Sex-dependent influence of endogenous estrogen in pulmonary hypertension

Rationale: The incidence of pulmonary arterial hypertension (PAH) is greater in women suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males exogenously administered estrogen can protect against PH; however in models that display female susceptibility estrogens may play a causative role. Objectives: To clarify the influence of endogenous estrogen and gender in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. Methods: We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH; the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of gender on pulmonary expression of aromatase in these models and in lungs from PAH patients. Results: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was due to reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor alpha also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased BMPR2 and Id1 expression compared to male. Anastrozole treatment reversed the impaired BMPR2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared to male. Conclusions: The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential

In situ hatching of invertebrate diapausing eggs from ships’ ballast sediment

Ships that enter the Great Lakes laden with cargo carry only residual ballast water and sediment in ballast tanks. These ships are designated ‘no ballast on board’ (NOBOB) and constitute > 90% of inbound traffic. We conducted in situ experiments using emergence traps to assess the viability and the introduction potential of invertebrate diapausing stages present in ships’ ballast sediment. All trials commenced while vessels operated on the lower lakes (Erie, Ontario) and were completed 6–11 days later at ports on the upper lakes (Michigan, Lake Superior). Eight trials were conducted on four ships using five different ballast sediments. Hatching was observed on every ship, although not from all sediments on all ships. Overall hatch rates were very low (0.5 individuals per 500 g sediment), typically involving activation of < 0.05% of total eggs present. Five species of rotifers and copepod nauplii were hatched from ballast sediments, although only one or two species typically hatched from any one sediment. Results of this study indicate that hatching of diapausing eggs contained in ballast sediment of NOBOB ships poses a relatively low risk of invasion to the Great Lakes. However, as reproduction may occur in tanks, and non-indigenous species may be involved in numerous introduction events, the risk posed by this vector is small but potentially important. While dormancy is a characteristic enabling enhanced survival during transportation in ballast tanks, it becomes a hindrance for introduction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72804/1/j.1366-9516.2005.00150.x.pd

Results of search for magnetized quark-nugget dark matter from radial impacts on Earth

Magnetized Quark Nuggets (MQNs) are a recently proposed dark-matter candidate consistent with the Standard Model and with Tatsumi's theory of quark-nugget cores in magnetars. Previous publications have covered their formation in the early universe, aggregation into a broad mass distribution before they can decay by the weak force, interaction with normal matter through their magnetopause, and first observation consistent MQNs, i.e. a nearly tangential impact limiting their surface-magnetic-field parameter B_o from Tatsumi's values of 0.1 to 10.0 TT to new value of 1.65 TT +/- 21%. The MQN mass distribution and interaction cross section depend strongly on B_o. Their magnetopause is much larger than their geometric dimensions and can cause sufficient energy deposition to form non-meteorite craters, which are reported approximately annually. We report computer simulations of the MQN energy deposition in water-saturated peat, soft sediments, and granite and report results from excavating such a crater. Five points of agreement between observations and hydrodynamic simulations of an MQN impact support this second observation consistent with MQN dark matter and suggest a method for qualifying additional MQN events. The results also redundantly constrain B_o to greater than 0.4 TT.Comment: 30 pages, 13 figures, submitted to Univers

Meta-analysis of 8q24 for seven cancers reveals a locus between NOV and ENPP2 associated with cancer development.

BACKGROUND: Human chromosomal region 8q24 contains several genes which could be functionally related to cancer, including the proto-oncogene c-MYC. However, the abundance of associations around 128 Mb on chromosome 8 could mask the appearance of a weaker, but important, association elsewhere on 8q24. METHODS: In this study, we completed a meta-analysis of results from nine genome-wide association studies for seven types of solid-tumor cancers (breast, prostate, pancreatic, lung, ovarian, colon, and glioma) to identify additional associations that were not apparent in any individual study. RESULTS: Fifteen SNPs in the 8q24 region had meta-analysis p-values < 1E-04. In particular, the region consisting of 120,576,000-120,627,000 bp contained 7 SNPs with p-values < 1.0E-4, including rs6993464 (p = 1.25E-07). This association lies in the region between two genes, NOV and ENPP2, which have been shown to play a role in tumor development and motility. An additional region consisting of 5 markers from 128,478,000 bp - 128,524,000 (around gene POU5F1B) had p-values < 1E-04, including rs6983267, which had the smallest p-value (p = 6.34E-08). This result replicates previous reports of association between rs6983267 and prostate and colon cancer. CONCLUSIONS: Further research in this area is warranted as these results demonstrate that the chromosomal region 8q24 may contain a locus that influences general cancer susceptibility between 120,576 and 120,630 kb.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Tuberculosis in cattle: the results of the four-area project

