The Internet AS-Level Topology: Three Data Sources and One Definitive Metric

We calculate an extensive set of characteristics for Internet AS topologies extracted from the three data sources most frequently used by the research community: traceroutes, BGP, and WHOIS. We discover that traceroute and BGP topologies are similar to one another but differ substantially from the WHOIS topology. Among the widely considered metrics, we find that the joint degree distribution appears to fundamentally characterize Internet AS topologies as well as narrowly define values for other important metrics. We discuss the interplay between the specifics of the three data collection mechanisms and the resulting topology views. In particular, we show how the data collection peculiarities explain differences in the resulting joint degree distributions of the respective topologies. Finally, we release to the community the input topology datasets, along with the scripts and output of our calculations. This supplement should enable researchers to validate their models against real data and to make more informed selection of topology data sources for their specific needs.Comment: This paper is a revised journal version of cs.NI/050803

AS-level topology collection through looking glass servers

While accurate and complete modeling of the Internet topol-ogy at the Autonomous System (AS) level is critical for future protocol design, performance evaluation, simulation and analysis, still it remains a challenge to construct its ac-curate representation. In this paper, we collect BGP route announcements of ASes from Looking glass (LG) servers. By querying LG servers, we build an AS topology estimate of around 116 K AS links, from which we discover 11 K new AS links and 686 new ASes. We conclude that collecting BGP traces from LG servers can help enhance the current view of the AS topology from the BGP collector projects (e.g., RouteViews)

RiPKI: The Tragic Story of RPKI Deployment in the Web Ecosystem

Previous arXiv version of this paper has been published under the title "When BGP Security Meets Content Deployment: Measuring and Analysing RPKI-Protection of Websites", Proc. of Fourteenth ACM Workshop on Hot Topics in Networks (HotNets), New York:ACM, 2015Previous arXiv version of this paper has been published under the title "When BGP Security Meets Content Deployment: Measuring and Analysing RPKI-Protection of Websites", Proc. of Fourteenth ACM Workshop on Hot Topics in Networks (HotNets), New York:ACM, 2015Web content delivery is one of the most important services on the Internet. Access to websites is typically secured via TLS. However, this security model does not account for prefix hijacking on the network layer, which may lead to traffic blackholing or transparent interception. Thus, to achieve comprehensive security and service availability, additional protective mechanisms are necessary such as the RPKI, a recently deployed Resource Public Key Infrastructure to prevent hijacking of traffic by networks. This paper argues two positions. First, that modern web hosting practices make route protection challenging due to the propensity to spread servers across many different networks, often with unpredictable client redirection strategies, and, second, that we need a better understanding why protection mechanisms are not deployed. To initiate this, we empirically explore the relationship between web hosting infrastructure and RPKI deployment. Perversely, we find that less popular websites are more likely to be secured than the prominent sites. Worryingly, we find many large-scale CDNs do not support RPKI, thus making their customers vulnerable. This leads us to explore business reasons why operators are hesitant to deploy RPKI, which may help to guide future research on improving Internet security

AS-Path Prepending: There is no rose without a thorn

Inbound traffic engineering (ITE) - -the process of announcing routes to, e.g., maximize revenue or minimize congestion - -is an essential task for Autonomous Systems (ASes). AS Path Prepending (ASPP) is an easy to use and well-known ITE technique that routing manuals show as one of the first alternatives to influence other ASes' routing decisions. We observe that origin ASes currently prepend more than 25% of all IPv4 prefixes. ASPP consists of inflating the BGP AS path. Since the length of the AS path is the second tie-breaker in the BGP best path selection, ASPP can steer traffic to other routes. Despite being simple and easy to use, the appreciation of ASPP among operators and researchers is diverse. Some have questioned its need, effectiveness, and predictability, as well as voiced security concerns. Motivated by these mixed views, we revisit ASPP. Our longitudinal study shows that ASes widely deploy ASPP, and its utilization has slightly increased despite public statements against it. We surprisingly spot roughly 6k ASes originating at least one prefix with prepends that achieve no ITE goal. With active measurements, we show that ASPP effectiveness as an ITE tool depends on the AS location and the number of available upstreams; that ASPP security implications are practical; identify that more than 18% of the prepended prefixes contain unnecessary prepends that achieve no apparent goal other than amplifying existing routing security risks. We validate our findings in interviews with 20 network operators

Far-Infrared Therapy Induces the Nuclear Translocation of PLZF Which Inhibits VEGF-Induced Proliferation in Human Umbilical Vein Endothelial Cells

