Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations

Damaging democracy? Security provision and turnout in Afghan elections†

In emerging democracies, elections are encouraged as a route to democratization. However, not only does violence often threaten these elections, but citizens often view as corrupt the security forces deployed to combat violence. We examine the effects of such security provision. In Afghanistan's 2010 parliamentary election, polling centers with similar histories of pre-election violence unintentionally received different deployments of the Afghan National Police, enabling identification of police's effects on turnout. Using data from the universe of polling sites and various household surveys, data usually unavailable in conflict settings, we estimate increases in police presence decreased voter turnout by an average of 30%. Our results adjudicate between competing theoretical mechanisms through which security forces could affect turnout, and show behavior is not driven by voter anticipation of election-day violence. This highlights a pitfall for building government legitimacy via elections in weakly institutionalized and conflict-affected states

Biological activity and LC-MS/MS profiling of extracts from the Australian medicinal plant <i>Acacia ligulata</i> (Fabaceae)

<p><i>Acacia ligulata</i> A.Cunn. ex Benth. (Fabaceae: Mimosoideae) is a native Australian plant used traditionally by Australian Aboriginal groups. This study was undertaken to investigate the bioactivity of <i>A. ligulata</i> extracts and to evaluate their chemical composition. Potential antibacterial, cytotoxic and enzyme inhibitory effects relevant to traditional medicinal and food uses of the species were examined and LC-MS/MS was performed to investigate the chemical composition. Antibacterial activity was observed for bark and leaf extracts with an MIC for the bark extract of 62.5 μg/mL against <i>Streptococcus pyogenes.</i> Pod extracts showed cytotoxic effects against cancer cells, with the highest activity against melanoma SK-MEL28 cells with IC₅₀ values between 40.8 and 80.6 μg/mL. Further, the leaf and pod extracts also inhibited α-amylase EC-3.2.1.1 and α-glucosidase EC-3.2.1.20 with IC₅₀ values between 9.7–34.8 and 12.6–64.3 μg/mL, respectively. The LC-MS/MS profiling indicated that several different saponins were present in the active extracts.</p

Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells

Mitochondrial DNA (mtDNA) replication stalling is considered an initial step in the formation of mtDNA deletions that associate with genetic inherited disorders and aging. However, the molecular details of how stalled replication forks lead to mtDNA deletions accumulation are still unclear. Mitochondrial DNA deletion breakpoints preferentially occur at sequence motifs predicted to form G-quadruplexes (G4s), four-stranded nucleic acid structures that can fold in guanine-rich regions. Whether mtDNA G4s form in vivo and their potential implication for mtDNA instability is still under debate. In here, we developed new tools to map G4s in the mtDNA of living cells. We engineered a G4-binding protein targeted to the mitochondrial matrix of a human cell line and established the mtG4-ChIP method, enabling the determination of mtDNA G4s under different cellular conditions. Our results are indicative of transient mtDNA G4 formation in human cells. We demonstrate that mtDNA-specific replication stalling increases formation of G4s, particularly in the major arc. Moreover, elevated levels of G4 block the progression of the mtDNA replication fork and cause mtDNA loss. We conclude that stalling of the mtDNA replisome enhances mtDNA G4 occurrence, and that G4s not resolved in a timely manner can have a negative impact on mtDNA integrity