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Fibromyalgia (FM) is a complex disease without any clear physiopathology, thus treating FM remains challenging for physicians. In this article Hung et al. propose a new mouse model of FM in which adult mice are exposed to repeated and intermittent sound stress (RISS). These stressors are shown to have an effect at the cellular level: leucocytes generate a high amount of reactive oxygen species (ROS), which triggers plasma lipid peroxidation and an excessive production of lysophosphatidylcholine (LPC) 16:0. LPC16:0 molecules then activate acid-sensing ion channel 3 (ASIC3) on muscle nociceptors, generating a central sensitization process responsible for the development of FM-like phenotypes (hyperalgesia, chronic fatigue, and anxiety). In the second part, a clinical investigation was performed on patients suffering from mild and severe FM. During the month preceding the study, FM patients perceived more daily stressors than healthy controls (HC). In severe FM patients, LPC16:0 levels are correlated with ongoing pain severity. This study suggests that LPC16:0 could be a biomarker for FM, particularly in its severe forms, and proposes to further investigate the effects of platelet-activating factor acetylhydrolase (PAF-AH) inhibitors such as darapladib on fibromyalgia. These molecules could prove to be interesting therapeutic compounds for the treatment of severe FM.

The Faraday effect is a magneto-optical (MO) phenomenon that causes the plane of linearly polarized light to rotate when passing through a medium subjected to a parallel magnetic field. Informed by the established quantum mechanical model developed by Buckingham and Stephens, we sought to identify molecules that would exhibit large MO responses. Magnetic circular dichroism studies of ferrocenium in the 1970s revealed its potential as an MO material; however, it has not been evaluated in the context of Faraday rotation and thin-film optical applications. Herein, we report near-infrared (NIR) Faraday rotation in thin films of decamethylferrocenium/poly(methyl methacrylate) composites with maximum Verdet constants of -3.45 × 104 deg T-1 m-1 at 810 nm (absorbance = 0.09) and -1.44 × 104 deg T-1 m-1 at 870 nm (absorbance = 0.01). These polymer-metallocene thin films deliver larger Verdet constants than commercially used NIR inorganic Faraday rotators and are facile and inexpensive to produce. The temperature dependence and distinct lineshape of the MO responses observed in decamethylferrocenium radical cations, decamethylmanganocene, and chromocene are in accordance with the quantum mechanical model. The observation of a strong C-term Faraday rotation in solid-state organometallic materials provides the groundwork for the development of high-performance metallocene-based Faraday rotators.

The magneto-optical phenomenon known as Faraday rotation involves the rotation of plane-polarized light as it passes through an optical medium in the presence of an external magnetic field oriented parallel to the direction of light propagation. Faraday rotators find applications in optical isolators and magnetic-field imaging technologies. In recent years, organic thin films comprised of polymeric and small-molecule chromophores have demonstrated Verdet constants, which measure the magnitude of rotation at a given magnetic field strength and material thickness, that exceed those found in conventional inorganic crystals. We report herein the thin-film magnetic circular birefringence (MCB) spectra and maximum Verdet constants of several commercially available and newly synthesized phthalocyanine and porphyrin derivatives. Five of these species achieved maximum Verdet constant magnitudes greater than 105 deg T-1 m-1 at wavelengths between 530 and 800 nm. Notably, a newly reported zinc(II) phthalocyanine derivative (ZnPc-OT) reached a Verdet constant of -33 × 104 deg T-1 m-1 at 800 nm, which is among the largest reported for an organic material, especially for an optical-quality thin film. The MCB spectra are consistent with resonance-enhanced Faraday rotation in the region of the Q-band electronic transition common to porphyrin and phthalocyanine derivatives, and the Faraday A-term describes the electronic origin of the magneto-optical activity. Overall, we demonstrate that phthalocyanines and porphyrins are a class of rationally designed magneto-optical materials suitable for applications demanding large Verdet constants and high optical quality.

As an alternative to inorganic fillers based composites which present high density, an epoxy based thermosetting (TS) phase was in situ created in a polypropylene (PP) matrix and compatibilized by ...

