Estimating the Burden of Malaria: The Need for Improved Surveillance

Ivo Mueller, Laurence Slutsker, and Marcel Tanner highlight the importance of using complementary methods to estimate the burden of malaria and call for a renewed focus on efficient malaria surveillance

Measuring luteinising hormone pulsatility with a robotic aptamer-enabled electrochemical reader

Normal reproductive functioning is critically dependent on pulsatile secretion of luteinising hormone (LH). Assessment of LH pulsatility is important for the clinical diagnosis of reproductive disorders, but current methods are hampered by frequent blood sampling coupled to expensive serial immunochemical analysis. Here, we report the development and application of a Robotic APTamer-enabled Electrochemical Reader (RAPTER) electrochemical analysis system to determine LH pulsatility. Through selective evolution of ligands by exponential enrichment (SELEX), we identify DNA aptamers that bind specifically to LH and not to related hormones. The aptamers are integrated into electrochemical aptamer-based (E-AB) sensors on a robotic platform. E-AB enables rapid, sensitive and repeatable determination of LH concentration profiles. Bayesian Spectrum Analysis is applied to determine LH pulsatility in three distinct patient cohorts. This technology has the potential to transform the clinical care of patients with reproductive disorders and could be developed to allow real-time in vivo hormone monitoring

A high-resolution geospatial surveillance-response system for malaria elimination in Solomon Islands and Vanuatu

BACKGROUND A high-resolution surveillance-response system has been developed within a geographic information system (GIS) to support malaria elimination in the Pacific. This paper examines the application of a GIS-based spatial decision support system (SDSS) to automatically locate and map the distribution of confirmed malaria cases, rapidly classify active transmission foci, and guide targeted responses in elimination zones. METHODS Customized SDSS-based surveillance-response systems were developed in the three elimination provinces of Isabel and Temotu, Solomon Islands and Tafea, Vanuatu. Confirmed malaria cases were reported to provincial malaria offices upon diagnosis and updated into the respective SDSS as part of routine operations throughout 2011. Cases were automatically mapped by household within the SDSS using existing geographical reconnaissance (GR) data. GIS queries were integrated into the SDSS-framework to automatically classify and map transmission foci based on the spatiotemporal distribution of cases, highlight current areas of interest (AOI) regions to conduct foci-specific targeted response, and extract supporting household and population data. GIS simulations were run to detect AOIs triggered throughout 2011 in each elimination province and conduct a sensitivity analysis to calculate the proportion of positive cases, households and population highlighted in AOI regions of a varying geographic radius. RESULTS A total of 183 confirmed cases were reported and mapped using the SDSS throughout 2011 and used to describe transmission within a target population of 90,354. Automatic AOI regions were also generated within each provincial SDSS identifying geographic areas to conduct response. 82.5% of confirmed cases were automatically geo-referenced and mapped at the household level, with 100% of remaining cases geo-referenced at a village level. Data from the AOI analysis indicated different stages of progress in each province, highlighting operational implications with regards to strategies for implementing surveillance-response in consideration of the spatiotemporal nature of cases as well as logistical and financial constraints of the respective programmes. CONCLUSIONS Geospatial systems developed to guide Pacific Island malaria elimination demonstrate the application of a high resolution SDSS-based approach to support key elements of surveillance-response including understanding epidemiological variation within target areas, implementing appropriate foci-specific targeted response, and consideration of logistical constraints and costs.A.C.A.C. is supported by a Career Development Award from the Australian National Health and Medical Research Council (#631619)

Dynamics of DNA replication loops reveal temporal control of lagging-strand synthesis

In all organisms, the protein machinery responsible for the replication of DNA, the replisome, is faced with a directionality problem. The antiparallel nature of duplex DNA permits the leading-strand polymerase to advance in a continuous fashion, but forces the lagging-strand polymerase to synthesize in the opposite direction. By extending RNA primers, the lagging-strand polymerase restarts at short intervals and produces Okazaki fragments. At least in prokaryotic systems, this directionality problem is solved by the formation of a loop in the lagging strand of the replication fork to reorient the lagging-strand DNA polymerase so that it advances in parallel with the leading-strand polymerase. The replication loop grows and shrinks during each cycle of Okazaki fragment synthesis. Here we use single-molecule techniques to visualize, in real time, the formation and release of replication loops by individual replisomes of bacteriophage T7 supporting coordinated DNA replication. Analysis of the distributions of loop sizes and lag times between loops reveals that initiation of primer synthesis and the completion of an Okazaki fragment each serve as a trigger for loop release. The presence of two triggers may represent a fail-safe mechanism ensuring the timely reset of the replisome after the synthesis of every Okazaki fragment.

