1,937 research outputs found
Sensitivity of Pliocene Arctic climate to orbital forcing, atmospheric CO2 and sea ice albedo parameterisation
General circulation model (GCM) simulations of the mid-Pliocene Warm Period (mPWP, 3.264 to 3.025Myr ago) do not reproduce the magnitude of Northern Hemisphere high latitude surface air and sea surface temperature (SAT and SST) warming that proxy data indicate. There is also large uncertainty regarding the state of sea ice cover in the mPWP. Evidence for both perennial and seasonal mPWP Arctic sea ice is found through analyses of marine sediments, whilst in a multi-model ensemble of mPWP climate simulations, half of the ensemble simulated ice-free summer Arctic conditions. Given the strong influence that sea ice exerts on high latitude temperatures, an understanding of the nature of mPWP Arctic sea ice would be highly beneficial. Using the HadCM3 GCM, this paper explores the impact of various combinations of potential mPWP orbital forcing, atmospheric CO2concentrations and minimum sea ice albedo on sea ice extent and high latitude warming. The focus is on the Northern Hemisphere, due to availability of proxy data, and the large data–model discrepancies in this region. Changes in orbital forcings are demonstrated to be sufficient to alter the Arctic sea ice simulated by HadCM3 from perennial to seasonal. However, this occurs only when atmospheric CO2concentrations exceed 300 ppm. Reduction of the minimum sea ice albedo from 0.5 to 0.2 is also sufficient to simulate seasonal sea ice, with any of the combinations of atmospheric CO2and orbital forcing. Compared to a mPWP control simulation, monthly mean increases north of 60◦N of up to 4.2◦C (SST) and 9.8◦C (SAT) are simulated. With varying CO2, orbit and sea ice albedo values we are able to reproduce proxy temperature records that lean towards modest levels of high latitude warming, but other proxy data showing greater warming remain beyond the reach of our model. This highlights the importance of additional proxy records at high latitudes and ongoing efforts to compare proxy signals between sites
"...they should be offering it": a qualitative study to investigate young peoples' attitudes towards chlamydia screening in GP surgeries
<p>Abstract</p> <p>Background</p> <p>Despite the known health and healthcare costs of untreated chlamydia infection and the efforts of the National Chlamydia Screening Programme (NCSP) to control chlamydia through early detection and treatment of asymptomatic infection, the rates of screening are well below the 2010-2011 target rate of 35%. General Practitioner (GP) surgeries are a key venue within the NCSP however; previous studies indicate that GP surgery staff are concerned that they may offend their patients by offering a screen. This study aimed to identify the attitudes to, and preferences for, chlamydia screening in 15-24 year old men and women attending GP surgeries (the target group).</p> <p>Methods</p> <p>We undertook 36 interviews in six surgeries of differing screening rates. Our participants were 15-24 year olds attending a consultation with a staff member. Data were analysed thematically.</p> <p>Results</p> <p>GP surgeries are acceptable to young people as a venue for opportunistic chlamydia screening and furthermore they think it is the duty of GP surgery staff to offer it. They felt strongly that it is important for surgery staff to have a non-judgemental attitude and they did not want to be singled out as 'needing' a chlamydia screen. Furthermore, our sample reported a strong preference for being offered a screen by staff and providing the sample immediately at the surgery rather than taking home a testing kit. The positive attitude and subjective norms demonstrated by interviewees suggest that young peoples' behaviour would be to accept a screen if it was offered to them.</p> <p>Conclusion</p> <p>Young people attending GP surgeries have a positive attitude towards chlamydia screening and given the right environment are likely to take up the offer in this setting. The right environment involves normalising screening by offering a chlamydia screen to all 15-24 year olds at every interaction with staff, offering screening with a non-judgemental attitude and minimising barriers to screening such as embarrassment. The GP surgery is the ideal place to screen young people for chlamydia as it is not a threatening place for them and our study has shown that they think it is the normal place to go to discuss health matters.</p
Can metabolomics in addition to genomics add to prognostic and predictive information in breast cancer?
Genomic data from breast cancers provide additional prognostic and predictive information that is beginning to be used for patient management. The question arises whether additional information derived from other 'omic' approaches such as metabolomics can provide additional information. In an article published this month in BMC Cancer, Borgan et al. add metabolomic information to genomic measures in breast tumours and demonstrate, for the first time, that it may be possible to further define subgroups of patients which could be of value clinically
Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer
INTRODUCTION
Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.
METHODS
More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.
RESULTS
The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working.
CONCLUSIONS
With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years
Type Ia Supernovae as Stellar Endpoints and Cosmological Tools
Empirically, Type Ia supernovae are the most useful, precise, and mature
tools for determining astronomical distances. Acting as calibrated candles they
revealed the presence of dark energy and are being used to measure its
properties. However, the nature of the SN Ia explosion, and the progenitors
involved, have remained elusive, even after seven decades of research. But now
new large surveys are bringing about a paradigm shift --- we can finally
compare samples of hundreds of supernovae to isolate critical variables. As a
result of this, and advances in modeling, breakthroughs in understanding all
aspects of SNe Ia are finally starting to happen.Comment: Invited review for Nature Communications. Final published version.
Shortened, update
An Inhibitory Antibody Blocks Interactions between Components of the Malarial Invasion Machinery
Host cell invasion by apicomplexan pathogens such as the malaria parasite Plasmodium spp. and Toxoplasma gondii involves discharge of proteins from secretory organelles called micronemes and rhoptries. In Toxoplasma a protein complex comprising the microneme apical membrane antigen 1 (AMA1), two rhoptry neck proteins, and a protein called Ts4705, localises to the moving junction, a region of close apposition between parasite and host cell during invasion. Antibodies against AMA1 prevent invasion and are protective in vivo, and so AMA1 is of widespread interest as a malaria vaccine candidate. Here we report that the AMA1 complex identified in Toxoplasma is conserved in Plasmodium falciparum. We demonstrate that the invasion-inhibitory monoclonal antibody (mAb) 4G2, which recognises P. falciparum AMA1 (PfAMA1), cannot bind when PfAMA1 is in a complex with its partner proteins. We further show that a single completely conserved PfAMA1 residue, Tyr251, lying within a conserved hydrophobic groove adjacent to the mAb 4G2 epitope, is required for complex formation. We propose that mAb 4G2 inhibits invasion by preventing PfAMA1 from interacting with other components of the invasion complex. Our findings should aid the rational design of subunit malaria vaccines based on PfAMA1
Maternal neurofascin-specific autoantibodies bind to structures of the fetal nervous system during pregnancy, but have no long term effect on development in the rat
Neurofascin was recently reported as a target for axopathic autoantibodies in patients with multiple sclerosis (MS), a response that will exacerbate axonal pathology and disease severity in an animal model of multiple sclerosis. As transplacental transfer of maternal autoantibodies can permanently damage the developing nervous system we investigated whether intrauterine exposure to this neurofascin-specific response had any detrimental effect on white matter tract development. To address this question we intravenously injected pregnant rats with either a pathogenic anti-neurofascin monoclonal antibody or an appropriate isotype control on days 15 and 18 of pregnancy, respectively, to mimic the physiological concentration of maternal antibodies in the circulation of the fetus towards the end of pregnancy. Pups were monitored daily with respect to litter size, birth weight, growth and motor development. Histological studies were performed on E20 embryos and pups sacrificed on days 2, 10, 21, 32 and 45 days post partum. Results: Immunohistochemistry for light and confocal microscopy confirmed passively transferred anti-neurofascin antibody had crossed the placenta to bind to distinct structures in the developing cortex and cerebellum. However, this did not result in any significant differences in litter size, birth weight, or general physical development between litters from control mothers or those treated with the neurofascin-specific antibody. Histological analysis also failed to identify any neuronal or white matter tract abnormalities induced by the neurofascin-specific antibody. Conclusions: We show that transplacental transfer of circulating anti-neurofascin antibodies can occur and targets specific structures in the CNS of the developing fetus. However, this did not result in any pre- or post-natal abnormalities in the offspring of the treated mothers. These results assure that even if anti-neurofascin responses are detected in pregnant women with multiple sclerosis these are unlikely to have a negative effect on their children
Quantitative Analysis Reveals that Actin and Src-Family Kinases Regulate Nuclear YAP1 and Its Export
The transcriptional regulator YAP1 is critical for the pathological activation of fibroblasts. In normal fibroblasts, YAP1 is located in the cytoplasm, while in activated cancer-associated fibroblasts, it is nuclear and promotes the expression of genes required for pro-tumorigenic functions. Here, we investigate the dynamics of YAP1 shuttling in normal and activated fibroblasts, using EYFP-YAP1, quantitative photobleaching methods, and mathematical modeling. Imaging of migrating fibroblasts reveals the tight temporal coupling of cell shape change and altered YAP1 localization. Both 14-3-3 and TEAD binding modulate YAP1 shuttling, but neither affects nuclear import. Instead, we find that YAP1 nuclear accumulation in activated fibroblasts results from Src and actomyosin-dependent suppression of phosphorylated YAP1 export. Finally, we show that nuclear-constrained YAP1, upon XPO1 depletion, remains sensitive to blockade of actomyosin function. Together, these data place nuclear export at the center of YAP1 regulation and indicate that the cytoskeleton can regulate YAP1 within the nucleus
Treatment of Highly Drug-Resistant Pulmonary Tuberculosis
BACKGROUND
Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.
METHODS
In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs — bedaquiline, pretomanid, and linezolid — that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.
RESULTS
A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.
CONCLUSIONS
The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799. opens in new tab.
Narrowband Biphotons: Generation, Manipulation, and Applications
In this chapter, we review recent advances in generating narrowband biphotons
with long coherence time using spontaneous parametric interaction in monolithic
cavity with cluster effect as well as in cold atoms with electromagnetically
induced transparency. Engineering and manipulating the temporal waveforms of
these long biphotons provide efficient means for controlling light-matter
quantum interaction at the single-photon level. We also review recent
experiments using temporally long biphotons and single photons.Comment: to appear as a book chapter in a compilation "Engineering the
Atom-Photon Interaction" published by Springer in 2015, edited by A.
Predojevic and M. W. Mitchel
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