Spectral calibration of the fluorescence telescopes of the Pierre Auger Observatory

We present a novel method to measure precisely the relative spectral response of the fluorescence telescopes of the Pierre Auger Observatory. We used a portable light source based on a xenon flasher and a monochromator to measure the relative spectral efficiencies of eight telescopes in steps of 5 nm from 280 nm to 440nm. Each point in a scan had approximately 2nm FWHM out of the monochromator. Different sets of telescopes in the observatory have different optical components, and the eight telescopes measured represent two each of the four combinations of components represented in the observatory. We made an end-to-end measurement of the response from different combinations of optical components, and the monochromator setup allowed for more precise and complete measurements than our previous multi-wavelength calibrations. We find an overall uncertainty in the calibration of the spectral response of most of the telescopes of 1.5% for all wavelengths; the six oldest telescopes have larger overall uncertainties of about 2.2%. We also report changes in physics measurables due to the change in calibration, which are generally small

SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

Cancer therapyTeràpia del càncerTerapia del cáncerDespite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients

Optimization of lipase production by solid-state fermentation of olive pomace: from flask to laboratory-scale packed-bed bioreactor

Lipases are versatile catalysts with many applications and can be produced by solid-state fermentation (SSF) using agro-industrial wastes. The aim of this work was to maximize the production of Aspergillus ibericus lipase under SSF of olive pomace (OP) and wheat bran (WB), evaluating the effect on lipase production of C/N ratio, lipids, phenols, content of sugars of substrates and nitrogen source addition. Moreover, the implementation of the SSF process in a packed-bed bioreactor and the improvement of lipase extraction conditions were assessed. Low C/N ratios and high content of lipids led to maximum lipase production. Optimum SSF conditions were achieved with a C/N mass ratio of 25.2 and 10.2% (w/w) lipids in substrate, by the mixture of OP:WB (1:1) and supplemented with 1.33% (w/w) (NH4)2SO4. Studies in a packed-bed bioreactor showed that the lower aeration rates tested prevented substrate dehydration, improving lipase production. In this work, the important role of Triton X-100 on lipase extraction from the fermented solid substrate has been shown. A final lipase activity of 223 ± 5 U g1 (dry basis) was obtained after 7 days of fermentation.Felisbela Oliveira acknowledges the financial support from Fundação para a Ciência e Tecnologia (FCT) of Portugal through grant SFRH/BD/87953/2012. José Manuel Salgado was supported by grant CEB/N2020–INV/01/2016 from Project ‘‘BIOTECNORTE-Underpinning Biotechnology to foster the north of Portugal bioeconomy’’ (NORTE-01-0145-FEDER-000004). Luı ´s Abrunhosa was supported by grant UMINHO/BPD/51/2015 from project UID/BIO/04469/2013 financed by FCT/MEC (OE). This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER006684) and BioTecNorte operation (NORTE-01-0145-FEDER000004) funded by the European Regional Development Fund under the scope of Norte2020–Programa Operacional Regional do Norte. Noelia Pérez-Rodríguez acknowledges the financial support of FPU fellowship from the Spanish Ministry of Education, Culture and Sports. The authors thank the Spanish Ministry of Economy and Competitiveness for the financial support of this work (Project CTQ2015-71436-C2-1-R), which has partial financial support from the FEDER funds of the European Union.info:eu-repo/semantics/publishedVersio

Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors.

The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.This work was supported by the Fundacion Cientifica Asociacion Española Contra el Cancer-AECC (grant number GCB14142170MONT) to LMM, MS-C, and EF; the Spanish Ministry of Economy and Competitivity-MINECO (grant number SAF-2017-82186R to MS-C; Rio Hortega-CM17/00180 to MS; PROYBAR17005NADA to EN); the Health Institute Carlos III-ISCIII, Fondo Europeo de Desarrollo Regional-FEDER (grant Number PT13/0001/0044, PT17/0009/0019, PI16 01821); the Government of Navarra (grant number DIANA project); and the Ramon Areces Foundation (no grant number is applicable) to LMM and RP.S

Species distribution modeling in the tropics: problems, potentialities, and the role of biological data for effective species conservation

