Ankyrin-G mediates targeting of both Na+ and K-ATP channels to the rat cardiac intercalated disc

We investigated targeting mechanisms of Na+ and KATP channels to the intercalated disk (ICD) of cardiomyocytes. Patch clamp and surface biotinylation data show reciprocal downregulation of each other’s surface density. Mutagenesis of the Kir6.2 ankyrin binding site disrupts this functional coupling. Duplex patch clamping and Angle SICM recordings show that INa and IKATP functionally co-localize at the rat ICD, but not at the lateral membrane. Quantitative STORM imaging show that Na+ and KATP channels are localized close to each other and to AnkG, but not to AnkB, at the ICD. Peptides corresponding to Nav1.5 and Kir6.2 ankyrin binding sites dysregulate targeting of both Na+ and KATP channels to the ICD, but not to lateral membranes. Finally, a clinically relevant gene variant that disrupts KATP channel trafficking also regulates Na+ channel surface expression. The functional coupling between these two channels need to be considered when assessing clinical variants and therapeutics

The dominant Anopheles vectors of human malaria in the Asia-Pacific region: occurrence data, distribution maps and bionomic précis

<p>Abstract</p> <p>Background</p> <p>The final article in a series of three publications examining the global distribution of 41 dominant vector species (DVS) of malaria is presented here. The first publication examined the DVS from the Americas, with the second covering those species present in Africa, Europe and the Middle East. Here we discuss the 19 DVS of the Asian-Pacific region. This region experiences a high diversity of vector species, many occurring sympatrically, which, combined with the occurrence of a high number of species complexes and suspected species complexes, and behavioural plasticity of many of these major vectors, adds a level of entomological complexity not comparable elsewhere globally. To try and untangle the intricacy of the vectors of this region and to increase the effectiveness of vector control interventions, an understanding of the contemporary distribution of each species, combined with a synthesis of the current knowledge of their behaviour and ecology is needed.</p> <p>Results</p> <p>Expert opinion (EO) range maps, created with the most up-to-date expert knowledge of each DVS distribution, were combined with a contemporary database of occurrence data and a suite of open access, environmental and climatic variables. Using the Boosted Regression Tree (BRT) modelling method, distribution maps of each DVS were produced. The occurrence data were abstracted from the formal, published literature, plus other relevant sources, resulting in the collation of DVS occurrence at 10116 locations across 31 countries, of which 8853 were successfully geo-referenced and 7430 were resolved to spatial areas that could be included in the BRT model. A detailed summary of the information on the bionomics of each species and species complex is also presented.</p> <p>Conclusions</p> <p>This article concludes a project aimed to establish the contemporary global distribution of the DVS of malaria. The three articles produced are intended as a detailed reference for scientists continuing research into the aspects of taxonomy, biology and ecology relevant to species-specific vector control. This research is particularly relevant to help unravel the complicated taxonomic status, ecology and epidemiology of the vectors of the Asia-Pacific region. All the occurrence data, predictive maps and EO-shape files generated during the production of these publications will be made available in the public domain. We hope that this will encourage data sharing to improve future iterations of the distribution maps.</p

Preservation of titanosaur egg clutches in Upper Cretaceous cumulative palaeosols (Los Llanos Formation, La Rioja, Argentina)

Studies of the palaeobiology of titanosaur eggs are significantly more common than studies of titanosaur-egg-bearing strata. Nevertheless, the latter provide significant insight into palaeoenvironmental conditions associated with the egg-laying behaviour. This study examines titanosaur-egg-bearing strata of the Upper Cretaceous Los Llanos Formation (La Rioja, Argentina) and relates them to the laying and preservation of titanosaur egg clutches. Los Llanos Formation is a predominantly sandstone succession throughout represented by palaeosol profiles. Five titanosaur egg clutches were recovered from the Bw horizon of an Inceptisol profile. This palaeosol type, named Tama pedotype, constitutes 69% of the entire succession, by thickness. Rare planar, and undulating lamination and cross stratification, quartz-grain surface microtextures and ventifacts are indicative of the interaction of fluvial-aeolian processes of sedimentation during accumulation of the parent material on the distal part of a coalescent alluvial fan system (bajada). Highly abundant root traces, reddish colour, clay coatings and calcium carbonate nodules testify that the Tama pedotype had abundant vegetation cover, and was developed in well-drained conditions under the influence of a semiarid climate regime. Palaeosol horizons with exaggerated thickness and diffuse boundaries indicate a cumulative pedotype, whereby the soil developed in response to continuous accretion via on-going sedimentary processes. Morphological features of eggshells suggest that titanosaurs dug holes in the topographic surface to lay eggs. Thus, palaeosols seem to have been putative areas for the laying of titanosaur eggs. Actually, it is uncommon for palaeosols to constitute sites for the preservation of eggs, since soils typically develop in response to long episodes of weathering. However, cumulative palaeosols can provide ideal conditions for egg burial and preservation. In cumulative soils, the residence time of an object within the weatherable thickness of a soil is reduced to &lt; 103 years, thereby significantly increasing the long-term preservation potential of eggs

