A proteomic investigation to discover candidate proteins involved in novel mechanisms of 5-fluorouracil resistance in colorectal cancer

YesOne of the main obstacles to therapeutic success in colorectal cancer (CRC) is the development of acquired resistance to treatment with drugs such as 5-fluorouracil (5-FU). Whilst some resistance mechanisms are well known, it is clear from the stasis in therapy success rate that much is still unknown. Here, a proteomics approach is taken towards identification of candidate proteins using 5-FU-resistant sublines of human CRC cell lines generated in house. Using a multiplexed stable isotope labelling with amino acids in cell culture (SILAC) strategy, 5-FU-resistant and equivalently passaged sensitive cell lines were compared to parent cell lines by growing in Heavy medium with 2D liquid chromatography and Orbitrap Fusion™ Tribrid™ Mass Spectrometry analysis. Among 3003 commonly quantified proteins, six (CD44, APP, NAGLU, CORO7, AGR2, PLSCR1) were found up-regulated, and six (VPS45, RBMS2, RIOK1, RAP1GDS1, POLR3D, CD55) down-regulated. A total of 11 of the 12 proteins have a known association with drug resistance mechanisms or role in CRC oncogenesis. Validation through immunodetection techniques confirmed high expression of CD44 and CD63, two known drug resistance mediators with elevated proteomics expression results. The information revealed by the sensitivity of this method warrants it as an important tool for elaborating the complexity of acquired drug resistance in CRC.Sadr ul-Shaheed and the University of Bradford Proteomics Facility were supported by Yorkshire Cancer Research, UK (Cancer Medicine Discovery II, grant B381PA)

Can Teachers Accurately Predict Student Performance?

In two studies, we examined the effect of professional development to improve mathematics instruction on the accuracy of teachers\u27 monitoring of student learning. Study 1 was conducted with 36 teachers participating in three years of professional development. Judgment accuracy was influenced by the fidelity with which what was learned in the professional development. Study 2 was conducted with 64 teachers from 8 schools, which were randomly assigned to receive professional development or serve as a control. Judgment accuracy was greater for teachers receiving professional development than for teachers who did not and teachers were better to predict students\u27 computational skills

The NuSTAR ULX program

We present the results of the first large program of broadband ULX observations with NuSTAR, XMM-Newton and Suzaku, yielding high-quality spectra and timing measurements from 0.3-30 keV in 6 ULXs, providing powerful information for understanding the accretion modes and nature of the central BHs. In particular, we find that all ULXs in our sample have a clear cutoff above 10 keV. This cutoff is less pronounced than expected by Comptonization from a cold, thick corona. We confirm the presence of a soft excess at low energies in the brightest ULXs, with temperatures below ~ 0.5 keV. We make an estimates on the masses of several ULXs based on spectral variability and model fitting

Characterizing the genetic diversity of the monkey malaria parasite Plasmodium cynomolgi

Plasmodium cynomolgi is a malaria parasite that typically infects Asian macaque monkeys, and humans on rare occasions. P. cynomolgi serves as a model system for the human malaria parasite Plasmodium vivax, with which it shares such important biological characteristics as formation of a dormant liver stage and a preference to invade reticulocytes. While genomes of three P. cynomolgi strains have been sequenced, genetic diversity of P. cynomolgi has not been widely investigated. To address this we developed the first panel of P. cynomolgi microsatellite markers to genotype eleven P. cynomolgi laboratory strains and 18 field isolates fromSarawak,Malaysian Borneo. We found diverse genotypes among most of the laboratory strains, though two nominally different strains were found to be genetically identical. We also investigated sequence polymorphism in two erythrocyte invasion gene families, the reticulocyte binding protein and Duffy binding protein genes, in these strains. Wealso observed copy number variation in rbp genes

B Cells Regulate Neutrophilia during Mycobacterium tuberculosis Infection and BCG Vaccination by Modulating the Interleukin-17 Response

We have previously demonstrated that B cells can shape the immune response to Mycobacterium tuberculosis, including the level of neutrophil infiltration and granulomatous inflammation at the site of infection. The present study examined the mechanisms by which B cells regulate the host neutrophilic response upon exposure to mycobacteria and how neutrophilia may influence vaccine efficacy. To address these questions, a murine aerosol infection tuberculosis (TB) model and an intradermal (ID) ear BCG immunization mouse model, involving both the μMT strain and B cell-depleted C57BL/6 mice, were used. IL (interleukin)-17 neutralization and neutrophil depletion experiments using these systems provide evidence that B cells can regulate neutrophilia by modulating the IL-17 response during M. tuberculosis infection and BCG immunization. Exuberant neutrophilia at the site of immunization in B cell-deficient mice adversely affects dendritic cell (DC) migration to the draining lymph nodes and attenuates the development of the vaccine-induced Th1 response. The results suggest that B cells are required for the development of optimal protective anti-TB immunity upon BCG vaccination by regulating the IL-17/neutrophilic response. Administration of sera derived from M. tuberculosis-infected C57BL/6 wild-type mice reverses the lung neutrophilia phenotype in tuberculous μMT mice. Together, these observations provide insight into the mechanisms by which B cells and humoral immunity modulate vaccine-induced Th1 response and regulate neutrophila during M. tuberculosis infection and BCG immunization. © 2013 Kozakiewicz et al

A multi-decade record of high quality fCO2 data in version 3 of the Surface Ocean CO2 Atlas (SOCAT)

The Surface Ocean CO2 Atlas (SOCAT) is a synthesis of quality-controlled fCO2 (fugacity of carbon dioxide) values for the global surface oceans and coastal seas with regular updates. Version 3 of SOCAT has 14.7 million fCO2 values from 3646 data sets covering the years 1957 to 2014. This latest version has an additional 4.6 million fCO2 values relative to version 2 and extends the record from 2011 to 2014. Version 3 also significantly increases the data availability for 2005 to 2013. SOCAT has an average of approximately 1.2 million surface water fCO2 values per year for the years 2006 to 2012. Quality and documentation of the data has improved. A new feature is the data set quality control (QC) flag of E for data from alternative sensors and platforms. The accuracy of surface water fCO2 has been defined for all data set QC flags. Automated range checking has been carried out for all data sets during their upload into SOCAT. The upgrade of the interactive Data Set Viewer (previously known as the Cruise Data Viewer) allows better interrogation of the SOCAT data collection and rapid creation of high-quality figures for scientific presentations. Automated data upload has been launched for version 4 and will enable more frequent SOCAT releases in the future. High-profile scientific applications of SOCAT include quantification of the ocean sink for atmospheric carbon dioxide and its long-term variation, detection of ocean acidification, as well as evaluation of coupled-climate and ocean-only biogeochemical models. Users of SOCAT data products are urged to acknowledge the contribution of data providers, as stated in the SOCAT Fair Data Use Statement. This ESSD (Earth System Science Data) “living data” publication documents the methods and data sets used for the assembly of this new version of the SOCAT data collection and compares these with those used for earlier versions of the data collection (Pfeil et al., 2013; Sabine et al., 2013; Bakker et al., 2014). Individual data set files, included in the synthesis product, can be downloaded here: doi:10.1594/PANGAEA.849770. The gridded products are available here: doi:10.3334/CDIAC/OTG.SOCAT_V3_GRID

Historical simulations with HadGEM3-GC3.1 for CMIP6

We describe and evaluate historical simulations which use the third Hadley Centre Global Environment Model in the Global Coupled configuration 3.1 (HadGEM3-GC3.1) model and which form part of the UK's contribution to the sixth Coupled Model Intercomparison Project, CMIP6. These simulations, run at two resolutions, respond to historically evolving forcings such as greenhouse gases, aerosols, solar irradiance, volcanic aerosols, land use, and ozone concentrations. We assess the response of the simulations to these historical forcings and compare against the observational record. This includes the evolution of global mean surface temperature, ocean heat content, sea ice extent, ice sheet mass balance, permafrost extent, snow cover, North Atlantic sea surface temperature and circulation, and decadal precipitation. We find that the simulated time evolution of global mean surface temperature broadly follows the observed record but with important quantitative differences which we find are most likely attributable to strong effective radiative forcing from anthropogenic aerosols and a weak pattern of sea surface temperature response in the low to middle latitudes to volcanic eruptions. We also find evidence that anthropogenic aerosol forcings play a role in driving the Atlantic Multidecadal Variability and the Atlantic Meridional Overturning Circulation, which are key features of the North Atlantic ocean. Overall, the model historical simulations show many features in common with the observed record over the period 1850–2014 and so provide a basis for future in-depth study of recent climate change