© 2020 World Scientific Publishing Company. Incorporating fluorine atoms into a molecule can endow it with various unique properties that enable materials applications. Selective solubility in fluorous solvents is achieved by a high fluorine content and selective partitioning into perfluorinated liquids over organic and aqueous phases provides orthogonal opportunities for chemistry and materials assembly. Although there is a growing number of partially fluorinated molecules, there are insufficient structural design principles to produce diverse fluorous soluble dyes. Herein, we report the synthesis of six fluorous phthalocyanine and subphthalocyanine dyes, and study their properties in the fluorous phase. Phthalocyanines generally display limited solubility and we also observed apparent aggregation in the fluorous phase. However, the nonplanar subphthalocyanines showed greater solubility. Subphthalocyanines also displayed fluorescence in selected solvents, and their emissive properties were investigated. The materials described expand the library of fluorous dyes and provide insights for the design of new molecules with fluorous solubility.

The Overhauser effect (OE), commonly observed in NMR spectra of liquids and conducting solids, was recently discovered in insulating solids doped with the radical 1,3-bisdiphenylene-2-phenylallyl (BDPA). However, the mechanism of polarization transfer in OE-DNP in insulators is yet to be established, but hyperfine coupling of the radical to protons in BDPA has been proposed. In this paper we present a study that addresses the role of hyperfine couplings via the EPR and DNP measurements on some selectively deuterated BDPA radicals synthesized for this purpose. Newly developed synthetic routes enable selective deuteration at orthogonal positions or perdeuteration of the fluorene moieties with (2)H incorporation of >93%. The fluorene moieties were subsequently used to synthesize two octadeuterated BDPA radicals, 1,3-[α,γ-d(8)]-BDPA and 1,3-[β,δ-d(8)]-BDPA, and a BDPA radical with perdeuterated fluorene moieties, 1,3-[α,β,γ,δ-d(16)]-BDPA. In contrast to the strong positive OE enhancement observed in degassed samples of fully protonated h(21)-BDPA (ε ~ +70), perdeuteration of the fluorenes results in a negative enhancement (ε ~ −13), while selective deuteration of α- and γ-positions (a(iso) ~ 5.4 MHz) in BDPA results in a weak negative OE enhancement (ε ~ −1). Furthermore, deuteration of β- and δ-positions (a(iso) ~ 1.2 MHz) results in a positive OE enhancement (ε ~ +36), albeit with a reduced magnitude relative to that observed in fully protonated BDPA. Our results clearly show the role of the hyperfine coupled α and γ (1)H spins in the BDPA radical in determining the dominance of the zero and double-quantum cross-relaxation pathways and the polarization-transfer mechanism to the bulk matrix.

Simple Summary The prevalence of TEM-1 in the vasculature and the stroma of solid tumors and in malignant cells of sarcomas suggests that targeting TEM-1 could have therapeutic benefit. In this context, an anti-TEM-1 companion diagnostic may assist in the personalized medicine approach, whereby TEM-1 expression is exploited as a biomarker to select patients that would most benefit from a treatment directed toward the TEM-1 antigen. In our previous works, we have selected 1C1m-Fc, a fusion protein antibody, radiolabeled it with 177Lu and demonstrated that [177Lu]Lu-1C1m-Fc has interesting therapeutic performance. To define a suitable radiopharmaceutical companion for theranostic applications, 64Cu was chosen to radiolabel the fusion protein antibody. The aim of this work was thus to determine if [64Cu]Cu-1C1m-Fc can be considered for TEM-1 PET imaging and to predict the dosimetry of the [177Lu]Lu-1C1m-Fc companion therapy. Abstract 1C1m-Fc, a promising anti-TEM-1 DOTA conjugate, was labeled with 64Cu to target cancer cells for PET imaging and predicting the efficacy and safety of a previously studied [177Lu]Lu-1C1m-Fc companion therapy. DOTA-conjugated 1C1m-Fc was characterized by mass spectrometry, thin layer chromatography and immunoreactivity assessment. PET/CT and biodistribution studies were performed in human neuroblastoma xenografted mice. Absorbed doses were assessed from biodistribution results and extrapolated to 177Lu based on the [64Cu]Cu-1C1m-Fc data. The immunoreactivity was ≥ 70% after 48 h of incubation in serum, and the specificity of [64Cu]Cu-1C1m-Fc for the target was validated. High-resolution PET/CT images were obtained, with the best tumor-to-organ ratios reached at 24 or 48 h and correlated with results of the biodistribution study. Healthy organs receiving the highest doses were the liver, the kidneys and the uterus. [64Cu]Cu-1C1m-Fc could be of interest to give an indication of 177Lu dosimetry for parenchymal organs. In the uterus and the tumor, characterized by specific TEM-1 expression, the 177Lu-extrapolated absorbed doses are overestimated because of the lack of later measurement time points. Nevertheless, 1C1m-Fc radiolabeled with 64Cu for imaging would appear as an interesting radionuclide companion for therapeutic application with [177Lu]Lu-1C1m-Fc.

Chemotherapy resistance is a critical barrier in cancer treatment. Metabolic adaptations have been shown to fuel therapy resistance; however, little is known regarding the generality of these changes and whether specific therapies elicit unique metabolic alterations. Using a combination of metabolomics, transcriptomics, and functional genomics, we show that two anthracyclines, doxorubicin and epirubicin, elicit distinct primary metabolic vulnerabilities in human breast cancer cells. Doxorubicin-resistant cells rely on glutamine to drive oxidative phosphorylation andde novoglutathione synthesis, while epirubicin-resistant cells display markedly increased bioenergetic capacity and mitochondrial ATP production. The dependence on these distinct metabolic adaptations is revealed by the increased sensitivity of doxorubicin-resistant cells and tumor xenografts to buthionine sulfoximine (BSO), a drug that interferes with glutathione synthesis, compared with epirubicin-resistant counterparts that are more sensitive to the biguanide phenformin. Overall, our work reveals that metabolic adaptations can vary with therapeutics and that these metabolic dependencies can be exploited as a targeted approach to treat chemotherapy-resistant breast cancer.

Ziritaxestat is a novel inhibitor of autotaxin, an enzyme responsible for the production of lysophosphatidic acid, the downstream signaling of which mediates responses to tissue injury and has been implicated in the pathogenesis of fibrotic conditions such as idiopathic pulmonary fibrosis and systemic sclerosis. This study (Clinical Trial Registration: NCT03787186) was designed to assess the absorption, distribution, metabolism, and excretion of orally administered 600-mg ziritaxestat labeled with a carbon-14 tracer (14 C-ziritaxestat). To understand the absolute bioavailability of ziritaxestat, an intravenous 100-μg microdose, labeled with a microtracer amount of 14 C radiation, was administered in a separate part of the study, following an unlabeled 600-mg therapeutic oral dose of ziritaxestat. Six healthy male subjects completed each study part. The majority of the labeled oral dose was recovered in feces (77%), with a total mass balance of 84%. The absolute bioavailability of ziritaxestat was 54%. Ziritaxestat was the main (76%) circulating drug-related product. There were 7 treatment-emergent adverse events, all of which were considered mild and not considered to be related to the study drug.

International audience; Three solid solutions of Tetragonal Tungsten Bronze structure containing Li were prepared by solid state route starting from the parent compound Ba2NdFeNb4O15. These solid solutions involve Li insertion compensated by cationic removal. All cationic sites were involved to investigate their influence on the dielectric transitions observed in Ba2NdFeNb4O15, i.e. from relaxor (R) to ferroelectric (FE) and finally to paraelectric (PE). All solid solutions display the same pattern, which is an evolution from a relaxor to ferroelectric crossover, leading to a single transition (relaxor to paraelectric). This evolution is accompanied by a sudden increase of the ordering temperature (Tm). A focus on structure refinements shows the slight differences induced by the insertion of Li and points towards the role of anionic framework as responsible for the dielectric properties of these materials. This study completes the work performed on other cationic substitutions performed in the title material, and represents a new example of Li substituted TTB materials.

1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with 177 Lu. TEM-1 specific tumor uptake was observed together with a non-saturation dependent liver uptake that could be related to the number of dodecane tetraacetic acid (DOTA) chelator per 1C1m-Fc. The objective of this study was to verify this hypothesis and to find the best DOTA per 1C1m-Fc ratio for theranostic applications. 1C1m-Fc was conjugated with six concentrations of DOTA. High-pressure liquid chromatography, mass spectrometry, immunoreactivity assessment, and biodistribution studies in mice bearing TEM-1 positive tumors were performed. A multi-compartment pharmacokinetic model was used to fit the data and a global pharmacokinetic model was developed to illustrate the effect of liver capture and immunoreactivity loss. Organ absorbed doses in mice were calculated from biodistribution results. A loss of immunoreactivity was observed with the highest DOTA per 1C1m-Fc ratio. Except for the spleen and bone, an increase of DOTA per 1C1m-Fc ratio resulted in an increase of liver uptake and absorbed dose and a decrease of uptake in tumor and other tissues. Pharmacokinetic models correlated these results. The number of DOTA per antibody played a determining role in tumor targeting. One DOTA per 1C1m-Fc gave the best pharmacokinetic behavior for a future translation of [ 177 Lu]Lu-1C1m-Fc in patients.

