Lambda-prophage induction modeled as a cooperative failure mode of lytic repression

We analyze a system-level model for lytic repression of lambda-phage in E. coli using reliability theory, showing that the repressor circuit comprises 4 redundant components whose failure mode is prophage induction. Our model reflects the specific biochemical mechanisms involved in regulation, including long-range cooperative binding, and its detailed predictions for prophage induction in E. coli under ultra-violet radiation are in good agreement with experimental data.Comment: added referenc

Systematic Variation of Ligand and Cation Parameters Enables Site-Selective C-C and C-N Cross-Coupling of Multiply Chlorinated Arenes through Substrate-Ligand Electrostatic Interactions.

Use of attractive noncovalent interactions between ligand and substrate is an emerging strategy for controlling positional selectivity. A key question relates to whether fine control on molecules with multiple, closely spaced reactive positions is achievable using typically less directional electrostatic interactions. Herein, we apply a 10-piece "toolkit" comprising of two closely related sulfonated phosphine ligands and five bases, each possessing varying cation size, to the challenge of site-selective cross-coupling of multiply chlorinated arenes. The fine tuning provided by these ligand/base combinations is effective for Suzuki-Miyaura coupling and Buchwald-Hartwig coupling on a range of isomeric dichlorinated and trichlorinated arenes, substrates that would produce intractable mixtures when typical ligands are used. This study develops a practical solution for site-selective cross-coupling to generate complex, highly substituted arenes

Smaller Cortisol Awakening Responses Are Associated with Greater Visual Dependence in Postural Control

There are known links between the hypothalamic–pituitary–adrenal (HPA) axis and systems responsible for regulating posture. Our aim was to explore directly, for the first time, whether an aspect of circadian HPA axis activity (the cortisol awakening response: CAR) was associated with greater visual dependency in postural control. For measurement of the CAR, electronically monitored saliva samples were collected by participants following morning awakening in their home environment. On the afternoons of the same days, postural sway was measured in the laboratory by exposing participants to static (control) and moving visual stimuli whilst standing still and upright on a force platform. Visual dependence was assessed as the increase in postural sway (path length) during exposure to the moving compared with the static condition. The 44 measurement days were derived from four days for each of eleven healthy participants (mean ± SD age: 51.18 ± 3.3 years). As expected, postural sway was greater when exposed to moving versus static cues. Mixed regression modelling showed that participants with smaller four day average CARs had greater deterioration in postural sway when presented with moving stimuli. These data are the first to document associations between the CAR and visual dependency in postural sway

Cohort profile: the avon longitudinal study of parents and children: ALSPAC mothers cohort

The Avon Longitudinal Study of Children and Parents (ALSPAC) was established to understand how genetic and environmental characteristics influence health and development in parents and children. All pregnant women resident in a defined area in the South West of England, with an expected date of delivery between 1st April 1991 and 31st December 1992, were eligible and 13 761 women (contributing 13 867 pregnancies) were recruited. These women have been followed over the last 19–22 years and have completed up to 20 questionnaires, have had detailed data abstracted from their medical records and have information on any cancer diagnoses and deaths through record linkage. A follow-up assessment was completed 17–18 years postnatal at which anthropometry, blood pressure, fat, lean and bone mass and carotid intima media thickness were assessed, and a fasting blood sample taken. The second follow-up clinic, which additionally measures cognitive function, physical capability, physical activity (with accelerometer) and wrist bone architecture, is underway and two further assessments with similar measurements will take place over the next 5 years. There is a detailed biobank that includes DNA, with genome-wide data available on >10 000, stored serum and plasma taken repeatedly since pregnancy and other samples; a wide range of data on completed biospecimen assays are available. Details of how to access these data are provided in this cohort profile

Scaling and crossovers in activated escape near a bifurcation point

Near a bifurcation point a system experiences critical slowing down. This leads to scaling behavior of fluctuations. We find that a periodically driven system may display three scaling regimes and scaling crossovers near a saddle-node bifurcation where a metastable state disappears. The rate of activated escape $W$ scales with the driving field amplitude $A$ as $\ln W \propto (A_c-A)^{\xi}$, where $A_c$ is the bifurcational value of $A$. With increasing field frequency the critical exponent $\xi$ changes from $\xi = 3/2$ for stationary systems to a dynamical value $\xi=2$ and then again to $\xi=3/2$. The analytical results are in agreement with the results of asymptotic calculations in the scaling region. Numerical calculations and simulations for a model system support the theory.Comment: 18 page

Living apart, losing sympathy? How neighbourhood context affects attitudes to redistribution and to welfare recipients

