Incorporating DNA Sequencing into Current Prenatal Screening Practice for Down's Syndrome

PMCID: PMC3604109This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Unraveling the B. pseudomallei Heptokinase WcbL: from structure to drug discovery

Journal ArticleOpen Access funded by Biotechnology and Biological Sciences Research Council under a Creative Commons Attribution 4.0 International Public LicenseGram-negative bacteria utilize heptoses as part of their repertoire of extracellular polysaccharide virulence determinants. Disruption of heptose biosynthesis offers an attractive target for novel antimicrobials. A critical step in the synthesis of heptoses is their 1-O phosphorylation, mediated by kinases such as HldE or WcbL. Here, we present the structure of WcbL from Burkholderia pseudomallei. We report that WcbL operates through a sequential ordered Bi-Bi mechanism, loading the heptose first and then ATP. We show that dimeric WcbL binds ATP anti-cooperatively in the absence of heptose, and cooperatively in its presence. Modeling of WcbL suggests that heptose binding causes an elegant switch in the hydrogen-bonding network, facilitating the binding of a second ATP molecule. Finally, we screened a library of drug-like fragments, identifying hits that potently inhibit WcbL. Our results provide a novel mechanism for control of substrate binding and emphasize WcbL as an attractive anti-microbial target for Gram-negative bacteria.Biotechnology and Biological Sciences Research Counci

Starting the polypill: the use of a single age cut-off in males and females

OBJECTIVE: Age screening and preventive medication for future myocardial infarction and stroke has been previously described. We aimed to ascertain whether different age cut-offs are needed for males and females. METHODS: We determined five parameters for each sex according to age cut-off: detection rate (sensitivity), false-positive rate, proportion of the population eligible for treatment with a polypill, proportion who benefit from taking a polypill (simvastatin 20 mg, losartan 25 mg, hydrochlorothiazide 12.5 mg, amlodipine 2.5 mg), and among these, years of life gained without a first myocardial infarction or stroke. RESULTS: Approximately one-third benefit, regardless of the age cut-off. For males and females combined, using ages 40 and 80, the detection rates are 98% and 52%, false-positive rates are 51% and 7%, population percentages eligible for treatment are 52% and 7%, and years of life gained without a first myocardial infarction or stroke are 8.4 and 3.6. Using age 50, detection rates are 93% (males) 98% (females), false-positive rates 37% (males) 40% (females), percentage of the population eligible for treatment 38% (males) 41% (females), percentage who benefit 35% (males) 33% (females), and years of life gained without an event 8.5 (males) 7.0 (females). At a given age cut-off, the sex differences are relatively small. CONCLUSION: A single age cut-off can be used for both sexes

Screening for Future Cardiovascular Disease Using Age Alone Compared with Multiple Risk Factors and Age

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

How antimalarial drug resistance affects post-treatment prophylaxis

Slowly eliminated antimalarial drugs suppress malaria reinfections for a period of time determined by the dose, the pharmacokinetic properties of the drug, and the susceptibility of the infecting parasites. This effect is called post-treatment prophylaxis (PTP). The clinical benefits of preventing recrudescence (reflecting treatment efficacy) compared with preventing reinfection (reflecting PTP) need further assessment. Antimalarial drug resistance shortens PTP. While blood concentrations are in the terminal elimination phase, the degree of shortening may be estimated from measurements of in-vitro susceptibility and the terminal elimination half-life. More information is needed on PTP following intermittent preventive treatments, and on the relationship between the duration of PTP and immunity, so that policy recommendations can have a firmer evidence base

Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated

Solar-type dynamo behaviour in fully convective stars without a tachocline

In solar-type stars (with radiative cores and convective envelopes), the magnetic field powers star spots, flares and other solar phenomena, as well as chromospheric and coronal emission at ultraviolet to X-ray wavelengths. The dynamo responsible for generating the field depends on the shearing of internal magnetic fields by differential rotation. The shearing has long been thought to take place in a boundary layer known as the tachocline between the radiative core and the convective envelope. Fully convective stars do not have a tachocline and their dynamo mechanism is expected to be very different, although its exact form and physical dependencies are not known. Here we report observations of four fully convective stars whose X-ray emission correlates with their rotation periods in the same way as in Sun-like stars. As the X-ray activity - rotation relationship is a well-established proxy for the behaviour of the magnetic dynamo, these results imply that fully convective stars also operate a solar-type dynamo. The lack of a tachocline in fully convective stars therefore suggests that this is not a critical ingredient in the solar dynamo and supports models in which the dynamo originates throughout the convection zone.Comment: 6 pages, 1 figure. Accepted for publication in Nature (28 July 2016). Author's version, including Method

Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding

Background: Atherosclerosis is an inflammatory process that develops in individuals with known risk factors that include hypertension and hyperlipidaemia, influenced by diet. However, the interplay between diet, inflammatory mechanisms and vascular risk factors requires further research. We hypothesised that interleukin-1 (IL-1) signaling in the vessel wall would raise arterial blood pressure and promote atheroma. Methodology/Principal Findings: Apoe(-/-) and Apoe(-/-)/IL-1R1(-/-) mice were fed high fat diets for 8 weeks, and their blood pressure and atherosclerosis development measured. Apoe(-/-)/IL-R1(-/-) mice had a reduced blood pressure and significantly less atheroma than Apoe(-/-) mice. Selective loss of IL-1 signaling in the vessel wall by bone marrow transplantation also reduced plaque burden (p<0.05). This was associated with an IL-1 mediated loss of endothelium-dependent relaxation and an increase in vessel wall Nox 4. Inhibition of IL-1 restored endothelium-dependent vasodilatation and reduced levels of arterial oxidative stress. Conclusions/Significance: The IL-1 cytokine system links atherogenic environmental stimuli with arterial inflammation, oxidative stress, increased blood pressure and atherosclerosis. This is the first demonstration that inhibition of a single cytokine can block the rise in blood pressure in response to an environmental stimulus. IL-1 inhibition may have profound beneficial effects on atherogenesis in man

Dermatitis associated with exposure to a marine cyanobacterium during recreational water exposure

<p>Abstract</p> <p>Background</p> <p>Anecdotal evidence reported an outbreak of symptoms on Fraser Island during the late 1990s similar to those expected from exposure to dermotoxins found in the cyanobacterium <it>L. majuscula</it>. This coincided with the presence of a bloom of <it>L. majuscula</it>.</p> <p>Methods</p> <p>Records from the Fraser Island National Parks First aid station were examined. Information on cyanobacterial blooms at Fraser Island were obtained from Queensland National Parks rangers.</p> <p>Results</p> <p>Examination of first aid records from Fraser Island revealed an outbreak of symptoms predominantly in January and February 1998.</p> <p>Conclusion</p> <p>During a bloom of <it>L. majuscula </it>there were numerous reports of symptoms that could be attributed to dermotoxins found in <it>L. majuscula</it>. The other four years examined had no <it>L. majuscula </it>blooms and the number of <it>L. majuscula </it>symptoms was much reduced. These cases comprised a high percentage of the cases treated at the first aid station.</p

Duration of Protection against Malaria and Anaemia Provided by Intermittent Preventive Treatment in Infants in Navrongo, Ghana

BACKGROUND: Intermittent preventive treatment for malaria in Infants (IPTi) has been shown to give effective and safe protection against malaria. It has been suggested that IPTi might have long-lasting beneficial effects but, in most settings, the protection provided by IPTi appears to be short-lived. Knowledge of the duration of protection given by IPTi would help interpret the results of existing trials and suggest optimal delivery schedules for IPTi. This study investigated how the protective efficacy of IPTi against malaria and anaemia changes over time. METHODS AND FINDINGS: A secondary analysis of data from a cluster-randomised, placebo-controlled trial of IPTi using sulfadoxine-pyrimethamine (SP) in Ghana was conducted. In this trial IPTi was given to 2485 infants at 3, 4, 9 and 12 months of age; children remained in follow-up until two years of age. Poisson regression with a random effect to adjust for the cluster-randomised design was used to determine protective efficacy of IPTi against clinical malaria and anaemia in defined time strata following administration of IPTi. Analysis of first-or-only clinical malaria episode following the individual IPTi doses showed that some protection against malaria lasted between 4 to 6 weeks. A similar pattern was seen when the incidence of all malaria episodes up to 2 years of age was analysed in relation to the most recent IPT, by pooling the incidence of malaria after the individual IPTi doses. Protective efficacy within four weeks of IPTi was 75.2% (95% CI: 66-82) against malaria, 78.9% (95% CI: 69-86) against high parasite density malaria, and 93.8% (95% CI: 73-99) against anaemia. Protection against these outcomes was short-lived, with evidence of any effect lasting for only 6, 6 and 4 weeks respectively. Protection in children who were parasitaemic when receiving IPTi appeared to be of shorter duration than in uninfected children. There was no evidence of any benefit of IPTi after the immediate period following the IPTi doses. CONCLUSIONS: Intermittent preventive treatment provides considerable protection against malaria and anaemia for short periods, even in an area of intense seasonal transmission. Due to the relatively short duration of protection provided by each dose of IPTi, this treatment will be of most benefit when delivered at the time of peak malaria incidence