Differential pattern of glycogen accumulation after protein phosphatase 1 glycogen-targeting subunit PPP1R6 overexpression, compared to PPP1R3C and PPP1R3A, in skeletal muscle cells

Background PPP1R6 is a protein phosphatase 1 glycogen-targeting subunit (PP1-GTS) abundant in skeletal muscle with an undefined metabolic control role. Here PPP1R6 effects on myotube glycogen metabolism, particle size and subcellular distribution are examined and compared with PPP1R3C/PTG and PPP1R3A/GM. Results PPP1R6 overexpression activates glycogen synthase (GS), reduces its phosphorylation at Ser-641/0 and increases the extracted and cytochemically-stained glycogen content, less than PTG but more than GM. PPP1R6 does not change glycogen phosphorylase activity. All tested PP1-GTS-cells have more glycogen particles than controls as found by electron microscopy of myotube sections. Glycogen particle size is distributed for all cell-types in a continuous range, but PPP1R6 forms smaller particles (mean diameter 14.4 nm) than PTG (36.9 nm) and GM (28.3 nm) or those in control cells (29.2 nm). Both PPP1R6- and GM-derived glycogen particles are in cytosol associated with cellular structures; PTG-derived glycogen is found in membrane- and organelle-devoid cytosolic glycogen-rich areas; and glycogen particles are dispersed in the cytosol in control cells. A tagged PPP1R6 protein at the C-terminus with EGFP shows a diffuse cytosol pattern in glucose-replete and -depleted cells and a punctuate pattern surrounding the nucleus in glucose-depleted cells, which colocates with RFP tagged with the Golgi targeting domain of β-1,4-galactosyltransferase, according to a computational prediction for PPP1R6 Golgi location. Conclusions PPP1R6 exerts a powerful glycogenic effect in cultured muscle cells, more than GM and less than PTG. PPP1R6 protein translocates from a Golgi to cytosolic location in response to glucose. The molecular size and subcellular location of myotube glycogen particles is determined by the PPP1R6, PTG and GM scaffolding.

Differential pharmacologic properties of the two C75 enantiomers: (+)-C75 is a strong anorectic drug. (-)-C75 has antitumour activity

C75 is a synthetic compound described as having antitumoral properties. It produces hypophagia and weight loss in rodents, limiting its use in cancer therapy but identify- ing it as a potential anti-obesity drug. C75 is a fatty acid synthase (FAS) inhibitor and, through its coenzyme A (CoA) derivative, it acts as a carnitine palmitoyltransferase (CPT) 1 inhibitor. Racemic mixtures of C75 have been used in all the previous studies; however, the potential dif- ferent biological activities of C75 enantiomers have not been examined yet. To address this question we synthesized the two C75 enantiomers separately. Our results showed that ( )- C75 inhibits FAS activity in vitro and has a cytotoxic effect on tumor cell lines, without affecting food consumption. (+)-C75 inhibits CPT1 and its administration produces anorexia, suggesting that central inhibition of CPT1 is essential for the anorectic effect of C75. The differential activity of C75 enantiomers may lead to the development of potential new specific drugs for cancer and obesity.

Differential pharmacologic properties of the two C75 enantiomers: (+)-C75 is a strong anorectic drug. (-)-C75 has antitumour activity

C75 is a synthetic compound described as having antitumoral properties. It produces hypophagia and weight loss in rodents, limiting its use in cancer therapy but identify- ing it as a potential anti-obesity drug. C75 is a fatty acid synthase (FAS) inhibitor and, through its coenzyme A (CoA) derivative, it acts as a carnitine palmitoyltransferase (CPT) 1 inhibitor. Racemic mixtures of C75 have been used in all the previous studies; however, the potential dif- ferent biological activities of C75 enantiomers have not been examined yet. To address this question we synthesized the two C75 enantiomers separately. Our results showed that ( )- C75 inhibits FAS activity in vitro and has a cytotoxic effect on tumor cell lines, without affecting food consumption. (+)-C75 inhibits CPT1 and its administration produces anorexia, suggesting that central inhibition of CPT1 is essential for the anorectic effect of C75. The differential activity of C75 enantiomers may lead to the development of potential new specific drugs for cancer and obesity.