International audience; Sterols are biologically important molecules that serve as membrane fluidity regulators and precursors of signaling molecules, either endogenous or involved in biotic interactions. There is currently no model of their biosynthesis pathways in brown algae. Here, we benefit from the availability of genome data and gas chromatography-mass spectrometry (GC-MS) sterol profiling using a database of internal standards to build such a model. We expand the set of identified sterols in 11 species of red, brown, and green macroalgae and integrate these new data with genomic data. Our analyses suggest that some metabolic reactions may be conserved despite the loss of canonical eukaryotic enzymes, like the sterol side-chain reductase (SSR). Our findings are consistent with the principle of metabolic pathway drift through enzymatic replacement and show that cholesterol synthesis from cycloartenol may be a widespread but variable pathway among chlorophyllian eukaryotes. Among the factors contributing to this variability, one could be the recruitment of cholesterol biosynthetic intermediates to make signaling molecules, such as the mozukulins. These compounds were found in some brown algae belonging to Ectocarpales, and we here provide a first mozukulin biosynthetic model. Our results demonstrate that integrative approaches can already be used to infer experimentally testable models, which will be useful to further investigate the biological roles of those newly identified algal pathways.

This contribution deals with a Deep Level Transient Spectroscopy study of emission and capture processes in innovative HEMT structures based on InAlGaN/GaN, grown on N+ doped SiC substrates with a SI epitaxial SiC layer and AlGaN back-barrier. Three different gate types (Schottky, FAT FET and GTLM) were examined. The attention was focused on identified deep energy levels and possible origins compared to various measurement conditions and the gate types. Arrhenius evaluations confirmed traces of Ga-vacancies, dislocations, self-donors associated with the Ga interstitial impurities. Measured DLTS spectra validated an excellent quality of the growth process.

Aims: These last years, pharmacists gained more and more importance in the clinical support of patients. However, few studies have explored the clinical outcomes of a pharmaceutical intervention on chronic patients. Methods: A randomized controlled study single blinded, evaluating the impact of a single pharmaceutical interview on hypertension, type 2 diabetes and hypercholesterolemia patients not reaching the therapeutic objectives despite a drug therapy. Patients in the intervention group were interviewed by a pharmacist who provided patient education on pathology management and advice on how to deal with the pathology on a daily basis, and identified any prescription problems. The primary outcome was the proportion of patients reaching the therapeutic objectives for blood pressure, glycated hemoglobin level and low-density lipoprotein cholesterol level at the three-month follow up consultation. Results: Seventy-three patients completed the study. In the control group, 33.3% patients reached the therapeutic objectives with the usual care versus 61.7% in the intervention group (p=0.015). The intervention was significantly more effective on patients with more than five different drugs prescribed (+16.7% vs +60.0%; p=0.005) and with a high education level (+29.4% vs +68.8%; p=0.024). A much lower rate of type 2 diabetes patients reached the therapeutic objectives whatever the group. Interestingly, the efficacy of the intervention did not depend on the number of chronic diseases or age after adjustment for the number of different drugs prescribed. Conclusions: There is a concrete clinical and public health impact of a single pharmaceutic interview, especially on polypharmacy patients with hypertension or hypercholesterolemia.

Hidradenitis suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway of tryptophan catabolism in dermal fibroblasts, correlating with the release of kynurenine pathway–inducing cytokines by inflammatory cell infiltrates. Notably, overactivation of the kynurenine pathway in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the aryl hydrocarbon receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in patients with HS, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin., Loss of homeostasis of tryptophan metabolism at the host-microbiota interface may contribute to Hidradenitis Suppurativa.

