Deterministic Concurrency: A Clock-Synchronised Shared Memory Approach

International audienceSynchronous Programming (SP) is a universal computational principle that provides deterministic concurrency. The same input sequence with the same timing always results in the same externally observable output sequence, even if the internal behaviour generates uncertainty in the scheduling of concurrent memory accesses. Consequently, SP languages have always been strongly founded on mathematical semantics that support formal program analysis. So far, however, communication has been constrained to a set of primitive clock-synchronised shared memory (csm) data types, such as data-flow registers, streams and signals with restricted read and write accesses that limit modularity and behavioural abstractions. This paper proposes an extension to the SP theory which retains the advantages of deterministic concurrency, but allows communication to occur at higher levels of abstraction than currently supported by SP data types. Our approach is as follows. To avoid data races, each csm type publishes a policy interface for specifying the admissibility and precedence of its access methods. Each instance of the csm type has to be policy-coherent, meaning it must behave deterministically under its own policy-a natural requirement if the goal is to build deterministic systems that use these types. In a policy-constructive system, all access methods can be scheduled in a policy-conformant way for all the types without deadlocking. In this paper, we show that a policy-constructive program exhibits deterministic concurrency in the sense that all policy-conformant interleavings produce the same input-output behaviour. Policies are conservative and support the csm types existing in current SP languages. Technically, we introduce a kernel SP language that uses arbitrary policy-driven csm types. A big-step fixed-point semantics for this language is developed for which we prove determinism and termination of constructive programs

A Randomized Placebo-Controlled Phase Ia Malaria Vaccine Trial of Two Virosome-Formulated Synthetic Peptides in Healthy Adult Volunteers

BACKGROUND AND OBJECTIVES: Influenza virosomes represent an innovative human-compatible antigen delivery system that has already proven its suitability for subunit vaccine design. The aim of the study was to proof the concept that virosomes can also be used to elicit high titers of antibodies against synthetic peptides. The specific objective was to demonstrate the safety and immunogenicity of two virosome-formulated P. falciparum protein derived synthetic peptide antigens given in two different doses alone or in combination. METHODOLOGY/PRINCIPAL FINDINGS: The design was a single blind, randomized, placebo controlled, dose-escalating study involving 46 healthy Caucasian volunteers aged 18-45 years. Five groups of 8 subjects received virosomal formulations containing 10 microg or 50 microg of AMA 49-CPE, an apical membrane antigen-1 (AMA-1) derived synthetic phospatidylethanolamine (PE)-peptide conjugate or 10 ug or 50 ug of UK39, a circumsporozoite protein (CSP) derived synthetic PE-peptide conjugate or 50 ug of both antigens each. A control group of 6 subjects received unmodified virosomes. Virosomal formulations of the antigens (designated PEV301 and PEV302 for the AMA-1 and the CSP virosomal vaccine, respectively) or unmodified virosomes were injected i. m. on days 0, 60 and 180. In terms of safety, no serious or severe adverse events (AEs) related to the vaccine were observed. 11/46 study participants reported 16 vaccine related local AEs. Of these 16 events, all being pain, 4 occurred after the 1(st), 7 after the 2(nd) and 5 after the 3(rd) vaccination. 6 systemic AEs probably related to the study vaccine were reported after the 1(st) injection, 10 after the 2(nd) and 6 after the 3(rd). Generally, no difference in the distribution of the systemic AEs between either the doses applied (10 respectively 50 microg) or the synthetic antigen vaccines (PEV301 and PEV302) used for immunization was found. In terms of immunogenicity, both PEV301 and PEV302 elicited already after two injections a synthetic peptide-specific antibody response in all volunteers immunized with the appropriate dose. In the case of PEV301 the 50 microg antigen dose was associated with a higher mean antibody titer and seroconversion rate than the 10 microg dose. In contrast, for PEV302 mean titer and seroconversion rate were higher with the lower dose. Combined delivery of PEV301 and PEV302 did not interfere with the development of an antibody response to either of the two antigens. No relevant antibody responses against the two malaria antigens were observed in the control group receiving unmodified virosomes. CONCLUSIONS: The present study demonstrates that three immunizations with the virosomal malaria vaccine components PEV301 or/and PEV302 (containing 10 microg or 50 microg of antigen) are safe and well tolerated. At appropriate antigen doses seroconversion rates of 100% were achieved. Two injections may be sufficient for eliciting an appropriate immune response, at least in individuals with pre-existing anti-malarial immunity. These results justify further development of a final multi-stage virosomal vaccine formulation incorporating additional malaria antigens. TRIAL REGISTRATION: ClinicalTrials.gov NCT00400101

Inverse Current Source Density Method in Two Dimensions: Inferring Neural Activation from Multielectrode Recordings

The recent development of large multielectrode recording arrays has made it affordable for an increasing number of laboratories to record from multiple brain regions simultaneously. The development of analytical tools for array data, however, lags behind these technological advances in hardware. In this paper, we present a method based on forward modeling for estimating current source density from electrophysiological signals recorded on a two-dimensional grid using multi-electrode rectangular arrays. This new method, which we call two-dimensional inverse Current Source Density (iCSD 2D), is based upon and extends our previous one- and three-dimensional techniques. We test several variants of our method, both on surrogate data generated from a collection of Gaussian sources, and on model data from a population of layer 5 neocortical pyramidal neurons. We also apply the method to experimental data from the rat subiculum. The main advantages of the proposed method are the explicit specification of its assumptions, the possibility to include system-specific information as it becomes available, the ability to estimate CSD at the grid boundaries, and lower reconstruction errors when compared to the traditional approach. These features make iCSD 2D a substantial improvement over the approaches used so far and a powerful new tool for the analysis of multielectrode array data. We also provide a free GUI-based MATLAB toolbox to analyze and visualize our test data as well as user datasets

Local Field Potential Modeling Predicts Dense Activation in Cerebellar Granule Cells Clusters under LTP and LTD Control

Local field-potentials (LFPs) are generated by neuronal ensembles and contain information about the activity of single neurons. Here, the LFPs of the cerebellar granular layer and their changes during long-term synaptic plasticity (LTP and LTD) were recorded in response to punctate facial stimulation in the rat in vivo. The LFP comprised a trigeminal (T) and a cortical (C) wave. T and C, which derived from independent granule cell clusters, co-varied during LTP and LTD. To extract information about the underlying cellular activities, the LFP was reconstructed using a repetitive convolution (ReConv) of the extracellular potential generated by a detailed multicompartmental model of the granule cell. The mossy fiber input patterns were determined using a Blind Source Separation (BSS) algorithm. The major component of the LFP was generated by the granule cell spike Na+ current, which caused a powerful sink in the axon initial segment with the source located in the soma and dendrites. Reproducing the LFP changes observed during LTP and LTD required modifications in both release probability and intrinsic excitability at the mossy fiber-granule cells relay. Synaptic plasticity and Golgi cell feed-forward inhibition proved critical for controlling the percentage of active granule cells, which was 11% in standard conditions but ranged from 3% during LTD to 21% during LTP and raised over 50% when inhibition was reduced. The emerging picture is that of independent (but neighboring) trigeminal and cortical channels, in which synaptic plasticity and feed-forward inhibition effectively regulate the number of discharging granule cells and emitted spikes generating “dense” activity clusters in the cerebellar granular layer

The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with >80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes

Translational considerations in injectable cell-based therapeutics for neurological applications: concepts, progress and challenges

Significant progress has been made during the past decade towards the clinical adoption of cell-based therapeutics. However, existing cell-delivery approaches have shown limited success, with numerous studies showing fewer than 5% of injected cells persisting at the site of injection within days of transplantation. Although consideration is being increasingly given to clinical trial design, little emphasis has been given to tools and protocols used to administer cells. The different behaviours of various cell types, dosing accuracy, precise delivery, and cell retention and viability post-injection are some of the obstacles facing clinical translation. For efficient injectable cell transplantation, accurate characterisation of cellular health post-injection and the development of standardised administration protocols are required. This review provides an overview of the challenges facing effective delivery of cell therapies, examines key studies that have been carried out to investigate injectable cell delivery, and outlines opportunities for translating these findings into more effective cell-therapy interventions

Nitrous oxide and methane emissions from a surface drip-irrigated system combined with fertilizer management

Drip-fertigated systems have variable distributions of water and nutrients in the soil, which influence soil microbial activity. Because there is a lack of data on greenhouse gas (GHG) fluxes for these systems, a field experiment comparing drip irrigation systems (fertigated and non-fertigated) was carried out in a melon crop. For the fertigated treatment, nitrogen (N) as NH4NO3 was dissolved in irrigation water and split into six applications (Fertigation treatment). In the non-fertigated soil (ANS treatment), granular NH4NO3 was incorporated homogeneously into the upper part of soil surface at planting. A control treatment without N fertilizer was also included. In order to evaluate the pattern of nitrous oxide (N2O) and methane (CH4), measurements were made at six different distances from the irrigation distributor point (dripper). An additional field experiment with N-15-labelled N fertilizer was carried out in parallel, with the aim of evaluating the contribution of nitrification and denitrification to the total N2O flux. Two different sources of N-15 were applied: (NH4NO3)-N-15 (20 at% excess N-15) ((NH4+)-N-15 treatment, TR1) and (NH4NO3)-N-15 (20 at% excess(15)N) ((NO3-)-N-15 treatment, TR2). Results indicated that both treatments (ANS and Fertigation) had small emission fluxes of N2O (< 0.1% of N applied). However, Fertigation produced larger emissions (175.3 g N2O-N ha(-1)) than ANS (90.1 g N2O N ha(-1)), with the pattern of N2O emission being strongly influenced by nitrification in both systems. Denitrification also contributed to emissions of (N2O)-N-15 but mainly on the day after fertilizer application in the Fertigation treatment. Methane fluxes were also affected by N fertilizer, with a decrease in the sink effect for CH4 when NH4+ was present in the soil