Peroxiredoxin Catalysis at Atomic Resolution

Peroxiredoxins (Prxs) are ubiquitous cysteine-based peroxidases that guard cells against oxidative damage, are virulence factors for pathogens, and are involved in eukaryotic redox regulatory pathways. We have analyzed catalytically active crystals to capture atomic resolution snapshots of a PrxQ-subfamily enzyme (from Xanthomonas campestris) proceeding through thiolate, sulfenate, and sulfinate species. These analyses provide structures of unprecedented accuracy for seeding theoretical studies, and show novel conformational intermediates giving insight into the reaction pathway. Based on a highly non-standard geometry seen for the sulfenate intermediate, we infer that the sulfenate formation itself can strongly promote local unfolding of the active site to enhance productive catalysis. Further, these structures reveal that preventing local unfolding, in this case via crystal contacts, results in facile hyperoxidative inactivation even for Prxs normally resistant to such inactivation. This supports previous proposals that conformation-specific inhibitors may be useful for achieving selective inhibition of Prxs that are drug targets

Counting Complex Disordered States by Efficient Pattern Matching: Chromatic Polynomials and Potts Partition Functions

Counting problems, determining the number of possible states of a large system under certain constraints, play an important role in many areas of science. They naturally arise for complex disordered systems in physics and chemistry, in mathematical graph theory, and in computer science. Counting problems, however, are among the hardest problems to access computationally. Here, we suggest a novel method to access a benchmark counting problem, finding chromatic polynomials of graphs. We develop a vertex-oriented symbolic pattern matching algorithm that exploits the equivalence between the chromatic polynomial and the zero-temperature partition function of the Potts antiferromagnet on the same graph. Implementing this bottom-up algorithm using appropriate computer algebra, the new method outperforms standard top-down methods by several orders of magnitude, already for moderately sized graphs. As a first application, we compute chromatic polynomials of samples of the simple cubic lattice, for the first time computationally accessing three-dimensional lattices of physical relevance. The method offers straightforward generalizations to several other counting problems.Comment: 7 pages, 4 figure

Evaluating peroxiredoxin sensitivity towards inactivation by peroxide substrates

Peroxiredoxins (Prxs) are very effective peroxide reducing enzymes, but also are susceptible to being oxidatively inactivated by their own substrates. The level of sensitivity to such hyperoxidation varies depending both on the enzyme involved and the type of peroxide substrate. For some Prxs, the hyperoxidation has physiological relevance, so it is important to define approaches that can be used to quantify sensitivity. Here we describe three distinct approaches that can be used to obtain quantitative or semiquantitative estimates of Prx sensitivity and define C[subscript hyp1%] as a simple way of quantifying sensitivity so that values can easily be compared.Keywords: mass spectrometry, cysteine sulfenic acid, oxidative inactivation, peroxidase, cysteine sulfinic acid, peroxide signaling, redox signaling, hyperoxidatio

Peroxiredoxins: Guardians Against Oxidative Stress and Modulators of Peroxide Signaling

Peroxiredoxins (Prxs) are a ubiquitous family of cysteine-dependent peroxidase enzymes that play dominant roles in regulating peroxide levels within cells. These enzymes, often present at high levels and capable of rapidly clearing peroxides, display a remarkable array of variations in their oligomeric states and susceptibility to regulation by hyperoxidative inactivation and other post-translational modifications. Key conserved residues within the active site promote catalysis by stabilizing the transition state required for transferring the terminal oxygen of hydroperoxides to the active site (peroxidatic) cysteine residue. Extensive investigations continue to expand our understanding of the scope of their importance as well as the structures and forces at play within these critical defense and regulatory enzymes.Keywords: redox signaling, peroxidase, antioxidant enzyme, antioxidant defens

Lower Bounds and Series for the Ground State Entropy of the Potts Antiferromagnet on Archimedean Lattices and their Duals

We prove a general rigorous lower bound for $W(\Lambda,q)=\exp(S_0(\Lambda,q)/k_B)$, the exponent of the ground state entropy of the $q$-state Potts antiferromagnet, on an arbitrary Archimedean lattice $\Lambda$. We calculate large-$q$ series expansions for the exact $W_r(\Lambda,q)=q^{-1}W(\Lambda,q)$ and compare these with our lower bounds on this function on the various Archimedean lattices. It is shown that the lower bounds coincide with a number of terms in the large-$q$ expansions and hence serve not just as bounds but also as very good approximations to the respective exact functions $W_r(\Lambda,q)$ for large $q$ on the various lattices $\Lambda$. Plots of $W_r(\Lambda,q)$ are given, and the general dependence on lattice coordination number is noted. Lower bounds and series are also presented for the duals of Archimedean lattices. As part of the study, the chromatic number is determined for all Archimedean lattices and their duals. Finally, we report calculations of chromatic zeros for several lattices; these provide further support for our earlier conjecture that a sufficient condition for $W_r(\Lambda,q)$ to be analytic at $1/q=0$ is that $\Lambda$ is a regular lattice.Comment: 39 pages, Revtex, 9 encapsulated postscript figures, to appear in Phys. Rev.

Perinatal outcomes after in-utero exposure to beta-blockers in women with heart disease:Data from the ESC EORP registry of pregnancy and cardiac disease (ROPAC)

Background: Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse. Differences between beta-blockers are not well-studied. Methods: In the Registry of Pregnancy And Cardiac disease (ROPAC, n = 5739), a prospective global registry of pregnancies in women with structural heart disease, perinatal outcomes (small for gestational age (SGA), birth weight, neonatal congenital heart disease (nCHD) and perinatal mortality) were compared between women with and without beta-blocker exposure, and between different beta-blockers. Multivariable regression analysis was used for the effect of beta-blockers on birth weight, SGA and nCHD (after adjustment for maternal and perinatal confounders). Results: Beta-blockers were used in 875 (15.2%) ROPAC pregnancies, with metoprolol (n = 323, 37%) and bisoprolol (n = 261, 30%) being the most frequent. Women with beta-blocker exposure had more SGA infants (15.3% vs 9.3%, p &lt; 0.001) and nCHD (4.7% vs 2.7%, p = 0.001). Perinatal mortality rates were not different (1.4% vs 1.9%, p = 0.272). The adjusted mean difference in birth weight was −177 g (−5.8%), the adjusted OR for SGA was 1.7 (95% CI 1.3–2.1) and for nCHD 2.3 (1.6–3.5). With metoprolol as reference, labetalol (0.2, 0.1–0.4) was the least likely to cause SGA, and atenolol (2.3, 1.1–4.9) the most. Conclusions: In women with heart disease an association was found between maternal beta-blocker use and perinatal outcomes. Labetalol seems to be associated with the lowest risk of developing SGA, while atenolol should be avoided.</p

Temperature development of glassy alpha-relaxation dynamics determined by broadband dielectric spectroscopy

We present the temperature dependence of alpha-relaxation times of 13 glass formers determined from broadband dielectric spectroscopy, also including data from aging measurements. The data sets partly cover relaxation-time ranges of up to 16 decades enabling a critical test of the validity of model predictions. For this purpose, the data are provided for electronic download. Here we employ these results to test the applicability of the Vogel-Fulcher-Tammann equation and a recently proposed new approach that was demonstrated to provide superior fits of a vast collection of viscosity data.Comment: 6 pages, 5 figures, final version with minor revisions according to referee demands. The relaxation time data published in the present work can be downloaded at http://link.aps.org/supplemental/10.1103/PhysRevE.81.05150

Training opportunities in thoracic ultrasound for respiratory trainees: are current guidelines practical?

Respiratory trainees in the UK face challenges in meeting current Royal College of Radiologists (RCR) Level 1 training requirements for thoracic ultrasound (TUS) competence, specified as attending 'at least one session per week over a period of no less than 3 months, with approximately five scans per session performed by the trainee (under supervision of an experienced practitioner)'. We aimed to clarify where TUS training opportunities currently exist for respiratory registrars.This is an Open Access article. Click on the Publisher URL to access the full-text

Exact T=0 Partition Functions for Potts Antiferromagnets on Sections of the Simple Cubic Lattice

We present exact solutions for the zero-temperature partition function of the $q$-state Potts antiferromagnet (equivalently, the chromatic polynomial $P$) on tube sections of the simple cubic lattice of fixed transverse size $L_x \times L_y$ and arbitrarily great length $L_z$, for sizes $L_x \times L_y = 2 \times 3$ and $2 \times 4$ and boundary conditions (a) $(FBC_x,FBC_y,FBC_z)$ and (b) $(PBC_x,FBC_y,FBC_z)$, where $FBC$ ($PBC$) denote free (periodic) boundary conditions. In the limit of infinite-length, $L_z \to \infty$, we calculate the resultant ground state degeneracy per site $W$ (= exponent of the ground-state entropy). Generalizing $q$ from ${\mathbb Z}_+$ to ${\mathbb C}$, we determine the analytic structure of $W$ and the related singular locus ${\cal B}$ which is the continuous accumulation set of zeros of the chromatic polynomial. For the $L_z \to \infty$ limit of a given family of lattice sections, $W$ is analytic for real $q$ down to a value $q_c$. We determine the values of $q_c$ for the lattice sections considered and address the question of the value of $q_c$ for a $d$-dimensional Cartesian lattice. Analogous results are presented for a tube of arbitrarily great length whose transverse cross section is formed from the complete bipartite graph $K_{m,m}$.Comment: 28 pages, latex, six postscript figures, two Mathematica file