Characterization of OSL dosimeters used at the ELI-beamlines laser-driven accelerator facility.

The Extreme Light Infrastructure (ELI) Beamlines laser-driven accelerator facility is set to operate the most intense non-military laser system in the world, with ultra-high power up to 10 PW, concentrated plasma intensities of up to 1024W cm-2, and ultra-short laser pulses of the order of few femtoseconds. A robust and redundant radiation monitoring system is in place to minimise risks to personnel and general public. Beryllium oxide optically stimulated luminescence (BeO-OSL) detectors are used to monitor radiation levels in the experimental building and surrounding grounds. In fact, in recent years, BeO-OSL have become an increasingly more popular choice for personal and environmental dosimetry. At ELI Beamlines, an exhaustive and thorough characterization process of the BeO-OSLs is in place. Dosimeter responses are studied as a function of delivered air kerma and photon energies. Calibration curves are calculated. Results from the latest calibration campaign are presented.

In Silico implementation of evolutionary paradigm in therapy design: Towards anti-cancer therapy as Darwinian process.

In here presented in silico study we suggest a way how to implement the evolutionary principles into anti-cancer therapy design. We hypothesize that instead of its ongoing supervised adaptation, the therapy may be constructed as a self-sustaining evolutionary process in a dynamic fitness landscape established implicitly by evolving cancer cells, microenvironment and the therapy itself. For these purposes, we replace a unified therapy with the 'therapy species', which is a population of heterogeneous elementary therapies, and propose a way how to turn the toxicity of the elementary therapy into its fitness in a way conforming to evolutionary causation. As a result, not only the therapies govern the evolution of different cell phenotypes, but the cells' resistances govern the evolution of the therapies as well. We illustrate the approach by the minimalistic ad hoc evolutionary model. Its results indicate that the resistant cells could bias the evolution towards more toxic elementary therapies by inhibiting the less toxic ones. As the evolutionary causation of cancer drug resistance has been intensively studied for a few decades, we refer to cancer as a special case to illustrate purely theoretical analysis.

Crystal structure of a xylulose 5-phosphate phosphoketolase. Insights into the substrate specificity for xylulose 5-phosphate.

Phosphoketolases (PK) are TPP-dependent enzymes which play essential roles in carbohydrate metabolism of numerous bacteria. Depending on the substrate specificity PKs can be subdivided into xylulose 5-phosphate (X5P) specific PKs (XPKs) and PKs which accept both X5P and fructose 6-phosphate (F6P) (XFPKs). Despite their key metabolic importance, so far only the crystal structures of two XFPKs have been reported. There are no reported structures for any XPKs and for any complexes between PK and substrate. One of the major unknowns concerning PKs mechanism of action is related to the structural determinants of PKs substrate specificity for X5P or F6P. We report here the crystal structure of XPK from Lactococcus lactis (XPK-Ll) at 2.1 Šresolution. Using small angle X-ray scattering (SAXS) we proved that XPK-Ll is a dimer in solution. Towards better understanding of PKs substrate specificity, we performed flexible docking of TPP-X5P and TPP-F6P on crystal structures of XPK-Ll, two XFPKs and transketolase (TK). Calculated structure-based binding energies consistently support XPK-Ll preference for X5P. Analysis of structural models thus obtained show that substrates adopt moderately different conformation in PKs active sites following distinct networks of polar interactions. Based on the here reported structure of XPK-Ll we propose the most probable amino acid residues involved in the catalytic steps of reaction mechanism. Altogether our results suggest that PKs substrate preference for X5P or F6P is the outcome of a fine balance between specific binding network and dissimilar catalytic residues depending on the enzyme (XPK or XFPK) - substrate (X5P or F6P) couples.

Interaction of Pure Marangoni Convection with a Propagating Reactive Interface under Microgravity.

A reactive interface in the form of an autocatalytic reaction front propagating in a bulk phase can generate a dynamic contact line upon reaching the free surface when a surface tension gradient builds up due to the change in chemical composition. Experiments in microgravity evidence the existence of a self-organized autonomous and localized coupling of a pure Marangoni flow along the surface with the reaction in the bulk. This dynamics results from the advancement of the contact line at the surface that acts as a moving source of the reaction, leading to the reorientation of the front propagation. Microgravity conditions allow one to isolate the transition regime during which the surface propagation is enhanced, whereas diffusion remains the main mode of transport in the bulk with negligible convective mixing, a regime typically concealed on Earth because of buoyancy-driven convection.

