Mechanism of Tacrine Block at Adult Human Muscle Nicotinic Acetylcholine Receptors

We used single-channel kinetic analysis to study the inhibitory effects of tacrine on human adult nicotinic receptors (nAChRs) transiently expressed in HEK 293 cells. Single channel recording from cell-attached patches revealed concentration- and voltage-dependent decreases in mean channel open probability produced by tacrine (IC50 4.6 μM at −70 mV, 1.6 μM at −150 mV). Two main effects of tacrine were apparent in the open- and closed-time distributions. First, the mean channel open time decreased with increasing tacrine concentration in a voltage-dependent manner, strongly suggesting that tacrine acts as an open-channel blocker. Second, tacrine produced a new class of closings whose duration increased with increasing tacrine concentration. Concentration dependence of closed-times is not predicted by sequential models of channel block, suggesting that tacrine blocks the nAChR by an unusual mechanism. To probe tacrine's mechanism of action we fitted a series of kinetic models to our data using maximum likelihood techniques. Models incorporating two tacrine binding sites in the open receptor channel gave dramatically improved fits to our data compared with the classic sequential model, which contains one site. Improved fits relative to the sequential model were also obtained with schemes incorporating a binding site in the closed channel, but only if it is assumed that the channel cannot gate with tacrine bound. Overall, the best description of our data was obtained with a model that combined two binding sites in the open channel with a single site in the closed state of the receptor

Field and Forage Crop Fertilization in the Rio Grande Plains.

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Issues and Opportunities in Exotic Hadrons

The last few years have been witness to a proliferation of new results concerning heavy exotic hadrons. Experimentally, many new signals have been discovered that could be pointing towards the existence of tetraquarks, pentaquarks, and other exotic configurations of quarks and gluons. Theoretically, advances in lattice field theory techniques place us at the cusp of understanding complex coupled-channel phenomena, modelling grows more sophisticated, and effective field theories are being applied to an ever greater range of situations. It is thus an opportune time to evaluate the status of the field. In the following, a series of high priority experimental and theoretical issues concerning heavy exotic hadrons is presented.Comment: White paper from INT workshop, "Modern Exotic Hadrons". References added. Version to appear in Chinese Physics

A methodology for the capture and analysis of hybrid data: a case study of program debugging

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Selection of quasar candidates from combined radio and optical surveys using neural networks

The application of supervised artificial neural networks (ANNs) for quasar selection from combined radio and optical surveys with photometric and morphological data is investigated, using the list of candidates and their classification from White et al. (2000). Seven input parameters and one output, evaluated to 1 for quasars and 0 for nonquasars, were used, with architectures 7:1 and 7:2:1. Both models were trained on samples of ~800 sources and yielded similar performance on independent test samples, with reliability as large as 87% at 80% completeness. For comparison the quasar fraction from the original candidate list was 56%. The accuracy is similar to that found by White et al. using supervised learning with oblique decision trees. This performance probably approaches the maximum value achievable with this database. Probabilities for the 98 candidates without spectroscopic classification in White et al. are presented and compared with the results from their work, showing a good agreement. This is the first analysis of the performance of ANNs for the selection of quasars. Our work shows that ANNs provide a promising technique for the selection of specific object types in astronomical databases.Comment: 11 pages, 15 figures, Accepted for publication in MNRA

Andean orogeny and the diversification of lowland neotropical rain forest trees:A case study in Sapotaceae

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordUnderstanding how species diversify and evolve in species-rich areas like the lowland rain forest in the Neotropics is critical for conservation in times of unprecedented threats. To determine how the Andean uplift, the formation of the Panama land bridge, and Pleistocene climatic fluctuations affected dispersal and diversification in the Sapotaceae subfamily Chrysophylloideae, we collected 146 Chrysophylloideae accessions in previously under-explored areas, generating one of the most geographically complete data sets for neotropical Sapotaceae. Sapotaceae is a good model to test diversification hypotheses in lowland neotropical rain forests as it predominantly occurs <1000 m altitude, and it is an abundant and species-rich group in this biome. We generated a time calibrated phylogeny of 123 Sapotaceae species based upon the nuclear ribosomal internal transcribed spacer region that suggests migration between lineages to the east and the west Andean Cordilleras occurred before and after periods of major uplift, indicating that the Andes did not represent a significant barrier to dispersal for Sapotaceae, although it may have promoted vicariance in some cases. Dispersal between South and Central America occurred mainly prior to the formation of the Panama land bridge, suggesting that this event did not affect migration patterns in Chrysophylloideae. We inferred diversification rates and detected three shifts in the phylogeny, but they are not congruent with tectonic movements during the middle Miocene and climatic changes during the Pleistocene. Finally, some species with restricted distributions appear to be phylogenetically nested within species with broader ranges, suggesting ancestor descendent relationships and insights into patterns of speciation in rain forest trees.Natural Environment Research Council (NERC)National Science Foundation (NSF)Geological Society of Americ

