Differential induction of 12-O-tetradecanoylphorbol 13-acetate sequence gene expression in murine melanocytes and melanoma cells

We previously showed that growth of the nontumorigenic, immortal murine melanocyte line Mel-ab correlates with the depletion of protein kinase C (PKC), whereas quiescence is associated with elevated levels of this enzyme (Brooks G, et al., Cancer Res 51: 3281–3288, 1991). Here we report responses that occur in these cells downstream of PKC activation or downregulation. We examined induction of 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducible sequence (TIS) gene expression in Mel-ab melanocytes and in their transformed counterparts, B16 melanoma cells. Exposure of quiescent Mel-ab cells to the PKC-activating phorbol esters TPA or sapintoxin A at 81 nM for 2 h increased levels of mRNA for six of seven TIS genes examined (twofold to 80-fold increase in steady-state RNA levels for TIS 1, 7, 8, 11, 21, and 28 (c-fos); TIS 10 expression was not affected). No induction of 115 gene expression was observed either in growing Mel-ab cells maintained in 324 nM phorbol 12,13-dibutyrate or in B16 cells previously unexposed to phorbol esters, in which normal PKC levels were endogenously depressed. The cAMP-elevating agents choleratoxin (10 nM) and dibutyryl cyclic AMP (2.5 mM) increased levels of TIS mRNA (with the exception of TIS 10) in both proliferating Mel-ab and B16 cells, suggesting that downregulation of the PKC pathway is specific and not a consequence of a general inhibition of all signalling pathways.

Equitability revisited: why the “equitable threat score” is not equitable

In the forecasting of binary events, verification measures that are “equitable” were defined by Gandin and Murphy to satisfy two requirements: 1) they award all random forecasting systems, including those that always issue the same forecast, the same expected score (typically zero), and 2) they are expressible as the linear weighted sum of the elements of the contingency table, where the weights are independent of the entries in the table, apart from the base rate. The authors demonstrate that the widely used “equitable threat score” (ETS), as well as numerous others, satisfies neither of these requirements and only satisfies the first requirement in the limit of an infinite sample size. Such measures are referred to as “asymptotically equitable.” In the case of ETS, the expected score of a random forecasting system is always positive and only falls below 0.01 when the number of samples is greater than around 30. Two other asymptotically equitable measures are the odds ratio skill score and the symmetric extreme dependency score, which are more strongly inequitable than ETS, particularly for rare events; for example, when the base rate is 2% and the sample size is 1000, random but unbiased forecasting systems yield an expected score of around −0.5, reducing in magnitude to −0.01 or smaller only for sample sizes exceeding 25 000. This presents a problem since these nonlinear measures have other desirable properties, in particular being reliable indicators of skill for rare events (provided that the sample size is large enough). A potential way to reconcile these properties with equitability is to recognize that Gandin and Murphy’s two requirements are independent, and the second can be safely discarded without losing the key advantages of equitability that are embodied in the first. This enables inequitable and asymptotically equitable measures to be scaled to make them equitable, while retaining their nonlinearity and other properties such as being reliable indicators of skill for rare events. It also opens up the possibility of designing new equitable verification measures.

The full-spectrum correlated k method for longwave atmospheric radiative transfer: treatment of gaseous overlap

The correlated k-distribution (CKD) method is widely used in the radiative transfer schemes of atmospheric models, and involves dividing the spectrum into a number of bands and then reordering the gaseous absorption coefficients within each one. The fluxes and heating rates for each band may then be computed by discretizing the reordered spectrum into of order 10 quadrature points per major gas, and performing a pseudo-monochromatic radiation calculation for each point. In this paper it is first argued that for clear-sky longwave calculations, sufficient accuracy for most applications can be achieved without the need for bands: reordering may be performed on the entire longwave spectrum. The resulting full-spectrum correlated k (FSCK) method requires significantly fewer pseudo-monochromatic calculations than standard CKD to achieve a given accuracy. The concept is first demonstrated by comparing with line-by-line calculations for an atmosphere containing only water vapor, in which it is shown that the accuracy of heating-rate calculations improves approximately in proportion to the square of the number of quadrature points. For more than around 20 points, the root-mean-squared error flattens out at around 0.015 K d−1 due to the imperfect rank correlation of absorption spectra at different pressures in the profile. The spectral overlap of m different gases is treated by considering an m-dimensional hypercube where each axis corresponds to the reordered spectrum of one of the gases. This hypercube is then divided up into a number of volumes, each approximated by a single quadrature point, such that the total number of quadrature points is slightly fewer than the sum of the number that would be required to treat each of the gases separately. The gaseous absorptions for each quadrature point are optimized such they minimize a cost function expressing the deviation of the heating rates and fluxes calculated by the FSCK method from line-by-line calculations for a number of training profiles. This approach is validated for atmospheres containing water vapor, carbon dioxide and ozone, in which it is found that in the troposphere and most of the stratosphere, heating-rate errors of less than 0.2 K d−1 can be achieved using a total of 23 quadrature points, decreasing to less than 0.1 K d−1 for 32 quadrature points. It would be relatively straightforward to extend the method to include other gases.

