In-situ formation of solidified hydrogen thin-membrane targets using a pulse tube cryocooler

An account is given of the Central Laser Facility's work to produce a cryogenic hydrogen targetry system using a pulse tube cryocooler. Due to the increasing demand for low Z thin laser targets, CLF (in collaboration with TUD) have been developing a system which allows the production of solid hydrogen membranes by engineering a design which can achieve this remotely; enabling the gas injection, condensation and solidification of hydrogen without compromising the vacuum of the target chamber. A dynamic sealing mechanism was integrated which allows targets to be grown and then remotely exposed to open vacuum for laser interaction. Further research was conducted on the survivability of the cryogenic targets which concluded that a warm gas effect causes temperature spiking when exposing the solidified hydrogen to the outer vacuum. This effect was shown to be mitigated by improving the pumping capacity of the environment and reducing the minimum temperature obtainable on the target mount. This was achieved by developing a two-stage radiation shield encased with superinsulating blanketing; reducing the base temperature from 14 0.5 K to 7.2 0.2 K about the coldhead as well as improving temperature control stability following the installation of a high-performance temperature controller and sensor apparatus. The system was delivered experimentally and in July 2014 the first laser shots were taken upon hydrogen targets in the Vulcan TAP facility.

Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib

New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G₁ -S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1Amutant OCCC. Mol Cancer Ther; 15(7); 1472-84. Ó2016 AACR.

Exchange protein directly activated by cyclic AMP (EPAC) activation reverses neutrophil dysfunction induced by β2-agonists, corticosteroids, and critical illness

Background Neutrophils play a role in the pathogenesis of asthma, chronic obstructive pulmonary disease, and pulmonary infection. Impaired neutrophil phagocytosis predicts hospital-acquired infection. Despite this, remarkably few neutrophil-specific treatments exist. 

Objectives We sought to identify novel pathways for the restoration of effective neutrophil phagocytosis and to activate such pathways effectively in neutrophils from patients with impaired neutrophil phagocytosis. 

Methods Blood neutrophils were isolated from healthy volunteers and patients with impaired neutrophil function. In healthy neutrophils phagocytic impairment was induced experimentally by using β₂-agonists. Inhibitors and activators of cyclic AMP (cAMP)-dependent pathways were used to assess the influence on neutrophil phagocytosis in vitro. 

Results β₂-Agonists and corticosteroids inhibited neutrophil phagocytosis. Impairment of neutrophil phagocytosis by β₂-agonists was associated with significantly reduced RhoA activity. Inhibition of protein kinase A (PKA) restored phagocytosis and RhoA activity, suggesting that cAMP signals through PKA to drive phagocytic impairment. However, cAMP can signal through effectors other than PKA, such as exchange protein directly activated by cyclic AMP (EPAC). An EPAC-activating analog of cAMP (8CPT-2Me-cAMP) reversed neutrophil dysfunction induced by β₂-agonists or corticosteroids but did not increase RhoA activity. 8CPT-2Me-cAMP reversed phagocytic impairment induced by Rho kinase inhibition but was ineffective in the presence of Rap-1 GTPase inhibitors. 8CPT-2Me-cAMP restored function to neutrophils from patients with known acquired impairment of neutrophil phagocytosis. 

Conclusions EPAC activation consistently reverses clinical and experimental impairment of neutrophil phagocytosis. EPAC signals through Rap-1 and bypasses RhoA. EPAC activation represents a novel potential means by which to reverse impaired neutrophil phagocytosis.

A green perspective on Structured parallel programming

Structured parallel programming, and in particular programming models using the algorithmic skeleton or parallel design pattern concepts, are increasingly considered to be the only viable means of supporting effective development of scalable and efficient parallel programs. Structured parallel programming models have been assessed in a number of works in the context of performance. In this paper we consider how the use of structured parallel programming models allows knowledge of the parallel patterns present to be harnessed to address both performance and energy consumption. We consider different features of structured parallel programming that may be leveraged to impact the performance/energy trade-off and we discuss a preliminary set of experiments validating our claims.

The Loop-of-Stencil-Reduce Paradigm

In this paper we advocate the Loop-of-stencil-reduce pattern as a way to simplify the parallel programming of heterogeneous platforms (multicore+GPUs). Loop-of-Stencil-reduce is general enough to subsume map, reduce, map-reduce, stencil, stencil-reduce, and, crucially, their usage in a loop. It transparently targets (by using OpenCL) combinations of CPU cores and GPUs, and it makes it possible to simplify the deployment of a single stencil computation kernel on different GPUs. The paper discusses the implementation of Loop-of-stencil-reduce within the FastFlow parallel framework, considering a simple iterative data-parallel application as running example (Game of Life) and a highly effective parallel filter for visual data restoration to assess performance. Thanks to the high-level design of the Loop-of-stencil-reduce, it was possible to run the filter seamlessly on a multicore machine, on multi-GPUs, and on both.

