457 research outputs found
Use of massively parallel computing to improve modelling accuracy within the nuclear sector
The extreme environments found within the nuclear sector impose large safety factors on modelling analyses to ensure components operate in their desired manner. Improving analysis accuracy has clear value of increasing the design space that could lead to greater efficiency and reliability.
Novel materials for new reactor designs often exhibit non-linear behaviour; additionally material properties evolve due to in-service damage a combination that is difficult to model accurately. To better describe these complex behaviours a range of modelling techniques previously under-pursued due to computational expense are being developed.
This work presents recent advancements in three techniques: Uncertainty quantification (UQ); Cellular automata finite element (CAFE); Image based finite element methods (IBFEM). Case studies are presented demonstrating their suitability for use in nuclear engineering made possible by advancements in parallel computing hardware that is projected to be available for industry within the next decade costing of the order of $100k
Associations between daily sitting time and the combinations of lifestyle risk factors in men
Background: Understanding the reciprocal role that multiple problematic behaviours play in men's health is important for intervention delivery and for reducing the healthcare burden. Data regarding the concurrence of problematic health behaviours is currently limited but offers insights into risk profiles, and should now include total time spent sitting/day. Methods: Self-reported data on lifestyle health behaviours was collected from 232 men aged ≥18 years who engaged in a men's health promotion programme delivered by 16 English Premier League Clubs. Results: Men at risk due to high sitting display multiple concurrent lifestyle risk factors, 88.6% displayed at least two ancillary risk factors and were three times more likely to report ≥2 lifestyle risk factors (OR. =3.13, 95% confidence interval (CI). =1.52-6.42) than those with low sitting risk. Significant differences in the mean number of risk factors reported between those participants in the higher risk (2.43. ±. 0.90) and lower risk (2.13. ±. 0.96) sitting categories were also found (P=0.015). Conclusions: Hard-to-reach men displayed multiple problematic concurrent behaviours, strongly linked to total sitting time. © 2012 WPMH GmbH
Multiwavelength observations of the extraordinary accretion event AT2021lwx
We present observations from X-ray to mid-infrared wavelengths of the most
energetic non-quasar transient ever observed, AT2021lwx. Our data show a single
optical brightening by a factor to a luminosity of erg
s, and a total radiated energy of erg, both greater
than any known optical transient. The decline is smooth and exponential and the
ultra-violet - optical spectral energy distribution resembles a black body with
temperature K. Tentative X-ray detections indicate a secondary
mode of emission, while a delayed mid-infrared flare points to the presence of
dust surrounding the transient. The spectra are similar to recently discovered
optical flares in known active galactic nuclei but lack some characteristic
features. The lack of emission for the previous seven years is inconsistent
with the short-term, stochastic variability observed in quasars, while the
extreme luminosity and long timescale of the transient disfavour the disruption
of a single solar-mass star. The luminosity could be generated by the
disruption of a much more massive star, but the likelihood of such an event
occurring is small. A plausible scenario is the accretion of a giant molecular
cloud by a dormant black hole of solar masses. AT2021lwx thus
represents an extreme extension of the known scenarios of black hole accretion.Comment: 11 pages, 5 figures, Accepted for publication in MNRA
Cardiovascular development: towards biomedical applicability: Regulation of cardiomyocyte differentiation of embryonic stem cells by extracellular signalling
Investigating the signalling pathways that regulate heart development is essential if stem cells are to become an effective source of cardiomyocytes that can be used for studying cardiac physiology and pharmacology and eventually developing cell-based therapies for heart repair. Here, we briefly describe current understanding of heart development in vertebrates and review the signalling pathways thought to be involved in cardiomyogenesis in multiple species. We discuss how this might be applied to stem cells currently thought to have cardiomyogenic potential by considering the factors relevant for each differentiation step from the undifferentiated cell to nascent mesoderm, cardiac progenitors and finally a fully determined cardiomyocyte. We focus particularly on how this is being applied to human embryonic stem cells and provide recent examples from both our own work and that of others
eXtraembryonic ENdoderm (XEN) Stem Cells Produce Factors that Activate Heart Formation
Initial specification of cardiomyocytes in the mouse results from interactions between the extraembryonic anterior visceral endoderm (AVE) and the nascent mesoderm. However the mechanism by which AVE activates cardiogenesis is not well understood, and the identity of specific cardiogenic factors in the endoderm remains elusive. Most mammalian studies of the cardiogenic potential of the endoderm have relied on the use of cell lines that are similar to the heart-inducing AVE. These include the embryonal-carcinoma-derived cell lines, END2 and PYS2. The recent development of protocols to isolate eXtraembryonic ENdoderm (XEN) stem cells, representing the extraembryonic endoderm lineage, from blastocyst stage mouse embryos offers new tools for the genetic dissection of cardiogenesis.Here, we demonstrate that XEN cell-conditioned media (CM) enhances cardiogenesis during Embryoid Body (EB) differentiation of mouse embryonic stem (ES) cells in a manner comparable to PYS2-CM and END2-CM. Addition of CM from each of these three cell lines enhanced the percentage of EBs that formed beating areas, but ultimately, only XEN-CM and PYS2-CM increased the total number of cardiomyocytes that formed. Furthermore, our observations revealed that both contact-independent and contact-dependent factors are required to mediate the full cardiogenic potential of the endoderm. Finally, we used gene array comparison to identify factors in these cell lines that could mediate their cardiogenic potential.These studies represent the first step in the use of XEN cells as a molecular genetic tool to study cardiomyocyte differentiation. Not only are XEN cells functionally similar to the heart-inducing AVE, but also can be used for the genetic dissection of the cardiogenic potential of AVE, since they can be isolated from both wild type and mutant blastocysts. These studies further demonstrate the importance of both contact-dependent and contact-independent factors in cardiogenesis and identify potential heart-inducing proteins in the endoderm
A Comparative Analysis of Extra-Embryonic Endoderm Cell Lines
Prior to gastrulation in the mouse, all endodermal cells arise from the primitive
endoderm of the blastocyst stage embryo. Primitive endoderm and its derivatives
are generally referred to as extra-embryonic endoderm (ExEn) because the
majority of these cells contribute to extra-embryonic lineages encompassing the
visceral endoderm (VE) and the parietal endoderm (PE). During gastrulation, the
definitive endoderm (DE) forms by ingression of cells from the epiblast. The DE
comprises most of the cells of the gut and its accessory organs. Despite their
different origins and fates, there is a surprising amount of overlap in marker
expression between the ExEn and DE, making it difficult to distinguish between
these cell types by marker analysis. This is significant for two main reasons.
First, because endodermal organs, such as the liver and pancreas, play important
physiological roles in adult animals, much experimental effort has been directed
in recent years toward the establishment of protocols for the efficient
derivation of endodermal cell types in vitro. Conversely,
factors secreted by the VE play pivotal roles that cannot be attributed to the
DE in early axis formation, heart formation and the patterning of the anterior
nervous system. Thus, efforts in both of these areas have been hampered by a
lack of markers that clearly distinguish between ExEn and DE. To further
understand the ExEn we have undertaken a comparative analysis of three ExEn-like
cell lines (END2, PYS2 and XEN). PYS2 cells are derived from embryonal
carcinomas (EC) of 129 strain mice and have been characterized as parietal
endoderm-like [1], END2 cells are derived from P19 ECs and
described as visceral endoderm-like, while XEN cells are derived from blastocyst
stage embryos and are described as primitive endoderm-like. Our analysis
suggests that none of these cell lines represent a bona fide
single in vivo lineage. Both PYS2 and XEN cells represent mixed
populations expressing markers for several ExEn lineages. Conversely END2 cells,
which were previously characterized as VE-like, fail to express many markers
that are widely expressed in the VE, but instead express markers for only a
subset of the VE, the anterior visceral endoderm. In addition END2 cells also
