The avian 'prefrontal cortex' and cognition

Both mammals and birds can flexibly organize their behavior over time. In mammals, the mental operations generating this ability are called executive functions and are associated with the prefrontal cortex. The corresponding structure in birds is the nidopallium caudolaterale. Anatomical, neurochemical, electrophysiological and behavioral studies show these structures to be highly similar. The avian forebrain displays no lamination that corresponds to the mammalian neocortex, hence lamination does not seem to be a requirement for higher cognitive functions. Because all other aspects of the neural architecture of the mammalian and the avian prefrontal areas are extremely comparable, the freedom to create different neural architectures that generate prefrontal functions seems to be very limited.     

Effects of HA-1077 and Y-27632, two rho-kinase inhibitors, in the human umbilical artery

A role for the small G protein rho and rho-kinase has been shown in smooth muscle contraction regarding Ca⁺⁺ sensitivity. However, there are no data in the literature assessing how this system operates in human umbilical arteries (HUA). Therefore, we evaluated the effects of HA-1077 and Y-27632, two rho-kinase inhibitors, on agonist-(5-hydroxytryptamine [5-HT]) and depolarization-induced (KCl) contractions of HUA. HA-1077 and Y-27632 inhibited 5-HT-induced contractile responses at 10⁻⁴ M concentration but not at 10⁻⁵ M. HA-1077 at 10⁻⁴ M also significantly attenuated contractions induced by 20 mM KCl. In addition, HUA precontracted with 5-HT relaxed concentration dependently in response to HA-1077 and Y-27632. When precontracted with KCl, HUA also relaxed dose-dependently in response to HA-1077, but the maximal relaxation was significantly smaller than the response obtained when precontracted with 5-HT. To determine possible involvement of rho-kinase on agonist-induced intracellular calcium-mediated contractions, tissues were precontracted with 5-HT in Ca⁺⁺-free Krebs solution before cumulative addition of HA-1077 or Y-27632 (10⁻⁷ to 10⁻⁴ M). Both rho-kinase inhibitors relaxed HUA completely. Maximum relaxations of HUA to HA-1077 and Y-27632 were significantly larger than the responses seen in normal Krebs solution and were obtained with lower concentrations of the drugs considered to be more specific for rho-kinase inhibition. However, preincubation of HUA with HA-1077 or Y-27632 (10⁻⁵ M for both) did not affect the 5-HT-induced contractions in this medium. Finally, immunoblot experiments revealed the expression of rho-kinase isoform rockII protein in HUA. These results indicate that rhoA/rho-kinase pathway can contribute to agonist-induced contractions of HUA. However, this effect appears to be limited to intracellular calcium-induced contractions and may be more important in sustaining contractions rather than the initial phase of force development.     

Serum and gastric fluid levels of cytokines and nitrates in gastric diseases infected with Helicobacter pylori

This case control study presents data on the concentrations of nitrite and nitrate and a variety of pro-inflammatory cytokines such as interleukin-1 beta (IL-1 beta), interleukin-2R (IL-2R), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor TNF-alpha in gastric fluid and serum. Patients with gastritis, gastric ulcer and gastric cancer are studied and grouped according to infection by Helicobacter pylori. The 208 patients who underwent upper gastrointestinal endoscopic examination were classified as follows; H. pylori-positive gastritis (n = 32), H. pylori-negative gastritis (n = 32), H. pylori-positive ulcers (n = 34), H. pylori-negative ulcers (n = 34), 43 patients with H. pylori-positive gastric cancer in addition to 33 H. pylori-negative healthy control individuals. Gastric fluids and blood samples were taken concomitantly. Cytokines and nitrite and nitrate determinations were attempted as soon as possible after collection of the samples. Nitrite and nitrate levels of serum and gastric fluids of H. pylori-positive gastritis and ulcers were higher than H. pylori-negative gastritis and ulcers. The concentrations of total nitrite and nitrate and cytokines (TNF-alpha, IL-2R, IL-6, and IL-8) in gastric fluids and sera of H. pylori-positive gastric cancer patients were higher than H. pylori-negative control groups. IL-1 beta level was significantly elevated in gastric fluid of infected cancer patients but not in serum. Taken together, the results suggest that an increase in cytokine-NO combination in gastric mucosa previously reported by many studies is not restricted to local infected gastric tissue but also detected in gastric fluid and sera of H. pylori-positive subjects and may have an important role in the pathogenesis and development of common gastric diseases.     

