Importance of tropospheric volcanic aerosol for indirect radiative forcing of climate

Observations and models have shown that continuously degassing volcanoes have a potentially large effect on the natural background aerosol loading and the radiative state of the atmosphere. We use a global aerosol microphysics model to quantify the impact of these volcanic emissions on the cloud albedo radiative forcing under pre-industrial (PI) and present-day (PD) conditions. We find that volcanic degassing increases global annual mean cloud droplet number concentrations by 40% under PI conditions, but by only 10% under PD conditions. Consequently, volcanic degassing causes a global annual mean cloud albedo effect of −1.06 W m−2 in the PI era but only −0.56 W m−2 in the PD era. This non-equal effect is explained partly by the lower background aerosol concentrations in the PI era, but also because more aerosol particles are produced per unit of volcanic sulphur emission in the PI atmosphere. The higher sensitivity of the PI atmosphere to volcanic emissions has an important consequence for the anthropogenic cloud radiative forcing because the large uncertainty in volcanic emissions translates into an uncertainty in the PI baseline cloud radiative state. Assuming a −50/+100% uncertainty range in the volcanic sulphur flux, we estimate the annual mean anthropogenic cloud albedo forcing to lie between −1.16 W m−2 and −0.86 W m−2. Therefore, the volcanically induced uncertainty in the PI baseline cloud radiative state substantially adds to the already large uncertainty in the magnitude of the indirect radiative forcing of climate

Impact of future Arctic shipping on high-latitude black carbon deposition

This is the final version of the article. Available from American Geophysical Union (AGU) via the DOI in this record.The retreat of Arctic sea ice has led to renewed calls to exploit Arctic shipping routes. The diversion of ship traffic through the Arctic will shorten shipping routes and possibly reduce global shipping emissions. However, deposition of black carbon (BC) aerosol emitted by additional Arctic ships could cause a reduction in the albedo of snow and ice, accelerating snowmelt and sea ice loss. Here we use recently compiled Arctic shipping emission inventories for 2004 and 2050 together with a global aerosol model to quantify the contribution of future Arctic shipping to high-latitude BC deposition. Our results show that Arctic shipping in 2050 will contribute less than 1% to the total BC deposition north of 60°N due to the much greater relative contribution of BC transported from non-shipping sources at lower latitudes. We suggest that regulation of the Arctic shipping industry will be an insufficient control on high-latitude BC deposition. Key Points Contribution of Arctic shipping to high-latitude BC deposition less than 1% Extra-Arctic sources contribute much greater Arctic BC mass than local shipping Regulation of Arctic shipping unlikely to control high-latitude BC deposition.J.B. was funded by a studentship from the Natural Environment Research Council (NERC) and by the Met Office through a CASE partnership and is now funded by a NERC grant [NE/I028858/1]. K.C. is a Royal Society Wolfson Merit Award holder. A.S.is funded by a NERC grant [NE/I015612/1] and a fellowship from the School of Earth and Environment, University of Leeds. The Editor thanks three anonymous reviewers for their assistance in evaluating this paper

Exploring How Eruption Source Parameters Affect Volcanic Radiative Forcing Using Statistical Emulation

The radiative forcing caused by a volcanic eruption is dependent on several eruption source parameters such as the mass of sulfur dioxide (SO2) emitted, the eruption column height, and the eruption latitude. General circulation models with prognostic aerosol and chemistry schemes can be used to investigate how each parameter influences the volcanic forcing. However, the range of multidimensional parameter space that can be explored is restricted because such simulations are computationally expensive. Here we use statistical emulation to explore the radiative impact of eruptions over a wide covarying range of SO2 emission magnitudes, injection heights, and eruption latitudes based on only 30 simulations. We use the emulators to build response surfaces to visualize and predict the sulfate aerosol e-folding decay time, the stratospheric aerosol optical depth, and net radiative forcing of thousands of different eruptions. We find that the volcanic stratospheric aerosol optical depth and net radiative forcing are primarily determined by the mass of SO2 emitted, but eruption latitude is the most important parameter in determining the sulfate aerosol e-folding decay time. The response surfaces reveal joint effects of the eruption source parameters in influencing the net radiative forcing, such as a stronger influence of injection height for tropical eruptions than high-latitude eruptions. We also demonstrate how the emulated response surfaces can be used to find all combinations of eruption source parameters that produce a particular volcanic response, often revealing multiple solutions

Exciton and trion dynamics in atomically thin MoSe2 and WSe2: effect of localization

We present a detailed investigation of the exciton and trion dynamics in naturally doped MoSe2 and WSe2 single atomic layers as a function of temperature in the range 10-300K under above band-gap laser excitation. By combining time-integrated and time-resolved photoluminescence (PL) spectroscopy we show the importance of exciton and trion localization in both materials at low temperatures. We also reveal the transition to delocalized exciton complexes at higher temperatures where the exciton and trion thermal energy exceeds the typical localization energy. This is accompanied with strong changes in PL including suppression of the trion PL and decrease of the trion PL life-time, as well as significant changes for neutral excitons in the temperature dependence of the PL intensity and appearance of a pronounced slow PL decay component. In MoSe2 and WSe2 studied here, the temperatures where such strong changes occur are observed at around 100 and 200 K, respectively, in agreement with their inhomogeneous PL linewidth of 8 and 20 meV at T~10K. The observed behavior is a result of a complex interplay between influences of the specific energy ordering of bright and dark excitons in MoSe2 and WSe2, sample doping, trion and exciton localization and various temperature-dependent non-radiative processes

Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors

Purpose: We evaluated longitudinal tracking of BRAF V600E in circulating cellfree DNA (cfDNA) as a marker of treatment response to BRAF inhibitor (BRAFi) combination therapies in non-melanoma solid tumors included in the Copenhagen Prospective Personalized Oncology (CoPPO) program. Experimental design: Patients with BRAF V600E-mutated tumors were treated with combination therapies including BRAFi. Quantification of mutant cfDNA from plasma was determined and correlated to clinical outcomes. Exome sequencing was performed to identify possible resistance mutations. Results: Twenty-three patients had BRAF-mutated tumors out of 455 patients included in CoPPO and 17 started BRAFi combination (EGFRi/MEKi) therapy. Tumor responses were achieved in 8 out of 16 evaluable patients and the median overalland progression-free survival (OS and PFS) was 15 and 4.8 months, respectively. Longitudinal measurements of BRAF V600E-mutant cfDNA indicated disease progression prior to radiological evaluation and a reduction in the mutant fraction of more than 50% after 4 and 12 weeks of therapy was associated with a significantly longer PFS (p=0.003 and p=0.029) and OS (p=0.029 and p=0.017). Furthermore, the baseline mutant fraction and total level of cfDNA positively correlated with tumor burden (p=0.026 and p=0.024). Finally, analysis of cfDNA at progression revealed novel mutations potentially affecting the MAPK pathway. Conclusion: BRAFi combination therapies showed a response rate of 50% in BRAF V600E-mutated non-melanoma tumors. The fraction of BRAF-mutant cfDNA represent a sensitive indicator for clinical outcomes with plasma collected at week 4 and 12 as crucial time points for monitoring response and disease progression.This study was supported by the Danish Cancer Society, The Harboe Foundation, and the Oncological Research Fund, Department of Oncology, Copenhagen University Hospital, Denmark

Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers

Introduction: We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy. Methods: Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years. Results: In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results. Conclusions: Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy

A European Academy of Neurology guideline on medical management issues in dementia

BACKGROUND AND PURPOSE: Dementia is one of the most common disorders and is associated with increased morbidity, mortality and decreased quality of life. The present guideline addresses important medical management issues including systematic medical follow‐up, vascular risk factors in dementia, pain in dementia, use of antipsychotics in dementia and epilepsy in dementia. METHODS: A systematic review of the literature was carried out. Based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, we developed a guideline. Where recommendations based on GRADE were not possible, a good practice statement was formulated. RESULTS: Systematic management of vascular risk factors should be performed in patients with mild to moderate dementia as prevention of cerebrovascular pathology may impact on the progression of dementia (Good Practice statement). Individuals with dementia (without previous stroke) and atrial fibrillation should be treated with anticoagulants (weak recommendation). Discontinuation of opioids should be considered in certain individuals with dementia (e.g. for whom there are no signs or symptoms of pain or no clear indication, or suspicion of side effects; Good Practice statement). Behavioral symptoms in persons with dementia should not be treated with mild analgesics (weak recommendation). In all patients with dementia treated with opioids, assessment of the individual risk–benefit ratio should be performed at regular intervals. Regular, preplanned medical follow‐up should be offered to all patients with dementia. The setting will depend on the organization of local health services and should, as a minimum, include general practitioners with easy access to dementia specialists (Good Practice statement). Individuals with dementia and agitation and/or aggression should be treated with atypical antipsychotics only after all non‐pharmacological measures have been proven to be without benefit or in the case of severe self‐harm or harm to others (weak recommendation). Antipsychotics should be discontinued after cessation of behavioral disturbances and in patients in whom there are side effects (Good Practice statement). For treatment of epilepsy in individuals with dementia, newer anticonvulsants should be considered as first‐line therapy (Good Practice statement). CONCLUSION: This GRADE‐based guideline offers recommendations on several important medical issues in patients with dementia, and thus adds important guidance for clinicians. For some issues, very little or no evidence was identified, highlighting the importance of further studies within these areas

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

Combustion in thermonuclear supernova explosions

Type Ia supernovae are associated with thermonuclear explosions of white dwarf stars. Combustion processes convert material in nuclear reactions and release the energy required to explode the stars. At the same time, they produce the radioactive species that power radiation and give rise to the formation of the observables. Therefore, the physical mechanism of the combustion processes, as reviewed here, is the key to understand these astrophysical events. Theory establishes two distinct modes of propagation for combustion fronts: subsonic deflagrations and supersonic detonations. Both are assumed to play an important role in thermonuclear supernovae. The physical nature and theoretical models of deflagrations and detonations are discussed together with numerical implementations. A particular challenge arises due to the wide range of spatial scales involved in these phenomena. Neither the combustion waves nor their interaction with fluid flow and instabilities can be directly resolved in simulations. Substantial modeling effort is required to consistently capture such effects and the corresponding techniques are discussed in detail. They form the basis of modern multidimensional hydrodynamical simulations of thermonuclear supernova explosions. The problem of deflagration-to-detonation transitions in thermonuclear supernova explosions is briefly mentioned.Comment: Author version of chapter for 'Handbook of Supernovae,' edited by A. Alsabti and P. Murdin, Springer. 24 pages, 4 figure