The DINGO dataset: a comprehensive set of data for the SAMPL challenge

Part of the latest SAMPL challenge was to predict how a small fragment library of 500 commercially available compounds would bind to a protein target. In order to assess the modellers’ work, a reasonably comprehensive set of data was collected using a number of techniques. These included surface plasmon resonance, isothermal titration calorimetry, protein crystallization and protein crystallography. Using these techniques we could determine the kinetics of fragment binding, the energy of binding, how this affects the ability of the target to crystallize, and when the fragment did bind, the pose or orientation of binding. Both the final data set and all of the raw images have been made available to the community for scrutiny and further work. This overview sets out to give the parameters of the experiments done and what might be done differently for future studies

On the need for an international effort to capture, share and use crystallization screening data

Development of an ontology for the description of crystallization experiments and results is proposed

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Constraining particle acceleration in Sgr A* with simultaneous GRAVITY, Spitzer, NuSTAR, and Chandra observations

High Energy Astrophysic

New constraints on the mid-IR EBL from the HESS discovery of VHE gamma-rays from 1ES 0229+200

Aims.To investigate the very high energy (VHE: >100 GeV) γ-ray emission from the high-frequency peaked BL Lac 1ES 0229+200. Methods: Observations of 1ES 0229+200 at energies above 580 GeV were performed with the High Energy Stereoscopic System (HESS) in 2005 and 2006. Results: 1ES 0229+200 is discovered by HESS to be an emitter of VHE photons. A signal is detected at the 6.6σ level in the HESS observations (41.8 h live time). The integral flux above 580 GeV is (9.4±1.5_stat±1.9_syst) × 10-13 cm-2 s-1, corresponding to ~1.8% of the flux observed from the Crab Nebula. The data show no evidence for significant variability on any time scale. The observed spectrum is characterized by a hard power law (Γ = 2.50±0.19_stat±0.10_syst) from 500 GeV to ~15 TeV. Conclusions: The high-energy range and hardness of the observed spectrum, coupled with the object's relatively large redshift (z = 0.1396), enable the strongest constraints so far on the density of the Extragalactic Background Light (EBL) in the mid-infrared band. Assuming that the emitted spectrum is not harder than Γ_int ≈ 1.5, the HESS data support an EBL spectrum ∝λ-1 and density close to the lower limit from source counts measured by Spitzer, confirming the previous indications from the HEGRA data of 1ES 1426+428 (z=0.129). Irrespective of the EBL models used, the intrinsic spectrum of 1ES 0229+200 is hard, thus locating the high-energy peak of its spectral energy distribution above a few TeV.Aharonian, F.; Akhperjanian, A. G.; Barres de Almeida, U.; Bazer-Bachi, A. R.; Behera, B.; Beilicke, M.; Benbow, W.; Bernlöhr, K.; Boisson, C.; Bolz, O.; Borrel, V.; Braun, I.; Brion, E.; Brown, A. M.; Bühler, R.; Bulik, T.; Büsching, I.; Boutelier, T.; Carrigan, S.; Chadwick, P. M.; Chounet, L.-M.; Clapson, A. C.; Coignet, G.; Cornils, R.; Costamante, L.; Dalton, M.; Degrange, B.; Dickinson, H. J.; Djannati-Ataï, A.; Domainko, W.; O'C. Drury, L.; Dubois, F.; Dubus, G.; Dyks, J.; Egberts, K.; Emmanoulopoulos, D.; Espigat, P.; Farnier, C.; Feinstein, F.; Fiasson, A.; Förster, A.; Fontaine, G.; Funk, Seb.; Füßling, M.; Gallant, Y. A.; Giebels, B.; Glicenstein, J. F.; Glück, B.; Goret, P.; Hadjichristidis, C.; Hauser, D.; Hauser, M.; Heinzelmann, G.; Henri, G.; Hermann, G.; Hinton, J. A.; Hoffmann, A.; Hofmann, W.; Holleran, M.; Hoppe, S.; Horns, D.; Jacholkowska, A.; de Jager, O. C.; Jung, I.; Katarzyński, K.; Kendziorra, E.; Kerschhaggl, M.; Khélifi, B.; Keogh, D.; Komin, Nu.; Kosack, K.; Lamanna, G.; Latham, I. J.; Lemière, A.; Lemoine-Goumard, M.; Lenain, J.-P.; Lohse, T.; Martin, J. M.; Martineau-Huynh, O.; Marcowith, A.; Masterson, C.; Maurin, D.; Maurin, G.; McComb, T. J. L.; Moderski, R.; Moulin, E.; de Naurois, M.; Nedbal, D.; Nolan, S. J.; Ohm, S.; Olive, J.-P.; de Oña Wilhelmi, E.; Orford, K. J.; Osborne, J. L.; Ostrowski, M.; Panter, M.; Pedaletti, G.; Pelletier, G.; Petrucci, P.-O.; Pita, S.; Pühlhofer, G.; Punch, M.; Ranchon, S.; Raubenheimer, B. C.; Raue, M.; Rayner, S. M.; Renaud, M.; Ripken, J.; Rob, L.; Rolland, L.; Rosier-Lees, S.; Rowell, G.; Rudak, B.; Ruppel, J.; Sahakian, V.; Santangelo, A.; Schlickeiser, R.; Schöck, F.; Schröder, R.; Schwanke, U.; Schwarzburg, S.; Schwemmer, S.; Shalchi, A.; Sol, H.; Spangler, D.; Stawarz, Ł.; Steenkamp, R.; Stegmann, C.; Superina, G.; Tam, P. H.; Tavernet, J.-P.; Terrier, R.; van Eldik, C.; Vasileiadis, G.; Venter, C.; Vialle, J. P.; Vincent, P.; Vivier, M.; Völk, H. J.; Volpe, F.; Wagner, S. J.; Ward, M.; Zdziarski, A. A.; Zech,

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects