Characterization of the impact of prenatal cigarette smoke exposure on age- and sex-specific SIRT1-mediated hepatic molecular phenotype in C57BL/6 mice.

In the U.S., 7.2% of women still report having smoked at some point during pregnancy despite known risks to fetal health. Prenatal cigarette smoke exposure (CSE) in children puts them at risk for low birth weight, premature birth, and other adverse impacts on developmental and postnatal health. Children subjected to prenatal CSE have a higher risk of adulthood metabolic disease predicted by the Barker Hypothesis. The hepatic molecular phenotype associated with this risk is unknown. This dissertation characterizes the prenatal CSE-induced hepatic molecular phenotype during three key life stages. We used a murine model of prenatal CSE utilizing a Teague TE-10C cigarette smoking apparatus that induces low birth weight with catch-up growth. This model was used in a preliminary study to observe the hepatic metabolic phenotype of prenatal (gestational day 6-18) CSE offspring during adulthood in conjunction with a high-fat diet (HFD) or control low-fat diet (CD) feeding for three months. The hepatic molecular phenotype was characterized by the expression of SIRT1, a Class III deacetylase NAD+ sensor, and associated genes and proteins. Female CSE offspring maintained on a HFD exhibited exacerbated weight gain and body fat accumulation while male CSE offspring exhibited decreased SIRT1-related protein expression. Follow up studies subjected offspring to prenatal (GD1-18) CSE and measured their hepatic molecular phenotype at the neonatal and post-weaning periods. Male CSE offspring at 1.5 weeks of age exhibited signs of elevated SIRT1 signaling independent of the main SIRT1 regulatory loop. Female CSE 1.5-week old offspring exhibited signs of delayed functional liver ontogeny via depressed expression of Sirt1, related enzymes, and serum glucose levels. Weaned fed male CSE offspring exhibited mixed expression in SIRT1-regulatory pathways. Fasted male CSE offspring exhibited signs of an exacerbated fasting response via increased SIRT1-related gluconeogenic mRNA expression. Fed female CSE offspring exhibited an exacerbated fed response and untimely gluconeogenic mRNA expression. Fasted female CSE offspring exhibited signs of an exacerbated fasting response via SIRT1-related mRNA and protein expression and untimely lipogenic mRNA expression. This work attempted to extend the Barker Hypothesis by characterizing the hepatic molecular phenotype at key life stages in offspring subjected to prenatal CSE

Statistical characteristics of formation and evolution of structure in the universe

An approximate statistical description of the formation and evolution of structure of the universe based on the Zel'dovich theory of gravitational instability is proposed. It is found that the evolution of DM structure shows features of self-similarity and the main structure characteristics can be expressed through the parameters of initial power spectrum and cosmological model. For the CDM-like power spectrum and suitable parameters of the cosmological model the effective matter compression reaches the observed scales $R_{wall}\sim$20 -- 25$h^{-1}$Mpc with the typical mean separation of wall-like elements $D_{SLSS}\sim$50 -- 70$h^{-1}$Mpc. This description can be directly applied to the deep pencil beam galactic surveys and absorption spectra of quasars. For larger 3D catalogs and simulations it can be applied to results obtained with the core-sampling analysis. It is shown that the interaction of large and small scale perturbations modulates the creation rate of early Zel'dovich pancakes and generates bias on the SLSS scale. For suitable parameters of the cosmological model and reheating process this bias can essentially improve the characteristics of simulated structure of the universe. The models with $0.3\leq \Omega_m \leq 0.5$ give the best description of the observed structure parameters. The influence of low mass "warm" dark matter particles, such as a massive neutrino, will extend the acceptable range of $\Omega_m$ and $h$.Comment: 20pages, 7 figures, MNRAS in pres

A bacterial tyrosine phosphatase modulates cell proliferation through targeting RGCC.