ϱ → 4π in chirally symmetric models

The decays rho0 → 2π+2π− and rho0 → 2π0π+π− are studied using various effective Lagrangians for π and rho (and in some case a1) mesons, all of which respect the approximate chiral symmetry of the strong interaction. Partial widths of the order of 1 keV or less are found in all cases. These are an order of magnitude smaller than recent predictions based on non-chiral models.

Distributed acceleration of mobile radio network optimisation algorithms

The past decade has witnessed explosive growth of mobile subscribers and services. With the purpose of providing better-swifter-cheaper services, radio network optimisation plays a crucial role but faces enormous challenges. The concept of Dynamic Network Optimisation (DNO), therefore, has been introduced to optimally and continuously adjust network configurations, in response to changes in network conditions and traffic. However, the realization of DNO has been seriously hindered by the bottleneck of optimisation speed performance. An advanced distributed parallel solution is presented in this paper, as to bridge the gap by accelerating the sophisticated proprietary network optimisation algorithm, while maintaining the optimisation quality and numerical consistency. The ariesoACP product from Arieso Ltd serves as the main platform for acceleration. This solution has been prototyped, implemented and tested. Real-project based results exhibit a high scalability and substantial acceleration at an average speed-up of 2.5, 4.9 and 6.1 on a distributed 5-core, 9-core and 16-core system, respectively. This significantly outperforms other parallel solutions such as multi-threading. Furthermore, augmented optimisation outcome, alongside high correctness and self-consistency, have also been fulfilled. Overall, this is a breakthrough towards the realization of DNO.

On the importance of interplanetary magnetic field (By)on polar cap patch formation

A number of poleward moving events were observed between 1130 and 1300 UT on 11 February 2004, during periods of southward interplanetary magnetic field (IMF), while the steerable antenna of the European Incoherent Scatter (EISCAT) Svalbard radar (ESR)and the Tromsø VHF radar pointed nearly northward at low elevation. In this interval, simultaneous SuperDARN CUTLASS Finland radar measurements showed poleward moving radar aurora forms (PMRAFs) which appeared very similar to the density enhancements observed by the ESR northward pointing antenna. These events appeared quasiperiodically with a period of about 10 min. Comparing the observations from the above three radars, it is inferred that there is an almost one‐to‐one correspondence between the poleward moving plasma concentration enhancements (PMPCEs) observed by the ESR and the VHF radar and the PMRAFs measured by the CUTLASS Finland radar. These observations are consistent with the interpretation that the polar cap patch material was generated by photoionization at subauroral latitudes and that the plasma was structured by bursts of magnetopause reconnection giving access to the polar cap. There is clear evidence that plasma structuring into patches was dependent on the variability in IMF |By|. The duration of these events implies that the average evolution time of the newly opened flux tubes from the subauroral region to the polar cap was about 33 min.

