DNA damage response (DDR) pathway prevents high level endogenous and environmental DNA damage being replicated and passed on to the next generation of cells via an orchestrated and integrated network of cell cycle checkpoint signalling and DNA repair pathways. Depending on the type of damage, and where in the cell cycle it occurs different pathways are involved, with the ATM-CHK2-p53 pathway controlling the G1 checkpoint or ATR-CHK1-Wee1 pathway controlling the S and G2/M checkpoints. Loss of G1 checkpoint control is common in cancer through TP53, ATM mutations, Rb loss or cyclin E overexpression, providing a stronger rationale for targeting the S/G2 checkpoints. This review will focus on the ATM-CHK2-p53-p21 pathway and the ATR-CHK1-WEE1 pathway and ongoing efforts to target these pathways for patient benefit.

The USA and Europe are developing plans – NextGen and SESAR – to transform the processes of Air Traffic Management (ATM). These will improve safety and efficiency, and match predicted increases in air transportation demand. They use advanced networking technology updated with information from satellite navigation and digital non-voice communication. The strategic goal, envisaged for 15–20 years hence, is a new ATM paradigm. Aircraft would fly on Four-Dimensional (4D) trajectories, incorporating altitude, position, time, and other aircraft positions and vectors. This vision would involve extremely large investments from the airline industry and ATM service providers. Thus, development priorities need to be based on sound business cases. But will these necessarily lead to the strategic vision of a 4D-trajectory system? Will the changes in practice be limited to a series of short and medium term operational improvements rather than strategic improvements? So, are there ‘Killer Apps’ for 4D-trajectory ATM? ‘Killer App(lication)s’ is jargon for innovations so valuable that they prove the core value of some larger technology. Killer Apps generate high degrees of stakeholder technical and financial cooperation. Ironically, most past ATM Killer Apps have improved safety, e.g., modern radar data processing led to collision avoidance systems. The analysis here attempts to identify and then size potential 4D-trajectory ATM Killer Apps. The evidence for Killer Apps has to pass key tests. Killer Apps obviously have to offer enormous benefits to stakeholders in the context of the potential costs. The bulk of these benefits must not be obtainable through technologically ‘cut down’ non−4D-trajectory versions. Part 1 of this paper (Brooker, 2012a) sets out the framework for investigating these questions. Part 2 examines potential Killer Apps derived from improvements in Fuel Efficiency, Capacity and Cost. An abbreviated version of this paper was first presented at the European Navigation Conference (ENC 2011), London in November 2011.

Europe and the USA are developing plans (‘SESAR’ and ‘NextGen’) to transform the processes of Air Traffic Management (ATM). These will improve safety and efficiency, and match predicted increases in air transportation demand. Aircraft would fly on Four Dimensional-Trajectories (4D-Trajectories), incorporating altitude, position, time, and other aircraft positions and vectors. This vision would involve extremely large investments from the airline industry and ATM service providers. Thus, development priorities need to be based on sound business cases. But will these necessarily lead to the strategic vision of a 4D-Trajectory system? Will the changes in practice be limited to a series of short and medium term operational improvements rather than strategic improvements? Killer App(lication)s is jargon for innovations so valuable that they prove the core value of some larger technology. So, are there ‘Killer Apps’ for 4D-Trajectory ATM? Killer Apps generate high degrees of stakeholder technical and financial cooperation. Ironically, most past ATM Killer Apps have improved safety. The analysis here attempts to identify and then size potential 4D-Trajectory ATM Killer Apps. The evidence for Killer Apps has to pass key tests. Killer Apps obviously have to offer enormous benefits to stakeholders in the context of the potential costs. The bulk of these benefits must not be obtainable through technologically ‘cut down’ non−4D-Trajectory versions. Part 1 of this paper sets out the framework for investigating these questions; Part 2 will be published subsequently and will examine potential Killer Apps derived from improvements in Fuel Efficiency, Capacity and Cost. An abbreviated version of this paper was first presented at the European Navigation Conference (ENC 2011), London in November 2011.

Current strategic plans for Air Traffic Management (ATM) envisage a transition from radar control to a trajectory-based system. Part 1 sketched the historical origins of separation minima and then analysed the safety thinking behind current minima and the issues involved in risk modelling. Part 2 examines the future situation. This focuses on the intermediate steps to the final system – upgraded capabilities in a mixed-equipage system. Future traffic mixes two categories of traffic: V aircraft, i.e. vectored traditional ATC-handled, and 4D aircraft, i.e. flying on 4D trajectories. Conflict probe and other decision support tools will need to be in place, inter alia to prevent controller workload from increasing. Conceptually, future risks in the transition period will be the sum of three types of aircraft encounter risk: V/V, 4D/4D and 4D/V. These pose different kinds of problem for ATC, appropriate conflict alerting systems and risk assessment. The numbers of 4D/V encounters increase rapidly with growth in the proportion of 4D aircraft. With reduced minima, airborne collision avoidance systems would be unlikely to resolve higher relative velocity encounters were the ATC system to fail. It would be a difficult decision to reduce markedly ATC separation minima for any category of aircraft encounters during the transition period.

Current strategic plans for air traffic management (ATM) envisage a transition from radar control to a trajectory-based system. The future ATM concepts are very different in a great number of aspects from the present system. The focus here is on the design of safe systems, in particular the appropriate air traffic control (ATC) separation minima. This Part 1 sketches the historical origins of ATC separation minima and then analyses the safety thinking behind current minima and the issues involved in risk modelling. Why have the critical minima largely remained unchanged for several decades – stasis? Part 2 then addresses key safety issues in the transition to the new ATM concept.

‘Give me a lever long enough and a fulcrum on which to place it, and I shall move the world.’ Archimedes.

It is now widely recognised that a paradigm shift in air traffic control concepts is needed. This requires state-of-the-art innovative technologies, making much better use of the information in the air traffic management (ATM) system. These paradigm shifts go under the names of NextGen in the USA and SESAR in Europe, which inter alia will make dramatic changes to the nature of airport operations. A vital part of moving from an existing system to a new paradigm is the operational implications of the transition process. There would be business incentives for early aircraft fitment, it is generally safer to introduce new technologies gradually, and researchers are already proposing potential transition steps to the new system. Simple queuing theory models are used to establish rough quantitative estimates of the impact of the transition to a more efficient time-based – four-dimensional (4D) – navigational and ATM system. Such models are approximate, but they do offer insight into the broad implications of system change and its significant features. 4D-equipped aircraft in essence have a contract with the airport runway – they would be required to turn up at a very precise time – and, in return, they would get priority over any other aircraft waiting for use of the runway. The main operational feature examined here is the queuing delays affecting non-4D-equipped arrivals. These get a reasonable service if the proportion of 4D-equipped aircraft is low, but this can deteriorate markedly for high proportions, and be economically unviable. Preventative measures would be to limit the additional growth of 4D-equipped flights and/or to modify their contracts to provide sufficient space for the non-4D-equipped flights to operate without excessive delays. There is a potential for non-Poisson models, for which there is little in the literature, and for more complex models, e.g. grouping a succession of 4D-equipped aircraft as a batch.

A version of this paper was first presented at the Royal Institute of Navigation NAV 08 Conference held at Church House, Westminster, London in October 2008.

SESAR is Europe's ‘Single European Sky Air traffic Research system’, targeted at post-2020. The vision is to integrate and implement new technologies to improve air traffic management (ATM) performance. The focus for planning and executing system operations will increasingly be aircraft navigating high-quality 4D trajectories: a 4D trajectory is the aircraft path, three space dimensions plus time, from gate-to-gate, i.e. including the path along the ground at the airport. A 20+year ATM plan has to use limited information on the success of innovations and the development of large-scale, often safety critical, software, which by its nature can take markedly longer and cost markedly more than early estimates. SESAR must be sufficiently flexible in deployment to maximise financial benefits to individual stakeholders using their specific financial criteria. Airline needs are the main ATM system/business drivers. Airlines do not want to commit to developing an ‘ultra-modern system’ per se, but rather to one that makes business-sensible investments in new technologies that are indispensable for achieving improved safety and meeting projected capacity requirements. The approach has been to use simple corporate finance ideas to examine the different viewpoints and business environments of air traffic service suppliers (ANSPs) and individual airlines. The key decision-making point is that ANSPs act as an agent for airlines as a whole. The key financial point is that a typical airline has to work hard to survive and needs quick paybacks on investment. The design of the SESAR R&D and project portfolios can learn lessons from information technology systems design and deployment. ‘Real option analysis’ of systems can increase business value by improving the sequencing and partitioning of projects, helping to ensure that the system is adaptable to technological innovation and changes in business needs.

SESAR is Europe's ‘Single European Sky Air traffic Research system’. NextGen is the USA's ‘Next Generation Air Transport System’. SESAR and NextGen are developments targeted at post 2020. The common vision is to integrate and implement new technologies to improve air traffic management (ATM) performance – a ‘new paradigm’. SESAR and NextGen combine increased automation with new procedures to achieve safety, economic, capacity, environmental, and security benefits. The systems do not have to be identical, but must have aligned requirements for equipment standards and technical interoperability.

A key component is a ‘cooperative surveillance’ model, where aircraft are constantly transmitting their position (from navigational satellites), flight path intent, and other useful aircraft parameters – known as ADS-B (Automatic Dependent Surveillance-Broadcast). The focus for planning and executing system operations will increasingly be aircraft 4D trajectories: a 4D trajectory is the aircraft path, three space dimensions plus time, from gate-to-gate, i.e. including the path along the ground at the airport.

In analysing potential major ATM system changes, a simple division into five Key Test areas might be: Safety Credibility, Operational Concept, Technological Feasibility, Benefits and Costs, and Transition Path. The main attention here is on Benefits and Costs of SESAR. The strategic challenge will be to convince customers and stakeholders of the benefits of paradigm shift expenditure, given the associated impacts on future user charges, aircraft equipment investments and public expenditure. The analysis here shows that the existing cost benefit analysis results for SESAR are not particularly robust, possibly over-estimating Net Present Values by some tens of € billions.

Many viruses, with distinct replication strategies, activate DNA-damage response pathways, including the lentivirus human immunodeficiency virus (HIV) and the DNA viruses Epstein–Barr virus (EBV), herpes simplex virus 1, adenovirus and SV40. DNA-damage response pathways involving DNA-dependent protein kinase, ataxia-telengiectasia mutated (ATM) and ‘ataxia-telengiectasia and Rad3-related’ (ATR) have all been implicated. This review focuses on the effects of HIV and EBV replication on DNA repair pathways. It has been suggested that activation of cellular DNA repair and recombination enzymes is beneficial for viral replication, as illustrated by the ability of suppressors of the ATM and ATR family to inhibit HIV replication. However, activation of DNA-damage response pathways can also promote apoptosis. Viruses can tailor the cellular response by suppressing downstream signalling from DNA-damage sensors, as exemplified by EBV. New small-molecule inhibitors of the DNA-damage response pathways could therefore be of value to treat viral infections.

The focus here is on the performance of and interaction between the Traffic Alert and Collision Avoidance System (TCAS) and the controller's short-term conflict alert (STCA) system. The data source used is UK Airprox Board Reports of close encounters between aircraft, and the focus is on commercial air transport aircraft using UK controlled airspace with a radar service. Do the systems work well together? Are controllers surprised when they find out that a pilot has received a TCAS resolution advisory? What do TCAS and STCA events say about collision risk? Generally, the systems seem to work together well. On most occasions, controllers are not surprised by TCAS advisories: either they have detected the problem themselves or STCA has alerted them to it. The statistically expected rate of future mid-air collisions is estimated by extrapolation of Airprox closest encounter distances.

