Transmembrane proton translocation by cytochrome c oxidase

AbstractRespiratory heme-copper oxidases are integral membrane proteins that catalyze the reduction of molecular oxygen to water using electrons donated by either quinol (quinol oxidases) or cytochrome c (cytochrome c oxidases, CcOs). Even though the X-ray crystal structures of several heme-copper oxidases and results from functional studies have provided significant insights into the mechanisms of O2-reduction and, electron and proton transfer, the design of the proton-pumping machinery is not known. Here, we summarize the current knowledge on the identity of the structural elements involved in proton transfer in CcO. Furthermore, we discuss the order and timing of electron-transfer reactions in CcO during O2 reduction and how these reactions might be energetically coupled to proton pumping across the membrane

Z3_3-graded differential geometry of quantum plane

In this work, the Z$_3$-graded differential geometry of the quantum plane is constructed. The corresponding quantum Lie algebra and its Hopf algebra structure are obtained. The dual algebra, i.e. universal enveloping algebra of the quantum plane is explicitly constructed and an isomorphism between the quantum Lie algebra and the dual algebra is given.Comment: 17 page

SUq(2)SU_q(2) Lattice Gauge Theory

We reformulate the Hamiltonian approach to lattice gauge theories such that, at the classical level, the gauge group does not act canonically, but instead as a Poisson-Lie group. At the quantum level, it then gets promoted to a quantum group gauge symmetry. The theory depends on two parameters - the deformation parameter $\lambda$ and the lattice spacing $a$. We show that the system of Kogut and Susskind is recovered when $\lambda \rightarrow 0$, while QCD is recovered in the continuum limit (for any $\lambda$). We thus have the possibility of having a two parameter regularization of QCD.Comment: 26 pages, LATEX fil

ATHENA: A Phase 3, Open-Label Study Of The Safety And Effectiveness Of Oliceridine (TRV130), A G-Protein Selective Agonist At The µ-Opioid Receptor, In Patients With Moderate To Severe Acute Pain Requiring Parenteral Opioid Therapy.

Background:Pain management with conventional opioids can be challenging due to dose-limiting adverse events (AEs), some of which may be related to the simultaneous activation of β-arrestin (a signaling pathway associated with opioid-related AEs) and G-protein pathways. The investigational analgesic oliceridine is a G-protein-selective agonist at the µ-opioid receptor with less recruitment of β-arrestin. The objective of this phase 3, open-label, multi-center study was to evaluate the safety and tolerability, of IV oliceridine for moderate to severe acute pain in a broad, real-world patient population, including postoperative surgical patients and non-surgical patients with painful medical conditions. Methods:Adult patients with a score ≥4 on 11-point NRS for pain intensity received IV oliceridine either by bolus or PCA; multimodal analgesia was permitted. Safety was assessed using AE reports, study discontinuations, clinical laboratory and vital sign measures. Results:A total of 768 patients received oliceridine. The mean age (SD) was 54.1 (16.1) years, with 32% ≥65 years of age. Most patients were female (65%) and Caucasian (78%). Surgical patients comprised the majority of the study population (94%), most common being orthopedic (30%), colorectal (15%) or gynecologic (15%) procedures. Multimodal analgesia was administered to 84% of patients. Oliceridine provided a rapid reduction in NRS pain score by 2.2 ± 2.3 at 30 mins from a score of 6.3 ± 2.1 (at baseline) which was maintained to the end of treatment. No deaths or significant cardiorespiratory events were reported. The incidence of AEs leading to early discontinuation and serious AEs were 2% and 3%, respectively. Nausea (31%), constipation (11%), and vomiting (10%) were the most common AEs. AEs were mostly of mild (37%) or moderate (25%) severity and considered possibly or probably related to oliceridine in 33% of patients. Conclusion:Oliceridine IV for the management of moderate to severe acute pain was generally safe and well tolerated in the patients studied. ClinicalTrialsgov identifier:NCT02656875

Proton transfer from glutamate 286 determines the transition rates between oxygen intermediates in cytochrome c oxidase

AbstractWe have investigated the electron–proton coupling during the peroxy (PR) to oxo-ferryl (F) and F to oxidised (O) transitions in cytochrome c oxidase from Rhodobacter sphaeroides. The kinetics of these reactions were investigated in two different mutant enzymes: (1) ED(I-286), in which one of the key residues in the D-pathway, E(I-286), was replaced by an aspartate which has a shorter side chain than that of the glutamate and, (2) ML(II-263), in which the redox potential of CuA is increased by ∼100 mV, which slows electron transfer to the binuclear centre during the F→O transition by a factor of ∼200. In ED(I-286) proton uptake during PR→F was slowed by a factor of ∼5, which indicates that E(I-286) is the proton donor to PR. In addition, in the mutant enzyme the F→O transition rate displayed a deuterium isotope effect of ∼2.5 as compared with ∼7 in the wild-type enzyme. Since the entire deuterium isotope effect was shown to be associated with a single proton-transfer reaction in which the proton donor and acceptor must approach each other (M. Karpefors, P. Ådelroth, P. Brzezinski, Biochemistry 39 (2000) 6850), the smaller deuterium isotope effect in ED(I-286) indicates that proton transfer from E(I-286) determines the rate also of the F→O transition. In ML(II-263) the electron-transfer to the binuclear centre is slower than the intrinsic proton-transfer rate through the D-pathway. Nevertheless, both electron and proton transfer to the binuclear centre displayed a deuterium isotope effect of ∼8, i.e., about the same as in the wild-type enzyme, which shows that these reactions are intimately coupled

Proton-transfer pathways in the mitochondrial S. cerevisiae cytochrome c oxidase

In cytochrome c oxidase (CytcO) reduction of O2 to water is linked to uptake of eight protons from the negative side of the membrane: four are substrate protons used to form water and four are pumped across the membrane. In bacterial oxidases, the substrate protons are taken up through the K and the D proton pathways, while the pumped protons are transferred through the D pathway. On the basis of studies with CytcO isolated from bovine heart mitochondria, it was suggested that in mitochondrial CytcOs the pumped protons are transferred though a third proton pathway, the H pathway, rather than through the D pathway. Here, we studied these reactions in S. cerevisiae CytcO, which serves as a model of the mammalian counterpart. We analyzed the effect of mutations in the D (Asn99Asp and Ile67Asn) and H pathways (Ser382Ala and Ser458Ala) and investigated the kinetics of electron and proton transfer during the reaction of the reduced CytcO with O2. No effects were observed with the H pathway variants while in the D pathway variants the functional effects were similar to those observed with the R. sphaeroides CytcO. The data indicate that the S. cerevisiae CytcO uses the D pathway for proton uptake and presumably also for proton pumping

Efeito do tratamento de sementes de soja com micronutrientes e bioestimulantes sobre o desenvolvimento de plântulas.

O objetivo deste trabalho foi o de avaliar os efeitos do tratamento de sementes de soja com micronutrientes (MN) e bioestimulantes (BE), sobre o desenvolvimento das plântulas. Os produtos com MN avaliados foram Broadacre CMZ, Broadacre Mn, Broadacre ZnCu e Maxi Zinc. Os BEs foram Kelpak e Booster. Foram conduzidos dois experimentos, um com a dose de 2,5 mL.kg-1 para cada produto e o outro com dose dobrada (5,0 mL.kg-1). Sementes da cultivar BRS 246RR foram utilizadas e submetidas aos testes de germinação, emergência de plântulas em areia, comprimento de plântula, de hipocótilo e de raiz, massa seca de plântula, de raiz e de parte aérea. Com relação aos testes de germinação e de comprimento de plântula, de hipocótilo e de raiz, os produtos Booster e Kelpak apresentaram baixa fitotoxicidade, caracterizada por encurtamento das plântulas, principalmente no sistema radicular. Em algumas situações, o Broadacre CMZ mostrou pouca fitotoxicidade. O Broadacre Mn propiciou melhor desenvolvimento das plântulas nesses testes. Efeitos positivos foram constatados também para o Broadacre CMZ e para o Maxi Zinc nas doses maiores. Nos testes de massa seca de plântula, raiz e parte aérea, foi verificado baixo efeito fitotóxico causado pelo Booster na dose maior. Entretanto, as fitotoxicidades aqui relatadas são consideradas aceitáveis e não se caracterizam num problema. Novamente, o Broadacre CMZ destacou-se pelo seu melhor desempenho quanto ao desenvolvimento das plântulas. De maneira geral, observou-se que os tratamentos com Broadacre CMZ, Mn e ZnCu e o Maxi Zinc propiciaram melhor desenvolvimento de plântulas, com maior massa seca em relação à testemunha

Coadditive differential complexes on quantum groups and quantum spaces

A regular way to define an additive coproduct (or ``coaddition'') on the q-deformed differential complexes is proposed for quantum groups and quantum spaces related to the Hecke-type R-matrices. Several examples of braided coadditive differential bialgebras (Hopf algebras) are presented.Comment: 9 page

The question of EU legitimacy in the Social OMC peer review process

This paper examines the structural kand relational factors that affect perceptions of legitimacy in the EU's Social Open Method of Coordination, particularly in its peer review process. Using multi-level governance as its analytical framework, the paper uses network analysis to examine the actor networks and relations within the peer review process over time, and links this with different conceptions of input and throughput legitimacy, and the findings show that the peer reviews do not significantly feed into either input or throughput legitimacy. While input legitimacy is improved somewhat by the inclusion of additional actors in the policy process, these actors do not have a clear role to play and the peer reviews remain driven by traditional actors. In terms of throughput, the process does positively address issues of transparency, procedure and information provision, there is no clear path for translating these processes into an increase in perceptions of legitimacy