What makes one person paranoid and another person anxious? The differential prediction of social anxiety and persecutory ideation in an experimental situation

The study shows that social anxiety and persecutory ideation share many of the same predictive factors. Non-clinical paranoia may be a type of anxious fear. However, perceptual anomalies are a distinct predictor of paranoia. In the context of an individual feeling anxious, the occurrence of odd internal feelings in social situations may lead to delusional ideas through a sense of" things not seeming right". The study illustrates the approach of focusing on experiences such as paranoid thinking rather than diagnoses such as schizophrenia.

Analysis of thermal properties of phase change materials (PCM) using differential scanning calorimeter (DSC)

Commercially available PCM RT 20, RT 27, SP 22, A17 and SP 25 A8. Were analyzed using dynamic and step method of heat flux DSC. The results of the dinamic and step method were compared with commercial valures. It was found that RT 20 & RT 27 showed good conforming of results with commercial values while SP 22 A17 & SP 25 A8 did not show conformity.

Weierstrass integrability of differential equations

The integrability problem consists in finding the class of functions a first integral of a given planar polynomial differential system must belong to. We recall the characterization of systems which admit an elementary or Liouvillian first integral. We define {\it Weierstrass integrability} and we determine which Weierstrass integrable systems are Liouvillian integrable. Inside this new class of integrable systems there are non--Liouvillian integrable systems.

Analysis of vineyard differential management zones and relation to vine development, grape maturity and quality

The objective of research was to analyse the potential of Normalized Difference Vegetation Index (NDVI) maps from satellite images, yield maps and grapevine fertility and load variables to delineate zones with different wine grape properties for selective harvesting. Two vineyard blocks located in NE Spain (Cabernet Sauvignon and Syrah) were analysed. The NDVI was computed from a Quickbird-2 multi-spectral image at veraison (July 2005). Yield data was acquired by means of a yield monitor during September 2005. Other variables, such as the number of buds, number of shoots, number of wine grape clusters and weight of 100 berries were sampled in a 10 rows × 5 vines pattern and used as input variables, in combination with the NDVI, to define the clusters as alternative to yield maps. Two days prior to the harvesting, grape samples were taken. The analysed variables were probable alcoholic degree, pH of the juice, total acidity, total phenolics, colour, anthocyanins and tannins. The input variables, alone or in combination, were clustered (2 and 3 Clusters) by using the ISODATA algorithm, and an analysis of variance and a multiple rang test were performed. The results show that the zones derived from the NDVI maps are more effective to differentiate grape maturity and quality variables than the zones derived from the yield maps. The inclusion of other grapevine fertility and load variables did not improve the results.

Signalling by neurotrophins and hepatocyte growth factor regulates axon morphogenesis by differential β-catenin phosphorylation

Tyrosine phosphorylation of ß-catenin, a component of adhesion complexes and the Wnt pathway, affects cell adhesion, migration and gene transcription. By reducing ßcatenin availability using shRNA-mediated gene silencing or expression of intracellular N-cadherin, we show that ß-catenin is required for axon growth downstream of Brain Derived Neurotrophic Factor (BDNF) and Hepatocyte Growth Factor (HGF) signalling. We demonstrate that receptor tyrosine kinases (RTK) Trk and Met interact with and phosphorylate ß-catenin. Neurotrophins (NT) stimulation of Trk receptors results in phosphorylation of ß-catenin at residue Y654 and increased axon growth and branching. Conversely, pharmacological inhibition of Trk or a Y654F mutant blocks these effects. ß-catenin phospho(P)-Y654 colocalizes with the cytoskeleton at growth cones. However, HGF that also increases axon growth and branching, induces ß-catenin phosphorylation at Y142 and a nuclear localization. Interestingly, dominant negative ΔN-TCF4 abolishes the effects of HGF in axon growth and branching, but not of NT. We conclude that NT and HGF signalling differentially phosphorylate ß-catenin, targeting ß-catenin to distinct compartments to regulate axon morphogenesis by TCF4-transcription-dependent and independent mechanisms. These results place ß-catenin downstream of growth factor/RTK signalling in axon differentiation.

