Muscarinic receptor-dependent long term depression in the perirhinal cortex and recognition memory are impaired in the rTg4510 mouse model of tauopathy.

This is the final version of the article. Available from the publisher via the DOI in this record.Neurodegenerative diseases affecting cognitive dysfunction, such as Alzheimer's disease and fronto-temporal dementia, are often associated impairments in the visual recognition memory system. Recent evidence suggests that synaptic plasticity, in particular long term depression (LTD), in the perirhinal cortex (PRh) is a critical cellular mechanism underlying recognition memory. In this study, we have examined novel object recognition and PRh LTD in rTg4510 mice, which transgenically overexpress tauP301L. We found that 8-9 month old rTg4510 mice had significant deficits in long- but not short-term novel object recognition memory. Furthermore, we also established that PRh slices prepared from rTg4510 mice, unlike those prepared from wildtype littermates, could not support a muscarinic acetylcholine receptor-dependent form of LTD, induced by a 5 Hz stimulation protocol. In contrast, bath application of the muscarinic agonist carbachol induced a form of chemical LTD in both WT and rTg4510 slices. Finally, when rTg4510 slices were preincubated with the acetylcholinesterase inhibitor donepezil, the 5 Hz stimulation protocol was capable of inducing significant levels of LTD. These data suggest that dysfunctional cholinergic innervation of the PRh of rTg4510 mice, results in deficits in synaptic LTD which may contribute to aberrant recognition memory in this rodent model of tauopathy.SES was supported by a Medical Research Council studentship. JTB was an Alzheimer’s Research UK Senior Research Fellow. Eli Lilly & Co supplied the rTg4510 mice

Computational modelling and analysis of the molecular network regulating sporulation initiation in Bacillus subtilis

BACKGROUND: Bacterial spores are important contaminants in food, and the spore forming bacteria are often implicated in food safety and food quality considerations. Spore formation is a complex developmental process involving the expression of more than 500 genes over the course of 6 to 8 hrs. The process culminates in the formation of resting cells capable of resisting environmental extremes and remaining dormant for long periods of time, germinating when conditions promote further vegetative growth. Experimental observations of sporulation and germination are problematic and time consuming so that reliable models are an invaluable asset in terms of prediction and risk assessment. In this report we develop a model which assists in the interpretation of sporulation dynamics. RESULTS: This paper defines and analyses a mathematical model for the network regulating Bacillus subtilis sporulation initiation, from sensing of sporulation signals down to the activation of the early genes under control of the master regulator Spo0A. Our model summarises and extends other published modelling studies, by allowing the user to execute sporulation initiation in a scenario where Isopropyl β-D-1-thiogalactopyranoside (IPTG) is used as an artificial sporulation initiator as well as in modelling the induction of sporulation in wild-type cells. The analysis of the model results and the comparison with experimental data indicate that the model is good at predicting inducible responses to sporulation signals. However, the model is unable to reproduce experimentally observed accumulation of phosphorelay sporulation proteins in wild type B. subtilis. This model also highlights that the phosphorelay sub-component, which relays the signals detected by the sensor kinases to the master regulator Spo0A, is crucial in determining the response dynamics of the system. CONCLUSION: We show that there is a complex connectivity between the phosphorelay features and the master regulatory Spo0A. Additional we discovered that the experimentally observed regulation of the phosphotransferase Spo0B for wild-type B. subtilis may be playing an important role in the network which suggests that modelling of sporulation initiation may require additional experimental support. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-014-0119-x) contains supplementary material, which is available to authorized users

Forty years studying British politics : the decline of Anglo-America

The still present belief some 40 years ago that British politics was both exceptional and superior has been replaced by more theoretically sophisticated analyses based on a wider and more rigorously deployed range of research techniques, although historical analysis appropriately remains important. The American influence on the study of British politics has declined, but the European Union dimension has not been fully integrated. The study of interest groups has been in some respects a fading paradigm, but important questions related to democratic health have still to be addressed. Public administration has been supplanted by public policy, but economic policy remains under-studied. A key challenge for the future is the study of the management of expectations

