Mechanisms of soluble beta-amyloid impairment of endothelial function

Alzheimer's disease (AD) has been recently associated with vascular risk factors. beta-amyloid peptides (AbetaP), the main component of senile plaques typical of AD, circulate in soluble globular form in bloodstream. Interestingly, AbetaP is able to induce endothelial dysfunction, and this effect may represent the link between vascular and neuronal pathophysiological factors involved in AD. We aimed to clarify the molecular mechanisms underlying globular AbetaP-induced vascular toxicity. Using several methodological approaches, we have observed that in vascular tissues globular AbetaP is unable to induce oxidative stress, one of the mechanisms hypothesized involved in beta-amyloid toxicity. More important, we have demonstrated that globular AbetaP is able to localize on vascular endothelium, where it inhibits eNOS enzymatic activity. In particular, AbetaP enhances eNOS phosphorylation on threonine 495 and serine 116 and reduces acetylcholine-induced phosphorylation on serine 1177. Such an effect depends on a PKC signaling pathway, as suggested by its phosphorylation on serine 660. In fact, selective inhibition of the calcium-dependent group of PKC is able to rescue beta-amyloid-induced alteration of eNOS phosphorylation, NO production, and endothelial vasorelaxation. The activation of these Ca(2+)-dependent pathways is probably due to the ability of AbetaP to evoke Ca(2+) leakage from inositol 1,4,5-triphosphate receptors on endoplasmic reticulum. Our data demonstrate that globular AbetaP-induced endothelial NO dysfunction can be attributed to an alteration of intracellular Ca(2+) homeostasis, which could lead to the activation of calcium-dependent group of PKC with a consequent change of the eNOS phosphorylation pattern. These mechanisms could contribute to shed further light on the toxic effect of beta-amyloid in vascular tissues.     

Ligand-gated ion channels: mechanisms underlying ion selectivity

Anion/cation selectivity is a critical property of ion channels and underpins their physiological function. Recently, there have been numerous mutagenesis studies, which have mapped sites within the ion channel-forming segments of ligand-gated ion channels that are determinants of the ion selectivity. Site-directed mutations to specific amino acids within or flanking the M2 transmembrane segments of the anion-selective glycine, GABA(A) and GABA(C) receptors and the cation-selective nicotinic acetylcholine and serotonin (type 3) receptors have revealed discrete, equivalent regions within the ion channel that form the principal selectivity filter, leading to plausible molecular mechanisms and mathematical models to describe how ions preferentially permeate these channels. In particular, the dominant factor determining anion/cation selectivity seems to be the sign and exposure of charged amino acids lining the selectivity filter region of the open channel. In addition, the minimum pore diameter, which can be influenced by the presence of a local proline residue, also makes a contribution to such ion selectivity in LGICs with smaller diameters increasing anion/cation selectivity and larger ones decreasing it.     

Biodiversity in model ecosystems, I: coexistence conditions for competing species

This is the first of two papers where we discuss the limits imposed by competition to the biodiversity of species communities. In this first paper, we study the coexistence of competing species at the fixed point of population dynamic equations. For many simple models, this imposes a limit on the width of the productivity distribution, which is more severe the more diverse the ecosystem is (1994, Theor. Popul. Biol. 45, 227-276). Here we review and generalize this analysis, beyond the "mean-field"-like approximation of the competition matrix used in previous works, and extend it to structured food webs. In all cases analysed, we obtain qualitatively similar relations between biodiversity and competition: the narrower the productivity distribution is, the more species can stably coexist. We discuss how this result, considered together with environmental fluctuations, limits the maximal biodiversity that a trophic level can host.     

Bcl-2 overexpression in melanoma cells increases tumor progression-associated properties and in vivo tumor growth

In this study, we demonstrated that bcl-2 overexpression in human melanoma cells consistently enhanced the activity of multiple metastasis-related proteinases, in vitro cell invasion, and in vivo tumor growth. In particular, by using the M14 parental cell line, the MN8 control clone, and two bcl-2 overexpressing derivatives, we found that bcl-2 overexpressing cells exposed to hypoxia, when compared to parental cells, expressed higher level of several metalloproteases (MMPs) such as MMP-2, MMP-7, MT1-MMP, and tissue inhibitors of metalloproteases-1 and -2. Moreover, bcl-2 overexpression in melanoma cells enhanced in vitro invasion on matrigel and, in vivo tumor growth. The more aggressive behavior of bcl-2 transfectants tumors is significantly associated to an increase in MMP-2 expression as well as in a more elevated microvessel density as compared to the parental line. Taken together, our data suggest that bcl-2 plays a pivotal role in the regulation of molecules associated with the migratory and invasive phenotype, contributing, in cooperation to hypoxia, to tumor progression.     

