Constitutive activation of the Raf-MAPK pathway causes negative feedback inhibition of Ras-PI3K-AKT and cellular arrest through the EphA(2) receptor

The Raf-mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)-AKT pathways are two downstream effectors of the small GTPase Ras. Although both pathways are positively regulated by Ras, the Raf-MAPK and PI3K-AKT pathways have been shown to control opposing functions within the cell, suggesting a need for cross-talk regulation. The PI3K -AKT pathway can inhibit the Raf-MAPK pathway directly during processes such as muscle differentiation. Here we describe the ability of the Raf-MAPK pathway to negatively regulate the PI3K-AKT pathway during cellular arrest. Constitutive activation of Raf or methyl ethyl ketone 1 (MEK1) leads to inhibition of AKT and cellular arrest. Furthermore, we show that activation of Raf-MEK1 signaling causes negative feedback inhibition of Ras through the ephrin receptor EphA(2). EphA(2)-mediated negative feedback inhibition is required for Raf-induced AKT inhibition and cell cycle arrest, therefore establishing the inhibition of the Ras-PI3K-AKT pathway as a necessary event for the Raf-MEK1-regulated cellular arrest.

Performance analysis of a metro WDM ring networks with variable-length packets under symmetric and asymmetric traffic

In this paper, we discuss and evaluate two proposed metro wavelength division multiplexing (WDM) ring network architectures for variable-length packet traffic in storage area networks (SANs) settings. The paper begins with a brief review of the relevant architectures and protocols in the literature. Subsequently, the network architectures along with their medium access control (MAC) protocols are described. Performance of the two network architectures is studied by means of computer simulation in terms of their queuing delay, node throughput and proportion of packets dropped. The network performance is evaluated under symmetric and asymmetric traffic scenarios with Poisson and self-similar traffic. (C) 2011 Elsevier Inc. All rights reserved.

Design of quantum-dot cellular automata circuits using cut-set retiming

As a potential alternative to CMOS technology, QCA provides an interesting paradigm in both communication and computation. However, QCAs unique four-phase clocking scheme and timing constraints present serious timing issues for interconnection and feedback. In this work, a cut-set retiming design procedure is proposed to resolve these QCA timing issues. The proposed design procedure can accommodate QCAs unique characteristics by performing delay-transfer and time-scaling to reallocate the existing delays so as to achieve efficient clocking zone assignment. Cut-set retiming makes it possible to effectively design relatively complex QCA circuits that include feedback. It utilizes the similar characteristics of synchronization, deep pipelines and local interconnections common to both QCA and systolic architectures. As a case study, a systolic Montgomery modular multiplier is designed to illustrate the procedure. Furthermore, a nonsystolic architecture, an S27 benchmark circuit, is designed and compared with previous designs. The comparison shows that the cut-set retiming method achieves a more efficient design, with a reduction of 22%, 44%, and 46% in terms of cell count, area, and latency, respectively.

An On Demand Queue Management Architecture for a Programmable Traffic Manager

A queue manager (QM) is a core traffic management (TM) function used to provide per-flow queuing in access andmetro networks; however current designs have limited scalability. An on-demand QM (OD-QM) which is part of a new modular field-programmable gate-array (FPGA)-based TM is presented that dynamically maps active flows to the available physical resources; its scalability is derived from exploiting the observation that there are only a few hundred active flows in a high speed network. Simulations with real traffic show that it is a scalable, cost-effective approach that enhances per-flow queuing performance, thereby allowing per-flow QM without the need for extra external memory at speeds up to 10 Gbps. It utilizes 2.3%–16.3% of a Xilinx XC5VSX50t FPGA and works at 111 MHz.