Tyrosine phosphatases are often weaponized by bacteria colonizing mucosal barriers to manipulate host cell signal transduction pathways. Porphyromonas gingivalis is a periodontal pathogen and emerging oncopathogen which interferes with gingival epithelial cell proliferation and migration, and induces a partial epithelial mesenchymal transition. P. gingivalis produces two tyrosine phosphatases, and we show here that the low molecular weight tyrosine phosphatase, Ltp1, is secreted within gingival epithelial cells and translocates to the nucleus. An ltp1 mutant of P. gingivalis showed a diminished ability to induce epithelial cell migration and proliferation. Ltp1 was also required for the transcriptional upregulation of Regulator of Growth and Cell Cycle (RGCC), one of the most differentially expressed genes in epithelial cells resulting from P. gingivalis infection. A phosphoarray and siRNA showed that P. gingivalis controlled RGCC expression through Akt, which was activated by phosphorylation on S473. Akt activation is opposed by PTEN, and P. gingivalis decreased the amount of PTEN in epithelial cells. Ectopically expressed Ltp1 bound to PTEN, and reduced phosphorylation of PTEN at Y336 which controls proteasomal degradation. Ltp-1 induced loss of PTEN stability was prevented by chemical inhibition of the proteasome. Knockdown of RGCC suppressed upregulation of Zeb2 and mesenchymal markers by P. gingivalis. RGCC inhibition was also accompanied by a reduction in production of the proinflammatory cytokine IL-6 in response to P. gingivalis. Elevated IL-6 levels can contribute to periodontal destruction, and the ltp1 mutant of P. gingivalis incited less bone loss compared to the parental strain in a murine model of periodontal disease. These results show that P. gingivalis can deliver Ltp1 within gingival epithelial cells, and establish PTEN as the target for Ltp1 phosphatase activity. Disruption of the Akt1/RGCC signaling axis by Ltp1 facilitates P. gingivalis-induced increases in epithelial cell migration, proliferation, EMT and inflammatory cytokine production

Impact of Polymicrobial Infection on Fitness of Streptococcus gordonii In Vivo

ABSTRACT Pathogenic microbial ecosystems are often polymicrobial, and interbacterial interactions drive emergent properties of these communities. In the oral cavity, Streptococcus gordonii is a foundational species in the development of plaque biofilms, which can contribute to periodontal disease and, after gaining access to the bloodstream, target remote sites such as heart valves. Here, we used a transposon sequencing (Tn-Seq) library of S. gordonii to identify genes that influence fitness in a murine abscess model, both as a monoinfection and as a coinfection with an oral partner species, Porphyromonas gingivalis. In the context of a monoinfection, conditionally essential genes were widely distributed among functional pathways. Coinfection with P. gingivalis almost completely changed the nature of in vivo gene essentiality. Community-dependent essential (CoDE) genes under the coinfection condition were primarily related to DNA replication, transcription, and translation, indicating that robust growth and replication are required to survive with P. gingivalis in vivo. Interestingly, a group of genes in an operon encoding streptococcal receptor polysaccharide (RPS) were associated with decreased fitness of S. gordonii in a coinfection with P. gingivalis. Individual deletion of two of these genes (SGO_2020 and SGO_2024) resulted in the loss of RPS production by S. gordonii and increased susceptibility to killing by neutrophils. P. gingivalis protected the RPS mutants by inhibiting neutrophil recruitment, degranulation, and neutrophil extracellular trap (NET) formation. These results provide insight into genes and functions that are important for S. gordonii survival in vivo and the nature of polymicrobial synergy with P. gingivalis. Furthermore, we show that RPS-mediated immune protection in S. gordonii is dispensable and detrimental in the presence of a synergistic partner species that can interfere with neutrophil killing mechanisms. IMPORTANCE Bacteria responsible for diseases originating at oral mucosal membranes assemble into polymicrobial communities. However, we know little regarding the fitness determinants of the organisms that initiate community formation. Here, we show that the extracellular polysaccharide of Streptococcus gordonii, while important for streptococcal survival as a monoinfection, is detrimental to survival in the context of a coinfection with Porphyromonas gingivalis. We found that the presence of P. gingivalis compensates for immune protective functions of extracellular polysaccharide, rendering production unnecessary. The results show that fitness determinants of bacteria in communities differ substantially from those of individual species in isolation. Furthermore, constituents of communities can undertake activities that relieve the burden of energetically costly biosynthetic reactions on partner species

The AT20G view of swift/BAT selected AGN: High-frequency radio waves meet hard X-rays

We cross-matched the 6-year Swift/Burst Alert Telescope (BAT) survey of active galactic nuclei (AGN) with the AT20G radio survey of the southern sky, which is one of the largest high-frequency radio surveys available.With these datawe investigated the possible correlation between the radio and the X-ray emission at the highest radio and X-ray frequencies.We found 37AGNwith a high probability of association (>80 per cent), among which 19 are local Seyfert galaxies (with median redshift z=0.03) and 18 blazars.We found that˜20 per cent of theAGN detected in hard X-rays are also bright radio sources at 20 GHz, but the apparent correlation between the radio and hard X-ray luminosity is completely driven by the different median redshifts of the two subgroups of AGN. When we consider only the local Seyfert sample we find no evidence of a correlation between their 20 GHz and 15-55 keV power. Therefore it appears that at high frequencies the radio-X connection, which had been previously observed at lower frequencies, disappears. The disappearance of the radio-X correlation at high radio and X-ray frequencies could be tested through Very Long Baseline Interferometry and the use of the Nuclear Spectroscopic Telescope Array (NuSTAR) satellite. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society