218 research outputs found
Nonlinear Statistical Filtering and Applications to Segregation in Steels from Microprobe Images
Microprobe images of solidification studies are well known to be subject to a Poisson noise. That is, the radiation count at a pixel x for a certain element may be considered to be an observation of a Poisson random variable whose parameter is equal to the true chemical concentration of the element at x. By modeling the image as a random function, we are able to use geostatistical techniques to perform various filtering operations. This filtering of the image itself may be done using linear kriging. For explicitely nonlinear problems such as the estimation of the underlying histogram of the noisy image, or the estimation of the probability that locally the concentration passes a certain value (this probability is needed for segregation studies), it is usually not possible to use linear techniques as they give biased results. For this reason, we applied the nonlinear technique of Disjunctive Kriging to these nonlinear problems. Linear kriging needs only second order statistical models ( covariance functions or variograms) while disjunctive kriging needs bivariate distribution models. This approach 1s illustrated by examples of filtering of various X-ray mappings in steel samples
On arbitrages arising from honest times
In the context of a general continuous financial market model, we study
whether the additional information associated with an honest time gives rise to
arbitrage profits. By relying on the theory of progressive enlargement of
filtrations, we explicitly show that no kind of arbitrage profit can ever be
realised strictly before an honest time, while classical arbitrage
opportunities can be realised exactly at an honest time as well as after an
honest time. Moreover, stronger arbitrages of the first kind can only be
obtained by trading as soon as an honest time occurs. We carefully study the
behavior of local martingale deflators and consider no-arbitrage-type
conditions weaker than NFLVR.Comment: 25 pages, revised versio
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Cross-resistance to elvitegravir and dolutegravir in 502 patients failing on raltegravir: a French national study of raltegravir-experienced HIV-1-infected patients
OBJECTIVES: The objectives of this study were to determine the prevalence and patterns of resistance to integrase strand transfer inhibitors (INSTIs) in patients experiencing virological failure on raltegravir-based ART and the impact on susceptibility to INSTIs (raltegravir, elvitegravir and dolutegravir).
PATIENTS AND METHODS: Data were collected from 502 treatment-experienced patients failing a raltegravir-containing regimen in a multicentre study. Reverse transcriptase, protease and integrase were sequenced at failure for each patient. INSTI resistance-associated mutations investigated were those included in the last ANRS genotypic algorithm (v23).
RESULTS: Among the 502 patients, at failure, median baseline HIV-1 RNA (viral load) was 2.9 log10 copies/mL. Patients had been previously exposed to a median of five NRTIs, one NNRTI and three PIs. Seventy-one percent harboured HIV-1 subtype B and the most frequent non-B subtype was CRF02_AG (13.3%). The most frequent mutations observed were N155H/S (19.1%), Q148G/H/K/R (15.4%) and Y143C/G/H/R/S (6.7%). At failure, viruses were considered as fully susceptible to all INSTIs in 61.0% of cases, whilst 38.6% were considered as resistant to raltegravir, 34.9% to elvitegravir and 13.9% to dolutegravir. In the case of resistance to raltegravir, viruses were considered as susceptible to elvitegravir in 11% and to dolutegravir in 64% of cases. High HIV-1 viral load at failure (P < 0.001) and low genotypic sensitivity score of the associated treatment with raltegravir (P < 0.001) were associated with the presence of raltegravir-associated mutations at failure. Q148 mutations were selected more frequently in B subtypes versus non-B subtypes (P = 0.004).