A new conceptual framework for the therapy by optimized multidimensional pulses of therapeutic activity. The case of multiple myeloma model.

We developed simulation methodology to assess eventual therapeutic efficiency of exogenous multiparametric changes in a four-component cellular system described by the system of ordinary differential equations. The method is numerically implemented to simulate the temporal behavior of a cellular system of multiple myeloma cells. The problem is conceived as an inverse optimization task where the alternative temporal changes of selected parameters of the ordinary differential equations represent candidate solutions and the objective function quantifies the goals of the therapy. The system under study consists of two main cellular components, tumor cells and their cellular environment, respectively. The subset of model parameters closely related to the environment is substituted by exogenous time dependencies - therapeutic pulses combining continuous functions and discrete parameters subordinated thereafter to the optimization. Synergistic interaction of temporal parametric changes has been observed and quantified whereby two or more dynamic parameters show effects that absent if either parameter is stimulated alone. We expect that the theoretical insight into unstable tumor growth provided by the sensitivity and optimization studies could, eventually, help in designing combination therapies.

Peristalticity-driven banded chemical garden.

Complex structures in nature are often formed by self-assembly. In order to mimic the formation, to enhance the production, or to modify the structures, easy-to-use methods are sought to couple engineering and self-assembly. Chemical-garden-like precipitation reactions are frequently used to study such couplings because of the intrinsic chemical and hydrodynamic interplays. In this work, we present a simple method of applying periodic pressure fluctuations given by a peristaltic pump which can be used to achieve regularly banded precipitate membranes in the copper-phosphate system.

Vitamin D deficiency and seasonal variation over the years in São Paulo, Brazil.

Brazil is a tropical/subtropical geographic area with elevated ultraviolet (UV) radiation. We report very high prevalence of vitamin D deficiency in a large database of Brazilian subjects and show seasonal and reciprocal relationship between vitamin D and parathyroid hormone (PTH) over the years in this tropical area. INTRODUCTION: We aim to examine the prevalence of vitamin D deficiency, characterize the temporal relationship between 25-hydroxyvitamin D levels (25(OH)D) and intact PTH (iPTH) according to seasons, and investigate potential associations between 25(OH)D levels and extra-skeletal outcomes in a Brazilian population. METHODS: We retrospectively determined population weekly mean concentrations of unpaired 25(OH)D and iPTH using 39,004 laboratory results of Brazilian individuals of both genders aged 2 to 95 years. The 25(OH)D and iPTH distributions were normalized, and the means fit with a sinusoidal function. Potential associations between 25(OH)D serum levels and inflammatory markers, fasting glucose, HbA1c and Homeostasis Model Assessment index (HOMA) were examined. RESULTS: Of the samples, 33.9 % had 25(OH)D serum concentrations lower than 20 ng/mL, while the vast majority (70.7 %) were found to be vitamin D deficient or insufficient (<30 ng/mL). Vitamin D deficiency was significantly higher during the winter as compared to the summer (38.4 % <20 ng/mL and 75.5 % <30 ng/mL versus 23.3 % <20 ng/mL and 62.5 % <30 ng/mL, respectively; p < 0.001). Seasonal variation was observed for both 25(OH)D and iPTH. 25(OH)D peaks occurred in March and troughs in September. iPTH levels showed an inverted pattern of peaks and troughs with a delay of 1 ± 5 week. 25(OH)D was significantly associated with inflammatory markers but not with glucose homeostasis. CONCLUSIONS: A sinusoidal interrelationship has been detected between vitamin D and PTH in this tropical population. A large percentage of the individuals showed vitamin D deficiency. Public health strategies are needed to better understand and manage this very high and apparently contradictory prevalence of vitamin D deficiency.

Expert system for predicting reaction conditions: the Michael reaction case.

