1 (IC(50) 0.071 nM). (4) Furthermore, I-RTX significantly inhibited both capsaicin-induced CGRP release from slices of rat dorsal spinal cord (IC(50) 0.27 nM) and contraction of isolated guinea-pig and rat urinary bladder (pK(B) of 10.68 and 9.63, respectively), whilst I-RTX failed to alter the response to high KCl or SP. (5) Finally, in vivo I-RTX significantly inhibited acetic acid-induced writhing in mice (ED(50) 0.42 micro mol kg(-1)) and plasma extravasation in mouse urinary bladder (ED(50) 0.41 micro mol kg(-1)). (6) In in vitro and in vivo TRPV1 activated responses I-RTX was approximately 3 log units and approximately 20 times more potent than capsazepine, respectively. This high affinity antagonist, I-RTX, may be an important tool for future studies in pain and neurogenic inflammatory models.

“Les petits renards qui détruisent la Vigne du Seigneur Sabaoth”. Innocent III et le Cantique des cantiques

This article examines medieval interpretations of the Song of Songs and their appearance in the correspondence of one of the greatest popes of the High Middle Ages: Innocent III (1198-1216). Innocent III’s depiction of heretics in the south of France as ‘the little foxes which destroy the vineyard of the Lord of Hosts’ was not unprecedented: decades earlier Saint Bernard of Clairvaux had also likened the ‘little foxes’ to heretics in his sermons. Bernard’s renown both as mystical theologian and tireless political advocate of the papacy meant that Innocent is likely to have drawn on such sermons for inspiration when composing his correspondence to the Christian faithful. Innocent’s references to the Song of Songs also provide conclusive evidence that a significant number of his letters have a highly personal flavour and that we really can discern a pope’s own ‘voice’ through his correspondence.

CDASH: a cloud-enabled program for structure solution from powder diffraction data

The simulated annealing approach to crystal structure determination from powder diffraction data, as implemented in the DASH program, is readily amenable to parallelization at the individual run level. Very large scale increases in speed of execution can be achieved by distributing individual DASH runs over a network of computers. The CDASH program delivers this by using scalable on-demand computing clusters built on the Amazon Elastic Compute Cloud service. By way of example, a 360 vCPU cluster returned the crystal structure of racemic ornidazole (Z0 = 3, 30 degrees of freedom) ca 40 times faster than a typical modern quad-core desktop CPU. Whilst used here specifically for DASH, this approach is of general applicability to other packages that are amenable to coarse-grained parallelism strategies.

Purinergic signalling is involved in the malaria parasite Plasmodium falciparum invasion to red blood cells

Plasmodium falciparum, the most important etiological agent of human malaria, is endowed with a highly complex cell cycle that is essential for its successful replication within the host. A number of evidence suggest that changes in parasite Ca(2+) levels occur during the intracellular cycle of the parasites and play a role in modulating its functions within the RBC. However, the molecular identification of Plasmodium receptors linked with calcium signalling and the causal relationship between Ca(2+) increases and parasite functions are still largely mysterious. We here describe that increases in P. falciparum Ca(2+) levels, induced by extracellular ATP, modulate parasite invasion. In particular, we show that addition of ATP leads to an increase of cytosolic Ca(2+) in trophozoites and segmented schizonts. Addition of the compounds KN62 and Ip5I on parasites blocked the ATP-induced rise in [Ca(2+)](c). Besides, the compounds or hydrolysis of ATP with apyrase added in culture drastically reduce RBC infection by parasites, suggesting strongly a role of extracellular ATP during RBC invasion. The use of purinoceptor antagonists Ip5I and KN62 in this study suggests the presence of putative purinoceptor in P. falciparum. In conclusion, we have demonstrated that increases in [Ca(2+)](c) in the malarial parasite P. falciparum by ATP leads to the modulation of its invasion of red blood cells.