Many studies suggest that far-infrared (FIR) therapy can reduce the frequency of some vascular-related diseases. The non-thermal effect of FIR was recently found to play a role in the long-term protective effect on vascular function, but its molecular mechanism is still unknown. In the present study, we evaluated the biological effect of FIR on vascular endothelial growth factor (VEGF)-induced proliferation in human umbilical vein endothelial cells (HUVECs). We found that FIR ranging 3∼10 µm significantly inhibited VEGF-induced proliferation in HUVECs. According to intensity and time course analyses, the inhibitory effect of FIR peaked at an effective intensity of 0.13 mW/cm2 at 30 min. On the other hand, a thermal effect did not inhibit VEGF-induced proliferation in HUVECs. FIR exposure also inhibited the VEGF-induced phosphorylation of extracellular signal-regulated kinases in HUVECs. FIR exposure further induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO generation in VEGF-treated HUVECs. Both VEGF-induced NO and reactive oxygen species generation was involved in the inhibitory effect of FIR. Nitrotyrosine formation significantly increased in HUVECs treated with VEGF and FIR together. Inhibition of phosphoinositide 3-kinase (PI3K) by wortmannin abolished the FIR-induced phosphorylation of eNOS and Akt in HUVECs. FIR exposure upregulated the expression of PI3K p85 at the transcriptional level. We further found that FIR exposure induced the nuclear translocation of promyelocytic leukemia zinc finger protein (PLZF) in HUVECs. This induction was independent of a thermal effect. The small interfering RNA transfection of PLZF blocked FIR-increased PI3K levels and the inhibitory effect of FIR. These data suggest that FIR induces the nuclear translocation of PLZF which inhibits VEGF-induced proliferation in HUVECs

3,4-Methylenedioxymethamphetamine Alters Left Ventricular Function and Activates Nuclear Factor-Kappa B (NF-κB) in a Time and Dose Dependent Manner

3,4-Methylenedioxymethamphetamine (MDMA) is an illicit psychoactive drug with cardiovascular effects that have not been fully described. In the current study, we observed the effects of acute MDMA on rabbit left ventricular function. We also observed the effects of MDMA on nuclear factor-kappa B (NF-κB) activity in cultured rat ventricular myocytes (H9c2). In the rabbit, MDMA (2 mg/kg) alone caused a significant increase in heart rate and a significant decrease in the duration of the cardiac cycle. Inhibition of nitric oxide synthase (NOS) by pretreatment with L-NAME (10 mg/kg) alone caused significant dysfunction in heart rate, systolic pressure, diastolic pressure, duration of relaxation, duration of cardiac cycle, and mean left ventricular pressure. Pretreatment with L-NAME followed by treatment with MDMA caused significant dysfunction in additional parameters that were not abnormal upon exposure to either compound in isolation: duration of contraction, inotropy, and pulse pressure. Exposure to 1.0 mM MDMA for 6 h or 2.0 μM MDMA for 12 h caused increased nuclear localization of NF-κB in cultured H9c2 cells. The current results suggest that MDMA is acutely detrimental to heart function and that an intact cardiovascular NOS system is important to help mitigate early sequelae in some functional parameters. The delayed timing of NF-κB activation suggests that this factor may be relevant to MDMA induced cardiomyopathy of later onset

In Vivo Mapping of Vascular Inflammation Using Multimodal Imaging

Plaque vulnerability to rupture has emerged as a critical correlate to risk of adverse coronary events but there is as yet no clinical method to assess plaque stability in vivo. In the search to identify biomarkers of vulnerable plaques an association has been found between macrophages and plaque stability--the density and pattern of macrophage localization in lesions is indicative of probability to rupture. In very unstable plaques, macrophages are found in high densities and concentrated in the plaque shoulders. Therefore, the ability to map macrophages in plaques could allow noninvasive assessment of plaque stability. We use a multimodality imaging approach to noninvasively map the distribution of macrophages in vivo. The use of multiple modalities allows us to combine the complementary strengths of each modality to better visualize features of interest. Our combined use of Positron Emission Tomography and Magnetic Resonance Imaging (PET/MRI) allows high sensitivity PET screening to identify putative lesions in a whole body view, and high resolution MRI for detailed mapping of biomarker expression in the lesions.Macromolecular and nanoparticle contrast agents targeted to macrophages were developed and tested in three different mouse and rat models of atherosclerosis in which inflamed vascular plaques form spontaneously and/or are induced by injury. For multimodal detection, the probes were designed to contain gadolinium (T1 MRI) or iron oxide (T2 MRI), and Cu-64 (PET). PET imaging was utilized to identify regions of macrophage accumulation; these regions were further probed by MRI to visualize macrophage distribution at high resolution. In both PET and MR images the probes enhanced contrast at sites of vascular inflammation, but not in normal vessel walls. MRI was able to identify discrete sites of inflammation that were blurred together at the low resolution of PET. Macrophage content in the lesions was confirmed by histology.The multimodal imaging approach allowed high-sensitivity and high-resolution mapping of biomarker distribution and may lead to a clinical method to predict plaque probability to rupture

