The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and ...traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1-2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib.
In the Standard Model, the Higgs boson is a CP-even state with CP-conserving couplings; any deviations from this would be a sign of new physics. These CP properties can be probed by measuring Higgs ...decays to τ lepton pairs, in which the transverse correlation between the τ spins depends on CP. This paper develops such an analysis, using full simulation of signal and background events in the International Large Detector concept for the International Linear Collider. We consider Higgs-strahlung events (e+e−→HZ) in which the Z boson decays to electrons, muons, or hadrons, and the Higgs boson decays to τ leptons, which then decay either to τ±→π±ν or τ±→π±π0ν. Assuming 2 ab−1 of integrated luminosity at a center-of-mass energy of 250 GeV, the mixing angle between even and odd CP components of the τ pair from Higgs boson decays can be measured to a precision of 75 mrad (4.3°).
We report Hubble Space Telescope optical to near-infrared transmission spectroscopy of the hot-Jupiter WASP-6b, measured with the Space Telescope Imaging Spectrograph and Spitzer's InfraRed Array ...Camera. The resulting spectrum covers the range 0.29–4.5 μm. We find evidence for modest stellar activity of WASP-6 and take it into account in the transmission spectrum. The overall main characteristic of the spectrum is an increasing radius as a function of decreasing wavelength corresponding to a change of Δ (R
p / R
*) = 0.0071 from 0.33 to 4.5 μm. The spectrum suggests an effective extinction cross-section with a power law of index consistent with Rayleigh scattering, with temperatures of 973 ± 144 K at the planetary terminator. We compare the transmission spectrum with hot-Jupiter atmospheric models including condensate-free and aerosol-dominated models incorporating Mie theory. While none of the clear-atmosphere models is found to be in good agreement with the data, we find that the complete spectrum can be described by models that include significant opacity from aerosols including Fe-poor Mg2SiO4, MgSiO3, KCl and Na2S dust condensates. WASP-6b is the second planet after HD 189733b which has equilibrium temperatures near ∼1200 K and shows prominent atmospheric scattering in the optical.
We measure the transmission spectrum of WASP-19b from three transits using low-resolution optical spectroscopy from the Hubble Space Telescope (HST) Space Telescope Imaging Spectrograph (STIS). The ...STIS spectra cover a wavelength range of 0.29-1.03 μm, with resolving power R = 500. The optical data are combined with archival near-infrared data from the HST Wide Field Camera 3 (WFC3) G141 grism, covering the wavelength range from 1.087 to 1.687 μm, with resolving power R = 130. We reach signal-to-noise levels between 3000 and 11 000 in 0.1 μm bins when measuring the transmission spectra from 0.53-1.687 μm. WASP-19 is known to be a very active star, with the optical stellar flux varying by a few per cent over time. We correct the transit light curves for the effects of stellar activity using ground-based activity monitoring with the Cerro Tololo Inter-American Observatory. While we were not able to construct a transmission spectrum using the blue optical data because of the presence of large occulted starspots, we were able to use the spot crossings to help constrain the mean stellar spot temperature. To search for predicted features in the hot-Jupiter atmosphere, in addition to the transmission spectrum we also define spectral indices for differential radius (ΔR
P/R
) measurements to specifically search for the presence of TiO and alkali line features. Our measurements rule out TiO features predicted for a planet of WASP-19b's equilibrium temperature (2050 K) in the transmission spectrum at the 2.7-2.9σ confidence level, depending on atmospheric model formalism. The WFC3 transmission spectrum shows strong absorption features due to the presence of H2O, which is detected at the 4σ confidence level between 1.1 and 1.4 μm. The transmission spectra results indicate that WASP-19b is a planet with no or low levels of TiO and without a high C/O ratio. The lack of observable TiO features are possibly due to rainout, breakdown from stellar activity or the presence of other absorbers in the optical.
We have profiled promoter DNA methylation alterations in 272 glioblastoma tumors in the context of The Cancer Genome Atlas (TCGA). We found that a distinct subset of samples displays concerted ...hypermethylation at a large number of loci, indicating the existence of a glioma-CpG island methylator phenotype (G-CIMP). We validated G-CIMP in a set of non-TCGA glioblastomas and low-grade gliomas. G-CIMP tumors belong to the proneural subgroup, are more prevalent among lower-grade gliomas, display distinct copy-number alterations, and are tightly associated with
IDH1 somatic mutations. Patients with G-CIMP tumors are younger at the time of diagnosis and experience significantly improved outcome. These findings identify G-CIMP as a distinct subset of human gliomas on molecular and clinical grounds.
► Identification of a CpG island methylator phenotype (G-CIMP) in gliomas ► G-CIMP is tightly associated with
IDH1 mutation ► G-CIMP patients are younger at diagnosis and display improved survival ► G-CIMP is more prevalent among low- and intermediate-grade gliomas
DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA ...double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies.
