Polybrominated Diphenyl Ethers (PBDEs) and Bioaccumulative Hydroxylated PBDE Metabolites in Young Humans from Managua, Nicaragua

OBJECTIVE: Our aim was to investigate exposure to polybrominated diphenyl ethers (PBDEs) in a young urban population in a developing country, with focus on potentially highly exposed children working informally as scrap scavengers at a large municipal waste disposal site. We also set out to investigate whether hydroxylated metabolites, which not hitherto have been found retained in humans, could be detected. METHODS: We assessed PBDEs in pooled serum samples obtained in 2002 from children 11-15 years of age, working and sometimes also living at the municipal waste disposal site in Managua, and in nonworking urban children. The influence of fish consumption was evaluated in the children and in groups of women 15-44 years of age who differed markedly in their fish consumption. Hydroxylated PBDEs were assessed as their methoxylated derivates. The chemical analyses were performed by gas chromatography/mass spectrometry, using authentic reference substances. RESULTS: The children living and working at the waste disposal site showed very high levels of medium brominated diphenyl ethers. The levels observed in the referent children were comparable to contemporary observations in the United States. The exposure pattern was consistent with dust being the dominating source. The children with the highest PBDE levels also had the highest levels of hydroxylated metabolites. CONCLUSIONS: Unexpectedly, very high levels of PBDEs were found in children from an urban area in a developing country. Also, for the first time, hydroxylated PBDE metabolites were found to bioaccumulate in human serum

A spectral line survey of Orion KL in the bands 486-492 and 541-577 GHz with the Odin satellite I. The observational data

Spectral line surveys are useful since they allow identification of new molecules and new lines in uniformly calibrated data sets. Nonetheless, large portions of the sub-millimetre spectral regime remain unexplored due to severe absorptions by H2O and O2 in the terrestrial atmosphere. The purpose of the measurements presented here is to cover wavelength regions at and around 0.55 mm -- regions largely unobservable from the ground. Using the Odin astronomy/aeronomy satellite, we performed the first spectral survey of the Orion KL molecular cloud core in the bands 486--492 and 541--576 GHz with rather uniform sensitivity (22--25 mK baseline noise). Odin's 1.1 m size telescope, equipped with four cryo-cooled tuneable mixers connected to broad band spectrometers, was used in a satellite position-switching mode. Two mixers simultaneously observed different 1.1 GHz bands using frequency steps of 0.5 GHz (25 hours each). An on-source integration time of 20 hours was achieved for most bands. The entire campaign consumed ~1100 orbits, each containing one hour of serviceable astro-observation. We identified 280 spectral lines from 38 known interstellar molecules (including isotopologues) having intensities in the range 80 to 0.05 K. An additional 64 weak lines remain unidentified. Apart from the ground state rotational 1(1,0)--1(0,1) transitions of ortho-H2O, H218O and H217O, the high energy 6(2,4)--7(1,7) line of para-H2O and the HDO(2,0,2--1,1,1) line have been observed, as well as the 1,0--0,1 lines from NH3 and its rare isotopologue 15NH3. We suggest assignments for some unidentified features, notably the new interstellar molecules ND and SH-. Severe blends have been detected in the line wings of the H218O, H217O and 13CO lines changing the true linewidths of the outflow emission.Comment: 21 pages, 10 figures, 7 tables, accepeted for publication in Astronomy and Astrophysics 30 August 200

Submillimeter Emission from Water in the W3 Region

We have mapped the submillimeter emission from the 1(10)-1(01) transition of ortho-water in the W3 star-forming region. A 5'x5' map of the W3 IRS4 and W3 IRS5 region reveals strong water lines at half the positions in the map. The relative strength of the Odin lines compared to previous observations by SWAS suggests that we are seeing water emission from an extended region. Across much of the map the lines are double-peaked, with an absorption feature at -39 km/s; however, some positions in the map show a single strong line at -43 km/s. We interpret the double-peaked lines as arising from optically thick, self-absorbed water emission near the W3 IRS5, while the narrower blue-shifted lines originate in emission near W3 IRS4. In this model, the unusual appearance of the spectral lines across the map results from a coincidental agreement in velocity between the emission near W3 IRS4 and the blue peak of the more complex lines near W3 IRS5. The strength of the water lines near W3 IRS4 suggests we may be seeing water emission enhanced in a photon-dominated region.Comment: Accepted to A&A Letters as part of the special Odin issue; 4 page

A systematic search strategy identifies cubilin as independent prognostic marker for renal cell carcinoma

