An interplay between a hydrogen atmosphere and dislocation characteristics in BCC Fe from time-averaged molecular dynamics.

The interplay between hydrogen and dislocations (e.g., core and elastic energies, and dislocation-dislocation interactions) has implications on hydrogen embrittlement but is poorly understood. Continuum models of hydrogen enhanced local plasticity have not considered the effect of hydrogen on dislocation core energies. Energy minimization atomistic simulations can only resolve dislocation core energies in hydrogen-free systems because hydrogen motion is omitted so hydrogen atmosphere formation can't occur. Additionally, previous studies focused more on face-centered-cubic than body-centered-cubic metals. Discrete dislocation dynamics studies of hydrogen-dislocation interactions assume isotropic elasticity, but the validity of this assumption isn't understood. We perform time-averaged molecular dynamics simulations to study the effect of hydrogen on dislocation energies in body-centered-cubic iron for several dislocation character angles. We see atmosphere formation and highly converged dislocation energies. We find that hydrogen reduces dislocation core energies but can increase or decrease elastic energies of isolated dislocations and dislocation-dislocation interaction energies depending on character angle. We also find that isotropic elasticity can be well fitted to dislocation energies obtained from simulations if the isotropic elastic constants are not constrained to their anisotropic counterparts. These results are relevant to ongoing efforts in understanding hydrogen embrittlement and provide a foundation for future work in this field.

Estimated salt intake and risk of atrial fibrillation in a prospective community-based cohort.

INTRODUCTION: Hypertension predisposes to atrial fibrillation (AF) - a major risk factor for ischaemic stroke. Since a high dietary salt consumption is associated with hypertension, we investigated the association between urinary sodium excretion as a marker for dietary sodium intake and risk of new-onset AF in community-dwelling adults. METHOD: The UK Biobank includes 40- to 69-year-old British residents recruited 2006-2010. Participants were divided into sex-specific quintiles according to 24-hour sodium excretion estimated based on spot samples with the Kawasaki equation. We excluded participants with AF at baseline. Cox regression adjusted for cardiovascular risk factors was used to assess associations with risk of AF, using the third quintile as reference. RESULTS: A total of 257 545 women and 215 535 men were included. During up to 10 years' follow-up, 2221 women and 3751 men were diagnosed with AF. There was a tendency for an increased risk of AF in the lowest and highest quintiles of estimated daily salt intake in both women and men. In the fully adjusted model, significant associations were seen amongst men in the lowest and highest quintiles of sodium excretion (hazard ratio, HRQv1 , 1.20; 95% CI, 1.08-1.32, P < 0.001, and HRQv5 1.15, 95% CI, 1.03-1.27, P = 0.011). CONCLUSION: We found evidence for a U-shaped association between estimated daily salt intake and AF risk amongst men. A suggestive J-shaped association in women was not statistically confirmed, but analyses were likely underpowered. Our results suggest that above a certain physiological minimum level progressively higher salt intake is associated with increasing risk of AF.

History-driven population structure and asymmetric gene flow in a recovering large carnivore at the rear-edge of its European range.

Understanding the mechanisms and patterns involved in population recoveries is challenging and important in shaping conservation strategies. We used a recovering rear-edge population of brown bears at their southernmost European range in Greece as a case study (2007-2010) to explore the recovery genetics at a species' distribution edge. We used 17 microsatellite and a mitochondrial markers to evaluate genetic structure, estimate effective population size and genetic diversity, and infer gene flow between the identified subpopulations. To understand the larger picture, we also compared the observed genetic diversity of each subpopulation with other brown bear populations in the region. The results indicate that the levels of genetic diversity for bears in western Greece are the lowest recorded in southeastern Europe, but still higher than those of other genetically depauperate bear populations. Apart from a complete separation of bear populations in eastern and western Greece, our results also indicate a considerable genetic sub-structuring in the West. As bear populations in Greece are now recovering, this structure is dissolving through a "recovery cascade" of asymmetric gene flow from South to North between neighboring subpopulations, mediated mainly by males. Our study outlines the importance of small, persisting populations, which can act as "stepping stones" that enable a rapid population expansion and recovery. This in turn makes their importance much greater than their numeric or genetic contribution to a species as a whole.

De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females.

Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X­linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss­of­function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole­exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X­linked dominant ID, and broadens the phenotype for KIAA2022 mutations.

Achieving elongated lesions employing cardiac cryoablation: a preclinical evaluation study.