Purpose TEM-1 (tumor endothelial marker-1) is a single-pass transmembrane cell surface glycoprotein expressed at high levels by tumor vasculature and malignant cells. We aimed to perform a preclinical investigation of a novel anti-TEM-1 scFv-Fc fusion antibody, 1C1m-Fc, which was radiolabeled with 177Lu for use in soft tissue sarcomas models. Methods 1C1m-Fc was first conjugated to p-SCN-Bn-DOTA using different excess molar ratios and labeled with 177Lu. To determine radiolabeled antibody immunoreactivity, Lindmo assays were performed. The in vivo behavior of [177Lu]Lu-1C1m-Fc was characterized in mice bearing TEM-1 positive (SK-N-AS) and negative (HT-1080) tumors by biodistribution and single-photon emission SPECT/CT imaging studies. Estimated organ absorbed doses were obtained based on biodistribution results. Results The DOTA conjugation and the labeling with 177Lu were successful with a radiochemical purity of up to 95%. Immunoreactivity after radiolabeling was 86% ± 4%. Biodistribution showed a specific uptake in TEM-1 positive tumor versus liver as critical non-specific healthy organ, and this specificity is correlated to the number of chelates per antibody. A 1.9-fold higher signal at 72 h was observed in SPECT/CT imaging in TEM-1 positive tumors versus control tumors. Conclusion TEM-1 is a promising target that could allow a theranostic approach to soft-tissue sarcoma, and 1C1m-Fc appears to be a suitable targeting candidate. In this study, we observed the influence of the ratio DOTA/antibody on the biodistribution. The next step will be to investigate the best conjugation to achieve an optimal tumor-to-organ radioactivity ratio and to perform therapy in murine xenograft models as a prelude to future translation in patients.

International audience; Well‐defined linear alkyl benzene surfactants (COxn) were successfully synthesized using cardanol as a green phenolic alternative and initiator for polyoxazoline (POx), the hydrophilic block of nonionic surfactants. Various hydrophilic lipophilic balance values were investigated by varying the POx length according to the [monomer]/[initiator] ratio. The chemical structure of the surfactants, in particular the terminal groups, was well identified by matrix assisted laser desorption ionization time of flight mass spectrometry demonstrating the good progress of the cationic ring‐opening polymerization. The COxn surfactants spontaneously self‐assembled in water at a critical aggregation concentration of 1–2 µmol L−1 into nano‐objects characterized by a hydrodynamic diameter of 11–24 nm and a number of aggregations ranging from 30 to 60 according to the worm‐like micelle model.

Background: An important part of the investigation of pleural effusion is the identification of markers that help separate exudate from transudate. Objectives: The purposes of this study were to compare the accuracy of published and new sets of criteria to distinguish between exudative and transudative pleural effusions, and to determine whether serum biochemical analysis is necessary. Methods: An externally validated cohort study was performed. Pleural effusions were determined to be transudative or exudative on the basis of an assessment of the medical record by two clinicians blinded to biochemical results. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and area under the receiver operating characteristic curve were determined for each proposed combination of criteria. Results: Pleural fluid analysis was available for 311 thoracenteses in the main cohort and for 112 thoracenteses in the validation cohort. The best sensitivity (97% [95% CI 94–99]) and negative likelihood ratio (0.04 [95% CI 0.02–0.08]) for identifying exudative effusions were observed with criteria combining pleural fluid lactate dehydrogenase greater than 0.6 the upper limit of normal serum lactate dehydrogenase and pleural fluid cholesterol greater than 1.04 mmol/L (40 mg/dL). The overall diagnostic accuracy was similar to Light’s criteria. Findings were similar in the validation cohort. Conclusions: Our proposed criteria using simultaneously pleural fluid lactate dehydrogenase and pleural fluid cholesterol can identify an exudate with a sensitivity and an overall diagnostic accuracy similar to Light’s criteria. It avoids simultaneous blood sampling, thus reducing patient discomfort and potential costs.

