Quantitative differences in developmental profiles of spontaneous activity in cortical and hippocampal cultures.

BACKGROUND: Neural circuits can spontaneously generate complex spatiotemporal firing patterns during development. This spontaneous activity is thought to help guide development of the nervous system. In this study, we had two aims. First, to characterise the changes in spontaneous activity in cultures of developing networks of either hippocampal or cortical neurons dissociated from mouse. Second, to assess whether there are any functional differences in the patterns of activity in hippocampal and cortical networks. RESULTS: We used multielectrode arrays to record the development of spontaneous activity in cultured networks of either hippocampal or cortical neurons every 2 or 3 days for the first month after plating. Within a few days of culturing, networks exhibited spontaneous activity. This activity strengthened and then stabilised typically around 21 days in vitro. We quantified the activity patterns in hippocampal and cortical networks using 11 features. Three out of 11 features showed striking differences in activity between hippocampal and cortical networks: (1) interburst intervals are less variable in spike trains from hippocampal cultures; (2) hippocampal networks have higher correlations and (3) hippocampal networks generate more robust theta-bursting patterns. Machine-learning techniques confirmed that these differences in patterning are sufficient to classify recordings reliably at any given age as either hippocampal or cortical networks. CONCLUSIONS: Although cultured networks of hippocampal and cortical networks both generate spontaneous activity that changes over time, at any given time we can reliably detect differences in the activity patterns. We anticipate that this quantitative framework could have applications in many areas, including neurotoxicity testing and for characterising the phenotype of different mutant mice. All code and data relating to this report are freely available for others to use.PC and AM were supported by the Wellcome Trust Genes to Cognition programme. PC received additional support from the Biotechnology and Biological Sciences Research Council (BB/H008608/1). EC was supported by a Wellcome Trust PhD studentship and Cambridge Biomedical Research Centre studentship. SJE was supported by an Engineering and Physical Sciences Research Council grant (EP/E002331/1).This is the final published version. It first appeared at http://link.springer.com/article/10.1186%2Fs13064-014-0028-0

Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial

Aims We studied the influence of heart rate (HR), systolic blood pressure (SBP), and beta-blocker dose on outcome in the 2599 out of 3029 patients in Carvedilol Or Metoprolol European Trial (COMET) who were alive and on study drug at 4 months after randomization (time of first visit on maintenance therapy). Methods and results By multivariable analysis, baseline HR, baseline SBP, and their change after 4 months were not independently related to subsequent outcome. In a multivariable analysis including clinical variables, HR above and SBP below the median value achieved at 4 months predicted subsequent increased mortality [relative risk (RR) for HR>68 b.p.m. 1.333; 95% confidence intervals (CI) 1.152-1.542; P120 mmHg 0.78; 95% CI 0.671-0.907; P<0.0013]. Achieving target beta-blocker dose was associated with a better outcome (RR 0.779; 95% CI 0.662-0.916; P<0.0025). The superiority of carvedilol as compared to metoprolol tartrate was maintained in a multivariable model (RR 0.767; 95% CI 0.663-0.887; P=0.0004) and there was no interaction with HR, SBP, or beta-blocker dose. Conclusion Beta-blocker dose, HR, and SBP achieved during beta-blocker therapy have independent prognostic value in heart failure. None of these factors influenced the beneficial effects of carvedilol when compared with metoprolol tartrate at the pre-defined target doses used in COME

Infiltration efficiency and subsurface water processes of a sustainable drainage system and consequences to flood management

With increased intensity rainfall events globally and urban expansion decreasing permeable surfaces, there is an increasing problem of urban flooding. This study aims to better understand rainfall infiltration into a Sustainable Drainage System (SuDS) permeable pavement, compared with an adjacent Green Area of made ground, in relationship to groundwater levels below both areas. Both areas were instrumented with soil water content and matric potential sensors and four shallow boreholes were instrumented with groundwater level sensors. Surface infiltration rates were measured using a double‐ring infiltrometer. Results showed that average infiltration rates of the SuDS (1,925 mm/hr) were significantly higher than the Green Area (56 mm/hr). The SuDS was well designed to transfer rainfall rapidly to the aquifer below, where groundwater levels rapidly rose within 1 hr of a 1 in 30 year event (32.8 mm/hr). In comparison, soil compaction of the made ground Green Area decreased infiltration rates, but still enabled the majority of rainfall events to infiltrate. The aquifer below the Green Area responded more slowly, as lower matrix potentials facilitated water retention in the soil profile, slowing water draining to the aquifer. This work reiterates the importance of ensuring a 1 m separation depth between the base of the SuDS infiltration zone and aquifer depth

Daisyworld: a review

Daisyworld is a simple planetary model designed to show the long-term effects of coupling between life and its environment. Its original form was introduced by James Lovelock as a defense against criticism that his Gaia theory of the Earth as a self-regulating homeostatic system requires teleological control rather than being an emergent property. The central premise, that living organisms can have major effects on the climate system, is no longer controversial. The Daisyworld model has attracted considerable interest from the scientific community and has now established itself as a model independent of, but still related to, the Gaia theory. Used widely as both a teaching tool and as a basis for more complex studies of feedback systems, it has also become an important paradigm for the understanding of the role of biotic components when modeling the Earth system. This paper collects the accumulated knowledge from the study of Daisyworld and provides the reader with a concise account of its important properties. We emphasize the increasing amount of exact analytic work on Daisyworld and are able to bring together and summarize these results from different systems for the first time. We conclude by suggesting what a more general model of life-environment interaction should be based on

Population Genomic Inferences from Sparse High-Throughput Sequencing of Two Populations of Drosophila melanogaster

