The malaria parasite cyclic GMP-dependent protein kinase plays a central role in blood-stage schizogony

A role for the Plasmodium falciparum cyclic GMP (cGMP)-dependent protein kinase (PfPKG) in gametogenesis in the malaria parasite was elucidated previously. In the present study we examined the role of PfPKG in the asexual blood-stage of the parasite life cycle, the stage that causes malaria pathology. A specific PKG inhibitor (compound 1, a trisubstituted pyrrole) prevented the progression of P. falciparum schizonts through to ring stages in erythrocyte invasion assays. Addition of compound 1 to ring-stage parasites allowed normal development up to 30 h postinvasion, and segmented schizonts were able to form. However, synchronized schizonts treated with compound 1 for ≥6 h became large and dysmorphic and were unable to rupture or liberate merozoites. To conclusively demonstrate that the effect of compound 1 on schizogony was due to its selective action on PfPKG, we utilized genetically manipulated P. falciparum parasites expressing a compound 1-insensitive PfPKG. The mutant parasites were able to complete schizogony in the presence of compound 1 but not in the presence of the broad-spectrum protein kinase inhibitor staurosporine. This shows that PfPKG is the primary target of compound 1 during schizogony and provides direct evidence of a role for PfPKG in this process. Discovery of essential roles for the P. falciparum PKG in both asexual and sexual development demonstrates that cGMP signaling is a key regulator of both of these crucial life cycle phases and defines this molecule as an exciting potential drug target for both therapeutic and transmission blocking action against malaria

«Desvoyé de la droitte voye ...» : Gadifer de La Salle, Jean de Béthencourt et "Le Canarien"

Résumé Le livre nommé Le Canarien est la chronique de la conquête, en 1402, des Îles Canaries par deux aventuriers normands, Jean de Béthencourt et Gadifer de La Salle : expédition qui sombra très tôt dans la mauvaise foi et dans la discorde. Deux clercs au service de chacun des chevaliers ont, paraît-il, rédigé ensemble l?histoire de l?expédition. Leur ?uvre a disparu, mais deux manuscrits remaniés ultérieurement conservent actuellement l?histoire, avec des points de vue différents : Rouen, BM, MS MM 129 celui de Jean ; Londres, British Library, MS Egerton 2709 celui de Gadifer. Ces récits permettent de peindre les deux protagonistes : Gadifer, révolté, estimant que son compatriote l?a trahi en assumant la souveraineté des îles et en abrogeant les recettes fiscales ; Jean, se montrant inflexible, dédaigneux et rigide. Chaque texte veut faire prévaloir sa version des événements : leurs réécritures respectives, leurs lexiques, et jusqu?à la mise en page de leurs manuscrits nous laissent percevoir la triste dynamique de l?expédition, et nous révèlent des man?uvres qu?on pourrait à bon droit appeler propagandistes. Abstract The book known as Le Canarien is the chronicle of the 1402 conquest of the Canary Islands by two Norman adventurers, Jean de Béthencourt and Gadifer de La Salle: an expedition which soon foundered into discord and betrayal. Our two heroes? chaplains, it seems, put together an account of the expedition; their work is lost, but two manuscripts, each considerably emended, each from the point of view of one of the protagonists, have survived: Rouen, BM MS MM129 preserves Jean?s angle, London, British Library MS Egerton 2709 that of Gadifer. This remarkable circumstance enables us to glimpse the point of view of each of the knights: Gadifer angry and resentful, convinced that his compatriot has betrayed him by assuming the sovereignty of the islands, and seizing their tax revenues; Jean always dismissive, unrelenting. Each text insists on its own version of events: their writers? rewritings, emendations, their choice of words, the very lay-out of the manuscript page, allow us to glimpse the bleak dynamics of the expedition, and each version shows evidence of manoeuvres which one might legitimately call propagandist

Helminth control as an entry point for healthpromoting schools in Kwazulu-Natal

No Abstract

Time of Suckling Implant Influences onWeaning Weight, Post-weaning Performance, and Carcass Traits in Steer Calves