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η6-p-cym)RuCl(PPh3)2]+, allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N′-di-Boc-N″-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycin-ruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 μM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 μM). However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 μM in DU-145 and IC50 = 11.33 μM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 μM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 μM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

Differential growth responses to water balance of coexisting deciduous tree species are linked to wood density in a Bolivian tropical dry forest

A seasonal period of water deficit characterizes tropical dry forests (TDFs). There, sympatric tree species exhibit a diversity of growth rates, functional traits, and responses to drought, suggesting that each species may possess different strategies to grow under different conditions of water availability. The evaluation of the long-term growth responses to changes in the soil water balance should provide an understanding of how and when coexisting tree species respond to water deficit in TDFs. Furthermore, such differential growth responses may be linked to functional traits related to water storage and conductance. We used dendrochronology and climate data to retrospectively assess how the radial growth of seven coexisting deciduous tree species responded to the seasonal soil water balance in a Bolivian TDF. Linear mixed-effects models were used to quantify the relationships between basal area increment and seasonal water balance. We related these relationships with wood density and sapwood production to assess if they affect the growth responses to climate. The growth of all species responded positively to water balance during the wet season, but such responses differed among species as a function of their wood density. For instance, species with a strong growth response to water availability averaged a low wood density which may facilitate the storage of water in the stem. By contrast, species with very dense wood were those whose growth was less sensitive to water availability. Coexisting tree species thus show differential growth responses to changes in soil water balance during the wet season. Our findings also provide a link between wood density, a trait related to the ability of trees to store water in the stem, and wood formation in response to water availability.

Anticipating linear stochastic differential equations driven by a Lévy process

In this paper we study the existence of a unique solution for linear stochastic differential equations driven by a Lévy process, where the initial condition and the coefficients are random and not necessarily adapted to the underlying filtration. Towards this end, we extend the method based on Girsanov transformations on Wiener space and developped by Buckdahn [7] to the canonical Lévy space, which is introduced in [25].

Myofascial pain associated to trigger points: A literature review. Part 2: Differential diagnosis and treatment

During the last decades the advance in knowledge of myofascial pain has been constant in the medical and dental community. However, although several aspects have been clarified in relation to its epidemiology, clinical characteristics and etiopathogenesis, many uncertainties remain. Many clinical conditions are included in the differential diagnosis of myofascial pain associated to trigger points. A good anamnesis and clinical exploration is thus required in order to ensure correct diagnosis and treatment. Among the numerous treatments used in application to trigger points, the spray-and-stretch technique and direct injection targeted to such trigger points have been found to be the most effective options. In chronic cases, psychosocial intervention is required, due to the high incidence of mood disorders and/or anxiety observed in these patients, who in turn present a poorer prognosis. This underscores the importance of early diagnosis and treatment.

Differential effects of polyphenols and alcohol of red wine on the expression of adhesion molecules and inflammatory cytokines related to atherosclerosis: a randomized clinical trial

