Protein Docking by the Underestimation of Free Energy Funnels in the Space of Encounter Complexes

Similarly to protein folding, the association of two proteins is driven by a free energy funnel, determined by favorable interactions in some neighborhood of the native state. We describe a docking method based on stochastic global minimization of funnel-shaped energy functions in the space of rigid body motions (SE(3)) while accounting for flexibility of the interface side chains. The method, called semi-definite programming-based underestimation (SDU), employs a general quadratic function to underestimate a set of local energy minima and uses the resulting underestimator to bias further sampling. While SDU effectively minimizes functions with funnel-shaped basins, its application to docking in the rotational and translational space SE(3) is not straightforward due to the geometry of that space. We introduce a strategy that uses separate independent variables for side-chain optimization, center-to-center distance of the two proteins, and five angular descriptors of the relative orientations of the molecules. The removal of the center-to-center distance turns out to vastly improve the efficiency of the search, because the five-dimensional space now exhibits a well-behaved energy surface suitable for underestimation. This algorithm explores the free energy surface spanned by encounter complexes that correspond to local free energy minima and shows similarity to the model of macromolecular association that proceeds through a series of collisions. Results for standard protein docking benchmarks establish that in this space the free energy landscape is a funnel in a reasonably broad neighborhood of the native state and that the SDU strategy can generate docking predictions with less than 5 � ligand interface Ca root-mean-square deviation while achieving an approximately 20-fold efficiency gain compared to Monte Carlo methods

Sleep deprivation increase the expression of inducible heat shock protein 70 in rat gastric mucosa

Aim: To investigate if sleep deprivation is able to increase the expression of inducible heat shock protein 70 in gastric mucosa and its possible role in mucosal defense. Methods: Rats for sleep disruption were placed inside a computerized rotating drum, gastric mucosa was taken from rats with 1, 3 and 7 d sleep deprivation. RT-PCR, immunohistochemistry and Western blotting were used to determine the expression of heat shock protein 70. Ethanol (500 mL.L-1, i.g.) was used to induce gastric mucosa damage. Results: RT-PCR, Western blotting and immunostaining confirmed that the sleep deprivation as a stress resulted in significantly greater expression of inducible heat shock protein 70 in gastric mucosa of rats. After the 500mL.L-1 ethanol challenge, the ulcer area found in the rats with 7 d sleep deprivation (19.15 ± 4.2) mm2 was significantly lower (P<0.01) than the corresponding control (53.7 ± 8.1) mm2. Conclusion: Sleep deprivation as a stress, in addition to lowering the gastric mucosal barrier, is able to stimulate the expression of inducible heat shock protein 70 in gastric mucosa of rats, the heat shock protein 70 may play an important role in gastric mucosal protection.published_or_final_versio

Gene expression profiles in gastric mucosa of sleep deprivation rats

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Expression and activities of three inducible enzymes in the healing of gastric ulcers in rats

Aim: To explore the roles of nitric oxide synthase (NOS), heme oxygenase (HO) and cyclooxygenase (COX) in gastric ulceration and to investigate the relationships of the expression and activities of these enzymes at different stages of gastric ulceration. Methods: Gastric ulcers (kissing ulcers) were induced by luminal application of acetic acid. Gastric tissue samples were obtained from the ulcer base, ulcer margin, and non-ulcerated area around the ulcer margin at different time intervals after ulcer induction. The mRNA expression and protein levels of inducible and constitutive isoforms of NOS, HO and COX were analyzed with RT-PCR and Western blotting methods. The activities of the total NOS, inducible NOS (iNOS), HO, and COX were also determined. Results: Differential expression of inducible iNOS, HO-1 and COX-2 and enzyme activities of NOS, HO and COX were found in the gastric ulcer base. High iNOS expression and activity were observed on day 1 to day 3 in severely inflamed ulcer tissues. Maximum expressions of HO-1 and COX-2 and enzyme activities of HO and COX lagged behind that of iNOS, and remained at high levels during the healing phase. Conclusion: The expression and activities of inducible NOS, HO-1 and COX-2 are found to be correlated to different stages of gastric ulceration. Inducible NOS may contribute to ulcer formation while HO-1 and COX-2 may promote ulcer healing.published_or_final_versio

Efficient simulation of the spatial transmission dynamics of influenza

Early data from the 2009 H1N1 pandemic (H1N1pdm) suggest that previous studies over-estimated the within-country rate of spatial spread of pandemic influenza. As large spatially resolved data sets are constructed, the need for efficient simulation code with which to investigate the spatial patterns of the pandemic becomes clear. Here, we present a significant improvement to the efficiency of an individual based stochastic disease simulation framework commonly used in multiple previous studies. We quantify the efficiency of the revised algorithm and present an alternative parameterization of the model in terms of the basic reproductive number. We apply the model to the population of Taiwan and demonstrate how the location of the initial seed can influence spatial incidence profiles and the overall spread of the epidemic. Differences in incidence are driven by the relative connectivity of alternate seed locations. The ability to perform efficient simulation allows us to run a batch of simulations and take account of their average in real time. The averaged data are stable and can be used to differentiate spreading patterns that are not readily seen by only conducting a few runs. © 2010 Tsai et al.published_or_final_versio

Algorithmic statistics: forty years later

Algorithmic statistics has two different (and almost orthogonal) motivations. From the philosophical point of view, it tries to formalize how the statistics works and why some statistical models are better than others. After this notion of a "good model" is introduced, a natural question arises: it is possible that for some piece of data there is no good model? If yes, how often these bad ("non-stochastic") data appear "in real life"? Another, more technical motivation comes from algorithmic information theory. In this theory a notion of complexity of a finite object (=amount of information in this object) is introduced; it assigns to every object some number, called its algorithmic complexity (or Kolmogorov complexity). Algorithmic statistic provides a more fine-grained classification: for each finite object some curve is defined that characterizes its behavior. It turns out that several different definitions give (approximately) the same curve. In this survey we try to provide an exposition of the main results in the field (including full proofs for the most important ones), as well as some historical comments. We assume that the reader is familiar with the main notions of algorithmic information (Kolmogorov complexity) theory.Comment: Missing proofs adde

Inherent Inhomogeneities in Tunneling Spectra of BSCCO Crystals in the Superconducting State

Scanning Tunneling Spectroscopy on cleaved BSCCO(2212) single crystals reveal inhomogeneities on length-scales of $\sim$30 $\AA$. While most of the surface yields spectra consistent with a d-wave superconductor, small regions show a doubly gapped structure with both gaps lacking coherence peaks and the larger gap having a size typical of the respective pseudo-gap for the same sample.Comment: 4 pages, 4 figure

Interrelation between the pseudogap and the incoherent quasi-particle features of high-Tc superconductors

Using a scenario of a hybridized mixture of localized bipolarons and conduction electrons, we demonstrate for the latter the simultaneous appearance of a pseudogap and of strong incoherent contributions to their quasi-particle spectrum which arise from phonon shake-off effects. This can be traced back to temporarily fluctuating local lattice deformations, giving rise to a double-peak structure in the pair distribution function, which should be a key feature in testing the origin of these incoherent contributions, recently seen in angle-resolved photoemission spectroscopy (ARPES).Comment: 4 pages, 3 figures, to be published in Phys. Rev. Let

Magnetic Phase Diagram of the Hole-doped Ca2−x_{2-x}Nax_{x}CuO2_{2}Cl2_{2} Cuprate Superconductor

We report on the magnetic phase diagram of a hole-doped cuprate Ca$_{2-x}$Na$_{x}$CuO$_{2}$Cl$_{2}$, which is free from buckling of CuO$_2$ planes, determined by muon spin rotation and relaxation. It is characterized by a quasi-static spin glass-like phase over a range of sodium concentration ($0.05\leq x\leq 0.12$), which is held between long range antiferromagnetic (AF) phase ($x\leq 0.02$) and superconducting phase where the system is non-magnetic for $x\geq 0.15$. The obtained phase diagram qualitatively agrees well with that commonly found for hole-doped high-\tc cuprates, strongly suggesting that the incomplete suppression of the AF order for $x>0.02$ is an essential feature of the hole-doped cuprates.Comment: 5 pages, submitted to Phys. Rev. Let

Halo properties and secular evolution in barred galaxies

The halo plays a crucial role in the evolution of barred galaxies. Its near-resonant material absorbs angular momentum emitted from some of the disc particles and helps the bar become stronger. As a result, a bar (oval) forms in the inner parts of the halo of strongly barred disc galaxies. It is thinner in the inner parts (but still considerably fatter than the disc bar) and tends to spherical at larger radii. Its length increases with time, while always staying shorter than the disc bar. It is roughly aligned with the disc bar, which it trails only slightly, and it turns with roughly the same pattern speed. The bi-symmetric component of the halo density continues well outside the halo bar, where it clearly trails behind the disc bar. The length and strength of the disc and halo bars correlate; the former being always much stronger than the latter. If the halo is composed of weakly interacting massive particles, then the formation of the halo bar, by redistributing the matter in the halo and changing its shape, could influence the expected annihilation signal. This is indeed found to be the case if the halo has a core, but not if it has a steep cusp. The formation and evolution of the bar strongly affect the halo orbits. A fraction of them becomes near-resonant, similar to the disc near-resonant orbits at the same resonance, while another fraction becomes chaotic. Finally, a massive and responsive halo makes it harder for a central mass concentration to destroy the disc bar.Comment: 6 pages, 3 figures, to appear in "Island Universes - Structure and Evolution of Disk Galaxies" ed. R. S. de Jon