A generic chemical transformation may often be achieved under various synthetic conditions. However, for any specific reagents, only one or a few among the reported synthetic protocols may be successful. For example, Michael ß-addition reactions may proceed under different choices of solvent (e.g., hydrophobic, aprotic polar, protic) and catalyst (e.g., Brønsted acid, Lewis acid, Lewis base, etc.). Chemoinformatics methods could be efficiently used to establish a relationship between the reagent structures and the required reaction conditions, which would allow synthetic chemists to waste less time and resources in trying out various protocols in search for the appropriate one. In order to address this problem, a number of 2-classes classification models have been built on a set of 198 Michael reactions retrieved from literature. Trained models discriminate between processes that are compatible and respectively processes not feasible under a specific reaction condition option (feasible or not with a Lewis acid catalyst, feasible or not in hydrophobic solvent, etc.). Eight distinct models were built to decide the compatibility of a Michael addition process with each considered reaction condition option, while a ninth model was aimed to predict whether the assumed Michael addition is feasible at all. Different machine-learning methods (Support Vector Machine, Naive Bayes, and Random Forest) in combination with different types of descriptors (ISIDA fragments issued from Condensed Graphs of Reactions, MOLMAP, Electronic Effect Descriptors, and Chemistry Development Kit computed descriptors) have been used. Models have good predictive performance in 3-fold cross-validation done three times: balanced accuracy varies from 0.7 to 1. Developed models are available for the users at http://infochim.u-strasbg.fr/webserv/VSEngine.html . Eventually, these were challenged to predict feasibility conditions for ∼50 novel Michael reactions from the eNovalys database (originally from patent literature).

Will we ever be able to accurately predict solubility?

Accurate prediction of thermodynamic solubility by machine learning remains a challenge. Recent models often display good performances, but their reliability may be deceiving when used prospectively. This study investigates the origins of these discrepancies, following three directions: a historical perspective, an analysis of the aqueous solubility dataverse and data quality. We investigated over 20 years of published solubility datasets and models, highlighting overlooked datasets and the overlaps between popular sets. We benchmarked recently published models on a novel curated solubility dataset and report poor performances. We also propose a workflow to cure aqueous solubility data aiming at producing useful models for bench chemist. Our results demonstrate that some state-of-the-art models are not ready for public usage because they lack a well-defined applicability domain and overlook historical data sources. We report the impact of factors influencing the utility of the models: interlaboratory standard deviation, ionic state of the solute and data sources. The herein obtained models, and quality-assessed datasets are publicly available.

Ca2+-dependent proteolysis of junctophilin-1 and junctophilin-2 in skeletal and cardiac muscle.

Excessive increases in intracellular [Ca(2+)] in skeletal muscle fibres cause failure of excitation-contraction coupling by disrupting communication between the dihydropyridine receptors in the transverse tubular system and the Ca(2+) release channels (RyRs) in the sarcoplasmic reticulum (SR), but the exact mechanism is unknown. Previous work suggested a possible role of Ca(2+)-dependent proteolysis in this uncoupling process but found no proteolysis of the dihydropyridine receptors, RyRs or triadin. Junctophilin-1 (JP1; ∼90 kDa) stabilizes close apposition of the transverse tubular system and SR membranes in adult skeletal muscle; its C-terminal end is embedded in the SR and its N-terminal associates with the transverse tubular system membrane. Exposure of skeletal muscle homogenates to precisely set [Ca(2+)] revealed that JP1 undergoes Ca(2+)-dependent proteolysis over the physiological [Ca(2+)] range in tandem with autolytic activation of endogenous µ-calpain. Cleavage of JP1 occurs close to the C-terminal, yielding a ∼75 kDa diffusible fragment and a fixed ∼15 kDa fragment. Depolarization-induced force responses in rat skinned fibres were abolished following 1 min exposure to 40 µm Ca(2+), with accompanying loss of full-length JP1. Supraphysiological stimulation of rat skeletal muscle in vitro by repeated tetanic stimulation in 30 mm caffeine also produced marked proteolysis of JP1 (and not RyR1). In dystrophic mdx mice, JP1 proteolysis is seen in limb muscles at 4 and not at 10 weeks of age. Junctophilin-2 in cardiac and skeletal muscle also undergoes Ca(2+)-dependent proteolysis, and junctophilin-2 levels are reduced following cardiac ischaemia-reperfusion. Junctophilin proteolysis may contribute to skeletal muscle weakness and cardiac dysfunction in a range of circumstances.

Time dynamics of the dose deposited by relativistic ultra-short electron beams.

Ultra-short electron beams are used as ultra-fast radiation source for radiobiology experiments aiming at very high energy electron beams (VHEE) radiotherapy with very high dose rates. Laser plasma accelerators are capable of producing electron beams as short as 1 fs and with tunable energy from few MeV up to multi-GeV with compact footprint. This makes them an attractive source for applications in different fields, where the ultra-short (fs) duration plays an important role. The time dynamics of the dose deposited by electron beams with energies in the range 50-250 MeV have been studied and the results are presented here. The results set a quantitative limit to the maximum dose rate at which the electron beams can impart dose.

Diffusion in liquid mixtures.

