Cell entry by enveloped viruses: redox considerations for HIV and SARS-coronavirus

For enveloped viruses, genome entry into the target cell involves two major steps: virion binding to the cell-surface receptor and fusion of the virion and cell membranes. Virus-cell membrane fusion is mediated by the virus envelope complex, and its fusogenicity is the result of an active virus-cell interaction process that induces conformation changes within the envelope. For some viruses, such as influenza, exposure to an acidic milieu within the cell during the early steps of infection triggers the necessary structural changes. However, for other pathogens which are not exposed to such environmental stress, activation of fusogenicity can result from precise thiol/disulfide rearrangements mediated by either an endogenous redox autocatalytic isomerase or a cell-associated oxidoreductase. Study of the activation of HIV envelope fusogenicity has revealed new knowledge about how redox changes within a viral envelope trigger fusion. We discuss these findings and their implication for anti-HIV therapy. In addition, to compare and contrast the situation outlined for HIV with an enveloped virus that can fuse with the cell plasma membrane independent of the redox status of its envelope protein, we review parallel data obtained on SARS coronavirus entry.

Do mitochondriotropic antioxidants prevent chlorinative stress-induced mitochondrial and cellular injury?

Reactive chlorine species such as hypochlorous acid ( HOCl) are cytotoxic oxidants generated by activated neutrophils at the sites of chronic inflammation. Since mitochondria are key mediators of apoptosis and necrosis, we hypothesized that mitochondriotropic antioxidants could limit HOCl-mediated intracellular oxidative injury to human fetal liver cells, preserve mitochondrial function, and prevent cell death. In this current study, we show that recently developed mitochondria-targeted antioxidants ( MitoQ and SS31) significantly protected against HOCl-induced mitochondrial damage and cell death at concentrations >= 25 nM. Our study highlights the potential application of mitochondria-specific targeted antioxidants for the prevention of cellular dysfunction and cell death under conditions of chlorinative stress, as occurs during chronic inflammation.

Winter floods in Britain are connected to atmospheric rivers

Damage from flooding in the winter and fall seasons has been widespread in the United Kingdom (UK) and Western Europe over recent decades. Here we show that winter flood events in the UK are connected to Atmospheric Rivers (ARs), narrow ribbons along which a large flux of moisture is transported from the subtropics to the mid-latitudes. Combining river flow records with rainfall measurements, satellite data and model simulations, we demonstrate that ARs occur simultaneously with the 10 largest winter flood events since 1970 in a range of British river basins, suggesting that ARs are persistently critical in explaining extreme winter flooding in the UK. Understanding the physical processes that determine the persistence of AR events will be of importance in assessing the risk of future flooding over north-western Europe and other mid-latitude regions.

Two-photon excitation with pico-second fluorescence lifetime imaging to detect nuclear association of flavanols

Two-photon excitation enabled for the first time the observation and measurement of excited state fluorescence lifetimes from three flavanols in solution, which were ∼1.0 ns for catechin and epicatechin, but <45 ps for epigallocatechin gallate (EGCG). The shorter lifetime for EGCG is in line with a lower fluorescence quantum yield of 0.003 compared to catechin (0.015) and epicatechin (0.018). In vivo experiments with onion cells demonstrated that tryptophan and quercetin, which tend to be major contributors of background fluorescence in plant cells, have sufficiently low cross sections for two-photon excitation at 630 nm and therefore do not interfere with detection of externally added or endogenous flavanols in Allium cepa or Taxus baccata cells. Applying two-photon excitation to flavanols enabled 3-D fluorescence lifetime imaging microscopy and showed that added EGCG penetrated the whole nucleus of onion cells. Interestingly, EGCG and catechin showed different lifetime behaviour when bound to the nucleus: EGCG lifetime increased from <45 to 200 ps, whilst catechin lifetime decreased from 1.0 ns to 500 ps. Semi-quantitative measurements revealed that the relative ratios of EGCG concentrations in nucleoli associated vesicles: nucleus: cytoplasm were ca. 100:10:1. Solution experiments with catechin, epicatechin and histone proteins provided preliminary evidence, via the appearance of a second lifetime (τ2 = 1.9–3.1 ns), that both flavanols may be interacting with histone proteins. We conclude that there is significant nuclear absorption of flavanols. This advanced imaging using two-photon excitation and biophysical techniques described here will prove valuable for probing the intracellular trafficking and functions of flavanols, such as EGCG, which is the major flavanol of green tea.

Peroxynitrite mediates disruption of Ca2+ homeostasis by carbon monoxide via Ca2+ ATPase degradation

CO stimulates formation of NO and reactive oxygen species which, via peroxynitrite formation, inhibit Ca(2+) extrusion via PMCA, leading to disruption of Ca(2+) signaling. We propose this contributes to the neurological damage associated with CO toxicity.

Modulation of ion channels by hydrogen sulfide

Increasing current awareness and understanding of the roles and mechanisms of action of ion channel regulation by H(2)S will open opportunities for therapeutic intervention with clear clinical benefits, and inform future therapies. In addition, more sensitive methods for detecting relevant physiological concentrations of H(2)S will allow for clarification of specific ion channel regulation with reference to physiological or pathophysiological settings.

The detection of atmospheric rivers in atmospheric reanalyses and their links to British winter floods and the large-scale climatic circulation

Atmospheric Rivers (ARs), narrow plumes of enhanced moisture transport in the lower troposphere, are a key synoptic feature behind winter flooding in midlatitude regions. This article develops an algorithm which uses the spatial and temporal extent of the vertically integrated horizontal water vapor transport for the detection of persistent ARs (lasting 18 h or longer) in five atmospheric reanalysis products. Applying the algorithm to the different reanalyses in the vicinity of Great Britain during the winter half-years of 1980–2010 (31 years) demonstrates generally good agreement of AR occurrence between the products. The relationship between persistent AR occurrences and winter floods is demonstrated using winter peaks-over-threshold (POT) floods (with on average one flood peak per winter). In the nine study basins, the number of winter POT-1 floods associated with persistent ARs ranged from approximately 40 to 80%. A Poisson regression model was used to describe the relationship between the number of ARs in the winter half-years and the large-scale climate variability. A significant negative dependence was found between AR totals and the Scandinavian Pattern (SCP), with a greater frequency of ARs associated with lower SCP values.

Future changes in atmospheric rivers and their implications for winter flooding in Britain

Within the warm conveyor belt of extra-tropical cyclones, atmospheric rivers (ARs) are the key synoptic features which deliver the majority of poleward water vapour transport, and are associated with episodes of heavy and prolonged rainfall. ARs are responsible for many of the largest winter floods in the mid-latitudes resulting in major socioeconomic losses; for example, the loss from United Kingdom (UK) flooding in summer/winter 2012 is estimated to be about $1.6 billion in damages. Given the well-established link between ARs and peak river flows for the present day, assessing how ARs could respond under future climate projections is of importance in gauging future impacts from flooding. We show that North Atlantic ARs are projected to become stronger and more numerous in the future scenarios of multiple simulations from five state-of-the-art global climate models (GCMs) in the fifth Climate Model Intercomparison Project (CMIP5). The increased water vapour transport in projected ARs implies a greater risk of higher rainfall totals and therefore larger winter floods in Britain, with increased AR frequency leading to more flood episodes. In the high emissions scenario (RCP8.5) for 2074–2099 there is an approximate doubling of AR frequency in the five GCMs. Our results suggest that the projected change in ARs is predominantly a thermodynamic response to warming resulting from anthropogenic radiative forcing.