Repressor element 1 silencing transcription factor couples loss of pluripotency with neural induction and neural differentiation

Neural differentiation of embryonic stem cells (ESCs) requires coordinated repression of the pluripotency regulatory program and reciprocal activation of the neurogenic regulatory program. Upon neural induction, ESCs rapidly repress expression of pluripotency genes followed by staged activation of neural progenitor and differentiated neuronal and glial genes. The transcriptional factors that underlie maintenance of pluripotency are partially characterized whereas those underlying neural induction are much less explored, and the factors that coordinate these two developmental programs are completely unknown. One transcription factor, REST (repressor element 1 silencing transcription factor), has been linked with terminal differentiation of neural progenitors and more recently, and controversially, with control of pluripotency. Here, we show that in the absence of REST, coordination of pluripotency and neural induction is lost and there is a resultant delay in repression of pluripotency genes and a precocious activation of both neural progenitor and differentiated neuronal and glial genes. Furthermore, we show that REST is not required for production of radial glia-like progenitors but is required for their subsequent maintenance and differentiation into neurons, oligodendrocytes, and astrocytes. We propose that REST acts as a regulatory hub that coordinates timely repression of pluripotency with neural induction and neural differentiation.

The impact of cognitive control on children's goal monitoring in a time-based prospective memory task

The present study investigated whether developmental changes in cognitive control may underlie improvements of time-based prospective memory. Five-, 7-, 9-, and 11-year-olds (N = 166) completed a driving simulation task (ongoing task) in which they had to refuel their vehicle at specific points in time (PM task). The availability of cognitive control resources was experimentally manipulated by imposing a secondary task that required divided attention. Children completed the driving simulation task both in a full attention condition and a divided attention condition where they had to carry out a secondary task. Results revealed that older children performed better than younger children on the ongoing task and PM task. Children performed worse on the ongoing and PM tasks in the divided attention condition compared to the full attention condition. With respect to time monitoring in the final interval prior to the PM target, divided attention interacted with age such that older children’s time monitoring was more negatively affected by the secondary task compared to younger children. Results are discussed in terms of developmental shifts from reactive to proactive monitoring strategies.

Formulation of a live bacterial vaccine for stable room temperature storage results in loss of acid, bile and bile salt resistance

Live bacterial vaccines have great promise both as vaccines against enteric pathogens and as heterologous antigen vectors against diverse diseases. Ideally, room temperature stable dry formulations of live bacterial vaccines will allow oral vaccination without cold-chain storage or injections. Attenuated Salmonella can cross the intestinal wall and deliver replicating antigen plus innate immune activation signals directly to the intestinal immune tissues, however the ingested bacteria must survive firstly gastric acid and secondly the antimicrobial defences of the small intestine. We found that the way in which cells are grown prior to formulation markedly affects sensitivity to acid and bile. Using a previously published stable storage formulation that maintained over 10% viability after 56 days storage at room temperature, we found dried samples of an attenuated S. typhimurium vaccine lost acid and bile resistance compared to the same bacteria taken from fresh culture. The stable formulation utilised osmotic preconditioning in defined medium plus elevated salt concentration to induce intracellular trehalose accumulation before drying. Dried bacteria grown in rich media without osmotic preconditioning showed more resistance to bile, but less stability during storage, suggesting a trade-off between bile resistance and stability. Further optimization is needed to produce the ultimate room-temperature stable oral live bacterial vaccine formulation.

Inbreeding and loss of genetic variation in a reintroduced population of Mauritius Kestrel

Many populations have recovered from severe bottlenecks either naturally or through intensive conservation management. In the past, however, few conservation programs have monitored the genetic health of recovering populations. We conducted a conservation genetic assessment of a small, reintroduced population of Mauritius Kestrel (Falco punctatus) to determine whether genetic deterioration has occurred since its reintroduction. We used pedigree analysis that partially accounted for individuals of unknown origin to document that (1) inbreeding occurred frequently (2.6% increase per generation; N-el = 18.9), (2) 25% of breeding pairs were composed of either closely or moderately related individuals, (3) genetic diversity has been lost from the population (1,6% loss per generation; N-ev = 32.1) less rapidly than the corresponding increase in inbreeding, and (4) ignoring the contribution of unknown individuals to a pedigree will bias the metrics derived from that pedigree, ultimately obscuring the prevailing genetic dynamics. The rates of inbreeding and loss of genetic variation in the subpopulation of Mauritius Kestrel we examined were extreme and among the highest yet documented in a wild vertebrate population. Thus, genetic deterioration may affect this population's long-term viability. Remedial conservation strategies are needed to reduce the impact of inbreeding and loss of genetic variation in this species, We suggest that schemes to monitor genetic variation after reintroduction should be an integral component of endangered species recovery programs