The understanding of transport and mixing in fluids in the presence and in the absence of external fields and reactions represents a challenging topic of strategic relevance for space exploration. Indeed, mixing and transport of components in a fluid are especially important during long-term space missions where fuels, food and other materials, needed for the sustainability of long space travels, must be processed under microgravity conditions. So far, the processes of transport and mixing have been investigated mainly at the macroscopic and microscopic scale. Their investigation at the mesoscopic scale is becoming increasingly important for the understanding of mass transfer in confined systems, such as porous media, biological systems and microfluidic systems. Microgravity conditions will provide the opportunity to analyze the effect of external fields and reactions on optimizing mixing and transport in the absence of the convective flows induced by buoyancy on Earth. This would be of great practical applicative relevance to handle complex fluids under microgravity conditions for the processing of materials in space.

Detection and treatment of spinal CSF leaks in idiopathic intracranial hypotension.

INTRODUCTION: This study aimed to evaluate the diagnostic imaging findings and treatment results of patients with idiopathic intracranial hypotension (IIH) due to cerebrospinal fluid (CSF) leaks. METHODS: Between February 2009 and April 2012, 26 IIH patients (15 men, median age 49 years) presenting with orthostatic headache (n = 20) and/or with spontaneous subdural effusions or subarachnoid hemorrhage (n = 19) were enrolled. Twenty-three patients underwent a whole spine CT and MRI myelography, starting 45 min after the intrathecal injection of 9 cc of iomeprol (Imeron 300 M) and 1 cc of gadobutrolum (Gadovist). Three patients only underwent MR myelography after intrathecal gadobutrolum injection. Adjacent to the level(s) of the detected CSF leak(s) along the nerve roots, 20 cc of fresh venous blood with 0.5 cc Gadovist was injected epidurally (blood patch, BP). The distribution of the BP was visualized by MRI the following day. Treatment results were evaluated clinically and by myelography 2 weeks after the application of the BP. Retreatment was offered to patients with persistent symptoms and continued CSF leakage. RESULTS: CSF leaks were detected at the cervical (n = 12), thoracic (n = 25), or lumbar (n = 21) spine. In 23 patients, more than one spinal segment was affected. One patient refused treatment. BP were applied in one (n = 9) or several (n = 16) levels. Clinical and/or radiological improvement was achieved after one (n = 16), two (n = 5), three (n = 3), or five (n = 1) BPs. CONCLUSION: CT and MRI myelography allow the reliable detection of spinal CSF leaks. The targeted and eventually repeated epidural BP procedure is a safe and efficacious treatment.

First observation of two hyperfine transitions in antiprotonic He.

We report on the first experimental results for microwave spectroscopy of the hyperfine structure of p¯3He+. Due to the helium nuclear spin, p¯3He+ has a more complex hyperfine structure than p¯4He+, which has already been studied before. Thus a comparison between theoretical calculations and the experimental results will provide a more stringent test of the three-body quantum electrodynamics (QED) theory. Two out of four super-super-hyperfine (SSHF) transition lines of the (n,L)=(36,34) state were observed. The measured frequencies of the individual transitions are 11.12559(14) GHz and 11.15839(18) GHz, less than 1 MHz higher than the current theoretical values, but still within their estimated errors. Although the experimental uncertainty for the difference of these frequencies is still very large as compared to that of theory, its measured value agrees with theoretical calculations. This difference is crucial to be determined because it is proportional to the magnetic moment of the antiproton.

Autoignition temperature: comprehensive data analysis and predictive models.

Here we report a new predictive model for autoignition temperature (AIT), an important physical parameter widely used to assess potential safety hazards of combustible materials. Available structure-AIT data extracted from different sources were critically analysed. Support vector regression (SVR) models on different data subsets were built in order to identify a reliable compound set on which a realistic model could be built. This led to a selection of the dataset containing 875 compounds annotated with AIT values. The thereupon-based SVR model performs reasonably well in cross-validation with the determination coefficient r 2 = 0.77 and mean absolute error MAE = 37.8°C. External validation on 20 industrial compounds missing in the training set confirmed its good predictive power (MAE = 28.7°C).

Modelling of ready biodegradability based on combined public and industrial data sources.