One HACCP, two approaches: experiences with and perceptions of the Hazard Analysis and Critical Control Points (HACCP) food safety management systems in the US and the EU

This paper explores the differences in the use of the Hazard Analysis Critical Control Point (HACCP) system to manage food safety risks in the food chain from farm to fork in the EU and the US. In particular, this paper investigates the current uses and potential expansion of HACCP as a mechanism for the delivery of safe agricultural products, particularly safe produce. It considers not only whether HACCP systems are the best mode of governance for delivering safe food, and describes why HACCP has achieved an important role in the regulatory framework that governs food safety, but asks why this role is different in the EU and US. Within the EU, HACCP is compulsory at all stages of the food chain other than primary production, whereas the mandatory use of HACCP in the US is less widespread. However, the empirical work found that HACCP is being used by businesses in both the EU and US as a basis for organizing their business, even when not required by regulation. Using data derived from semi-structured interviews with regulatory actors in the EU and US, this paper argues that the different approach to HACCP is a result of differing ideas about the role that it plays in the governance of food safety, and the different concepts of the role of regulation in securing safe food. Finally, the paper explores the difficulties of utilizing HACCP to manage produce safety risks, and raises further challenges that must be met in order to ensure that HACCP can successfully fulfill its potential as a governance mechanism

Options for possible changes to the blood donation service: health economics modelling

BackgroundEvidence is required on the cost-effectiveness of alternative changes to the blood collection service.Objectives(1) To estimate the cost-effectiveness of alternative minimum interdonation intervals between whole-blood donations. (2) To investigate donors’ frequency of whole-blood donation according to alternative changes to the blood collection service. (3) To estimate the cost-effectiveness of alternative strategies for maintaining the supply of whole blood.MethodsWe undertook a within-trial cost-effectiveness analysis (CEA) of the INTERVAL trial, stated preference (SP) surveys to elicit donor preferences and a CEA of different strategies for blood collection. The strategies considered were reduced minimum intervals between whole-blood donations, introduction of a donor health report and changes to appointment availability and opening times at blood collection venues. The within-trial CEA included 44,863 donors, with men randomly assigned to 12- versus 10- versus 8-week interdonation intervals, and women to 16- versus 14- versus 12-week interdonation intervals. We undertook a SP survey of non-INTERVAL donors (100,000 invitees). We asked donors to state the frequency with which they would be willing to donate blood, according to the service attribute and level. The CEA compared changes to the blood service with current practice by combining the survey estimates with information from the NHS Blood and Transpant database (PULSE) and cost data. The target population was existing whole-blood donors in England, of whom approximately 85% currently donate whole blood at mobile (temporary) blood collection venues, with the remainder donating at static (permanent) blood collection centres. We reported the effects of the alternative strategies on the number of whole-blood donations, costs and cost-effectiveness.ResultsThe reduced donation interval strategies had higher deferral rates caused by low haemoglobin (Hb), but increased frequency of successful donation. For men in the 8- versus 12-week arm of the INTERVAL trial [Di Angelantonio E, Thompson SG, Kaptoge S, Moore C, Walker M, Armitage J,et al.Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors.Lancet2017;390:2360–71], the Hb-related deferral rate was 5.7% per session versus 2.6% per session, but the average number of donations over 2 years increased by 1.71 (95% confidence interval 1.60 to 1.80). A total of 25,187 (25%) donors responded to the SP survey. For static donor centres, extending appointment availability to weekday evenings or weekends, or reduced intervals between blood donations, increased stated donation frequency by, on average, 0.5 donations per year. The CEA found that reducing the minimum interval, extending opening times to weekday evenings and extending opening times to weekends in all static donor centres would provide additional whole blood at a cost per additional unit of £10, £23 and £29, respectively, with similar results for donors with high-demand blood types.LimitationsThe study did not consider the long-term rates at which donors will leave the donation register, for example following higher rates of Hb-related deferral.ConclusionsExtending opening hours for blood donation to weekday evenings or weekends for all static donor centres are cost-effective ways of increasing the supply of high-demand blood types.Future workTo monitor the effects of new strategies on long-term donation frequency.FundingThe National Institute for Health Research Health Services and Delivery Research programme.</jats:sec

