The Effect of Focusing and Caustics on Exit Phenomena in Systems Lacking Detailed Balance

We study the trajectories followed by a particle subjected to weak noise when escaping from the domain of attraction of a stable fixed point. If detailed balance is absent, a _focus_ may occur along the most probable exit path, leading to a breakdown of symmetry (if present). The exit trajectory bifurcates, and the exit location distribution may become `skewed' (non-Gaussian). The weak-noise asymptotics of the mean escape time are strongly affected. Our methods extend to the study of skewed exit location distributions in stochastic models without symmetry.Comment: REVTEX macros (latest version). Two accompanying PS figures, one of which is large (over 600K unpacked

Structural insights into thrombolytic activity of destabilase from medicinal leech

Destabilase from the medical leech Hirudo medicinalis belongs to the family of i-type lysozymes. It has two different enzymatic activities: microbial cell walls destruction (muramidase activity), and dissolution of the stabilized fibrin (isopeptidase activity). Both activities are known to be inhibited by sodium chloride at near physiological concentrations, but the structural basis remains unknown. Here we present two crystal structures of destabilase, including a 1.1 Å-resolution structure in complex with sodium ion. Our structures reveal the location of sodium ion between Glu34/Asp46 residues, which were previously recognized as a glycosidase active site. While sodium coordination with these amino acids may explain inhibition of the muramidase activity, its influence on previously suggested Ser49/Lys58 isopeptidase activity dyad is unclear. We revise the Ser49/Lys58 hypothesis and compare sequences of i-type lysozymes with confirmed destabilase activity. We suggest that the general base for the isopeptidase activity is His112 rather than Lys58. pKa calculations of these amino acids, assessed through the 1 μs molecular dynamics simulation, confirm the hypothesis. Our findings highlight the ambiguity of destabilase catalytic residues identification and build foundations for further research of structure–activity relationship of isopeptidase activity as well as structure-based protein design for potential anticoagulant drug development.</p

Manifestation of Huntington's disease pathology in human induced pluripotent stem cell-derived neurons

© 2016 Nekrasov et al.Background: Huntington's disease (HD) is an incurable hereditary neurodegenerative disorder, which manifests itself as a loss of GABAergic medium spiny (GABA MS) neurons in the striatum and caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. There is no cure for HD, existing pharmaceutical can only relieve its symptoms. Results: Here, induced pluripotent stem cells were established from patients with low CAG repeat expansion in the huntingtin gene, and were then efficiently differentiated into GABA MS-like neurons (GMSLNs) under defined culture conditions. The generated HD GMSLNs recapitulated disease pathology in vitro, as evidenced by mutant huntingtin protein aggregation, increased number of lysosomes/autophagosomes, nuclear indentations, and enhanced neuronal death during cell aging. Moreover, store-operated channel (SOC) currents were detected in the differentiated neurons, and enhanced calcium entry was reproducibly demonstrated in all HD GMSLNs genotypes. Additionally, the quinazoline derivative, EVP4593, reduced the number of lysosomes/autophagosomes and SOC currents in HD GMSLNs and exerted neuroprotective effects during cell aging. Conclusions: Our data is the first to demonstrate the direct link of nuclear morphology and SOC calcium deregulation to mutant huntingtin protein expression in iPSCs-derived neurons with disease-mimetic hallmarks, providing a valuable tool for identification of candidate anti-HD drugs. Our experiments demonstrated that EVP4593 may be a promising anti-HD drug

Liquid Crystalline Azobenzene-Containing Polymer as a Matrix for Distributed Feedback Lasers

For the first time a liquid crystalline azobenzene-containing side-chain copolymer was employed as matrix material for distributed feedback lasers based on orientation gratings. Effective polarization gratings with periods of 245-290 nm could be inscribed within just one second using moderate light intensity. Using a number of near-infrared laser dyes and different grating frequencies, tuning of wavelength of the emitted radiation from 760 to 883 nm was obtained. It was also found that the lasing wavelength depends on the angle between the liquid crystal director and the grating vector. Wavelength tuning in the range of 30 nm was demonstrated using this method

Development, spread of root rot on plowing, disking and direct sowing

The results of the study showed that various methods of tillage affect the population of the soil with pathogens. Less populated was the soil where traditional tillage was carried out - autumn plowing. With this treatment, in the 0-10 cm layer, the soil colonization with root rot conidia was lower than with minimal tillage and zero sowing. In the 10–20 cm layer, the same trend persisted. The presence of conidia of the genus Alternaria was observed mainly in layer 0-10; 0-20cm and was negligible. At zero sowing, the conidia in the 10-20 cm layer were mostly semi-decomposed