Cardiac cryoablation applied for treating cardiac arrhythmias has shown promising results after intervention, particularly for the creation of elongated lesions. A model for simulating and assessing cryoablation interventions was developed, evaluated and validated with animal experiments. We employed two simulations of different freezing outlet settings for a loop shaped cryocatheter, applying Pennes heat equation for cardiac tissue. Our experiments demonstrated that an equidistantly spaced freezing outlet distribution of 5mm led to an improved formation of lesions, i.e., elongated lesions were observed throughout the transmural cardiac volume and on the epicardial structure. A complete transmural frozen lesion was not achieved with a freezing outlet distance of 10mm. These simulation results could be experimentally verified by morphological and histological examinations. Using our simulation model we were able to optimize the intervention procedure by predicting and assessing the freezing process. This should further increase the success rate of cardiac cryoablation in clinical interventions.

Cognitive Digital Biomarkers from Automated Transcription of Spoken Language.

BACKGROUND: Although patients with Alzheimer's disease and other cognitive-related neurodegenerative disorders may benefit from early detection, development of a reliable diagnostic test has remained elusive. The penetration of digital voice-recording technologies and multiple cognitive processes deployed when constructing spoken responses might offer an opportunity to predict cognitive status. OBJECTIVE: To determine whether cognitive status might be predicted from voice recordings of neuropsychological testing. DESIGN: Comparison of acoustic and (para)linguistic variables from low-quality automated transcriptions of neuropsychological testing (n = 200) versus variables from high-quality manual transcriptions (n = 127). We trained a logistic regression classifier to predict cognitive status, which was tested against actual diagnoses. SETTING: Observational cohort study. PARTICIPANTS: 146 participants in the Framingham Heart Study. MEASUREMENTS: Acoustic and either paralinguistic variables (e.g., speaking time) from automated transcriptions or linguistic variables (e.g., phrase complexity) from manual transcriptions. RESULTS: Models based on demographic features alone were not robust (area under the receiver-operator characteristic curve [AUROC] 0.60). Addition of clinical and standard acoustic features boosted the AUROC to 0.81. Additional inclusion of transcription-related features yielded an AUROC of 0.90. CONCLUSIONS: The use of voice-based digital biomarkers derived from automated processing methods, combined with standard patient screening, might constitute a scalable way to enable early detection of dementia.

Beta-1,3-glucanase from Delftia tsuruhatensis strain MV01 and its potential application in vinification.

During vinification microbial activities can spoil wine quality. As the wine-related lactic acid bacterium Pediococcus parvulus is able to produce slimes consisting of a ß-1,3-glucan, must and wine filtration can be difficult or impossible. In addition, the metabolic activities of several wild-type yeasts can also negatively affect wine quality. Therefore, there is a need for measures to degrade the exopolysaccharide from Pediococcus parvulus and to inhibit the growth of certain yeasts. We examined an extracellular ß-1,3-glucanase from Delftia tsuruhatensis strain MV01 with regard to its ability to hydrolyze both polymers, the ß-1,3-glucan from Pediococcus and that from yeast cell walls. The 29-kDa glycolytic enzyme was purified to homogeneity. It exhibited an optimal activity at 50°C and pH 4.0. The sequencing of the N terminus revealed significant similarities to ß-1,3-glucanases from different bacteria. In addition, the investigations indicated that this hydrolytic enzyme is still active under wine-relevant parameters such as elevated ethanol, sulfite, and phenol concentrations as well as at low pH values. Therefore, the characterized enzyme seems to be a useful tool to prevent slime production and undesirable yeast growth during vinification.

[A priori prediction of gentamicin peak concentrations: Use of a simple and practical tool]. / Prédiction a priori des concentrations en gentamicine au pic : utilisation d'un outil simple et pratique.

Aminoglycosides are concentration-dependent killing antibiotics, so that it is necessary to obtain elevated peak levels to reach the pharmacokinetic-pharmacodynamic objectives. Because of their nephrotoxicity, this class of antibiotics are frequently underprescribed and giving at an insufficient dosage when prescribed. That is why therapeutical drug monitoring (TDM) of aminoglycosides is recommanded to assess efficacy. Unfortunately, this TDM allows not a dosage adaptation on the first dose of aminoglycosides. The aim of the work was to elaborate a model using simple pharmacokinetics formulae to estimate gentamicin peak levels and so to propose an optimal a priori dosage on the first dose of gentamicin. The final model was tested out on 24 patients treated by gentamicin. The model was able to predict gentamicin peak levels in 62% of patients with a 10% precision and in 79% of patients with a 15% precision. Using this simple and practical tool might avoid under-dosage of gentamicin and clinical failure due to the selection of resistant bacteriae.

Synthetic biology as driver for the biologization of materials sciences.

Materials in nature have fascinating properties that serve as a continuous source of inspiration for materials scientists. Accordingly, bio-mimetic and bio-inspired approaches have yielded remarkable structural and functional materials for a plethora of applications. Despite these advances, many properties of natural materials remain challenging or yet impossible to incorporate into synthetic materials. Natural materials are produced by living cells, which sense and process environmental cues and conditions by means of signaling and genetic programs, thereby controlling the biosynthesis, remodeling, functionalization, or degradation of the natural material. In this context, synthetic biology offers unique opportunities in materials sciences by providing direct access to the rational engineering of how a cell senses and processes environmental information and translates them into the properties and functions of materials. Here, we identify and review two main directions by which synthetic biology can be harnessed to provide new impulses for the biologization of the materials sciences: first, the engineering of cells to produce precursors for the subsequent synthesis of materials. This includes materials that are otherwise produced from petrochemical resources, but also materials where the bio-produced substances contribute unique properties and functions not existing in traditional materials. Second, engineered living materials that are formed or assembled by cells or in which cells contribute specific functions while remaining an integral part of the living composite material. We finally provide a perspective of future scientific directions of this promising area of research and discuss science policy that would be required to support research and development in this field.

Using proximity extension proteomics assay to discover novel biomarkers associated with circulating leptin levels in patients with type 2 diabetes.

We aimed to discover novel associations between leptin and circulating proteins which could link leptin to the development of cardiovascular disease in patients with type 2 diabetes (T2DM). In a discovery phase, we investigated associations between 88 plasma proteins, assessed with a proximity extension assay, and plasma leptin in a cohort of middle-aged patients with T2DM. Associations passing the significance threshold of a False discovery rate of 5% (corresponding to p < 0.0017) were replicated in patients with T2DM in an independent cohort. We also investigated if proteins mediated the longitudinal association between plasma leptin and the incidence of major cardiovascular events (MACE). One protein, adipocyte fatty acid binding protein (A-FABP), was significantly associated with leptin in both the discovery phase [95% CI (0.06, 0.17) p = 0.00002] and the replication cohort [95% CI (0.12, 0.39) p = 0.0003]. Multiplicative interaction analyses in the two cohorts suggest a stronger association between A-FABP and leptin in men than in women. In longitudinal analyses, the association between leptin and MACE was slightly attenuated after adding A-FABP to the multivariate model. Our analysis identified a consistent association between leptin and A-FABP in two independent cohorts of patients with T2DM, particularly in men.Trial registration: ClinicalTrials.gov identifier NCT01049737.

Introgression as a likely cause of mtDNA paraphyly in two allopatric skippers (Lepidoptera: Hesperiidae).

Gene transfer between species during interspecific hybridization is a widely accepted reality in plants but is considered a relatively rare phenomenon among animals. Here we describe a unique case of mitochondrial DNA (mtDNA) paraphyly in the skipper genus, Erynnis, that involves well-diverged allopatric species. Using molecular evidence from both mitochondrial and nuclear genomes, we found high levels of intraspecific divergence in the mitochondrial genome within E. propertius (over 4% pair-wise sequence divergence) but no such differentiation in the nuclear genome. Sequence comparisons with related Erynnis suggest that past, but recent and infrequent introgression between E. propertius and E. horatius is the most reasonable explanation for the observed pattern of mtDNA paraphyly. This example of putative introgression highlights the complexity of mtDNA evolution and suggests that similar processes could be operating in other taxa that have not been extensively sampled. Our observations reinforce the importance of involving multiple genes with different modes of inheritance in the analysis of population history of congeneric taxa.

Reactive diffusion under Laplace tension.

Nanostructures such as nanospheres or nanowires may contain surfaces and interfaces of pronounced curvature. To investigate the impact of severe curvature on the kinetic of reactions, thin-film Al/Cu/Al and Cu/Al/Cu triple layers are deposited on tungsten tips of 25nm curvature radius. The thermal reaction of the layer structure is studied by atom probe tomography. Experiments demonstrate that the reaction rate depends significantly on the deposition sequence of metals. Interpretation of the observed reaction kinetics leads to the conclusion that under the influence of interfacial tension probably the two limiting cases of atomic transport, Darken and Nernst-Planck kinetics, are realized in dependence on the stacking sequence.

A finite element formulation for atrial tissue monolayer.

