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Following the collapse of the Delahoyde and Lucett joint enterprise, James Lucett resumed practice on his own account. He continued to implement his 'process', promoting it as a unique cure for intractable cases of insanity. For two decades he pursued his activities, with varying success, at different locations in the London area. He maintained his public profile by extensive advertising, letters to newspapers and published pamphlets, extolling his unique 'discovery' and recounting claims of successful cures achieved. Accusations of quackery persisted along with other hostile criticism, particularly from medical men, which Lucett strongly challenged. Periodically he faced more serious difficulties due to legal infractions or financial hardships, but somehow Lucett survived most of these and persevered with his endeavours. [ABSTRACT FROM AUTHOR]

James Lucett, a London clerk, claimed possession of a secret remedy for curing chronic insanity. In 1813, he and the Irish surgeon Charles Delahoyde secured royal and aristocratic patronage to implement their 'process' and opened a private asylum. They aroused great public interest after apparently remarkable results with hitherto intractable patients from Bethlem and Hoxton. Delahoyde and Lucett attained brief celebrity, but within a year it was evident that the dramatic recoveries were only temporary. Their venture collapsed in disarray and bankruptcy, and the episode was soon largely forgotten. Delahoyde fled to Ireland, but Lucett managed to re-establish himself in practice. This article narrates the origins, operation and failure of the enterprise. A second article will consider Lucett's subsequent career. [ABSTRACT FROM AUTHOR]

Myths inform real-world decision making. Scientific simulation models can do the same. Neither reflects their real-world targets perfectly. They are most useful in an apophatic sense: employing them as the best tools available without confusing their indications with Truth. The actions and choices of wizards often reflect those of scientists; drawing parallels is informative and several questions will be explored within this framework. How is a climate scientist to respond when offered a Faustian agreement promising limited insights? As scientists, how might we better communicate scientific limits regarding which aspects of the future we can see clearly and which we cannot? Should we risk casting doubt on the as-good-as-it-gets science underlying anthropogenic climate change? If an electorate requires certainty of a threat before it will vote for action, are lies of omission or misrepresentation justified? Is it ethical for scientists whose research is relevant to the policy process to pause their typical vigorous scientific criticism of overinterpretation by others (particularly in sciences downstream from physical science) when their science is thought not adequate for purpose? Should scientists merely advise, presenting the relevant science as neutrally as they can, or advocate by emphasizing evidence that supports their preferred course of action, or become activists overselling their science to achieve well-motivated policy ends by whatever means required? [ABSTRACT FROM AUTHOR]

In recent publications we have drawn attention to the fact that if the dynamics of a model is structurally unstable, then the presence of structural model error places in-principle limits on the model's ability to generate decision-relevant probability forecasts. Writing with a varying array of co-authors, Eric Winsberg has now produced at least four publications in which he dismisses our points as unfounded; the most recent of these appeared in this journal. In this paper we respond to the arguments of Winsberg and his co-workers, and we point out that their criticisms fail. We take this as an opportunity to restate and explain our arguments, and to point to fruitful directions for future research. [ABSTRACT FROM AUTHOR]

Probabilistic forecasting is common in a wide variety offields including geo science, social science, and finance. It is some times the case that one has multiple probability forecasts for the same target. How is the informationin these multiple nonlinear forecast systems best ‘‘combined’’? Assuming stationarity, in the limit of a very large forecast–outcome archive, each model-based probability density function can be weighted to form a ‘‘multimodel forecast’’ that will, in expectation, provide at least as much information as the most informative single model forecast system. If one of the forecast systems yields a probability distribution that reflects the distribution from which the outcome will be drawn, Bayesian model averaging will identify this forecast system as the preferred system in the limit as the number of forecast–outcome pairs goes to infinity. In many applications, like those of seasonal weather forecasting, data are precious; the archive is often limited to fewer than 26 entries. In addition, no perfect model is in hand. It is shown that in this case forming a single ‘‘multimodel probabilistic forecast’’can be expected toprovemis leading. These issues are investigated in the surrogate model (hereaforecastsystem) regime, where using probabilistic forecasts of a simple mathematical system allowsmany limiting behaviors offore cast systemstobe quantifiedandcomparedwiththoseunder morerealistic conditions. [ABSTRACT FROM AUTHOR]

The mandate system took shape at an inflexion point in the evolution from an international system based on rule over territories to one based on rule over peoples. Political compromises made at the Paris Peace Conference resulted in the creation of a new political agent, the League of Nations Mandate, with no clear sovereign. In seeking to systematize this political outcome, jurists located sovereignty with the victorious Great Powers, the League itself, and with the peoples of the mandate territories. Yet they never achieved a consensus, which created an absence at the centre of the mandate system that politics would have to fill throughout the interwar period. [ABSTRACT FROM AUTHOR]

Predictability varies. In geophysical systems, and related mathematical dynamical systems, variations are often expressed as serial dependence in the skill with which the system is, or can be, predicted. It is well known, of course, that estimation is more complicated in cases where the time series sample in hand does not reflect an independent from the target population; failure to account for this results in erroneous estimates both of the skill of the forecast system and of the statistical uncertainty in the estimated skill. This effect need not be indicated in the time series of the predictand; specifically, it is proven by example that linear correlation in the predictand is neither necessary nor sufficient to identify misestimation. It has been shown that temporal correlations in forecast skill give rise to biased estimates of skill of a forecast system, and progress has been made on accounting for this effect in probability‐of‐precipitation forecasts. Related effects are explored in probability density forecasts of a continuous target in three different dynamical systems (demonstrating that linear correlation in the predictand is neither necessary nor sufficient), and a simple procedure is presented as a straightforward, good practice test for the effect when estimating the skill of a forecast system. Serial dependence in forecast skill results in misleading estimates of the quality of a forecast system when evaluated in a time‐series fashion. A wide variety of impacts are possible in addition to systematic biases established elsewhere which demonstrate that sample size corrections are required to correctly interpret the statistical significance of the estimated skill. Extensions to forecast systems which display (a) no linear correlation in the predictand yet serial dependence in the prediction skill, (b) linear correlation in the predictand yet no serial dependence in skill, and (c) linear correlation in both the predictand and skill are discussed; empirical approaches to estimated sample size corrections (when analytic results are not available) are introduced. [ABSTRACT FROM AUTHOR]

Human botulism is most commonly caused by botulinum neurotoxin (BoNT) serotypes A, B, and E. For this work, we sought to develop a human monoclonal antibody (mAb)-based antitoxin capable of binding and neutralizing multiple subtypes of BoNT/E. Libraries of yeast-displayed single chain Fv (scFv) antibodies were created from the heavy and light chain variable region genes of humans immunized with pentavalent-toxoid-and BoNT/E-binding scFv isolated by Fluorescence-Activated Cell Sorting (FACS). A total of 10 scFv were isolated that bound one or more BoNT/E subtypes with nanomolar-level equilibrium dissociation constants (KD). By diversifying the V-regions of the lead mAbs and selecting for cross-reactivity, we generated three scFv that bound all four BoNT/E subtypes tested at three non-overlapping epitopes. The scFvs were converted to IgG that had KD values for the different BoNT/E subtypes ranging from 9.7 nM to 2.28 pM. An equimolar combination of the three mAbs was able to potently neutralize BoNT/E1, BoNT/E3, and BoNT/E4 in a mouse neutralization assay. The mAbs have potential utility as therapeutics and as diagnostics capable of recognizing multiple BoNT/E subtypes. A derivative of the three-antibody combination (NTM-1633) is in pre-clinical development with an investigational new drug (IND) application filing expected in 2018. [ABSTRACT FROM AUTHOR]

The standard of treatment for botulism, equine antitoxin, is a foreign protein with associated safety issues and a short serum half-life which excludes its use as a prophylactic antitoxin and makes it a less-than-optimal therapeutic. Due to these limitations, a recombinant monoclonal antibody (mAb) product is preferable. It has been shown that combining three mAbs that bind non-overlapping epitopes leads to highly potent botulinum neurotoxin (BoNT) neutralization. Recently, a triple human antibody combination for BoNT/A has demonstrated potent toxin neutralization in mouse models with no serious adverse events when tested in a Phase I clinical trial. However, a triple antibody therapeutic poses unique development and manufacturing challenges. Thus, potentially to streamline development of BoNT antitoxins, we sought to achieve the potency of multiple mAb combinations in a single IgG-based molecule that has a long serum half-life. The design, production, and testing of a single tri-epitopic IgG1-based mAb (TeAb) containing the binding sites of each of the three parental BoNT/A mAbs yielded an antibody of nearly equal potency to the combination. The approach taken here could be applied to the design and creation of other multivalent antibodies that could be used for a variety of applications, including toxin elimination. [ABSTRACT FROM AUTHOR]

There are few available medical countermeasures against botulism and the discontinuation of the pentavalent botulinum toxoid vaccine by the Centers for Disease Control and Prevention in 2011 has resulted in the need for a safe and effective prophylactic alternative. Advances in genetic engineering have resulted in subsequent vaccine efforts being primarily focused on the production of highly purified recombinant protein antigens representing one or more domains of the botulinum neurotoxin. Recombinant subunit vaccines based on the carboxy one-third of the toxin (Hc) developed in our lab against serotypes A-F have been shown to be safe and effective. However, in response to the identification of an ever increasing number of BoNT subtypes with significant amino acid heterogeneity, we have developed catalytically inactive BoNT holoproteins (ciBoNT HPs) in an attempt to elicit greater protective immunity to address these toxin variants. Here we report the production of ciBoNT/B1 HP, ciBoNT/C1 HP, ciBoNT/E1 HP and ciBoNT/F1 HP and compare the immunological and protective abilities of ciBoNT HPs and BoNT/A Hc, BoNT/B Hc, BoNT/C Hc, BoNT/E Hc and BoNT/F Hc vaccines when challenged with homologous and heterologous toxins. Our results suggest the ciBoNT HP vaccines exhibit superior potency after single vaccinations but multiple vaccinations with BoNT/Hc antigens resulted in increased survival rates at the toxin challenge levels used. [ABSTRACT FROM AUTHOR]