The impact of varying the GaN channel layer thickness ( ${t}_{\text {ch}}$ ) in InAlGaN/AlN/GaN HEMTs with C-doped AlGaN back barriers is investigated. ${t}_{\text {ch}}$ was 50, 100, and 150 nm, and the gate length of the fabricated HEMTs ranged from 50 to 200 nm. It is found that short-channel effects (SCEs) are significantly mitigated with a small ${t}_{\text {ch}}$ . For HEMTs with a gate length of 50 nm, the drain-induced barrier lowering changes from 40 to 93 mV/V as ${t}_{\text {ch}}$ is increased from 50 to 150 nm. On the other hand, it is shown that dispersive effects are more severe for a smaller ${t}_{\text {ch}}$ , as demonstrated by a sixfold increase in the dynamic ON-resistance for ${t}_{\text {ch}} = 50$ nm compared to ${t}_{\text {ch}} = 150$ nm. The tradeoff between dispersion and SCEs is reflected in large-signal measurements at 30 GHz. The 50-nm channel, mainly limited by dispersion, exhibits an output power of 3.5 W/mm. The thicker channels reach a maximum of around 5 W/mm, but for different gate lengths due to the difference in severity of the SCEs. This paper elucidates the interplay between SCEs and dispersion related to ${t}_{\text {ch}}$ , its consequences for the large-signal performance and for the limitation in downscaling of the gate length.

In swelling shales, significant clay–water interactions take place along the faces of the smectite minerals contained in the clay fraction, giving rise to the distinction between free water and adsorbed water. Further insight was recently gained by means of microstructure investigations, showing that the hydration mechanisms of pure or compacted smectites also explain the hydration and swelling behaviour of the Callovo-Oxfordian claystone, a possible host rock for deep radioactive waste disposal in France. In this rock, the proportion of water molecules adsorbed in intra-platelet pores was estimated to be around 25% of the total porosity, with 75% of the porosity containing free water. On the basis of these findings, the data of high-precision poroelastic measurements conducted in an isotropic compression cell showed that the porosity to account for a proper calculation of Skempton's B coefficient is not the total porosity, but the 75% proportion of the porosity corresponding to free water. This conclusion is believed to be of some interest with respect to the prediction of the rock response around the disposals at great depth, given that hydro-mechanical numerical simulations are often carried out within the framework of poroelasticity.

The shear viscosity of asymmetric, binary mixtures, consisting of small and long-chain molecules, was computed by means of reversed non-equilibrium molecular dynamics simulations. The molecules were modelled as flexible chains of tangent spheres that interact through a combination of site–site Lennard-Jones (LJ) 12–6 intermolecular forces. The calculations were performed in order to elucidate the mechanisms responsible for the experimentally observed marked decrease in the viscosity of a fluid consisting of large molecules, on addition of lighter species. The simulations of pure species indicate that the chains exhibit a range of configurational shapes, but are in general quite folded, even in a dilute state, when there are no other chains or monomers present; the average radius of gyration of a particular chain is nearly temperature independent and only weakly dependent on density. Analysis of the behaviour of the chains with the different number of segments indicates that the resulting viscosity is proportional to the square root of their moment of inertia. The simulations carried out on the binary mixture, consisting of a monomer and a 16-segment chain species, indicate that the viscosity decrease can be broadly attributed to density, mixing and structural effects. The decrease in density and mixing effects led to a large decrease in viscosity, primarily dominated by the effect of mixing the two species. The structural changes resulted in an increase in viscosity, as the presence of monomers led to configurational relaxation of hexadecamer and to a localization of monomers in the vicinity of the hexadecamers.

The orchestration of intercellular communication is essential for multicellular organisms. One mechanism by which cells communicate is through long, actin-rich membranous protrusions called tunneling nanotubes (TNTs), which allow the intercellular transport of various cargoes, between the cytoplasm of distant cells in vitro and in vivo. With most studies failing to establish their structural identity and examine whether they are truly open-ended organelles, there is a need to study the anatomy of TNTs at the nanometer resolution. Here, we use correlative FIB-SEM, light- and cryo-electron microscopy approaches to elucidate the structural organization of neuronal TNTs. Our data indicate that they are composed of a bundle of open-ended individual tunneling nanotubes (iTNTs) that are held together by threads labeled with anti-N-Cadherin antibodies. iTNTs are filled with parallel actin bundles on which different membrane-bound compartments and mitochondria appear to transfer. These results provide evidence that neuronal TNTs have distinct structural features compared to other cell protrusions., The architecture of functional TNTs is still under debate. Here, the authors combine correlative FIB-SEM, light- and cryo-electron microscopy approaches to elucidate the structure of TNTs in neuronal cells, showing that they form structures that are distinct form other membrane protrusions.