The effect of time of suckling calf implant (SCI) use on weaning weight (WW), post-weaning performance and subsequent carcass traits was compared in steer calves produced on one ranch in western SD. Calves were born in March and April of each year and were reared on native range prior to weaning. The SCI strategies used included: non implanted controls (NI) or implanted with Synovex C either in May (MAY), or August (AUG). Age groups of dams (≥4 years) were managed separately through the breeding seasons. At weaning (late October) all calves were weaned and relocated to the SDSU Ruminant Nutrition Center feedlot. Steers were individually weighed, vaccinated, and treated for parasites and the processing body weight recorded was considered the WW. Steers were sorted into feedlot pens by SCI treatment (8 or 9 steers/pen; 8 pens/treatment; 24 pens/yr). Steers were backgrounded and finished using diets and management typical for this region and included the use of implants uniformly across SCI treatments. Both the MAY and AUG implant treatments increased WW over non-implanted calves. The magnitude of this was response interacted with the age of the dams. Steers nursing mature cows and implanted in May had the greatest increase in WW over NI (40 lb). The WW advantage for steers nursing mature cows and implanted in August was reduced to 17 lb. Timing of implant administration had the opposite effect in young cows and was more beneficial when steers were implanted in August. The weight advantage due to suckling implants persisted through to carcass weight. The SCI treatments did not affect the post-weaning ADG or feed efficiency of the steers and had no adverse effects on Quality Grade of the carcasses produced. There was a substantial benefit to the cow calf producer to match the time of implant administration with the age of the dam with no adverse impact on overall beef production

The transfer of fibres in the carding machine

The problem of understanding the transfer of fibres between carding-machine surfaces is addressed by considering the movement of a single fibre in an airflow. The structure of the aerodynamic flow field predicts how and when fibres migrate between the different process surfaces. In the case of a revolving-flats carding machine the theory predicts a “strong” aerodynamic mechanism between taker-in and cylinder and a “weak” mechanism between cylinder and removal cylinder resulting in effective transfer in the first case and a more limited transfer in the second

Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis

Background: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease. Hyperkalaemia is a concern with the use of mineralocorticoid receptor antagonists. We aimed to determine whether the renal protective benefits of mineralocorticoid antagonists outweigh the risk of hyperkalaemia associated with this treatment in patients with chronic kidney disease. Methods: We conducted a meta-analysis investigating renoprotective effects and risk of hyperkalaemia in trials of mineralocorticoid receptor antagonists in chronic kidney disease. Trials were identified from MEDLINE (1966–2014), EMBASE (1947–2014) and the Cochrane Clinical Trials Database. Unpublished summary data were obtained from investigators. We included randomised controlled trials, and the first period of randomised cross over trials lasting ≥4 weeks in adults. Results: Nineteen trials (21 study groups, 1 646 patients) were included. In random effects meta-analysis, addition of mineralocorticoid receptor antagonists to renin angiotensin system inhibition resulted in a reduction from baseline in systolic blood pressure (−5.7 [−9.0, −2.3] mmHg), diastolic blood pressure (−1.7 [−3.4, −0.1] mmHg) and glomerular filtration rate (−3.2 [−5.4, −1.0] mL/min/1.73 m2). Mineralocorticoid receptor antagonism reduced weighted mean protein/albumin excretion by 38.7 % but with a threefold higher relative risk of withdrawing from the trial due to hyperkalaemia (3.21, [1.19, 8.71]). Death, cardiovascular events and hard renal end points were not reported in sufficient numbers to analyse. Conclusions: Mineralocorticoid receptor antagonism reduces blood pressure and urinary protein/albumin excretion with a quantifiable risk of hyperkalaemia above predefined study upper limit

On the global hydration kinetics of tricalcium silicate cement

We reconsider a number of measurements for the overall hydration kinetics of tricalcium silicate pastes having an initial water to cement weight ratio close to 0.5. We find that the time dependent ratio of hydrated and unhydrated silica mole numbers can be well characterized by two power-laws in time, $x/(1-x)\sim (t/t_x)^\psi$. For early times $t < t_x$ we find an `accelerated' hydration ($\psi = 5/2$) and for later times $t > t_x$ a `deaccelerated' behavior ($\psi = 1/2$). The crossover time is estimated as $t_x \approx 16 hours$. We interpret these results in terms of a global second order rate equation indicating that (a) hydrates catalyse the hydration process for $t<t_x$, (b) they inhibit further hydration for $t > t_x$ and (c) the value of the associated second order rate constant is of magnitude 6x10^{-7} - 7x10^{-6} liter mol^{-1} s^{-1}. We argue, by considering the hydration process actually being furnished as a diffusion limited precipitation that the exponents $\psi = 5/2$ and $\psi = 1/2$ directly indicate a preferentially `plate' like hydrate microstructure. This is essentially in agreement with experimental observations of cellular hydrate microstructures for this class of materials.Comment: RevTeX macros, 6 pages, 4 postscript figure

Recognition of Regional Water Table Patterns for Estimating Recharge Rates in Shallow Aquifers

We propose a new method for groundwater recharge rate estimation in regions with stream-aquifer interactions, at a linear scale on the order of 10 km and more. The method is based on visual identification and quantification of classically recognized water table contour patterns. Simple quantitative analysis of these patterns can be done manually from measurements on a map, or from more complex GIS data extraction and curve fitting. Recharge rate is then estimated from the groundwater table contour parameters, streambed gradients, and aquifer transmissivity using an analytical model for groundwater flow between parallel perennial streams. Recharge estimates were obtained in three regions (areas of 1500, 2200, and 3300 km2) using available water table maps produced by different methods at different times in the area of High Plains Aquifer in Nebraska. One region is located in the largely undeveloped Nebraska Sand Hills area, while the other two regions are located at a transition zone from Sand Hills to loess-covered area and include areas where groundwater is used for irrigation. Obtained recharge rates are consistent with other independent estimates. The approach is useful and robust diagnostic tool for preliminary estimates of recharge rates, evaluation of the quality of groundwater table maps, identification of priority areas for further aquifer characterization and expansion of groundwater monitoring networks prior to using more detailed methods. Includes supplemental materials

Blood pressure response to renal denervation is correlated with baseline blood pressure variability: a patient-level meta-analysis

Background: Sympathetic tone is one of the main determinants of blood pressure (BP) variability and treatment-resistant hypertension. The aim of our study was to assess changes in BP variability after renal denervation (RDN). In addition, on an exploratory basis, we investigated whether baseline BP variability predicted the BP changes after RDN. Methods: We analyzed 24-h BP recordings obtained at baseline and 6 months after RDN in 167 treatmentresistant hypertension patients (40% women; age, 56.7 years; mean 24-h BP, 152/90 mmHg) recruited at 11 expert centers. BP variability was assessed by weighted SD [SD over time weighted for the time interval between consecutive readings (SDiw)], average real variability (ARV), coefficient of variation, and variability independent of the mean (VIM). Results: Mean office and 24-h BP fell by 15.4/6.6 and 5.5/ 3.7 mmHg, respectively (P &lt; 0.001). In multivariable-adjusted analyses, systolic/diastolic SDiw and VIM for 24-h SBP/DBP decreased by 1.18/0.63 mmHg (P 0.01) and 0.86/0.42 mmHg (P 0.05), respectively, whereas no significant changes in ARV or coefficient of variation occurred. Furthermore, baseline SDiw (P ¼ 0.0006), ARV (P ¼ 0.01), and VIM (P ¼ 0.04) predicted the decrease in 24-h DBP but not 24-h SBP after RDN. Conclusion: RDN was associated with a decrease in BP variability independent of the BP level, suggesting that responders may derive benefits from the reduction in BP variability as well. Furthermore, baseline DBP variability estimates significantly correlated with mean DBP decrease after RDN. If confirmed in younger patients with less arterial damage, in the absence of the confounding effect of drugs and drug adherence, baseline BP variability may prove a good predictor of BP response to RDN

Worldwide incidence of cervical lesions: a systematic review

We conducted a systematic review summarizing data on incidence of high- and low-grade lesions in women with normal baseline cervical cytology, stratified by age (<30 and ⩾30 years), and baseline human papillomavirus (HPV) infection. Incidence of high- and low-grade lesions in women aged ⩾30 years with a baseline HPV infection increased over follow-up time (5-127 months), although incidence generally remained <10%. Without baseline HPV infection, incidence of high-grade lesions remained low over follow-up time (<5% over 5-122 months). Incidence of high-grade lesions in women aged ⩾30 years with baseline HPV infection appeared similar to that in women aged <30 years. In some women aged <30 years, high-grade lesions can develop relatively shortly after initial HPV infection. We observed an increase in low-grade lesions over time in women aged ⩾30 years with baseline HPV infection, potentially indicative of an HPV infection that is potentially progressing to higher grade lesions