DDoS defense by offense

This article presents the design, implementation, analysis, and experimental evaluation of speak-up, a defense against application-level distributed denial-of-service (DDoS), in which attackers cripple a server by sending legitimate-looking requests that consume computational resources (e.g., CPU cycles, disk). With speak-up, a victimized server encourages all clients, resources permitting, to automatically send higher volumes of traffic. We suppose that attackers are already using most of their upload bandwidth so cannot react to the encouragement. Good clients, however, have spare upload bandwidth so can react to the encouragement with drastically higher volumes of traffic. The intended outcome of this traffic inflation is that the good clients crowd out the bad ones, thereby capturing a much larger fraction of the server's resources than before. We experiment under various conditions and find that speak-up causes the server to spend resources on a group of clients in rough proportion to their aggregate upload bandwidths, which is the intended result.National Science Foundation (U.S.) (NSF grant CNS-0225660)National Science Foundation (U.S.) (NSF grant CNS-0520241)United States. Dept. of Defense (National Security Science and Engineering Faculty Fellowship

A Novel Intracellular Isoform of Matrix Metalloproteinase-2 Induced by Oxidative Stress Activates Innate Immunity

Experimental and clinical evidence has pinpointed a critical role for matrix metalloproteinase-2 (MMP-2) in ischemic ventricular remodeling and systolic heart failure. Prior studies have demonstrated that transgenic expression of the full-length, 68 kDa, secreted form of MMP-2 induces severe systolic failure. These mice also had unexpected and severe mitochondrial structural abnormalities and dysfunction. We hypothesized that an additional intracellular isoform of MMP-2, which affects mitochondrial function is induced under conditions of systolic failure-associated oxidative stress.Western blots of cardiac mitochondria from the full length MMP-2 transgenics, ageing mice and a model of accelerated atherogenesis revealed a smaller 65 kDa MMP-2 isoform. Cultured cardiomyoblasts subjected to transient oxidative stress generated the 65 kDa MMP-2 isoform. The 65 kDa MMP-2 isoform was also induced by hypoxic culture of cardiomyoblasts. Genomic database analysis of the MMP-2 gene mapped transcriptional start sites and RNA transcripts induced by hypoxia or epigenetic modifiers within the first intron of the MMP-2 gene. Translation of these transcripts yields a 65 kDa N-terminal truncated isoform beginning at M(77), thereby deleting the signal sequence and inhibitory prodomain. Cellular trafficking studies demonstrated that the 65 kDa MMP-2 isoform is not secreted and is present in cytosolic and mitochondrial fractions, while the full length 68 kDa isoform was found only in the extracellular space. Expression of the 65 kDa MMP-2 isoform induced mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-κB, NFAT and IRF transcriptional pathways. By microarray, the 65 kDa MMP-2 induces an innate immunity transcriptome, including viral stress response genes, innate immunity transcription factor IRF7, chemokines and pro-apoptosis genes.A novel N-terminal truncated intracellular isoform of MMP-2 is induced by oxidative stress. This isoform initiates a primary innate immune response that may contribute to progressive cardiac dysfunction in the setting of ischemia and systolic failure

ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression

<p>Abstract</p> <p>Background</p> <p><b>A D</b>isintegrin <b>A</b>nd <b>M</b>etalloprotease (ADAM) 9 has been implicated in tumour progression of various solid tumours, however, little is known about its role in renal cell carcinoma. We evaluated the expression of ADAM9 on protein and transcript level in a clinico-pathologically characterized renal cell cancer cohort.</p> <p>Methods</p> <p>108 renal cancer cases were immunostained for ADAM9 on a tissue-micro-array. For 30 additional cases, ADAM9 mRNA of microdissected tumour and normal tissue was analyzed via quantitative RT-PCR. SPSS 14.0 was used to apply crosstables (Fisher's exact test and χ²-test), correlations and univariate as well as multivariate survival analyses.</p> <p>Results</p> <p>ADAM9 was significantly up-regulated in renal cancer in comparison to the adjacent normal tissue on mRNA level. On protein level, ADAM9 was significantly associated with higher tumour grade, positive nodal status and distant metastasis. Furthermore, ADAM9 protein expression was significantly associated with shortened patient survival in the univariate analysis.</p> <p>Conclusion</p> <p>ADAM9 is strongly expressed in a large proportion of renal cell cancers, concordant with findings in other tumour entities. Additionally, ADAM9 expression is significantly associated with markers of unfavourable prognosis. Whether the demonstrated prognostic value of ADAM9 is independent from other tumour parameters will have to be verified in larger study cohorts.</p