Factors affecting the adsorption of buchnericin LB,a bacteriocin produced by Lactobacillus [correction of Lactocobacillus] buchneri

Buchnericin-LB adsorbs to gram-positive but not to gram-negative bacteria. The tested gram-positive bacteria were species of Lactobacillus, Pediococcus, Leuconostoc, Enterococcus, Lactococcus, Listeria, Bacillus, Staphylococcus; gram-negative bacteria belonged to the genera Salmonella, Escherichia, Yersinia and Pseudomonas. Buchnericin-LB adsorption depended on pH but not on time and temperature. Also some anions of salts and lipoteichoic acid reduced or inhibited its adsorption. Treatment of cells and cell walls of sensitive bacteria with detergents, organic solvents or enzymes did not affect subsequent binding of buchnericin-LB. Treatment with buchnericin-LB caused sensitive cells to lose high amounts of intracellular K+ ions and UV-absorbing materials and became more permeable to o-nitrophenol-beta-D-galactopyranoside. Buchnericin-LB (640-2560 AU/ml) decreased the colony forming units (99%) and absorbance values of Listeria monocytogenes and Bacillus cereus. These results indicate that the mode of action of buchnericin-LB is bactericidal and its lethal effect is very rapid.     

FL3, a Synthetic Flavagline and Ligand of Prohibitins,Protects Cardiomyocytes via STAT3 from Doxorubicin Toxicity

Aims

The clinical use of doxorubicin for the treatment of cancer is limited by its cardiotoxicity. Flavaglines are natural products that have both potent anticancer and cardioprotective properties. A synthetic analog of flavaglines, FL3, efficiently protects mice from the cardiotoxicity of doxorubicin. The mechanism underlying this cardioprotective effect has yet to be elucidated.

Methods and Results

Here, we show that FL3 binds to the scaffold proteins prohibitins (PHBs) and thus promotes their translocation to mitochondria in the H9c2 cardiomyocytes. FL3 induces heterodimerization of PHB1 with STAT3, thereby ensuring cardioprotection from doxorubicin toxicity. This interaction is associated with phosphorylation of STAT3. A JAK2 inhibitor, WP1066, suppresses both the phosphorylation of STAT3 and the protective effect of FL3 in cardiomyocytes. The involvement of PHBs in the FL3-mediated cardioprotection was confirmed by means of small interfering RNAs (siRNAs) targeting PHB1 and PHB2. The siRNA knockdown of PHBs inhibits both phosphorylation of STAT3 and the cardioprotective effect of FL3.

Conclusion

Activation of mitochondrial STAT3/PHB1 complex by PHB ligands may be a new strategy against doxorubicin-induced cardiotoxicity and possibly other cardiac problems.     

Computational approaches to understanding protein aggregation in neurodegeneration

The generation of toxic non-native protein conformers has emerged as a unifying thread among disorders such as Alzheimer＇s disease, Parkinson＇s disease, and amyotrophic lateral sclerosis. Atomic-level detail regarding dynamical changes that facilitate protein aggre- gation, as well as the structural features of large-scale ordered aggregates and soluble non-native oligomers, would contribute signifi- cantly to current understanding of these complex phenomena and offer potential strategies for inhibiting formation of cytotoxic species. However, experimental limitations often preclude the acquisition of high-resolution structural and mechanistic information for aggregating systems. Computational methods, particularly those combine both aU-atom and coarse-grained simulations to cover a wide range of time and length scales, have thus emerged as crucial tools for investigating protein aggregation. Here we review the current state of computational methodology for the study of protein self-assembly, with a focus on the application of these methods toward understanding of protein aggregates in human neurodegenerative disorders.