Therapeutic implications of osteoprotegerin

Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) receptor superfamily, contributes determinatively to the bone remodeling as well as to the pathogenetic mechanism of bone malignancies and disorders of mineral metabolism. There is additional evidence that OPG can promote cell survival by inhibiting TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. A number of recent in vitro, in vivo and clinical studies have defined the role of the RANK/RANKL/OPG pathway in skeletal and vascular diseases. These works were the milestone of the deep understanding of the mechanism of OPG. This review provides an overview of the potential innovative therapeutic strategies of OPG in metastatic breast and prostate carcinoma, multiple myeloma, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis and rheumatoid arthritis. Special reference is given to the increasing evidence that RANKL and OPG may link the skeletal with the vascular system.     

Application of Bioinspired Superhydrophobic Surfaces in Two-phase Heat Transfer Experiments

This paper addresses the potential to use Lotus leaf bioinspired surfaces in applications involving heat transfer with phase change,namely pool boiling and spray impingement.Besides describing the role of bioinspired topographical features,using an innovative technique combining high-speed visualization and time-resolved infrared thermography,surface durability is also addressed.Water is used for pool boiling and for spray impingement systems (simplified as single droplet impact),while HFE7000 is used in a pool boiling cooler for electronic components.Results show that surface durability is quickly compromised for water pool boiling applications,as the chemical treatment does not withstand high temperatures (T ＞ 100 ℃) during long time intervals (3 h-4 h).For HFE7000 pool boiling (depicting lower saturation temperature-34 ℃),heat transfer enhancement is governed by the topography.The regular hierarchical pattern of the bioinspired surfaces promotes the heat transfer coefficient to increase up to 22.2％,when compared to smooth surfaces,while allowing good control of the interaction mechanisms until a distance between micro-structures of 300 μm-400 μm.Droplet impingement was studied for surface temperatures ranging between 60 ℃-100 ℃.The results do not support the use of superhydrophobic surfaces for cooling applications,but reveal great potential for other applications involving droplet impact on heated surfaces (e.g.metallurgy industry).     

Experimental pathogenicity ofSporothrix schenckii preserved in water (Castellani)

Five strains ofSporothrix schenckii preserved in sterile destillated water were found morphologically stable, viable and pure after a period ranging from 16 to 13 years, in the mycology section culture collection from the Instituto de Medicina Tropical, Universidad Central de Venezuela. Each strain was inoculated into the testes of 3 hamsters. All the animals developed disseminated sporotrichosis.     

Early effects of TPA on protein kinase activity in murine thymocytes : Reduction of protein kinase C activity in the cytosol and increase of Ca and phospholipid-independent kinase activity in the particulate fractions

Brief treatment of intact thymocytes with TPA and other tumor promoters causes a reduction in protein kinase C activity from the cytosol and an increase in kinase activity in the pariculate fraction. In contrast to the activity in the cytosol, which is absolutely dependent on the addition of Ca²⁺, phosphatidylserine and diolein, the activity in the particulate fraction is independent of these agents. Analysis of target specificity of the particulate kinase activity using exogenous and endogenous substrates suggests that the increased phosphorylation in the particulate fraction is catalysed by protein kinase C with altered catalytic properties. Although interleukin-1 and TPA are both co-mitogens for murine thymocytes, interleukin-1 does not share with TPA its property to alter protein kinase activity in the cytosolic and particulate fractions.     

Effect of CuSO4 and Cu(II)(Gly)2 on some indirect assays for superoxide dismutase activity

The effect of CuSO₄ and Cu(II)(Gly)₂ has been compared with that of superoxide dismutase on the ferricytochrome c reduction and on the nitroblue tetrazolium reduction by an enzymic or chemical flux of superoxide anion radicals as well as on o-dianisidine photooxidation. Both CuSO₄ and Cu(II)(Gly)₂ have been found to inhibit ferricytochrome c reduction as well as the aerobic and anaerobic nitroblue tetrazolium reduction with approximately equal efficiency. Unlike superoxide dismutase they proved capable of inhibiting o-dianisdine photooxidation. The effect of copper either as CuSO₄ or as Cu(II)(Cly)₂ has been established as being due to its interference with the indirect assays for superoxide dismutase activity used. The reasons for this interference have been examined and it is concluded that copper can react with a component of the indirect assay system and depending on the method used it either mimics SOD or acts contrary to the enzyme.     

Ultrafast ligand binding dynamics in the active site of native bacterial nitric oxide reductase

The active site of nitric oxide reductase from Paracoccus denitrificans contains heme and non-heme iron and is evolutionarily related to heme-copper oxidases. The CO and NO dynamics in the active site were investigated using ultrafast transient absorption spectroscopy. We find that, upon photodissociation from the active site heme, 20% of the CO rebinds in 170 ps, suggesting that not all the CO transiently binds to the non-heme iron. The remaining 80% does not rebind within 4 ns and likely migrates out of the active site without transient binding to the non-heme iron. Rebinding of NO to ferrous heme takes place in approximately 13 ps. Our results reveal that heme-ligand recombination in this enzyme is considerably faster than in heme-copper oxidases and are consistent with a more confined configuration of the active site.     