Short-read sequencing techniques provide the opportunity to capture genome-wide sequence data in a single experiment. A current challenge is to identify questions that shallow-depth genomic data can address successfully and to develop corresponding analytical methods that are statistically sound. Here, we apply the Roche/454 platform to survey natural variation in strains of Drosophila melanogaster from an African (n = 3) and a North American (n = 6) population. Reads were aligned to the reference D. melanogaster genomic assembly, single nucleotide polymorphisms were identified, and nucleotide variation was quantified genome wide. Simulations and empirical results suggest that nucleotide diversity can be accurately estimated from sparse data with as little as 0.2× coverage per line. The unbiased genomic sampling provided by random short-read sequencing also allows insight into distributions of transposable elements and copy number polymorphisms found within populations and demonstrates that short-read sequencing methods provide an efficient means to quantify variation in genome organization and content. Continued development of methods for statistical inference of shallow-depth genome-wide sequencing data will allow such sparse, partial data sets to become the norm in the emerging field of population genomics

Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes

The human X and Y chromosomes evolved from an ordinary pair of autosomes during the past 200–300 million years[superscript 1, 2, 3]. The human MSY (male-specific region of Y chromosome) retains only three percent of the ancestral autosomes’ genes owing to genetic decay[superscript 4, 5]. This evolutionary decay was driven by a series of five ‘stratification’ events. Each event suppressed X–Y crossing over within a chromosome segment or ‘stratum’, incorporated that segment into the MSY and subjected its genes to the erosive forces that attend the absence of crossing over[superscript 2, 6]. The last of these events occurred 30 million years ago, 5 million years before the human and Old World monkey lineages diverged. Although speculation abounds regarding ongoing decay and looming extinction of the human Y chromosome[superscript 7, 8, 9, 10], remarkably little is known about how many MSY genes were lost in the human lineage in the 25 million years that have followed its separation from the Old World monkey lineage. To investigate this question, we sequenced the MSY of the rhesus macaque, an Old World monkey, and compared it to the human MSY. We discovered that during the last 25 million years MSY gene loss in the human lineage was limited to the youngest stratum (stratum 5), which comprises three percent of the human MSY. In the older strata, which collectively comprise the bulk of the human MSY, gene loss evidently ceased more than 25 million years ago. Likewise, the rhesus MSY has not lost any older genes (from strata 1–4) during the past 25 million years, despite its major structural differences to the human MSY. The rhesus MSY is simpler, with few amplified gene families or palindromes that might enable intrachromosomal recombination and repair. We present an empirical reconstruction of human MSY evolution in which each stratum transitioned from rapid, exponential loss of ancestral genes to strict conservation through purifying selection

Privacy Impact Assessments: International Experience as a Basis for UK Guidance

This article was subsequently published in the journal Computer Law & Security Report [Elsevier / © The authors]. The definitive version is available at: http://www.sciencedirect.com/science/journal/02673649. Whilst this paper was submitted in response to referee comments, it may not exactly match the final published versions.In July 2007, the UK Information Commissioner’s Office commissioned a team of researchers, coordinated by Loughborough University, to conduct a study into Privacy Impact Assessments (PIAs). This was with a view to developing PIA guidance for the UK. The project resulted in two key deliverables: a study of the use of PIAs in other jurisdictions, identifying lessons to be learnt for the UK; and a handbook that can be used to guide organisations through the PIA process, taking into account the provisions of the UK Data Protection Act (DPA) 1998. This paper draws on the original research undertaken as part of that assignment to provide an overview of the ICO-funded project and the extent to which PIAs can be used in the current UK context. Firstly, the authors consider the findings of the comparative study and how the UK experience can be informed by developments overseas. Secondly, the paper outlines the development of the handbook during the course of the project and the extent to which it has been influenced by the overseas experience and the current UK political context. Thirdly, aspects of the handbook itself are considered and explained. Particular attention is paid to: its format; its key features; and feedback received on an interim version from a focus group of experienced data protection and project management practitioners. Finally, the paper concludes by stating why the study and the handbook provide appropriate tools for guidance in the current UK context, and how they can be developed further

Genome-wide fine-scale recombination rate variation in Drosophila melanogaster

Estimating fine-scale recombination maps of Drosophila from population genomic data is a challenging problem, in particular because of the high background recombination rate. In this paper, a new computational method is developed to address this challenge. Through an extensive simulation study, it is demonstrated that the method allows more accurate inference, and exhibits greater robustness to the effects of natural selection and noise, compared to a well-used previous method developed for studying fine-scale recombination rate variation in the human genome. As an application, a genome-wide analysis of genetic variation data is performed for two Drosophila melanogaster populations, one from North America (Raleigh, USA) and the other from Africa (Gikongoro, Rwanda). It is shown that fine-scale recombination rate variation is widespread throughout the D. melanogaster genome, across all chromosomes and in both populations. At the fine-scale, a conservative, systematic search for evidence of recombination hotspots suggests the existence of a handful of putative hotspots each with at least a tenfold increase in intensity over the background rate. A wavelet analysis is carried out to compare the estimated recombination maps in the two populations and to quantify the extent to which recombination rates are conserved. In general, similarity is observed at very broad scales, but substantial differences are seen at fine scales. The average recombination rate of the X chromosome appears to be higher than that of the autosomes in both populations, and this pattern is much more pronounced in the African population than the North American population. The correlation between various genomic features—including recombination rates, diversity, divergence, GC content, gene content, and sequence quality—is examined using the wavelet analysis, and it is shown that the most notable difference between D. melanogaster and humans is in the correlation between recombination and diversity

Rapid Evolution of Enormous, Multichromosomal Genomes in Flowering Plant Mitochondria with Exceptionally High Mutation Rates

A pair of species within the genus Silene have evolved the largest known mitochondrial genomes, coinciding with extreme changes in mutation rate, recombination activity, and genome structure