The European Registration, Evaluation, Authorization and Restriction of Chemical Substances Regulation, requires marketed chemicals to be evaluated for Ready Biodegradability (RB), considering in silico prediction as valid alternative to experimental testing. However, currently available models may not be relevant to predict compounds of industrial interest, due to accuracy and applicability domain restriction issues. In this work, we present a new and extended RB dataset (2830 compounds), issued by the merging of several public data sources. It was used to train classification models, which were externally validated and benchmarked against already-existing tools on a set of 316 compounds coming from the industrial context. New models showed good performances in terms of predictive power (Balance Accuracy (BA) = 0.74-0.79) and data coverage (83-91%). The Generative Topographic Mapping approach identified several chemotypes and structural motifs unique to the industrial dataset, highlighting for which chemical classes currently available models may have less reliable predictions. Finally, public and industrial data were merged into global dataset containing 3146 compounds. This is the biggest dataset reported in the literature so far, covering some chemotypes absent in the public data. Thus, predictive model developed on the Global dataset has larger applicability domain than the existing ones.

Teosinte (Zea mays ssp parviglumis) growth and transcriptomic response to weed stress identifies similarities and differences between varieties and with modern maize varieties.

Transcriptomic responses of plants to weed presence gives insight on the physiological and molecular mechanisms involved in the stress response. This study evaluated transcriptomic and morphological responses of two teosinte (Zea mays ssp parviglumis) (an ancestor of domesticated maize) lines (Ames 21812 and Ames 21789) to weed presence and absence during two growing seasons. Responses were compared after 6 weeks of growth in Aurora, South Dakota, USA. Plant heights between treatments were similar in Ames 21812, whereas branch number decreased when weeds were present. Ames 21789 was 45% shorter in weedy vs weed-free plots, but branch numbers were similar between treatments. Season-long biomass was reduced in response to weed stress in both lines. Common down-regulated subnetworks in weed-stressed plants were related to light, photosynthesis, and carbon cycles. Several unique response networks (e.g. aging, response to chitin) and gene sets were present in each line. Comparing transcriptomic responses of maize (determined in an adjacent study) and teosinte lines indicated three common gene ontologies up-regulated when weed-stressed: jasmonic acid response/signaling, UDP-glucosyl and glucuronyltransferases, and quercetin glucosyltransferase (3-O and 7-O). Overall, morphologic and transcriptomic differences suggest a greater varietal (rather than a conserved) response to weed stress, and implies multiple responses are possible. These findings offer insights into opportunities to define and manipulate gene expression of several different pathways of modern maize varieties to improve performance under weedy conditions.

Precipitation pattern formation in the copper(II) oxalate system with gravity flow and axial symmetry.

Chemical systems that are far from thermodynamic equilibrium may form complex temporal and spatiotemporal structures. In our paper, we present unusual precipitation patterns that have been observed in the system of Cu(II)-oxalate. Starting with a pellet of copper sulfate immersed in or by pumping copper sulfate solution into a horizontal layer of sodium oxalate solution, we have observed the formation of a precipitate ring and an array of radially oriented thin fingers. The development of these patterns is related to the internal structure of the different crystals, the gravity flow, and the circular symmetry of the experimental arrangement.

Pressure oscillations in a chemical garden.

When soluble metal salts are placed in a silicate solution, chemical gardens grow. These gardens are treelike structures formed of long thin hollow tubes. The growth is driven by the increase in internal pressure from osmosis. One particular case is examined here, calcium chloride in a solution of sodium trisilicate. We directly measure the internal pressure of a silicate garden as it grows via a series of relaxation oscillations. From these observations we deduce the stresses in the membrane and discuss how they influence the growth of tubes. Also we estimate the critical stress and the average Young's modulus for the silicate garden's membrane.

Influence of thermal effects on buoyancy-driven convection around autocatalytic chemical fronts propagating horizontally.

The spatiotemporal dynamics of vertical autocatalytic fronts traveling horizontally in thin solution layers closed to the air can be influenced by buoyancy-driven convection induced by density gradients across the front. We perform here a combined experimental and theoretical study of the competition between solutal and thermal effects on such convection. Experimentally, we focus on the antagonistic chlorite-tetrathionate reaction for which solutal and thermal contributions to the density jump across the front have opposite signs. We show that in isothermal conditions the heavier products sink below the lighter reactants, providing an asymptotic constant finger shape deformation of the front by convection. When thermal effects are present, the hotter products, on the contrary, climb above the reactants for strongly exothermic conditions. These various observations as well as the influence of the relative weight of the solutal and thermal effects and of the thickness of the solution layer on the dynamics are discussed in terms of a two-dimensional reaction-diffusion-convection model parametrized by a solutal R(C) and a thermal R(T) Rayleigh number.