Variation in ITGB3 has sex-specific associations with plasma lipoprotein(a) and whole blood serotonin levels in a population-based sample

A recent genome-scan identified the Leu33Pro polymorphism in the 3 integrin (ITGB3) gene as a quantitative trait locus for whole blood serotonin level in a large Hutterite pedigree. Because both the Leu33Pro polymorphism and the serotonin system have been implicated in cardiovascular disease (CVD) risk and treatment response, we studied additional variation in ITGB3 and its relationship to intermediate phenotypes associated with CVD in the same population. We examined associations between 15 single nucleotide polymorphisms (SNPs) across ITGB3 and five CVD-related traits in the Hutterites: plasma levels of high density lipoprotein-cholesterol (HDL-c), triglycerides (TG), low density lipoprotein-cholesterol (LDL-c), and lipoprotein(a) [Lp(a)] and blood pressure or hypertension. Seven of these SNPs in ITGB3 were associated with whole blood serotonin. Among the intermediate CVD-related phenotypes, only Lp(a) was associated with multiple ITGB3 SNPs, five of which were also associated with serotonin. A sex-stratified analysis revealed that the association between ITGB3 and Lp(a) is present only in females, whereas the association between ITGB3 and serotonin is concentrated in males. Our results suggest that variation in ITGB3 in addition to Leu33Pro could contribute to susceptibility to CVD and serotonin in a sex-specific manner.     

Pigment epithelium-derived factor is differentially expressed in peripheral neuropathies

Peripheral neuropathies are characterized by asymmetrical slowly progressive weakness with no upper motor neuron signs, and can occur either with or without pain. Due to poor knowledge of the disease mechanisms, available pain treatment is very limited. Because of the difficulties and invasiveness involved when performing direct analysis on peripheral and CNS, pathological markers can be searched for in the cerebrospinal fluid (CSF) as an alternative. To investigate pain mechanisms in peripheral neuropathy and find diagnostic markers, CSF samples were analyzed by a differential expression proteomic approach. We studied CSF from: neuropathic patients with pain (PN), without pain (NPN) and healthy controls (CN). 2-DE analysis showed ten protein spots differentially expressed, and six of these were identified by MS. In NPN patients we found an expression level decrease of three pigment epithelium-derived factor (PEDF) protein isoforms. Immunoblot with a specific antibody revealed the presence of additional PEDF isoforms not highlighted by differential expression analysis. Fucose residues on the oligosaccharide chain were found only in the isoforms down regulated in NPN patients. Considered as PEDF has important neurobiological effects, it might be considered an interesting pathology marker.     

Ricerche sul tessuto parasimpatico dell'ovaio umano

Zusammenfassung Die vom Verf. am menschlichen Material angestellten Forschungen haben den Beweis erbracht, da? mit einer fast konstanten H?ufigkeit im Ovargebiet (Markteil, Hilus, Ligamentum latum) Zellanh?ufungen epithelioidalen Aussehens vorkommen, die eine chromaffine Reaktion aufweisen und in der N?he oder an der Peripherie der sympathischen Nerven oder auch im Innern derselben zwischen den einzelnen Nervenfasern zu liegen kommen. Diese Elemente, meist oval?rer oder polygonaler Form, bergen in sich ein acidophiles, k?rnchenhaltiges oder spugn?ses Protoplasma; der Kern, gew?hnlich klein und exzentrisch gelagert, besitzt eine rundliche Form und ist nur schwer f?rbbar. Das Zellprotoplasma enth?lt oft Fett, Pigmente, manchmal auch Kristalloide. Solche Zellanh?ufungen fehlen wahrscheinlich nie in der Ovargegend des reifen Weibes; nur selten müssen zwecks ihrer Auffindung besondere Serienschnitte angefertigt werden, w?hrend gew?hnlich schon ein entsprechendes Fixierungsverfahren genügt, die Beobachtung oft sehr zahlreicher solcher Gebilde zu erm?glichen. Mit gro?er Wahrscheinlichkeit kann angenommen werden, da? es zwischen diesem im reifen Alter vorzufindenden Gewebe und dem im F?tus und bei Neugeborenen vorhandenen, mit analoger genitaler Lokalisierung, eine gewisse Kontinuit?t gibt. Die vermutliche Homologie der parasympathischen Zellen mit der sogenannten interstitiellen Drüse des Hodens kann nicht ohne weiteres angenommen werden, da ja sonst auch eine sichere bindegewebige Herkunft der parasympathischen Elemente angenommen werden mü?te. Von einem allgemeinen Standpunkt aus ist es nicht ausgeschlossen, da? das parasympathische Ovargewebe auch des innigen topographischen Zusammenhanges wegen, dazu bestimmt sei lokal auf dieselben einzuwirken, sei es vermittels des Adrenalins sei es an Hand eines anderen Inkrets; man kann auch einen Zusammenhang dieses Gewebes und anderer Genitaldrüsen (innensekretorischer) nicht ausschlie?en.

