Genes contributing to Porphyromonas gingivalis fitness in abscess and epithelial cell colonization environments

Porphyromonas gingivalis is an important cause of serious periodontal diseases, and is emerging as a pathogen in several systemic conditions including some forms of cancer. Initial colonization by P. gingivalis involves interaction with gingival epithelial cells, and the organism can also access host tissues and spread haematogenously. To better understand the mechanisms underlying these properties, we utilized a highly saturated transposon insertion library of P. gingivalis, and assessed the fitness of mutants during epithelial cell colonization and survival in a murine abscess model by high-throughput sequencing (Tn-Seq). Transposon insertions in many genes previously suspected as contributing to virulence showed significant fitness defects in both screening assays. In addition, a number of genes not previously associated with P. gingivalis virulence were identified as important for fitness. We further examined fitness defects of four such genes by generating defined mutations. Genes encoding a carbamoyl phosphate synthetase, a replication-associated recombination protein, a nitrosative stress responsive HcpR transcription regulator, and RNase Z, a zinc phosphodiesterase, showed a fitness phenotype in epithelial cell colonization and in a competitive abscess infection. This study verifies the importance of several well-characterized putative virulence factors of P. gingivalis and identifies novel fitness determinants of the organism

Critical wave-packet dynamics in the power-law bond disordered Anderson Model

We investigate the wave-packet dynamics of the power-law bond disordered one-dimensional Anderson model with hopping amplitudes decreasing as $H_{nm}\propto |n-m|^{-\alpha}$. We consider the critical case ($\alpha=1$). Using an exact diagonalization scheme on finite chains, we compute the participation moments of all stationary energy eigenstates as well as the spreading of an initially localized wave-packet. The eigenstates multifractality is characterized by the set of fractal dimensions of the participation moments. The wave-packet shows a diffusive-like spread developing a power-law tail and achieves a stationary non-uniform profile after reflecting at the chain boundaries. As a consequence, the time-dependent participation moments exhibit two distinct scaling regimes. We formulate a finite-size scaling hypothesis for the participation moments relating their scaling exponents to the ones governing the return probability and wave-function power-law decays

Structural determinants of inhibition of Porphyromonas gingivalis gingipain K by KYT-36, a potent, selective, and bioavailable peptidase inhibitor

Abstract Porphyromonas gingivalis is a member of the dysbiotic oral microbiome and a “keystone pathogen” that causes severe periodontal disease, which is among the most prevalent infectious diseases. Part of the virulence factors secreted by P. gingivalis are the essential cysteine peptidases gingipain K (Kgp) and R (RgpA and RgpB), which account for 85% of the extracellular proteolytic activity of the pathogen and are thus prime targets for inhibition. We report the high-resolution (1.20 Å) complex structure of Kgp with KYT-36, a peptide-derived, potent, bioavailable and highly selective inhibitor, which is widely used for studies in vitro, in cells and in vivo. Sub-nanomolar inhibition of Kgp is achieved by tight binding to the active-site cleft, which is covered for its sub-sites S3 through S1’ under establishment of nine hydrophobic interactions, 14 hydrogen bonds and one salt bridge. In addition, an inhibitor carbonyl carbon that mimics the scissile carbonyl of substrates is pyramidalized and just 2.02 Å away from the catalytic nucleophile of Kgp, C477Sγ. Thus, the crystal structure emulates a reaction intermediate of the first nucleophilic attack during catalysis of cysteine peptidases. The present study sets the pace for the development of tailored next-generation drugs to tackle P. gingivalis

Critical conductance of two-dimensional chiral systems with random magnetic flux

The zero temperature transport properties of two-dimensional lattice systems with static random magnetic flux per plaquette and zero mean are investigated numerically. We study the two-terminal conductance and its dependence on energy, sample size, and magnetic flux strength. The influence of boundary conditions and of the oddness of the number of sites in the transverse direction is also studied. We confirm the existence of a critical chiral state in the middle of the energy band and calculate the critical exponent nu=0.35 +/- 0.03 for the divergence of the localization length. The sample averaged scale independent critical conductance _c turns out to be a function of the amplitude of the flux fluctuations whereas the variance of the respective conductance distributions appears to be universal. All electronic states outside of the band center are found to be localized.Comment: to appear in Phys. Rev.

Metal-insulator transitions in anisotropic 2d systems

Several phenomena related to the critical behaviour of non-interacting electrons in a disordered 2d tight-binding system with a magnetic field are studied. Localization lengths, critical exponents and density of states are computed using transfer matrix techniques. Scaling functions of isotropic systems are recovered once the dimension of the system in each direction is chosen proportional to the localization length. It is also found that the critical point is independent of the propagation direction, and that the critical exponents for the localization length for both propagating directions are equal to that of the isotropic system (approximately 7/3). We also calculate the critical value of the scaling function for both the isotropic and the anisotropic system. It is found that the isotropic value equals the geometric mean of the two anisotropic values. Detailed numerical studies of the density of states for the isotropic system reveals that for an appreciable amount of disorder the critical energy is off the band center.Comment: 6 pages RevTeX, 6 figures included, submitted to Physical Review

Integrating the HIV-1 assembly/maturation pathway

In PNAS, Jurado et al. (1) describe an unexpected mechanism of action of a new class of HIV type 1 (HIV-1) integrase (IN) inhibitors. Several years ago it was discovered that the HIV-1 IN was targeted to sites in chromatin by the host protein lens epithelium-derived growth factor (LEDGF)/p75 (2). The site of interaction between IN and LEDGF/p75 was defined, and inhibitors to block that interaction were sought and identified. In PNAS, Jurado et al. (1) show that although these inhibitors (termed Allosteric IN inhibitors, or ALLINIs) have some potency to block steps involved in integration, their most dramatic effect is to cause the virus particle to assemble into a noninfectious structure

Застосування українського досвіду визначення кроку встановлення рамного кріплення підготовчих виробок для польських шахт

На основі детального аналізу наявного досвіду встановлення рамного кріплення підготовчих виробок на шахтах України та застосування перевірених методик визначення навантажень на окремі його елементи запропоновано концепцію збільшення кроку інсталяції рамноаркового кріплення на шахтах Польщі. Економічну оцінку запропонованого технологічного удосконалення проведено, ґрунтуючись на відносних одиницях для більш точного відображення мінливого ринку гірничої промисловості. Як удосконалення запропоновано стандартний для український шахт крок встановлення кріплення

BET bromodomain inhibitors suppress inflammatory activation of gingival fibroblasts and epithelial cells from periodontitis patients

BET bromodomain proteins are important epigenetic regulators of gene expression that bind acetylated histone tails and regulate the formation of acetylation-dependent chromatin complexes. BET inhibitors suppress inflammatory responses in multiple cell types and animal models, and protect against bone loss in experimental periodontitis in mice. Here, we analyzed the role of BET proteins in inflammatory activation of gingival fibroblasts (GFs) and gingival epithelial cells (GECs). We show that the BET inhibitors I-BET151 and JQ1 significantly reduced expression and/or production of distinct, but overlapping, profiles of cytokine-inducible mediators of inflammation and bone resorption in GFs from healthy donors (IL6, IL8, IL1B, CCL2, CCL5, COX2, and MMP3) and the GEC line TIGK (IL6, IL8, IL1B, CXCL10, MMP9) without affecting cell viability. Activation of mitogen-activated protein kinase and nuclear factor-κB pathways was unaffected by I-BET151, as was the histone acetylation status, and new protein synthesis was not required for the anti-inflammatory effects of BET inhibition. I-BET151 and JQ1 also suppressed expression of inflammatory cytokines, chemokines, and osteoclastogenic mediators in GFs and TIGKs infected with the key periodontal pathogen Porphyromonas gingivalis. Notably, P. gingivalis internalization and intracellular survival in GFs and TIGKs remained unaffected by BET inhibitors. Finally, inhibition of BET proteins significantly reduced P. gingivalis-induced inflammatory mediator expression in GECs and GFs from patients with periodontitis. Our results demonstrate that BET inhibitors may block the excessive inflammatory mediator production by resident cells of the gingival tissue and identify the BET family of epigenetic reader proteins as a potential therapeutic target in the treatment of periodontal disease

Levitation of quantum Hall critical states in a lattice model with spatially correlated disorder

The fate of the current carrying states of a quantum Hall system is considered in the situation when the disorder strength is increased and the transition from the quantum Hall liquid to the Hall insulator takes place. We investigate a two-dimensional lattice model with spatially correlated disorder potentials and calculate the density of states and the localization length either by using a recursive Green function method or by direct diagonalization in connection with the procedure of level statistics. From the knowledge of the energy and disorder dependence of the localization length and the density of states (DOS) of the corresponding Landau bands, the movement of the current carrying states in the disorder--energy and disorder--filling-factor plane can be traced by tuning the disorder strength. We show results for all sub-bands, particularly the traces of the Chern and anti-Chern states as well as the peak positions of the DOS. For small disorder strength $W$ we recover the well known weak levitation of the critical states, but we also reveal, for larger $W$, the strong levitation of these states across the Landau gaps without merging. We find the behavior to be similar for exponentially, Gaussian, and Lorentzian correlated disorder potentials. Our study resolves the discrepancies of previously published work in demonstrating the conflicting results to be only special cases of a general lattice model with spatially correlated disorder potentials. To test whether the mixing between consecutive Landau bands is the origin of the observed floating, we truncate the Hilbert space of our model Hamiltonian and calculate the behavior of the current carrying states under these restricted conditions.Comment: 10 pages, incl. 13 figures, accepted for publication in PR