Production and dissolution rates of earthworm-secreted calcium carbonate

Earthworms secrete granules of calcium carbonate. These are potentially important in soil biogeochemical cycles and are routinely recorded in archaeological studies of Quaternary soils. Production rates of calcium carbonate granules by the earthworm Lumbricus terrestris L. were determined over 27 days in a range of soils with differing chemical properties (pH, organic matter content, water holding capacity, bulk composition, cation exchange capacity and exchangeable cations). Production rate varied between soils, lay in the range 0–0.043 mmolCaCO3 (0–4.3 mg) earthworm−1 d−1 with an average rate of 8 × 10−3 mmolCaCO3 (0.8 mg) earthworm−1 d−1 and was significantly correlated (r = 0.68, P ≤ 0.01) with soil pH. In a second experiment lasting 315 days earthworms repeatedly (over periods of 39–57 days) produced comparable masses of granules. Converting individual earthworm granule production rates into fluxes expressed on per hectare of land per year basis depends heavily on estimates of earthworm numbers. Using values of 10–20 L. terrestris m−2 suggests a rate of 18– 3139 molCaCO3 ha−1 yr−1. Data obtained from flow-through dissolution experiments suggest that at near neutral pH, granule geometric surface areanormalised dissolution rates are similar to those for other biogenic and inorganic calcium carbonate. Fits of the data to the dissolution relationship r = k(1 − ˝)n where r = dissolution rate, k = a rate constant, ˝ = relative saturation and n = the reaction order gave values of k = 1.72 × 10−10 mol cm−2 s−1 and n = 1.8 for the geometric surface area-normalised rates and k = 3.51 × 10−13 mol cm−2 s−1 and n = 1.8 for the BET surface area-normalised rates. In 196 day leaching column experiments trends in granule dissolution rate referenced to soil chemistry corresponded to predictions made by the SLIM model for dissolution of limestone in soil. If soil solution approaches saturation with respect to calcium carbonate granule dissolution will slow or even stop and granules be preserved indefinitely. Granules have the potential to be a small but significant component of the biogeochemical cycling of C and Ca in soil.

Evaluation of the environmental specificity of fluorescence in situ hybridization (FISH) using fluorescence-activated cell sorting (FACS) of probe (PSE1284)-positive cells extracted from rhizosphere soil

We explicitly tested for the first time the ‘environmental specificity’ of traditional 16S rRNAtargeted fluorescence in situ hybridization (FISH) through comparison of the bacterial diversity actually targeted in the environment with the diversity that should be exactly targeted (i.e. without mismatches) according to in silico analysis. To do this, we exploited advances in modern Flow Cytometry that enabled improved detection and therefore sorting of sub-micron-sized particles and used probe PSE1284 (designed to target Pseudomonads) applied to Lolium perenne rhizosphere soil as our test system. The 6-carboxyfluorescein (6-FAM)-PSE1284-hybridised population, defined as displaying enhanced green fluorescence in Flow Cytometry, represented 3.51±1.28% of the total detected population when corrected using a nonsense (NON-EUB338) probe control. Analysis of 16S rRNA gene libraries constructed from Fluorescence Activated Cell Sorted (FACS) -recovered fluorescent populations (n=3), revealed that 98.5% (Pseudomonas spp. comprised 68.7% and Burkholderia spp. 29.8%) of the total sorted population was specifically targeted as evidenced by the homology of the 16S rRNA sequences to the probe sequence. In silico evaluation of probe PSE1284 with the use of RDP-10 probeMatch justified the existence of Burkholderia spp. among the sorted cells. The lack of novelty in Pseudomonas spp. sequences uncovered was notable, probably reflecting the well-studied nature of this functionally important genus. To judge the diversity recorded within the FACS-sorted population, rarefaction and DGGE analysis were used to evaluate, respectively, the proportion of Pseudomonas diversity uncovered by the sequencing effort and the representativeness of the Nycodenz® method for the extraction of bacterial cells from soil.

