1,403 research outputs found
Protein biomarkers in cystic fibrosis research: where next?
Cystic fibrosis is one of the most common life-limiting inherited disorders. Its clinical impact manifests chiefly in the lung, pancreas, gastrointestinal tract and sweat glands, with lung disease typically being most detrimental to health. The median age for survival has increased dramatically over the past decades, largely thanks to advances in understanding of the mechanisms and consequences of disease, leading to the development of better therapies and treatment regimes. The discovery of dysregulated protein biomarkers linked to cystic fibrosis has contributed considerably to this end. This article outlines clinical trials targeting known protein biomarkers, and the current and future contributions of proteomic techniques to cystic fibrosis research. The treatments described range from those designed to provide functional copies of the mutant protein responsible for cystic fibrosis, to others addressing the associated symptoms of chronic inflammation. Preclinical research has employed proteomics to help elucidate pathways and processes implicated in disease that might present opportunities for therapy or prognosis. Global analyses of cystic fibrosis have detected the differential expression of proteins involved in inflammation, proteolytic activity and oxidative stress, which are recognized symptoms of the cystic fibrosis phenotype. The dysregulation of other processes, such as the complement and mitochondrial systems, has also been implicated. A number of studies have focused specifically on proteins that interact with the cystic fibrosis protein, with the goal of restoring its normal proteostasis. Consequently, proteins involved in synthesis, folding, degradation, translocation and localization of the protein have been identified as potential therapeutic targets. Cystic fibrosis patients are prone to lung infections that are thought to contribute to chronic inflammation, and thus proteomic studies have also searched for microbiological biomarkers to use in early infection diagnosis or as indicators of virulence. The review concludes by proposing a future role for proteomics in the high-throughput validation of protein biomarkers under consideration as outcome measures for use in clinical trials and routine disease monitoring
Cooperative Jahn-Teller Distortion in PrO2
We report neutron diffraction data on single crystal PrO2 which reveal a
cooperative Jahn-Teller distortion at TD = 120 +/- 2 K. Below this temperature
an internal distortion of the oxygen sublattice causes the unit cell of the
crystallographic structure to become doubled along one crystal axis. We discuss
several possible models for this structure. The antiferromagnetic structure
below TN = 13.5 K is found to consist of two components, one of which shares
the same doubled unit cell as the distorted crystallographic structure. We also
present measurements of the magnetic susceptibility, the specific heat capacity
and the electrical conductivity of PrO2. The susceptibility data show an
anomaly at a temperature close to TD. From the specific heat capacity data we
deduce that the ground state is doubly degenerate, consistent with a distortion
of the cubic local symmetry. We discuss possible mechanisms for this. The
conductivity shows an activated behaviour with an activation energy Ea = 0.262
+/- 0.003 eV.Comment: 12 pages, 14 figures, 2 tables. Additional suggested structure in v
Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation
BACKGROUND AND OBJECTIVES: Locus heterogeneity is well established in autosomal recessive primary
microcephaly (MCPH) and to date five loci have been mapped. However, the relative contributions of
these loci have not been assessed and genotype-phenotype correlations have not been investigated.
DESIGN: A study population of 56 consanguineous families resident in or originating from northern
Pakistan was ascertained and assessed by the authors. A panel of microsatellite markers spanning
each of the MCPH loci was designed, against which the families were genotyped.
RESULTS: The head circumference of the 131 affected subjects ranged from 4 to 14 SD below the mean,
but there was little intrafamilial variation among affecteds (± 1 SD). MCPH5 was the most prevalent,
with 24/56 families consistent with linkage; 2/56 families were compatible with linkage to MCPH1,
10/56 to MCPH2, 2/56 to MCPH3, none to MCPH4, and 18/56 did not segregate with any of the
loci.
CONCLUSIONS: MCPH5 is the most common locus in this population. On clinical grounds alone, the
phenotype of families linked to each MCPH locus could not be distinguished. We have also shown that
further MCPH loci await discovery with a number of families as yet unlinked
Experimental Investigation of the Nature of the Knee in the Primary Cosmic Ray Energy Spectrum with the GAMMA experiment
We present preliminary results obtained by a novel difference method for the
study of the nature of the knee in the energy spectrum of the primary cosmic
radiation. We have applied this method to data from the GAMMA experiment in
Armenia. The analysis provides evidence for the possible existence of a nearby
source of primary cosmic rays in the Southern hemisphere.Comment: 17 pages, 5 figure
Modelling a Hot Horizon in Global 21 cm Experimental Foregrounds
The 21 cm signal from cosmic hydrogen is one of the most propitious probes of
the early Universe. The detection of this signal would reveal key information
about the first stars, the nature of dark matter, and early structure
formation. We explore the impact of an emissive and reflective, or `hot',
horizon on the recovery of this signal for global 21 cm experiments. It is
demonstrated that using physically motivated foreground models to recover the
sky-averaged 21 cm signal one must accurately describe the horizon around the
radiometer. We show that not accounting for the horizon will lead to a signal
recovery with residuals an order of magnitude larger than the injected signal,
with a log Bayesian evidence of almost 1600 lower than when one does account
for the horizon. It is shown that signal recovery is sensitive to incorrect
values of soil temperature and reflection coefficient in describing the
horizon, with even a 10% error in reflectance causing twofold increases in the
RMSE of a given fit. We also show these parameters may be fitted using Bayesian
inference to mitigate for these issues without overfitting and
mischaracterising a non-detection. We further demonstrate that signal recovery
is sensitive to errors in measurements of the horizon projection onto the sky,
but fitting for soil temperature and reflection coefficients with priors that
extend beyond physical expectation can resolve these problems. We show that
using an expanded prior range can reliably recover the signal even when the
height of the horizon is mismeasured by up to 20%, decreasing the RMSE from the
model that does not perform this fitting by a factor of 9.Comment: 12 pages, 11 figures, 5 table
Behavioural interventions for primary and secondary dysmenorrhoea
Background: Dysmenorrhoea refers to the occurrence of painful menstrual cramps of uterine origin and is a common gynaecological condition with considerable morbidity. The behavioural approach assumes that psychological and environmental factors interact with, and influence, physiological processes. Behavioural interventions for dysmenorrhoea may include both physical and cognitive procedures and focus on both physical and psychological coping strategies for dysmenorrhoeic symptoms rather than modification of any underlying organic pathology. Objectives: To determine the effectiveness of any behavioural interventions for the treatment of primary or secondary dysmenorrhoea when compared to each other, placebo, no treatment, or conventional medical treatments for example non-steroidal anti-inflammatory drugs (NSAIDs). Search strategy: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched April 2005), Cochrane Central Register of Controlled Trials (CENTRAL on The Cochrane Library, Issue 2, 2005), MEDLINE (1966 to April 2005), EMBASE (1980 to April 2005), Social Sciences Index (1980 to April 2005), PsycINFO (1972 to April 2005) and CINAHL (1982 to April 2005) and reference lists of articles. Selection criteria: Randomised controlled trials comparing behavioural interventions with placebo or other interventions in women with dysmenorrhoea. Data collection and analysis: Two authors independently assessed trial quality and extracted data. Main results: Five trials involving 213 women were included. Behavioural intervention vs control: One trial of pain management training reported reduction in pain and symptoms compared to a control. Three trials of relaxation compared to control reported varied results, two trials showed no difference in symptom severity scores however one trial reported relaxation was effective for reducing symptoms in menstrual sufferers with spasmodic symptoms. Two trials reported less restriction in daily activities following treatment with either relaxation of pain management training compared to a control. One trial also reported less time absent from school following treatment wit pain management training compared to a control. Behavioural intervention vs other behavioural interventions: Three trials showed no difference between behavioural interventions for the outcome of improvement in symptoms. One trial showed that relaxation resulted in a decrease in the need for resting time compared to the relaxation and imagery. Authors' conclusions: There is some evidence from five RCTs that behavioural interventions may be effective for dysmenorrhoea however results should be viewed with caution as they varied greatly between trials due to inconsistency in the reporting of data, small trial size, poormethodological quality and age of the trials
The effect of phase angle on crack growth mechanisms under thermo-mechanical fatigue loading
The current paper describes TMF crack growth behaviour in an advanced nickel-based superalloy. Changes in behaviour are examined which occur as a function of the phase angle between applied stress and temperature. The fractography of the failed specimens reveals changes from transgranular to intergranular growth between high and low phase angle tests as a result of the onset of high temperature damage mechanisms. More targeted testing has also been undertaken to isolate the contributions of these mechanisms, with specific transitions in behaviour becoming clear in 90° diamond cycles, where dynamic crack growth and oxidation strongly interact
Arming the Outlaws: On the Moral Limits of the Arms Trade
There is a general presumption against arming outlaw states. But can that
presumption sometimes be overturned? The argument considered here
maintains that outlaw states can have legitimate security interests, and
that transferring weapons to these states can be an appropriate way of
promoting those interests. Weapons enable governments to engage in
wrongful oppression and aggression, but they also enable them to fend off predators in a manner that can be beneficial to their citizens. It clearly
does not follow from the fact that a state is oppressive or aggressive that it will never be a victim of wrongful aggression itself, and while an outlaw
state’s primary aim in repelling such aggression will often be the
preservation of its own power, its defensive manoeuvres will sometimes
also serve its citizens’ interests. In short, supplying weapons to outlaw
states may sometimes contribute to the protection of innocents
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An online study combining the constructs from the theory of planned behaviour and protection motivation theory in predicting intention to test for chlamydia in two testing contexts
Chlamydia is a common sexually-transmitted infection that has potentially serious consequences unless detected and treated early. The health service in the UK offers clinic-based testing for chlamydia but uptake is low. Identifying the predictors of testing behaviours may inform interventions to increase uptake. Self-tests for chlamydia may facilitate testing and treatment in people who avoid clinic-based testing. Self-testing and being tested by a health care professional (HCP) involve two contrasting contexts that may influence testing behaviour. However, little is known about how predictors of behaviour differ as a function of context. In this study, theoretical models of behaviour were used to assess factors that may predict intention to test in two different contexts: self-testing and being tested by a HCP. Individuals searching for, or reading about chlamydia testing online were recruited using Google Adwords. Participants completed an online questionnaire that addressed previous testing behaviour and measured constructs of the Theory of Planned Behaviour and Protection Motivation Theory, which propose a total of eight possible predictors of intention. The questionnaire was completed by 310 participants. Sufficient data for multiple regression were provided by 102 and 118 respondents for self-testing and testing by a HCP respectively. Intention to self-test was predicted by vulnerability and self-efficacy, with a trend-level effect for response efficacy. Intention to be tested by a HCP was predicted by vulnerability, attitude and subjective norm. Thus, intentions to carry out two testing behaviours with very similar goals can have different predictors depending on test context. We conclude that interventions to increase self-testing should be based on evidence specifically related to test context
X-ray Raman scattering study of aligned polyfluorene
We present a non-resonant inelastic x-ray scattering study at the carbon
K-edge on aligned poly[9,9-bis(2-ethylhexyl)-fluorene-2,7-diyl] and show that
the x-ray Raman scattering technique can be used as a practical alternative to
x-ray absorption measurements. We demonstrate that this novel method can be
applied to studies on aligned -conjugated polymers complementing
diffraction and optical studies. Combining the experimental data and a very
recently proposed theoretical scheme we demonstrate a unique property of x-ray
Raman scattering by performing the symmetry decomposition on the density of
unoccupied electronic states into - and -type symmetry contributions.Comment: 19 pages, 8 figure
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