Essential role of Isd11 in mitochondrial iron-sulfur cluster synthesis on Isu scaffold proteins

Mitochondria are indispensable for cell viability; however, major mitochondrial functions including citric acid cycle and oxidative phosphorylation are dispensable. Most known essential mitochondrial proteins are involved in preprotein import and assembly, while the only known essential biosynthetic process performed by mitochondria is the biogenesis of iron-sulfur clusters (ISC). The components of the mitochondrial ISC-assembly machinery are derived from the prokaryotic ISC-assembly machinery. We have identified an essential mitochondrial matrix protein, Isd11 (YER048w-a), that is found in eukaryotes only. Isd11 is required for biogenesis of cellular Fe/S proteins and thus is a novel subunit of the mitochondrial ISC-assembly machinery. It forms a complex with the cysteine desulfurase Nfs1 and is required for formation of an Fe/S cluster on the Isu scaffold proteins. We conclude that Isd11 is an indispensable eukaryotic component of the mitochondrial machinery for biogenesis of Fe/S proteins.     

Structure of a flavonoid glucosyltransferase reveals the basis for plant natural product modification

Glycosylation is a key mechanism for orchestrating the bioactivity, metabolism and location of small molecules in living cells. In plants, a large multigene family of glycosyltransferases is involved in these processes, conjugating hormones, secondary metabolites, biotic and abiotic environmental toxins, to impact directly on cellular homeostasis. The red grape enzyme UDP-glucose:flavonoid 3-O-glycosyltransferase (VvGT1) is responsible for the formation of anthocyanins, the health-promoting compounds which, in planta, function as colourants determining flower and fruit colour and are precursors for the formation of pigmented polymers in red wine. We show that VvGT1 is active, in vitro, on a range of flavonoids. VvGT1 is somewhat promiscuous with respect to donor sugar specificity as dissected through full kinetics on a panel of nine sugar donors. The three-dimensional structure of VvGT1 has also been determined, both in its 'Michaelis' complex with a UDP-glucose-derived donor and the acceptor kaempferol and in complex with UDP and quercetin. These structures, in tandem with kinetic dissection of activity, provide the foundation for understanding the mechanism of these enzymes in small molecule homeostasis.     

Ascorbate removes key precursors to oxidative damage by cell-free haemoglobin in vitro and in vivo

Haemoglobin initiates free radical chemistry. In particular, the interactions of peroxides with the ferric (met) species of haemoglobin generate two strong oxidants: ferryl iron and a protein-bound free radical. We have studied the endogenous defences to this reactive chemistry in a rabbit model following 20% exchange transfusion with cell-free haemoglobin stabilized in tetrameric form [via cross-linking with bis-(3,5-dibromosalicyl)fumarate]. The transfusate contained 95% oxyhaemoglobin, 5% methaemoglobin and 25 microM free iron. EPR spectroscopy revealed that the free iron in the transfusate was rendered redox inactive by rapid binding to transferrin. Methaemoglobin was reduced to oxyhaemoglobin by a slower process (t(1/2) = 1 h). No globin-bound free radicals were detected in the plasma. These redox defences could be fully attributed to a novel multifunctional role of plasma ascorbate in removing key precursors of oxidative damage. Ascorbate is able to effectively reduce plasma methaemoglobin, ferryl haemoglobin and globin radicals. The ascorbyl free radicals formed are efficiently re-reduced by the erythrocyte membrane-bound reductase (which itself uses intra-erythrocyte ascorbate as an electron donor). As well as relating to the toxicity of haemoglobin-based oxygen carriers, these findings have implications for situations where haem proteins exist outside the protective cell environment, e.g. haemolytic anaemias, subarachnoid haemorrhage, rhabdomyolysis.     

