Effect of the curvature and the {\beta} parameter on the nonlinear dynamics of a drift tearing magnetic island

We present numerical simulation studies of 2D reduced MHD equations investigating the impact of the electronic \beta parameter and of curvature effects on the nonlinear evolution of drift tearing islands. We observe a bifurcation phenomenon that leads to an amplification of the pressure energy, the generation of E \times B poloidal flow and a nonlinear diamagnetic drift that affects the rotation of the magnetic island. These dynamical modifications arise due to quasilinear effects that generate a zonal flow at the onset point of the bifurcation. Our simulations show that the transition point is influenced by the \beta parameter such that the pressure gradient through a curvature effect strongly stabilizes the transition. Regarding the modified rotation of the island, a model for the frequency is derived in order to study its origin and the effect of the \beta parameter. It appears that after the transition, an E \times B poloidal flow as well as a nonlinear diamagnetic drift are generated due to an amplification of the stresses by pressure effects

Olive tree in circular economy as a source of secondary metabolites active for human and animal health beyond oxidative stress and inflammation

none10noExtra-virgin olive oil (EVOO) contains many bioactive compounds with multiple biological activities that make it one of the most important functional foods. Both the constituents of the lipid fraction and that of the unsaponifiable fraction show a clear action in reducing oxidative stress by acting on various body components, at concentrations established by the European Food Safety Authority’s claims. In addition to the main product obtained by the mechanical pressing of the fruit, i.e., the EVOO, the residual by-products of the process also contain significant amounts of antioxidant molecules, thus potentially making the Olea europea L. an excellent example of the circular economy. In fact, the olive mill wastewaters, the leaves, the pomace, and the pits discharged from the EVOO production process are partially recycled in the nutraceutical and cosmeceutical fields also because of their antioxidant effect. This work presents an overview of the biological activities of these by-products, as shown by in vitro and in vivo assays, and also from clinical trials, as well as their main formulations currently available on the market.openMallamaci R.; Budriesi R.; Clodoveo M.L.; Biotti G.; Micucci M.; Ragusa A.; Curci F.; Muraglia M.; Corbo F.; Franchini C.Mallamaci, R.; Budriesi, R.; Clodoveo, M. L.; Biotti, G.; Micucci, M.; Ragusa, A.; Curci, F.; Muraglia, M.; Corbo, F.; Franchini, C

Bioisosteric Modification of To042: Synthesis and Evaluation of Promising Use-Dependent Inhibitors of Voltage-Gated Sodium Channels

Three analogues of To042, a tocainide-related lead compound recently reported for the treatment of myotonia, were synthesized and evaluated in vitro as skeletal muscle sodium channel blockers possibly endowed with enhanced use-dependent behavior. Patch-clamp experiments on hNav1.4 expressed in HEK293 cells showed that N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine, the aryloxyalkyl bioisostere of To042, exerted a higher use-dependent block than To042 thus being able to preferentially block the channels in over-excited membranes while preserving healthy tissue function. It also showed the lowest active transport across BBB according to the results of P-glycoprotein (P-gp) interacting activity evaluation and the highest cytoprotective effect on HeLa cells. Quantum mechanical calculations and dockings gave insights on the most probable conformation of the aryloxyalkyl bioisostere of To042 in solution and the target residues involved in the binding, respectively. Both approaches indicated the conformations that might be adopted in both the unbound and bound state of the ligand. Overall, N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine exhibits an interesting toxico-pharmacological profile and deserves further investigation

The role of Gr‐1+ cells and tumour necrosis factor‐α signalling during Clostridium difficile colitis in mice

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110845/1/imm12425.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110845/2/imm12425-sup-0001-FigS1-2.pd

Totarol content and cytotoxicity varies significantly in different types of propolis

Propolis is a complex honeybee product deposited in the beehives, where it protects the hive and its occupants from microbial infection. Propolis has several reported medical applications in view of its numerous bioactive properties. The water insoluble fraction of crude Maltese honeybee propolis was extracted in methanol. Analysis by gas chromatography – mass spectrometry (GC-MS) showed the diterpenoid totarol to be the predominant constituent in all samples. The evaporated methanol residue was dissolved in dimethyl sulphoxide (DMSO) and used for cytotoxicity testing on human cancer cell lines using standard 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assays. Results obtained show that the propolis collected from Malta has cytotoxic activity in cancer cells in vitro. However, propolis collected from different sites, only a few miles apart and at different times of the year, showed marked variations in the cytotoxicity, which correlated clearly with totarol content. This reflects the differences in the species of plants, on which the bees had foraged and indicates the importance of collection site and season of collection on the bioactivity of propolis products.peer-reviewe

Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain depending on clinical probability and in clinically important subgroups: meta-analysis of individual patient data

OBJECTIVE: To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients. DESIGN: Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies. DATA SOURCES: Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups. RESULTS: Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)). CONCLUSIONS: In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42012002780

Fibroblast Growth Factor-2 Primes Human Mesenchymal Stem Cells for Enhanced Chondrogenesis

Human mesenchymal stem cells (hMSCs) are multipotent cells capable of differentiating into a variety of mature cell types, including osteoblasts, adipocytes and chondrocytes. It has previously been shown that, when expanded in medium supplemented with fibroblast growth factor-2 (FGF-2), hMSCs show enhanced chondrogenesis (CG). Previous work concluded that the enhancement of CG could be attributed to the selection of a cell subpopulation with inherent chondrogenic potential. In this study, we show that FGF-2 pretreatment actually primed hMSCs to undergo enhanced CG by increasing basal Sox9 protein levels. Our results show that Sox9 protein levels were elevated within 30 minutes of exposure to FGF-2 and progressively increased with longer exposures. Further, we show using flow cytometry that FGF-2 increased Sox9 protein levels per cell in proliferating and non-proliferating hMSCs, strongly suggesting that FGF-2 primes hMSCs for subsequent CG by regulating Sox9. Indeed, when hMSCs were exposed to FGF-2 for 2 hours and subsequently differentiated into the chondrogenic lineage using pellet culture, phosphorylated-Sox9 (pSox9) protein levels became elevated and ultimately resulted in an enhancement of CG. However, small interfering RNA (siRNA)-mediated knockdown of Sox9 during hMSC expansion was unable to negate the prochondrogenic effects of FGF-2, suggesting that the FGF-2-mediated enhancement of hMSC CG is only partly regulated through Sox9. Our findings provide new insights into the mechanism by which FGF-2 regulates predifferentiation hMSCs to undergo enhanced CG

Nomenclature and heterogeneity : consequences for the use of mesenchymal stem cells in regenerative medicine

Mesenchymal stem cells (MSCs) are in development for many clinical indications, based both on “stem” properties (tissue repair or regeneration) and on signalling repertoire (immunomodulatory and anti-inflammatory effects). Potential conflation of MSC properties with those of tissue-derived stromal cells presents difficulties in comparing study outcomes and represents a source of confusion in cell therapy development. Cultured MSCs demonstrate significant heterogeneity in clonogenicity and multi-lineage differentiation potential. However in vivo biology of MSCs includes native functions unrelated to regenerative medicine applications, so do nomenclature and heterogeneity matter? In this perspective we examine some consequences of the nomenclature debate and heterogeneity of MSCs. Regulatory expectations are considered, emphasising that product development should prioritise detailed characterisation of therapeutic cell populations for specific indications