Depletion of B2 but Not B1a B Cells in BAFF Receptor-Deficient ApoE−/− Mice Attenuates Atherosclerosis by Potently Ameliorating Arterial Inflammation

We have recently identified conventional B2 cells as atherogenic and B1a cells as atheroprotective in hypercholesterolemic ApoE−/− mice. Here, we examined the development of atherosclerosis in BAFF-R deficient ApoE−/− mice because B2 cells but not B1a cells are selectively depleted in BAFF-R deficient mice. We fed BAFF-R−/− ApoE−/− (BaffR.ApoE DKO) and BAFF-R+/+ApoE−/− (ApoE KO) mice a high fat diet (HFD) for 8-weeks. B2 cells were significantly reduced by 82%, 81%, 94%, 72% in blood, peritoneal fluid, spleen and peripheral lymph nodes respectively; while B1a cells and non-B lymphocytes were unaffected. Aortic atherosclerotic lesions assessed by oil red-O stained-lipid accumulation and CD68+ macrophage accumulation were decreased by 44% and 50% respectively. B cells were absent in atherosclerotic lesions of BaffR.ApoE DKO mice as were IgG1 and IgG2a immunoglobulins produced by B2 cells, despite low but measurable numbers of B2 cells and IgG1 and IgG2a immunoglobulin concentrations in plasma. Plasma IgM and IgM deposits in atherosclerotic lesions were also reduced. BAFF-R deficiency in ApoE−/− mice was also associated with a reduced expression of VCAM-1 and fewer macrophages, dendritic cells, CD4+ and CD8+ T cell infiltrates and PCNA+ cells in lesions. The expression of proinflammatory cytokines, TNF-α, IL1-β and proinflammatory chemokine MCP-1 was also reduced. Body weight and plasma cholesterols were unaffected in BaffR.ApoE DKO mice. Our data indicate that B2 cells are important contributors to the development of atherosclerosis and that targeting the BAFF-R to specifically reduce atherogenic B2 cell numbers while preserving atheroprotective B1a cell numbers may be a potential therapeutic strategy to reduce atherosclerosis by potently reducing arterial inflammation

Human antimicrobial peptide LL-37 is present in atherosclerotic plaques and induces death of vascular smooth muscle cells: a laboratory study

BACKGROUND: Death of smooth muscle cells in the atherosclerotic plaques makes the plaques more prone to rupture, which can initiate an acute ischemic event. The development of atherosclerosis includes the migration of immune cells e.g. monocytes/macrophages and T lymphocytes into the lesions. Immune cells can release antimicrobial peptides. One of these, human cathelicidin antimicrobial peptide hCAP-18, is cleaved by proteinase 3 generating a 4.5 kDa C-terminal fragment named LL-37, which has been shown to be cytotoxic. The aim of the study was to explore a potential role of LL-37 in the pathophysiology of atherosclerosis. METHODS: We investigated the presence of LL-37 in human atherosclerotic lesions obtained at autopsy using immunohistochemistry. The direct effects of LL-37 on cultured vascular smooth muscle cells and isolated neutrophil granulocytes were investigated with morphological, biochemical and flow cytometry analysis. RESULTS: The neointima of atherosclerotic plaques was found to contain LL-37-like immunoreactivity, mainly in macrophages. In cultured smooth muscle cells, LL-37 at 30 μg/ml caused cell shrinkage, membrane blebbing, nuclear condensation, DNA fragmentation and an increase in caspase-3 activity as studied by microscopy, ELISA and enzyme activity assay, respectively. Flow cytometry demonstrated that LL-37 in a subset of the cells caused a small but rapidly developing increase in membrane permeability to propidium iodide, followed by a gradual development of FITC-annexin V binding. Another cell population stained heavily with both propidium iodide and FITC-annexin V. Neutrophil granulocytes were resistant to these effects of LL-37. CONCLUSION: This study shows that LL-37 is present in atherosclerotic lesions and that it induces death of vascular smooth muscle cells. In a subset of cells, the changes indicate the development of apoptosis triggered by an initial mild perturbation of plasma membrane integrity. The findings suggest a role for LL-37 as a mediator of immune cell-induced death of vascular smooth muscle cells in atherosclerosis