The ‘mad-doctor’ Dr Francis Willis achieved national and international celebrity following his successful treatment of King George III’s first major episode of insanity in 1788–9. At the time of his summons to attend the King, Willis was a well-established provincial practitioner and madhouse proprietor. An anonymous French visitor published a description of Willis’s Lincolnshire madhouse and his therapeutic practices in 1796. The translated text of the full article provides a unique insight into the work of a key figure in the historical development of psychological medicine. The accompanying Introduction summarizes Francis Willis’s career as a mad-doctor and uses salient information from the original text to place him and his madhouse practice within a contemporary context. [ABSTRACT FROM AUTHOR]

Botulism is a disease involving intoxication with botulinum neurotoxins (BoNTs), toxic proteins produced by Clostridium botulinum and other clostridia. The 150 kDa neurotoxin is produced in conjunction with other proteins to form the botulinum progenitor toxin complex (PTC), alternating in size from 300 kDa to 500 kDa. These progenitor complexes can be classified into hemagglutinin positive or hemagglutinin negative, depending on the ability of some of the neurotoxin-associated proteins (NAPs) to cause hemagglutination. The hemagglutinin positive progenitor toxin complex consists of BoNT, nontoxic non-hemagglutinin (NTNH), and three hemagglutinin proteins; HA-70, HA-33, and HA-17. Hemagglutinin negative progenitor toxin complexes contain BoNT and NTNH as the minimally functional PTC (M-PTC), but not the three hemagglutinin proteins. Interestingly, the genome of hemagglutinin negative progenitor toxin complexes comprises open reading frames (orfs) which encode for three proteins, but the existence of these proteins has not yet been extensively demonstrated. In this work, we demonstrate that these three proteins exist and form part of the PTC for hemagglutinin negative complexes. Several hemagglutinin negative strains producing BoNT/A, /E, and /F were found to contain the three open reading frame proteins. Additionally, several BoNT/A-containing bivalent strains were examined, and NAPs from both genes, including the open reading frame proteins, were associated with BoNT/A. The open reading frame encoded proteins are more easily removed from the botulinum complex than the hemagglutinin proteins, but are present in several BoNT/A and /F toxin preparations. These are not easily removed from the BoNT/E complex, however, and are present even in commercially-available purified BoNT/E complex. [ABSTRACT FROM AUTHOR]

In recent years there has been growing acknowledgement of the place of workhouses within the range of institutional provision for mentally disordered people in nineteenth-century England. This article explores the situation in Bristol, where an entrenched workhouse-based model was retained for an extended period in the face of mounting external ideological and political pressures to provide a proper lunatic asylum. It signified a contest between the modernising, reformist inclinations of central state agencies and local bodies seeking to retain their freedom of action. The conflict exposed contrasting conceptions regarding the nature of services to which the insane poor were entitled.Bristol pioneered establishment of a central workhouse under the old Poor Law; ‘St Peter’s Hospital’ was opened in 1698. As a multi-purpose welfare institution its clientele included ‘lunatics’ and ‘idiots’, for whom there was specific accommodation from before the 1760s. Despite an unhealthy city centre location and crowded, dilapidated buildings, the enterprising Bristol authorities secured St Peter’s Hospital’s designation as a county lunatic asylum in 1823. Its many deficiencies brought condemnation in the national survey of provision for the insane in 1844. In the period following the key lunacy legislation of 1845, the Home Office and Commissioners in Lunacy demanded the replacement of the putative lunatic asylum within Bristol’s workhouse by a new borough asylum outside the city. The Bristol authorities resisted stoutly for several years, but were eventually forced to succumb and adopt the prescribed model of institutional care for the pauper insane. [ABSTRACT FROM PUBLISHER]

Human botulism is primarily caused by botulinum neurotoxin (BoNT) serotypes A, B and E, with around 1% caused by serotype F (BoNT/F). BoNT/F comprises at least seven different subtypes with the amino acid sequence difference between subtypes as high as 36%. The sequence differences present a significant challenge for generating monoclonal antibodies (mAbs) that can bind, detect and neutralize all BoNT/F subtypes. We used repertoire cloning of immune mouse antibody variable (V) regions and yeast display to generate a panel of 33 lead single chain Fv (scFv) mAbs that bound one or more BoNT/F subtypes with a median equilibrium dissociation constant (KD) of 4.06 × 10−9 M. By diversifying the V-regions of the lead mAbs and selecting for cross reactivity we generated five mAbs that bound each of the seven subtypes. Three scFv binding non-overlapping epitopes were converted to IgG that had KD for the different BoNT/F subtypes ranging from 2.2×10−8 M to 1.47×10−12 pM. An equimolar combination of the mAbs was able to potently neutralize BoNT/F1, F2, F4 and F7 in the mouse neutralization assay. The mAbs have potential utility as diagnostics capable of recognizing the known BoNT/F subtypes and could be developed as antitoxins to prevent and treat type F botulism. [ABSTRACT FROM AUTHOR]