OBJECTIVES: Using computer models for the study of complex atrial arrhythmias such as atrial fibrillation is computationally demanding as long observation periods in the order of tens of seconds are required. A well established approach for reducing computational workload is to approximate the thin atrial walls by curved monolayers. On the other hand, the finite element method (FEM) is a well established approach to solve the underlying partial differential equations. METHODS: A generalized 2D finite element method (FEM) is presented which computes the corresponding stiffness and coupling matrix for arbitrarily shaped monolayers (ML). Compared to standard 2D FEM, only one additional coordinate transformation is required. This allows the use of existing FEM software with minor modifications. The algorithm was tested to simulate wave propagation in benchmark geometries and in a model of atrial anatomy. RESULTS: The ML model was able to simulate electric activation in curved tissue with anisotropic conductivity. Simulations in branching tissue yielded slightly different patterns when compared to a volumetric model with finite thickness. In the model of atrial anatomy the computed activation times for five different pacing protocols displayed a correlation of 0.88 compared to clinical data. CONCLUSIONS: The presented method provides a useful and easily implemented approach to model wave propagation in MLs with a few restrictions to volumetric models.

Fibrillatory conduction in branching atrial tissue--Insight from volumetric and monolayer computer models.

Increased local load in branching atrial tissue (muscle fibers and bundle insertions) influences wave propagation during atrial fibrillation (AF). This computer model study reveals two principal phenomena: if the branching is distant from the driving rotor (>19 mm), the load causes local slowing of conduction or wavebreaks. If the driving rotor is close to the branching, the increased load causes first a slow drift of the rotor towards the branching. Finally, the rotor anchors, and a stable, repeatable pattern of activation can be observed. Variation of the bundle geometry from a cylindrical, volumetric structure to a flat strip of a comparable load in a monolayer model changed the local activation sequence in the proximity of the bundle. However, the global behavior and the basic effects are similar in all models. Wavebreaks in branching tissue contribute to the chaotic nature of AF (fibrillatory conduction). The stabilization (anchoring) of driving rotors by branching tissue might contribute to maintain sustained AF.

Intein-mediated in vitro synthesis of lipidated Ras proteins.

Fully functional lipid-modified Ras proteins suitable for the study of Ras-membrane interactions and embodying exclusively native amide bonds can be synthesized in preparative amounts by means of Expressed Protein Ligation.

Protoporphyrin IX occurs naturally in colorectal cancers and their metastases.

Colorectal cancers exhibit a red fluorescence. The nature of the responsible fluorophore and its eventual diagnostic potential were investigated. Thirty-three consecutive colorectal resection specimen, 32 of which with histologically confirmed cancer, and a total of 1053 palpable mesenteric nodes were fluorimetrically characterized ex vivo. Furthermore, frozen material from 28 patients was analyzed, selected for the availability of primary tumor material and metastatic tissue, e.g., lymphatic and liver metastases from the same patient. Biochemical characterization was carried out through chemical extraction and reversed phase high-performance liquid chromatography. The fluorescence spectra of tissues, tissue extracts, and standard solutions of porphyrins were determined using a pulsed solid-state laser system for excitation and an imaging polychromator, together with an intensified CCD camera for time-delayed observation. Protoporphyrin IX (PpIX) was identified as the predominant fluorophore in primary tumors and their metastases. The fluorophore occurred in the absence of necrosis and in sterile locations. In untreated cases (n = 24), PpIX fluorescence discriminates metastatically involved lymph nodes from all other palpable nodes with a sensitivity of 62% at a specificity of 78% (P < 0.0001). After neoadjuvant treatment of rectal cancer, the PpIX fluorescence level of the primary tumors was reduced and a discrimination of lymph nodes based on PpIX-fluorescence was impossible. We conclude that colorectal cancer metastases accumulate diagnostic levels of endogenous PpIX as a result of a tumor-specific metabolic alteration.

[Obstetric outcomes after uterine compression suture for treatment of postpartum hemorrhage: Long-term monitoring of 40 cases]. / Devenir obstétrical après plicatures utérines dans le traitement de l'hémorragie de la délivrance : suivi à long terme de 40 cas.