<p/> <p>The four-area project was undertaken to further assess the impact of badger removal on the control of tuberculosis in cattle herds in Ireland. It was conducted between 1997 and 2002 in matched removal and reference areas in four counties, namely Cork, Donegal, Kilkenny and Monaghan, representing a wide range of Irish farming environments. In the removal areas, a proactive programme of badger removal was conducted, on two or three occasions each year, whereas in the reference areas, badger removal was entirely reactive following severe outbreaks of tuberculosis amongst cattle. A detailed statistical analysis of this study has already been presented by Griffin <it>et al. </it><abbrgrp><abbr bid="B13">13</abbr></abbrgrp>; this paper presents further, mainly descriptive, findings from the study. In total, 2,360 badgers were captured in the removal areas of which 450 (19.5%) were considered positive for tuberculosis and 258 badgers were captured in the reference areas, with 57 (26.1%) positive for tuberculosis. The annual incidence of confirmed herd restrictions was lower in the removal area compared to the reference area in every year of the study period in each of the four counties. These empirical findings were consistent with the hazard ratios found by Griffin <it>et al. </it><abbrgrp><abbr bid="B13">13</abbr></abbrgrp>. Further, the effect of proactive badger removal on cattle tuberculosis in the four-area project and in the earlier east-Offaly project, as measured using the number of reactors per 1,000 cattle tested, were very similar, providing compelling evidence of the role of badgers in the epidemiology of tuberculosis in Irish cattle herds. The validity of the four-area project was discussed in detail. Efforts to minimise badger-to-cattle transmission in Ireland must be undertaken in association with the current comprehensive control programme, which has effectively minimised opportunities for cattle-to-cattle transmission.</p

Abnormal Cortical Development after Premature Birth Shown by Altered Allometric Scaling of Brain Growth

BACKGROUND: We postulated that during ontogenesis cortical surface area and cerebral volume are related by a scaling law whose exponent gives a quantitative measure of cortical development. We used this approach to investigate the hypothesis that premature termination of the intrauterine environment by preterm birth reduces cortical development in a dose-dependent manner, providing a neural substrate for functional impairment. METHODS AND FINDINGS: We analyzed 274 magnetic resonance images that recorded brain growth from 23 to 48 wk of gestation in 113 extremely preterm infants born at 22 to 29 wk of gestation, 63 of whom underwent neurodevelopmental assessment at a median age of 2 y. Cortical surface area was related to cerebral volume by a scaling law with an exponent of 1.29 (95% confidence interval, 1.25–1.33), which was proportional to later neurodevelopmental impairment. Increasing prematurity and male gender were associated with a lower scaling exponent (p < 0.0001) independent of intrauterine or postnatal somatic growth. CONCLUSIONS: Human brain growth obeys an allometric scaling relation that is disrupted by preterm birth in a dose-dependent, sexually dimorphic fashion that directly parallels the incidence of neurodevelopmental impairments in preterm infants. This result focuses attention on brain growth and cortical development during the weeks following preterm delivery as a neural substrate for neurodevelopmental impairment after premature delivery

Foundations of Digital Arch{\ae}oludology

Digital Archaeoludology (DAL) is a new field of study involving the analysis and reconstruction of ancient games from incomplete descriptions and archaeological evidence using modern computational techniques. The aim is to provide digital tools and methods to help game historians and other researchers better understand traditional games, their development throughout recorded human history, and their relationship to the development of human culture and mathematical knowledge. This work is being explored in the ERC-funded Digital Ludeme Project. The aim of this inaugural international research meeting on DAL is to gather together leading experts in relevant disciplines - computer science, artificial intelligence, machine learning, computational phylogenetics, mathematics, history, archaeology, anthropology, etc. - to discuss the key themes and establish the foundations for this new field of research, so that it may continue beyond the lifetime of its initiating project.Comment: Report on Dagstuhl Research Meeting. Authored/edited by all participants. Appendices by Thierry Depauli

Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial

BACKGROUND: Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gemcitabine [CisGem], improved the response rate, but did not improve the progression-free survival (PFS) in the ABC-03 study. Minimally invasive biomarkers predictive of cediranib benefit may improve patient outcomes. METHODS: Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC). RESULTS: Samples were available from n=117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of the therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analysis revealed CK18 and VEGFR2 increases correlated with poorer OS in all patients (P< 0.001 and P=0.02, respectively). CONCLUSIONS: Rising circulating VEGFA levels in patients with ABC, treated with CisGem, are associated with worse PFS and OS, not seen in patients receiving cediranib. Rising levels of markers of tumour burden (CK18) and potential resistance (VEGFR2) are associated with worse outcomes and warrant validation