Comparisons of global topographic/isostatic models to the Earth's observed gravity field

The Earth's gravitational potential, as described by a spherical harmonic expansion to degree 180, was compared to the potential implied by the topography and its isostatic compensation using five different hypothesis. Initially, series expressions for the Airy/Heiskanen topographic isostatic model were developed to the third order in terms of (h/R), where h is equivalent rock topography and R is a mean Earth radius. Using actual topographic developments for the Earth, it was found that the second and third terms of the expansion contributed 30 and 3 percents, of the first of the expansion. With these new equations it is possible to compute depths (D) of compensation, by degree, using 3 different criteria. The results show that the average depth implied by criterion I is 60 km while it is about 33 km for criteria 2 and 3 with smaller compensation depths at the higher degrees. Another model examined was related to the Vening-Meinesz regional hypothesis implemented in the spectral domain. Finally, oceanic and continental response functions were derived for the global data sets and comparisons made to locally determined values

Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN

Circular RNAs (circRNAs) are a regulatory RNA class. While cancer-driving functions have been identified for single circRNAs, how they modulate gene expression in cancer is not well understood. We investigate circRNA expression in the pediatric malignancy, neuroblastoma, through deep whole-transcriptome sequencing in 104 primary neuroblastomas covering all risk groups. We demonstrate that MYCN amplification, which defines a subset of high-risk cases, causes globally suppressed circRNA biogenesis directly dependent on the DHX9 RNA helicase. We detect similar mechanisms in shaping circRNA expression in the pediatric cancer medulloblastoma implying a general MYCN effect. Comparisons to other cancers identify 25 circRNAs that are specifically upregulated in neuroblastoma, including circARID1A. Transcribed from the ARID1A tumor suppressor gene, circARID1A promotes cell growth and survival, mediated by direct interaction with the KHSRP RNA-binding protein. Our study highlights the importance of MYCN regulating circRNAs in cancer and identifies molecular mechanisms, which explain their contribution to neuroblastoma pathogenesis

Identification of sirtuin 5 inhibitors by ultrafast microchip electrophoresis using nanoliter volume samples

Sirtuin 5 (SIRT5) is a member of the sirtuin family of protein deacylases that catalyzes removal of post-translational modifications, such as succinyl and malonyl moieties, on lysine residues. In light of SIRT5’s roles in regulating metabolism, and its reported oncogenic functions, SIRT5 modulators would be valuable tools for basic biological research and perhaps clinically. Several fluorescence assays for sirtuin modulators have been developed; however, the use of fluorogenic substrates has the potential to cause false positive results due to interactions of engineered substrates with enzyme or test compounds. Therefore, development of high-throughput screening (HTS) assays based on other methods is valuable. In this study, we report the development of a SIRT5 assay using microchip electrophoresis (MCE) for identification of SIRT5 modulators. A novel SIRT5 substrate based on succinate dehydrogenase (SDH) was developed to allow rapid and efficient separation of substrate and product peptide. To achieve high throughput, samples were injected onto the microchip using a droplet-based scheme. By coupling this approach to existing HTS sample preparation workflows, 1408 samples were analyzed at 0.5 Hz in 46 min. Using a 250 ms separation time, 8 MCE injections could be made from each sample generating >11,000 electropherograms during analysis. Of the 1280 chemicals tested, eight were identified as inhibiting SIRT5 activity by at least 70 percent and verified by dose-response analysis