Biochemical properties of Paracoccus denitrificans FnrP:Reactions with molecular oxygen and nitric oxide

In Paracoccus denitrificans, three CRP/FNR family regulatory proteins, NarR, NnrR and FnrP, control the switch between aerobic and anaerobic (denitrification) respiration. FnrP is a [4Fe-4S] cluster containing homologue of the archetypal O2 sensor FNR from E. coli and accordingly regulates genes encoding aerobic and anaerobic respiratory enzymes in response to O2, and also NO, availability. Here we show that FnrP undergoes O2-driven [4Fe-4S] to [2Fe-2S] cluster conversion that involves up to 2 O2 per cluster, with significant oxidation of released cluster sulfide to sulfane observed at higher O2 concentrations. The rate of the cluster reaction was found to be ~6-fold lower than that of E. coli FNR, suggesting that FnrP can remain transcriptionally active under microaerobic conditions. This is consistent with a role for FnrP in activating expression of the high O2 affinity cytochrome c oxidase under microaerobic conditions. Cluster conversion resulted in dissociation of the transcriptionally active FnrP dimer into monomers. Therefore, along with E. coli FNR, FnrP belongs to the subset of FNR proteins in which cluster type is correlated with association state. Interestingly, two key charged residues, Arg140 and Asp154, that have been shown to play key roles in the monomer-dimer equilibrium in E. coli FNR are not conserved in FnrP, indicating that different protomer interactions are important for this equilibrium. Finally, the FnrP [4Fe-4S] cluster is shown to undergo reaction with multiple NO molecules, resulting in iron nitrosyl species and dissociation into monomers

Teaching, research or balanced? An exploration of the experiences of biomedical scientists working in UK medical schools

Driven by demand for high standards in university education, efforts have been made in the UK to address the perceived imbalance between teaching and research. However, teaching is still perceived by many as having less credibility and is attributed less importance. The purpose of our research was to explore how distinct types of academic job profiles (‘research’ or ‘education’ focused, or ‘balanced’) impact on biomedical scientists' perceptions of the lecturer role. Specifically, we investigated the experiences of biomedical scientists in ‘post-1990’ medical schools, which are known for their commitment to excellence in both research and education. We conducted 22 face-to-face, semi-structured interviews with biomedical scientists in five schools. Focusing on experiences of work, the interviews covered: ‘motivations’, ‘role expectations’, ‘teaching’, ‘research’ and ‘career’. The recorded qualitative data were transcribed and then analysed thematically. Our results, offering an insight into the working lives of biomedical scientists in medical education, suggest that in settings with a dual emphasis on education and research, individuals on ‘balanced’ contracts can experience a strong pull between research and teaching. In addition to posing significant challenges with respect to workload management, this can impact profoundly on professional identity. In contrast to the balanced role, ‘research’ or ‘education’ focused roles appear to have clearer requirements, leading to higher employee satisfaction. We conclude that to assist the educational mission of Higher Education, attention should be paid to balanced contracts, to (a) ensure employee support, (b) mitigate against negative perceptions of teaching, and ultimately, (c) guard against staff attrition

Quantitative analysis of regulatory flexibility under changing environmental conditions

The circadian clock controls 24-h rhythms in many biological processes, allowing appropriate timing of biological rhythms relative to dawn and dusk. Known clock circuits include multiple, interlocked feedback loops. Theory suggested that multiple loops contribute the flexibility for molecular rhythms to track multiple phases of the external cycle. Clear dawn- and dusk-tracking rhythms illustrate the flexibility of timing in Ipomoea nil. Molecular clock components in Arabidopsis thaliana showed complex, photoperiod-dependent regulation, which was analysed by comparison with three contrasting models. A simple, quantitative measure, Dusk Sensitivity, was introduced to compare the behaviour of clock models with varying loop complexity. Evening-expressed clock genes showed photoperiod-dependent dusk sensitivity, as predicted by the three-loop model, whereas the one- and two-loop models tracked dawn and dusk, respectively. Output genes for starch degradation achieved dusk-tracking expression through light regulation, rather than a dusk-tracking rhythm. Model analysis predicted which biochemical processes could be manipulated to extend dusk tracking. Our results reveal how an operating principle of biological regulators applies specifically to the plant circadian clock

Spontaneous Stratification in Granular Mixtures

Granular materials size segregate when exposed to external periodic perturbations such as vibrations. Moreover, mixtures of grains of different sizes spontaneously segregate in the absence of external perturbations: when a mixture is simply poured onto a pile, the large grains are more likely to be found near the base, while the small grains are more likely to be near the top. Here, we report a spontaneous phenomenon arising when we pour a mixture between two vertical plates: the mixture spontaneously stratifies into alternating layers of small and large grains whenever the large grains are rougher than the small grains. In contrast, we find only spontaneous segregation when the large grains are more rounded than the small grains. The stratification is related to the occurrence of avalanches; during each avalanche the grains comprising the avalanche spontaneously stratify into a pair of layers through a "kink" mechanism, with the small grains forming a sublayer underneath the layer of large grains.Comment: 4 pages, 6 figures, http://polymer.bu.edu/~hmakse/Home.htm

A Genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology

We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of "amyloid" transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and "TAU" transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org

The Debrisoft ® monofilament debridement pad for use in acute or chronic wounds: A NICE medical technology guidance

