A mammalian circadian clock model incorporating daytime expression elements

Models of the mammalian clock have traditionally been based around two feedback loops-the self-repression of Per/Cry by interfering with activation by BMAL/CLOCK, and the repression of Bmal/Clock by the REV-ERB proteins. Recent experimental evidence suggests that the D-box, a transcription factor binding site associated with daytime expression, plays a larger role in clock function than has previously been understood. We present a simplified clock model that highlights the role of the D-box and illustrate an approach for finding maximum-entropy ensembles of model parameters, given experimentally imposed constraints. Parameter variability can be mitigated using prior probability distributions derived from genome-wide studies of cellular kinetics. Our model reproduces predictions concerning the dual regulation of Cry1 by the D-box and Rev-ErbA/ROR response element (RRE) promoter elements and allows for ensemble-based predictions of phase response curves (PRCs). Nonphotic signals such as Neuropeptide Y (NPY) may act by promoting Cry1 expression, whereas photic signals likely act by stimulating expression from the E/E' box. Ensemble generation with parameter probability restraints reveals more about a model's behavior than a single optimal parameter set

A gene-by-gene population genomics platform: de novo assembly, annotation and genealogical analysis of 108 representative Neisseria meningitidis genomes

Background: Highly parallel,‘second generation’ sequencing technologies have rapidly expanded the number of bacterial whole genome sequences available for study, permitting the emergence of the discipline of population genomics. Most of these data are publically available as unassembled short-read sequence files that require extensive processing before they can be used for analysis. The provision of data in a uniform format, which can be easily assessed for quality, linked to provenance and phenotype and used for analysis, is therefore necessary. Results: The performance of de novo short-read assembly followed by automatic annotation using the pubMLST. orgNeisseriadatabase was assessed and evaluated for 108 diverse, representative, and well-characterisedNeisseria meningitidisisolates. High-quality sequences were obtained for >99% of known meningococcal genes among the de novoassembled genomes and four resequenced genomes and less than 1% of reassembled genes had sequence discrepancies or misassembled sequences. A core genome of 1600 loci, present in at least 95% of the population, was determined using the Genome Comparator tool. Genealogical relationships compatible with, but at a higher resolution than, those identified by multilocus sequence typing were obtained with core genome comparisons and ribosomal protein gene analysis which revealed a genomic structure for a number of previously described phenotypes. This unified system for cataloguing Neisseria genetic variation in the genome was implemented and used for multiple analyses and the data are publically available in the PubMLST Neisseria database. Conclusions: The de novo assembly, combined with automated gene-by-gene annotation, generates high quality draft genomes in which the majority of protein-encoding genes are present with high accuracy. The approach catalogues diversity efficiently, permits analyses of a single genome or multiple genome comparisons, and is a practical approach to interpreting WGS data for large bacterial population samples. The method generates novel insights into the biology of the meningococcus and improves our understanding of the whole population structure, not just disease causing lineages.</p

Common Carp Disrupt Ecosystem Structure and Function Through Middle-out Effects

Middle-out effects or a combination of top-down and bottom-up processes create many theoretical and empirical challenges in the realm of trophic ecology. We propose using specific autecology or species trait (i.e. behavioural) information to help explain and understand trophic dynamics that may involve complicated and nonunidirectional trophic interactions. The common carp (Cyprinus carpio) served as our model species for whole-lake observational and experimental studies; four trophic levels were measured to assess common carp-mediated middle-out effects across multiple lakes. We hypothesised that common carp could influence aquatic ecosystems through multiple pathways (i.e. abiotic and biotic foraging, early life feeding, nutrient). Both studies revealed most trophic levels were affected by common carp, highlighting strong middle-out effects likely caused by common carp foraging activities and abiotic influence (i.e. sediment resuspension). The loss of water transparency, submersed vegetation and a shift in zooplankton dynamics were the strongest effects. Trophic levels furthest from direct pathway effects were also affected (fish life history traits). The present study demonstrates that common carp can exert substantial effects on ecosystem structure and function. Species capable of middle-out effects can greatly modify communities through a variety of available pathways and are not confined to traditional top-down or bottom-up processes

Improving implementation of evidence based practice for people with psychosis through training the wider workforce: results of the GOALS feasibility randomised controlled trial

Background and objectives There is a pressing need to improve access to evidence-based practice for people with psychosis. The primary aim of this study was to assess clinical feasibility of a manualised, evidence-based CBT intervention (GOALS) targeting a personalised recovery goal, delivered by the frontline workforce, following brief training. Secondly, we aimed to conduct preliminary statistical analyses of key outcomes and costs. Methods The GOALS study is a feasibility randomised controlled trial (ISRCTN 73188383). 75 participants with current psychosis were recruited and randomly allocated to receive either treatment as usual alone or with GOALS therapy. Results Brief training enabled frontline staff to deliver the therapy according to protocol and 74% of therapy participants partially or fully achieved their goals. There were significant improvements with a moderate effect size of 0.56 on goal attainment. However, preliminary statistical analyses found no significant differences between groups on our primary outcome of activity levels or other secondary outcomes Health economic analysis found that point estimates of costs, controlling for baseline costs, implied savings (even including intervention costs), but the difference was not statistically significant. Limitations The study was designed as a feasibility RCT, and therefore the results of secondary estimates of efficacy effects should be treated with caution. Conclusions This approach holds promise in supporting people with psychosis to reach personal recovery goals, cost effectively

Improving Access to psychological therapies for people with severe mental illness (IAPT-SMI): Lessons from the South London and Maudsley psychosis demonstration site

Implementation of evidence-based cognitive behavioural therapy for psychosis (CBTp) remains low in routine services. The United Kingdom Improving Access to Psychological Therapies for people with Severe Mental Illness (IAPT-SMI) initiative aimed to address this issue. The project evaluated whether existing services could improve access to CBTp and demonstrate effectiveness using a systematic approach to therapy provision and outcome monitoring (in a similar way to the Improving Access to Psychological Therapies (IAPT) model for people with anxiety and depression). We report the clinical outcomes and key learning points from the South London and Maudsley NHS Foundation Trust IAPT-SMI demonstration site for psychosis. Additional funding enabled increased therapist capacity within existing secondary care community mental health services. Self-reported wellbeing and psychotic symptom outcomes were assessed, alongside service use and social/occupational functioning. Accepted referrals/year increased by 89% (2011/12: n = 106/year; 2012–2015: n = 200/year); 90% engaged (attended ≥5 sessions) irrespective of ethnicity, age and gender. The assessment protocol proved feasible, and pre-post outcomes (n = 280) showed clinical improvements and reduced service use, with medium effects. We conclude that, with appropriate service structure, investment allocated specifically for competent therapy provision leads to increased and effective delivery of CBTp. Our framework is replicable in other settings and can inform the wider implementation of psychological therapies for psychosis

Improving implementation of evidence based practice for people with psychosis through training the wider workforce: Results of the GOALS feasibility randomised controlled trial

BACKGROUND AND OBJECTIVES: There is a pressing need to improve access to evidence-based practice for people with psychosis. The primary aim of this study was to assess clinical feasibility of a manualised, evidence-based CBT intervention (GOALS) targeting a personalised recovery goal, delivered by the frontline workforce, following brief training. Secondly, we aimed to conduct preliminary statistical analyses of key outcomes and costs. METHODS:\ud The GOALS study is a feasibility randomised controlled trial (ISRCTN 73188383). 75 participants with current psychosis were recruited and randomly allocated to receive either treatment as usual alone or with GOALS therapy. RESULTS: Brief training enabled frontline staff to deliver the therapy according to protocol and 74% of therapy participants partially or fully achieved their goals. There were significant improvements with a moderate effect size of 0.56 on goal attainment. However, preliminary statistical analyses found no significant differences between groups on our primary outcome of activity levels or other secondary outcomes Health economic analysis found that point estimates of costs, controlling for baseline costs, implied savings (even including intervention costs), but the difference was not statistically significant. LIMITATIONS: The study was designed as a feasibility RCT, and therefore the results of secondary estimates of efficacy effects should be treated with caution. CONCLUSIONS: This approach holds promise in supporting people with psychosis to reach personal recovery goals, cost effectively

Agricultural intensification and the evolution of host specialism in the enteric pathogen Campylobacter jejuni.

Modern agriculture has dramatically changed the distribution of animal species on Earth. Changes to host ecology have a major impact on the microbiota, potentially increasing the risk of zoonotic pathogens being transmitted to humans, but the impact of intensive livestock production on host-associated bacteria has rarely been studied. Here, we use large isolate collections and comparative genomics techniques, linked to phenotype studies, to understand the timescale and genomic adaptations associated with the proliferation of the most common food-born bacterial pathogen (Campylobacter jejuni) in the most prolific agricultural mammal (cattle). Our findings reveal the emergence of cattle specialist C. jejuni lineages from a background of host generalist strains that coincided with the dramatic rise in cattle numbers in the 20th century. Cattle adaptation was associated with horizontal gene transfer and significant gene gain and loss. This may be related to differences in host diet, anatomy, and physiology, leading to the proliferation of globally disseminated cattle specialists of major public health importance. This work highlights how genomic plasticity can allow important zoonotic pathogens to exploit altered niches in the face of anthropogenic change and provides information for mitigating some of the risks posed by modern agricultural systems

A long-term study of stable isotopes as tracers of processes governing water flow and quality in a lowland river basin: the upper Thames, UK

A long-term study of O, H and C stable isotopes has been undertaken on river waters across the 7000 km2 upper Thames lowland river basin in the southern UK. During the period, flow conditions ranged from drought to flood. A 10-year monthly record (2003–2012) of the main River Thames showed a maximum variation of 3‰ (δ18O) and 20‰ (δ2H), though inter-annual average values varied little around a mean of –6.5‰ (δ18O) and –44‰ (δ2H). The δ2H/δ18O slope of 5.3 suggested a degree of evaporative enrichment, consistent with derivation from local rainfall with a weighted mean of –7.2‰ (δ18O) and –48‰ (δ2H) for the period. A tendency towards isotopic depletion of the river with increasing flowrate was noted, but at very high flows (>100 m3/s) a reversion to the mean was interpreted as the displacement of bank storage by rising groundwater levels (corroborated by measurements of specific electrical conductivity). A shorter quarterly study (October 2011 – April 2013) of isotope variations in 15 tributaries with varying geology revealed different responses to evaporation, with a high inverse correlation between Δ18O and baseflow index (BFI) for most of the rivers. A comparison with aquifer waters in the basin showed that even at low flow, rivers rarely consist solely of isotopically unmodified groundwater. Long-term monitoring (2003–2007) of carbon stable isotopes in dissolved inorganic carbon (DIC) in the Thames revealed a complex interplay between respiration, photosynthesis and evasion, but with a mean inter-annual δ13C-DIC value of –14.8 ± 0.5‰, exchange with atmospheric carbon could be ruled out. Quarterly monitoring of the tributaries (October 2011 – April 2013) indicated that in addition to the above factors, river flow variations and catchment characteristics were likely to affect δ13C-DIC. Comparison with basin groundwaters of different alkalinity and δ13C-DIC values showed that the origin of river baseflow is usually obscured. The findings show how long-term monitoring of environmental tracers can help to improve the understanding of how lowland river catchments function

Detection of theophylline utilising portable electrochemical sensors

The electrochemical oxidation of theophylline (TP) is investigated utilising screen-printed electrodes. Through thorough investigation of pH, we propose a reaction mechanism, finding that the oxidation of TP is stable over a wide pH range, in particular under acidic conditions. Conversely under alkaline conditions, theophylline fouls the electrode surface. The screen-printed carbon sensors are applied towards the electroanalytical sensing of TP with a remarkable amount of success in aqueous solution at physiological pH. The screen-printed sensors have been shown to be applicable to the detection of TP at unharmful, medicinally relevant (55–110 mM), and toxic concentrations in aqueous media at physiological pH. Thus this work presents a proof-of-concept approach towards TP detection utilising sensors commonly implemented in point-of-care applications