Constrained models of evolution lead to improved prediction of functional linkage from correlated gain and loss of genes

Motivation: We compare phylogenetic approaches for inferring functional gene links. The approaches detect independent instances of the correlated gain and loss of pairs of genes from species' genomes. We investigate the effect on results of basing evidence of correlations on two phylogenetic approaches, Dollo parsminony and maximum likelihood (ML). We further examine the effect of constraining the ML model by fixing the rate of gene gain at a low value, rather than estimating it from the data. Results: We detect correlated evolution among a test set of pairs of yeast (Saccharomyces cerevisiae) genes, with a case study of 21 eukaryotic genomes and test data derived from known yeast protein complexes. If the rate at which genes are gained is constrained to be low, ML achieves by far the best results at detecting known functional links. The model then has fewer parameters but it is more realistic by preventing genes from being gained more than once. Availability: BayesTraits by M. Pagel and A. Meade, and a script to configure and repeatedly launch it by D. Barker and M. Pagel, are available at http://www.evolution.reading.ac.uk .

Failure of a control strategy for a hybrid air-conditioning and wind catchers/towers system at Bluewater shopping malls in Kent

Purpose – To evaluate the control strategy for a hybrid natural ventilation wind catchers and air-conditioning system and to assess the contribution of wind catchers to indoor air environments and energy savings if any. Design/methodology/approach – Most of the modeling techniques for assessing wind catchers performance are theoretical. Post-occupancy evaluation studies of buildings will provide an insight into the operation of these building components and help to inform facilities managers. A case study for POE was presented in this paper. Findings – The monitoring of the summer and winter month operations showed that the indoor air quality parameters were kept within the design target range. The design control strategy failed to record data regarding the operation, opening time and position of wind catchers system. Though the implemented control strategy was working effectively in monitoring the operation of mechanical ventilation systems, i.e. AHU, did not integrate the wind catchers with the mechanical ventilation system. Research limitations/implications – Owing to short-falls in the control strategy implemented in this project, it was found difficult to quantify and verify the contribution of the wind catchers to the internal conditions and, hence, energy savings. Practical implications – Controlling the operation of the wind catchers via the AHU will lead to isolation of the wind catchers in the event of malfunctioning of the AHU. Wind catchers will contribute to the ventilation of space, particularly in the summer months. Originality/value – This paper demonstrates the value of POE as indispensable tool for FM professionals. It further provides insight into the application of natural ventilation systems in building for healthier indoor environments at lower energy cost. The design of the control strategy for natural ventilation and air-conditioning should be considered at the design stage involving the FM personnel.

Loss of 3-chlorotyrosine by inflammatory oxidants: Implications for the use of 3-chlorotyrosine as a bio-marker in vivo

Activated neutrophils generate the potent oxidant hypochlorous acid (HOCl) from the enzyme myeloperoxidase (MPO). A proposed bio-marker for MPO-derived HOCl in vivo is 3-chlorotyrosine, elevated levels of which have been measured in several human inflammatory pathologies. However, it is unlikely that HOCl is produced as the sole oxidant at sites of chronic inflammation as other reactive species are also produced during the inflammatory response. The work presented shows that free and protein bound 3-chlorotyrosine is lost upon addition of the pro-inflammatory oxidants, HOCl, peroxynitrite, and acidified nitrite. Furthermore, incubation of 3-chlorotyrosine with activated RAW264.7 macrophages or neutrophil-like HL-60 cells resulted in significant loss of 3-chlorotyrosine. Therefore, at sites of chronic inflammation where there is concomitant ONOO- and HOCl formation, it is possible measurement of 3-chlorotyrosine may represent an underestimate of the true extent of tyrosine chlorination. This finding could account for some of the discrepancies reported between 3-chlorotyrosine levels in tissues in the literature. (c) 2008 Elsevier Inc. All rights reserved.

