Small-world networks, distributed hash tables and the e-resource discovery problem

Resource discovery is one of the most important underpinning problems behind producing a scalable, robust and efficient global infrastructure for e-Science. A number of approaches to the resource discovery and management problem have been made in various computational grid environments and prototypes over the last decade. Computational resources and services in modern grid and cloud environments can be modelled as an overlay network superposed on the physical network structure of the Internet and World Wide Web. We discuss some of the main approaches to resource discovery in the context of the general properties of such an overlay network. We present some performance data and predicted properties based on algorithmic approaches such as distributed hash table resource discovery and management. We describe a prototype system and use its model to explore some of the known key graph aspects of the global resource overlay network - including small-world and scale-free properties

Mixing multi-core CPUs and GPUs for scientific simulation software

Recent technological and economic developments have led to widespread availability of multi-core CPUs and specialist accelerator processors such as graphical processing units (GPUs). The accelerated computational performance possible from these devices can be very high for some applications paradigms. Software languages and systems such as NVIDIA's CUDA and Khronos consortium's open compute language (OpenCL) support a number of individual parallel application programming paradigms. To scale up the performance of some complex systems simulations, a hybrid of multi-core CPUs for coarse-grained parallelism and very many core GPUs for data parallelism is necessary. We describe our use of hybrid applica- tions using threading approaches and multi-core CPUs to control independent GPU devices. We present speed-up data and discuss multi-threading software issues for the applications level programmer and o er some suggested areas for language development and integration between coarse-grained and ne-grained multi-thread systems. We discuss results from three common simulation algorithmic areas including: partial di erential equations; graph cluster metric calculations and random number generation. We report on programming experiences and selected performance for these algorithms on: single and multiple GPUs; multi-core CPUs; a CellBE; and using OpenCL. We discuss programmer usability issues and the outlook and trends in multi-core programming for scienti c applications developers

Simulation modelling and visualisation: toolkits for building artificial worlds

Simulations users at all levels make heavy use of compute resources to drive computational simulations for greatly varying applications areas of research using different simulation paradigms. Simulations are implemented in many software forms, ranging from highly standardised and general models that run in proprietary software packages to ad hoc hand-crafted simulations codes for very specific applications. Visualisation of the workings or results of a simulation is another highly valuable capability for simulation developers and practitioners. There are many different software libraries and methods available for creating a visualisation layer for simulations, and it is often a difficult and time-consuming process to assemble a toolkit of these libraries and other resources that best suits a particular simulation model. We present here a break-down of the main simulation paradigms, and discuss differing toolkits and approaches that different researchers have taken to tackle coupled simulation and visualisation in each paradigm

Kinetics of the Multiferroic Switching in MnWO4_4

The time dependence of switching multiferroic domains in MnWO$_4$ has been studied by time-resolved polarized neutron diffraction. Inverting an external electric field inverts the chiral magnetic component within rise times ranging between a few and some tens of milliseconds in perfect agreement with macroscopic techniques. There is no evidence for any faster process in the inversion of the chiral magnetic structure. The time dependence is well described by a temperature-dependent rise time suggesting a well-defined process of domain reversion. As expected, the rise times decrease when heating towards the upper boundary of the ferroelectric phase. However, switching also becomes faster upon cooling towards the lower boundary, which is associated with a first-order phase transition

Nucleosomes in serum as a marker for cell death

The concentration of nucleosomes is elevated in blood of patients with diseases which are associated with enhanced cell death. In order to detect these circulating nucleosomes, we used the Cell Death Detection-ELISA(Plus) (CDDE) from Roche Diagnostics (Mannheim, Germany) (details at http:\textbackslash{}\textbackslash{}biochem.roche.com). For its application in liquid materials we performed various modifications: we introduced a standard curve with nucleosome-rich material, which enabled direct quantification and improved comparability of the values within (CVinterassay:3.0-4.1%) and between several runs (CVinterassay:8.6-13.5%), and tested the analytical specificity of the ELISA. Because of the fast elimination of nucleosomes from circulation and their limited stability, we compared plasma and serum matrix and investigated in detail the pre-analytical handling of serum samples which can considerably influence the test results. Careless venipuncture producing hemolysis, delayed centrifugation and bacterial contamination of the blood samples led to false-positive results; delayed stabilization with EDTA and insufficient storage conditions resulted in false-negative values. At temperatures of -20 degreesC, serum samples which were treated with 10 mM EDTA were stable for at least 6 months. In order to avoid possible interfering factors, we recommend a schedule for the pre-analytical handling of the samples. As the first stage, the possible clinical application was investigated in the sera of 310 persons. Patients with solid tumors (n = 220; mean = 361 Arbitrary Units (AU)) had considerably higher values than healthy persons (n = 50; mean = 30 AU; P = 0.0001) and patients with inflammatory diseases (n = 40; mean = 296 AU; p = 0.096). Within the group of patients with tumors, those in advanced stages (UICC 4) showed significantly higher values than those in early stages (UICC 1-3) (P = 0.0004)

Effect of tetragonal distortion on ferroelectric domain switching: A case study on La-doped BiFeO3-PbTiO3 ceramics

