Modelling hCDKL5 heterologous expression in bacteria

hCDKL5 refers to the human cyclin-dependent kinase like 5 that is primarily expressed in the brain. Mutations in its coding sequence are often causative of hCDKL5 deficiency disorder, a devastating neurodevelopmental disorder currently lacking a cure. The large-scale recombinant production of hCDKL5 is desirable to boost the translation of preclinical therapeutic approaches into the clinic. However, this is hampered by the intrinsically disordered nature of almost two-thirds of the hCDKL5 sequence, making this region more susceptible to proteolytic attack, and the observed toxicity when the enzyme is accumulated in the cytoplasm of eukaryotic host cells. The bacterium Pseudoalteromonas haloplanktis TAC125 (PhTAC125) is the only prokaryotic host in which the full-length production of hCDKL5 has been demonstrated. To date, a system-level understanding of the metabolic burden imposed by hCDKL5 production is missing, although it would be crucial for upscaling of the production process. Here, we combined experimental data on protein production and nutrients assimilation with metabolic modelling to infer the global consequences of hCDKL5 production in PhTAC125 and to identify potential overproduction targets. Our analyses showed a remarkable accuracy of the model in simulating the recombinant strain phenotype and also identified priority targets for optimised protein production

The influence of spacecraft latitudinal offset on the accuracy of corotation forecasts

Knowledge of the ambient solar wind is important for accurate space-weather forecasting. A simple-but-effective method of forecasting near-Earth solar-wind speed is “corotation”, wherein solar-wind structure is assumed to be fixed in the reference frame rotating with the Sun. Under this approximation, observations at a source spacecraft can be rotated to a target location, such as Earth. Forecast accuracy depends upon the rate of solar-wind evolution, longitudinal and latitudinal separation between the source and target, and latitudinal structure in the solar wind itself. The time-evolution rate and latitudinal structure of the solar wind are both strongly influenced by the solar cycle, though in opposing ways. A latitudinal separation (offset) between source and target spacecraft is typically present, introducing an error to corotation forecasts. In this study, we use observations from the STEREO and near-Earth spacecraft to quantify the latitudinal error. Aliasing between the solar cycle and STEREO orbits means that individual contributions to the forecast error are difficult to isolate. However, by considering an 18-month interval near the end of solar minimum, we find that the latitudinal-offset contribution to corotation-forecast error cannot be directly detected for offsets < 6°, but is increasingly important as offsets increase. This result can be used to improve solar-wind data assimilation, allowing representivity errors in solar-wind observations to be correctly specified. Furthermore, as the maximum latitudinal offset between L5 and Earth is ≈ 5°, corotation forecasts from a future L5 spacecraft should not be greatly affected by latitudinal offset

Quantifying pyroconvective injection heights using observations of fire energy: sensitivity of space-borne observations of carbon monoxide

We use observations of active fire area and fire radiative power (FRP) from the NASA Moderate Resolution Imaging Spectroradiometers (MODIS), together with a parameterized plume rise model, to estimate biomass burning injection heights during 2006. We use these injection heights in the GEOS-Chem (Goddard Earth Observing System Chemistry) atmospheric chemistry transport model to vertically distribute biomass burning emissions of carbon monoxide (CO) and to study the resulting atmospheric distribution. For 2006, we use over half a million FRP and fire area observations as input to the plume rise model. We find that convective heat fluxes and active fire area typically lie in the range of 1–100 kW m&minus;2 and 0.001–100 ha, respectively, although in rare circumstances the convective heat flux can exceed 500 kW m&minus;2. The resulting injection heights have a skewed probability distribution with approximately 80% of the injections remaining within the local boundary layer (BL), with occasional injection height exceeding 8 km. We do not find a strong correlation between the FRP-inferred surface convective heat flux and the resulting injection height, with environmental conditions often acting as a barrier to rapid vertical mixing even where the convective heat flux and active fire area are large. We also do not find a robust relationship between the underlying burnt vegetation type and the injection height. We find that CO columns calculated using the MODIS-inferred injection height (MODIS-INJ) are typically −9 to +6% different to the control calculation in which emissions are emitted into the BL, with differences typically largest over the point of emission. After applying MOPITT (Measurement of Pollution in the Troposphere) v5 scene-dependent averaging kernels we find that we are much less sensitive to our choice of injection height profile. The differences between the MOPITT and the model CO columns (max bias ~ 50%), due largely to uncertainties in emission inventories, are much larger than those introduced by the injection heights. We show that including a realistic diurnal variation in FRP (peaking in the afternoon) or accounting for subgrid-scale emission errors does not alter our main conclusions. Finally, we use a Bayesian maximum a posteriori approach constrained by MOPITT CO profiles to estimate the CO emissions but because of the inherent bias between model and MOPITT we find little impact on the resulting emission estimates. Studying the role of pyroconvection in the distribution of gases and particles in the atmosphere using global MOPITT CO observations (or any current spaceborne measurement of the atmosphere) is still associated with large errors, with the exception of a small subset of large fires and favourable environmental conditions, which will consequently lead to a bias in any analysis on a global scale

A comparison of OEM CO retrievals from the IASI and MOPITT instruments

Observations of atmospheric carbon monoxide (CO) can only be made on continental and global scales by remote sensing instruments situated in space. One such instrument is the Infrared Atmospheric Sounding Interferometer (IASI), producing spectrally resolved, top-of-atmosphere radiance measurements from which CO vertical layers and total columns can be retrieved. This paper presents a technique for intercomparisons of satellite data with low vertical resolution. The example in the paper also generates the first intercomparison between an IASI CO data set, in this case that produced by the University of Leicester IASI Retrieval Scheme (ULIRS), and the V3 and V4 operationally retrieved CO products from the Measurements Of Pollution In The Troposphere (MOPITT) instrument. The comparison is performed for a localised region of Africa, primarily for an ocean day-time configuration, in order to develop the technique for instrument intercomparison in a region with well defined a priori.By comparing both the standard data and a special version of MOPITT data retrieved using the ULIRS a priori for CO, it is shown that standard intercomparisons of CO are strongly affected by the differing a priori data of the retrievals, and by the differing sensitivities of the two instruments. In particular, the differing a priori profiles for MOPITT V3 and V4 data result in systematic retrieved profile changes as expected. An application of averaging kernels is used to derive a difference quantity which is much less affected by smoothing error, and hence more sensitive to systematic error. These conclusions are confirmed by simulations with model profiles for the same region. This technique is used to show that for the data that has been processed the systematic bias between MOPITT V4 and ULIRS IASI data, at MOPITT vertical resolution, is less than 7 % for the comparison data set, and on average appears to be less than 4 %. The results of this study indicate that intercomparisons of satellite data sets with low vertical resolution should ideally be performed with: retrievals using a common a priori appropriate to the geographic region studied; the application of averaging kernels to compute difference quantities with reduced a priori influence; and a comparison with simulated differences using model profiles for the target gas in the region

Measurements of branching fraction ratios and CP-asymmetries in suppressed B^- -> D(-> K^+ pi^-)K^- and B^- -> D(-> K^+ pi^-)pi^- decays

We report the first reconstruction in hadron collisions of the suppressed decays B^- -> D(-> K^+ pi^-)K^- and B^- -> D(-> K^+ pi^-)pi^-, sensitive to the CKM phase gamma, using data from 7 fb^-1 of integrated luminosity collected by the CDF II detector at the Tevatron collider. We reconstruct a signal for the B^- -> D(-> K^+ pi^-)K^- suppressed mode with a significance of 3.2 standard deviations, and measure the ratios of the suppressed to favored branching fractions R(K) = [22.0 \pm 8.6(stat)\pm 2.6(syst)]\times 10^-3, R^+(K) = [42.6\pm 13.7(stat)\pm 2.8(syst)]\times 10^-3, R^-(K)= [3.8\pm 10.3(stat)\pm 2.7(syst]\times 10^-3, as well as the direct CP-violating asymmetry A(K) = -0.82\pm 0.44(stat)\pm 0.09(syst) of this mode. Corresponding quantities for B^- -> D(-> K^+ pi^-)pi^- decay are also reported.Comment: 8 pages, 1 figure, accepted by Phys.Rev.D Rapid Communications for Publicatio

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE

Measurement of the t t-bar production cross section in the dilepton channel in pp collisions at sqrt(s) = 7 TeV

The t t-bar production cross section (sigma[t t-bar]) is measured in proton-proton collisions at sqrt(s) = 7 TeV in data collected by the CMS experiment, corresponding to an integrated luminosity of 2.3 inverse femtobarns. The measurement is performed in events with two leptons (electrons or muons) in the final state, at least two jets identified as jets originating from b quarks, and the presence of an imbalance in transverse momentum. The measured value of sigma[t t-bar] for a top-quark mass of 172.5 GeV is 161.9 +/- 2.5 (stat.) +5.1/-5.0 (syst.) +/- 3.6(lumi.) pb, consistent with the prediction of the standard model.Comment: Replaced with published version. Included journal reference and DO

Search for anomalous t t-bar production in the highly-boosted all-hadronic final state

A search is presented for a massive particle, generically referred to as a Z', decaying into a t t-bar pair. The search focuses on Z' resonances that are sufficiently massive to produce highly Lorentz-boosted top quarks, which yield collimated decay products that are partially or fully merged into single jets. The analysis uses new methods to analyze jet substructure, providing suppression of the non-top multijet backgrounds. The analysis is based on a data sample of proton-proton collisions at a center-of-mass energy of 7 TeV, corresponding to an integrated luminosity of 5 inverse femtobarns. Upper limits in the range of 1 pb are set on the product of the production cross section and branching fraction for a topcolor Z' modeled for several widths, as well as for a Randall--Sundrum Kaluza--Klein gluon. In addition, the results constrain any enhancement in t t-bar production beyond expectations of the standard model for t t-bar invariant masses larger than 1 TeV.Comment: Submitted to the Journal of High Energy Physics; this version includes a minor typo correction that will be submitted as an erratu

Combined search for the quarks of a sequential fourth generation

Results are presented from a search for a fourth generation of quarks produced singly or in pairs in a data set corresponding to an integrated luminosity of 5 inverse femtobarns recorded by the CMS experiment at the LHC in 2011. A novel strategy has been developed for a combined search for quarks of the up and down type in decay channels with at least one isolated muon or electron. Limits on the mass of the fourth-generation quarks and the relevant Cabibbo-Kobayashi-Maskawa matrix elements are derived in the context of a simple extension of the standard model with a sequential fourth generation of fermions. The existence of mass-degenerate fourth-generation quarks with masses below 685 GeV is excluded at 95% confidence level for minimal off-diagonal mixing between the third- and the fourth-generation quarks. With a mass difference of 25 GeV between the quark masses, the obtained limit on the masses of the fourth-generation quarks shifts by about +/- 20 GeV. These results significantly reduce the allowed parameter space for a fourth generation of fermions.Comment: Replaced with published version. Added journal reference and DO