Impaired decidual natural killer cell regulation of vascular remodelling in early human pregnancies with high uterine artery resistance

During human pregnancy, natural killer (NK) cells accumulate in the maternal decidua, but their specific roles remain to be determined. Decidual NK (dNK) cells are present during trophoblast invasion and uterine spiral artery remodelling. These events are crucial for successful placentation and the provision of an adequate blood supply to the developing fetus. Remodelling of spiral arteries is impaired in the dangerous pregnancy complication pre-eclampsia. We studied dNK cells isolated from pregnancies at 9-14 weeks' gestation, screened by uterine artery Doppler ultrasound to determine resistance indices which relate to the extent of spiral artery remodelling. dNK cells were able to promote the invasive behaviour of fetal trophoblast cells, partly through HGF. Cells isolated from pregnancies with higher resistance indices were less able to do this and secreted fewer pro-invasive factors. dNK cells from pregnancies with normal resistance indices could induce apoptotic changes in vascular smooth muscle and endothelial cells in vitro, events of importance in vessel remodelling, partly through Fas signalling. dNK cells isolated from high resistance index pregnancies failed to induce vascular apoptosis and secreted fewer pro-apoptotic factors. We have modelled the cellular interactions at the maternal-fetal interface and provide the first demonstration of a functional role for dNK cells in influencing vascular cells. A potential mechanism contributing to impaired vessel remodelling in pregnancies with a higher uterine artery resistance is presented. These findings may be informative in determining the cellular interactions contributing to the pathology of pregnancy disorders where remodelling is impaired, such as pre-eclampsia. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Delivery of sTRAIL variants by MSCs in combination with cytotoxic drug treatment leads to p53-independent enhanced antitumor effects

Mesenchymal stem cells (MSCs) are able to infiltrate tumor tissues and thereby effectively deliver gene therapeutic payloads. Here, we engineered murine MSCs (mMSCs) to express a secreted form of the TNF-related apoptosis-inducing ligand (TRAIL), which is a potent inducer of apoptosis in tumor cells, and tested these MSCs, termed MSC.sTRAIL, in combination with conventional chemotherapeutic drug treatment in colon cancer models. When we pretreated human colorectal cancer HCT116 cells with low doses of 5-fluorouracil (5-FU) and added MSC.sTRAIL, we found significantly increased apoptosis as compared with single-agent treatment. Moreover, HCT116 xenografts, which were cotreated with 5-FU and systemically delivered MSC.sTRAIL, went into remission. Noteworthy, this effect was protein 53 (p53) independent and was mediated by TRAIL-receptor 2 (TRAIL-R2) upregulation, demonstrating the applicability of this approach in p53-defective tumors. Consequently, when we generated MSCs that secreted TRAIL-R2-specific variants of soluble TRAIL (sTRAIL), we found that such engineered MSCs, labeled MSC.sTRAIL DR5, had enhanced antitumor activity in combination with 5-FU when compared with MSC.sTRAIL. In contrast, TRAIL-resistant pancreatic carcinoma PancTu1 cells responded better to MSC.sTRAIL DR4 when the antiapoptotic protein XIAP (X-linked inhibitor of apoptosis protein) was silenced concomitantly. Taken together, our results demonstrate that TRAIL-receptor selective variants can potentially enhance the therapeutic efficacy of MSC-delivered TRAIL as part of individualized and tumor-specific combination treatments. © 2013 Macmillan Publishers Limited All rights reserved

Anti-müllerian hormone is not associated with cardiometabolic risk factors in adolescent females

<p>Objectives: Epidemiological evidence for associations of Anti-Müllerian hormone (AMH) with cardiometabolic risk factors is lacking. Existing evidence comes from small studies in select adult populations, and findings are conflicting. We aimed to assess whether AMH is associated with cardiometabolic risk factors in a general population of adolescent females.</p> <p>Methods: AMH, fasting insulin, glucose, HDLc, LDLc, triglycerides and C-reactive protein (CRP) were measured at a mean age 15.5 years in 1,308 female participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Multivariable linear regression was used to examine associations of AMH with these cardiometabolic outcomes.</p> <p>Results: AMH values ranged from 0.16–35.84 ng/ml and median AMH was 3.57 ng/ml (IQR: 2.41, 5.49). For females classified as post-pubertal (n = 848) at the time of assessment median (IQR) AMH was 3.81 ng/ml (2.55, 5.82) compared with 3.25 ng/ml (2.23, 5.05) in those classed as early pubertal (n = 460, P≤0.001). After adjusting for birth weight, gestational age, pubertal stage, age, ethnicity, socioeconomic position, adiposity and use of hormonal contraceptives, there were no associations with any of the cardiometabolic outcomes. For example fasting insulin changed by 0% per doubling of AMH (95%CI: −3%,+2%) p = 0.70, with identical results if HOMA-IR was used. Results were similar after additional adjustment for smoking, physical activity and age at menarche, after exclusion of 3% of females with the highest AMH values, after excluding those that had not started menarche and after excluding those using hormonal contraceptives.</p> <p>Conclusion: Our results suggest that in healthy adolescent females, AMH is not associated with cardiometabolic risk factors.</p&gt

