Conformational changes in mitochondrial complex I of the thermophilic eukaryote Chaetomium thermophilum

Mitochondrial complex I is a redox-driven proton pump that generates proton-motive force across the inner mitochondrial membrane, powering oxidative phosphorylation and ATP synthesis in eukaryotes. We report the structure of complex I from the thermophilic fungus Chaetomium thermophilum, determined by cryoEM up to 2.4-Å resolution. We show that the complex undergoes a transition between two conformations, which we refer to as state 1 and state 2. The conformational switch is manifest in a twisting movement of the peripheral arm relative to the membrane arm, but most notably in substantial rearrangements of the Q-binding cavity and the E-channel, resulting in a continuous aqueous passage from the E-channel to subunit ND5 at the far end of the membrane arm. The conformational changes in the complex interior resemble those reported for mammalian complex I, suggesting a highly conserved, universal mechanism of coupling electron transport to proton pumping

Southern hemispheric halon trends and global halon emissions, 1978–2011

The atmospheric records of four halons, H-1211 (CBrClF2), H-1301 (CBrF3), H-2402 (CBrF2CBrF2) and H-1202 (CBr2F2), measured from air collected at Cape Grim, Tasmania, between 1978 and 2011, are reported. Mixing ratios of H-1211, H-2402 and H-1202 began to decline in the early to mid-2000s, but those of H-1301 continue to increase up to mid-2011. These trends are compared to those reported by NOAA (National Oceanic and Atmospheric Administration) and AGAGE (Advanced Global Atmospheric Experiment). The observations suggest that the contribution of the halons to total tropospheric bromine at Cape Grim has begun to decline from a peak in 2008 of about 8.1 ppt. An extrapolation of halon mixing ratios to 2060, based on reported banks and predicted release factors, shows this decline becoming more rapid in the coming decades, with a contribution to total tropospheric bromine of about 3 ppt in 2060. Top-down global annual emissions of the halons were derived using a two-dimensional atmospheric model. The emissions of all four have decreased since peaking in the late 1980s–mid-1990s, but this decline has slowed recently, particularly for H-1301 and H-2402 which have shown no decrease in emissions over the past five years. The UEA (University of East Anglia) top-down model-derived emissions are compared to those reported using a top-down approach by NOAA and AGAGE and the bottom-up estimates of HTOC (Halons Technical Options Committee). The implications of an alternative set of steady-state atmospheric lifetimes are discussed. Using a lifetime of 14 yr or less for H-1211 to calculate top-down emissions estimates would lead to small, or even negative, estimated banks given reported production data. Finally emissions of H-1202, a product of over-bromination during the production process of H-1211, have continued despite reported production of H-1211 ceasing in 2010. This raises questions as to the source of these H-1202 emissions

A new multi-gas constrained model of trace gas non-homogeneous transport in firn: evaluation and behaviour at eleven polar sites

Insoluble trace gases are trapped in polar ice at the firn-ice transition, at approximately 50 to 100 m below the surface, depending primarily on the site temperature and snow accumulation. Models of trace gas transport in polar firn are used to relate firn air and ice core records of trace gases to their atmospheric history. We propose a new model based on the following contributions. First, the firn air transport model is revised in a poromechanics framework with emphasis on the non-homogeneous properties and the treatment of gravitational settling. We then derive a nonlinear least square multi-gas optimisation scheme to calculate the effective firn diffusivity (automatic diffusivity tuning). The improvements gained by the multi-gas approach are investigated (up to ten gases for a single site are included in the optimisation process). We apply the model to four Arctic (Devon Island, NEEM, North GRIP, Summit) and seven Antarctic (DE08, Berkner Island, Siple Dome, Dronning Maud Land, South Pole, Dome C, Vostok) sites and calculate their respective depth-dependent diffusivity profiles. Among these different sites, a relationship is inferred between the snow accumulation rate and an increasing thickness of the lock-in zone defined from the isotopic composition of molecular nitrogen in firn air (denoted d15N). It is associated with a reduced diffusivity value and an increased ratio of advective to diffusive flux in deep firn, which is particularly important at high accumulation rate sites. This has implications for the understanding of d15N of N2 records in ice cores, in relation with past variations of the snow accumulation rate. As the snow accumulation rate is clearly a primary control on the thickness of the lock-in zone, our new approach that allows for the estimation of the lock-in zone width as a function of accumulation may lead to a better constraint on the age difference between the ice and entrapped gases

Agmatine modulates spontaneous activity in neurons of the rat medial habenular complex—a relevant mechanism in the pathophysiology and treatment of depression?

The dorsal diencephalic conduction system connects limbic forebrain structures to monaminergic mesencephalic nuclei via a distinct relay station, the habenular complexes. Both habenular nuclei, the lateral as well as the medial nucleus, are considered to play a prominent role in mental disorders like major depression. Herein, we investigate the effect of the polyamine agmatine on the electrical activity of neurons within the medial habenula in rat. We present evidence that agmatine strongly decreases spontaneous action potential firing of medial habenular neurons by activating I1-type imidazoline receptors. Additionally, we compare the expression patterns of agmatinase, an enzyme capable of inactivating agmatine, in rat and human habenula. In the medial habenula of both species, agmatinase is similarly distributed and observed in neurons and, in particular, in distinct neuropil areas. The putative relevance of these findings in the context of depression is discussed. It is concluded that increased activity of the agmatinergic system in the medial habenula may strengthen midbrain dopaminergic activity. Consequently, the habenular-interpeduncular axis may be dysregulated in patients with major depression

Einfluss der Lebensmittelprozessierung auf die Bioverfügbarkeit von Kupfer: Untersuchungen zur zellulären Kupferaufnahme aus CuSO4 und Melanoidin-Cu-Komplexen

AbstractKupfer gilt als essentielles Spurenelement, da es als struktureller und katalytischer Cofaktor Bestandteil vieler lebenswichtiger Enzyme ist. Andererseits kann jedoch eine exzessive Zufuhr von Kupfer nachfolgend zu irreversiblen Gewebeschäden führen. Um pathophysiologische Erscheinungen zu vermeiden, muss deshalb sowohl die physiologische Kupferhomöostase als auch die Aufnahme von Kupfer aus der Nahrung streng reguliert werden. Obwohl Melanoidine als finale Produkte der thermischen Prozessierung von kohlenhydratreichen Lebensmitteln nachgewiesenermaßen über metallchelatisierende Eigenschaften verfügen, ist ihre Bedeutung für die Resorption von lebensnotwendigen Mineralien und Spurenelementen bisher nur unzureichend geklärt. In der vorliegenden Studie konnte gezeigt werden, dass lebensmittelrelevante Melanoidine über ein revertierbares Kupferbindungsvermögen verfügen. Hierbei konnte ein Zusammenhang zwischen der Menge aus den Maillard-Reaktionsprodukten (MRPs) freisetzbarer Kupferionen und der Hemmung des Cu-sensitiven Enzyms poly (ADP-Ribose) Polymerase 1 nachgewiesen werden. Die Aufnahme der Cu-Ionen aus Melanoidin-Cu Komplexen in humane HCT116-Kolonkarzinomzellen erfolgt im Vergleich zu der anorganischen Verbindung CuSO4 in gleichem Ausmaß, jedoch mit deutlich größerer Geschwindigkeit. Die durchgeführten Genexpressionsanalysen weisen zudem auf Unterschiede in der zellulären Bioverfügbarkeit der aufgenommenen Kupferionen hin. Diese Ergebnisse verdeutlichen, dass Melanoidine als Endprodukte der Maillard-Reaktion regulierend in den Prozess der Kupferaufnahme in intestinalen Zellen eingreifen und thermisch prozessierte Lebensmittel somit als wichtige Modulatoren der Kupferhomöostase angesehen werden müssen

Chlorine isotope composition in chlorofluorocarbons CFC-11, CFC-12 and CFC-113 in firn, stratospheric and tropospheric air

The stratospheric degradation of chlorofluorocarbons (CFCs) releases chlorine, which is a major contributor to the destruction of stratospheric ozone (O3). A recent study reported strong chlorine isotope fractionation during the breakdown of the most abundant CFC (CFC-12, CCl2F2, Laube et al., 2010a), similar to effects seen in nitrous oxide (N2O). Using air archives to obtain a long-term record of chlorine isotope ratios in CFCs could help to identify and quantify their sources and sinks. We analyse the three most abundant CFCs and show that CFC-11 (CCl3F) and CFC-113 (CClF2CCl2F) exhibit significant stratospheric chlorine isotope fractionation, in common with CFC-12. The apparent isotope fractionation (εapp) for mid- and high-latitude stratospheric samples are (-2.4±0.5) ‰ and (-2.3±0.4) ‰ for CFC-11, (-12.2±1.6) ‰ and (-6.8±0.8) ‰ for CFC-12 and (-3.5±1.5) ‰ and (-3.3±1.2) ‰ for CFC-113, respectively. Assuming a constant isotope composition of emissions, we calculate the expected trends in the tropospheric isotope signature of these gases based on their stratospheric 37Cl enrichment and stratosphere-troposphere exchange. We compare these projections to the long-term δ(37Cl) trends of all three CFCs, measured on background tropospheric samples from the Cape Grim air archive (Tasmania, 1978 – 2010) and tropospheric firn air samples from Greenland (NEEM site) and Antarctica (Fletcher Promontory site). From 1970 to the present-day, projected trends agree with tropospheric measurements, suggesting that within analytical uncertainties a constant average emission isotope delta is a compatible scenario. The measurement uncertainty is too high to determine whether the average emission isotope delta has been affected by changes in CFC manufacturing processes, or not. Our study increases the suite of trace gases amenable to direct isotope ratio measurements in small air volumes (approximately 200 ml), using a single-detector gas chromatography-mass spectrometry system

Adhesion mechanisms of the contact interface of TiO2 nanoparticles in films and aggregates

Fundamental knowledge about the mechanisms of adhesion between oxide particles with diameters of few nanometers is impeded by the difficulties associated with direct measurements of contact forces at such a small size scale. Here we develop a strategy based on AFM force spectroscopy combined with all-atom molecular dynamics simulations to quantify and explain the nature of the contact forces between 10 nm small TiO2 nanoparticles. The method is based on the statistical analysis of the force peaks measured in repeated approaching/retracting loops of an AFM cantilever into a film of nanoparticle agglomerates and relies on the in-situ imaging of the film stretching behavior in an AFM/TEM setup. Sliding and rolling events first lead to local rearrangements in the film structure when subjected to tensile load, prior to its final rupture caused by the reversible detaching of individual nanoparticles. The associated contact force of about 2.5 nN is in quantitative agreement with the results of molecular dynamics simulations of the particle–particle detachment. We reveal that the contact forces are dominated by the structure of water layers adsorbed on the particles’ surfaces at ambient conditions. This leads to nonmonotonous force–displacement curves that can be explained only in part by classical capillary effects and highlights the importance of considering explicitly the molecular nature of the adsorbates

Hyperekplexia Phenotype of Glycine Receptor α1 Subunit Mutant Mice Identifies Zn2+ as an Essential Endogenous Modulator of Glycinergic Neurotransmission

SummaryZn2+ is thought to modulate neurotransmission by affecting currents mediated by ligand-gated ion channels and transmitter reuptake by Na+-dependent transporter systems. Here, we examined the in vivo relevance of Zn2+ neuromodulation by producing knockin mice carrying the mutation D80A in the glycine receptor (GlyR) α1 subunit gene (Glra1). This substitution selectively eliminates the potentiating effect of Zn2+ on GlyR currents. Mice homozygous for Glra1(D80A) develop a severe neuromotor phenotype postnatally that resembles forms of human hyperekplexia (startle disease) caused by mutations in GlyR genes. In spinal neurons and brainstem slices from Glra1(D80A) mice, GlyR expression, synaptic localization, and basal glycinergic transmission were normal; however, potentiation of spontaneous glycinergic currents by Zn2+ was significantly impaired. Thus, the hyperekplexia phenotype of Glra1(D80A) mice is due to the loss of Zn2+ potentiation of α1 subunit containing GlyRs, indicating that synaptic Zn2+ is essential for proper in vivo functioning of glycinergic neurotransmission