A critical experimental study of the classical tactile threshold theory

<p>Abstract</p> <p>Background</p> <p>The tactile sense is being used in a variety of applications involving tactile human-machine interfaces. In a significant number of publications the classical threshold concept plays a central role in modelling and explaining psychophysical experimental results such as in stochastic resonance (SR) phenomena. In SR, noise enhances detection of sub-threshold stimuli and the phenomenon is explained stating that the required amplitude to exceed the sensory threshold barrier can be reached by adding noise to a sub-threshold stimulus. We designed an experiment to test the validity of the classical vibrotactile threshold. Using a second choice experiment, we show that individuals can order sensorial events below the level known as the classical threshold. If the observer's sensorial system is not activated by stimuli below the threshold, then a second choice could not be above the chance level. Nevertheless, our experimental results are above that chance level contradicting the definition of the classical tactile threshold.</p> <p>Results</p> <p>We performed a three alternative forced choice detection experiment on 6 subjects asking them first and second choices. In each trial, only one of the intervals contained a stimulus and the others contained only noise. According to the classical threshold assumptions, a correct second choice response corresponds to a guess attempt with a statistical frequency of 50%. Results show an average of 67.35% (STD = 1.41%) for the second choice response that is not explained by the classical threshold definition. Additionally, for low stimulus amplitudes, second choice correct detection is above chance level for any detectability level.</p> <p>Conclusions</p> <p>Using a second choice experiment, we show that individuals can order sensorial events below the level known as a classical threshold. If the observer's sensorial system is not activated by stimuli below the threshold, then a second choice could not be above the chance level. Nevertheless, our experimental results are above that chance level. Therefore, if detection exists below the classical threshold level, then the model to explain the SR phenomenon or any other tactile perception phenomena based on the psychophysical classical threshold is not valid. We conclude that a more suitable model of the tactile sensory system is needed.</p

Investigating the association between obesity and asthma in 6- to 8-year-old Saudi children:a matched case-control study

Background: Previous studies have demonstrated an association between obesity and asthma, but there remains considerable uncertainty about whether this reflects an underlying causal relationship. Aims: To investigate the association between obesity and asthma in pre-pubertal children and to investigate the roles of airway obstruction and atopy as possible causal mechanisms. Methods: We conducted an age- and sex-matched case–control study of 1,264 6- to 8-year-old schoolchildren with and without asthma recruited from 37 randomly selected schools in Madinah, Saudi Arabia. The body mass index (BMI), waist circumference and skin fold thickness of the 632 children with asthma were compared with those of the 632 control children without asthma. Associations between obesity and asthma, adjusted for other potential risk factors, were assessed separately in boys and girls using conditional logistic regression analysis. The possible mediating roles of atopy and airway obstruction were studied by investigating the impact of incorporating data on sensitisation to common aeroallergens and measurements of lung function. Results: BMI was associated with asthma in boys (odds ratio (OR)=1.14, 95% confidence interval (CI), 1.08–1.20; adjusted OR=1.11, 95% CI, 1.03–1.19) and girls (OR=1.37, 95% CI, 1.26–1.50; adjusted OR=1.38, 95% CI, 1.23–1.56). Adjusting for forced expiratory volume in 1 s had a negligible impact on these associations, but these were attenuated following adjustment for allergic sensitisation, particularly in girls (girls: OR=1.25; 95% CI, 0.96–1.60; boys: OR=1.09, 95% CI, 0.99–1.19). Conclusions: BMI is associated with asthma in pre-pubertal Saudi boys and girls; this effect does not appear to be mediated through respiratory obstruction, but in girls this may at least partially be mediated through increased risk of allergic sensitisation

The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells