An instantaneous control model for flow control in an ATM network

This paper is concerned with the optimal flow control of an ATM switching element in a broadband-integrated services digital network. We model the switching element as a stochastic fluid flow system with a finite buffer, a constant output rate server, and a Gaussian process to characterize the input, which is a heterogeneous set of traffic sources. The fluid level should be maintained between two levels namely b1 and b2 with b1ATM network is considered

ATM- and ATR-mediated phosphorylation of XRCC3 regulates DNA double-strand break-induced checkpoint activation and repair

The RAD51 paralogs XRCC3 and RAD51C have been implicated in homologous recombination (HR) and DNA damage responses. However, the molecular mechanism(s) by which these paralogs regulate HR and DNA damage signaling remains obscure. Here, we show that an SQ motif serine 225 in XRCC3 is phosphorylated by ATR kinase in an ATM signaling pathway. We find that RAD51C but not XRCC2 is essential for XRCC3 phosphorylation, and this modification follows end resection and is specific to S and G(2) phases. XRCC3 phosphorylation is required for chromatin loading of RAD51 and HR-mediated repair of double-strand breaks (DSBs). Notably, in response to DSBs, XRCC3 participates in the intra-S-phase checkpoint following its phosphorylation and in the G(2)/M checkpoint independently of its phosphorylation. Strikingly, we find that XRCC3 distinctly regulates recovery of stalled and collapsed replication forks such that phosphorylation is required for the HR-mediated recovery of collapsed replication forks but is dispensable for the restart of stalled replication forks. Together, these findings suggest that XRCC3 is a new player in the ATM/ATR-induced DNA damage responses to control checkpoint and HR-mediated repair.

Temporally distinct roles of ATM and ROS in genotoxic- stress-dependent induction and maintenance of cellular senescence

Cells exposed to genotoxic stress induce cellular senescence through a DNA damage response (DDR) pathway regulated by ATM kinase and reactive oxygen species (ROS). Here, we show that the regulatory roles for ATM kinase and ROS differ during induction and maintenance of cellular senescence. Cells treated with different genotoxic agents were analyzed using specific pathway markers and inhibitors to determine that ATM kinase activation is directly proportional to the dose of the genotoxic stress and that senescence initiation is not dependent on ROS or the p53 status of cells. Cells in which ROS was quenched still activated ATM and initiated the DDR when insulted, and progressed normally to senescence. By contrast, maintenance of a viable senescent state required the presence of ROS as well as activated ATM. Inhibition or removal of either of the components caused cell death in senescent cells, through a deregulated ATM-ROS axis. Overall, our work demonstrates existence of an intricate temporal hierarchy between genotoxic stress, DDR and ROS in cellular senescence. Our model reports the existence of different stages of cellular senescence with distinct regulatory networks.

Analysing the contribution of ATM/ATR pathway activation in establishing the premature senescence of E2F1/E2F2-/- bone-marrow-derived macrophages

E2F1 and E2F2 transcription factors have an important role during the regulation of cell cycle. In experiments done with E2F1/E2F2 knockout mice, it has been described that bone-marrow-derived macrophages (BMDM) undergo an early rapid proliferation event related to DNA hyper-replication. As a consequence, DNA damage response (DDR) pathway is triggered and E2F1/E2F2 knockout macrophages enter premature senescence related to G2/M phase arrest. The exact mechanism trough which DNA hyper-replication leads to DDR in absence of E2F1 and E2F2 remains undiscovered. To determine whether the ATR/ATM pathway, the master regulator of G2/M checkpoint, might be the surveillance mechanism in order to regulate uncontrolled proliferation in the DKO model, we monitored and analysis biochemical properties of BMDM cultures in the presence of caffeine, a potent inhibitor of ATM/ATR activity. Our results show that the addition of caffeine abolishes premature senescence in DKO BMDM, stimulates γ-H2AX accumulation and decreases Mcm2 expression.

ATM与BRCA1的双杂合性通过影响若干通路增加肿瘤发生风险

<正>目的:流行病学统计数据表明杂合性与肿瘤发生相关。ATM和BRCA1都是DNA损伤修复通路中的多功能基因,其单杂合性对于肿瘤易感性的影响已见报道,但双杂合

ATM蛋白表达与四种肿瘤细胞的辐射敏感性的关系

<正>毛细管扩张共济失调症(AT)由ATM基因引起,其特点是对放射线非常敏感。ATM基因是电离辐射所致的DNA损伤信号转导途径中必不可少的一部分,因此,ATM的表

Radiosensitivity to high energy iron ions is influenced by heterozygosity for Atm, Rad9 and Brca1

Loss of function of DNA repair genes has been implicated in the development of many types of cancer. In the last several years, heterozygosity leading to haploinsufficiency for proteins involved in DNA repair was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced, for example by ionizing radiation. Since the effect of heterozygosity for one gene is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes critical to pathways that control DNA damage signaling, repair or apoptosis. We investigated the role of heterozygosity for Aim, Rad9 and Brad on cell oncogenic transformation and cell survival induced by 1 GeV/n Fe-56 ions. Our results show that cells heterozygous for both Aim and Rad9 or A tin and Brca1 have high survival rates and are more sensitive to transformation by high energy iron ions when compared with wild-type controls or cells haploinsufficient for only one of these proteins. Since mutations or polymorphisms for similar genes exist in a small percentage of the human population, we have identified a radiosensitive sub-population. This finding has several implications. First, the existence of a radiosensitive sub-population may distort the shape of the dose response relationship. Second, it would not be ethical to put exceptionally radiosensitive individuals into a setting where they may potentially be exposed to substantial doses of radiation. (C) 2010 COSPAR. Published by Elsevier Ltd. All rights reserved.

Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis

Background: In recent years data from both mouse models and human tumors suggest that loss of one allele of genes involved in DNA repair pathways may play a central role in genomic instability and carcinogenesis. Additionally several examples in mouse models confirmed that loss of one allele of two functionally related genes may have an additive effect on tumor development. To understand some of the mechanisms involved, we examined the role of monoallelic loss or Atm and Brca1 on cell transformation and apoptosis induced by radiation. Methods: Cell transformation and apoptosis were measured in mouse embryo fibroblasts (MEF) and thymocytes respectively. Combinations of wild type and hemizygous genotypes for ATM and BRCA1 were tested in various comparisons. Results: Haploinsufficiency of either ATM or BRCA1 resulted in an increase in the incidence of radiation-induced transformation of MEF and a corresponding decrease in the proportion of thymocytes dying an apoptotic death, compared with cells from wild-type animals. Combined haploinsufficiency for both genes resulted in an even larger effect on apoptosis. Conclusions: Under stress, the efficiency and capacity for DNA repair mediated by the ATM/BRCA1 cell signalling network depends on the expression levels of both proteins.

TCP Boston: A Fragmentation-tolerant TCP Protocol for ATM Networks

The popularity of TCP/IP coupled with the premise of high speed communication using Asynchronous Transfer Mode (ATM) technology have prompted the network research community to propose a number of techniques to adapt TCP/IP to ATM network environments. ATM offers Available Bit Rate (ABR) and Unspecified Bit Rate (UBR) services for best-effort traffic, such as conventional file transfer. However, recent studies have shown that TCP/IP, when implemented using ABR or UBR, leads to serious performance degradations, especially when the utilization of network resources (such as switch buffers) is high. Proposed techniques-switch-level enhancements, for example-that attempt to patch up TCP/IP over ATMs have had limited success in alleviating this problem. The major reason for TCP/IP's poor performance over ATMs has been consistently attributed to packet fragmentation, which is the result of ATM's 53-byte cell-oriented switching architecture. In this paper, we present a new transport protocol, TCP Boston, that turns ATM's 53-byte cell-oriented switching architecture into an advantage for TCP/IP. At the core of TCP Boston is the Adaptive Information Dispersal Algorithm (AIDA), an efficient encoding technique that allows for dynamic redundancy control. AIDA makes TCP/IP's performance less sensitive to cell losses, thus ensuring a graceful degradation of TCP/IP's performance when faced with congested resources. In this paper, we introduce AIDA and overview the main features of TCP Boston. We present detailed simulation results that show the superiority of our protocol when compared to other adaptations of TCP/IP over ATMs. In particular, we show that TCP Boston improves TCP/IP's performance over ATMs for both network-centric metrics (e.g., effective throughput) and application-centric metrics (e.g., response time).

Preserving Bandwidth Using A Lazy Packet Discard Policy in ATM Networks

A number of recent studies have pointed out that TCP's performance over ATM networks tends to suffer, especially under congestion and switch buffer limitations. Switch-level enhancements and link-level flow control have been proposed to improve TCP's performance in ATM networks. Selective Cell Discard (SCD) and Early Packet Discard (EPD) ensure that partial packets are discarded from the network "as early as possible", thus reducing wasted bandwidth. While such techniques improve the achievable throughput, their effectiveness tends to degrade in multi-hop networks. In this paper, we introduce Lazy Packet Discard (LPD), an AAL-level enhancement that improves effective throughput, reduces response time, and minimizes wasted bandwidth for TCP/IP over ATM. In contrast to the SCD and EPD policies, LPD delays as much as possible the removal from the network of cells belonging to a partially communicated packet. We outline the implementation of LPD and show the performance advantage of TCP/LPD, compared to plain TCP and TCP/EPD through analysis and simulations.

Traffic policing in ATM networks with multimedia traffic: the super leaky bucket

Traffic policing and bandwidth management strategies at the User Network Interface (UNI) of an ATM network are investigated by simulation. The network is assumed to transport real time (RT) traffic like voice and video as well as non-real time (non-RT) data traffic. The proposed policing function, called the super leaky bucket (S-LB), is based on the leaky bucket (LB), but handles the three types of traffic differently according to their quality of service (QoS) requirements. Separate queues are maintained for RT and non-RT traffic. They are normally served alternately, but if the number of RT cells exceeds a threshold, it gets non-pre-emptive priority. Further increase of the RT queue causes low priority cells to be discarded. Non-RT cells are buffered and the sources are throttled back during periods of congestion. The simulations clearly demonstrate the advantages of the proposed strategy in providing improved levels of service (delay, jitter and loss) for all types of traffic.