Rising levels of income inequality have been directly linked to rising levels of spatial segregation. In this paper, we explore whether rising segregation may in turn erode support for the redistributive policies of the welfare state, further increasing levels of inequality – a form of positive feedback. The role of the neighbourhood has been neglected in attitudes research but, building on both political geography and ‘neighbourhood effects’ literatures, we theorise that neighbourhood context may shape attitudes through the transmission of attitudes directly and through the accumulation of relevant knowledge. We test this through multilevel modelling of data from England on individual attitudes to redistribution in general and to welfare benefit recipients in particular. We show that the individual factors shaping these attitudes are quite different and that the influence of neighbourhood context also varies as a result. The findings support the idea that neighbourhood context shapes attitudes, with the knowledge accumulation mechanism likely to be the more important. Rising spatial segregation would appear to erode support for redistribution but to increase support for welfare recipients – at least in a context where the dominant media discourse presents such a stigmatising image of those on welfare benefits

Dynamics of a tunneling magnetic impurity: Kondo effect induced incoherence

We study how the formation of the Kondo compensation cloud influences the dynamical properties of a magnetic impurity that tunnels between two positions in a metal. The Kondo effect dynamically generates a strong tunneling impurity-conduction electron coupling, changes the temperature dependence of the tunneling rate, and may ultimately result in the destruction of the coherent motion of the particle at zero temperature. We find an interesting two-channel Kondo fixed point as well for a vanishing overlap between the electronic states that screen the magnetic impurity. We propose a number of systems where the predicted features could be observed.Comment: 4 pages, 3 figures, ReVTe

PTPN23 binds the dynein adaptor BICD1 and is required for endocytic sorting of neurotrophin receptors

Signalling by target-derived neurotrophins is essential for the correct development of the nervous system and its maintenance throughout life. Several aspects concerning the lifecycle of neurotrophins and their receptors have been characterised over the years, including formation of signalling-competent ligand-receptor complexes, their endocytosis and trafficking. However, the molecular mechanisms directing the sorting of activated neurotrophin receptors are still elusive. Previously, our laboratory identified Bicaudal-D1 (BICD1), a dynein motor adaptor, as a key factor for lysosomal degradation of brain-derived neurotrophic factor (BDNF) -activated TrkB and p75NTR in motor neurons. Here, using a proteomic approach, we identified protein tyrosine phosphatase, non-receptor type 23 (PTPN23), a member of the endosomal sorting complexes required for transport (ESCRT) machinery, in the BICD1 interactome. Molecular mapping revealed that PTPN23 is not a canonical BICD1 cargo; instead, PTPN23 binds the N-terminus of BICD1, which is also essential for the recruitment of cytoplasmic dynein. In line with the BICD1 knockdown phenotype, loss of PTPN23 leads to increased accumulation of BDNF-activated p75NTR and TrkB in swollen vacuole-like compartments, suggesting that neuronal PTPN23 is a novel regulator of the endocytic sorting of neurotrophin receptors

Attenuated cortisol reactivity to psychosocial stress is associated with greater visual dependency in postural control

Despite known anatomical links between the hypothalamic-pituitary-adrenal (HPA) axis and the vestibular system, there are no studies on the relationship between postural control and HPA axis function. Visual dependence in postural control, often measured by increased postural sway on exposure to visual motion, is an indication of altered visual-vestibular integration with greater weighting towards visual cues for balance. Visual dependence is more common in older age and a range of vestibular and non-vestibular health conditions. The relationship between visual dependence in postural control was investigated in relation to cortisol reactivity to psychosocial stress (using the Trier Social Stress Test for groups: TSST-G), as an index of HPA axis function, in healthy young females. In those who exhibited a cortisol response (>2 nmol/l), a negative relationship between stress-induced cortisol reactivity and visual dependence in postural control was observed, since those with the largest cortisol response showed less visual motion induced postural sway (measured by force platform). This finding in healthy females indicates that subtle non-clinical differences in vestibular function are associated with dysregulated HPA axis activity as indicated by lower cortisol reactivity to psychosocial stress. It adds to the growing body of evidence linking blunted cortisol reactivity to stress to poor homeostatic regulation and potential negative health and behavioural outcomes

UK Large-scale Wind Power Programme from 1970 to 1990: the Carmarthen Bay experiments and the Musgrove Vertical-Axis Turbines

This article describes the development of the Musgrove Vertical Axis Wind Turbine (VAWT) concept, the UK ‘Carmarthen Bay’ wind turbine test programme, and UK government’s wind power programme to 1990. One of the most significant developments in the story of British wind power occurred during the 1970s, 1980s, and 1990s, with the development of the Musgrove vertical axis wind turbine and its inclusion within the UK Government’s wind turbine test programme. Evolving from a supervisor’s idea for an undergraduate project at Reading University, the Musgrove VAWT was once seen as an able competitor to the horizontal axis wind systems that were also being encouraged at the time by both the UK government and the Central Electricity Generating Board, the then nationalised electricity utility for England and Wales. During the 1980s and 1990s the most developed Musgrove VAWT system, along with three other commercial turbine designs was tested at Carmarthen Bay, South Wales as part of a national wind power test programme. From these developmental tests, operational data was collected and lessons learnt, which were incorporated into subsequent wind power operations.http://dx.doi.org/10.1260/03095240677860621