CONCLUSIONS: This study shows that a high proportion of viruses remain susceptible to dolutegravir in the case of failure on a raltegravir-containing regimen
Mapping an atlas of tissue-specific drosophila melanogaster metabolomes by high resolution mass spectrometry
Metabolomics can provide exciting insights into organismal function, but most work on simple models has focussed on the whole organism metabolome, so missing the contributions of individual tissues. Comprehensive metabolite profiles for ten tissues from adult Drosophila melanogaster were obtained here by two chromatographic methods, a hydrophilic interaction (HILIC) method for polar metabolites and a lipid profiling method also based on HILIC, in combination with an Orbitrap Exactive instrument. Two hundred and forty two polar metabolites were putatively identified in the various tissues, and 251 lipids were observed in positive ion mode and 61 in negative ion mode. Although many metabolites were detected in all tissues, every tissue showed characteristically abundant metabolites which could be rationalised against specific tissue functions. For example, the cuticle contained high levels of glutathione, reflecting a role in oxidative defence; the alimentary canal (like vertebrate gut) had high levels of acylcarnitines for fatty acid metabolism, and the head contained high levels of ether lipids. The male accessory gland uniquely contained decarboxylated S-adenosylmethionine. These data thus both provide valuable insights into tissue function, and a reference baseline, compatible with the FlyAtlas.org transcriptomic resource, for further metabolomic analysis of this important model organism, for example in the modelling of human inborn errors of metabolism, aging or metabolic imbalances such as diabetes
Molecular and functional expression of anion exchangers in cultured normal human nasal epithelial cells
AIMS:
Anions have an important role in the regulation of airway surface liquid (ASL) volume, viscosity and pH. However, functional localization and regulation of anion exchangers (AEs) have not been clearly described. The aim of this study was to investigate the regulation of AE mRNA expression level in accordance with mucociliary differentiation and the functional expression of AEs cultured normal human nasal epithelial (NHNE) cells.
METHODS:
Nasal mucosal specimens from three patients are obtained and serially cultured cells are subjected to morphological examinations, RT-PCR, Western blot analysis and immunocytochemistry. AE activity is assessed by pHi measurements.
RESULTS:
Expression of ciliated cells on the apical membrane and expression of MUC5AC, a marker of mucous differentiation, increased with time. AE2 and SLC26A4 mRNA expression decreased as mucociliary differentiation progressed, and AE4, SLC26A7 and SLC26A8 mRNA expression increased on the 14th and 28th day after confluence. Accordingly, AE4 protein expression also progressively increased. AE activity in 100 mM K(+) buffer solutions was nearly twofold higher than that in 5 mM K(+) buffer solutions. Moreover, only luminal AE activity increased about fourfold over the control in the presence of 5 microM forskolin. In the presence of 100 microM adenosine-5'-triphosphate (ATP) which evokes intracellular calcium signalling through activation of purinergic receptors, only luminal AE activity was again significantly increased. On the other hand, 500 microM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of most SLC4 and SLC26AE isoforms, nearly abolished AE activity in both luminal and basolateral membranes. We found that AE activity was affected by intracellular cAMP and calcium signalling in the luminal membrane and was DIDS-sensitive in both membranes of cultured NHNE cells.
CONCLUSION:
Our findings through molecular and functional studies using cultured NHNE cells suggest that AEs may have an important role in the regulation of ASL.ope
Chronic Cyclodextrin Treatment of Murine Niemann-Pick C Disease Ameliorates Neuronal Cholesterol and Glycosphingolipid Storage and Disease Progression
BACKGROUND:Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs). While current treatment therapies are limited, a few drugs tested in Npc1(-/-) mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ) and allopregnanolone, we noted increased lifespan for Npc1(-/-) mice receiving only 2-hydroxypropyl-beta-cyclodextrin (CD), the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit. METHODOLOGY/PRINCIPAL FINDINGS:Administration of CD to Npc1(-/-) mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS) type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/-) mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage. CONCLUSIONS/SIGNIFICANCE:Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/-) and Npc2(-/-) mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s) by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis
Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma
Objectives The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. Results On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P = 0.0455) and T215Y (P = 0.0455). Conclusions In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performe
Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children
Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C
Computational Homogenization of Architectured Materials
Architectured materials involve geometrically engineered distributions of microstructural phases at a scale comparable to the scale of the component, thus calling for new models in order to determine the effective properties of materials. The present chapter aims at providing such models, in the case of mechanical properties. As a matter of fact, one engineering challenge is to predict the effective properties of such materials; computational homogenization using finite element analysis is a powerful tool to do so. Homogenized behavior of architectured materials can thus be used in large structural computations, hence enabling the dissemination of architectured materials in the industry. Furthermore, computational homogenization is the basis for computational topology optimization which will give rise to the next generation of architectured materials. This chapter covers the computational homogenization of periodic architectured materials in elasticity and plasticity, as well as the homogenization and representativity of random architectured materials
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