Kaposi’s Sarcoma Associated Herpesvirus Encoded Viral FLICE Inhibitory Protein K13 Activates NF-κB Pathway Independent of TRAF6, TAK1 and LUBAC

BACKGROUND: Kaposi's sarcoma associated herpesvirus encoded viral FLICE inhibitory protein (vFLIP) K13 activates the NF-κB pathway by binding to the NEMO/IKKγ subunit of the IκB kinase (IKK) complex. However, it has remained enigmatic how K13-NEMO interaction results in the activation of the IKK complex. Recent studies have implicated TRAF6, TAK1 and linear ubiquitin chains assembled by a linear ubiquitin chain assembly complex (LUBAC) consisting of HOIL-1, HOIP and SHARPIN in IKK activation by proinflammatory cytokines. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that K13-induced NF-κB DNA binding and transcriptional activities are not impaired in cells derived from mice with targeted disruption of TRAF6, TAK1 and HOIL-1 genes and in cells derived from mice with chronic proliferative dermatitis (cpdm), which have mutation in the Sharpin gene (Sharpin(cpdm/cpdm)). Furthermore, reconstitution of NEMO-deficient murine embryonic fibroblast cells with NEMO mutants that are incapable of binding to linear ubiquitin chains supported K13-induced NF-κB activity. K13-induced NF-κB activity was not blocked by CYLD, a deubiquitylating enzyme that can cleave linear and Lys63-linked ubiquitin chains. On the other hand, NEMO was required for interaction of K13 with IKK1/IKKα and IKK2/IKKβ, which resulted in their activation by "T Loop" phosphorylation. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that K13 activates the NF-κB pathway by binding to NEMO which results in the recruitment of IKK1/IKKα and IKK2/IKKβ and their subsequent activation by phosphorylation. Thus, K13 activates NF-κB via a mechanism distinct from that utilized by inflammatory cytokines. These results have important implications for the development of therapeutic agents targeting K13-induced NF-κB for the treatment of KSHV-associated malignancies

Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation

Mutations in the tumor suppressor gene TP53 contribute to the development of approximately half of all human cancers. One mechanism by which mutant p53 (mtp53) acts is through interaction with other transcription factors, which can either enhance or repress the transcription of their target genes. Mtp53 preferentially interacts with the erythroblastosis virus E26 oncogene homologue 2 (ETS2), an ETS transcription factor, and increases its protein stability. To study the mechanism underlying ETS2 degradation, we knocked down ubiquitin ligases known to interact with ETS2. We observed that knockdown of the constitutive photomorphogenesis protein 1 (COP1) and its binding partner De-etiolated 1 (DET1) significantly increased ETS2 stability, and conversely, their ectopic expression led to increased ETS2 ubiquitination and degradation. Surprisingly, we observed that DET1 binds to ETS2 independently of COP1, and we demonstrated that mutation of multiple sites required for ETS2 degradation abrogated the interaction between DET1 and ETS2. Furthermore, we demonstrate that mtp53 prevents the COP1/DET1 complex from ubiquitinating ETS2 and thereby marking it for destruction. Mechanistically, we show that mtp53 destabilizes DET1 and also disrupts the DET1/ETS2 complex thereby preventing ETS2 degradation. Our study reveals a hitherto unknown function in which DET1 mediates the interaction with the substrates of its cognate ubiquitin ligase complex and provides an explanation for the ability of mtp53 to protect ETS2

AKT and 14-3-3 regulate Notch4 nuclear localization

Members of the Notch family of transmembrane receptors, Notch1-4 in mammals, are involved in the regulation of cell fate decisions and cell proliferation in various organisms. The Notch4 isoform, which is specific to mammals, was originally identified as a viral oncogene in mice, Int3, able to initiate mammary tumors. In humans, Notch4 expression appears to be associated with breast cancer stem cells and endocrine resistance. Following ligand binding, the Notch4 receptor undergoes cleavage at the membrane and the Notch4-intracellular domain (ICD), translocates to the nucleus and regulates gene transcription. Little is known on the mechanisms regulating Notch4-ICD and its nuclear localization. Here, we describe the identification of four distinct AKT phosphorylation sites in human Notch4-ICD and demonstrate that AKT binds Notch4-ICD and phosphorylates all four sites in vitro and in vivo. The phosphorylation in cells is regulated by growth factors and is sensitive to phosphatidyl inositol-3 kinase (PI3K) inhibitors. This phosphorylation generates binding sites to the 14-3-3 regulatory proteins, which are involved in the regulation of nucleocytoplasmic shuttling of target proteins, restricting phosphorylated Notch4-ICD to the cytoplasm. Our findings provide a novel mechanism for Notch4-ICD regulation, suggesting a negative regulatory role for the PI3K-AKT pathway in Notch4 nuclear signaling

Regional and experiential differences in surgeon preference for the treatment of cervical facet injuries: a case study survey with the AO Spine Cervical Classification Validation Group

