► The proposed method aims at assessing small failure probabilities. ► The basic underlying concept is similar to subset simulation. ► A SVM surrogate is adaptively built at each threshold of the ...limit state function. ► The efficiency of the method is assessed on some challenging examples.
Estimating small probabilities of failure remains quite a challenging task in structural reliability when models are computationally demanding. FORM/SORM are very suitable solutions when applicable but, due to their inherent assumptions, they sometimes lead to incorrect results for problems involving for instance multiple design points and/or nonsmooth failure domains. Recourse to simulation methods could therefore be the only viable solution for these kinds of problems. However, a major shortcoming of simulation methods is that they require a large number of calls to the structural model, which may be prohibitive for industrial applications. This paper presents a new approach for estimating small failure probabilities by considering subset simulation proposed by S.-K. Au and J. Beck from the point of view of Support Vector Machine (SVM) classification. This approach referred as
2SMART (“
Two SMART”) is detailed and its efficiency, accuracy and robustness are assessed on three representative examples. A specific attention is paid to series system reliability and problems involving moderately large numbers of random variables.
Implementation of vapor/phase dosing of small molecule inhibitors (SMIs) in advanced atomic layer deposition (ALD) cycles is currently being considered for bottom-up fabrication by area-selective ...ALD. When SMIs are used, it can be challenging to completely block precursor adsorption due to the inhibitor size and the relatively short vapor/phase exposures. Two strategies for precursor blocking are explored: (i) physically covering precursor adsorption sites, i.e., steric shielding, and (ii) eliminating precursor adsorption sites from the surface, i.e., chemical passivation. In this work, it is determined whether steric shielding is enough for effective precursor blocking during area-selective ALD or whether chemical passivation is required as well. At the same time, we address why some ALD precursors are more difficult to block than others. To this end, the blocking of the Al precursor molecules trimethylaluminum (TMA), dimethylaluminum isopropoxide (DMAI), and tris(dimethylamino)aluminum (TDMAA) was studied by using acetylacetone (Hacac) as inhibitor. It was found that DMAI and TDMAA are more easily blocked than TMA because they adsorb on the same surface sites as Hacac, while TMA is also reactive with other surface sites. This work shows that chemical passivation plays a crucial role for precursor blocking in concert with steric shielding. Moreover, the reactivity of the precursor with the surface groups on the non-growth area dictates the effectiveness of blocking precursor adsorption.
Anisotropy is a good indicator of white matter fascicle macrostructure and organization but the interpretation of its changes with age remains difficult. The increase of WM fascicle fractional ...anisotropy with time and its relationship with WM fascicle volume have never been examined during childhood. We studied the maturation of associative WM fascicles during childhood using MR imaging-based DTI. We explored whether the fractional anisotropy increase of the main WM fascicles persists beyond the period of brain growth and is related to WM fascicle volume increase.
In a series of 25 healthy children, the fractional anisotropy and volume of 15 associative WM fascicles were calculated. Several regression linear mixed models were used to study maturation parameters (fractional anisotropy, volume, and total telencephalon volume) considered as dependent variables, while age and sex were independent variables (the variable identifying the different WM fascicles was considered as a repeated measure).
In children older than 8 years of age, WM fascicle fractional anisotropy increased with age (
value = .045) but not its volume (
value = .7) or the telencephalon volume (
value = .16). The time course of WM fascicle fractional anisotropy and volume suggested that each WM fascicle might follow a specific pattern of maturation.
The fractional anisotropy increase of several WM fascicles after 8 years of age may not result from an increase in WM fascicle volume. It might be the consequence of other developmental processes such as myelination.
Zinc co-crystallizes with insulin in dense core secretory granules, but its role in insulin biosynthesis, storage and secretion is unknown. In this study we assessed the role of the zinc transporter ...ZnT8 using ZnT8-knockout (ZnT8⁻/⁻) mice. Absence of ZnT8 expression caused loss of zinc release upon stimulation of exocytosis, but normal rates of insulin biosynthesis, normal insulin content and preserved glucose-induced insulin release. Ultrastructurally, mature dense core insulin granules were rare in ZnT8⁻/⁻ beta cells and were replaced by immature, pale insulin "progranules," which were larger than in ZnT8⁺/⁺ islets. When mice were fed a control diet, glucose tolerance and insulin sensitivity were normal. However, after high-fat diet feeding, the ZnT8⁻/⁻ mice became glucose intolerant or diabetic, and islets became less responsive to glucose. Our data show that the ZnT8 transporter is essential for the formation of insulin crystals in beta cells, contributing to the packaging efficiency of stored insulin. Interaction between the ZnT8⁻/⁻ genotype and diet to induce diabetes is a model for further studies of the mechanism of disease of human ZNT8 gene mutations.
Data mining and metagenomic analysis of 277 open reading frame sequences of bipartite RNA viruses of the genus
Nepovirus
, family
Secoviridae
, were performed, documenting how challenging it can be ...to unequivocally assign a virus to a particular species, especially those in subgroups A and C, based on some of the currently adopted taxonomic demarcation criteria. This work suggests a possible need for their amendment to accommodate pangenome information. In addition, we revealed a host-dependent structure of arabis mosaic virus (ArMV) populations at a cladistic level and confirmed a phylogeographic structure of grapevine fanleaf virus (GFLV) populations. We also identified new putative recombination events in members of subgroups A, B and C. The evolutionary specificity of some capsid regions of ArMV and GFLV that were described previously and biologically validated as determinants of nematode transmission was circumscribed
in silico
. Furthermore, a C-terminal segment of the RNA-dependent RNA polymerase of members of subgroup A was predicted to be a putative host range determinant based on statistically supported higher π (substitutions per site) values for GFLV and ArMV isolates infecting
Vitis
spp. compared with non-
Vitis
-infecting ArMV isolates. This study illustrates how sequence information obtained via high-throughput sequencing can increase our understanding of mechanisms that modulate virus diversity and evolution and create new opportunities for advancing studies on the biology of economically important plant viruses.
Although the proteins that read the gene regulatory code, transcription factors (TFs), have been largely identified, it is not well known which sequences TFs can recognize. We have analyzed the ...sequence-specific binding of human TFs using high-throughput SELEX and ChIP sequencing. A total of 830 binding profiles were obtained, describing 239 distinctly different binding specificities. The models represent the majority of human TFs, approximately doubling the coverage compared to existing systematic studies. Our results reveal additional specificity determinants for a large number of factors for which a partial specificity was known, including a commonly observed A- or T-rich stretch that flanks the core motifs. Global analysis of the data revealed that homodimer orientation and spacing preferences, and base-stacking interactions, have a larger role in TF-DNA binding than previously appreciated. We further describe a binding model incorporating these features that is required to understand binding of TFs to DNA.
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► High-resolution binding profiles representing most human transcription factors ► High-throughput SELEX can identify long and dimeric sites ► Full-length protein and DNA-binding domain specificities are similar ► Adjacent bases affect TF-DNA binding more than previously thought
High-throughput SELEX is used to determine high-resolution binding profiles representing most human transcription factors. Base-stacking interactions, and dimer orientation and spacing preferences, have a larger role in TF-DNA binding than previously appreciated.
The first example of direct structural characterization of polyaromatic ions by coupling a Fourier transform ion cyclotron resonance mass spectrometer with an infrared free-electron laser is ...presented. Measurement of the IR spectra of selectively prepared ionic reactive intermediates is allowed by the association of the high peak power and wide tunability of the laser with the flexibility of the spectrometer, where several mass selection and ion reaction steps can be combined, as demonstrated in the case of iron cation complexes of hydrocarbons. The present experimental setup opens the way to understanding chemical reaction paths.
The Laboratoire National des Champs Magnétiques Intenses (LNCMI) is a French host facility for experiments in high magnetic fields. Internal research is carried out in the lab and experimental time ...is allocated to external researchers. The LNCMI is a founding member of the European Magnetic Field Laboratory (EMFL) with the Hochfeld-Magnetlabor in Dresden (HLD) and the High Field Magnet Laboratory in Nijmegen (HFML). While static fields up to 37 T are produced in Grenoble, the Toulouse facility is dedicated to the generation of pulsed magnetic fields. It offers 98.8 T nondestructively and 209 T with a semi-destructive Megagauss installation. We focus here on the nondestructive activities. All the electromagnets that generate these high fields and their associated capacitor banks are developed in the laboratory. Here, we present the developments realized during the last five years with the complete reconstruction of the main capacitor banks of the laboratory.
Cadmium is an environmental pollutant well known for its nephrotoxic effects. Nevertheless, mechanisms underlying nephrotoxicity continue to be elucidated. MicroRNAs (miRNAs) have emerged in recent ...years as modulators of xenobiotic-induced toxicity. In this context, our study aimed at elucidating whether miRNAs are involved in renal proximal tubular toxicity induced by cadmium exposure. We showed that cadmium exposure, in 2 distinct renal proximal tubular cell models (renal proximal tubular epithelial cell RPTEC/human telomerase reverse transcriptase hTERT and human kidney-2), resulted in cytotoxicity associated with morphological changes, overexpression of renal injury markers, and induction of apoptosis and inflammation processes. Cadmium exposure also resulted in miRNA modulation, including the significant upregulation of 38 miRNAs in RPTEC/hTERT cells. Most of these miRNAs are known to target genes whose coding proteins are involved in oxidative stress, inflammation, and apoptosis, leading to tissue remodeling. In conclusion, this study provides a list of dysregulated miRNAs which may play a role in the pathophysiology of cadmium-induced kidney damages and highlights promising cadmium molecular biomarkers that warrants to be further evaluated.
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