Constructive alignment in Computer Engineering and Informatics departments at Dalarna University : An empirical investigation

Background: Constructive alignment (CA) is a pedagogical approach that emphasizes the alignment between the intended learning outcomes (ILOs), teaching and learning activities (TLAs) and assessment tasks (ATs) as well as creation of a teaching/learning environment where students will be able to actively create their knowledge. Objectives: This paper aims at investigating the extent of constructively-aligned courses in Computer Engineering and Informatics department at Dalarna University, Sweden. This study is based on empirical observations of teacher’s perceptions of implementation of CA in their courses. Methods: Ten teachers (5 from each department) were asked to fill a paper-based questionnaire, which included a number of questions related to issues of implementing CA in courses. Results: Responses to the items of the questionnaire were mixed. Teachers clearly state the ILOs in their courses and try to align the TLAs and ATs to the ILOs. Computer Engineering teachers do not explicitly communicate the ILOs to the students as compared to Informatics teachers. In addition, Computer Engineering teachers stated that their students are less active in learning activities as compared to Informatics teachers. When asked about their subjective ratings of teaching methods all teachers stated that their current teaching is teacher-centered but they try to shift the focus of activity from them to the students. Conclusions: From teachers’ perspectives, the courses are partially constructively-aligned. Their courses are “aligned”, i.e. ILOs, TLAs and ATs are aligned to each other but they are not “constructive” since, according to them, there was a low student engagement in learning activities, especially in Computer Engineering department.

Atração de investimentos como instrumento de política industrial: o caso do ceará no período 1985-2002

This paper aims to assess the performance of credit and fiscal mechanisms in attracting industrial investment to the state of Ceará during 1985-2002, a period characterized by the political and administrative continuity which begun with the implementation of the so-called "Plan of Changes", during the term in office of former state governor Tasso Jereissati. In order to accomplish that, a survey was conducted of the state's credit, fiscal and infrastructure incentive mechanisms, industrial policy and the period's political context, as well as data from the Department of Industry and Commerce and on the economic performance of the state of Ceará. Over 700 industrial businesses were found to have been attracted into the state by means of the Industrial Investment Attraction Program, which amounted to a process of industry expansion while the country as a whole was going through a period of deindustrialization. The analysis points out that, if on one hand, the industrialization model then adopted was able to generate economic growth, on the other hand, it increased income concentration and could not drive industry into the less developed areas across the state's interior, as expected by Ceará's state government officials.

Incorporação de resíduo cerâmico para prevenção da retrogressão da resistência de cimentos de poços de petróleo submetidos à injeção de vapor

Steam injection is the most used thermal recovery method of oil nowadays because of the high degree of development of the technique that allows high recovery factors. However, injection of superheated steam into the reservoir affects the entire structure of the well, including the cemented layer that presents a retrogression of compressive strength and increases the permeability due to formation of more crystalline and denser phases at temperatures above 110 °C. These changes result in failures in the cement that favor the entrance of formation fluids into the annulus space resulting in unsafe operations and restrictions in the economic life of the well. But the strength retrogression can be prevented by partial replacement of cement by silica-based materials that reduce the CaO/SiO2 ratio of cement slurries changing the trajectory of the reactions, converting those deleterious phases in phases with satisfactory mechanical strength and permeability. The aim of this study was to evaluate the behavior of a ceramic waste material rich in silica in partial and total substitution of a mineral additive used to fight the strength retrogression of cement slurries subjected to high temperatures. The evaluation was made by compression, X-ray diffraction (XRD) and thermogravimetry (TG/DTG). The samples were submitted to a cycle of low temperature (38 °C) for 28 days and a cycle of low temperature followed by exposure to 280 ºC and 1000 psi by 3 days. The results showed that slurries with additions of up to 30% of the waste material are not enough to prevent the strength retrogression, while slurries with additions of the waste material combined with silica flour in various proportions produced hydrated products of low Ca/Si ratios that maintained the compressive strength at satisfactory levels

Avaliação agronômica da aplica��ão do resíduo da indústria processadora de goiabas em pomar comercial de goiabeiras

Dada a escassez de informações na literatura e a importância do manejo adequado de resíduos orgânicos na agricultura, objetivou-se avaliar os efeitos da aplica��ão do resíduo da indústria processadora de goiabas em um Argissolo Vermelho-Amarelo, determinando-se as alterações provocadas na química do solo, no estado nutricional de goiabeiras e na produção de frutos. As doses de resíduo aplicadas no pomar foram estabelecidas em função dos teores de N no resíduo. O delineamento empregado foi o de blocos casualizados, com cinco tratamentos e quatro repetições, sendo as doses do resíduo (moído) de 0, 9, 18, 27 e 36 t ha-1 (peso do material seco). Foram feitas três aplica��ões do resíduo: em 2006, 2007 e 2008. O resíduo da indústria processadora de goiabas promoveu aumento nos teores de P no solo; as goiabeiras apresentaram aumento dos teores de N, Ca, Mg e Mn; a produção de frutos foi alterada positiva e significativamente no terceiro ano do experimento.