Background: Few clinical studies have focused on the alcoholindependent cardiovascular effects of the phenolic compounds of red wine (RW). Objective: We aimed to evaluate the effects of ethanol and phenolic compounds of RW on the expression of inflammatory biomarkers related to atherosclerosis in subjects at high risk of cardiovascular disease. Design: Sixty-seven high-risk, male volunteers were included in a randomized, crossover consumption trial. After a washout period, all subjects received RW (30 g alcohol/d), the equivalent amount of dealcoholized red wine (DRW), or gin (30 g alcohol/d) for 4 wk. Before and after each intervention period, 7 cellular and 18 serum inflammatory biomarkers were evaluated. Results: Alcohol increased IL-10 and decreased macrophage-derived chemokine concentrations, whereas the phenolic compounds of RW decreased serum concentrations of intercellular adhesion molecule- 1, E-selectin, and IL-6 and inhibited the expression of lymphocyte function-associated antigen 1 in T lymphocytes and macrophage-1 receptor, Sialil-Lewis X, and C-C chemokine receptor type 2 expression in monocytes. Both ethanol and phenolic compounds of RW downregulated serum concentrations of CD40 antigen, CD40 ligand, IL-16, monocyte chemotactic protein-1, and vascular cell adhesion molecule-1. Conclusion: The results suggest that the phenolic content of RW may modulate leukocyte adhesion molecules, whereas both ethanol and polyphenols of RW may modulate soluble inflammatory mediators in high-risk patients. The trial was registered in the International Standard Randomized Controlled Trial Number Register at http://www. isrctn.org/ as ISRCTN88720134

Differential effects of polyphenols and alcohol of red wine on the expression of adhesion molecules and inflammatory cytokines related to atherosclerosis: a randomized clinical trial

Background: Few clinical studies have focused on the alcoholindependent cardiovascular effects of the phenolic compounds of red wine (RW). Objective: We aimed to evaluate the effects of ethanol and phenolic compounds of RW on the expression of inflammatory biomarkers related to atherosclerosis in subjects at high risk of cardiovascular disease. Design: Sixty-seven high-risk, male volunteers were included in a randomized, crossover consumption trial. After a washout period, all subjects received RW (30 g alcohol/d), the equivalent amount of dealcoholized red wine (DRW), or gin (30 g alcohol/d) for 4 wk. Before and after each intervention period, 7 cellular and 18 serum inflammatory biomarkers were evaluated. Results: Alcohol increased IL-10 and decreased macrophage-derived chemokine concentrations, whereas the phenolic compounds of RW decreased serum concentrations of intercellular adhesion molecule- 1, E-selectin, and IL-6 and inhibited the expression of lymphocyte function-associated antigen 1 in T lymphocytes and macrophage-1 receptor, Sialil-Lewis X, and C-C chemokine receptor type 2 expression in monocytes. Both ethanol and phenolic compounds of RW downregulated serum concentrations of CD40 antigen, CD40 ligand, IL-16, monocyte chemotactic protein-1, and vascular cell adhesion molecule-1. Conclusion: The results suggest that the phenolic content of RW may modulate leukocyte adhesion molecules, whereas both ethanol and polyphenols of RW may modulate soluble inflammatory mediators in high-risk patients. The trial was registered in the International Standard Randomized Controlled Trial Number Register at http://www. isrctn.org/ as ISRCTN88720134

Differential regulation of horizontally acquired and core genome genes by the bacterial modulator H-NS

Horizontal acquisition of DNA by bacteria dramatically increases genetic diversity and hence successful bacterial colonization of several niches, including the human host. A relevant issue is how this newly acquired DNA interacts and integrates in the regulatory networks of the bacterial cell. The global modulator H-NS targets both core genome and HGT genes and silences gene expression in response to external stimuli such as osmolarity and temperature. Here we provide evidence that H-NS discriminates and differentially modulates core and HGT DNA. As an example of this, plasmid R27-encoded H-NS protein has evolved to selectively silence HGT genes and does not interfere with core genome regulation. In turn, differential regulation of both gene lineages by resident chromosomal H-NS requires a helper protein: the Hha protein. Tight silencing of HGT DNA is accomplished by H-NS-Hha complexes. In contrast, core genes are modulated by H-NS homoligomers. Remarkably, the presence of Hha-like proteins is restricted to the Enterobacteriaceae. In addition, conjugative plasmids encoding H-NS variants have hitherto been isolated only from members of the family. Thus, the H-NS system in enteric bacteria presents unique evolutionary features. The capacity to selectively discriminate between core and HGT DNA may help to maintain horizontally transmitted DNA in silent form and may give these bacteria a competitive advantage in adapting to new environments, including host colonization.