As part of its Medical Technology Evaluation Programme, the National Institute for Health and Care Excellence (NICE) invited a manufacturer to provide clinical and economic evidence for the evaluation of the Debrisoft ® monofilament debridement pad for use in acute or chronic wounds. The University of Birmingham and Brunel University, acting as a consortium, was commissioned to act as an External Assessment Centre (EAC) for NICE, independently appraising the submission. This article is an overview of the original evidence submitted, the EAC’s findings and the final NICE guidance issued. The sponsor submitted a simple cost analysis to estimate the costs of using Debrisoft® to debride wounds compared with saline and gauze, hydrogel and larvae. Separate analyses were conducted for applications in home and applications in a clinic setting. The analysis took an UK National Health Service (NHS) perspective. It incorporated the costs of the technologies and supplementary technologies (such as dressings) and the costs of their application by a district nurse. The sponsor concluded that Debrisoft® was cost saving relative to the comparators. The EAC made amendments to the sponsor analysis to correct for errors and to reflect alternative assumptions. Debrisoft® remained cost saving in most analyses and savings ranged from £77 to £222 per patient compared with hydrogel, from £97 to £347 compared with saline and gauze, and from £180 to £484 compared with larvae depending on the assumptions included in the analysis and whether debridement took place in a home or clinic setting. All analyses were severely limited by the available data on effectiveness, in particular a lack of comparative studies and that the effectiveness data for the comparators came from studies reporting different clinical endpoints compared with Debrisoft®. The Medical Technologies Advisory Committee made a positive recommendation for adoption of Debrisoft® and this has been published as a NICE medical technology guidance (MTG17).The Birmingham and Brunel Consortium is funded by NICE to act as an External Assessment Centre for the Medical Technologies Evaluation Programme

Precalibrating an intermediate complexity climate model

Credible climate predictions require a rational quantification of uncertainty, but full Bayesian calibration requires detailed estimates of prior probability distributions and covariances, which are difficult to obtain in practice. We describe a simplified procedure, termed precalibration, which provides an approximate quantification of uncertainty in climate prediction, and requires only that uncontroversially implausible values of certain inputs and outputs are identified. The method is applied to intermediate-complexity model simulations of the Atlantic meridional overturning circulation (AMOC) and confirms the existence of a cliff-edge catastrophe in freshwaterforcing input space. When uncertainty in 14 further parameters is taken into account, an implausible, AMOC-off, region remains as a robust feature of the model dynamics, but its location is found to depend strongly on values of the other parameters

The migratory pathways of the cells that form the endocardium, dorsal aortae, and head vasculature in the mouse embryo

BACKGROUND: Vasculogenesis in amniotes is often viewed as two spatially and temporally distinct processes, occurring in the yolk sac and in the embryo. However, the spatial origins of the cells that form the primary intra-embryonic vasculature remain uncertain. In particular, do they obtain their haemato-endothelial cell fate in situ, or do they migrate from elsewhere? Recently developed imaging techniques, together with new Tal1 and existing Flk1 reporter mouse lines, have allowed us to investigate this question directly, by visualising cell trajectories live and in three dimensions. RESULTS: We describe the pathways that cells follow to form the primary embryonic circulatory system in the mouse embryo. In particular, we show that Tal1-positive cells migrate from within the yolk sac, at its distal border, to contribute to the endocardium, dorsal aortae and head vasculature. Other Tal1 positive cells, similarly activated within the yolk sac, contribute to the yolk sac vasculature. Using single-cell transcriptomics and our imaging, we identify VEGF and Apela as potential chemo-attractants that may regulate the migration into the embryo. The dorsal aortae and head vasculature are known sites of secondary haematopoiesis; given the common origins that we observe, we investigate whether this is also the case for the endocardium. We discover cells budding from the wall of the endocardium with high Tal1 expression and diminished Flk1 expression, indicative of an endothelial to haematopoietic transition. CONCLUSIONS: In contrast to the view that the yolk sac and embryonic circulatory systems form by two separate processes, our results indicate that Tal1-positive cells from the yolk sac contribute to both vascular systems. It may be that initial Tal1 activation in these cells is through a common mechanism

Peripheral trauma and risk of dystonia: What are the evidences and potential co-risk factors from a population insurance database?

BACKGROUND: Dystonia is a neurological syndrome typically resulting in abnormal postures. OBJECTIVES: We tested the role of physical injury as potential risk factor for development of dystonia using The National Health Insurance Research Database of Taiwan. METHODS: We identified 65704 people who were coded in the database as having had peripheral traumatic injuries (ICD-9-CM 807-848 and 860-959) in the year 2000. Patients with traumatic brain or spine injuries were excluded from analysis. We matched them using purposive sampling with 65704 people in the database who had not suffered peripheral trauma. We looked then at the incidence of dystonia occurring at least 1 year from the date of the peripheral trauma until 2011. Psychiatric symptoms (depression and anxiety) and sleeps difficulties have been investigated as potential covariates. RESULTS: We found 189 patients with dystonia (0.28%) in the trauma group, and 52 patients with dystonia (0.08%) in the non-trauma group. Trauma was independently associated with dystonia (adjusted HR = 3.12, 95% CI = 2.30-4.24). The incidence density of dystonia in the trauma group was 2.27 per 10000 person-years, while it was 0.71 per 10000 person-years in the non-trauma group Beyond the peripheral trauma, other variables associated to the incidence of dystonia included female sex, aged 40 years and above, depression and sleep disorders. CONCLUSION: These data from a large population dataset support traumatic injury as a risk factor for the development of dystonia