905 research outputs found
Altered cellular redox homeostasis and redox responses under standard oxygen cell culture conditions versus physioxia.
In vivo, mammalian cells reside in an environment of 0.5-10% O2 (depending on the tissue location within the body), whilst standard in vitro cell culture is carried out under room air. Little is known about the effects of this hyperoxic environment on treatment-induced oxidative stress, relative to a physiological oxygen environment. In the present study we investigated the effects of long-term culture under hyperoxia (air) on photodynamic treatment. Upon photodynamic irradiation, cells which had been cultured long-term under hyperoxia generated higher concentrations of mitochondrial reactive oxygen species, compared with cells in a physioxic (2% O2) environment. However, there was no significant difference in viability between hyperoxic and physioxic cells. The expression of genes encoding key redox homeostasis proteins and the activity of key antioxidant enzymes was significantly higher after the long-term culture of hyperoxic cells compared with physioxic cells. The induction of antioxidant genes and increased antioxidant enzyme activity appear to contribute to the development of a phenotype that is resistant to oxidative stress-induced cellular damage and death when using standard cell culture conditions. The results from experiments using selective inhibitors suggested that the thioredoxin antioxidant system contributes to this phenotype. To avoid artefactual results, in vitro cellular responses should be studied in mammalian cells that have been cultured under physioxia. This investigation provides new insights into the effects of physioxic cell culture on a model of a clinically relevant photodynamic treatment and the associated cellular pathways
A dynamic network approach for the study of human phenotypes
The use of networks to integrate different genetic, proteomic, and metabolic
datasets has been proposed as a viable path toward elucidating the origins of
specific diseases. Here we introduce a new phenotypic database summarizing
correlations obtained from the disease history of more than 30 million patients
in a Phenotypic Disease Network (PDN). We present evidence that the structure
of the PDN is relevant to the understanding of illness progression by showing
that (1) patients develop diseases close in the network to those they already
have; (2) the progression of disease along the links of the network is
different for patients of different genders and ethnicities; (3) patients
diagnosed with diseases which are more highly connected in the PDN tend to die
sooner than those affected by less connected diseases; and (4) diseases that
tend to be preceded by others in the PDN tend to be more connected than
diseases that precede other illnesses, and are associated with higher degrees
of mortality. Our findings show that disease progression can be represented and
studied using network methods, offering the potential to enhance our
understanding of the origin and evolution of human diseases. The dataset
introduced here, released concurrently with this publication, represents the
largest relational phenotypic resource publicly available to the research
community.Comment: 28 pages (double space), 6 figure
The Tyrosine Kinase Csk Dimerizes through Its SH3 Domain
The Src family kinases possess two sites of tyrosine phosphorylation that are critical to the regulation of kinase activity. Autophosphorylation on an activation loop tyrosine residue (Tyr 416 in commonly used chicken c-Src numbering) increases catalytic activity, while phosphorylation of a C-terminal tyrosine (Tyr 527 in c-Src) inhibits activity. The latter modification is achieved by the tyrosine kinase Csk (C-terminal Src Kinase), but the complete inactivation of the Src family kinases also requires the dephosphorylation of the activation loop tyrosine. The SH3 domain of Csk recruits the tyrosine phosphatase PEP, allowing for the coordinated inhibition of Src family kinase activity. We have discovered that Csk forms homodimers through interactions mediated by the SH3 domain in a manner that buries the recognition surface for SH3 ligands. The formation of this dimer would therefore block the recruitment of tyrosine phosphatases and may have important implications for the regulation of Src kinase activity
Challenges and strategies of children and adolescents with inflammatory bowel disease: a qualitative examination
© 2007 Nicholas et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens
Climate warming, marine protected areas and the ocean-scale integrity of coral reef ecosystems
Coral reefs have emerged as one of the ecosystems most vulnerable to climate variation and change. While the contribution
of a warming climate to the loss of live coral cover has been well documented across large spatial and temporal scales, the
associated effects on fish have not. Here, we respond to recent and repeated calls to assess the importance of local
management in conserving coral reefs in the context of global climate change. Such information is important, as coral reef
fish assemblages are the most species dense vertebrate communities on earth, contributing critical ecosystem functions
and providing crucial ecosystem services to human societies in tropical countries. Our assessment of the impacts of the
1998 mass bleaching event on coral cover, reef structural complexity, and reef associated fishes spans 7 countries, 66 sites
and 26 degrees of latitude in the Indian Ocean. Using Bayesian meta-analysis we show that changes in the size structure,
diversity and trophic composition of the reef fish community have followed coral declines. Although the ocean scale
integrity of these coral reef ecosystems has been lost, it is positive to see the effects are spatially variable at multiple scales,
with impacts and vulnerability affected by geography but not management regime. Existing no-take marine protected areas
still support high biomass of fish, however they had no positive affect on the ecosystem response to large-scale disturbance.
This suggests a need for future conservation and management efforts to identify and protect regional refugia, which should
be integrated into existing management frameworks and combined with policies to improve system-wide resilience to
climate variation and change
Community-based pre-pregnancy care programme improves pregnancy preparation in women with pregestational diabetes.
