The PPARbeta/delta agonist GW0742 relaxes pulmonary vessels and limits right heart hypertrophy in rats with hypoxia-induced pulmonary hypertension.

BACKGROUND: Pulmonary vascular diseases are increasingly recognised as important clinical conditions. Pulmonary hypertension associated with a range of aetiologies is difficult to treat and associated with progressive morbidity and mortality. Current therapies for pulmonary hypertension include phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, or prostacyclin mimetics. However, none of these provide a cure and the clinical benefits of these drugs individually decline over time. There is, therefore, an urgent need to identify new treatment strategies for pulmonary hypertension. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that the PPARbeta/delta agonist GW0742 induces vasorelaxation in systemic and pulmonary vessels. Using tissue from genetically modified mice, we show that the dilator effects of GW0742 are independent of the target receptor PPARbeta/delta or cell surface prostacyclin (IP) receptors. In aortic tissue, vascular relaxant effects of GW0742 were not associated with increases in cGMP, cAMP or hyperpolarisation, but were attributed to inhibition of RhoA activity. In a rat model of hypoxia-induced pulmonary hypertension, daily oral dosing of animals with GW0742 (30 mg/kg) for 3 weeks significantly reduced the associated right heart hypertrophy and right ventricular systolic pressure. GW0742 had no effect on vascular remodelling induced by hypoxia in this model. CONCLUSIONS/SIGNIFICANCE: These observations are the first to show a therapeutic benefit of 'PPARbeta/delta' agonists in experimental pulmonary arterial hypertension and provide pre-clinical evidence to favour clinical trials in man.

Hidden Markov analysis describes dive patterns in semiaquatic animals

Existing methods of dive analysis, developed for fully aquatic animals, tend to focus on frequency of behaviors rather than transitions between them. They, therefore, do not account for the variability of behavior of semiaquatic animals, and the switching between terrestrial and aquatic environments. This is the first study to use hidden Markov models (HMM) to divide dives of a semiaquatic animal into clusters and thus identify the environmental predictors of transition between behavioral modes. We used 18 existing data sets of the dives of 14 American mink (Neovison vison) fitted with time-depth recorders in lowland England. Using HMM, we identified 3 behavioral states (1, temporal cluster of dives; 2, more loosely aggregated diving within aquatic activity; and 3, terminal dive of a cluster or a single, isolated dive). Based on the higher than expected proportion of dives in State 1, we conclude that mink tend to dive in clusters. We found no relationship between temperature and the proportion of dives in each state or between temperature and the rate of transition between states, meaning that in our study area, mink are apparently not adopting different diving strategies at different temperatures. Transition analysis between states has shown that there is no correlation between ambient temperature and the likelihood of mink switching from one state to another, that is, changing foraging modes. The variables provided good discrimination and grouped into consistent states well, indicating promise for further application of HMM and other state transition analyses in studies of semiaquatic animals.

Persistence in diving American mink

Background American mink forage on land and in water, with aquatic prey often constituting a large proportion of their diet. Their long, thin body shape and relatively poor insulation make them vulnerable to heat loss, particularly in water, yet some individuals dive over 100 times a day. At the level of individual dives, previous research found no difference in dive depth or duration, or the total number of dives per day between seasons, but mink did appear to make more dives per active hour in winter than in summer. There was also no difference in the depth or duration of individual dives between the sexes, but there was some evidence that females made more dives per day than males. However, because individual mink dives tend to be extremely short in duration, persistence (quantified as the number of consecutive dives performed) may be a more appropriate metric with which to compare diving behaviour under different scenarios. Results Mink performed up to 28 consecutive dives, and dived continually for up to 36 min. Periods of more loosely aggregated diving (termed ‘aquatic activity sessions’) comprised up to 80 dives, carried out over up to 162.8 min. Contrary to our predictions, persistence was inversely proportional to body weight, with small animals more persistent than large ones, and (for females, but not for males) increased with decreasing temperature. For both sexes, persistence was greater during the day than during the night. Conclusions The observed body weight effect may point to inter-sexual niche partitioning, since in mink the smallest animals are females and the largest are males. The results may equally point to individual specialism’s, since persistence was also highly variable among individuals. Given the energetic costs involved, the extreme persistence of some animals observed in winter suggests that the costs of occasional prolonged activity in cold water are outweighed by the energetic gains. Analysing dive persistence can provide information on an animal���s physical capabilities for performing multiple dives and may reveal how such behaviour is affected by different conditions. Further development of monitoring and biologging methodology to allow quantification of hunting success, and thus the rewards obtained under alternative scenarios, would be insightful.

