\u3ci\u3eYersinia pestis\u3c/i\u3e VIRULENCE FACTOR YopM UNDERMINES THE FUNCTION OF DISTINCT CCR2\u3csup\u3e+\u3c/sup\u3eGr1\u3csup\u3e+\u3c/sup\u3e CELLS IN SPLEEN AND LIVER DURING SYSTEMIC PLAGUE

Yersinia pestis, the infective agent of bubonic and pneumonic plague, is classified as a category A agent of bioterrorism. YopM, a protein toxin of Y. pestis, is necessary for full virulence in a systemic plague mouse model with ambient-temperature grown bacteria. We used this model to identify the cells undermined by YopM. Natural killer (NK) cells were previously reported to be lost in spleen and blood in a YopM-associated way; however, NK cell depletion was found not to occur in liver, and ablation of NK cells had no effect on bacterial growth, indicating that NK cells are redundant for the YopM-mediated virulence mechanism. In mice either ablated for Gr1+ cells or lacking the chemokine receptor CCR2, wildtype growth was at least partially restored to the ΔyopM Y. pestis in both spleen and liver. In a mouse model of bubonic plague, CCR2 also was shown to be required for the ΔyopM Y. pestis to show wildtype growth in skin. These data pointed towards Gr1+CCR2+ cells, which include polymorphonuclear leukocytes (PMNs), inflammatory monocytes and inflammatory dendritic cells (iDCs), as key cellular components in controlling the in vivo growth of the ΔyopM Y. pestis. Recruitment of Gr1+CCR2+ cells into both organs was not YopM-dependent, except iDCs, whose influx from blood into spleen was blocked by the YopM-producing Y. pestis parent strain, but not the ΔyopM mutant. Ablation of PMNs, another main subset of Gr1+CCR2+ cells, relieved the growth limitation of the ΔyopM Y. pestis in liver, but not in spleen. Taken together, the data imply that YopM disables the recruitment of CCR2+Gr1+ iDCs into spleen but compromises the function of CCR2+Gr1+ PMNs in liver. These results were recapitulated when the infecting ambient-temperature-grown bacteria received 3 hours of incubation at 37°C. However, the appearance of the ΔyopM mutant phenotype was postponed at least 24 hours, indicating that some virulence property of Y. pestis that was induced by the temperature transition compensated for the loss of YopM in the ΔyopM strain at an early stage of the infection. In general, these findings provide a framework for focusing future research to identify YopM’s direct molecular targets

An Evasion and Counter-Evasion Study in Malicious Websites Detection

Malicious websites are a major cyber attack vector, and effective detection of them is an important cyber defense task. The main defense paradigm in this regard is that the defender uses some kind of machine learning algorithms to train a detection model, which is then used to classify websites in question. Unlike other settings, the following issue is inherent to the problem of malicious websites detection: the attacker essentially has access to the same data that the defender uses to train its detection models. This 'symmetry' can be exploited by the attacker, at least in principle, to evade the defender's detection models. In this paper, we present a framework for characterizing the evasion and counter-evasion interactions between the attacker and the defender, where the attacker attempts to evade the defender's detection models by taking advantage of this symmetry. Within this framework, we show that an adaptive attacker can make malicious websites evade powerful detection models, but proactive training can be an effective counter-evasion defense mechanism. The framework is geared toward the popular detection model of decision tree, but can be adapted to accommodate other classifiers

Nox4 is critical for hypoxia-inducible factor 2-alpha transcriptional activity in von Hippel-Lindau-deficient renal cell carcinoma

Inactivation of the von Hippel-Lindau tumor suppressor (VHL) is an early event in \u3e60% of sporadic clear cell renal cell carcinoma (RCC). Loss of VHL E3 ubiquitin ligase function results in accumulation of the alpha-subunit of the hypoxia-inducible heterodimeric transcription factor (HIF-alpha) and transcription of an array of genes including vascular endothelial growth factor, transforming growth factor-alpha, and erythropoietin. Studies have shown that HIF-alpha can be alternatively activated by reactive oxygen species. Nox4 is an NADP(H) oxidase that generates signaling levels of superoxide and is found in greatest abundance in the distal renal tubules. To determine if Nox4 contributes to HIF activity in RCC, we examined the impact of Nox4 expression on HIF-alpha expression and transactivation. We report here that small inhibitory RNA (siRNA) knockdown of Nox4 in 786-0 human renal tumor cells expressing empty vector (PRC) or wild-type VHL (WT) results in 50% decrease in intracellular reactive oxygen species as measured by a fluorescent 2\u27,7\u27-dichlorofluorescin diacetate assay, and \u3e85% reduction in HIF2-alpha mRNA and protein levels by quantitative reverse transcription-PCR and Western blot analysis. Furthermore, expression of the HIF target genes, vascular endothelial growth factor, transforming growth factor-alpha, and Glut-1 was abrogated by 93%, 74%, and 99%, respectively, after stable transfection with Nox4 siRNA relative to nontargeting siRNA, as determined by quantitative reverse transcription-PCR. Thus, renal Nox4 expression is essential for full HIF2-alpha expression and activity in 786-0 renal tumor cells, even in the absence of functional VHL. We propose the use of Nox4 as a target in the treatment of clear cell RCC

New universal gates for topological quantum computation with Fibonacci-ε\boldsymbol{\varepsilon} composite Majorana edge modes on topological superconductor multilayers

We propose a new design of universal topological quantum computer device through a hybrid of the 1-, 2- and 7-layers of chiral topological superconductor ($\chi$TSC) thin films. Based on the $SO(7)_1/(G_2)_1$ coset construction, strongly correlated Majorana fermion edge modes on the 7-layers of $\chi$TSC are factorized into the composite of the Fibonacci $\tau$-anyon and $\varepsilon$-anyon modes in the tricritical Ising model. Furthermore, the deconfinement of $\tau$ and $\varepsilon$ via the interacting potential gives the braiding of either $\tau$ or $\varepsilon$. Topological phase gates are assembled by the braidings. With these topological phase gates, we find a set of fully topological universal gates for the $(\tau,\varepsilon)$ composite Majorana-Ising-type quantum computation. Because the Hilbert space still possesses a tensor product structure of quibts and is characterized by the fermion parities, encoding quantum information in this machine is more efficient and substantial than that with Fibonacci anyons. The computation results is easier to be read out by electric signals, so are the initial data inputted.Comment: 6 pages, 3 figues, revised versio

MPI application of 3D hydroelasticity on a barge deployed above the uneven seabed

1154-1163Nowadays, some floating structures with simple shapes such as barges near the reefs can be deployed as support bases. Unlike the open sea, the greatest feature of the marine environment near the island is the non-uniform complex seabed. In this paper, the hydroelastic analysis method with variable water depths is used to calculate the seakeeping of the floating structures, considering the uneven seabed as the boundary condition. Based on the three-dimensional hydroelasticity theory, the hydroelastic motion and response analysis of the barge is studied, coupled with parallel codes due to a lot of equations caused by the meshes. Considering different water depths and the complex bathymetry, the motion and loads of barge structures have been compared. The design wave parameters have been confirmed by the short-term forecast extreme results, and the whole stress distribution of barge structures near the reef has been shown plus modal stress by model summation. At last, strength evaluation of barge indicates that the effect of inhomogeneous seabed plays a large role in the arrangement of the barge near reefs and parallel calculations save the CPU time