Numerical Analysis on a Dual-Loop Waste Heat Recovery System Coupled with an ORC for Vehicle Applications

The internal combustion (IC) engines exploits only about 30% of the chemical energy ejected through combustion, whereas the remaining part is rejected by means of cooling system and exhausted gas. Nowadays, a major global concern is finding sustainable solutions for better fuel economy which in turn results in a decrease of carbon dioxide (CO2) emissions. The Waste Heat Recovery (WHR) is one of the most promising techniques to increase the overall efficiency of a vehicle system, allowing the recovery of the heat rejected by the exhaust and cooling systems. In this context, Organic Rankine Cycles (ORCs) are widely recognized as a potential technology to exploit the heat rejected by engines to produce electricity. The aim of the present paper is to investigate a WHR system, designed to collect both coolant and exhausted gas heats, coupled with an ORC cycle for vehicle applications. In particular, a coolant heat exchanger (CLT) allows the heat exchange between the water coolant and the ORC working fluid, whereas the exhausted gas heat is recovered by using a secondary circuit with diathermic oil. By using an in-house numerical model, a wide range of working conditions and ORC design parameters are investigated. In particular, the analyses are focused on the regenerator location inside the ORC circuits. Five organic fluids, working in both subcritical and supercritical conditions, have been selected in order to detect the most suitable configuration in terms of energy and exergy efficiencies.

Coupling short-term (B2G model) and long-term (g-function) models for ground source heat exchanger simulation in TRNSYS. Application in a real installation

Ground-source heat pump (GSHP) systems represent one of the most promising techniques for heating and cooling in buildings. These systems use the ground as a heat source/sink, allowing a better efficiency thanks to the low variations of the ground temperature along the seasons. The ground-source heat exchanger (GSHE) then becomes a key component for optimizing the overall performance of the system. Moreover, the short-term response related to the dynamic behaviour of the GSHE is a crucial aspect, especially from a regulation criteria perspective in on/off controlled GSHP systems. In this context, a novel numerical GSHE model has been developed at the Instituto de Ingeniería Energética, Universitat Politècnica de València. Based on the decoupling of the short-term and the long-term response of the GSHE, the novel model allows the use of faster and more precise models on both sides. In particular, the short-term model considered is the B2G model, developed and validated in previous research works conducted at the Instituto de Ingeniería Energética. For the long-term, the g-function model was selected, since it is a previously validated and widely used model, and presents some interesting features that are useful for its combination with the B2G model. The aim of the present paper is to describe the procedure of combining these two models in order to obtain a unique complete GSHE model for both short- and long-term simulation. The resulting model is then validated against experimental data from a real GSHP installation.

Charge migration induced by attosecond pulses in bio-relevant molecules

After sudden ionization of a large molecule, the positive charge can migrate throughout the system on a sub-femtosecond time scale, purely guided by electronic coherences. The possibility to actively explore the role of the electron dynamics in the photo-chemistry of bio-relevant molecules is of fundamental interest for understanding, and perhaps ultimately controlling, the processes leading to damage, mutation and, more generally, to the alteration of the biological functions of the macromolecule. Attosecond laser sources can provide the extreme time resolution required to follow this ultrafast charge flow. In this review we will present recent advances in attosecond molecular science: after a brief description of the results obtained for small molecules, recent experimental and theoretical findings on charge migration in bio-relevant molecules will be discussed.

Early warning systems for cyber defence

Cybercriminals ramp up their efforts with sophisticated techniques while defenders gradually update their typical security measures. Attackers often have a long-term interest in their targets. Due to a number of factors such as scale, architecture and nonproductive traffic however it makes difficult to detect them using typical intrusion detection techniques. Cyber early warning systems (CEWS) aim at alerting such attempts in their nascent stages using preliminary indicators. Design and implementation of such systems involves numerous research challenges such as generic set of indicators, intelligence gathering, uncertainty reasoning and information fusion. This paper discusses such challenges and presents the reader with compelling motivation. A carefully deployed empirical analysis using a real world attack scenario and a real network traffic capture is also presented.

Towards automated Android app collusion detection

Android OS supports multiple communication methods between apps. This opens the possibility to carry out threats in a collaborative fashion, c.f. the Soundcomber example from 2011. In this paper we provide a concise definition of collusion and report on a number of automated detection approaches, developed in co-operation with Intel Security.