Farinha de resíduos da indústria de filetagem de tilápias como fonte de proteína e minerais para alevinos de tilápia-do-nilo (Oreochromis niloticus)

Neste trabalho, objetivou-se avaliar a utilização da farinha de resíduos da indústria de filetagem de tilápias (FR) como fonte de proteína e de minerais em rações práticas na alimentação de alevinos de tilápia do Nilo. Foram utilizados 120 alevinos de tilápias do Nilo com peso e comprimento iniciais de 0,58 ± 0,05 g e 3,49 ± 0,09 cm, respectivamente, distribuídos em 24 aquários com capacidade para 30 L, em um delineamento inteiramente casualisado, com quatro tratamentos e seis repetições. Os peixes foram alimentados com rações contendo 30% de proteína digestível e 3.000 kcal de energia digestível/kg, de acordo com os seguintes tratamentos: CO - ração à base de milho e farelo de soja, sem suplementação de fósforo; FB - ração à base de milho e farelo de soja, com fosfato bicálcico; FB + FR - ração à base de milho e farelo de soja, suplementada com fosfato bicálcico (50%) e farinha de resíduos (50%); FT - ração à base de milho e farelo de soja, suplementada com farinha de resíduos. Ao final do experimento, os melhores resultados de desempenho foram observados nos animais que receberam suplementação de P. Quanto às características de carca��a, os animais que receberam a ração CO apresentaram maior teor de gordura corporal e menores teores de cinzas, Ca e P. A FR pode ser utilizada em rações para alevinos de tilápia do Nilo como fonte de P, sem prejuízos no desempenho e na composição corporal.

Níveis nutricionais de cálcio para aves de corte ISA Label criadas sob semiconfinamento

Determinaram-se os níveis nutricionais de cálcio (Ca) para aves, machos e fêmeas, da linhagem ISA Label, nas fases inicial (um a 28 dias), crescimento (28 a 56 dias) e final (56 a 84 dias). Foram realizados três ensaios, um para cada fase, e, em cada ensaio, 480 aves com idade correspondente à fase de criação foram alojadas em 24 unidades experimentais com áreas de abrigo e de pastejo. Foi utilizado delineamento inteiramente ao acaso, em esquema fatorial 4x2 (Ca e sexo), totalizando oito tratamentos com três repetiç ões de 20 aves. Avaliaram-se: ganho de peso (GP); consumo de dieta (CD); conversão alimentar (CA); teores de fósforo (PT), de cálcio (CaT) e de cinzas na tíbia (CT) e resistência à quebra óssea (RQO). Na fase inicial, recomenda-se 1,16% de Ca na dieta, para aves de ambos os sexos, na fase de crescimento, 0,78 e 0,88% de Ca para machos e fêmeas, respectivamente, e, na fase final, 0,69% de Ca na dieta para ambos os sexos.

Ideais formativos de homem da emissora de Educa��ão Rural de Caicó (Rio Grande do Norte, 1963-1978)

Under the aegis of the third diocese bishop of Caicó, Dom Manuel Tavares de Araújo, the Broadcasting Station of Rural Education of that city was founded, in May 1 s" 1963 with the ideal of being then an educational city, preferentially for youths and adults, rural meu and women of the arca of Seridó in Rio Grande do Norte state. In the year of its 40th birthday (2003), we began the investigation of that radio station choosing as study object its educational and formative programming, in the inc1usion of the first fifteen years of its existence (1963-1978), period that reaches the official inauguration of the Radio Station and the end of the bishopric of its fOllllder as Bishop of Caicó. Elucidating and showing Man's formative ideaIs longed by that Catholic educational broadcasting station, underlying to its radiophonic programming, such as the idealization for it reached, is the objective of this Doctorate work. It was considered pertinent to discover the guidelines that historically have permeated the Social Doçtrine of the Catholic Church addressing its aggiornamento, especially in what concerns to the employment of the modern ways of communication for the distance with the aim of evangelizing and educating. In arder to understand the ideaIs of the investigated educational Radio, we have delimited the research to the thematic Catholic Church, means of social communication and base education. In face of the study object and the aim to be reached it was appealed, methodologically, to the notion of cultural action present in Certeau (1995), and to the understanding of educational formation backgrounded fIam the modern thinkers that discuss it. Such frame references have allowed us to analyze in a wider spectrum tl)e programming broadcasted on the air by the sound wavys of that educ(itional Çatholic Radio, as well as, the very acts of cultural idealizations that has orientated it in its foundations. The thesis here defended is that. the Radio, at procJaiming itself as a broadcasting station of rural education directed preferably to the rural sertanejo countrymen, without neglecting its admitted ends, has surpassed them in its overall range. It was identified an articulate approach of its programmatic modules with the guid,elines emanateq from the Catholic Teaching about the use of the. means of social communication. At conceiving, establishin,g and executing an ec1ectic programmatic and div,ersified grating, the Rural Radio of Caicó has transcended to a strict human-Christian formation to request the development of the human, spiritual and cQrporaldimensions, jointly. With suchprogramming, it addressed to the seridoenses as real meu and women inserted in the "sertanej.o" environment with effective structural and existential problems of alI types, induding the hunger, the thirst, the syndical organization, the cQoperativism, the colIective modero work and the absence of universalizing school education. Its radiophonic transmissions, I}lled by the demands of an enlarged, open, dialogic and responsible communication, wheneIllbracing dedicated modules to religious and catechetical emissions, to the entertainment, to the radiojoumalism, to the country root culture, and to the school education of b se for the modality of the School and of the radiophonic classes, subsumed to ideaIs that longed for the formation of a multifaceted and pluridimensional sertanejo Man; of men and women that, without abjuring the Catholicism, were able to understand, to dialogued and to live together with the general demands of a society in progressive mutation, whose economical, social, cultural and educational demands it IDade themselves to be felt through the sertão potiguar of the Serido region, equal way of the intemationalized world