$\textbf{Background:}$ There is an unmet clinical need for better prognostic and diagnostic tools for renal cell carcinoma (RCC). $\textbf{Methods:}$ Human Protein Atlas data resources, including the transcriptomes and proteomes of normal and malignant human tissues, were searched for RCC-specific proteins and cubilin (CUBN) identified as a candidate. Patient tissue representing various cancer types was constructed into a tissue microarray ($n$ = 940) and immunohistochemistry used to investigate the specificity of CUBN expression in RCC as compared to other cancers. Two independent RCC cohorts ($n$ = 181; $n$ = 114) were analyzed to further establish the sensitivity of CUBN as RCC-specific marker and to explore if the fraction of RCCs lacking CUBN expression could predict differences in patient survival. $\textbf{Results:}$ CUBN was identified as highly RCC-specific protein with 58% of all primary RCCs staining positive for CUBN using immunohistochemistry. In venous tumor thrombi and metastatic lesions, the frequency of CUBN expression was increasingly lost. Clear cell RCC (ccRCC) patients with CUBN positive tumors had a significantly better prognosis compared to patients with CUBN negative tumors, independent of T-stage, Fuhrman grade and nodal status (HR 0.382, CI 0.203–0.719, $P$ = 0.003). $\textbf{Conclusions:}$ CUBN expression is highly specific to RCC and loss of the protein is significantly and independently associated with poor prognosis. CUBN expression in ccRCC provides a promising positive prognostic indicator for patients with ccRCC. The high specificity of CUBN expression in RCC also suggests a role as a new diagnostic marker in clinical cancer differential diagnostics to confirm or rule out RCC.This work was supported by the Swedish Cancer Society and the Knut and Alice Wallenberg Foundation. The work of DJH and GDS was funded by the Chief Scientist Office (grant number ETM37), Renal Cancer Research Fund and Kidney Cancer Scotland

Removing Critical Gaps in Chemical Test Methods by Developing New Assays for the Identification of Thyroid Hormone System-Disrupting Chemicals—The ATHENA Project

Copyright © 2020 by the authors. The test methods that currently exist for the identification of thyroid hormone system-disrupting chemicals are woefully inadequate. There are currently no internationally validated in vitro assays, and test methods that can capture the consequences of diminished or enhanced thyroid hormone action on the developing brain are missing entirely. These gaps put the public at risk and risk assessors in a difficult position. Decisions about the status of chemicals as thyroid hormone system disruptors currently are based on inadequate toxicity data. The ATHENA project (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies) has been conceived to address these gaps. The project will develop new test methods for the disruption of thyroid hormone transport across biological barriers such as the blood–brain and blood–placenta barriers. It will also devise methods for the disruption of the downstream effects on the brain. ATHENA will deliver a testing strategy based on those elements of the thyroid hormone system that, when disrupted, could have the greatest impact on diminished or enhanced thyroid hormone action and therefore should be targeted through effective testing. To further enhance the impact of the ATHENA test method developments, the project will develop concepts for better international collaboration and development in the area of thyroid hormone system disruptor identification and regulation.EU Horizon 2020 programme, grant number 82516

Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.Peer reviewe

Unknown cadaver: its historical and academic importance for human anatomy

Observações feitas na maioria das universidades brasileiras estrangeiras, e, inclusive, em algumas sobre o aspecto acadêmico do uso de cadáveres humanos como principal material que suporta e direciona a Anatomia Humana nos cursos da área da saúde, traz, dentre outras conclusões de caráter didático, uma questão de formação, muito mais importante do que uma simples questão de, apenas, informação universitária. Há de se concordar que, mesmo com o fabuloso avanço tecnológico e suas possibilidades, nossas universidades hoje, primam mais pela questão informativa do que propriamente pela formativa, ao passo que ternos consciência de que o ser humano necessita igualmente de ambas. Em consequência disto, o principal objetivo deste trabalho é enfocar o valor acadêmico do cadáver, evidenciando sua importante relação histórica, sem a qual a Anatomia não existiria e, certamente, a Medicina também não teria ultrapassado suas fronteiras limitadas do passado. O fato de ser este um trabalho realizado em uma universidade brasileira é revestido de responsabilidade e determinação em tentar colocar a figura do cadáver humano no lugar, no qual ele realmente deva estar, não apenas como simples material e instrumento de ensino da anatomia, mas também como lição de vida através da morte, criando Ciência e Arte, valorizando sua importância no contexto artístico e religioso, fatores estes imprescindíveis para a formação sócio-cultural humana. Por outro lado, este estudo com abordagem de caráter acadêmico, tornou-se dificil quanto a bibliografia específica, tendo sido feita portanto, quase toda a sua pesquisa em tratados históricos e anatômicos e, apenas alguns poucos trabalhos sobre a importância do cadáver para a Anatomia. Neste trabalho, procuramos usar ilustrações e figuras como documentação de caráter informativo e estético. Assim sendo, para uma abordagem mais ampla, o cadáver foi discutido desde sua relação histórica e acadêmica, até os dias de hoje, onde ainda se enfrenta, quase, as mesmas dificuldades do passado, no que diz respeito as questões de doação de corpo e órgãos, que deixaram de ser apenas institucionalmente acadêmicas, para ser mais rigorosamente sociais, segundo as Leis vigentes.Observations about most of brazilian universities and, even some of foreign ones, concerning the academic aspects of the use of human cadavers or corpses as the principal human anatomy method of studying, which maintain the basic courses of Health Sciences Field, that is, the cadaver or corpse himself should be also seen as a noble and magnificent way of transmitting knowledge and human values. Indeed, these observations have been showing some didactic results concerning much more, a matter of individual information than individual formation itself. Nowadays, this happens because scholasticism, differently from the past, seems to emphasize quantitative rather than qualitative teaching philosophy. We must admit that, even living in a technological era and being able to take advantages of its possibilities, our universities today emphasize much more the information itself than individual formation of our professionals of tomorrow, while we know that the individual needs both, equally. Therefore, the main goal of this work is focusing the academic importance of the human cadaver or corpse as a practical studying material, which is related to the own history of the practical Anatomy and consequently Medicine and, if it were not because of that, Medicine itself would not have gone beyond its limited frontiers of the past. On the other hand, the inedited academic meaning of this work became too difficult to come abroad, because of its specific bibliographical lack among scientific publications and, that's why, most of its text was found in the old Health Sciences, books and texts in general. However, another particular characteristic of this work is the great number of pictures and illustrations, which enrich the present text and substitute the lack of similar works' bibliography, In this work, the corpse is seen, from his historical relation and academical aspects the to present circumstances, where the need for anatomical study faces the same difficulties of the past, when Vesalius opened the way to the study of Human Anatomy, but as we know many years passed before Anatomy could be taught to medical students by means of dissection, the only method by which physicians and surgeons can fully acquire this knowledge. The scarcity of anatomical material seemed to be over at the present time, when laws were just enacted, such as specified law for the use of the corpse, organs and structures donation, that unfortunately did not solve the old and permanent problem, such as the absence of corpses for anatomical dissections.BV UNIFESP: Teses e dissertaçõe

Cloning retinoid and peroxisome proliferator-activated nuclear receptors of the Pacific oyster and in silico binding to environmental chemicals

This is the final version of the article. Available from Public Library of Science via the DOI in this record.Disruption of nuclear receptors, a transcription factor superfamily regulating gene expression in animals, is one proposed mechanism through which pollution causes effects in aquatic invertebrates. Environmental pollutants have the ability to interfere with the receptor's functions through direct binding and inducing incorrect signals. Limited knowledge of invertebrate endocrinology and molecular regulatory mechanisms, however, impede the understanding of endocrine disruptive effects in many aquatic invertebrate species. Here, we isolated three nuclear receptors of the Pacific oyster, Crassostrea gigas: two isoforms of the retinoid X receptor, CgRXR-1 and CgRXR-2, a retinoic acid receptor ortholog CgRAR, and a peroxisome proliferator-activated receptor ortholog CgPPAR. Computer modelling of the receptors based on 3D crystal structures of human proteins was used to predict each receptor's ability to bind to different ligands in silico. CgRXR showed high potential to bind and be activated by 9-cis retinoic acid and the organotin tributyltin (TBT). Computer modelling of CgRAR revealed six residues in the ligand binding domain, which prevent the successful interaction with natural and synthetic retinoid ligands. This supports an existing theory of loss of retinoid binding in molluscan RARs. Modelling of CgPPAR was less reliable due to high discrepancies in sequence to its human ortholog. Yet, there are suggestions of binding to TBT, but not to rosiglitazone. The effect of potential receptor ligands on early oyster development was assessed after 24h of chemical exposure. TBT oxide (0.2μg/l), all-trans retinoic acid (ATRA) (0.06 mg/L) and perfluorooctanoic acid (20 mg/L) showed high effects on development (>74% abnormal developed D-shelled larvae), while rosiglitazone (40 mg/L) showed no effect. The results are discussed in relation to a putative direct (TBT) disruption effect on nuclear receptors. The inability of direct binding of ATRA to CgRAR suggests either a disruptive effect through a pathway excluding nuclear receptors or an indirect interaction. Our findings provide valuable information on potential mechanisms of molluscan nuclear receptors and the effects of environmental pollution on aquatic invertebrates.The study was funded by the Centre for Environment, Fisheries and Aquaculture Science (Cefas; https://www.cefas.co.uk) and by the University of Exeter (http://www.exeter.ac.uk)

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe