Retrotransposon silencing by DNA methylation can drive mammalian genomic imprinting

Among mammals, only eutherians and marsupials are viviparous and have genomic imprinting that leads to parent-of-origin-specific differential gene expression. We used comparative analysis to investigate the origin of genomic imprinting in mammals. PEG10 (paternally expressed 10) is a retrotransposon-derived imprinted gene that has an essential role for the formation of the placenta of the mouse. Here, we show that an orthologue of PEG10 exists in another therian mammal, the marsupial tammar wallaby (Macropus eugenii), but not in a prototherian mammal, the egg-laying platypus (Ornithorhynchus anatinus), suggesting its close relationship to the origin of placentation in therian mammals. We have discovered a hitherto missing link of the imprinting mechanism between eutherians and marsupials because tammar PEG10 is the first example of a differentially methylated region (DMR) associated with genomic imprinting in marsupials. Surprisingly, the marsupial DMR was strictly limited to the 5′ region of PEG10, unlike the eutherian DMR, which covers the promoter regions of both PEG10 and the adjacent imprinted gene SGCE. These results not only demonstrate a common origin of the DMR-associated imprinting mechanism in therian mammals but provide the first demonstration that DMR-associated genomic imprinting in eutherians can originate from the repression of exogenous DNA sequences and/or retrotransposons by DNA methylation

The impact of corporate philanthropy on reputation for corporate social performance

This study seeks to examine the mechanisms by which a corporation’s use of philanthropy affects its reputation for corporate social performance (CSP), which the authors conceive of as consisting of two dimensions: CSP awareness and CSP perception. Using signal detection theory (SDT), the authors model signal amplitude (the amount contributed), dispersion (number of areas supported), and consistency (presence of a corporate foundation) on CSP awareness and perception. Overall, this study finds that characteristics of firms' portfolio of philanthropic activities are a greater predictor of CSP awareness than of CSP perception. Awareness increases with signal amplitude, dispersion, and consistency. CSP perception is driven by awareness and corporate reputation. The authors’ contention that corporate philanthropy is a complex variable is upheld, as we find that CSP signal characteristics influence CSP awareness and perception independently and asymmetrically. The authors conclude by proposing avenues for future research

Cox-2 Inhibition Enhances the Activity of Sunitinib in Human Renal Cell Carcinoma Xenografts

Background: Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su. Methods: COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared. Results: COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy. Conclusion: COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC

The Sunyaev-Zel'dovich Infrared Experiment: A Millimeter-wave Receiver for Cluster Cosmology

Measurements of the Sunyaev-Zel'dovich (S-Z) effect towards distant clusters of galaxies can be used to determine the Hubble constant and the radial component of cluster peculiar velocities. Determination of the cluster peculiar velocity requires the separation of the two components of the S-Z effect, which are due to the thermal and bulk velocities of the intracluster plasma. The two components can be separated practically only at millimeter (mm) wavelengths. Measurements of the S-Z effect at mm wavelengths are subject to minimal astrophysical confusion and, therefore, provide an important test of results obtained at longer wavelengths. We describe the instrument used to make the first significant detections of the S-Z effect at millimeter wavelengths. This instrument employs new filter, detector, and readout technologies to produce sensitive measurements of differential sky brightness stable on long time scales. These advances allow drift scan observations which achieve high sensitivity while minimizing common sources of systematic error.Comment: 19 pages, 15 postscript figures, LaTeX(aaspptwo.sty), ApJ(in press

Accurate prediction of saw blade thicknesses from false start measurements

Background: False start analysis is the examination of incomplete saw marks created on bone in an effort to establish information on the saw that created them. The present study aims to use quantitative data from micro-CT cross-sections to predict the thickness of the saw blade used to create the mark. Random forest statistical models are utilised for prediction to present a methodology that is useful to both forensic researchers and practitioners. Method: 340 false starts were created on 32 fleshed cadaveric leg bones by 38 saws of various classes. False starts were micro-CT scanned and seven measurements taken digitally. A regression random forest model was produced from the measurement data of all saws to predict the saw blade thickness from false starts with an unknown class. A further model was created, consisting of three random forests, to predict the saw blade thickness when the class of the saw is known. The predictive capability of the models was tested using a second sample of data, consisting of measurements taken from a further 17 false starts created randomly selected saws from the 38 in the experiment. Results: Random forest models were able to accurately predict up to 100% of saw blade thicknesses for both samples of false starts. Conclusion: This study demonstrates the applicability of random forest statistical regression models for reliable prediction of saw blade thicknesses from false start data. The methodology proposed enables prediction of saw blade thickness from empirical data and offers a significant step towards reduced subjectivity and database formation in false start analysis. Application of this methodology to false start analysis, with a more complete database, will allow complementary results to current analysis techniques to provide more information on the saw used in dismemberment casework

High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model.</p> <p>Methods</p> <p>Mice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10.</p> <p>Results</p> <p>Tumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion.</p> <p>Conclusions</p> <p>A modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.</p

The BOOMERANG North America Instrument: a balloon-borne bolometric radiometer optimized for measurements of cosmic background radiation anisotropies from 0.3 to 4 degrees

We describe the BOOMERANG North America (BNA) instrument, a balloon-borne bolometric radiometer designed to map the Cosmic Microwave Background (CMB) radiation with 0.3 deg resolution over a significant portion of the sky. This receiver employs new technologies in bolometers, readout electronics, millimeter-wave optics and filters, cryogenics, scan and attitude reconstruction. All these subsystems are described in detail in this paper. The system has been fully calibrated in flight using a variety of techniques which are described and compared. It has been able to obtain a measurement of the first peak in the CMB angular power spectrum in a single balloon flight, few hours long, and was a prototype of the BOOMERANG Long Duration Balloon (BLDB) experiment.Comment: 40 pages, 22 figures, submitted to Ap