Melting relations of anhydrous olivine-free pyroxenite Px1 at 2 GPa

The reaction between melt derived by mafic heterogeneities and peridotites in an upwelling mantle may form hybrid olivine-free pyroxenites. In order to evaluate the impact of these lithologies on the chemistry of primitive magmas and their ability to give rise to new mantle heterogeneities, we experimentally investigate the melting relations at 2 GPa of the model olivine-free pyroxenite Px1 (X-Mg = 0.81, SiO2 = 52.9 wt %, Al2O3 = 11.3 wt %, CaO = 7.6 wt %). The subsolidus assemblage consists of clinopyroxene, orthopyroxene, and garnet. At 2 GPa, the solidus of Px1 is located between 1250 and 1280 degrees C, at a temperature about 70 degrees C lower than the solidus of fertile lherzolite. At increasing melt fraction, the sequence of mineral phase disappearance is garnet-clinopyroxene-orthopyroxene. Across the solidus, partial melting of Px1 is controlled by reaction garnet + clinopyroxene = liquid + orthopyroxene, and above 1300 degrees C, once garnet is completely consumed, by reaction clinopyroxene + orthopyroxene = liquid. Orthopyroxene is the liquidus phase, and at 1480 degrees C olivine-free pyroxenite Px1 is completely molten indicating a melting interval of about 200 degrees C. Isobaric melt productivity is similar to garnet clinopyroxenites, and it is more than 3 times that of a fertile lherzolite at 1400 degrees C. Px1 partial melts cover a wide range of X-Mg (0.57-0.84), with SiO2, Al2O3 and Na2O decreasing and Cr2O3 increasing with the degree of melting. CaO content in partial melts increases as long as clinopyroxene is involved in melting reactions and decreases after its exhaustion. At 2 GPa and for melting degrees higher than 10 %, Px1 produces MgO-rich basaltic andesites matching the composition of eclogitic melts in terms of silica and alkali contents but with significantly higher X-Mg values. These melts differ from those derived from lherzolites at 2 GPa by higher SiO2 and lower CaO contents. Their high silica activity makes them very reactive with mantle peridotite producing hybrid orthopyroxene-rich lithologies and residual websterites. Melt-rock reactions likely prevent direct extraction of melts produced by olivine-free pyroxenites

Modelization of Thermal Fluctuations in G Protein-Coupled Receptors

We simulate the electrical properties of a device realized by a G protein coupled receptor (GPCR), embedded in its membrane and in contact with two metallic electrodes through which an external voltage is applied. To this purpose, recently, we have proposed a model based on a coarse graining description, which describes the protein as a network of elementary impedances. The network is built from the knowledge of the positions of the C-alpha atoms of the amino acids, which represent the nodes of the network. Since the elementary impedances are taken depending of the inter-nodes distance, the conformational change of the receptor induced by the capture of the ligand results in a variation of the network impedance. On the other hand, the fluctuations of the atomic positions due to thermal motion imply an impedance noise, whose level is crucial to the purpose of an electrical detection of the ligand capture by the GPCR. Here, in particular, we address this issue by presenting a computational study of the impedance noise due to thermal fluctuations of the atomic positions within a rhodopsin molecule. In our model, the C-alpha atoms are treated as independent, isotropic, harmonic oscillators, with amplitude depending on the temperature and on the position within the protein (alpha-helix or loop). The relative fluctuation of the impedance is then calculated for different temperatures.Comment: 5 pages, 2 figures, Proceeding of the 18-th International Conference on Fluctuations and Noise, 19-23 September 2005, Salamanca, Spain -minor proofreadings

the stability of plagioclase in the upper mantle subsolidus experiments on fertile and depleted lherzolite

Plagioclase peridotites are important markers of processes that characterize the petrological and tectonic evolution of the lithospheric mantle in extensional tectonic settings. Studies on equilibrated plagioclase peridotites have documented continuous chemical changes in mantle minerals in response to plagioclase crystallization, potentially tracing the re-equilibration of mantle peridotites up to very low pressure.This experimental study provides new constraints on the stability of plagioclase in mantle peridotites as a function of bulk composition, and the compositional and modal changes in minerals occurring within the plagioclase stability field as a function of P^T^bulk composition. Subsolidus experiments have been performed at pressures ranging from 0·25 to 1·0 GPa, and temperatures ranging from 900 to 12008C on fertile and depleted anhydrous lherzolites modelled in the system TiO2^Cr2O3^Na2O^CaO^FeO^ MgO^Al2O3^SiO2 (Ti,Cr-NCFMAS). In the fertile lherzolite (Na2O/CaO 1⁄4 0·08; XCr 1⁄4 0·07) a plagioclase-bearing assemblage is stable up to 0·7 GPa, 10008C and 0·8 GPa, 11008C, whereas in the depleted lherzolite (Na2O/CaO 1⁄4 0·09; XCr 1⁄4 0·10) the upper limit of plagioclase stability is shifted to lower pressure.The boundary between plagioclase lherzolite and spinel lherzolite has a positive slope in P^T space. In a complex chemical system, the plagioclase-out boundary is multivariant and sensitive to the XCr value [XCr 1⁄4 Cr/(Cr þAl)] of spinel.This latter is controlled by the reaction MgCr2O4 þ CaAl2Si2O8 1⁄4 MgCrAlSiO6 þ CaCrAlSiO6, which is a function of the Cr^Al partitioning between spinel and pyroxenes, and varies with the XCr value and chromite/ anorthite normative ratio of the bulk composition. Within the plagioclase stability field, the Al content of pyroxenes decreases, coupled with an increase in the anorthite content in plagioclase, and Ti and XCr in spinel with decreasing pressure; these chemical variations are combined with systematic changes in modal mineralogy governed by a continuous reaction involving both plagioclase and spinel. As a consequence, the composition of plagioclase varies significantly over a rather narrow pressure range and is similar at the same P^T conditions in the investigated bulk-rocks.This suggests the potential application of plagioclase composition as a geobarometer for plagioclase peridotites

Insurance Between Firms: The Role of Internal Labor Markets

We investigate how Internal Labor Markets (ILMs) allow organizations to accommodate shocks calling for costly labor adjustments. Using data on workers' mobility within French business groups, we find that adverse shocks affecting affiliated firms boost the proportion of workers redeployed to other group units rather than external firms. This effect is stronger when labor regulations are stricter and destination-firms are more efficient or enjoy better growth opportunities. Affiliated firms hit by positive shocks rely on the ILM for new hires, especially high-skilled workers. Overall, ILMs emerge as a co-insurance mechanism within organizations, providing job stability to employees as a by-product

A single cocaine administration alters dendritic spine morphology and impairs glutamate receptor synaptic retention in the medial prefrontal cortex of adolescent rats

The brain is still maturing during adolescence and interfering with such a vulnerable period may lead to structural and functional consequences. We investigated the effect of a single cocaine exposure on dendritic spine structure and glutamate dynamics in the medial prefrontal cortex (mPFC) of adolescent rats 7 days after a single cocaine administration. We found a reduced number of dendritic spines, suggesting that cocaine lowers the density of dendritic spines in the mPFC of adolescent rats. Since dendritic spines are postsynaptic glutamatergic protrusions, we investigated the main determinants of glutamate postsynaptic responsiveness. In the postsynaptic density, cocaine reduced the expression of the NMDA receptor subunits GluN1, GluN2A and GluN2B as well as of the AMPA GluA1 and GluA2 subunits. Cocaine also impaired their synaptic stability since the expression of the scaffolding proteins SAP102 and SAP97, critical for the anchoring of such receptors at the postsynaptic membrane, was reduced as well. The expression of PSD-95 and Arc/Arg3.1, which play structural and functional roles in glutamate neurons, was also similarly reduced. Such changes were not found in the whole homogenate, ruling out a translational effect of cocaine and implying, rather, an impaired synaptic retention at the active zones of the synapse. Notably, neither these critical glutamate determinants nor the density and morphology of the dendritic spines were altered in the mPFC of adult animals, suggesting that a single cocaine exposure selectively impairs the developmental trajectory of the glutamate synapse. These results indicate a dynamic impairment of mPFC glutamate homeostasis during a critical developmental window that persists for at least one week after a single cocaine administration. Our results identify dysfunctional glutamate synapse as a major contributor to the mechanisms that distinguish adolescent vs. adult outcomes of a single cocaine exposure

Impairment of the autophagic flux in astrocytes intoxicated by trimethyltin

Autophagy is a lysosomal catabolic route for protein aggregates and damaged organelles which in different stress conditions, such as starvation, generally improves cell survival. An impairment of this degradation pathway has been reported to occur in many neurodegenerative processes. Trimethyltin (TMT) is a potent neurotoxin present as an environmental contaminant causing tremors, seizures and learning impairment in intoxicated subjects. The present data show that in rat primary astrocytes autophagic vesicles (AVs) appeared after few hours of TMT treatment. The analysis of the autophagic flux in TMT-treated astrocytes was consistent with a block of the late stages of autophagy and was accompanied by a progressive accumulation of the microtubule associated protein light chain 3 (LC3) and of p62/SQSTM1. Interestingly, an increased immunoreactivity for p62/SQSTM1 was also observed in hippocampal astrocytes detected in brain slices of TMT-intoxicated rats. The time-lapse recordings of AVs in EGFP-mCherry-LC3B transfected astrocytes demonstrated a reduced mobility of autophagosomes after TMT exposure respect to control cells. The observed block of the autophagic flux cannot be overcome by known autophagy inducers such as rapamycin or 0.5mM lithium. Although ineffective when used at 0.5mM, lithium at higher concentrations (2mM) was able to protect astrocyte cultures from TMT toxicity. This effect correlated well with its ability to determine the phosphorylation/inactivation of glycogen kinase synthase-3β (GSK-3β)

Type 2 Diabetes Mellitus: A Review of Multi-Target Drugs

Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the number of adults living with diabetes is expected to increase. Since type 2 diabetes mellitus (T2DM) is suffered by the majority of diabetic patients (around 90-95%) and often the mono-target therapy fails in managing blood glucose levels and the other comorbidities, this review focuses on the potential drugs acting on multi-targets involved in the treatment of this type of diabetes. In particular, the review considers the main systems directly involved in T2DM or involved in diabetes comorbidities. Agonists acting on incretin, glucagon systems, as well as on peroxisome proliferation activated receptors are considered. Inhibitors which target either aldose reductase and tyrosine phosphatase 1B or sodium glucose transporters 1 and 2 are taken into account. Moreover, with a view at the multi-target approaches for T2DM some phytocomplexes are also discussed

DRUG-CONJUGATES FOR SELF-ASSEMBLED NANOPARTICLES IN ANTICANCER TREATMENT

This dissertation is an overview on the functionalization of known anticancer compounds in order to form different drug-conjugates able to self-assemble in water to form nanoparticles. This approach is useful to improve the drug delivery properties and pharmacokinetic profile of anticancer drugs. All the described conjugates, except for the ones illustrated in chapter 5, have the same general structure: the anticancer drug is connected to the self-assembly inducer trough a linker. Chapter 1 regards a general introduction about nanomedicine, the advantages of the use of nanotechnology-based systems in cancer treatment and the benefits of nano- formulated drugs in the improvement of drug-delivery. Furthermore, nanoparticles are presented with a focus on their classification, characterization and preparation techniques. Chapter 2 regards the preparation of different types of self-assembled nanoparticles using various anticancer compounds and dyes but with the same lipophilic tail as self- assembling inducer: squalene. Different natural anticancer compounds such as paclitaxel, cyclopamine and doxorubicin and dyes, as fluorescein and tetramethylrhodamine, were functionalized to obtain squalene-based conjugates. Both hetero-nanoparticles composed by two drug-conjugates and drug- and dye-conjugates were prepared and tested. Chapter 3 is focused on the importance of the self-assembly inducer and describes the preparation of new conjugates containing an active moiety as self-assembly inducer. In particular, in this section, is described the preparation of conjugates composed by aloin or podophyllotoxin as active compounds and 4-(1,2-diphenylbut-1-en-1-yl) aniline, an analog of the know anticancer compound tamoxifen, as self-assembly inducer. Chapter 4 highlights the influence of the linker between the active compound and the self-assembly inducer to obtain an effective release of the free drug. In particular, it is described the synthesis of a new self-immolative linker able to trigger the drug release in particular conditions, specifically in the presence of a lipase. This linker was used for the preparation of two conjugates containing the known anticancer compound N- desacetylthiocolchicine. Chapter 5 concerns the preparation of dual drug-conjugates able to form nanoparticles without the presence of a self-assembly inducer. These conjugates have a symmetrical structure: two molecules of the same drug are linked by a chain able to guarantee the drug release in particular conditions. The natural anticancer compounds involved in the preparation of this type of conjugates are paclitaxel, epothilone A, podophyllotoxin and camptothecin and the linker used contain a disulfide moiety able to be cleaved in cellular environment