Poorest countries experience earlier anthropogenic emergence of daily temperature extremes

Understanding how the emergence of the anthropogenic warming signal from the noise of internal variability translates to changes in extreme event occurrence is of crucial societal importance. By utilising simulations of cumulative carbon dioxide (CO2) emissions and temperature changes from eleven earth system models, we demonstrate that the inherently lower internal variability found at tropical latitudes results in large increases in the frequency of extreme daily temperatures (exceedances of the 99.9th percentile derived from pre-industrial climate simulations) occurring much earlier than for mid-to-high latitude regions. Most of the world's poorest people live at low latitudes, when considering 2010 GDP-PPP per capita; conversely the wealthiest population quintile disproportionately inhabit more variable mid-latitude climates. Consequently, the fraction of the global population in the lowest socio-economic quintile is exposed to substantially more frequent daily temperature extremes after much lower increases in both mean global warming and cumulative CO2 emissions.

MÍDIAS SOCIAIS DIGITAIS: ESPAÇO DE RELACIONAMENTO E COMUNICAÇÃO ESTRATÉGICA

O trabalho tem como proposta avaliar a postura das organizações nas mídias sociais digitais, considerando o fato de que esses novos ambientes virtuais têm modificado drasticamente a maneira pela qual elas promovem o relacionamento com seus públicos estratégicos. O objetivo principal da pesquisa é identificar e compreender como as organizações se posicionam diante de comentários desfavoráveis nas mídias sociais digitais que possam impactar sua imagem e reputação, bem como mostrar a importância de monitorar constantemente o consumidor e dialogar com ele nos canais digitais para evitar riscos à marca. A metodologia aplicada denomina-se Estudo de Casos Múltiplos, por meio da qual analisaram-se os comentários desfavoráveis às marcas: Vivo, Tim e Oi, na página do Facebook, durante o mês de setembro de 2015. Construiu-se um protocolo de pesquisa, e realizou-se o acompanhamento dessas marcas analisando-lhes os posts e os comentários desfavoráveis coletados no período. Constatou-se, após tais procedimentos que as operadoras apresentam frequentemente dificuldades para se relacionar com os públicos nas mídias sociais digitais, o que as coloca em risco quanto à sua imagem e reputação.

Notes of proceedings and cases determined in the high court of errors and appeals, the court of chancery, and the orphans court of the state of Delaware, 1792-1832

Contains summaries of cases heard by the Delaware Supreme Court and the Delaware Appeals Court in the counties of Sussex, Kent, and Newcastle covering a variety of legal topics. Supposedly based on Wilson's Red Book.

The enthalpy and heat capacity of uranium monocarbide to 1200C /

"Contract AT(30-1)-2789."

Les moeurs du jour, ou Histoire de Sir William Harrington. Partie 2 / , écrite du vivant de M. Richardson,... revue et retouchée par lui sur le manuscrit de l'auteur

Titre original : The history of sir William Harrington

Les moeurs du jour, ou Histoire de Sir William Harrington. Partie 4 / , écrite du vivant de M. Richardson,... revue et retouchée par lui sur le manuscrit de l'auteur

Titre original : The history of sir William Harrington

Les moeurs du jour, ou Histoire de Sir William Harrington. Partie 3 / , écrite du vivant de M. Richardson,... revue et retouchée par lui sur le manuscrit de l'auteur

Titre original : The history of sir William Harrington

Les moeurs du jour, ou Histoire de Sir William Harrington. Partie 1 / , écrite du vivant de M. Richardson,... revue et retouchée par lui sur le manuscrit de l'auteur

Titre original : The history of sir William Harrington

Oeuvres politiques de Jacques Harrington, écuyer : contenant la République d'Océana, les Aphorismes, & les autres traités du même auteur ; précédées de l'Histoire de sa vie, écrite par Jean - Toland ; Ouvrage traduit de l'anglois [par Pierre François Henry] ; Tome premier [-troisième]

Mode of access: Internet.

Home lighting - how to make it comfortable and effective. By A.L. Powell and R.E. Harrington.

Mode of access: Internet.