Private madhouses made a significant contribution to the development of psychiatric practices in eighteenth-century England. Joseph Mason of Bristol, proprietor of a madhouse at Stapleton and then at nearby Fishponds, was part of a dynasty of successful and respected mad-doctors. A deeply religious man, his Christian ethics constituted the guiding force in his work with patients and interactions with their relatives. He was also an astute man of business, who recognized that comfortable domestic surroundings and the achievement of recoveries would enhance his reputation and attract lucrative middle-class custom. His treatment approaches, illustrated in a 1763 diary, were eclectic and pragmatic, comprising various medicines, dietary regulation, graded social interactions, and the cultivation of individualized therapeutic relationships with his patients. [ABSTRACT FROM AUTHOR]

This article discusses the impact of World War I, also known as the Great War, from 1914-1918 on French society and politics. The author comments on the comparisons made between World War I and the French Revolution and describes the psychological research into WWI veterans. The literary production during and after the war, particularly by French veterans, is also examined.

Purpose The purpose of this article is to analyse electricity supply in the Solomon Islands face extraordinarily expensive electricity tariffs – currently set at 96 c/kWh – making them amongst the highest in the world. Power is supplied by a fleet of diesel generators reliant on imported liquid fuels. In this article, the authors model the 14,100 kW power system on the island of Guadalcanal and demonstrate that by investing in a combination of hydroelectric and solar photovoltaic generating capacity, power system costs and reliability can be improved marginally. However, when the authors model a 3-Party Covenant (3PC) Financing structure involving a credit wrap by the Commonwealth of Australia, electricity production costs fall by 50 per cent, thus resulting in meaningful increases in consumer welfare.Design/methodology/approach This study’s approach uses an integrated levelised cost of electricity model and dynamic partial equilibrium power system model. Doing so enables the authors to quickly analyse the rich blend of fixed, variable and sunk costs of generating technology options. The authors also focus on the cost of capital that is likely to be achieved under various policy settings.Findings The authors find that a 3PC Financing policy can substantially reduce the production costs associated with capital-intensive power projects in an unrated sovereign nation. Such a policy and associated prescriptions are not specific to the Solomon Islands or power generation. The conceptual framework and associated financial logic that underpins the initiative can be generalised to other “user pays” infrastructure projects and to other developing nations. The broad applicability of 3PC financing means that it is not country specific, project specific or asset class specific.Research Limitations/implications It is important to note that the analysis in this paper has a number of limitations in that the authors do not deal with rural electrification or distribution network costs. The focus of this paper is to identify policy interventions that are capable of making profound changes to the cost and the reliability of wholesale electricity production.Originality/value The focus of this paper is to identify a policy intervention capable of making profound changes to the cost and the reliability of wholesale electricity production. While there is nothing novel associated with a 3PC Financing per se, the authors are unaware of its direct use as a form of delivering foreign aid. A 3PC Financing has the effect of shifting the source of aid funding from fiscal account surplus/deficit (i.e. cash outlays) to balance sheet (i.e. credit wrap). However, this is not a “magic pudding” – 3PC Financing creates an asset-backed contingent liability and will have the effect of reducing the donor country’s own debt capacity by a commensurate amount, holding the nation’s credit rating constant. [ABSTRACT FROM AUTHOR]

Background: Clostridium botulinum is a diverse group of bacteria characterized by the production of botulinum neurotoxin. Botulinum neurotoxins are classified into serotypes (BoNT/A-G), which are produced by six species/ Groups of Clostridia, but the genetic background of the bacteria remains poorly understood. The purpose of this study was to use comparative genomics to provide insights into the genetic diversity and evolutionary history of bacteria that produce the potent botulinum neurotoxin. Results: Comparative genomic analyses of over 170 Clostridia genomes, including our draft genome assemblies for 59 newly sequenced Clostridia strains from six continents and publicly available genomic data, provided in-depth insights into the diversity and distribution of BoNT-producing bacteria. These newly sequenced strains included Group I and II strains that express BoNT/A,/B,/E, or/F as well as bivalent strains. BoNT-producing Clostridia and closely related Clostridia species were delineated with a variety of methods including 16S rRNA gene, concatenated marker genes, core genome and concatenated multi-locus sequencing typing (MLST) gene phylogenies that related whole genome sequenced strains to publicly available strains and sequence types. These analyses illustrated the phylogenetic diversity in each Group and the diversity of genomic backgrounds that express the same toxin type or subtype. Comparisons of the botulinum neurotoxin genes did not identify novel toxin types or variants. Conclusions: This study represents one of the most comprehensive analyses of whole genome sequence data for Group I and II BoNT-producing strains. Read data and draft genome assemblies generated for 59 isolates will be a resource to the research community. Core genome phylogenies proved to be a powerful tool for differentiating BoNT-producing strains and can provide a framework for the study of these bacteria. Comparative genomic analyses of Clostridia species illustrate the diversity of botulinum-neurotoxin-producing strains and the plasticity of the genomic backgrounds in which bont genes are found. [ABSTRACT FROM AUTHOR]