Incentives for smoking cessation

Background Financial incentives, monetary or vouchers, are widely used in an attempt to precipitate, reinforce and sustain behaviour change, including smoking cessation. They have been used in workplaces, in clinics and hospitals, and within community programmes. Objectives To determine the long‐term effect of incentives and contingency management programmes for smoking cessation. Search methods For this update, we searched the Cochrane Tobacco Addiction Group Specialised Register, clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP). The most recent searches were conducted in July 2018. Selection criteria We considered only randomised controlled trials, allocating individuals, workplaces, groups within workplaces, or communities to smoking cessation incentive schemes or control conditions. We included studies in a mixed‐population setting (e.g. community, work‐, clinic‐ or institution‐based), and also studies in pregnant smokers. Data collection and analysis We used standard Cochrane methods. The primary outcome measure in the mixed‐population studies was abstinence from smoking at longest follow‐up (at least six months from the start of the intervention). In the trials of pregnant women we used abstinence measured at the longest follow‐up, and at least to the end of the pregnancy. Where available, we pooled outcome data using a Mantel‐Haenzel random‐effects model, with results reported as risk ratios (RRs) and 95% confidence intervals (CIs), using adjusted estimates for cluster‐randomised trials. We analysed studies carried out in mixed populations separately from those carried out in pregnant populations. Main results Thirty‐three mixed‐population studies met our inclusion criteria, covering more than 21,600 participants; 16 of these are new to this version of the review. Studies were set in varying locations, including community settings, clinics or health centres, workplaces, and outpatient drug clinics. We judged eight studies to be at low risk of bias, and 10 to be at high risk of bias, with the rest at unclear risk. Twenty‐four of the trials were run in the USA, two in Thailand and one in the Phillipines. The rest were European. Incentives offered included cash payments or vouchers for goods and groceries, offered directly or collected and redeemable online. The pooled RR for quitting with incentives at longest follow‐up (six months or more) compared with controls was 1.49 (95% CI 1.28 to 1.73; 31 RCTs, adjusted N = 20,097; I2 = 33%). Results were not sensitive to the exclusion of six studies where an incentive for cessation was offered at long‐term follow up (result excluding those studies: RR 1.40, 95% CI 1.16 to 1.69; 25 RCTs; adjusted N = 17,058; I2 = 36%), suggesting the impact of incentives continues for at least some time after incentives cease. Although not always clearly reported, the total financial amount of incentives varied considerably between trials, from zero (self‐deposits), to a range of between USD 45 and USD 1185. There was no clear direction of effect between trials offering low or high total value of incentives, nor those encouraging redeemable self‐deposits. We included 10 studies of 2571 pregnant women. We judged two studies to be at low risk of bias, one at high risk of bias, and seven at unclear risk. When pooled, the nine trials with usable data (eight conducted in the USA and one in the UK), delivered an RR at longest follow‐up (up to 24 weeks post‐partum) of 2.38 (95% CI 1.54 to 3.69; N = 2273; I2 = 41%), in favour of incentives. Authors' conclusions Overall there is high‐certainty evidence that incentives improve smoking cessation rates at long‐term follow‐up in mixed population studies. The effectiveness of incentives appears to be sustained even when the last follow‐up occurs after the withdrawal of incentives. There is also moderate‐certainty evidence, limited by some concerns about risks of bias, that incentive schemes conducted among pregnant smokers improve smoking cessation rates, both at the end of pregnancy and post‐partum. Current and future research might explore more precisely differences between trials offering low or high cash incentives and self‐incentives (deposits), within a variety of smoking populations

Sagittal crest morphology decoupled from relative bite performance in Pleistocene tapirs (Perissodactyla: Tapiridae)

peer reviewedBite force is often associated with specific morphological features, such as sagittal crests. The presence of a pronounced sagittal crest in some tapirs (Perissodactyla: Tapiridae) was recently shown to be negatively correlated with hard-object feeding, in contrast with similar cranial structures in carnivorans. The aim of this study was to investigate bite forces and sagittal crest heights across a wide range of modern and extinct tapirs and apply a comparative investigation to establish whether these features are correlated across a broad phylogenetic scope. We examined a sample of 71 specimens representing 15 tapir species (5 extant, 10 extinct) using the dry-skull method, linear measurements of cranial features, phylogenetic reconstruction, and comparative analyses. Tapirs were found to exhibit variation in bite force and sagittal crest height across their phylogeny and between different biogeographical realms, with high-crested morphologies occurring mostly in Neotropical species. The highest bite forces within tapirs appear to be driven by estimates for the masseter-pterygoid muscle complex, rather than predicted forces for the temporalis muscle. Our results demonstrate that relative sagittal crest height is poorly correlated with relative cranial bite force, suggesting high force application is not a driver for pronounced sagittal crests in this sample. The divergent biomechanical capabilities of different contemporaneous tapirids may have allowed multiple species to occupy overlapping territories and partition resources to avoid excess competition. Bite forces in tapirs peak in Pleistocene species, independent of body size, suggesting possible dietary shifts as a potential result of climatic changes during this epoch