Effective network security monitoring: from attribution to target-centric monitoring

Network security monitoring remains a challenge. As global networks scale up, in terms of traffic, volume and speed, effective attribution of cyber attacks is increasingly difficult. The problem is compounded by a combination of other factors, including the architecture of the Internet, multi-stage attacks and increasing volumes of nonproductive traffic. This paper proposes to shift the focus of security monitoring from the source to the target. Simply put, resources devoted to detection and attribution should be redeployed to efficiently monitor for targeting and prevention of attacks. The effort of detection should aim to determine whether a node is under attack, and if so, effectively prevent the attack. This paper contributes by systematically reviewing the structural, operational and legal reasons underlying this argument, and presents empirical evidence to support a shift away from attribution to favour of a target-centric monitoring approach. A carefully deployed set of experiments are presented and a detailed analysis of the results is achieved.

Towards a knowledge-based approach for effective decision-making in railway safety

Purpose – This paper aims to contribute towards understanding how safety knowledge can be elicited from railway experts for the purposes of supporting effective decision-making. Design/methodology/approach – A consortium of safety experts from across the British railway industry is formed. Collaborative modelling of the knowledge domain is used as an approach to the elicitation of safety knowledge from experts. From this, a series of knowledge models is derived to inform decision-making. This is achieved by using Bayesian networks as a knowledge modelling scheme, underpinning a Safety Prognosis tool to serve meaningful prognostics information and visualise such information to predict safety violations. Findings – Collaborative modelling of safety-critical knowledge is a valid approach to knowledge elicitation and its sharing across the railway industry. This approach overcomes some of the key limitations of existing approaches to knowledge elicitation. Such models become an effective tool for prediction of safety cases by using railway data. This is demonstrated using passenger–train interaction safety data. Practical implications – This study contributes to practice in two main directions: by documenting an effective approach to knowledge elicitation and knowledge sharing, while also helping the transport industry to understand safety. Social implications – By supporting the railway industry in their efforts to understand safety, this research has the potential to benefit railway passengers, staff and communities in general, which is a priority for the transport sector. Originality/value – This research applies a knowledge elicitation approach to understanding safety based on collaborative modelling, which is a novel approach in the context of transport.

Detecting stealthy attacks: Efficient monitoring of suspicious activities on computer networks

Stealthy attackers move patiently through computer networks - taking days, weeks or months to accomplish their objectives in order to avoid detection. As networks scale up in size and speed, monitoring for such attack attempts is increasingly a challenge. This paper presents an efficient monitoring technique for stealthy attacks. It investigates the feasibility of proposed method under number of different test cases and examines how design of the network affects the detection. A methodological way for tracing anonymous stealthy activities to their approximate sources is also presented. The Bayesian fusion along with traffic sampling is employed as a data reduction method. The proposed method has the ability to monitor stealthy activities using 10-20% size sampling rates without degrading the quality of detection.

An investigation of routes to cancer diagnosis in 10 international jurisdictions, as part of the International Cancer Benchmarking Partnership: survey development and implementation

Objectives This paper describes the methods used in the International Cancer Benchmarking Partnership Module 4 Survey (ICBPM4) which examines time intervals and routes to cancer diagnosis in 10 jurisdictions. We present the study design with defining and measuring time intervals, identifying patients with cancer, questionnaire development, data management and analyses.
Design and setting Recruitment of participants to the ICBPM4 survey is based on cancer registries in each jurisdiction. Questionnaires draw on previous instruments and have been through a process of cognitive testing and piloting in three jurisdictions followed by standardised translation and adaptation. Data analysis focuses on comparing differences in time intervals and routes to diagnosis in the jurisdictions.
Participants Our target is 200 patients with symptomatic breast, lung, colorectal and ovarian cancer in each jurisdiction. Patients are approached directly or via their primary care physician (PCP). Patients’ PCPs and cancer treatment specialists (CTSs) are surveyed, and ‘data rules’ are applied to combine and reconcile conflicting information. Where CTS information is unavailable, audit information is sought from treatment records and databases.
Main outcomes Reliability testing of the patient questionnaire showed that agreement was complete (κ=1) in four items and substantial (κ=0.8, 95% CI 0.333 to 1) in one item. The identification of eligible patients is sufficient to meet the targets for breast, lung and colorectal cancer. Initial patient and PCP survey response rates from the UK and Sweden are comparable with similar published surveys. Data collection was completed in early 2016 for all cancer types.
Conclusion An international questionnaire-based survey of patients with cancer, PCPs and CTSs has been developed and launched in 10 jurisdictions. ICBPM4 will help to further understand international differences in cancer survival by comparing time intervals and routes to cancer diagnosis.