Offshore Antarctic polynyas-large openings in the winter sea ice cover-are thought to be maintained by a rapid ventilation of deep-ocean heat through convective mixing. These rare phenomena may alter ...abyssal properties and circulation, yet their formation mechanisms are not well understood. Here we demonstrate that concurrent upper-ocean preconditioning and meteorological perturbations are responsible for the appearance of polynyas in the Weddell Sea region of the Southern Ocean. Autonomous profiling float observations-collected in 2016 and 2017 during the largest polynyas to form near the Maud Rise seamount since 1976-reveal that the polynyas were initiated and modulated by the passage of severe storms, and that intense heat loss drove deep overturning within them. Wind-driven upwelling of record strength weakened haline stratification in the upper ocean, thus favouring destabilization in 2016 and 2017. We show that previous Weddell polynyas probably developed under similarly anomalous conditions, which are associated with a mode of Southern Hemisphere climate variability that is predicted to strengthen as a result of anthropogenic climate change.
We present an optical to near-infrared transmission spectrum of the hot Jupiter HAT-P-1b, based on Hubble Space Telescope observations, covering the spectral regime from 0.29 to 1.027 μm with Space ...Telescope Imaging Spectrograph (STIS), which is coupled with a recent Wide Field Camera 3 (WFC3) transit (1.087 to 1.687 μm). We derive refined physical parameters of the HAT-P-1 system, including an improved orbital ephemeris. The transmission spectrum shows a strong absorption signature shortward of 0.55 μm, with a strong blueward slope into the near-ultraviolet. We detect atmospheric sodium absorption at a 3.3σ significance level, but find no evidence for the potassium feature. The red data imply a marginally flat spectrum with a tentative absorption enhancement at wavelength longer than ∼ 0.85 μm. The STIS and WFC3 spectra differ significantly in absolute radius level (4.3 ± 1.6 pressure scaleheights), implying strong optical absorption in the atmosphere of HAT-P-1b. The optical to near-infrared difference cannot be explained by stellar activity, as simultaneous stellar activity monitoring of the G0V HAT-P-1b host star and its identical companion show no significant activity that could explain the result. We compare the complete STIS and WFC3 transmission spectrum with theoretical atmospheric models which include haze, sodium and an extra optical absorber. We find that both an optical absorber and a supersolar sodium to water abundance ratio might be a scenario explaining the HAT-P-1b observations. Our results suggest that strong optical absorbers may be a dominant atmospheric feature in some hot Jupiter exoplanets.
Understanding how seabirds use the marine environment is key for marine spatial planning, and maps of their marine distributions derived from transect-based surveys and from tracking of individual ...bird's movements are increasingly available for the same geographic areas. Although the value of integrating these different datasets is well recognised, few studies have undertaken quantitative comparisons of the resulting distributions. Here we take advantage of four existing distribution maps and conduct a quantitative comparison for four seabird species (black-legged kittiwake Rissa tridactyla; European shag Phalacrocorax aristotelis; common guillemot Uria aalge; and razorbill Alca torda). We quantify the amount of overlap and agreement in the location of high use areas identified from either tracking or transect samples and use Bhattacharyya's Affinity to quantify levels of similarity in the general distribution patterns. Despite multiple differences in the properties of the datasets, there was a far greater degree of overlap than would be expected by chance, except when adopting the most constrained definition of high use. Distance to the nearest conspecific colony appeared to be an important driver of the degree of similarity. Agreed areas of highest use tended to occur close to colonies and, with increasing distance from colonies, similarity between datasets declined and/or there was similarity in respect of their being relatively low usage. Interpreting reasons for agreement between data sources in some areas and not others was limited by an inability to control for the multiple potential sources of differences from both the sampling and modelling processes of the underlying datasets. Nevertheless, our quantitative comparative approach provides a valuable tool to quantify the degree to which an area's importance is corroborated across multiple datasets, and therefore confidence that an important area has been correctly identified. This can help prioritise where the implementation of conservation measures should be targeted and identify where greatest scrutiny is required of the potential adverse environmental effects of any planned anthropogenic activities.
Overview of the CCP4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. ...
Acta crystallographica. Section D, Biological crystallography.,
April 2011, Volume:
67, Issue:
4
Journal Article
Peer reviewed
Open access
The CCP4 (Collaborative Computational Project, Number 4) software suite is a collection of programs and associated data and software libraries which can be used for macromolecular structure ...determination by X‐ray crystallography. The suite is designed to be flexible, allowing users a number of methods of achieving their aims. The programs are from a wide variety of sources but are connected by a common infrastructure provided by standard file formats, data objects and graphical interfaces. Structure solution by macromolecular crystallography is becoming increasingly automated and the CCP4 suite includes several automation pipelines. After giving a brief description of the evolution of CCP4 over the last 30 years, an overview of the current suite is given. While detailed descriptions are given in the accompanying articles, here it is shown how the individual programs contribute to a complete software package.
PDF