A luta do Bispo Dom José de Medeiros Delgado por educa��ão escolar para todos (Caicó-RN, 1941-1951)

The socioeducational program of actions developed by Dom José de Medeiros Delgado, first Bishop of Diocese of Caicó city in Rio Grande do Norte, from 1941 to 1951, is analyzed by the present work in a historical perspective, based upon the school culture refecence.Through this reference point, the general and peculiar school culture proper of catholic schools founded by Dom Delgado was learned.The schools are: the Ginásio Diocesano Seridoense (1942), the Escola Doméstica Popular Darci Vargas (1943, the Prevocacional School of Caicó (1944) and the Santo Cura d ars Seminar (1946). The socioeducational actions of Dom Delgado Bishop affected seven other towns surrounding Caicó. Places where catholic schools were founded and named after Escola do Pobre . In fight for schools for all social segments of city and rural natures, Dom Delgado founded four rural schools in the surroundings of Serra Negra, São João do Sabugi, Jardim do Seridó e Lagoa Nova. It is also part of his beneficial work the creation of rural cooperatives for the parents of the students from such schools

The locus coeruleus and central chemosensitivity

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Balancing guava nutrition with liming and fertilization

A resposta da goiabeira à calagem e à adubação pode ser monitorada por análises de tecido vegetal. O perfil nutricional é definido em relação a padrões de teores de nutrientes. No entanto, os teores de nutrientes-padrão são constantemente criticados por não considerarem as interações que ocorrem entre nutrientes e por gerarem tendências numéricas, decorrentes da redundância dos dados, da dependência de escala e da distribuição não normal. As técnicas de análise composicional de dados podem controlar esses dados tendenciosos, equilibrando os grupos de nutrientes, tais como os envolvidos na calagem e na adubação. A utilização das relações log isométricas (ilr) ortonormais, sequencialmente dispostas, evita tendências numéricas inerentes aos dados de composição. Os objetivos do trabalho foram relacionar o balanço de nutrientes dos tecidos vegetais com a produção de goiabeiras em pomares de 'Paluma' diferentemente corrigidos e adubados, e ajustar os atuais padrões de nutrientes com a faixa de equilíbrio das goiabeiras mais produtivas. Um experimento de calagem de sete anos e três, experimentos de três anos com doses de N, P2O5 e K2O, foram conduzidos em pomares de goiabeiras 'Paluma' em um Latossolo Vermelho-Amarelo. Os teores de N, P, K, Ca e Mg na planta foram monitorados anualmente. Selecionaram-se os balanços [N, P, K | Ca, Mg], [N, P | K], [N | P] e [Ca | Mg] para separar os efeitos da calagem (Ca-Mg) e dos fertilizantes (N-K) nos balanços de macronutrientes. Os balanços foram mais influenciados pela calagem do que pela fertilização. A produtividade das goiabeiras e seu balanço nutricional permitiram a definição de faixas de equilíbrio de nutrientes e sua validação com as faixas de concentrações críticas atualmente utilizadas no Brasil e combinadas em coordenadas ilr.