Association between tobacco use and body mass index in urban Indian population: implications for public health in India

BACKGROUND: Body mass index [BMI, weight (kg)/height (m(2))], a measure of relative weight, is a good overall indicator of nutritional status and predictor of overall health. As in many developing countries, the high prevalence of very low BMIs in India represents an important public health risk. Tobacco, smoked in the form of cigarettes or bidis (handmade by rolling a dried rectangular piece of temburni leaf with 0.15–0.25 g of tobacco) or chewed, is another important determinant of health. Tobacco use also may exert a strong influence on BMI. METHODS: The relationship between very low BMI (< 18.5 kg/m(2)) and tobacco use was examined using data from a representative cross-sectional survey of 99,598 adults (40,071 men and 59,527 women) carried out in the city of Mumbai (formerly known as Bombay) in western India. Participants were men and women aged ≥ 35 years who were residents of the main city of Mumbai. RESULTS: All forms of tobacco use were associated with low BMI. The prevalence of low BMI was highest in bidi-smokers (32% compared to 13% in non-users). For smokers, the adjusted odds ratio (OR) and 95% confidence interval (CI) were OR = 1.80(1.65 to 1.96) for men and OR = 1.59(1.09 to 2.32) for women, respectively, relative to non-users. For smokeless tobacco and mixed habits (smoking and smokeless tobacco), OR = 1.28(1.19 to 1.38) and OR = 1.83(1.67 to 2.00) for men and OR = 1.50(1.43 to 1.59) and OR = 2.19(1.90 to 3.41) for women, respectively. CONCLUSION: Tobacco use appears to be an independent risk factor for low BMI in this population. We conclude that in such populations tobacco control research and interventions will need to be conducted in concert with nutrition research and interventions in order to improve the overall health status of the population

Gene Expression Profiles of the NCI-60 Human Tumor Cell Lines Define Molecular Interaction Networks Governing Cell Migration Processes

Although there is extensive information on gene expression and molecular interactions in various cell types, integrating those data in a functionally coherent manner remains challenging. This study explores the premise that genes whose expression at the mRNA level is correlated over diverse cell lines are likely to function together in a network of molecular interactions. We previously derived expression-correlated gene clusters from the database of the NCI-60 human tumor cell lines and associated each cluster with function categories of the Gene Ontology (GO) database. From a cluster rich in genes associated with GO categories related to cell migration, we extracted 15 genes that were highly cross-correlated; prominent among them were RRAS, AXL, ADAM9, FN14, and integrin-beta1. We then used those 15 genes as bait to identify other correlated genes in the NCI-60 database. A survey of current literature disclosed, not only that many of the expression-correlated genes engaged in molecular interactions related to migration, invasion, and metastasis, but that highly cross-correlated subsets of those genes engaged in specific cell migration processes. We assembled this information in molecular interaction maps (MIMs) that depict networks governing 3 cell migration processes: degradation of extracellular matrix, production of transient focal complexes at the leading edge of the cell, and retraction of the rear part of the cell. Also depicted are interactions controlling the release and effects of calcium ions, which may regulate migration in a spaciotemporal manner in the cell. The MIMs and associated text comprise a detailed and integrated summary of what is currently known or surmised about the role of the expression cross-correlated genes in molecular networks governing those processes

The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract

Acknowledgments: The authors thank all of the participants who took part in this research and the funders and support and technical staff who made this study possible. We also acknowledge and thank The Cancer Genome Atlas initiative whose data contributed heavily to this study. Funding: Funding for study coordination, genotyping of replication studies and statistical analysis was provided by the US National Institutes of Health (R01 CA092039 05/05S1) and the National Institute of Dental and Craniofacial Research (1R03DE020116). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

N-Terminal Truncated Intracellular Matrix Metalloproteinase-2 Induces Cardiomyocyte Hypertrophy, Inflammation and Systolic Heart Failure

Matrix metalloproteinase-2 (MMP-2) is increasingly recognized as a major contributor to progressive cardiac injury within the setting of ischemia-reperfusion injury and ischemic ventricular remodeling. A common feature of these conditions is an increase i