Early target cells of measles virus after aerosol infection of non-human primates

Measles virus (MV) is highly infectious, and has long been thought to enter the host by infecting epithelial cells of the respiratory tract. However, epithelial cells do not express signaling lymphocyte activation molecule (CD150), which is the high-affinity cellular receptor for wild-type MV strains. We have generated a new recombinant MV strain expressing enhanced green fluorescent protein (EGFP), based on a wild-type genotype B3 virus isolate from Khartoum, Sudan (KS). Cynomolgus macaques were infected with a high dose of rMV(KS)EGFP by aerosol inhalation to ensure that the virus could reach the full range of potential target cells throughout the entire respiratory tract. Animals were euthanized 2, 3, 4 or 5 days post-infection (d.p.i., n?=?3 per time point) and infected (EGFP(+)) cells were identified at all four time points, albeit at low levels 2 and 3 d.p.i. At these earliest time points, MV-infected cells were exclusively detected in the lungs by fluorescence microscopy, histopathology and/or virus isolation from broncho-alveolar lavage cells. On 2 d.p.i., EGFP(+) cells were phenotypically typed as large mononuclear cells present in the alveolar lumen or lining the alveolar epithelium. One to two days later, larger clusters of MV-infected cells were detected in bronchus-associated lymphoid tissue (BALT) and in the tracheo-bronchial lymph nodes. From 4 d.p.i. onward, MV-infected cells were detected in peripheral blood and various lymphoid tissues. In spite of the possibility for the aerosolized virus to infect cells and lymphoid tissues of the upper respiratory tract, MV-infected cells were not detected in either the tonsils or the adenoids until after onset of viremia. These data strongly suggest that in our model MV entered the host at the alveolar level by infecting macrophages or dendritic cells, which traffic the virus to BALT or regional lymph nodes, resulting in local amplification and subsequent systemic dissemination by viremia.

Cellular and subcellular localization of SALMFamide (S1)-like immunoreactivity within the central nervous system of the nematode Ascaris suum (Nematoda, Ascaroidea)

The localization and distribution of SALMFamide (S1)-like immunoreactivity (IR), was determined at both the cellular and subcellular level in the central nervous system (CNS) of the nematode roundworm Ascaris suum. The techniques of indirect immunofluorescence in conjunction with confocal scanning laser microscopy and post-embedding, IgG-conjugated colloidal gold immunostaining were used, respectively. Immunostaining was widespread in the CNS of adult A. suum, with immunoreactivity (IR) being localized in nerve cells and fibres in the ganglia associated with the anterior nerve ring and in the main nerve cords and their commissures. At the subcellular level, gold labeling of peptide was localized exclusively over dense-cored vesicles within nerve cell bodies, nerve axons and nerve terminals of the neuropile of the anterior nerve ring, main ganglia and nerve cords in the CNS. Double-labeling demonstrated an apparent co-localization of S1- and FMRFamide-IR-together IR-together with S1- and pancreatic polypeptide (PP)-IR in the same dense-cored vesicles. Antigen preabsorption experiments indicated little cross-reactivity, if any, between the three antisera; indeed, neither FMRFamide nor PP antigens abolished S1 immunostaining.

A computational model of cellular response to modulated radiation fields

Purpose:
To develop a model to describe the response of cell populations to spatially modulated radiation exposures of relevance to advanced radiotherapies.

Materials and Methods:
A Monte Carlo model of cellular radiation response was developed. This model incorporated damage from both direct radiation and intercellular communication including bystander signaling. The predictions of this model were compared to previously measured survival curves for a normal human fibroblast line (AGO1522) and prostate tumor cells (DU145) exposed to spatially modulated fields.

Results:
The model was found to be able to accurately reproduce cell survival both in populations which were directly exposed to radiation and those which were outside the primary treatment field. The model predicts that the bystander effect makes a significant contribution to cell killing even in uniformly irradiated cells. The bystander effect contribution varies strongly with dose, falling from a high of 80% at low doses to 25% and 50% at 4 Gy for AGO1522 and DU145 cells, respectively. This was verified using the inducible nitric oxide synthase inhibitor aminoguanidine to inhibit the bystander effect in cells exposed to different doses, which showed significantly larger reductions in cell killing at lower doses.

Conclusions:
The model presented in this work accurately reproduces cell survival following modulated radiation exposures, both in and out of the primary treatment field, by incorporating a bystander component. In addition, the model suggests that the bystander effect is responsible for a significant portion of cell killing in uniformly irradiated cells, 50% and 70% at doses of 2 Gy in AGO1522 and DU145 cells, respectively. This description is a significant departure from accepted radiobiological models and may have a significant impact on optimization of treatment planning approaches if proven to be applicable in vivo.