Permanent changes in growth and physiology of Bacillus subtilis ToC46 after loss of a recombinant plasmid

The physiology and growth of plasmid-bearing Bacillus subtilis carrying plasmid pPFF1, the non-transformed host, and cells after loss of the plasmid (so-called plasmid-cured cells) were investigated. It was found that, following plasmid loss, cells exhibited phenotypic characteristics different from those of the non-transformed host strains. Compared to plasmid-bearing cells and non-transformed host cells, an approximate 25% increase in the maximum specific growth rate and a more rapid increase in total RNA per unit cell mass were observed in plasmid-cured cells. The total enthalpy associated with irreversible denaturation events was determined in whole cells by differential scanning calorimetry. This showed higher enthalpies for plasmid-cured cells compared with the non-transformed host, which suggests increased ribosome numbers. The result from cellular DNA hybridisation suggests that there was no direct evidence of plasmid integration into the host chromosome. (C) 2004 Elsevier Inc. All rights reserved.

Risk taking from the participant's perspective: the case of driving and accident risk

Although perceived health risk plays a prominent role in theories of health behavior, its empirical role in risk taking is less clear. In Study 1 (N = 129), 2 measures of drivers' risk-taking behavior were found to be unrelated to self-estimates of accident concern but to be related to self-ratings of driving skill and the perceived thrill of driving. In Study 2 (N = 405), out of a wide range of potential influences, accident concern had the weakest relationship with risk taking. The authors concluded that although health risk is a key feature in many theories of health behavior and a central focus for researchers and policy makers, it may not be such a prominent factor for those actually taking the risk.

The geometry of optimal control solutions on some six dimensional lie groups

This paper examines optimal solutions of control systems with drift defined on the orthonormal frame bundle of particular Riemannian manifolds of constant curvature. The manifolds considered here are the space forms Euclidean space E-3, the spheres S-3 and the hyperboloids H-3 with the corresponding frame bundles equal to the Euclidean group of motions SE(3), the rotation group SO(4) and the Lorentz group SO(1,3). The optimal controls of these systems are solved explicitly in terms of elliptic functions. In this paper, a geometric interpretation of the extremal solutions is given with particular emphasis to a singularity in the explicit solutions. Using a reduced form of the Casimir functions the geometry of these solutions are illustrated.

Singularities of optimal control problems on some 6-D lie groups

This paper considers the motion planning problem for oriented vehicles travelling at unit speed in a 3-D space. A Lie group formulation arises naturally and the vehicles are modeled as kinematic control systems with drift defined on the orthonormal frame bundles of particular Riemannian manifolds, specifically, the 3-D space forms Euclidean space E-3, the sphere S-3, and the hyperboloid H'. The corresponding frame bundles are equal to the Euclidean group of motions SE(3), the rotation group SO(4), and the Lorentz group SO (1, 3). The maximum principle of optimal control shifts the emphasis for these systems to the associated Hamiltonian formalism. For an integrable case, the extremal curves are explicitly expressed in terms of elliptic functions. In this paper, a study at the singularities of the extremal curves are given, which correspond to critical points of these elliptic functions. The extremal curves are characterized as the intersections of invariant surfaces and are illustrated graphically at the singular points. It. is then shown that the projections, of the extremals onto the base space, called elastica, at these singular points, are curves of constant curvature and torsion, which in turn implies that the oriented vehicles trace helices.

The relationship between membrane damage, release of protein and loss of viability in Escherichia coli exposed to high hydrostatic pressure

The aim of this work was to examine a possible association between resistance of two Escherichia coli strains to high hydrostatic pressure and the susceptibility of their cell membranes to pressure-induced damage. Cells were exposed to pressures between 100 and 700 MPa at room temperature (~20C) in phosphate-buffered-saline. In the more pressure-sensitive strain E. coli 8164, loss of viability occurred at pressures between 100 MPa and 300 MPa and coincided with irreversible loss of membrane integrity as indicated by uptake of propidium iodide (PI) and leakage of protein of molecular mass between 9 and 78 kDa from the cells. Protein release increased to a maximum at 400 MPa then decreased, possibly due to intracellular aggregation at the higher pressures. In the pressure-resistant strain E. coli J1, PI was taken up during pressure treatment but not after decompression indicating that cells were able to reseal their membranes. Loss of viability in strain J1 coincided with the transient loss of membrane integrity between approximately 200 MPa and 600 MPa. In E. coli J1 leakage of protein occurred before loss of viability and the released protein was of low molecular mass, between 8 and 11 kDa and may have been of periplasmic origin. In these two strains differences in pressure resistance appeared to be related to differences in the ability of their membranes to withstand disruption by pressure. However it appears that transient loss of membrane integrity during pressure can lead to cell death irrespective of whether cells can reseal their membranes afterwards.