Global Networks of Trade and Bits

Considerable efforts have been made in recent years to produce detailed topologies of the Internet. Although Internet topology data have been brought to the attention of a wide and somewhat diverse audience of scholars, so far they have been overlooked by economists. In this paper, we suggest that such data could be effectively treated as a proxy to characterize the size of the "digital economy" at country level and outsourcing: thus, we analyse the topological structure of the network of trade in digital services (trade in bits) and compare it with that of the more traditional flow of manufactured goods across countries. To perform meaningful comparisons across networks with different characteristics, we define a stochastic benchmark for the number of connections among each country-pair, based on hypergeometric distribution. Original data are thus filtered by means of different thresholds, so that we only focus on the strongest links, i.e., statistically significant links. We find that trade in bits displays a sparser and less hierarchical network structure, which is more similar to trade in high-skill manufactured goods than total trade. Lastly, distance plays a more prominent role in shaping the network of international trade in physical goods than trade in digital services.Comment: 25 pages, 6 figure

JTE-522, a selective COX-2 inhibitor, inhibits growth of pulmonary metastases of colorectal cancer in rats

BACKGROUND: Epidemiological studies have shown that individuals who regularly consume NSAIDs have lower rates of mortality associated with colorectal cancer. Because COX-2 inhibitors prevent tumor growth through some mechanisms, we assessed the effect of JTE-522, a selective COX-2 inhibitor, on pulmonary metastases of colon cancer in a rat model. METHODS: A suspension of 5 × 10(6 )RCN-9 (rat colon cancer cells) was injected into the tail vein of 24 anesthetized male F344/DuCrj rats. Oral JTE-522 (0, 3, 10, or 30 mg/kg/day) was administered from the day before RCN-9 injection until the end of the study. Twenty-four days later, the lungs were removed from sacrificed rats and weighed. Pulmonary metastatic tumors were microscopically evaluated in the largest cross sections. We also performed immunohistochemical staining for both COX-2 and VEGF. RESULTS: JTE-522 dose-dependently decreased lung weight (p = 0.001) and the size of pulmonary metastatic tumors (p = 0.0002). However, the differences in the number of metastatic tumors among 4 groups were insignificant. Significant adverse effects of JTE-522 were undetectable. Immunohistochemical staining showed high levels of both COX-2 and VEGF in pulmonary metastatic tumors. CONCLUSION: JTE-522 dose-dependently decreased the size, but not the number of pulmonary metastases. COX-2 inhibitors might block metastatic tumor growth, but not actual metastasis. Selective COX-2 inhibitors might be useful as therapeutic agents that inhibit the growth of metastatic tumors, as well as the tumorigenesis of colorectal cancer

Inhibition of haematogenous metastasis of colon cancer in mice by a selective COX-2 inhibitor, JTE-522

It is proposed that non-steroidal anti-inflammatory drugs (NSAIDs) reduce colorectal tumorigenesis by inhibition of cyclooxygenase (COX). COX is a key enzyme in the conversion of arachidonic acid to prostaglandins and two isoforms of COX have been characterized, COX-1 and COX-2. Multiple studies have shown that COX-2 is expressed at high levels in colorectal tumours and play a role in colorectal tumorigenesis. Recently it has been reported that selective inhibition of COX-2 inhibits colon cancer cell growth. In this study we investigated the effect of a selective COX-2 inhibitor (JTE-522) on haematogenous metastasis of colon cancer. For this purpose, we selected a murine colon cancer cell line, colon-26, that constitutively expresses the COX-2 protein. The subclone P expressed a high level of COX-2 and the subclone 5 expressed a low level. The colon-26 subclones were injected into the tail vein of BALB/c mice. JTE-522 was given intraperitoneally every day from the day prior to cancer cell injection, and the mice were sacrificed 16 days after cell injection. Lung metastases were compared between groups with and without JTE-522. In the mice injected with subclone P, the number of lung metastatic nodules was significantly reduced in the treated group. However, in the mice injected with subclone 5, there was little difference between the control and the treated groups. These results indicate that there may be a direct link between inhibition of haematogenous metastasis of colon cancer and selective inhibition of COX-2, and that selective COX-2 inhibitors may be a novel class of therapeutic agents not only for colorectal tumorigenesis but also for haematogenous metastasis of colon cancer. © 1999 Cancer Research Campaig

EGb761, a Ginkgo Biloba Extract, Is Effective Against Atherosclerosis In Vitro, and in a Rat Model of Type 2 Diabetes

BACKGROUND: EGb761, a standardized Ginkgo biloba extract, has antioxidant and antiplatelet aggregation and thus might protect against atherosclerosis. However, molecular and functional properties of EGb761 and its major subcomponents have not been well characterized. We investigated the effect of EGb761 and its major subcomponents (bilobalide, kaemferol, and quercetin) on preventing atherosclerosis in vitro, and in a rat model of type 2 diabetes. METHODS AND RESULTS: EGb761 (100 and 200 mg/kg) or normal saline (control) were administered to Otsuka Long-Evans Tokushima Fatty rats, an obese insulin-resistant rat model, for 6 weeks (from 3 weeks before to 3 weeks after carotid artery injury). Immunohistochemical staining was performed to investigate cell proliferation and apoptosis in the injured arteries. Cell migration, caspase-3 activity and DNA fragmentation, monocyte adhesion, and ICAM-1/VCAM-1 levels were explored in vitro. Treatment with EGb761 dose-dependently reduced intima-media ratio, proliferation of vascular smooth muscle cells (VSMCs) and induced greater apoptosis than the controls. Proliferation and migration of VSMCs in vitro were also decreased by the treatment of EGb761. Glucose homeostasis and circulating adiponectin levels were improved, and plasma hsCRP concentrations were decreased in the treatment groups. Caspase-3 activity and DNA fragmentation increased while monocyte adhesion and ICAM-1/VCAM-1 levels decreased significantly. Among subcomponents of EGb761, kaemferol and quercetin reduced VSMC migration and increased caspase activity. CONCLUSIONS: EGb761 has a protective role in the development of atherosclerosis and is a potential therapeutic agent for preventing atherosclerosis