The ferroelectric and piezoelectric properties of (1-x)BiFeO3-xPbTiO(3) (BF-PT) ceramics were investigated as a function of tetragonal distortion. The latter was adjusted by employing La-doping (0-30 at %) while keeping the material near the morphotropic phase boundary by varying x between 0.35 and 0.46. This allows changing the c/a ratio of tetragonal BF-PT in the range from 1.10-1.01 and consequently alters the level of compatibility stresses. It was found that the c/a ratio has a significant influence on domain switching as inferred from electric field induced polarization, strain hysteresis, and Rayleigh measurements. Specifically, a threshold c/a ratio of about 1.045 was identified below which the electric field induced domain mobility increases sharply.open342

Orientations of the lamellar phase of block copolymer melts under oscillatory shear flow

We develop a theory to describe the reorientation phenomena in the lamellar phase of block copolymer melt under reciprocating shear flow. We show that similar to the steady-shear, the oscillating flow anisotropically suppresses fluctuations and gives rise to the parallel-perpendicular orientation transition. The experimentally observed high-frequency reverse transition is explained in terms of interaction between the melt and the shear-cell walls.Comment: RevTex, 3 pages, 1 figure, submitted to PR

Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research

Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease\u2014secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide\u2014and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future

Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis

Background: Long-term safety data are of particular interest for any newly approved treatment in multiple sclerosis such as cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg), which is approved in Europe and the USA. Here we provide the final report on the integrated analysis of the safety profile of cladribine tablets 3.5 mg/kg from the clinical development program, including final data from the PREMIERE registry. Methods: Safety data for cladribine tablets 3.5 mg/kg from three previously reported Phase III studies (CLARITY, CLARITY Extension and ORACLE-MS), as well as the prospective, observational PREMIERE registry (which ran from November 2009 to October 2018; consisting of patients who had participated in at least one of the Phase III trials) were combined to provide the Monotherapy Oral cohort. Serious adverse events (SAEs) and predefined SAEs of special interest were recorded. Observation-adjusted incidence rates per 100 patient-years (Adj-AE per 100 PY) were used to assess adverse events (AEs). Standardized incidence ratios for malignancies were calculated in relation to a matched GLOBOCAN reference population, and risk differences (cladribine tablets versus placebo) were estimated. Results: The Monotherapy Oral cohort comprised 923 patients who received cladribine tablets 3.5 mg/kg and 641 patients who received placebo. Overall, the reported number of SAEs was higher in the cladribine tablets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 SAE), versus the placebo group (68/641 [10.6%] patients with at least 1 SAE). Four patients in the cladribine tablets 3.5 mg/kg group had lymphopenia classified as a serious event (resulting in an Adj-AE of 0.10 per 100 PY) and 2 patients had serious herpes zoster (resulting in an Adj-AE of 0.05 per 100 PY). There were no cases in the corresponding placebo groups. There was no difference between the cladribine tablets 3.5 mg/kg group and placebo in the overall incidence of infections. However herpetic infection AEs occurred more frequently in the cladribine tablets 3.5 mg/kg group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Overall, there was a numerical imbalance in malignancy incidence between cladribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however the difference was not statistically significant. The rate of malignancies observed with cladribine tablets 3.5 mg/kg in the final integrated safety analysis was not different from the expected rate in the matched GLOBOCAN reference population (standardized incidence ratio, 0.88; 95% CI, 0.44-1.69). Conclusion: Additional patient-years of observation do not significantly alter the conclusions of earlier interim analyses, and no new major safety findings were identified in this consolidated analysis of safety data of cladribine tablets 3.5 mg/kg monotherapy in patients with relapsing-remitting multiple sclerosis

Therapy optimization in multiple sclerosis: a prospective observational study of therapy compliance and outcomes.

BACKGROUND: Data sources for MS research are numerous but rarely provide an objective measure of drug therapy compliance coupled with patient-reported health outcomes. The objective of this paper is to describe the methods and baseline characteristics of the Therapy Optimization in MS (TOP MS) study designed to investigate the relationship between disease-modifying therapy compliance and health outcomes. METHODS: TOP MS was designed as a prospective, observational, nationwide patient-focused study using an internet portal for data entry. The protocol was reviewed and approved by Sterling IRB. The study was registered with ClinicalTrials.gov. It captured structured survey data monthly from MS patients recruited by specialty pharmacies. Data collection included the clinical characteristics of MS such as MS relapses. Disability, quality of life and work productivity and activity impairment were assessed quarterly with well-validated scales. When events like severe fatigue or new or worsening depression were reported, feedback was provided to treating physicians. The therapy compliance measure was derived from pharmacy drug shipment records uploaded to the study database. The data presented in this paper use descriptive statistics. RESULTS: The TOP MS Study enrolled 2966 participants receiving their disease-modifying therapy (DMT) from specialty pharmacies. The mean age of the sample was 49 years, 80.4% were female, 89.9% were Caucasian and 55.7% were employed full or part time. Mean time since first symptoms was 11.5 years; mean duration since diagnosis was 9.5 years. Patient-reported EDSS was 3.5; 72.2% had a relapsing-remitting disease course. The most commonly reported symptoms at the time of enrollment were fatigue (74.7%), impaired coordination or balance (61.8%) and numbness and tingling (61.2%). Half of the sample was using glatiramer acetate and half was using beta-interferons. CONCLUSION: Demographic and clinical characteristics of the TOP MS sample at enrollment are consistent with other community-based MS samples, and the sample appears to be representative of DMT users in the US. TOP MS data can be used to explore the associations between disease-modifying therapy compliance and health outcomes. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00819000)