“Subject Peoples” arrived in the language of peacemaking after the Great War primarily as a way to understand post-imperial peoples of Central and Eastern Europe. As applied to the peoples of the former Ottoman Empire, however, peoples were categorized and assigned political characteristics according to specific schools of national political geography. British, French and American political geographers demarcated the ways thinking about the peoples of the Middle East that resonated throughout the century that followed. [ABSTRACT FROM AUTHOR]

The United Kingdom Climate Impacts Programme's UKCP09 project makes high-resolution projections of the climate out to 2100 by post-processing the outputs of a large-scale global climate model. The aim of this paper is to describe and analyse the methodology used and then urge some caution. Given the acknowledged systematic, shared errors of all current climate models, treating model outputs as decision-relevant projections can be significantly misleading. In extrapolatory situations, such as projections of future climate change, there is little reason to expect that post-processing of model outputs can correct for the consequences of such errors. This casts doubt on our ability, today, to make trustworthy probabilistic projections at high resolution out to the end of the century. [ABSTRACT FROM AUTHOR]

Existing antibodies (Abs) used to treat botulism cannot enter the cytosol of neurons and bind to botulinum neurotoxin (BoNT) at its site of action, and thus cannot reverse paralysis. However, Abs targeting the proteolytic domain of the toxin could inhibit the proteolytic activity of the toxin intracellularly and potentially reverse intoxication, if they could be delivered intracellularly. As such, antibodies that neutralize toxin activity could serve as potent inhibitory cargos for therapeutic antitoxins against botulism. BoNT serotype B (BoNT/B) contains a zinc endopeptidase light chain (LC) domain that cleaves synaoptobrevin-2, a SNARE protein responsible for vesicle fusion and acetylcholine vesicle release. To generate monoclonal Abs (mAbs) that could reverse paralysis, we targeted the protease domain for Ab generation. Single-chain variable fragment (scFv) libraries from immunized mice or humans were displayed on yeast, and 19 unique BoNT/B LC-specific mAbs isolated by fluorescence-activated cell sorting (FACS). The equilibrium dissociation constants (KD) of these mAbs for BoNT/B LC ranged from 0.24 nM to 14.3 nM (mean KD 3.27 nM). Eleven mAbs inhibited BoNT/B LC proteolytic activity. The fine epitopes of selected mAbs were identified by alanine-scanning mutagenesis, revealing that inhibitory mAbs bound near the active site, substrate-binding site or the extended substrate-binding site. The results provide mAbs that could prove useful for intracellular reversal of paralysis and identify epitopes that could be targeted by small molecules inhibitors. [ABSTRACT FROM AUTHOR]

The evaluation of forecast performance plays a central role both in the interpretation and use of forecast systems and in their development. Different evaluation measures (scores) are available, often quantifying different characteristics of forecast performance. The properties of several proper scores for probabilistic forecast evaluation are contrasted and then used to interpret decadal probability hindcasts of global mean temperature. The Continuous Ranked Probability Score (CRPS), Proper Linear (PL) score, and IJ Good's logarithmic score (also referred to as Ignorance) are compared; although information from all three may be useful, the logarithmic score has an immediate interpretation and is not insensitive to forecast busts. Neither CRPS nor PL is local; this is shown to produce counter intuitive evaluations by CRPS. Benchmark forecasts from empirical models like Dynamic Climatology place the scores in context. Comparing scores for forecast systems based on physical models (in this case HadCM3, from the CMIP5 decadal archive) against such benchmarks is more informative than internal comparison systems based on similar physical simulation models with each other. It is shown that a forecast system based on HadCM3 out performs Dynamic Climatology in decadal global mean temperature hindcasts; Dynamic Climatology previously outperformed a forecast system based upon HadGEM2 and reasons for these results are suggested. Forecasts of aggregate data (5-year means of global mean temperature) are, of course, narrower than forecasts of annual averages due to the suppression of variance; while the average 'distance' between the forecasts and a target may be expected to decrease, little if any discernible improvement in probabilistic skill is achieved. [ABSTRACT FROM AUTHOR]

The paralytic disease botulism is caused by botulinum neurotoxins (BoNT), multi-domain proteins containing a zinc endopeptidase that cleaves the cognate SNARE protein, thereby blocking acetylcholine neurotransmitter release. Antitoxins currently used to treat botulism neutralize circulating BoNT but cannot enter, bind to or neutralize BoNT that has already entered the neuron. The light chain endopeptidase domain (LC) of BoNT serotype A (BoNT/A) was targeted for generation of monoclonal antibodies (mAbs) that could reverse paralysis resulting from intoxication by BoNT/A. Single-chain variable fragment (scFv) libraries from immunized humans and mice were displayed on the surface of yeast, and 19 BoNT/A LC-specific mAbs were isolated by using fluorescence-activated cell sorting (FACS). Affinities of the mAbs for BoNT/A LC ranged from a KD value of 9.0×10−11 M to 3.53×10−8 M (mean KD 5.38×10−9 M and median KD 1.53×10−9 M), as determined by flow cytometry analysis. Eleven mAbs inhibited BoNT/A LC catalytic activity with IC50 values ranging from 8.3 ~73×10−9 M. The fine epitopes of selected mAbs were also mapped by alanine-scanning mutagenesis, revealing that the inhibitory mAbs bound the α-exosite region remote from the BoNT/A LC catalytic center. The results provide mAbs that could prove useful for intracellular reversal of paralysis post-intoxication and further define epitopes that could be targeted by small molecule inhibitors. [ABSTRACT FROM AUTHOR]