A shared Y-chromosomal heritage between Muslims and Hindus in India

Arab forces conquered the Indus Delta region in 711 AD and, although a Muslim state was established there, their influence was barely felt in the rest of South Asia at that time. By the end of the tenth century, Central Asian Muslims moved into India from the northwest and expanded throughout the subcontinent. Muslim communities are now the largest minority religion in India, comprising more than 138 million people in a predominantly Hindu population of over one billion. It is unclear whether the Muslim expansion in India was a purely cultural phenomenon or had a genetic impact on the local population. To address this question from a male perspective, we typed eight microsatellite loci and 16 binary markers from the Y chromosome in 246 Muslims from Andhra Pradesh, and compared them to published data on 4,204 males from East Asia, Central Asia, other parts of India, Sri Lanka, Pakistan, Iran, the Middle East, Turkey, Egypt and Morocco. We find that the Muslim populations in general are genetically closer to their non-Muslim geographical neighbors than to other Muslims in India, and that there is a highly significant correlation between genetics and geography (but not religion). Our findings indicate that, despite the documented practice of marriage between Muslim men and Hindu women, Islamization in India did not involve large-scale replacement of Hindu Y chromosomes. The Muslim expansion in India was predominantly a cultural change and was not accompanied by significant gene flow, as seen in other places, such as China and Central Asia.Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.Ramana Gutala and Denise R. Carvalho-Silva contributed equally to the article.     

Nitroreductase-based therapy of prostate cancer, enhanced by raising expression of heat shock protein 70, acts through increased anti-tumour immunity

Gene-directed enzyme-prodrug therapy (GDEPT) using nitroreductase (NTR), with efficient adenoviral delivery, and CB1954 (CB), is an effective means of directly killing tumours. However, an immune-mediated bystander effect remains an important product of GDEPT since it is often critical to the elimination of untransduced tumour cells both locally and at distal metastatic sites through generation of tumour-specific immunity without the need for tumour antigen identification or the generation of a personalised vaccine. The mode of induced tumour cell death is thought to contribute to the immunisation process, together with the induction and release of stress proteins. Here, RM-9 murine prostate tumour cells were efficiently killed by adenovirally delivered NTR/CB treatment both in vitro and in vivo, and bystander effects were observed. Cells appeared to die by pathways that suggest necrosis more than that of classical apoptosis. NTR/CB-induced expression of a range of stress proteins was determined by proteomic analysis, revealing chiefly heat shock protein (HSP)25 and HSP70 upregulation, whilst immune responses in vivo were weak. In an attempt to enhance the anti-tumour effect, an adenoviral vector was constructed that co-expressed NTR and HSP70, the latter being a known immune stimulator and chaperone of antigen. This combination elicited significantly enhanced protection over NTR alone for both the treated tumour and a subsequent re-challenge. Protection was CD4⁺ and CD8⁺ T cell-dependent and was associated with tumour-specific CTL, IFNγ and IL-5 responses. The use of such a cytotoxic and immunomodulatory gene combination in cancer therapy warrants further pursuit.     

Dancing between the devil and deep blue sea: the stabilizing effect of enemy-free and victimless sinks

Theoretical and empirical studies have shown that enemy–victim interactions in spatially homogenous environments can exhibit diverging oscillations which result in the extinction of one or both species. For enemy–victim models with overlapping generations, we investigate the dynamical implications of spatial heterogeneity created by enemy-free sinks or victimless sinks. An enemy-free sink is a behavioral, physiological or ecological state that reduces or eliminates the victim's vulnerability to the enemy but cannot sustain the victim population. For victims that move in an ideal-free manner, we prove that the inclusion of an enemy-free sink shifts the population dynamics from diverging oscillations to stable oscillations. During these stable oscillations, the victim disperses in an oscillatory manner between the enemy-free sink and the enemy-occupied patch. Enemy-free sinks with lower mortality rates exhibit oscillations with smaller amplitudes and longer periods. A victimless sink, on the other hand, is a behavioral, physiological or ecological state in which the enemy has limited (or no) access to its victims. For enemies that move in an ideal-free manner, we prove that victimless sinks also stabilize diverging oscillations. Simulations suggest that suboptimal behavior due to information gathering or learning limitations amplify oscillations for systems with enemy-free sinks and dampen oscillations for systems with victimless sinks. These results illustrate that the coupling of a sink created by unstable enemy–victim interactions and a sink created by unsuitable environmental conditions can result in population persistence at the landscape level.     

