11,679 research outputs found

    Reverse engineering of drug induced DNA damage response signalling pathway reveals dual outcomes of ATM kinase inhibition

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    The DNA Damage Response (DDR) pathway represents a signalling mechanism that is activated in eukaryotic cells following DNA damage and comprises of proteins involved in DNA damage detection, DNA repair, cell cycle arrest and apoptosis. This pathway consists of an intricate network of signalling interactions driving the cellular ability to recognise DNA damage and recruit specialised proteins to take decisions between DNA repair or apoptosis. ATM and ATR are central components of the DDR pathway. The activities of these kinases are vital in DNA damage induced phosphorylational induction of DDR substrates. Here, firstly we have experimentally determined DDR signalling network surrounding the ATM/ATR pathway induced following double stranded DNA damage by monitoring and quantifying time dependent inductions of their phosphorylated forms and their key substrates. We next involved an automated inference of unsupervised predictive models of time series data to generate in silico (molecular) interaction maps. We characterized the complex signalling network through system analysis and gradual utilisation of small time series measurements of key substrates through a novel network inference algorithm. Furthermore, we demonstrate an application of an assumption-free reverse engineering of the intricate signalling network of the activated ATM/ATR pathway. We next studied the consequences of such drug induced inductions as well as of time dependent ATM kinase inhibition on cell survival through further biological experiments. Intermediate and temporal modelling outcomes revealed the distinct signaling profile associated with ATM kinase activity and inhibition and explained the underlying signalling mechanism for dual ATM functionality in cytotoxic and cytoprotective pathways

    Source Behavior for ATM ABR Traffic Management: An Explanation

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    The Available Bit Rate (ABR) service has been developed to support data applications over Asynchronous Transfer Mode (ATM) networks. The network continuously monitors its traffic and provides feedback to the source end systems. This paper explains the rules that the sources have to follow to achieve a fair and efficient allocation of network resources.Comment: IEEE Communications Magazine, November 1, 1996, vol 34, no11, pp50-5

    Modelling the onset of senescence at the G1/S cell cycle checkpoint

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    DNA damage (single or double-strand breaks) triggers adapted cellular responses. These responses are elicited through signalling pathways, which activate cell cycle checkpoints and basically lead to three cellular fates: cycle arrest promoting DNA repair, senescence (permanent arrest) or cell death. Cellular senescence is known for having a tumour-suppressive function and its regulation arouses a growing scientific interest. Here, we advance a qualitative model covering DNA damage response pathways, focusing on G1/S checkpoint enforcement, supposedly more sensitive to arrest than G2/M checkpoint.Instituto Gulbenkian de Ciência (IGC), the Brazilian agency CNPq for financial support (grants 236673/2012-2, 304805/2012-2, 402547/2012-8)

    TCP/IP traffic over ATM network with ABR flow and congestion control

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    Most traffics over the existing ATM network are generated by applications running over TCP/IP protocol stack. In the near future, the success of ATM technology will depend largely on how well it supports the huge legacy of existing TCP/IP applications. In this thesis, we study and compare the performance of TCP/IP traffic running on different rate based ABR flow control algorithms such as EFCI, ERICA and FMMRA by extensive simulations. Infinite source-end traffic behavior is chosen to represent, FTP application running on TCP/IP. Background VBR traffic with different ON-OFF frequency is introduced to produce transient network states as well as congestion. The simulations produce many insights on issues such as: ABR queue length in congested ATM switch, source-end ACR (Allowed Cell Rate), link utilization at congestion point, efficient end to end TCP throughput, the TCP congestion control window size, and the TCP round trip time. Based on the simulation results, zero cell loss switch buffer requirement of the three algorithms are compared, and the fairness of ABR bandwidth allocation among TCP connections are analyzed. The interaction between the TCP layer and the ATM layer flow and congestion control mechanism is analyzed. Our simulation results show that in order to get a good TCP throughput and affordable switch buffer requirement, some kind of switch queue length monitoring and control mechanism is necessary in the ABR. congestion algorithm

    Studying DNA Double-Strand Break Repair: An Ever-Growing Toolbox

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    To ward off against the catastrophic consequences of persistent DNA double-strand breaks (DSBs), eukaryotic cells have developed a set of complex signaling networks that detect these DNA lesions, orchestrate cell cycle checkpoints and ultimately lead to their repair. Collectively, these signaling networks comprise the DNA damage response (DDR). The current knowledge of the molecular determinants and mechanistic details of the DDR owes greatly to the continuous development of ground-breaking experimental tools that couple the controlled induction of DSBs at distinct genomic positions with assays and reporters to investigate DNA repair pathways, their impact on other DNA-templated processes and the specific contribution of the chromatin environment. In this review, we present these tools, discuss their pros and cons and illustrate their contribution to our current understanding of the DDR.European Research Council (ERC-2014-CoG 647344

    Explicit congestion control algorithms for available bit rate services in asynchronous transfer mode networks

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    Congestion control of available bit rate (ABR) services in asynchronous transfer mode (ATM) networks has been the recent focus of the ATM Forum. The focus of this dissertation is to study the impact of queueing disciplines on ABR service congestion control, and to develop an explicit rate control algorithm. Two queueing disciplines, namely, First-In-First-Out (FIFO) and per-VC (virtual connection) queueing, are examined. Performance in terms of fairness, throughput, cell loss rate, buffer size and network utilization are benchmarked via extensive simulations. Implementation complexity analysis and trade-offs associated with each queueing implementation are addressed. Contrary to the common belief, our investigation demonstrates that per-VC queueing, which is costlier and more complex, does not necessarily provide any significant improvement over simple FIFO queueing. A new ATM switch algorithm is proposed to complement the ABR congestion control standard. The algorithm is designed to work with the rate-based congestion control framework recently recommended by the ATM Forum for ABR services. The algorithm\u27s primary merits are fast convergence, high throughput, high link utilization, and small buffer requirements. Mathematical analysis is done to show that the algorithm converges to the max-min fair allocation rates in finite time, and the convergence time is proportional to the distinct number of fair allocations and the round-trip delays in the network. At the steady state, the algorithm operates without causing any oscillations in rates. The algorithm does not require any parameter tuning, and proves to be very robust in a large ATM network. The impact of ATM switching and ATM layer congestion control on the performance of TCP/IP traffic is studied and the results are presented. The study shows that ATM layer congestion control improves the performance of TCP/IP traffic over ATM, and implementing the proposed switch algorithm drastically reduces the required switch buffer requirements. In order to validate claims, many benchmark ATM networks are simulated, and the performance of the switch is evaluated in terms of fairness, link utilization, response time, and buffer size requirements. In terms of performance and complexity, the algorithm proposed here offers many advantages over other proposed algorithms in the literature
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