Simulation models are widely employed to make probability forecasts of future conditions on seasonal to annual lead times. Added value in such forecasts is reflected in the information they add, either to purely empirical statistical models or to simpler simulation models. An evaluation of seasonal probability forecasts from the Development of a European Multimodel Ensemble system for seasonal to inTERannual prediction (DEMETER) and ENSEMBLES multi-model ensemble experiments is presented. Two particular regions are considered: Nino3.4 in the Pacific and the Main Development Region in the Atlantic; these regions were chosen before any spatial distribution of skill was examined. The ENSEMBLES models are found to have skill against the climatological distribution on seasonal time-scales. For models in ENSEMBLES that have a clearly defined predecessor model in DEMETER, the improvement from DEMETER to ENSEMBLES is discussed. Due to the long lead times of the forecasts and the evolution of observation technology, the forecast-outcome archive for seasonal forecast evaluation is small; arguably, evaluation data for seasonal forecasting will always be precious. Issues of information contamination from in-sample evaluation are discussed and impacts (both positive and negative) of variations in cross-validation protocol are demonstrated. Other difficulties due to the small forecast-outcome archive are identified. The claim that the multi-model ensemble provides a 'better' probability forecast than the best single model is examined and challenged. Significant forecast information beyond the climatological distribution is also demonstrated in a persistence probability forecast. The ENSEMBLES probability forecasts add significantly more information to empirical probability forecasts on seasonal time-scales than on decadal scales. Current operational forecasts might be enhanced by melding information from both simulation models and empirical models. Simulation models based on physical principles are sometimes expected, in principle, to outperform empirical models; direct comparison of their forecast skill provides information on progress toward that goal. [ABSTRACT FROM AUTHOR]

Pattern scaling offers the promise of exploring spatial details of the climate system response to anthropogenic climate forcings without their full simulation by state-of-the-art Global Climate Models. The circumstances in which pattern scaling methods are capable of delivering on this promise are explored by quantifying its performance in an idealized setting. Given a large ensemble that is assumed to sample the full range of variability and provide quantitative decision-relevant information, the soundness of applying the pattern scaling methodology to generate decision relevant climate scenarios is explored. Pattern scaling is not expected to reproduce its target exactly, of course, and its generic limitations have been well documented since it was first proposed. In this work, using as a particular example the quantification of the risk of heat waves in Southern Europe, it is shown that the magnitude of the error in the pattern scaled estimates can be significant enough to disqualify the use of this approach in quantitative decision-support. This suggests that future application of pattern scaling in climate science should provide decision makers not just a restatement of the assumptions made, but also evidence that the methodology is adequate for purpose in practice for the case under consideration. [ABSTRACT FROM AUTHOR]

Data assimilation and state estimation for nonlinear models is a challenging task mathematically. Performing this task in real time, as in operational weather forecasting, is even more challenging as the models are imperfect: the mathematical system that generated the observations (if such a thing exists) is not a member of the available model class (i.e., the set of mathematical structures admitted as potential models). To the extent that traditional approaches address structural model error at all, most fail to produce consistent treatments. This results in questionable estimates both of the model state and of its uncertainty. A promising alternative approach is proposed to produce more consistent estimates of the model state and to estimate the (state dependent) model error simultaneously. This alternative consists of pseudo-orbit data assimilation with a stopping criterion. It is argued to be more efficient and more coherent than one alternative variational approach [a version of weak-constraint four-dimensional variational data assimilation (4DVAR)]. Results that demonstrate the pseudo-orbit data assimilation approach can also outperform an ensemble Kalman filter approach are presented. Both comparisons are made in the context of the 18-dimensional Lorenz96 flow and the two-dimensional Ikeda map. Many challenges remain outside the perfect model scenario, both in defining the goals of data assimilation and in achieving high-quality state estimation. The pseudo-orbit data assimilation approach provides a new tool for approaching this open problem. [ABSTRACT FROM AUTHOR]

State estimation lies at the heart of many meteorological tasks. Pseudo-orbit-based data assimilation provides an attractive alternative approach to data assimilation in nonlinear systems such as weather forecasting models. In the perfect model scenario, noisy observations prevent a precise estimate of the current state. In this setting, ensemble Kalman filter approaches are hampered by their foundational assumptions of dynamical linearity, while variational approaches may fail in practice owing to local minima in their cost function. The pseudo-orbit data assimilation approach improves state estimation by enhancing the balance between the information derived from the dynamic equations and that derived from the observations. The potential use of this approach for numerical weather prediction is explored in the perfect model scenario within two deterministic chaotic systems: the two-dimensional Ikeda map and 18-dimensional Lorenz96 flow. Empirical results demonstrate improved performance over that of the two most common traditional approaches of data assimilation (ensemble Kalman filter and four-dimensional variational assimilation). [ABSTRACT FROM AUTHOR]

