Improving the resolution in soft X-ray emission spectrometers through photon-counting using an Electron Multiplying CCD

In 2007, a study of back-illuminated Charge-Coupled Devices (CCDs) for soft X-ray photon detection demonstrated the improvements that could be brought over more traditional micro-channel plate detectors for X-ray spectrometers based on diffraction gratings and position sensitive detectors. Whilst the spatial resolution was reported to be improved dramatically, an intrinsic limit of approximately 25 micrometers was found due to the spreading of the charge cloud generated in the CCD across several pixels. To overcome this resolution limit, it is necessary to move away from the current integrated imaging methods and consider a photon-counting approach, recording the photon interaction locations to the sub-pixel level. To make use of photon-counting techniques it is important that the individual events are separable. To maintain the throughput of the spectrometer for high intensity lines, higher frame rates and therefore higher readout speeds are required. With CCD based systems, the increased noise at high readout speeds can limit the photon-counting performance. The Electron-Multiplying CCD shares a similar architecture with the standard CCD but incorporates a "gain register". This novel addition allows controllable gain to be applied to the signal before the read noise is introduced, therefore allowing individual events to be resolved above the noise even at much higher readout rates. In the past, the EM-CCD has only been available with imaging areas too small to be practical in soft X-ray emission spectrometers. The current drive for large area Electron-Multiplying CCDs is opening this technology to new photon-counting applications, requiring in-depth analysis of the processes and techniques involved. Early results indicate that through the introduction of photon-counting techniques the resolution in such systems can be dramatically improved

Mitigating radiation-induced charge transfer inefficiency in full-frame CCD applications by ‘pumping’ traps

The charge transfer efficiency of a CCD is based on the average level of signal lost per pixel over a number of transfers. This value can be used to directly compare the relative performances of different structures, increases in radiation damage or to quantify improvements in operating parameters. This number does not however give sufficient detail to mitigate for the actual signal loss/deference in either of the transfer directions that may be critical to measuring shapes to high accuracy, such as those required in astronomy applications (e.g. for Gaia’s astrometry or the galaxy distortion measurements for Euclid) based in the radiation environment of space. Pocket-pumping is an established technique for finding the location and activation levels of traps; however, a number of parameters in the process can also be explored to identify the trap species and location to sub-pixel accuracy. This information can be used in two ways to increase the sensitivity of a camera. Firstly, the clocking process can be optimised for the time constant of the majority of traps in each of the transfer directions, reducing deferred charge during read out. Secondly, a correction algorithm can be developed and employed during the post-processing of individual frames to move most of any deferred signal back into the charge packet it originated from. Here we present the trap-pumping techniques used to optimise the charge transfer efficiency of p- and n-channel e2v CCD204s and describe the use of trap-pumped images for on-orbit calibration and ground based image correction algorithms

Improving the spatial resolution of a soft X-ray Charge Coupled Device used for Resonant Inelastic X-ray Scattering

The Super Advanced X-ray Emission Spectrometer (SAXES) at the Advanced Resonant Scattering (ADRESS) beamline of the Swiss Light Source is a high-resolution X-ray spectrometer used as an end station for Resonant Inelastic X-ray Scattering from 400 eV to 1600 eV. Through the dispersion of photons across a CCD, the energy of scattered photons may be determined by their detected spatial position. The limiting factor of the energy resolution is currently the spatial resolution achieved with the CCD, reported at 24 μm FWHM. For this energy range the electron clouds are formed by interactions in the `field free' region of the back-illuminated CCD. These clouds diffuse in all directions whilst being attracted to the electrodes, leading to events that are made up of signals in multiple pixels. The spreading of the charge allows centroiding techniques to be used to improve the CCD spatial resolution and therefore improve the energy resolution of SAXES. The PolLux microscopy beamline at the SLS produces an X-ray beam with a diameter of 20 nm. The images produced from scanning the narrow beam across CCD pixels (13.5 x 13.5 μm2 ) can aid in the production of event recognition algorithms, allowing the matching of event profiles to photon interactions in a specific region of a pixel. Through the use of this information software analysis can be refined with the aim of improving the energy resolution

Electron-multiplying CCDs for future soft X-ray spectrometers

CCDs have been used in several high resolution soft X-ray spectrometers for both space and terrestrial applications such as the Reflection Grating Spectrometer on XMM-Newton and the Super Advanced X-ray Emission Spectrometer at the Paul Scherrer Institut in Switzerland. However, with their ability to use multiplication gain to amplify signal and suppress readout noise, EM-CCDs are being considered instead of CCDs for future soft X-ray spectrometers. When detecting low energy X-rays, EM-CCDs are able to increase the Signal-to-Noise ratio of the device, making the X-rays much easier to detect. If the signal is also significantly split between neighbouring pixels, the increase in the size of the signal will make complete charge collection and techniques such as centroiding easier to accomplish. However, multiplication gain from an EM-CCD does cause a degradation of the energy resolution of the device and there are questions about how the high field region in an EM-CCD will behave over time in high radiation environments. This paper analyses the possible advantages and disadvantages of using EM-CCDs for high resolution soft X-ray spectroscopy and suggests in which situations using them would not only be possible, but also beneficial to the instrument

Compact CMOS camera demonstrator (C3D) for Ukube-1

The Open University, in collaboration with e2v technologies and XCAM Ltd, have been selected to fly an EO (Earth Observation) technology demonstrator and in-orbit radiation damage characterisation instrument on board the UK Space Agency's UKube-1 pilot Cubesat programme. Cubesat payloads offer a unique opportunity to rapidly build and fly space hardware for minimal cost, providing easy access to the space environment. Based around the e2v 1.3 MPixel 0.18 micron process eye-on-Si CMOS devices, the instrument consists of a radiation characterisation imager as well as a narrow field imager (NFI) and a wide field imager (WFI). The narrow and wide field imagers are expected to achieve resolutions of 25 m and 350 m respectively from a 650 km orbit, providing sufficient swathe width to view the southern UK with the WFI and London with the NFI. The radiation characterisation experiment has been designed to verify and reinforce ground based testing that has been conducted on the e2v eye-on-Si family of devices and includes TEC temperature control circuitry as well as RADFET in-orbit dosimetry. Of particular interest are SEU and SEL effects. The novel instrument design allows for a wide range of capabilities within highly constrained mass, power and space budgets providing a model for future use on similarly constrained missions, such as planetary rovers. Scheduled for launch in December 2011, this 1 year low cost programme should not only provide valuable data and outreach opportunities but also help to prove flight heritage for future missions

PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.

The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

A mitotic function for the high-mobility group protein HMG20b regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor.

The inactivation of BRCA2, a suppressor of breast, ovarian and other epithelial cancers, triggers instability in chromosome structure and number, which are thought to arise from defects in DNA recombination and mitotic cell division, respectively. Human BRCA2 controls DNA recombination via eight BRC repeats, evolutionarily conserved motifs of ∼35 residues, that interact directly with the recombinase RAD51. How BRCA2 controls mitotic cell division is debated. Several studies by different groups report that BRCA2 deficiency affects cytokinesis. Moreover, its interaction with HMG20b, a protein of uncertain function containing a promiscuous DNA-binding domain and kinesin-like coiled coils, has been implicated in the G2-M transition. We show here that HMG20b depletion by RNA interference disturbs the completion of cell division, suggesting a novel function for HMG20b. In vitro, HMG20b binds directly to the BRC repeats of BRCA2, and exhibits the highest affinity for BRC5, a motif that binds poorly to RAD51. Conversely, the BRC4 repeat binds strongly to RAD51, but not to HMG20b. In vivo, BRC5 overexpression inhibits the BRCA2-HMG20b interaction, recapitulating defects in the completion of cell division provoked by HMG20b depletion. In contrast, BRC4 inhibits the BRCA2-RAD51 interaction and the assembly of RAD51 at sites of DNA damage, but not the completion of cell division. Our findings suggest that a novel function for HMG20b in cytokinesis is regulated by its interaction with the BRC repeats of BRCA2, and separate this unexpected function for the BRC repeats from their known activity in DNA recombination. We propose that divergent tumor-suppressive pathways regulating chromosome segregation as well as chromosome structure may be governed by the conserved BRC motifs in BRCA2

Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy

Graphene Photonics and Optoelectronics

The richness of optical and electronic properties of graphene attracts enormous interest. Graphene has high mobility and optical transparency, in addition to flexibility, robustness and environmental stability. So far, the main focus has been on fundamental physics and electronic devices. However, we believe its true potential to be in photonics and optoelectronics, where the combination of its unique optical and electronic properties can be fully exploited, even in the absence of a bandgap, and the linear dispersion of the Dirac electrons enables ultra-wide-band tunability. The rise of graphene in photonics and optoelectronics is shown by several recent results, ranging from solar cells and light emitting devices, to touch screens, photodetectors and ultrafast lasers. Here we review the state of the art in this emerging field.Comment: Review Nature Photonics, in pres