A function-based typology for Earth’s ecosystems

As the United Nations develops a post-2020 global biodiversity framework for the Convention on Biological Diversity, attention is focusing on how new goals and targets for ecosystem conservation might serve its vision of ‘living in harmony with nature’(1,2). Advancing dual imperatives to conserve biodiversity and sustain ecosystem services requires reliable and resilient generalizations and predictions about ecosystem responses to environmental change and management(3). Ecosystems vary in their biota(4), service provision(5) and relative exposure to risks(6), yet there is no globally consistent classification of ecosystems that reflects functional responses to change and management. This hampers progress on developing conservation targets and sustainability goals. Here we present the International Union for Conservation of Nature (IUCN) Global Ecosystem Typology, a conceptually robust, scalable, spatially explicit approach for generalizations and predictions about functions, biota, risks and management remedies across the entire biosphere. The outcome of a major cross-disciplinary collaboration, this novel framework places all of Earth’s ecosystems into a unifying theoretical context to guide the transformation of ecosystem policy and management from global to local scales. This new information infrastructure will support knowledge transfer for ecosystem-specific management and restoration, globally standardized ecosystem risk assessments, natural capital accounting and progress on the post-2020 global biodiversity framework

PRNP variation in UK sporadic and variant Creutzfeldt Jakob disease highlights genetic risk factors and a novel non-synonymous polymorphism

<p>Abstract</p> <p>Background</p> <p>Genetic analysis of the human prion protein gene (<it>PRNP</it>) in suspect cases of Creutzfeldt-Jakob disease (CJD) is necessary for accurate diagnosis and case classification. Previous publications on the genetic variation at the <it>PRNP </it>locus have highlighted the presence of numerous polymorphisms, in addition to the well recognised one at codon 129, with significant variability between geographically distinct populations. It is therefore of interest to consider their influence on susceptibility or the clinico-pathological disease phenotype. This study aimed to characterise the frequency and effect of <it>PRNP </it>open reading frame polymorphisms other than codon 129 in both disease and control samples sourced from the United Kingdom population.</p> <p>Methods</p> <p>DNA was extracted from blood samples and genetic data obtained by full sequence analysis of the prion protein gene or by restriction fragment length polymorphism analysis using restriction enzymes specific to the gene polymorphism under investigation.</p> <p>Results</p> <p>147 of 166 confirmed cases of variant CJD (vCJD) in the UK have had <it>PRNP </it>codon 129 genotyping and all are methionine homozygous at codon 129; 118 have had full <it>PRNP </it>gene sequencing. Of the latter, 5 cases have shown other polymorphic loci: at codon 219 (2, 1.69%), at codon 202 (2, 1.69%), and a 24 bp deletion in the octapeptide repeat region (1, 0.85%). E219K and D202D were not found in sporadic CJD (sCJD) cases and therefore may represent genetic risk factors for vCJD.</p> <p>Genetic analysis of 309 confirmed UK sCJD patients showed codon 129 genotype frequencies of MM: 59.5% (n = 184), MV: 21.4% (n = 66), and VV: 19.1% (n = 59). Thirteen (4.2%) had the A117A polymorphism, one of which also had the P68P polymorphism, four (1.3%) had a 24 bp deletion, and a single patient had a novel missense variation at codon 167. As the phenotype of this latter case is similar to sCJD and in the absence of a family history of CJD, it is unknown whether this is a form of genetic CJD, or simply a neutral polymorphism.</p> <p>Conclusions</p> <p>This analysis of <it>PRNP </it>genetic variation in UK CJD patients is the first to show a comprehensive comparison with healthy individuals (n = 970) from the same population, who were genotyped for the three most common variations (codon 129, codon 117, and 24 bp deletion). These latter two genetic variations were equally frequent in UK sCJD or vCJD cases and a normal (healthy blood donor) UK population.</p