The sensitive dependence on initial conditions (SDIC) associated with nonlinear models imposes limitations on the models' predictive power. We draw attention to an additional limitation than has been underappreciated, namely, structural model error (SME). A model has SME if the model dynamics differ from the dynamics in the target system. If a nonlinear model has only the slightest SME, then its ability to generate decision-relevant predictions is compromised. Given a perfect model, we can take the effects of SDIC into account by substituting probabilistic predictions for point predictions. This route is foreclosed in the case of SME, which puts us in a worse epistemic situation than SDIC. [ABSTRACT FROM AUTHOR]

While state-of-the-art models of Earth's climate system have improved tremendously over the last 20 years, nontrivial structural flaws still hinder their ability to forecast the decadal dynamics of the Earth system realistically. Contrasting the skill of these models not only with each other but also with empirical models can reveal the space and time scales on which simulation models exploit their physical basis effectively and quantify their ability to add information to operational forecasts. The skill of decadal probabilistic hindcasts for annual global-mean and regional-mean temperatures from the EU Ensemble-Based Predictions of Climate Changes and Their Impacts (ENSEMBLES) project is contrasted with several empirical models. Both the ENSEMBLES models and a 'dynamic climatology' empirical model show probabilistic skill above that of a static climatology for global-mean temperature. The dynamic climatology model, however, often outperforms the ENSEMBLES models. The fact that empirical models display skill similar to that of today's state-of-the-art simulation models suggests that empirical forecasts can improve decadal forecasts for climate services, just as in weather, medium-range, and seasonal forecasting. It is suggested that the direct comparison of simulation models with empirical models becomes a regular component of large model forecast evaluations. Doing so would clarify the extent to which state-of-the-art simulation models provide information beyond that available from simpler empirical models and clarify current limitations in using simulation forecasting for decision support. Ultimately, the skill of simulation models based on physical principles is expected to surpass that of empirical models in a changing climate; their direct comparison provides information on progress toward that goal, which is not available in model-model intercomparisons. [ABSTRACT FROM AUTHOR]

The United Kingdom Climate Impacts Program's UKCP09 project makes high-resolution forecasts of climate during the twenty-first century using state of the art global climate models. The aim of this article is to introduce and analyze the methodology used and then urge some caution. Given the acknowledged systematic errors in all current climate models, treating model outputs as decision-relevant probabilistic forecasts can be seriously misleading. This casts doubt on our ability, today, to make trustworthy, high-resolution predictions out to the end of this century. [ABSTRACT FROM AUTHOR]

Botulism is a severe neuroparalytic disease caused by the toxins produced from several Clostridium species. Botulinum neurotoxins (BoNTs) cause flaccid paralysis by inducing a blockade at voluntary motor and autonomic cholinergic junctions that, if not treated, can be fatal. Vaccination to elicit protective circulating antibodies that bind, neutralize and clear toxins before they can be internalized and affect cholinergic neurons remains the most effective form of protection against BoNT. A pentavalent BoNT toxoid vaccine administered in the USA under an Investigational New Drug protocol to at-risk workers was discontinued by the CDC in 2011 due to diminished potency and reactogenic effects. Subsequent research efforts have primarily focused on recombinant protein antigens. This review focuses on the development of a recombinant bivalent vaccine (rBV A/B) composed of purified recombinant BoNT/A and BoNT/B receptor-binding domain proteins, as well as presenting a summary of progress and issues associated with alternative vaccines currently being developed against botulism. [ABSTRACT FROM AUTHOR]

This paper analyses the impact of educational interventions made in the first- and second-year microeconomics courses on academic development students' final mark in the second-year course. It also addresses issues of methodology, specification, and statistical analysis with respect to other studies in the field. The results suggest that the educational interventions in the first-year had a positive impact on the academic performance of the academic development cohort, relative to the mainstream cohort for the first period (2000-2002). The results also suggest that the educational interventions introduced in the second period (2003-2005), in the form of voluntary workshops, improved the academic performance of the academic development and mainstream cohorts. [ABSTRACT FROM AUTHOR]

