A ternary mechanism for NADH oxidation by positively charged electron acceptors, catalyzed at the flavin site in respiratory complex I

AbstractThe flavin mononucleotide in complex I (NADH:ubiquinone oxidoreductase) catalyzes NADH oxidation, O2 reduction to superoxide, and the reduction of several ‘artificial’ electron acceptors. Here, we show that the positively-charged electron acceptors paraquat and hexaammineruthenium(III) react with the nucleotide-bound reduced flavin in complex I, by an unusual ternary mechanism. NADH, ATP, ADP and ADP-ribose stimulate the reactions, indicating that the positively-charged acceptors interact with their negatively-charged phosphates. Our mechanism for paraquat reduction defines a new mechanism for superoxide production by complex I (by redox cycling); in contrast to direct O2 reduction the rate is stimulated, not inhibited, by high NADH concentrations

Radiative Inflation and Dark Energy

We propose a model based on radiative symmetry breaking that combines inflation with Dark Energy and is consistent with the WMAP 7-year regions. The radiative inflationary potential leads to the prediction of a spectral index 0.955 \lesssim n_S \lesssim 0.967 and a tensor to scalar ratio 0.142 \lesssim r \lesssim 0.186, both consistent with current data but testable by the Planck experiment. The radiative symmetry breaking close to the Planck scale gives rise to a pseudo Nambu-Goldstone boson with a gravitationally suppressed mass which can naturally play the role of a quintessence field responsible for Dark Energy. Finally, we present a possible extra dimensional scenario in which our model could be realised.Comment: 15 pages, 4 figures; v2: references added, appendix added, Section 5 slightly modified; content matches published versio

Major Powers and Militarized Conflict

This article attempts to answer the question of why major powers engage in more active foreign policy behaviors than minor powers. It does so by comparing two explanations for the increased conflict propensity of major powers. The first explanation focuses on major powers’ observable capabilities, while the second stresses their different behavior. We incorporate both into an ultimatum model of conflict in which a state’s cost of conflict consists of both observable and behavioral components. Using data from the period from 1870 to 2001, we empirically illustrate the observable and behavioral differences between major and minor powers. We then utilize a decomposition model to assess the relative significance of the two explanations. The results suggest that most of the difference in conflict propensity between major and minor powers can be attributed to observable differences

A Tumbling Top-Quark Condensate Model

We propose a renormalizable model with no fundamental scalars which breaks itself in the manner of a "tumbling" gauge theory down to the standard model with a top-quark condensate. Because of anomaly cancellation requirements, this model contains two color sextet fermions (quixes), which are vector-like with respect to the standard model gauge group. The model also has a large number of pseudo-Nambu-Goldstone bosons, some of which can be light. The top-quark condensate is responsible for breaking the electroweak gauge symmetry and gives the top quark a large mass. We discuss the qualitative features and instructive shortcomings of the model in its present form. We also show that this model can be naturally embedded into an aesthetically pleasing model in which the standard model fermion families appear symmetrically.Comment: 16 pages. v2: TeX formatting fixed, no other change

Evaluation of two lyophilized molecular assays to rapidly detect foot-and-mouth disease virus directly from clinical samples in field settings

Accurate, timely diagnosis is essential for the control, monitoring and eradication of foot‐and‐mouth disease (FMD). Clinical samples from suspect cases are normally tested at reference laboratories. However, transport of samples to these centralized facilities can be a lengthy process that can impose delays on critical decision making. These concerns have motivated work to evaluate simple‐to‐use technologies, including molecular‐based diagnostic platforms, that can be deployed closer to suspect cases of FMD. In this context, FMD virus (FMDV)‐specific reverse transcription loop‐mediated isothermal amplification (RT‐LAMP) and real‐time RT‐PCR (rRT‐PCR) assays, compatible with simple sample preparation methods and in situ visualization, have been developed which share equivalent analytical sensitivity with laboratory‐based rRT‐PCR. However, the lack of robust ‘ready‐to‐use kits’ that utilize stabilized reagents limits the deployment of these tests into field settings. To address this gap, this study describes the performance of lyophilized rRT‐PCR and RT‐LAMP assays to detect FMDV. Both of these assays are compatible with the use of fluorescence to monitor amplification in real‐time, and for the RT‐LAMP assays end point detection could also be achieved using molecular lateral flow devices. Lyophilization of reagents did not adversely affect the performance of the assays. Importantly, when these assays were deployed into challenging laboratory and field settings within East Africa they proved to be reliable in their ability to detect FMDV in a range of clinical samples from acutely infected as well as convalescent cattle. These data support the use of highly sensitive molecular assays into field settings for simple and rapid detection of FMDV

The SLC25 Carrier Family: Important Transport Proteins in Mitochondrial Physiology and Pathology.

Members of the mitochondrial carrier family (SLC25) transport a variety of compounds across the inner membrane of mitochondria. These transport steps provide building blocks for the cell and link the pathways of the mitochondrial matrix and cytosol. An increasing number of diseases and pathologies has been associated with their dysfunction. In this review, the molecular basis of these diseases is explained based on our current understanding of their transport mechanism

Mitochondrial ADP/ATP Carrier in Dodecylphosphocholine Binds Cardiolipins with Non-native Affinity.

Biophysical investigation of membrane proteins generally requires their extraction from native sources using detergents, a step that can lead, possibly irreversibly, to protein denaturation. The propensity of dodecylphosphocholine (DPC), a detergent widely utilized in NMR studies of membrane proteins, to distort their structure has been the subject of much controversy. It has been recently proposed that the binding specificity of the yeast mitochondrial ADP/ATP carrier (yAAC3) toward cardiolipins is preserved in DPC, thereby suggesting that DPC is a suitable environment in which to study membrane proteins. In this communication, we used all-atom molecular dynamics simulations to investigate the specific binding of cardiolipins to yAAC3. Our data demonstrate that the interaction interface observed in a native-like environment differs markedly from that inferred from an NMR investigation in DPC, implying that in this detergent, the protein structure is distorted. We further investigated yAAC3 solubilized in DPC and in the milder dodecylmaltoside with thermal-shift assays. The loss of thermal transition observed in DPC confirms that the protein is no longer properly folded in this environment

Characterization of drug-induced human mitochondrial ADP/ATP carrier inhibition.

An increasing number of commonly prescribed drugs are known to interfere with mitochondrial function, causing cellular toxicity, but the underlying mechanisms are largely unknown. Although often not considered, mitochondrial transport proteins form a significant class of potential mitochondrial off-targets. So far, most drug interactions have been reported for the mitochondrial ADP/ATP carrier (AAC), which exchanges cytosolic ADP for mitochondrial ATP. Here, we show inhibition of cellular respiratory capacity by only a subset of the 18 published AAC inhibitors, which questions whether all compound do indeed inhibit such a central metabolic process. This could be explained by the lack of a simple, direct model system to evaluate and compare drug-induced AAC inhibition. Methods: For its development, we have expressed and purified human AAC1 (hAAC1) and applied two approaches. In the first, thermostability shift assays were carried out to investigate the binding of these compounds to human AAC1. In the second, the effect of these compounds on transport was assessed in proteoliposomes with reconstituted human AAC1, enabling characterization of their inhibition kinetics. Results: Of the proposed inhibitors, chebulinic acid, CD-437 and suramin are the most potent with IC50-values in the low micromolar range, whereas another six are effective at a concentration of 100 μM. Remarkably, half of all previously published AAC inhibitors do not show significant inhibition in our assays, indicating that they are false positives. Finally, we show that inhibitor strength correlates with a negatively charged surface area of the inhibitor, matching the positively charged surface of the substrate binding site. Conclusion: Consequently, we have provided a straightforward model system to investigate AAC inhibition and have gained new insights into the chemical compound features important for inhibition. Better evaluation methods of drug-induced inhibition of mitochondrial transport proteins will contribute to the development of drugs with an enhanced safety profile

Universality of low-energy scattering in (2+1) dimensions

We prove that, in (2+1) dimensions, the S-wave phase shift, $\delta_0(k)$, k being the c.m. momentum, vanishes as either $\delta_0 \to {c\over \ln (k/m)} or \delta_0 \to O(k^2)$ as $k\to 0$. The constant $c$ is universal and $c=\pi/2$. This result is established first in the framework of the Schr\"odinger equation for a large class of potentials, second for a massive field theory from proved analyticity and unitarity, and, finally, we look at perturbation theory in $\phi_3^4$ and study its relation to our non-perturbative result. The remarkable fact here is that in n-th order the perturbative amplitude diverges like $(\ln k)^n$ as $k\to 0$, while the full amplitude vanishes as $(\ln k)^{-1}$. We show how these two facts can be reconciled.Comment: 23 pages, Late