Genetic deletion or TWEAK blocking antibody administration reduce atherosclerosis and enhance plaque stability in mice

Clinical complications associated with atherosclerotic plaques arise from luminal obstruction due to plaque growth or destabilization leading to rupture. Tumour necrosis factor ligand superfamily member 12 (TNFSF12) also known as TNF-related weak inducer of apoptosis (TWEAK) is a proinflammatory cytokine that participates in atherosclerotic plaque development, but its role in plaque stability remains unclear. Using two different approaches, genetic deletion of TNFSF12 and treatment with a TWEAK blocking mAb in atherosclerosis-prone mice, we have analysed the effect of TWEAK inhibition on atherosclerotic plaques progression and stability. Mice lacking both TNFSF12 and Apolipoprotein E (TNFSF12^−/−ApoE^−/−) exhibited a diminished atherosclerotic burden and lesion size in their aorta. Advanced atherosclerotic plaques of TNFSF12^−/−ApoE^−/− or anti-TWEAK treated mice exhibited an increase collagen/lipid and vascular smooth muscle cell/macrophage ratios compared with TNFSF12^+/+ApoE^−/− control mice, reflecting a more stable plaque phenotype. These changes are related with two different mechanisms, reduction of the inflammatory response (chemokines expression and secretion and nuclear factor kappa B activation) and decrease of metalloproteinase activity in atherosclerotic plaques of TNFSF12^−/−ApoE^−/−. A similar phenotype was observed with anti-TWEAK mAb treatment in TNFSF12^+/+ApoE^−/− mice. Brachiocephalic arteries were also examined since they exhibit additional features akin to human atherosclerotic plaques associated with instability and rupture. Features of greater plaque stability including augmented collagen/lipid ratio, reduced macrophage content, and less presence of lateral xanthomas, buried caps, medial erosion, intraplaque haemorrhage and calcium content were present in TNFSF12^−/−ApoE^−/− or anti-TWEAK treatment in TNFSF12^+/+ApoE^−/− mice. Overall, our data indicate that anti-TWEAK treatment has the capacity to diminish proinflamatory response associated with atherosclerotic plaque progression and to alter plaque morphology towards a stable phenotype.     

Identification of new central nervous system specific mouse microRNAs

MicroRNAs (miRNAs) are small regulatory molecules suppressing mRNA activity in metazoans. Here we describe two new miRNAs cloned from brain tissue of mouse embryos. These miRNAs are expressed mainly during embryogenesis and specifically in the central nervous system. We also established the expression patterns of three recently identified miRNAs that were found in our short RNA library. All of them were expressed in the brain and spinal chord but while miR-410 and miR-431 were central nervous system specific, miR-500 was also expressed in limb buds. In addition, the expression of miR-500 in limb buds showed very strong asymmetry in favour of the left hand side.     

Disparity in elevational shifts of European trees in response to recent climate warming

Predicting climate‐driven changes in plant distribution is crucial for biodiversity conservation and management under recent climate change. Climate warming is expected to induce movement of species upslope and towards higher latitudes. However, the mechanisms and physiological processes behind the altitudinal and latitudinal distribution range of a tree species are complex and depend on each tree species features and vary over ontogenetic stages. We investigated the altitudinal distribution differences between juvenile and adult individuals of seven major European tree species along elevational transects covering a wide latitudinal range from southern Spain (37°N) to northern Sweden (67°N). By comparing juvenile and adult distributions (shifts on the optimum position and the range limits) we assessed the response of species to present climate conditions in relation to previous conditions that prevailed when adults were established. Mean temperature increased by 0.86 °C on average at our sites during the last decade compared with previous 30‐year period. Only one of the species studied, Abies alba, matched the expected predictions under the observed warming, with a maximum abundance of juveniles at higher altitudes than adults. Three species, Fagus sylvatica, Picea abies and Pinus sylvestris, showed an opposite pattern while for other three species, such as Quercus ilex, Acer pseudoplatanus and Q. petraea, we were no able to detect changes in distribution. These findings are in contrast with theoretical predictions and show that tree responses to climate change are complex and are obscured not only by other environmental factors but also by internal processes related to ontogeny and demography.     

The first ferrocene analogues of muramyldipeptide

The two structurally interesting bioorganometallic analogues of muramyldipeptide (MDP) with potential immunomodulatory activity were synthesized starting from the O-protected N-acetylmuramic acid (MurNAc), l- or d-Ala and 1′-aminoferrocene-1-carboxylic acid (Fca). They were fully characterized by IR, ¹H NMR, ¹³C NMR and CD spectroscopy as well as by FD mass spectrometry.     

Rapid responses of C14 clone of Eucalyptus globulus to root drought stress: Time-course of hormonal and physiological signaling

The responses of juvenile plants of forest crops to drought stress are a key stage in the survival of forest populations. In this work, a suitable experimental system to study the early drought resistance mechanisms and signaling in a drought-tolerant clone (C14) of Eucalyptus globulus Labill is proposed. This system, using hydroponic culture and an osmotic agent, polyethylene glycol 8000, was demonstrated to induce severe stress in the root area, affecting the responses of the plantlets at the aerial level. These responses were very fast, beginning only 3 h after the induction of stress, and the results highlight the roles of xylematic abscisic acid (ABA) and pH changes over other signals, such as cytokinins, as early chemical signals in rapid water stress. The relationship between these chemical factors, ABA and pH, and the physiological and water parameters observed were significant, supporting their proposed principal role. This work aids our understanding of underlying responses to hydrological limitations of forest crops, and provides valuable information for further physiological and molecular studies of water stress in this and other tree species.     

Tracking the impact of drought on functionally different woody plants in a Mediterranean scrubland ecosystem

Climate warming is predicted to amplify drought stress. Thus, it is important to understand how coexisting plant species respond to severe droughts. Here we study how seven Mediterranean woody plant species with different evolutionary history and functional characteristics (Pinus halepensis Mill., Juniperus phoenicea L., Pistacia lentiscus L., Rhamnus lycioides L., Rosmarinus officinalis L., Genista scorpius (L.) DC., and Globularia alypum L.) responded to a severe winter drought during 2011–2012 in Spain. The study site is located in the Valcuerna valley, Monegros desert, northeastern Spain. We evaluated how the drought affected the annual growth-ring formation of the species by using dendrochronology and quantified the intensity of drought-induced defoliation and mortality and compared it between species and groups of species with different evolutionary history. Radial growth of all species was strongly reduced by the 2012 drought. The pre-Mediterranean species (P. halepensis, J. phoenicea, P. lentiscus and R. lycioides) reduced growth more than the Mediterranean species (R. officinalis, G. scorpius and G. alypum). Defoliation was significantly higher in pre-Mediterranean than in Mediterranean species. When species were analyzed separately we found that P. halepensis was the species with the highest growth reduction but J. phoenicea was defoliated more severely and showed higher mortality rates as a consequence of drought. In the case of the Mediterranean shrubs, drought-induced mortality was only noticeable in R. officinalis. Drought impacted growth of all species but this did not induce mortality in all of them. Growth reduction was dependent on evolutionary history. However, functional characteristics of the species such as leaf stomatal regulation and root architecture may be more important than evolutionary history on explaining drought-induced mortality. Indeed, species with shallow root systems such as J. phoenicea and R. officinalis were the most adversely affected by the drought.     

Albumin promotes neuronal survival by increasing the synthesis and release of glutamate

It is well known that the presence of albumin within the brain and the CSF is developmentally regulated. However, the physiological relevance of this phenomenon is not well established. We have previously shown that albumin specifically increases the flux of glucose and lactate through the pyruvate dehydrogenase reaction in astrocytes. Here we show that, in neurones, albumin also increases the oxidation of glucose and lactate through the pyruvate dehydrogenase-catalysed reaction, the final purpose of this being the synthesis of glutamate. Thus, in neurones, the presence of albumin strongly increased the synthesis and release of glutamate to the extracellular medium. Our results also suggest that glutamate release caused by albumin is designed to promote neuronal survival. Thus, under culture conditions in which neurones die by apoptosis, the presence of albumin promoted neuronal survival and maintained the differentiation programme of these cells, as judged by the expression of the axonal protein, GAP-43. The effect of albumin on neuronal survival was counteracted by the presence of DNQX, an antagonist of non-NMDA-glutamate receptors, suggesting that the glutamate synthesized and released due to the presence of albumin is responsible for neuronal survival. In addition, the effect of albumin seemed to depend on the activity of the NGF receptor, TrkA, suggesting that the glutamate synthesized and released due to the presence of albumin promotes neuronal survival through the activity of TrkA.