The first GCT camera for the Cherenkov Telescope Array

The Gamma Cherenkov Telescope (GCT) is proposed to be part of the Small Size Telescope (SST) array of the Cherenkov Telescope Array (CTA). The GCT dual-mirror optical design allows the use of a compact camera of diameter roughly 0.4 m. The curved focal plane is equipped with 2048 pixels of ~0.2{\deg} angular size, resulting in a field of view of ~9{\deg}. The GCT camera is designed to record the flashes of Cherenkov light from electromagnetic cascades, which last only a few tens of nanoseconds. Modules based on custom ASICs provide the required fast electronics, facilitating sampling and digitisation as well as first level of triggering. The first GCT camera prototype is currently being commissioned in the UK. On-telescope tests are planned later this year. Here we give a detailed description of the camera prototype and present recent progress with testing and commissioning.Comment: In Proceedings of the 34th International Cosmic Ray Conference (ICRC2015), The Hague, The Netherlands. All CTA contributions at arXiv:1508.0589

The potential of flood forecasting using a variable-resolution global Digital Terrain Model and flood extents from Synthetic Aperture Radar images

A basic data requirement of a river flood inundation model is a Digital Terrain Model (DTM) of the reach being studied. The scale at which modeling is required determines the accuracy required of the DTM. For modeling floods in urban areas, a high resolution DTM such as that produced by airborne LiDAR (Light Detection And Ranging) is most useful, and large parts of many developed countries have now been mapped using LiDAR. In remoter areas, it is possible to model flooding on a larger scale using a lower resolution DTM, and in the near future the DTM of choice is likely to be that derived from the TanDEM-X Digital Elevation Model (DEM). A variable-resolution global DTM obtained by combining existing high and low resolution data sets would be useful for modeling flood water dynamics globally, at high resolution wherever possible and at lower resolution over larger rivers in remote areas. A further important data resource used in flood modeling is the flood extent, commonly derived from Synthetic Aperture Radar (SAR) images. Flood extents become more useful if they are intersected with the DTM, when water level observations (WLOs) at the flood boundary can be estimated at various points along the river reach. To illustrate the utility of such a global DTM, two examples of recent research involving WLOs at opposite ends of the spatial scale are discussed. The first requires high resolution spatial data, and involves the assimilation of WLOs from a real sequence of high resolution SAR images into a flood model to update the model state with observations over time, and to estimate river discharge and model parameters, including river bathymetry and friction. The results indicate the feasibility of such an Earth Observation-based flood forecasting system. The second example is at a larger scale, and uses SAR-derived WLOs to improve the lower-resolution TanDEM-X DEM in the area covered by the flood extents. The resulting reduction in random height error is significant

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER

Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities.

Combination of CDK4/6 inhibitors and endocrine therapy improves clinical outcome in advanced oestrogen receptor (ER)-positive breast cancer, however relapse is inevitable. Here, we show in model systems that other than loss of RB1 few gene-copy number (CN) alterations are associated with irreversible-resistance to endocrine therapy and subsequent secondary resistance to palbociclib. Resistance to palbociclib occurred as a result of tumour cell re-wiring leading to increased expression of EGFR, MAPK, CDK4, CDK2, CDK7, CCNE1 and CCNE2. Resistance altered the ER genome wide-binding pattern, leading to decreased expression of 'classical' oestrogen-regulated genes and was accompanied by reduced sensitivity to fulvestrant and tamoxifen. Persistent CDK4 blockade decreased phosphorylation of tuberous sclerosis complex 2 (TSC2) enhancing EGFR signalling, leading to the re-wiring of ER. Kinome-knockdown confirmed dependency on ERBB-signalling and G2/M-checkpoint proteins such as WEE1, together with the cell cycle master regulator, CDK7. Noteworthy, sensitivity to CDK7 inhibition was associated with loss of ER and RB1 CN. Overall, we show that resistance to CDK4/6 inhibitors is dependent on kinase re-wiring and the redeployment of signalling cascades previously associated with endocrine resistance and highlights new therapeutic networks that can be exploited upon relapse after CDK4/6 inhibition

Socio-sexuality and episodic memory function in women: further evidence of an adaptive “mating mode”

The functionalist memory perspective predicts that information of adaptive value may trigger specific processing modes. It was recently demonstrated that women's memory is sensitive to cues of male sexual dimorphism (i.e., masculinity) that convey information of adaptive value for mate choice because they signal health and genetic quality, as well as personality traits important in relationship contexts. Here, we show that individual differences in women's mating strategies predict the effect of facial masculinity cues upon memory, strengthening the case for functional design within memory. Using the revised socio-sexual orientation inventory, Experiment 1 demonstrates that women pursuing a short-term, uncommitted mating strategy have enhanced source memory for men with exaggerated versus reduced masculine facial features, an effect that reverses in women who favor long-term committed relationships. The reversal in the direction of the effect indicates that it does not reflect the sex typicality of male faces per se. The same pattern occurred within women's source memory for women's faces, implying that the memory bias does not reflect the perceived attractiveness of faces per se. In Experiment 2, we reran the experiment using men's faces to establish the reliability of the core finding and replicated Experiment 1's results. Masculinity cues may therefore trigger a specific mode within women's episodic memory. We discuss why this mode may be triggered by female faces and its possible role in mate choice. In so doing, we draw upon the encoding specificity principle and the idea that episodic memory limits the scope of stereotypical inferences about male behavior

Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance.

