Interactions of multiple signaling pathways in neuropeptide Y-mediated bimodal vascular smooth muscle cell growth

Neuropeptide Y (NPY), a sympathetic cotransmitter, acts via G protein-coupled receptors to stimulate constriction and vascular smooth muscle cell (VSMC) proliferation through interactions with its Y1 receptors. However, VSMC proliferation appears bimodal, with high- and low-affinity peaks differentially blocked by antagonists of both Y1 and Y5 receptors. Here, we sought to determine the signaling mechanisms of NPY-mediated bimodal mitogenesis. In rat aortic VSMCs, NPY's mitogenic effect at all concentrations was blocked by pertussis toxin and was associated with decreased forskolin-stimulated cAMP levels. NPY also increased intracellular calcium levels; in contrast to mitogenesis, this effect was dose dependent. The rise in intracellular Ca2+ depended on extracellular Ca2+ and was mediated via activation of Y1 receptors, but not Y5 receptors. Despite differences in calcium, the signaling pathways activated at low and high NPY concentrations were similar. The mitogenic effect of the peptide at all doses was completely blocked by inhibitors of calcium/calmodulin-dependent kinase II (CaMKII), protein kinase C (PKC), and mitogen-activated protein kinase kinase, MEK1/2. Thus, in VSMCs, NPY-mediated mitogenesis signals primarily via Y1 receptors activating 2 Ca2+-dependent, growth-promoting pathways -- PKC and CaMKII. At the high-affinity peak, these 2 pathways are amplified by Y5 receptor-mediated, calcium-independent inhibition of the adenylyl cyclase - protein kinase A (PKA) pathway. All 3 mechanisms converge to the extracellular signal-regulated kinases (ERK1/2) signaling cascade and lead to VSMC proliferation.     

Necrotic core thickness and positive arterial remodeling index: emergent biomechanical factors for evaluating the risk of plaque rupture

Fibrous cap thickness is often considered as diagnostic of the degree of plaque instability. Necrotic core area (Core(area)) and the arterial remodeling index (Remod(index)), on the other hand, are difficult to use as clinical morphological indexes: literature data show a wide dispersion of Core(area) thresholds above which plaque becomes unstable. Although histopathology shows a strong correlation between Core(area) and Remod(index), it remains unclear how these interact and affect peak cap stress (Cap(stress)), a known predictor of rupture. The aim of this study was to investigate the change in plaque vulnerability as a function of necrotic core size and plaque morphology. Cap(stress) value was calculated on 5,500 idealized atherosclerotic vessel models that had the original feature of mimicking the positive arterial remodeling process described by Glagov. Twenty-four nonruptured plaques acquired by intravascular ultrasound on patients were used to test the performance of the associated idealized morphological models. Taking advantage of the extensive simulations, we investigated the effects of anatomical plaque features on Cap(stress). It was found that: 1) at the early stages of positive remodeling, lesions were more prone to rupture, which could explain the progression and growth of clinically silent plaques and 2) in addition to cap thickness, necrotic core thickness, rather than area, was critical in determining plaque stability. This study demonstrates that plaque instability is to be viewed not as a consequence of fibrous cap thickness alone but rather as a combination of cap thickness, necrotic core thickness, and the arterial remodeling index.     

On humans and wildlife in Mediterranean islands

Aim To investigate the effects of human‐induced landscape changes in Mediterranean islands on the ecological and evolutionary responses of bird communities and populations. The combination of mass extinction of large mammals and massive deforestation by humans was hypothesized to produce new selection regimes to which organisms were likely to respond. Habitat selection and niche breadth have been investigated at the scale of species, and phenotypic variation at the scale of local populations. Location The study was carried out along habitat gradients and in habitat mosaics at different spatial scales on the island of Corsica and in areas of similar size and structure in continental France. Methods Two sets of gradients have been used for investigating habitat selection and niche breadth: gradients of altitude, and gradients of vegetation structure. Population studies focused on the blue tit, Cyanistes caeruleus. Large samples of breeding attempts by this species in 10 habitats provided detailed data on phenotypic variation of fitness‐related traits both on Corsica and on the mainland. Results The extent of niche space used by birds differed substantially depending on which habitat gradient was considered. Many species have been found to contract their habitat niche along the elevation gradient on Corsica compared with the mainland, whereas all species in the vegetation gradient broadened their niche on the island. Breeding patterns of the blue tit differed considerably depending on whether they settle in deciduous oaks (Quercus humilis) or in evergreen sclerophyllous oaks (Quercus ilex). Phenotypic variation of breeding traits was much higher on the island, where more populations were correctly timed for the best breeding period than on the mainland, a pattern that is likely to result from lower dispersal of organisms on the island. Main conclusions The differences in observed niche breadth between the two series of habitat gradients is explained both by the species‐specific ecology of the species and the human‐induced environmental history of Corsica. Large‐scale landscape changes provided new opportunities for island colonization by non‐forest species, which are isolated as small, ‘fugitive’ local populations. In both gradients, forest species that are typical components of the Corsican bird fauna definitely expanded their niche and occupied a wider range of habitats on Corsica than on the mainland. At the population scale, landscapes included habitat patches with contrasted selection regimes, which resulted in high phenotypic variation for many fitness‐related traits. Reduced dispersal of birds on the island resulted in a much higher degree of local differentiation on Corsica than on the mainland.     

Changes in serum DHEA and eleven of its metabolites during 12-month percutaneous administration of DHEA

Healthy postmenopausal women aged 60-65 years (n=150) were randomized to receive twice daily application on the skin of 3g of a 0.3% dehydroepiandrosterone (DHEA) or placebo emulsion for 12 months. Serum DHEA and eleven of its metabolites were measured at screening and on day 1, as well as at 1, 3, 6, 9 and 12 months to study long-term metabolism. While serum DHEA and androst-5-ene-3beta, 17beta-diol (5-diol) increased by 203% and 178%, respectively, on average, during the 12-month period, the sum of concentrations of the metabolites of androgens, namely androsterone glucuronide (ADT-G), androstane-3alpha,17beta-diol-3G and -17G increased by only 71% while usually non statistically significant changes of 30%, 17% and 20% were observed for estrone (E(1)), estradiol (E(2)) and E(1) sulfate (E(1)-S), respectively. Despite the return of serum DHEA to normal premenopausal values with the present DHEA treatment regimen, the 65% decrease in the androgen pool found in this group of postmenopausal women is in fact corrected by only 24%, thus remaining 41% below the values found in normal premenopausal women. In fact, the changes in serum DHEA observed after percutaneous DHEA administration are a 186% overestimate of the true changes in androgen formation while the overestimate of estrogen production is even much higher. On the other hand, the pharmacokinetics of the steroids are stable over the 12-month period with no significant induction or decrease of activity of the enzymatic systems transforming DHEA predominantly into androgens.     

Genetic analysis of emotional reactivity in sheep: effects of the genotypes of the lambs and of their dams

A total of 1347 weaned lambs from eight genotypes were tested over five consecutive years: Romanov (ROM) and Lacaune (LAC) pure breeds, the two F1 crossbreeds (RL and LR) and the offspring of ewes from these four genotypes sired with Berrichon-du-Cher rams (BCF). The lambs were individually exposed to three challenging tests involving novelty, human contact and social isolation. Ten synthetic variables were used to express social reactivity (i.e., active vs. passive strategy), exploratory activity and reactivity to humans. BCF crossbreds were more active (i.e., high bleats, locomotion and attempts to escape) than purebreds and F1. In contrast, ROM expressed more passive responses (i.e., low bleats and vigilance postures) than LAC and BCF crossbreds. In addition, ROM approached a motionless human less and had longer flight distances to an approaching human than did LAC and BCF crossbreds. When restrained, ROM, and to a lesser extent B×ROM and B×LR, avoided human contact more than did LAC, RL and B×LAC. Most of these differences were explained by direct additive genetic effects while maternal influences or heterosis effects were rarely significant. The highest heritability was for high bleats (h² = 0.48). Females were more active and avoided human contact more than did males.     

Infliximab therapy in rheumatoid arthritis and ankylosing spondylitis-induced specific antinuclear and antiphospholipid autoantibodies without autoimmune clinical manifestations: a two-year prospective study

Dysfunction in various parts of immune defence, such as immune response, immune complex clearance, and inflammation, has an impact on pathogenesis in systemic lupus erythematosus (SLE). We hypothesised that combinations of common variants of genes involved in these immune functions are associated with susceptibility to SLE. The following variants were analysed: HLA DR3, HLA DQ2, C4AQ0, Fcγ receptor IIa (FcγRIIa) genotype R/R, Fcγ receptor IIIa (FcRγIIIa) genotype F/F, mannan-binding lectin (MBL) genotype conferring a low serum concentration of MBL (MBL-low), and interleukin-1 receptor antagonist (IL-1Ra) genotype 2/2. Polymorphisms were analysed in 143 Caucasian patients with SLE and 200 healthy controls. HLA DR3 in SLE patients was in 90% part of the haplotype HLA DR3-DQ2-C4AQ0, which was strongly associated with SLE (odds ratio [OR] 2.8, 95% CI 1.7–4.5). Analysis of combinations of gene variants revealed that the strong association with SLE for HLA DR3-DQ2-C4AQ0 remained after combination with FcγRIIa R/R, FcγRIIIa F/F, and MBL-low (OR>2). Furthermore, the combination of the FcγRIIa R/R and IL-1Ra 2/2 genotypes yielded a strong correlation with SLE (OR 11.8, 95% CI 1.5–95.4). This study demonstrates that certain combinations of gene variants may increase susceptibility to SLE, suggesting this approach for future studies. It also confirms earlier findings regarding the HLA DR3-DQ2-C4AQ0 haplotype.     

Hyperhydricity of Micropropagated Shoots: A Typically Stress-induced Change of Physiological State

Hyperhydricity of micropropagated shoots, formerly called vitrification, undoubtedly results from growth and culture conditions, subjectively reputated as stressing factors: wounding, infiltration of soft culture medium, generally of a high ionic strength, rich in nitrogen and in growth regulators in a special balance, in a humid and gaseous confined atmosphere. Stress is (objectively) defined as a disruption of homeostasis resulting from a constraint escaping the usual flexibility of metabolism. It induces another temporary (reversible) or definitive (irreversible) thermodynamic physiological state. The state-change concept developed by Strasser (1988) and Strasser and Tsimilli-Michael (2001) is applicable to the phenomenon of hyperhydricity. An appraisal of the redox capacities of hyperhydrated shoots together with a study of some enzymic activities that catalyse pentose phosphate and glycolytic pathways has indeed shown that such shoots have evolved towards a temporary state of lower differentiation or a juvenile state with a sufficient activity to survive and to defend themselves.