The JCMT Transient Survey: Identifying Submillimeter Continuum Variability over Several Year Timescales Using Archival JCMT Gould Belt Survey Observations

This is the final version of the article. Available from American Astronomical Society via the DOI in this record.Investigating variability at the earliest stages of low-mass star formation is fundamental in understanding how a protostar assembles mass. While many simulations of protostellar disks predict non-steady accretion onto protostars, deeper investigation requires robust observational constraints on the frequency and amplitude of variability events characterized across the observable SED. In this study, we develop methods to robustly analyze repeated observations of an area of the sky for submillimeter variability in order to determine constraints on the magnitude and frequency of deeply embedded protostars. We compare 850 μm JCMT Transient Survey data with archival JCMT Gould Belt Survey data to investigate variability over 2–4 year timescales. Out of 175 bright, independent emission sources identified in the overlapping fields, we find seven variable candidates, five of which we classify as Strong, and the remaining two we classify as Extended to indicate that the latter are associated with larger-scale structure. For the Strong variable candidates, we find an average fractional peak brightness change per year of $| 4.0| \% \,{\mathrm{yr}}^{-1}$, with a standard deviation of $2.7 \% \,{\mathrm{yr}}^{-1}$. In total, 7% of the protostars associated with 850 μm emission in our sample show signs of variability. Four of the five Strong sources are associated with a known protostar. The remaining source is a good follow-up target for an object that is anticipated to contain an enshrouded, deeply embedded protostar. In addition, we estimate the 850 μm periodicity of the submillimeter variable source, EC 53, to be 567 ± 32 days, based on the archival Gould Belt Survey data.Steve Mairs was partially supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada graduate scholarship program. Doug Johnstone is supported by the National Research Council of Canada and by an NSERC Discovery Grant. Gregory Herczeg is supported by general grant 11473005 awarded by the National Science Foundation of China. Andy Pon received partial salary support from a Canadian Institute for Theoretical Astrophysics (CITA) National Fellowship. Miju Kang was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, & Future Planning (No. NRF-2015R1C1A1A01052160). J.-E. Lee was supported by the Basic Science Research Program through the National Research Foundation of Korea (grant No. NRF-2015R1A2A2A01004769) and the Korea Astronomy and Space Science Institute under the R&D program (Project No. 2015-1-320-18) supervised by the Ministry of Science and ICT. The authors wish to recognize and acknowledge the very significant cultural role and reverence that the summit of Maunakea has always had within the indigenous Hawaiian community. We are most fortunate to have the opportunity to conduct observations from this mountain. The James Clerk Maxwell Telescope is operated by the East Asian Observatory on behalf of the National Astronomical Observatory of Japan, Academia Sinica Institute of Astronomy and Astrophysics, the Korea Astronomy and Space Science Institute, the National Astronomical Observatories of China, and the Chinese Academy of Sciences (Grant No. XDB09000000), with additional funding support from the Science and Technology Facilities Council of the United Kingdom and participating universities in the United Kingdom and Canada. The James Clerk Maxwell Telescope has historically been operated by the Joint Astronomy Centre on behalf of the Science and Technology Facilities Council of the United Kingdom, the National Research Council of Canada, and the Netherlands Organisation for Scientific Research. Additional funds for the construction of SCUBA-2 were provided by the Canada Foundation for Innovation. The identification number for the JCMT Transient Survey data used in this paper is M16AL001. The identification numbers for the archival Gould Belt Survey data used in this paper are MJLSG31, MJLSG32, MJLSG33, MJLSG38, and MJLSG41. The authors thank the JCMT staff for their support of the data collection and reduction efforts. This research has made use of NASA's Astrophysics Data System and the facilities of the Canadian Astronomy Data Centre operated by the National Research Council of Canada, with the support of the Canadian Space Agency. The authors would especially like to thank Chang Won Lee and Harriet Parsons for their useful insights and suggestions, along with the extended JCMT Transient Team21 for their support. This research used the services of the Canadian Advanced Network for Astronomy Research (CANFAR), which in turn is supported by CANARIE, Compute Canada, University of Victoria, the National Research Council of Canada, and the Canadian Space Agency. This research made use of APLpy, an open-source plotting package for Python hosted at http://aplpy.github.com, and matplotlib, a 2D plotting library for Python (Hunter 2007)

Lack of cortico-limbic coupling in bipolar disorder and schizophrenia during emotion regulation

Bipolar disorder (BD) and schizophrenia (Sz) share dysfunction in prefrontal inhibitory brain systems, yet exhibit distinct forms of affective disturbance. We aimed to distinguish these disorders on the basis of differential activation in cortico-limbic pathways during voluntary emotion regulation. Patients with DSM-IV diagnosed Sz (12) or BD-I (13) and 15 healthy control (HC) participants performed a well-established emotion regulation task while undergoing functional magnetic resonance imaging. The task required participants to voluntarily upregulate or downregulate their subjective affect while viewing emotionally negative images or maintain their affective response as a comparison condition. In BD, abnormal overactivity (hyperactivation) occurred in the right ventrolateral prefrontal cortex (VLPFC) during up- and downregulation of negative affect, relative to HC. Among Sz, prefrontal hypoactivation of the right VLPFC occurred during downregulation (opposite to BD), whereas upregulation elicited hyperactivity in the right VLPFC similar to BD. Amygdala activity was significantly related to subjective negative affect in HC and BD, but not Sz. Furthermore, amygdala activity was inversely coupled with the activity in the left PFC during downregulation in HC (r=−0.76), while such coupling did not occur in BD or Sz. These preliminary results indicate that differential cortico-limbic activation can distinguish the clinical groups in line with affective disturbance: BD is characterized by ineffective cortical control over limbic regions during emotion regulation, while Sz is characterized by an apparent failure to engage cortical (hypofrontality) and limbic regions during downregulation

The JCMT Transient Survey: Stochastic and Secular Variability of Protostars and Disks In the Submillimeter Region Observed over 18 Months

This is the final version of the article. Available from American Astronomical Society via the DOI in this record.We analyze results from the first 18 months of monthly submillimeter monitoring of eight star-forming regions in the JCMT Transient Survey. In our search for stochastic variability in 1643 bright peaks, only the previously identified source, EC 53, shows behavior well above the expected measurement uncertainty. Another four sources—two disks and two protostars—show moderately enhanced standard deviations in brightness, as expected for stochastic variables. For the two protostars, this apparent variability is the result of single epochs that are much brighter than the mean. In our search for secular brightness variations that are linear in time, we measure the fractional brightness change per year for 150 bright peaks, 50 of which are protostellar. The ensemble distribution of slopes is well fit by a normal distribution with σ ~ 0.023. Most sources are not rapidly brightening or fading at submillimeter wavelengths. Comparison against time-randomized realizations shows that the width of the distribution is dominated by the uncertainty in the individual brightness measurements of the sources. A toy model for secular variability reveals that an underlying Gaussian distribution of linear fractional brightness change σ = 0.005 would be unobservable in the present sample, whereas an underlying distribution with σ = 0.02 is ruled out. Five protostellar sources, 10% of the protostellar sample, are found to have robust secular measures deviating from a constant flux. The sensitivity to secular brightness variations will improve significantly with a sample over a longer time duration, with an improvement by factor of two expected by the conclusion of our 36 month survey.The JCMT is operated by the East Asian Observatory on behalf of The National Astronomical Observatory of Japan, Academia Sinica Institute of Astronomy and Astrophysics, the Korea Astronomy and Space Science Institute, the National Astronomical Observatories of China and the Chinese Academy of Sciences (Grant No. XDB09000000), with additional funding support from the Science and Technology Facilities Council of the United Kingdom and participating universities in the United Kingdom and Canada. The identification number for the JCMT Transient Survey under which the SCUBA-2 data used in this paper can be found is M16AL001. The authors thank the JCMT staff for their support of the GBS team in data collection and reduction efforts. The Starlink software (Currie et al. 2014) is supported by the East Asian Observatory. This research has made use of NASA's Astrophysics Data System and the facilities of the Canadian Astronomy Data Centre operated by the National Research Council of Canada with the support of the Canadian Space Agency. This research used the services of the Canadian Advanced Network for Astronomy Research (CANFAR), which in turn is supported by CANARIE, Compute Canada, University of Victoria, the National Research Council of Canada, and the Canadian Space Agency

Chalk-steel Interface testing for marine energy foundations

The Energy Technology Partnership (ETP) and Lloyd’s Register EMEA are gratefully acknowledged for the funding of this project. The authors would also like to acknowledge the support of the European Regional Development Fund (ERDF) SMART Centre at the University of Dundee that allowed purchase of the equipment used during this study. The views expressed are those of the authors alone, and do not necessarily represent the views of their respective companies or employing organizations.Peer reviewedPostprin

Knee-clicks and visual traits indicate fighting ability in eland antelopes: multiple messages and back-up signals

Abstract Background Given the costs of signalling, why do males often advertise their fighting ability to rivals using several signals rather than just one? Multiple signalling theories have developed largely in studies of sexual signals, and less is known about their applicability to intra-sexual communication. We here investigate the evolutionary basis for the intricate agonistic signalling system in eland antelopes, paying particular attention to the evolutionary phenomenon of loud knee-clicking. Results A principal components analysis separated seven male traits into three groups. The dominant frequency of the knee-clicking sound honestly indicated body size, a main determinant of fighting ability. In contrast, the dewlap size increased with estimated age rather than body size, suggesting that, by magnifying the silhouette of older bulls disproportionately, the dewlap acts as an indicator of age-related traits such as fighting experience. Facemask darkness, frontal hairbrush size and body greyness aligned with a third underlying variable, presumed to be androgen-related aggression. A longitudinal study provided independent support of these findings. Conclusion The results show that the multiple agonistic signals in eland reflect three separate components of fighting ability: (1) body size, (2) age and (3) presumably androgen-related aggression, which is reflected in three backup signals. The study highlights how complex agonistic signalling systems can evolve through the simultaneous action of several selective forces, each of which favours multiple signals. Specifically, loud knee-clicking is discovered to be an honest signal of body size, providing an exceptional example of the potential for non-vocal acoustic communication in mammals.</p

Management of congestive heart failure: a gender gap may still exist. Observations from a contemporary cohort

BACKGROUND: Unlike other cardiovascular diseases the incidence and prevalence of congestive heart failure (CHF) continues to increase. While gender differences in coronary artery disease have been well described, to date, there has been a relative paucity of similar data in patients with CHF. We conducted a pilot study to evaluate the profile and management of patients with CHF at a tertiary care centre to determine if a gender difference exists. METHODS: A chart review was performed at a tertiary care centre on consecutive patients admitted with a primary diagnosis of CHF between June 1997 and 1998. Co-morbidity, diagnostic investigations, and management of CHF were recorded. Comparisons between male and female patients were conducted. RESULTS: One hundred and forty five patients were reviewed. There were 80 male (M) and 65 female (F) patients of similar age [71.6 vs. 71.3 (M vs. F), p = NS]. Male patients were more likely to have had a previous myocardial infarction (66% vs. 35%, p < 0.01) and revascularization (41% vs. 20%, p < 0.05), and had worse left ventricular ejection fraction (LVEF) than women, [median LVEF 3 vs. 2 (M vs. F), p < 0.01]. Male patients were more likely to have a non-invasive assessment of left ventricular (LV) function [85% vs. 69%, (M vs. F), p < 0.05]. A logistic regression analysis suggests that amongst those without coronary disease, males were more likely to receive non-invasive testing. There were no differences in the use of prescribed medications, in this cohort. CONCLUSIONS: This pilot study demonstrated that there seem to be important gender differences in the profile and management of patients with CHF. Importantly women were less likely to have an evaluation of LV function. As assessment of LV function has significant implications on patient management, this data justifies the need for larger studies to assess gender differences in CHF profile and treatment

Photodisintegration of 4^4He into p+t

The two-body photodisintegration of $^4$He into a proton and a triton has been studied using the CEBAF Large-Acceptance Spectrometer (CLAS) at Jefferson Laboratory. Real photons produced with the Hall-B bremsstrahlung-tagging system in the energy range from 0.35 to 1.55 GeV were incident on a liquid $^4$He target. This is the first measurement of the photodisintegration of $^4$He above 0.4 GeV. The differential cross sections for the $\gamma$$^4$He$\to pt$ reaction have been measured as a function of photon-beam energy and proton-scattering angle, and are compared with the latest model calculations by J.-M. Laget. At 0.6-1.2 GeV, our data are in good agreement only with the calculations that include three-body mechanisms, thus confirming their importance. These results reinforce the conclusion of our previous study of the three-body breakup of $^3$He that demonstrated the great importance of three-body mechanisms in the energy region 0.5-0.8 GeV .Comment: 13 pages submitted in one tgz file containing 2 tex file and 22 postscrip figure