OBJECTIVE: Uterine atony is the first cause of postpartum hemorrhage. In caesarean section, different techniques of uterine compression suture exist when uterotonic drugs fail. Their effectiveness is shown but little data on their effects on subsequent pregnancies are available. The aim of this work is analyze of the obstetrical long-term consequences after uterine compression suture. PATIENTS AND METHODS: This is a retrospective study of 40 cases of uterine compression suture performed in a level III maternity, between 2004 and 2010. The main objective is the evaluation of the obstetrical prognosis of subsequent pregnancies. The efficacy and safety of surgical techniques, according to their transfixing character or not, were analyzed. RESULTS: Eleven pregnancies after uterine compression suture were reported among 14 women whishing another pregnancy. The median time to be pregnant was 27 months (6-78 months). Nine pregnancies were conducted at term. One case of intrauterine growth restriction and a moderate prematurity at 32 weeks were observed. There was no significant difference in efficacy and early surgical complications according to the surgical technique; however, both infectious and ischemic complications were observed after transfixing compression suture. CONCLUSION: The obstetric prognosis after a uterine compression suture is kept. The transfixing techniques may cause more infectious and ischemic complications. An evaluation of surgical techniques depending on their transfixing, or not, character on a large cohort is necessary for the evaluation of the influence of the technique on fertility and postoperative complications.

Chronic anabolic-androgenic steroid treatment during adolescence increases anterior hypothalamic vasopressin and aggression in intact hamsters.

The present study examines the hypothesis that exposure to anabolic-androgenic steroids (AAS) during adolescent development predisposes hamsters to heightened levels of aggressive behavior by influencing the anterior hypothalamic-arginine vasopressin (AH-AVP) neural system. To test this, adolescent male hamsters (Mesocricetus auratus) were treated with high doses of AAS, tested for offensive aggression in the absence or presence of AH-AVP receptor antagonists, and then examined for changes in AH-AVP expression and neural organization. AAS exposure during adolescence significantly increased aggression intensity (number of attacks and bites) and initiation (latency to the first bite). Yet, only increases in aggression intensity were inhibited by AH-AVP receptor antagonism. Adolescent AAS-treated hamsters showed significant increases in AH-AVP fiber density and peptide content. However, no alterations in AH-AVP neuronal organization or mRNA expression were found. Together, these data suggest that adolescent AAS exposure increase aggression intensity by altering AH-AVP expression and activity, providing direct evidence for a causal role of AH-AVP expression and function in early onset AAS-stimulated aggression.

Induction of chromosomal aberrations by hypotonic culture conditions is independent of the S-phase in V79 hamster cells.

A deviation from physiological osmolality (300 mOsm/kg H2O) can lead to genotoxic effects. A 30-min treatment of V79 hamster cells with hypotonic sodium chloride of 60 mOsm/kg H2O or with diluted culture medium of the same osmolality induces extraordinarily high frequencies of chromosomal aberrations. In this study, multiple fixation times over a 24-hr period were used to identify cells in various stages of the cell cycle at the time of treatment and to find out whether or not hypotonic conditions are able to induce aberrations in all cell cycle stages. Because of the aberration pattern observed, it is suggested that hypotonic treatment acts as an S-independent agent, like X-rays or restriction endonucleases. Whether the aberrations originate from directly induced DNA damage or from a release of DNase after lysosomal breakdown is discussed.

Photophysical properties and photodynamic activity in vivo of some tetrapyrroles.

Some of the photophysical properties (stationary absorbance and fluorescence, fluorescence decay times and singlet oxygen quantum yields) of pheophorbide a, metal-free, ClAl-, Cu- and Mg-t-butyl-substituted phthalocyanines, metal-free, ClAl- and Cu-t-butyl-substituted naphthalocyanines and of a number of tetraphenylporphyrins (5,10,15,20-tetraphenylporphyrin, 5,10,15,20-tetra(m-hydroxyphenyl)porphyrin, 5,10,15,20-tetra(p-hydroxyphenyl)porphyrin) have been studied in comparison with hematoporphyrin IX in order to select potent photosensitizers for the photodynamic treatment of cancer. The photodynamic activity of these compounds was investigated using Lewis lung carcinoma in mice. As a consequence of the photophysical parameters (relatively short singlet state lifetimes, and high singlet oxygen quantum yields) the photodynamic activities of pheophorbide a, t-butyl-substituted ClAl-phthalocyanine and ClAl-naphthalocyanine were selected for study in greater detail. Under the conditions employed in the present study, pheophorbide a was found to be the most effective sensitizer, as judged from its strong absorption at the excitation wavelength as compared with the hematoporphyrin derivative and greater singlet oxygen quantum yield relative to the phthalocyanines and naphthalocyanines. The photodynamic activity was observed to be strongly dependent on the photophysical parameters of the compounds. The primary mechanism underlying the photodynamic activity of these sensitizers probably consists of energy transfer from the lowest triplet state of the dyes to molecular oxygen, resulting in the formation of singlet oxygen (type II of photosensitization).