Self-assembly of Fmoc-tetrapeptides based on the RGDS cell adhesion motif

Self-assembly in aqueous solution has been investigated for two Fmoc [Fmoc ¼ N-(fluorenyl)-9-methoxycarbonyl] tetrapeptides comprising the RGDS cell adhesion motif from fibronectin or the scrambled sequence GRDS. The hydrophobic Fmoc unit confers amphiphilicity on the molecules, and introduces aromatic stacking interactions. Circular dichroism and FTIR spectroscopy show that the self-assembly of both peptides at low concentration is dominated by interactions among Fmoc units, although Fmoc-GRDS shows b-sheet features, at lower concentration than Fmoc-RGDS. Fibre X-ray diffraction indicates b-sheet formation by both peptides at sufficiently high concentration. Strong alignment effects are revealed by linear dichroism experiments for Fmoc-GRDS. Cryo-TEM and smallangle X-ray scattering (SAXS) reveal that both samples form fibrils with a diameter of approximately 10 nm. Both Fmoc-tetrapeptides form self-supporting hydrogels at sufficiently high concentration. Dynamic shear rheometry enabled measurements of the moduli for the Fmoc-GRDS hydrogel, however syneresis was observed for the Fmoc-RGDS hydrogel which was significantly less stable to shear. Molecular dynamics computer simulations were carried out considering parallel and antiparallel b-sheet configurations of systems containing 7 and 21 molecules of Fmoc-RGDS or Fmoc-GRDS, the results being analyzed in terms of both intermolecular structural parameters and energy contributions.

The shape and tempo of language evolution

There are approximately 7000 languages spoken in the world today. This diversity reflects the legacy of thousands of years of cultural evolution. How far back we can trace this history depends largely on the rate at which the different components of language evolve. Rates of lexical evolution are widely thought to impose an upper limit of 6000-10,000 years on reliably identifying language relationships. In contrast, it has been argued that certain structural elements of language are much more stable. Just as biologists use highly conserved genes to uncover the deepest branches in the tree of life, highly stable linguistic features hold the promise of identifying deep relationships between the world's languages. Here, we present the first global network of languages based on this typological information. We evaluate the relative evolutionary rates of both typological and lexical features in the Austronesian and Indo-European language families. The first indications are that typological features evolve at similar rates to basic vocabulary but their evolution is substantially less tree-like. Our results suggest that, while rates of vocabulary change are correlated between the two language families, the rates of evolution of typological features and structural subtypes show no consistent relationship across families.

Tropical cyclone climatology in a 10-km global atmospheric GCM: toward weather-resolving climate modeling

Northern Hemisphere tropical cyclone (TC) activity is investigated in multiyear global climate simulations with theECMWFIntegrated Forecast System (IFS) at 10-km resolution forced by the observed records of sea surface temperature and sea ice. The results are compared to analogous simulationswith the 16-, 39-, and 125-km versions of the model as well as observations. In the North Atlantic, mean TC frequency in the 10-km model is comparable to the observed frequency, whereas it is too low in the other versions. While spatial distributions of the genesis and track densities improve systematically with increasing resolution, the 10-km model displays qualitatively more realistic simulation of the track density in the western subtropical North Atlantic. In the North Pacific, the TC count tends to be too high in thewest and too low in the east for all resolutions. These model errors appear to be associated with the errors in the large-scale environmental conditions that are fairly similar in this region for all model versions. The largest benefits of the 10-km simulation are the dramatically more accurate representation of the TC intensity distribution and the structure of the most intense storms. The model can generate a supertyphoon with a maximum surface wind speed of 68.4 m s21. The life cycle of an intense TC comprises intensity fluctuations that occur in apparent connection with the variations of the eyewall/rainband structure. These findings suggest that a hydrostatic model with cumulus parameterization and of high enough resolution could be efficiently used to simulate the TC intensity response (and the associated structural changes) to future climate change.

Sources of multi-decadal variability in Arctic sea ice extent

The observed dramatic decrease in September sea ice extent (SIE) has been widely discussed in the scientific literature. Though there is qualitative agreement between observations and ensemble members of the Third Coupled Model Intercomparison Project (CMIP3), it is concerning that the observed trend (1979–2010) is not captured by any ensemble member. The potential sources of this discrepancy include: observational uncertainty, physical model limitations and vigorous natural climate variability. The latter has received less attention and is difficult to assess using the relatively short observational sea ice records. In this study multi-centennial pre-industrial control simulations with five CMIP3 climate models are used to investigate the role that the Arctic oscillation (AO), the Atlantic multi-decadal oscillation (AMO) and the Atlantic meridional overturning circulation (AMOC) play in decadal sea ice variability. Further, we use the models to determine the impact that these sources of variability have had on SIE over both the era of satellite observation (1979–2010) and an extended observational record (1953–2010). There is little evidence of a relationship between the AO and SIE in the models. However, we find that both the AMO and AMOC indices are significantly correlated with SIE in all the models considered. Using sensitivity statistics derived from the models, assuming a linear relationship, we attribute 0.5–3.1%/decade of the 10.1%/decade decline in September SIE (1979–2010) to AMO driven variability.

Parabens enable suspension growth of MCF-10A immortalized, non-transformed human breast epithelial cells

Parabens (alkyl esters of p-hydroxybenzoic acid) are used extensively as preservatives in consumer products, and intact esters have been measured in several human tissues. Concerns of a potential link between parabens and breast cancer have been raised, but mechanistic studies have centred on their oestrogenic activity and little attention has been paid to any carcinogenic properties. In the present study, we report that parabens can induce anchorage-independent growth of MCF-10A immortalized but non-transformed human breast epithelial cells, a property closely related to transformation and a predictor of tumour growth in vivo. In semi-solid methocel suspension culture, MCF-10A cells produced very few colonies and only of a small size but the addition of 5 × 10-4 M methylparaben, 10–5 M n-propylparaben or 10–5 M n-butylparaben resulted in a greater number of colonies per dish (P < 0.05 in each case) and an increased average colony size (P < 0.001 in each case). Dose-responses showed that concentrations as low as 10–6 M methylparaben, 10–7 M n-propylparaben and 10–7 M n-butylparaben could increase colony numbers (P = 0.016, P = 0.010, P = 0.008, respectively): comparison with a recent measurement of paraben concentrations in human breast tissue samples from 40 mastectomies (Barr et al., 2012) showed that 22/40 of the patients had at least one of the parabens at the site of the primary tumour at or above these concentrations. To our knowledge, this is the first study to report that parabens can induce a transformed phenotype in human breast epithelial cells in vitro, and further investigation is now justified into a potential link between parabens and breast carcinogenesis.

Ocean heat uptake and its consequences for the magnitude of sea level rise and climate change

Under increasing greenhouse gas concentrations, ocean heat uptake moderates the rate of climate change, and thermal expansion makes a substantial contribution to sea level rise. In this paper we quantify the differences in projections among atmosphere-ocean general circulation models of the Coupled Model Intercomparison Project in terms of transient climate response, ocean heat uptake efficiency and expansion efficiency of heat. The CMIP3 and CMIP5 ensembles have statistically indistinguishable distributions in these parameters. The ocean heat uptake efficiency varies by a factor of two across the models, explaining about 50% of the spread in ocean heat uptake in CMIP5 models with CO2 increasing at 1%/year. It correlates with the ocean global-mean vertical profiles both of temperature and of temperature change, and comparison with observations suggests the models may overestimate ocean heat uptake and underestimate surface warming, because their stratification is too weak. The models agree on the location of maxima of shallow ocean heat uptake (above 700 m) in the Southern Ocean and the North Atlantic, and on deep ocean heat uptake (below 2000 m) in areas of the Southern Ocean, in some places amounting to 40% of the top-to-bottom integral in the CMIP3 SRES A1B scenario. The Southern Ocean dominates global ocean heat uptake; consequently the eddy-induced thickness diffusivity parameter, which is particularly influential in the Southern Ocean, correlates with the ocean heat uptake efficiency. The thermal expansion produced by ocean heat uptake is 0.12 m YJ−1, with an uncertainty of about 10% (1 YJ = 1024 J).

Aerosol contribution to the rapid warming of near-term climate under RCP 2.6

The importance of aerosol emissions for near term climate projections is investigated by analysing simulations with the HadGEM2-ES model under two different emissions scenarios: RCP2.6 and RCP4.5. It is shown that the near term warming projected under RCP2.6 is greater than under RCP4.5, even though the greenhouse gas forcing is lower. Rapid and substantial reductions in sulphate aerosol emissions due to a reduction of coal burning in RCP2.6 lead to a reduction in the negative shortwave forcing due to aerosol direct and indirect effects. Indirect effects play an important role over the northern hemisphere oceans, especially the subtropical northeastern Pacific where an anomaly of 5-10\,Wm$^{-2}$ develops. The pattern of surface temperature change is consistent with the expected response to this surface radiation anomaly, whilst also exhibiting features that reflect redistribution of energy, and feedbacks, within the climate system. These results demonstrate the importance of aerosol emissions as a key source of uncertainty in near term projections of global and regional climate.