Molecular dynamics simulation studies of the structural response of an isolated Aβ1–42 monomer localized in the vicinity of the hydrophilic TiO2 surface

We have probed the effect of a model hydrophilic surface, rutile TiO₂, on the full-length amyloid beta (Aβ_1–42) monomer using molecular dynamics simulations. The rutile surface brings about sharp changes in the peptide’s intrinsic behavior in a distance-dependent manner. The intrinsic collapse of the peptide is disrupted, while the β-sheet propensity is sharply enhanced with increased proximity to the surface. The results may have implications for Aβ self-assembly and fibrillogenesis on hydrophilic surfaces and should be taken into consideration in the design of novel nanomaterials for perturbing amyloidogenic behavior.     

Role of adrenergic and cholinergic mediators in salivary phospholipids secretion.

The influence of adrenergic and cholinergic mediators on phospholipid secretion in rat sublingual salivary gland cells maintained in the presence of [3H]choline was investigated. The secretion of [3H]choline-containing phospholipids over 30 min period averaged 1.93% of the total cellular labeled phospholipids in the absence of any mediator, and was enhanced by beta-adrenergic agonist, isoproterenol, to a greater extent than the cholinergic agonists, pilocarpine and carbachol. A 2.9-fold increase in phospholipid secretion occurred with isoproterenol, while pilocarpine and carbachol evoked only 1.3-fold increase. The effect of isoproterenol was inhibited by alprenolol and that of pilocarpine and carbachol by atropine. In contrast to pilocarpine and carbachol, the enhanced phospholipid secretion due to isoproterenol was accompanied by an increase in cAMP concentration. The secretion of phospholipids was also stimulated by dibutyryl-cAMP and the protein kinase C activator, phorbol myristate acetate, but not by 4 alpha-phorbol 12,13-didecanoate which does not activate protein kinase C. Furthermore, the effects of dibutyryl-cAMP and phorbol myristate acetate were additive. The phospholipids secreted in response to isoproterenol exhibited a 52% decrease in lysophosphatidylcholine, while those secreted in response to pilocarpine and carbachol showed a 21-23% lower content of phosphatidylcholine, and were enriched in lysophosphatidylcholine (2.6-2.8-fold) and sphingomyelin (1.5-1.6-fold). The results indicate that salivary phospholipid secretion remains mainly under beta-adrenergic regulation, while the phospholipid makeup of the secretion is under cholinergic control.     

How strategy environment and wealth shape altruistic behaviour: cooperation rules affecting wealth distribution in dynamic networks

Societies rely on individual contributions to sustain public goods that benefit the entire community. Several mechanisms, that specify how individuals change their decisions based on past experiences, have been proposed to explain how altruists are not outcompeted by selfish counterparts. A key aspect of such strategy updates involves a comparison of an individual''s latest payoff with that of a random neighbour. In reality, both the economic and social milieu often shapes cooperative behaviour. We propose a new decision heuristic, where the propensity of an individual to cooperate depends on the local strategy environment in which she is embedded as well as her wealth relative to that of her neighbours. Our decision-making model allows cooperation to be sustained and also explains the results of recent experiments on social dilemmas in dynamic networks. Final cooperation levels depend only on the extent to which the strategy environment influences altruistic behaviour but are largely unaffected by network restructuring. However, the extent of wealth inequality in the community is affected by a subtle interplay between the environmental influence on a person''s decision to contribute and the likelihood of reshaping social ties, with wealth-inequality levels rising with increasing likelihood of network restructuring in some situations.     

Evidence that anti-muscarinic antibodies in Sj?gren's syndrome recognise both M3R and M1R

Inhibitory anti-muscarinic receptor type 3 (M3R) antibodies may contribute to the pathogenesis of Sj?gren's syndrome (SS), and putative anti-M3R blocking antibodies in intravenous immunoglobulin (IVIg) have been suggested as a rationale for treatment with IVIg. We investigated the presence of subtype-specific anti-MR autoantibodies in healthy donor and SS sera using MR-transfected whole-cell binding assays as well as M1R and M3R peptide ELISAs. Control antibodies against the second extracellular loop of the M3R, a suggested target epitope, were induced in rabbits and found to be cross-reactive on the peptides M3R and M1R. The rabbit antibodies had neither an agonistic nor an antagonistic effect on M3R-dependent ERK1/2 signalling. Only one primary SS (out of 5 primary SS, 2 secondary SS and 5 control sera) reacted strongly with M3R transfected cells. The same SS serum also reacted strongly with M1R and M2R transfectants, as well as M1R and two different M3R peptides. Strong binding to M1R and low-level activities against M3R peptides were observed both in SS and control sera. IVIg showed a strong reactivity against all three peptides, especially M1R. Our results indicate that certain SS individuals may have antibodies against M1R, M2R and M3R. Our results also suggest that neither the linear M3R peptide nor M3R transfectants represent suitable tools for discrimination of pathogenic from natural autoantibodies in SS.     

Neurobehavioral responses in swiss albino mice induced by an aqueous leaf extract from a medicinal plant named Heliotropium incanum Ruiz & Pav.

It is of interest to examine the adverse neuro-behavioural responses on mice treated with the aqueous crude extract of Heliotropium incanum (AEHI), which were evaluated using various behavioral paradigms. On the basis of median lethal dose value, doses of AEHI were chosen to be 150mg/kg and 440mg/kg for further experiment. Four groups comprising of five mice each were divided for the 14 days experiment. Group I, the control group, received distilled water; Group II and III received AEHI (150 mg/kg body weight and 440 mg/kg body weight) respectively; Group IV received standard drugs, Diazepam/Fluoxetine, administered orally. On administration of AEHI, it was revealed that dose 440 mg/kg showed less exploration activity in the hole board test; decrease in the number of squares crossed in locomotory test, time period in the open arm in the plus maze test was significantly reduced and the immobility time was significantly extended in comparison to control and standard drugs. The microscopic study of brain revealed damaged hippocampus along with nerve cells degeneration. Consequently, the results concluded that the outcome of the AEHI produced evidences for the anxiogenic activity in mice.     

Altered expression of P2X3 in vagal and spinal afferents following esophagitis in rats

Purinergic P2X₃ receptors are predominantly expressed in small diameter primary afferent neurons and activation of these receptors by adenosine triphosphate is reported to play an important role in nociceptive signaling. The objective of this study was to investigate the expression of P2X₃ receptors in spinal and vagal sensory neurons and esophageal tissues following esophagitis in rats. Two groups of rats were used including 7 days fundus-ligated (7D-ligated) esophagitis and sham-operated controls. Esophagitis was produced by ligating the fundus and partial obstruction of pylorus that initiated reflux of gastric contents. The sham-operated rats underwent midline incision without surgical manipulation of the stomach. Expressions of P2X₃ receptors in thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophageal tissues were evaluated by RT–PCR, western blot and immunohistochemistry. Esophageal neurons were identified by retrograde transport of Fast Blue from the esophagus. There were no significant differences in P2X₃ mRNA expressions in DRGs (T1–T3) and NGs between 7D-ligated and sham-operated rats. However, there was an upregulation of P2X₃ mRNA in DRGs (T6–T12) and in the esophageal muscle. At protein level, P2X₃ exhibited significant upregulation both in DRGs and in NGs of rats having chronic esophagitis. Immunohistochemical analysis exhibited a significant increase in P2X₃ and TRPV1 co-expression in DRGs and NGs in 7D-ligated rats compared to sham-operated rats. The present findings suggest that chronic esophagitis results in upregulation of P2X₃ and its co-localization with TRPV1 receptor in vagal and spinal afferents. Changes in P2X₃ expression in vagal and spinal sensory neurons may contribute to esophageal hypersensitivity following acid reflux-induced esophagitis.     

CRTC1/MAML2 directs a PGC-1α-IGF-1 circuit that confers vulnerability to PPARγ inhibition

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