AIMS/HYPOTHESIS: Women with diabetes remain at increased risk of adverse pregnancy outcomes associated with poor pregnancy preparation. However, women with type 2 diabetes are less aware of and less likely to access pre-pregnancy care (PPC) compared with women with type 1 diabetes. We developed and evaluated a community-based PPC programme with the aim of improving pregnancy preparation in all women with pregestational diabetes. METHODS: This was a prospective cohort study comparing pregnancy preparation measures before and during/after the PPC intervention in women with pre-existing diabetes from 1 June 2013 to 28 February 2017. The setting was 422 primary care practices and ten National Health Service specialist antenatal diabetes clinics. A multifaceted approach was taken to engage women with diabetes and community healthcare teams. This included identifying and sending PPC information leaflets to all eligible women, electronic preconception care templates, online education modules and resources, and regional meetings and educational events. Key outcomes were preconception folic acid supplementation, maternal HbA1c level, use of potentially harmful medications at conception and gestational age at first presentation, before and during/after the PPC programme. RESULTS: A total of 306 (73%) primary care practices actively participated in the PPC programme. Primary care databases were used to identify 5075 women with diabetes aged 18-45 years. PPC leaflets were provided to 4558 (89.8%) eligible women. There were 842 consecutive pregnancies in women with diabetes: 502 before and 340 during/after the PPC intervention. During/after the PPC intervention, pregnant women with type 2 diabetes were more likely to achieve target HbA1c levels ≤48 mmol/mol (6.5%) (44.4% of women before vs 58.5% of women during/after PPC intervention; p = 0.016) and to take 5 mg folic acid daily (23.5% and 41.8%; p = 0.001). There was an almost threefold improvement in 'optimal' pregnancy preparation in women with type 2 diabetes (5.8% and 15.1%; p = 0.021). Women with type 1 diabetes presented for earlier antenatal care during/after PPC (54.0% vs 67.3% before 8 weeks' gestation; p = 0.003) with no other changes. CONCLUSIONS/INTERPRETATION: A pragmatic community-based PPC programme was associated with clinically relevant improvements in pregnancy preparation in women with type 2 diabetes. To our knowledge, this is the first community-based PPC intervention to improve pregnancy preparation for women with type 2 diabetes. DATA AVAILABILITY: Further details of the data collection methodology, individual clinic data and the full audit reports for healthcare professionals and service users are available from https://digital.nhs.uk/data-and-information/clinical-audits-and-registries/our-clinical-audits-and-registries/national-pregnancy-in-diabetes-audit
A systematic variation of the stellar initial mass function in early-type galaxies
Much of our knowledge of galaxies comes from analysing the radiation emitted
by their stars. It depends on the stellar initial mass function (IMF)
describing the distribution of stellar masses when the population formed.
Consequently knowledge of the IMF is critical to virtually every aspect of
galaxy evolution. More than half a century after the first IMF determination,
no consensus has emerged on whether it is universal in different galaxies.
Previous studies indicated that the IMF and the dark matter fraction in galaxy
centres cannot be both universal, but they could not break the degeneracy
between the two effects. Only recently indications were found that massive
elliptical galaxies may not have the same IMF as our Milky Way. Here we report
unambiguous evidence for a strong systematic variation of the IMF in early-type
galaxies as a function of their stellar mass-to-light ratio, producing
differences up to a factor of three in mass. This was inferred from detailed
dynamical models of the two-dimensional stellar kinematics for the large
Atlas3D representative sample of nearby early-type galaxies spanning two orders
of magnitude in stellar mass. Our finding indicates that the IMF depends
intimately on a galaxy's formation history.Comment: 4 pages, 2 figures, LaTeX. Accepted for publication as a Nature
Letter. More information about our Atlas3D project is available at
http://purl.org/atlas3
Viral population estimation using pyrosequencing
The diversity of virus populations within single infected hosts presents a
major difficulty for the natural immune response as well as for vaccine design
and antiviral drug therapy. Recently developed pyrophosphate based sequencing
technologies (pyrosequencing) can be used for quantifying this diversity by
ultra-deep sequencing of virus samples. We present computational methods for
the analysis of such sequence data and apply these techniques to pyrosequencing
data obtained from HIV populations within patients harboring drug resistant
virus strains. Our main result is the estimation of the population structure of
the sample from the pyrosequencing reads. This inference is based on a
statistical approach to error correction, followed by a combinatorial algorithm
for constructing a minimal set of haplotypes that explain the data. Using this
set of explaining haplotypes, we apply a statistical model to infer the
frequencies of the haplotypes in the population via an EM algorithm. We
demonstrate that pyrosequencing reads allow for effective population
reconstruction by extensive simulations and by comparison to 165 sequences
obtained directly from clonal sequencing of four independent, diverse HIV
populations. Thus, pyrosequencing can be used for cost-effective estimation of
the structure of virus populations, promising new insights into viral
evolutionary dynamics and disease control strategies.Comment: 23 pages, 13 figure
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