In this paper we aim to investigate the problems and potentialities of species distribution modeling (SDM) as a tool for conservation planning and policy development and implementation in tropical regions. We reviewed 123 studies published between 1995 and 2007 in five of the leading journals in ecology and conservation, and examined two tropical case studies in which distribution modeling is currently being applied to support conservation planning. We also analyzed the characteristics of data typically used for fitting models within the specific context of modeling tree species distribution in Central America. The results showed that methodological papers outnumbered reports of SDMs being used in an applied context for setting conservation priorities, particularly in the tropics. Most applications of SDMs were in temperate regions and biased towards certain organisms such as mammals and birds. Studies from tropical regions were less likely to be validated than those from temperate regions. Unpublished data from two major tropical case studies showed that those species that are most in need of conservation actions, namely those that are the rarest or most threatened, are those for which SDM is least likely to be useful. We found that only 15% of the tree species of conservation concern in Central America could be reliably modelled using data from a substantial source (Missouri Botanical Garden VAST database). Lack of data limits model validation in tropical areas, further restricting the value of SDMs. We concluded that SDMs have a great potential to support biodiversity conservation in the tropics, by supporting the development of conservation strategies and plans, identifying knowledge gaps, and providing a tool to examine the potential impacts of environmental change. However, for this potential to be fully realized, problems of data quality and availability need to be overcome. Weaknesses in current biological datasets need to be systematically addressed, by increasing collection of field survey data, improving data sharing and increasing structural integration of data sources. This should include use of distributed databases with common standards, referential integrity, and rigorous quality control. Integration of data management with SDMs could significantly add value to existing data resources by improving data quality control and enabling knowledge gaps to be identified

Identification of coherent flood regions across Europe by using the longest streamflow records

This study compiles a new dataset, consisting of the longest available flow series from across Europe, and uses it to study the spatial and temporal clustering of flood events across the continent. Hydrological series at 102 gauging stations were collected from 25 European countries. Five geographically distinct large-scale homogeneous regions are identified: (i) an Atlantic region, (ii) a Continental region, (iii) a Scandinavian region, (iv) an Alpine region, and (v) a Mediterranean region. The months with a higher likelihood of flooding were identified in each region. The analysis of the clustering of annual counts of floods revealed an over-dispersion in the Atlantic and Continental regions, forming flood-rich and flood-poor periods, as well as an under-dispersion in the Scandinavian region that points to a regular pattern of flood occurrences at the inter-annual scale. The detection of trends in flood series is attempted by basing it on the identified regions, interpreting the results at a regional scale and for various time periods: 1900-1999; 1920-1999; 1939-1998 and 1956-1995. The results indicate that a decreasing trend in the magnitude of floods was observed mainly in the Continental region in the period 1920-1999 with 22% of the catchments revealing such a trend, as well as a decreasing trend in the timing of floods in the Alpine region in the period 1900-1999 with 75% of the catchments revealing this trend. A mixed pattern of changes in the frequency of floods over a threshold and few significant changes in the timing of floods were detected

MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer

Elucidating the adaptive mechanisms that prevent host immune response in cancer will help predict efficacy of anti-programmed death-1 (PD1)/L1 therapies. Here, we study the cell-intrinsic response of lung cancer (LC) to interferon-y (IFNy), a cytokine that promotes immunoresponse and modulates programmed death-ligand 1 (PD-L1) levels. We report complete refractoriness to IFNy in a subset of LCs as a result of JAK2 or IFNGR1 inactivation. A submaximal response affects another subset that shows constitutive low levels of IFNy-stimulated genes (IySGs) coupled with decreased H3K27ac (histone 3 acetylation at lysine 27) depo-sition and promoter hypermethylation and reduced IFN regulatory factor 1 (IRF1) recruitment to the DNA on IFNy stimulation. Most of these are neuroendocrine small cell LCs (SCLCs) with oncogenic MYC/MYCL1/ MYCN. The oncogenic activation of MYC in SCLC cells downregulates JAK2 and impairs IySGs stimulation by IFNy. MYC amplification tends to associate with a worse response to anti-PD1/L1 therapies. Hence alterations affecting the JAK/STAT pathway and MYC activation prevent stimulation by IFNy and may predict anti-PD1/L1 efficacy in LC