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Con 5 figure nel testo.     

Applications of ecological stoichiometry for sustainable acquisition of ecosystem services

Human activities have differentially altered biogeochemical cycling at local, regional and global scales. We propose that a stoichiometric approach, examining the fluxes of multiple elements and the ratio between them, may be a useful tool for better understanding human effects on ecosystem processes and services. The different scale of impacts of the elements carbon, nitrogen and phosphorus and the different nature of their biogeochemical cycles, imply a large variation of their stoichiometric ratios in space and time and thus divergent impacts on biota.
In this paper, we examine the effects of anthropogenic perturbations on nutrient ratios in ecosystems in two examples and one case study. Altered stoichiometry in agricultural systems (example 1) can affect not only crop yield and quality but also the interactions between plants and their pollinators, pests and pathogens. Human activities have also altered stoichiometry in coastal ecosystems (example 2). Increased N loading has especially lead to increased N:P and reduced Si:N ratios, with detrimental effects on ecosystem services derived from coastal pelagic food webs, such as fish yield and water quality. The terrestrial–aquatic linkage in stoichiometric alterations is illustrated with a case study, the Mississippi River watershed, where anthropogenic activities have caused stoichiometric changes that have propagated through the watershed into the northern Gulf of Mexico.
Coupled with altered stoichiometric nutrient inputs are the inherent differences in variation and sensitivity of different ecosystems to anthropogenic disturbance. Furthermore, the connections among the components of a watershed may result in downstream cascades of disrupted functioning. Applying a multiple element perspective to understanding and addressing societal needs is a new direction for both ecological stoichiometry and sustainability.     

Do domatia mediate mutualistic interactions between coffee plants and predatory mites?

Many plant species possess structures on their leaves that often harbour predatory or fungivorous mites. These so‐called domatia are thought to mediate a mutualistic interaction; the plant gains protection because mites decimate plant pathogenic fungi or herbivores, whereas the mites find shelter in the domatia. We tested this hypothesis using two species of coffee (Coffea spp.) plants that posses domatia consisting of small cavities at the underside of the leaves, and which often harbour mites. We assessed densities of domatia, of the predatory mite Iphiseiodes zuluagai Denmark and Muma (Acari: Phytoseiidae) and of herbivorous mites Oligonychus ilicis (McGregor) (Acari: Tetranychidae) and Brevipalpus phoenicis (Geijskes) (Acari: Tenuipalpidae) on Coffea arabica L. (Rubiaceae) and Coffea canephora Pierre in the field. Over a period of 50 days, C. arabica harboured on average 7.5 times more predatory mites and 0.4–0.66 fewer prey mites than C. canephora. Hence, the higher density of predatory mites on C. arabica could not be explained by higher densities of prey. However, the density of domatia on C. arabica was on average 1.65 times higher than on C. canephora, and within each species, leaves with higher densities of domatia also harboured more predators. This suggests a positive effect of domatia on predatory mites. In the laboratory, survival of adult female predatory mites on leaves of C. arabica with open domatia was indeed significantly higher than on leaves with closed domatia. Hence, predatory mites benefited from the domatia. However, plants with higher densities of domatia did not harbour fewer herbivores. Taken together, our study only provides partial evidence for a mutualistic interaction between coffee plants and predatory mites, mediated by domatia.