The crystal structure of Desulfovibrio vulgaris dissimilatory sulfite reductase bound to DsrC provides novel insights into the mechanism of sulfate respiration

Sulfate reduction is one of the earliest types of energy metabolism used by ancestral organisms to sustain life. Despite extensive studies, many questions remain about the way respiratory sulfate reduction is associated with energy conservation. A crucial enzyme in this process is the dissimilatory sulfite reductase (dSiR), which contains a unique siroheme-[4Fe4S] coupled cofactor. Here, we report the structure of desulfoviridin from Desulfovibrio vulgaris, in which the dSiR DsrAB (sulfite reductase) subunits are bound to the DsrC protein. The alpha(2)beta(2)gamma(2) assembly contains two siroheme-[4Fe4S] cofactors bound by DsrB, two sirohydrochlorins and two [4Fe4S] centers bound by DsrA, and another four [4Fe4S] centers in the ferredoxin domains. A sulfite molecule, coordinating the siroheme, is found at the active site. The DsrC protein is bound in a cleft between DsrA and DsrB with its conserved C-terminal cysteine reaching the distal side of the siroheme. We propose a novel mechanism for the process of sulfite reduction involving DsrAB, DsrC, and the DsrMKJOP membrane complex (a membrane complex with putative disulfide/thiol reductase activity), in which two of the six electrons for reduction of sulfite derive from the membrane quinone pool. These results show that DsrC is involved in sulfite reduction, which changes the mechanism of sulfate respiration. This has important implications for models used to date ancient sulfur metabolism based on sulfur isotope fractionations.     

Spatial population structure of a specialist leaf-mining moth

1. The spatial structure of natural populations may profoundly influence their dynamics. Depending on the frequency of movements among local populations and the consequent balance between local and regional population processes, earlier work has attempted to classify metapopulations into clear-cut categories, ranging from patchy populations to sets of remnant populations. In an alternative, dichotomous scheme, local populations have been classified as self-sustaining populations generating a surplus of individuals (sources) and those depending on immigration for persistence (sinks). 2. In this paper, we describe the spatial population structure of the leaf-mining moth Tischeria ekebladella, a specialist herbivore of the pedunculate oak Quercus robur. We relate moth dispersal to the distribution of oaks on Wattkast, a small island (5 km(2)) off the south-western coast of Finland. 3. We build a spatially realistic metapopulation model derived from assumptions concerning the behaviour of individual moths, and show that the model is able to explain part of the variation in observed patterns of occurrence and colonization. 4. While the species was always present on large trees, a considerable proportion of the local populations associated with small oaks showed extinction-recolonization dynamics. The vast majority of moth individuals occur on large trees. 5. According to model predictions, the dominance of local vs. regional processes in tree-specific moth dynamics varies drastically across the landscape. Most local populations may be defined broadly as 'sinks', as model simulations suggest that in the absence of immigration, only the largest oaks will sustain viable moth populations. Large trees in areas of high oak density will contribute most to the overall persistence of the metapopulation by acting as sources of moths colonizing other trees. 6. No single 'metapopulation type' will suffice to describe the oak-moth system. Instead, our study supports the notion that real populations are often a mix of earlier identified categories. The level to which local populations may persist after landscape modification will vary across the landscape, and sweeping classifications of metapopulations into single categories will contribute little to understanding how individual local populations contribute to the overall persistence of the system.     

PI3-K- and PKC-dependent up-regulation of APP processing enzymes by retinoic acid

Retinoic acid stimulates α-secretase processing of amyloid precursor protein (APP) and decreases β-secretase cleavage that leads to amyloid-β formation. Here, we investigated the effect of retinoic acid on the two putative α-secretases, the disintegrin metalloproteinases ADAM10 and TACE, and the β-site cleaving enzyme BACE1, in human neuroblastoma SH-SY5Y cells. Western blot analysis showed that exposure to retinoic acid resulted in significantly increased levels of ADAM10 and TACE, suggesting that regulation of α-secretases causes the effects on APP processing. The presence of the phosphatidylinositol 3-kinase inhibitor LY 294002 selectively reduced the effect on ADAM10 protein levels but not on ADAM10 mRNA levels as determined by RT-PCR. On the other hand, the effect on TACE was shown to be dependent on protein kinase C, since it was completely blocked in the presence of the inhibitor bisindolylmaleimide XI. Our data indicate that different signalling pathways are involved in retinoic acid-induced up-regulation of the secretases.