express markers for the PE. We extended these observations with microarray
analysis which was used to probe and refine previously published data sets of
genes proposed to distinguish between DE and VE. Finally, genome-wide pathway
analysis revealed that SMAD-independent TGFbeta signaling through a TAK1/p38/JNK
or TAK1/NLK pathway may represent one mode of intracellular signaling shared by
all three of these lines, and suggests that factors downstream of these pathways
may mediate some functions of the ExEn. These studies represent the first step
in the development of XEN cells as a powerful molecular genetic tool to study
the endodermal signals that mediate the important developmental functions of the
extra-embryonic endoderm. Our data refine our current knowledge of markers that
distinguish various subtypes of endoderm. In addition, pathway analysis suggests
that the ExEn may mediate some of its functions through a non-classical MAP
Kinase signaling pathway downstream of TAK1
The impact of disseminating the whole-community project '10,000 Steps': a RE-AIM analysis
<p>Abstract</p> <p>Background</p> <p>There are insufficient research reports on the wide-scale dissemination of effective whole-community physical activity (PA) programs. The purpose of this paper is to evaluate the impact of the wide-scale dissemination of '10,000 Steps', using the RE-AIM framework.</p> <p>Methods</p> <p>Dissemination efforts targeted a large region of Belgium and were concentrated on media strategies and peer networks of specific professional organizations, such as local health promotion services. Heads of department of 69 organizations received an on-line survey to assess project awareness, adoption, implementation and intended continuation of '10,000 Steps'. On the individual level, 755 citizens living in the work area of the organizations were interviewed for project awareness and PA levels. Measures were structured according to the RE-AIM dimensions (reach, effectiveness, adoption, implementation, maintenance). Independent sample <it>t </it>and chi-square tests were used to compare groups for representativeness at the organizational and individual level, and for individual PA differences.</p> <p>Results</p> <p>Of all organizations, 90% was aware of '10,000 Steps' (effectiveness - organizational level) and 36% adopted the project (adoption). The global implementation score was 52%. One third intended to continue the project in the future (maintenance) and 48% was still undecided. On the individual level, 35% of citizens were aware of '10,000 Steps' (reach). They reported significantly higher leisure-time PA levels than those not aware of '10,000 Steps' (256 ± 237 and 207 ± 216 min/week, respectively; <it>t </it>= -2.8; p < .005) (effectiveness - individual level). When considering representativeness, adoption of '10.000 Steps' was independent of most organizational characteristics, except for years of experience in PA promotion (7.6 ± 4.6 and 2.9 ± 5.9 years for project staff and non-project staff members, respectively; <it>t </it>= 2.79; <it>p </it>< 0.01). Project awareness in citizens was independent of all demographic characteristics.</p> <p>Conclusions</p> <p>'10,000 Steps' shows potential for wide-scale dissemination but a supportive linkage system seems recommended to encourage adoption levels and high quality implementation.</p
Clinical and genetic characterization of leukoencephalopathies in adults
Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults
BMP-SMAD Signaling Regulates Lineage Priming, but Is Dispensable for Self-Renewal in Mouse Embryonic Stem Cells
Naive mouse embryonic stem cells (mESCs) are in a metastable state and fluctuate between inner cell mass- and epiblast-like phenotypes. Here, we show transient activation of the BMP-SMAD signaling pathway in mESCs containing a BMP-SMAD responsive reporter transgene. Activation of the BMP-SMAD reporter transgene in naive mESCs correlated with lower levels of genomic DNA methylation, high expression of 5-methylcytosine hydroxylases Tet1/2 and low levels of DNA methyltransferases Dnmt3a/b. Moreover, naive mESCs, in which the BMP-SMAD reporter transgene was activated, showed higher resistance to differentiation. Using double Smad1;Smad5 knockout mESCs, we showed that BMP-SMAD signaling is dispensable for self-renewal in both naive and ground state. These mutant mESCs were still pluripotent, but they exhibited higher levels of DNA methylation than their wild-type counterparts and had a higher propensity to differentiate. We showed that BMP-SMAD signaling modulates lineage priming in mESCs, by transiently regulating the enzymatic machinery responsible for DNA methylation
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