Resistance to endocrine therapy remains a major clinical problem in breast cancer. Genetic studies highlight the potential role of estrogen receptor-α (ESR1) mutations, which show increased prevalence in the metastatic, endocrine-resistant setting. No naturally occurring ESR1 mutations have been reported in in vitro models of BC either before or after the acquisition of endocrine resistance making functional consequences difficult to study. We report the first discovery of naturally occurring ESR1 Y537C and ESR1 Y537S mutations in MCF7 and SUM44 ESR1-positive cell lines after acquisition of resistance to long-term-estrogen-deprivation (LTED) and subsequent resistance to fulvestrant (ICIR). Mutations were enriched with time, impacted on ESR1 binding to the genome and altered the ESR1 interactome. The results highlight the importance and functional consequence of these mutations and provide an important resource for studying endocrine resistance.Cancer Research U

Unos L-alanil-L-glutamina tijekom kratkotrajne visokointenzivne vježbe u uvjetima blagoga hidracijskoga stresa

The effect of acute L-alanyl-L-glutamine (AG) ingestion on selected hormonal and electrolyte measures was examined during repetitive, short duration, high intensity exercise with mild hypohydration. Subjects (20.3±1.1 yrs; 180.3±10.4 cm; 83.1±14.0 kg; 11.6±3.6% body fat) reported to the Human Performance Laboratory on four occasions. During each trial subjects were hypohydrated to -2.5% of their baseline body mass. During one trial (DHY) subjects rested in a recumbent position for 45 minutes before commencing the exercise session. During the other three trials subjects were rehydrated to 1.5% of their baseline body mass, before exercise, by drinking water only (W), or with two different doses of AG – a low dose (LDAG: 0.05 g�kg-1) and a high dose (HDAG: 0.2 g�kg-1). The exercise protocol consisted of ten 10-second sprints on a cycle ergometer with a 1-min rest between each sprint. Blood draws were collected once the subject achieved the desired level of hypohydration, immediately pre-exercise, immediately post-exercise, and 24 hrs postexercise. Blood samples were analyzed for glutamine, potassium, sodium, aldosterone, arginine vasopressin, C-reactive protein, interleukin-6, malondialdehyde, testosterone, cortisol, ACTH, and growth hormone. The area under the curve (AUC) analysis demonstrated significantly greater sodium concentrations for DHY compared to all other trials. The AUC analysis for aldosterone showed significantly lower concentrations at LDAG compared to DHY. No other differences between trials were observed in any other hormonal or biochemical responses. AG ingestion during a short duration, anaerobic exercise and mild hypohydration stress had a limited effect on selected hormonal and biochemical measures.Učinci akutnoga, trenutačnoga uzimanja L-alanil-L-glutamina (AG) na odabrane hormonske i elektrolitne pokazatelje ispitani su tijekom ponavljajuće kratkotrajne visokointenzivne aktivnosti u uvjetima blage hipohidracije ispitanika. Ispitanici (20,3±1,1 godina; 180,3±10,4 cm; 83,1±14,0 kg; 11,6±3,6% tjelesne masti) bili su testirani u Human Performance Laboratory u četiri navrata. Tijekom svakoga pojedinačnoga mjerenja ispitanici su bili hipohidrirani do -2,5% svoje početne, osnovne tjelesne mase. Tijekom prvoga testiranja (DHY) ispitanici su se odmarali ležeći 45 minuta prije no što su počeli provoditi protokol vježbanja. Tijekom sljedeća tri mjerenja ispitanici su rehidrirani do 1,5% njihove početne tjelesne mase prije vježbanja, i to: pijenjem samo vode (W) te unosom dviju različitih doza AG - male doze (LDAG: 0,05 g∙kg-1) i velike doze (HDAG: 0,2 g∙kg-1). Protokol vježbanja sastojao se od po deset sprintova na bicikl-ergometru u trajanju od 10 sekunda s jednominutnim odmorom između svakoga sprinta. Uzorci krvi vađeni su odmah nakon što je ispitanik dosegao željenu razinu hipohidracije, neposredno prije početka vježbanja, neposredno nakon završetka vježbanja i 24 sata nakon vježbanja. U uzorcima krvi analizirana je koncentracija glutamina, kalija, natrija, aldosterona, arginin vazopresina, C-reaktivnoga proteina, interleukina-6, malondialdehida, testosterona, kortizola, ACTH-a i hormona rasta. Analiza površine ispod krivulje pokazala je statistički značajno veću razinu koncentracije natrija u ispitanika u prvom testu (DHY) u odnosu na sva ostala mjerenja. Analiza površine ispod krivulje za aldosteron je pokazala značajno nižu koncentraciju u testu LDAG u odnosu na test DHY. Nisu zapažene značajne razlike između pojedinih mjerenja ni u jednoj drugoj hormonskoj i biokemijskoj reakciji na protokol vježbanja. Uzimanje AG tijekom kratkotrajne anaerobne aktivnosti i u stanju blagoga hipohidracijskoga stresa pokazalo je ograničene učinke na odabrane hormonske i biokemijske pokazatelje