A targeted drug carrier (TDC) is described for transferring functional proteins or peptides into motor nerve terminals, a pivotal locus for therapeutics to treat neuromuscular disorders. It exploits the pronounced selectivity of botulinum neurotoxin type B (BoNT/B) for interacting with acceptors on these cholinergic nerve endings and becoming internalized. The gene encoding an innocuous BoNT/B protease-inactive mutant (BoTIM) was fused to that for core streptavidin, expressed in Escherichia coli and the purified protein was conjugated to surface-biotinylated liposomes. Such decorated liposomes, loaded with fluorescein as traceable cargo, acquired pronounced specificity for motor nerve terminals in isolated mouse hemidiaphragms and facilitated the intraneuronal transfer of the fluor, as revealed by confocal microscopy. Delivery of the protease light chain of botulinum neurotoxin type A (BoNT/A) via this TDC accelerated the onset of neuromuscular paralysis, indicative of improved translocation of this enzyme into the presynaptic cytosol with subsequent proteolytic inactivation of synaptosomal-associated protein of molecular mass 25 kDa (SNAP-25), an exocytotic soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) essential for neurotransmitter release. BoTIM-coupled liposomes, loaded with peptide inhibitors of proteases, yielded considerable attenuation of the neuroparalytic effects of BoNT/A or BoNT/F as a result of their cytosolic transfer, the first in situ demonstration of the ability of designer antiproteases to suppress the symptoms of botulism ex vivo. Delivery of the BoNT/A inhibitor by liposomes targeted with the full-length BoTIM proved more effective than that mediated by its C-terminal neuroacceptor-binding domain. This demonstrated versatility of TDC for nonviral cargo transfer into cholinergic nerve endings has unveiled its potential for direct delivery of functional targets into motor nerve endings. [ABSTRACT FROM AUTHOR]

Botulinum neurotoxins (BoNTs) cause the disease botulism, which can be lethal if untreated. There are seven known serotypes of BoNT, A-G, defined by their response to antisera. Many serotypes are distinguished into differing subtypes based on amino acid sequence, and many subtypes are further differentiated into toxin variants. Previous work in our laboratory described the use of a proteomics approach to distinguish subtype BoNT/A1 from BoNT/A2 where BoNT identities were confirmed after searching data against a database containing protein sequences of all known BoNT/A subtypes. We now describe here a similar approach to differentiate subtypes BoNT/B1, /B2, /B3, /B4, and /B5. Additionally, to identify new subtypes or hitherto unpublished amino acid substitutions, we created an amino acid substitution database covering every possible amino acid change. We used this database to differentiate multiple toxin variants within subtypes of BoNT/B1 and B2. More importantly, with our amino acid substitution database, we were able to identify a novel BoNT/B subtype, designated here as BoNT/B7. These techniques allow for subtype and strain level identification of both known and unknown BoNT/B rapidly with no DNA required. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

The authors discuss the development of a virtual observatory, which will serve as a manufacture to virtual observations based on model simulations. The authors say that in hydrology, virtual observatory is derived from water level measurements using a rating curve. They mention the uncertainties arising from the modeling processes such as inconsistencies and incommensurabilities. They add that a virtual observatory is a description of the real system under a study.

Deaths in the asylum could be interpreted as a sign of failure, particularly if they were related to the poor condition of those admitted, the spread of disease among patients, or the direct consequences of severe mental disorders. County asylum superintendents lamented the bad physical state in which many were sent to the asylum and the consequences for death rates. Due to limited consideration of environmental and sanitary matters before the 1830s, there was great risk of contracting fatal diseases in the asylum. Combined with the deteriorated physical condition of many patients, and the growing overcrowding, this had a notable influence on mortality. For some individual patients, death came about as a direct consequence of a profound mental disorder. Without effective treatments to confront manifestations of disordered thinking, mental symptoms might precipitate physical deterioration to the point of death, while severe distress led some to kill themselves in the asylum. [ABSTRACT FROM PUBLISHER]

Editor's Hightlight: Ricin is a highly toxic agent that could be utilized as a bioterrorism weapon. This study tested the efficacy of two different recombinant ricin subunit vaccines to protect against ricin administered via inhalation exposure. Both vaccines were found to be effective in preventing the lethal effects of ricin exposure. This study supports the potential use of ricin vaccines in human populations at risk of ricin exposure.Ricin, isolated from the castor bean plant Ricinus communis, is included on the Centers for Disease Control and Prevention Category B list of bioterrorism agents, indicating that the toxin is moderately easy to disseminate and could result in moderate morbidity rates. This study evaluated two promising recombinant ricin subunit vaccines, one made using an Escherichia coli codon–optimized gene and the other using a yeast codon–optimized gene in E. coli-based fermentations. Rabbits were vaccinated four times over a period of 6 months and challenged with ∼10 to 30 times the median lethal dose of aerosolized ricin. All unvaccinated control rabbits were either found dead or humanely euthanized within 30 h postchallenge, while the rabbits vaccinated with either vaccine survived the exposure without adverse clinical signs. When the protective antibody responses were analyzed, no significant difference was seen between the two vaccines. However, there was a significant difference in the immune response over time for both vaccines tested. Although clinical pathology was unremarkable, significant histological lesions in the control animals included fibrinonecrotic pneumonia, acute necrotizing lesions in the upper respiratory tract, and necrotizing lymphadenitis in the lymph nodes draining the upper and lower respiratory tract. Vaccine-treated rabbits exhibited resolving lesions associated with ricin exposure, namely chronic inflammation in the upper respiratory tract and lungs, fibrosis, type II pneumocyte hyperplasia, and bronchiolitis obliterans. This study confirmed the safety and efficacy of two recombinant ricin subunit vaccines in rabbits, offering potential protection to warfighters and select populations. [ABSTRACT FROM PUBLISHER]