G-quadruplex DNA motifs in the malaria parasite Plasmodium falciparum and their potential as novel antimalarial drug targets

G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occur in vivo in the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or, in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasite Plasmodium falciparum, which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences, P. falciparum parasites are sensitive to several G-quadruplex-stabilizing drugs, including quarfloxin, which previously reached phase 2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilizing drugs, including quarfloxin, can suppress the transcription of a G-quadruplex-containing reporter gene in P. falciparum but that quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology in P. falciparum may present a target for development of other new antimalarial drugs

Mackintosh lecture: Association and cognition: two processes, one system

This is the author accepted manuscript. The final version is available from SAGE Publications via the DOI in this record.There is another ORE record for this item: http://hdl.handle.net/10871/33264This paper argues that the dual-process position can be a useful first approximation when studying human mental life, but it cannot be the whole truth. Instead, we argue that cognition is built on association, in that associative processes provide the fundamental building blocks that enable propositional thought. One consequence of this position is to suggest that humans are able to learn associatively in a similar fashion to a rat or a pigeon, but another is that we must typically suppress the expression of basic associative learning in favour of rule-based computation. This stance conceptualizes us as capable of symbolic computation, but acknowledges that, given certain circumstances, we will learn associatively and, more importantly, be seen to do so. We present three types of evidence that support this position: The first is data on human Pavlovian conditioning that directly supports this view. The second is data taken from task switching experiments that provides convergent evidence for at least two modes of processing, one of which is automatic and carried out “in the background”. And the last suggests that when the output of propositional processes is uncertain, then the influence of associative processes on behaviour can manifest

Overview of the contemporary management of supracondylar humeral fractures in children.

PURPOSE: Supracondylar fractures are common injuries accounting for approximately 15% of all fractures in children with a large body of literature on this subject. METHODS:  This article critically appraises the available evidence to provide an overview of the treatment options including the role and timing of surgery, the geometry of wire fixation and the management of nerve and arterial injury. CONCLUSION:  Management decisions are based on a number of considerations particularly fracture stability. Closed reduction and percutaneous K-wire stabilisation are commonly recommended for an unstable displaced fracture. These techniques are however associated with the potential for iatrogenic neurological injury. Vascular injury is also rare but must be recognised and treated promptly to avoid significant permanent morbidity

The clinical features, management options and complications of paediatric femoral fractures.

This article discusses the incidence, applied anatomy and classification of paediatric femoral fractures based on critical appraisal of the available evidence. The aim is to identify techniques that are relevant to contemporary practice whilst excluding the technical details of individual procedures that are beyond the scope of this review. Injuries of the proximal, diaphyseal and distal segments are considered individually as there are considerations that are specific to each anatomical site. Femoral neck fractures are rare injuries and require prompt anatomical reduction and stable fixation to minimise the potentially devastating consequences of avascular necrosis. Diaphyseal fractures are relatively common, and there is a spectrum of management options that depend on patient age and size. Distal femoral fractures often involve the physis, which contributes up to 70% of femoral length. Growth arrest is common consequence of fractures in this region, resulting in angular and length-related deformity. Long-term surveillance is recommended to identify deformity in evolution and provide an opportunity for early intervention. Deliberate injury should be considered in all fractures, particularly distal femoral physeal injuries and fractures in the non-walking child

How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?

BACKGROUND: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. METHODS: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. RESULTS: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. CONCLUSION: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. IMPACT: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes

Improving patient outcomes in fibrous dysplasia/McCune-Albright syndrome: an international multidisciplinary workshop to inform an international partnership.

Bone and mineral researc

No-go trials can modulate switch cost by interfering with effects of task preparation

It has recently been shown that the cost associated with switching tasks is eliminated following ‘no-go’ trials, in which response selection is not completed, suggesting that the switch cost depends on response selection. However, no-go trials may also affect switch costs by interfering with the effects of task preparation that precede response selection. To test this hypothesis we evaluated switch costs following standard go trials with those following two types of non-response trials: no-go trials, for which a stimulus is presented that indicates no response should be made (Experiment 1); and cue-only trials in which no stimulus is presented following the task cue (Experiment 2). We hypothesized that eliminating no-go stimuli would reveal effects of task preparation on the switch cost in cue-only trials. We found no switch cost following no-go trials (Experiment 1), but a reliable switch cost in cue-only trials (i.e., when no-go stimuli were removed; Experiment 2). We conclude that no-go trials can modulate the switch cost, independent of their effect on response selection, by interfering with task preparation, and that the effects of task preparation on switch cost are more directly assessed by cue-only trials