Purpose: The management of cervical facet dislocation injuries remains controversial. The main purpose of this investigation was to identify whether a surgeon’s geographic location or years in practice influences their preferred management of traumatic cervical facet dislocation injuries. Methods: A survey was sent to 272 AO Spine members across all geographic regions and with a variety of practice experience. The survey included clinical case scenarios of cervical facet dislocation injuries and asked responders to select preferences among various diagnostic and management options. Results: A total of 189 complete responses were received. Over 50% of responding surgeons in each region elected to initiate management of cervical facet dislocation injuries with an MRI, with 6 case exceptions. Overall, there was considerable agreement between American and European responders regarding management of these injuries, with only 3 cases exhibiting a significant difference. Additionally, results also exhibited considerable management agreement between those with ≤ 10 and > 10 years of practice experience, with only 2 case exceptions noted. Conclusion: More than half of responders, regardless of geographical location or practice experience, identified MRI as a screening imaging modality when managing cervical facet dislocation injuries, regardless of the status of the spinal cord and prior to any additional intervention. Additionally, a majority of surgeons would elect an anterior approach for the surgical management of these injuries. The study found overall agreement in management preferences of cervical facet dislocation injuries around the globe

IMAGE ENCRYPTION IN BLOCK-WISE WITH MULTIPLE CHAOTIC MAPS FOR PERMUTATION AND DIFFUSION

This paper presents an efficient block-wise image encryption method based on multiple chaotic maps. The image is divided into four overlapping blocks and each block is permutated with Cat map and its parameters are controlled by Henon map using multiple keys. Due to overlapping division of blocks, it produces effect of double permutation in the middle portion of overlapped image in single permutation itself. For diffusion, the whole image is divided into four non-overlapping blocks and diffused with logistic map. Each block pixel values were completely modified in the diffusion process in order to avoid known-plaintext and chosen-plaintext attacks. For each division of blocks different keys were selected for both permutation and diffusion process in the proposed method. The simulation results of several statistical analysis shows that the proposed cryptosystem is efficient and highly secure

Optimal Path Planning of Mobile Robot with Multiple Target Using Ant Colony Optimization

In this paper, we present a path-planning algorithm for mobile robots in an environment with obstacles. We investigate the used of Ant Colony Optimization (ACO) for determining the optimal path for a wheeled mobile robot to visit multiple targets. THe environment in which the robot operates is modeled in the form of discrete cells and the robot is modeled as a point probot. The robot has knowledge about the targets\u27 positions but has limited local sensing capability to sense obstacles. The paper investiages the use of multiple autonomous robots for solving the shortest path problem. ACO algorithm is used for dynamic planning of the path to avoid obstacles visit all the targets

Optimal Content Placement for a Large-scale VoD System

IPTV service providers offering Video-on-Demand currently use servers at each metropolitan office to store all the videos in their library. With the rapid increase in library sizes, it will soon become infeasible to replicate the entire library at each office. We present an approach for intelligent content placement that scales to large library sizes (e.g., 100Ks of videos). We formulate the problem as a mixed integer program (MIP) that takes into account constraints such as disk space, link bandwidth, and content popularity. To overcome the challenges of scale, we employ a Lagrangian relaxation-based decomposition technique combined with integer rounding. Our technique finds a near-optimal solution (e.g., within 1-2%) with orders of magnitude speedup relative to solving even the LP relaxation via standard software. We also present simple strategies to address practical issues such as popularity estimation, content updates, short-term popularity fluctuation, and frequency of placement updates. Using traces from an operational system, we show that our approach significantly outperforms simpler placement strategies. For instance, our MIP-based solution can serve all requests using only half the link bandwidth used by LRU or LFU cache replacement policies. We also investigate the trade-off between disk space and network bandwidth. 1

Towards a SPDY’ier Mobile Web?

Despite its widespread adoption and popularity, the Hypertext Transfer Protocol (HTTP) suffers from fundamental performance limitations. SPDY, a recently proposed alternative to HTTP, tries to address many of the limitations of HTTP (e.g., multiple connections, setup latency). With cellular networks fast becoming the communication channel of choice, we perform a detailed measurement study to understand the benefits of using SPDY over cellular networks. Through careful measurements conducted over four months, we provide a detailed analysis of the performance of HTTP and SPDY, how they interact with the various layers, and their implications on web design. Our results show that unlike in wired and 802.11 networks, SPDY does not clearly outperform HTTP over cellular networks. We identify, as the underlying cause, a lack of harmony between how TCP and cellular networks interact. In particular, we identify a fundamental flaw in TCP implementations where TCP does not account for a change in network latencies after an idle period, as is common in cellular networks. This causes spurious retransmissions and degraded throughput for both HTTP and SPDY. We conclude that a viable solution has to account for these unique cross-layer dependencies to achieve improved performance over cellular networks. 1