A new ICAO Policy on Airborne Collision Avoidance Systems is needed, which recognizes it to be an integrated part of the air traffic management system's safety defences; and that should be fully included in hazard analyses for the total system's design safety targets.

Current Eurocontrol Safety Regulation Commission (SRC) policy says that the Air Traffic Management (ATM) system (including safety minima) must be demonstrated through risk assessments to meet the Target Level of Safety (TLS) without needing to take safety nets (such as Short Term Conflict Alert) into account. This policy is wrong. The policy is invalid because it does not build rationally and consistently from ATM's firm foundations of TLS and hazard analysis. The policy is bad because it would tend to retard safety improvements. Safety net policy must rest on a clear and rational treatment of integrated ATM system safety defences. A new safety net policy, appropriate to safe ATM system improvements, is needed, which recognizes that safety nets are an integrated part of ATM system defences. The effects of safety nets in reducing deaths from mid-air collisions should be fully included in hazard analysis and safety audits in the context of the TLS for total system design.

The pleiotropic nature of the clinical phenotypes of patients with ataxia-telangiectasia (A-T) – which encompass cerebellar degeneration (leading to ataxia), gonadal atrophy, and cancer predisposition – suggests multiple functions of the gene responsible for the disease. The ataxia-telangiectasia mutated gene product (ATM), whose loss of function is responsible for ataxia-telangiectasia, is a protein kinase that interacts with several substrates and is implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, cell-cycle control and telomere maintenance. This review focuses on the critical roles that ATM appears to play in cell-cycle checkpoints, DNA repair, telomere metabolism and oxidative stress, indicating how defects in these processes might lead to ataxia-telangiectasia.

Breast cancer is one of the most common causes of cancer-related mortality in women. It affects more than one in nine women over their lifetime. Although most breast cancers are sporadic, the genetics and molecular biology of the heritable forms of breast cancer have provided valuable insights into not only breast cancer but also cancers in general. Among the mutations linked to heritable breast cancers, the mutations in the breast cancer 1 (BRCA1) gene are the best characterised. The BRCA1 gene encodes a nuclear protein that is important for maintaining genome integrity. However, a growing list of BRCA1-associated proteins suggests that BRCA1 has diverse and unexpected functions.

In this paper we derive asymptotically exact expressions for buffer overflow probabilities and cell loss probabilities for a finite buffer which is fed by a large number of independent and stationary sources. The technique is based on scaling, measure change and local limit theorems and extends the recent results of Courcoubetis and Weber on buffer overflow asymptotics. We discuss the cases when the buffers are of the same order as the transmission bandwidth as well as the case of small buffers. Moreover we show that the results hold for a wide variety of traffic sources including ON/OFF sources with heavy-tailed distributed ON periods, which are typical candidates for so-called ‘self-similar’ inputs, showing that the asymptotic cell loss probability behaves in much the same manner for such sources as for the Markovian type of sources, which has important implications for statistical multiplexing. Numerical validation of the results against simulations are also reported.

We approximate the exit distribution of a Markov jump process into a set of forbidden states and we apply these general results to an ATM multiplexor. In this case the forbidden states represent an overloaded multiplexor. Statistics for this overload or busy period are difficult to obtain since this is such a rare event. Starting from the approximate exit distribution, one may simulate the busy period without wasting simulation time waiting for the overload to occur.

This paper is devoted to the study of a stationary G/G/1 queue in which work input is gradually injected into the system and the work load is processed at unit rate. First, assuming that the input process is stationary, the key formula for the stationary distribution of work in system is derived by appeal to the waiting time of the associated regular G/G/1 queue. The main contribution of this paper is the derivation of Laplace-Stieltjes transforms (LSTs) for the stationary distributions of work in system and related random variables in terms of integrations with respect to a waiting time distribution of the associated regular queue. The results are exemplified by giving explicit formulas for the LST of total work for M/Ek/1 and M/H2/1. The results generalize the results of Pan et al. (1991) for the M/M/1 gradual input queue.