Genome-Scale Reconstruction of Escherichia coli's Transcriptional and Translational Machinery: A Knowledge Base, Its Mathematical Formulation, and Its Functional Characterization

Metabolic network reconstructions represent valuable scaffolds for ‘-omics’ data integration and are used to computationally interrogate network properties. However, they do not explicitly account for the synthesis of macromolecules (i.e., proteins and RNA). Here, we present the first genome-scale, fine-grained reconstruction of Escherichia coli's transcriptional and translational machinery, which produces 423 functional gene products in a sequence-specific manner and accounts for all necessary chemical transformations. Legacy data from over 500 publications and three databases were reviewed, and many pathways were considered, including stable RNA maturation and modification, protein complex formation, and iron–sulfur cluster biogenesis. This reconstruction represents the most comprehensive knowledge base for these important cellular functions in E. coli and is unique in its scope. Furthermore, it was converted into a mathematical model and used to: (1) quantitatively integrate gene expression data as reaction constraints and (2) compute functional network states, which were compared to reported experimental data. For example, the model predicted accurately the ribosome production, without any parameterization. Also, in silico rRNA operon deletion suggested that a high RNA polymerase density on the remaining rRNA operons is needed to reproduce the reported experimental ribosome numbers. Moreover, functional protein modules were determined, and many were found to contain gene products from multiple subsystems, highlighting the functional interaction of these proteins. This genome-scale reconstruction of E. coli's transcriptional and translational machinery presents a milestone in systems biology because it will enable quantitative integration of ‘-omics’ datasets and thus the study of the mechanistic principles underlying the genotype–phenotype relationship

Optimization in computational systems biology

Optimization aims to make a system or design as effective or functional as possible. Mathematical optimization methods are widely used in engineering, economics and science. This commentary is focused on applications of mathematical optimization in computational systems biology. Examples are given where optimization methods are used for topics ranging from model building and optimal experimental design to metabolic engineering and synthetic biology. Finally, several perspectives for future research are outlined

Epigenetic Regulation of a Murine Retrotransposon by a Dual Histone Modification Mark

Large fractions of eukaryotic genomes contain repetitive sequences of which the vast majority is derived from transposable elements (TEs). In order to inactivate those potentially harmful elements, host organisms silence TEs via methylation of transposon DNA and packaging into chromatin associated with repressive histone marks. The contribution of individual histone modifications in this process is not completely resolved. Therefore, we aimed to define the role of reversible histone acetylation, a modification commonly associated with transcriptional activity, in transcriptional regulation of murine TEs. We surveyed histone acetylation patterns and expression levels of ten different murine TEs in mouse fibroblasts with altered histone acetylation levels, which was achieved via chemical HDAC inhibition with trichostatin A (TSA), or genetic inactivation of the major deacetylase HDAC1. We found that one LTR retrotransposon family encompassing virus-like 30S elements (VL30) showed significant histone H3 hyperacetylation and strong transcriptional activation in response to TSA treatment. Analysis of VL30 transcripts revealed that increased VL30 transcription is due to enhanced expression of a limited number of genomic elements, with one locus being particularly responsive to HDAC inhibition. Importantly, transcriptional induction of VL30 was entirely dependent on the activation of MAP kinase pathways, resulting in serine 10 phosphorylation at histone H3. Stimulation of MAP kinase cascades together with HDAC inhibition led to simultaneous phosphorylation and acetylation (phosphoacetylation) of histone H3 at the VL30 regulatory region. The presence of the phosphoacetylation mark at VL30 LTRs was linked with full transcriptional activation of the mobile element. Our data indicate that the activity of different TEs is controlled by distinct chromatin modifications. We show that activation of a specific mobile element is linked to a dual epigenetic mark and propose a model whereby phosphoacetylation of histone H3 is crucial for full transcriptional activation of VL30 elements

State of the Field: Extreme Precision Radial Velocities

The Second Workshop on Extreme Precision Radial Velocities defined circa 2015 the state of the art Doppler precision and identified the critical path challenges for reaching 10 cm/s measurement precision. The presentations and discussion of key issues for instrumentation and data analysis and the workshop recommendations for achieving this precision are summarized here. Beginning with the HARPS spectrograph, technological advances for precision radial velocity measurements have focused on building extremely stable instruments. To reach still higher precision, future spectrometers will need to produce even higher fidelity spectra. This should be possible with improved environmental control, greater stability in the illumination of the spectrometer optics, better detectors, more precise wavelength calibration, and broader bandwidth spectra. Key data analysis challenges for the precision radial velocity community include distinguishing center of mass Keplerian motion from photospheric velocities, and the proper treatment of telluric contamination. Success here is coupled to the instrument design, but also requires the implementation of robust statistical and modeling techniques. Center of mass velocities produce Doppler shifts that affect every line identically, while photospheric velocities produce line profile asymmetries with wavelength and temporal dependencies that are different from Keplerian signals. Exoplanets are an important subfield of astronomy and there has been an impressive rate of discovery over the past two decades. Higher precision radial velocity measurements are required to serve as a discovery technique for potentially habitable worlds and to characterize detections from transit missions. The future of exoplanet science has very different trajectories depending on the precision that can ultimately be achieved with Doppler measurements.Comment: 45 pages, 23 Figures, workshop summary proceeding