Recent changes in body weight and wing length among some British passerine birds

We tested the prediction that global warming has caused recent decreases in body weight (Bergmann's rule) and increases in wing length (Allen's rule) in 14 species of passerine birds at two localities in England: Wicken Fen (1968–2003) and Treswell Wood (1973–2003).
Predicted long-term linear decreases in residual body weight occurred in four species: dunnocks (Wicken Fen), and great tits, blue tits and bullfinches (Treswell Wood). Non-linear decreases also occurred in reed warblers and blackcaps at Wicken Fen, which also had a surprising linear increase in residual body weight in blackbirds.
Residual wing lengths increased linearly, as predicted, in six of seven species at Wicken Fen. Whereas there were non-linear long-term increases in wrens, dunnocks and blackbirds in Treswell Wood. Unexpected linear decreases also occurred in residual wing lengths in willow warblers (Wicken Fen), and blue tits, great tits and chaffinches (Treswell Wood).
The most parsimonious explanation for such long-term changes in body weight is global warming, as predicted by Bergmann's rule. Greater site and species-specific effects on wing length (e.g. non-linear changes plus shorter wings in the woodland habitat) suggest a less straightforward conclusion concerning Allen's rule, probably because wing length involved variation in both bone and feather growth.
Changes in residual body weights and wing lengths often differed between species and were sometimes non-linear, perhaps reflecting short-term modifications in selection pressures. Human-induced influences are discussed, such as avian predator population densities and land-use change. Short-term variation in temperature had little effect, but rainfall did explain the unusual increase in blackbird body weight, possibly as a result of improving food (earthworm) availability.     

Evidence for Megalake Chad, north-central Africa, during the late Quaternary from satellite data

The existence of a very large Lake Chad during the late Quaternary, Megalake Chad, has long been questioned. A Megalake Chad would present strong evidence for climatic fluctuations of great magnitude during the Holocene in tropical Africa. In this paper we used satellite data from Landsat and Modis sensors to collect and analyse new information on landforms in a 2 000 000 km² region of the Lake Chad Basin. We detected 2300 km of remains marking the ancient shoreline of Megalake Chad. The satellite data also indicated many Saharan rivers and relict deltas leading to the long paleoshoreline. Large dunefield flattenings were observed and interpreted as the result of wave-cut erosion by the paleolake. Similarities were noticed between the landforms observed along the paleoshoreline of Megalake Chad and that of the former Aral Sea. This finding has significant consequences for reconstructing paleohydrology and paleoenvironments through the Lake Chad basin, and continental climate change.     

Can occupancy patterns be used to predict distributions in widely separated geographic regions?

Occupancy models, that describe the presence and absence patterns of a species in a given area, are increasingly being used to predict the occurrence of the species in unsurveyed sites, as an aid to conservation planning. In this paper, we consider whether conclusions about local distributions derived from one landscape can be extrapolated to others. We found that habitat patchiness influenced the distribution and abundance of the host-specific moth Wheeleria spilodactylus in a similar way in two landscapes widely separated geographically. In both geographic regions, the spatial location (positive effect of connectivity), and quantity of resource (positive effect of host plant density) increased the likelihood that the moth would be present, consistent with the expectations of metapopulation dynamics. Though some biological attributes of the species appeared to be slightly different, including population density and the timing of the life cycle (phenology), occupancy patterns in one landscape accurately predict occupancy in the other landscape. Our results suggest that it maybe possible to make predictions from one landscape to another, even when the landscapes are widely separated.