Salinity dependence of parasite infestation in the European eel Anguilla anguilla in northern Germany

The aim of the study was to examine metazoan parasite communities of European eels (Anguilla anguilla) in fresh-water, brackish water and marine localities in northern Germany. In all, 29 parasite species/taxa were found in 170 eels: eight digeneans, one monogenean, five cestodes, ten nematodes, two acanthocephalans, and three crustaceans. Measures of diversity characteristics of the helminth communities included species richness, Shannon's diversity index and its evenness, and the Berger–Parker dominance index. The highest species diversity and lowest dominance values were calculated for the helminth communities of eels from the two Baltic Sea localities. Parasite communities of European eels clearly exhibit the habitat preferences of their hosts, salinity-dependent specificities, and a clustering into fresh-water, brackish, and marine groups. The highly pathogenic parasite species Anguillicola crassus and Pseudodactylogyrus spp. were found at all sampling sites in fresh water and brackish water, with high prevalence. Basic information is provided on the risks of restocking programmes solely focusing on fresh-water sites

Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols

The chirality, or ‘handedness’, of a biologically active molecule can alter its physiological properties. Thus it is routine procedure in the drug discovery and development process to prepare and fully characterize all possible stereoisomers of a drug candidate for biological evaluation. Despite many advances in asymmetric synthesis, developing general and practical strategies for obtaining all possible stereoisomers of an organic compound that has multiple contiguous stereocentres remains a challenge3. Here, we report a stereodivergent copper-based approach for the expeditious construction of amino alcohols with high levels of chemo-, regio-, diastereo- and enantioselectivity. Specifically, we synthesized these amino-alcohol products using sequential, copper-hydride-catalysed hydrosilylation and hydroamination of readily available enals and enones. This strategy provides a route to all possible stereoisomers of the amino-alcohol products, which contain up to three contiguous stereocentres. We leveraged catalyst control and stereospecificity simultaneously to attain exceptional control of the product stereochemistry. Beyond the immediate utility of this protocol, our strategy could inspire the development of methods that provide complete sets of stereoisomers for other valuable synthetic targets.National Institutes of Health (U.S.) (Grant GM-58160

Climate Change, Foodborne Pathogens, and Illness in Higher Income Countries

Purpose of review: We present a review of the likely consequences of climate change for foodborne pathogens and associated human illness in higher income countries. Recent findings: The relationships between climate and food are complex and hence the impacts of climate change uncertain. This makes it difficult to know which foodborne pathogens will be most affected, what the specific effects will be, and on what timescales changes might occur. Hence, a focus upon current capacity and adaptation potential against foodborne pathogens is essential. We highlight a number of developments that may enhance preparedness for climate change. These include: • Adoption of novel surveillance methods, such as syndromic methods, to speed up detection and increase the fidelity of intervention in foodborne outbreaks • Genotype based approaches to surveillance of food pathogens to enhance spatio-temporal resolution in tracing and tracking of illness • Ever increasing integration of plant, animal and human surveillance systems, one-health, to maximize potential for identifying threats • Increased commitment to cross-border (global) information initiatives (including big data) • Improved clarity regarding the governance of complex societal issues such as the conflict between food safety and food waste • Strong user centric (social) communications strategies to engage diverse stakeholder groups Summary: The impact of climate change upon foodborne pathogens and associated illness is uncertain. This emphasises the need to enhance current capacity and adaptation potential against foodborne illness. A range of developments are explored in this paper to enhance preparedness

A genetic algorithm-Bayesian network approach for the analysis of metabolomics and spectroscopic data: application to the rapid detection of Bacillus spores and identification of Bacillus species

Background The rapid identification of Bacillus spores and bacterial identification are paramount because of their implications in food poisoning, pathogenesis and their use as potential biowarfare agents. Many automated analytical techniques such as Curie-point pyrolysis mass spectrometry (Py-MS) have been used to identify bacterial spores giving use to large amounts of analytical data. This high number of features makes interpretation of the data extremely difficult We analysed Py-MS data from 36 different strains of aerobic endospore-forming bacteria encompassing seven different species. These bacteria were grown axenically on nutrient agar and vegetative biomass and spores were analyzed by Curie-point Py-MS. Results We develop a novel genetic algorithm-Bayesian network algorithm that accurately identifies sand selects a small subset of key relevant mass spectra (biomarkers) to be further analysed. Once identified, this subset of relevant biomarkers was then used to identify Bacillus spores successfully and to identify Bacillus species via a Bayesian network model specifically built for this reduced set of features. Conclusions This final compact Bayesian network classification model is parsimonious, computationally fast to run and its graphical visualization allows easy interpretation of the probabilistic relationships among selected biomarkers. In addition, we compare the features selected by the genetic algorithm-Bayesian network approach with the features selected by partial least squares-discriminant analysis (PLS-DA). The classification accuracy results show that the set of features selected by the GA-BN is far superior to PLS-DA

Differential sensitivity of Src-family kinases to activation by SH3 domain displacement

Src-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12) to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo. © 2014 Moroco et al

Optogenetic Stimulation of Prefrontal Glutamatergic Neurons Enhances Recognition Memory

Finding effective cognitive enhancers is a major health challenge; however, modulating glutamatergic neurotransmission has the potential to enhance performance in recognition memory tasks. Previous studies using glutamate receptor antagonists have revealed that the medial prefrontal cortex (mPFC) plays a central role in associative recognition memory. The present study investigates short-term recognition memory using optogenetics to target glutamatergic neurons within the rodent mPFC specifically. Selective stimulation of glutamatergic neurons during the online maintenance of information enhanced associative recognition memory in normal animals. This cognitive enhancing effect was replicated by local infusions of the AMPAkine CX516, but not CX546, which differ in their effects on EPSPs. This suggests that enhancing the amplitude, but not the duration, of excitatory synaptic currents improves memory performance. Increasing glutamate release through infusions of the mGluR7 presynaptic receptor antagonist MMPIP had no effect on performance. SIGNIFICANCE STATEMENT These results provide new mechanistic information that could guide the targeting of future cognitive enhancers. Our work suggests that improved associative-recognition memory can be achieved by enhancing endogenous glutamatergic neuronal activity selectively using an optogenetic approach. We build on these observations to recapitulate this effect using drug treatments that enhance the amplitude of EPSPs; however, drugs that alter the duration of the EPSP or increase glutamate release lack efficacy. This suggests that both neural and temporal specificity are needed to achieve cognitive enhancement

A systematic quality assessment of Environmental Impact Statements in the oil and gas industry

The global economy relies heavily on oil and gas resources. However, hydrocarbon exploitation projects can cause significant impacts on the environment. But despite the production of numerous Environmental Impact Statements (EISs) to identify/mitigate such impacts, no study has specifically assessed the quality of EISs for both onshore and offshore oil and gas projects, with tested hypotheses. To address this research gap, our paper, for the first time, develops a modified Lee and Colley evaluation model to assess the quality of 19 sampled oil and gas project EISs produced from 1998 to 2008 in Nigeria. Our findings show that Project Description and Communication of Results are the main areas of strength. However, Environmental Impact Prediction, and Project Decommissioning, were among the key areas requiring attention. A key finding, though, is that Mann-Whitney tests suggest that there is no evidence that the quality of EISs for the latter period (2004–2008) is higher than that of the earlier period (1998–2004). We suggest that periodic systematic review of the quality of submitted/approved EISs (c. every 3–5 years) should be established to monitor trends in EIS quality and identify strong and weak areas. This would help to drive continual improvement in both the EIA processes and the resultant EISs of technical engineering projects. Such reviews have the potential to illuminate some of the underlying problems of, and solutions to, oil and gas exploration, production and transportation, and their related environmental impacts. This suggested change would also be useful internationally, including for the burgeoning exploration and production of unconventional hydrocarbon resources.Publisher Statement: NOTICE: this is the author’s version of a work that was accepted for publication in Science of The Total Environment. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Science of The Total Environment, [572, (2016)] DOI: 10.1016/j.scitotenv.2016.07.083© 2016, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0