The detoxification enzyme UDP-glucuronosyltransferase UGT2B10 is specialized in the N-linked glucuronidation of many drugs and xenobiotics. Preferred substrates possess tertiary aliphatic amines and heterocyclic amines, such as tobacco carcinogens and several antidepressants and antipsychotics. We hypothesized that alternative splicing (AS) constitutes a means to regulate steady-state levels of UGT2B10 and enzyme activity. We established the transcriptome of UGT2B10 in normal and tumoral tissues of multiple individuals. The highest expression was in the liver, where 10 AS transcripts represented 50% of the UGT2B10 transcriptome in 50 normal livers and 44 hepatocellular carcinomas. One abundant class of transcripts involves a novel exonic sequence and leads to two alternative (alt.) variants with novel in-frame C termini of 10 or 65 amino acids. Their hepatic expression was highly variable among individuals, correlated with canonical transcript levels, and was 3.5-fold higher in tumors. Evidence for their translation in liver tissues was acquired by mass spectrometry. In cell models, they colocalized with the enzyme and influenced the conjugation of amitriptyline and levomedetomidine by repressing or activating the enzyme (40%–70%; P < 0.01) in a cell context–specific manner. A high turnover rate for the alt. proteins, regulated by the proteasome, was observed in contrast to the more stable UGT2B10 enzyme. Moreover, a drug-induced remodeling of UGT2B10 splicing was demonstrated in the HepaRG hepatic cell model, which favored alt. variants expression over the canonical transcript. Our findings support a significant contribution of AS in the regulation of UGT2B10 expression in the liver with an impact on enzyme activity.

Aims Tenascin-C (TNC) is an endogenous danger signal molecule strongly associated with inflammatory diseases and with poor outcome in patients with cardiomyopathies. Its function within pathological cardiac tissue during pressure overload remains poorly understood. Methods and results We showed that TNC accumulates after 1 week of transverse aortic constriction (TAC) in the heart of 12-week-old male mice. By cross bone marrow transplantation experiments, we determined that TNC deposition relied on cardiac cells and not on haematopoietic cells. The expression of TNC induced by TAC, or by administration of a recombinant lentivector coding for TNC, triggered a pro-inflammatory cardiac microenvironment, monocyte/macrophage (MO/MΦ) accumulation, and systolic dysfunction. TNC modified macrophage polarization towards the pro-inflammatory phenotype and stimulated RhoA/Rho-associated protein kinase (ROCK) pathways to promote mesenchymal to amoeboid transition that enhanced macrophage migration into fibrillar collagen matrices. The amplification of inflammation and MO/MΦ recruitment by TNC was abrogated by genetic invalidation of TNC in knockout mice. These mice showed less ventricular remodelling and an improved cardiac function after TAC as compared with wild-type mice. Conclusions By promoting a pro-inflammatory microenvironment and macrophage migration, TNC appears to be a key factor to enable the MO/MΦ accumulation within fibrotic hearts leading to cardiac dysfunction. As TNC is highly expressed during inflammation and sparsely during the steady state, its inhibition could be a promising therapeutic strategy to control inflammation and immune cell infiltration in heart disease.

A preliminary study of the design of an electrically small plasma-based resonator using a localized surface plasmon resonance (LSPR) above 1 GHz is presented. Such a resonator is intended to be used to develop an electrically small antenna with frequency agility. This resonator consists of a plasma discharge confined in a hemispherical glass shell 3 cm in diameter on a ground plane. From 1 to 1.5 GHz, the plasma electron density required to achieve the LSPR must be between 0. $5\times 10^{11}$ and $1.4\times 10^{11}\mathrm{c}\mathrm{m}^{-3}$. Plasma losses are taken into account in this study and provide information on the required gas pressure. Typically for neon gas, the working pressure must be around 50 mTorr. A practical implementation using a miniature inductively coupled plasma (mICP) source is finally discussed.

Summary Inferring genome-scale metabolic networks in emerging model organisms is challenged by incomplete biochemical knowledge and partial conservation of biochemical pathways during evolution. Therefore, specific bioinformatic tools are necessary to infer biochemical reactions and metabolic structures that can be checked experimentally. Using an integrative approach combining genomic and metabolomic data in the red algal model Chondrus crispus, we show that, even metabolic pathways considered as conserved, like sterols or mycosporine-like amino acid synthesis pathways, undergo substantial turnover. This phenomenon, here formally defined as “metabolic pathway drift,” is consistent with findings from other areas of evolutionary biology, indicating that a given phenotype can be conserved even if the underlying molecular mechanisms are changing. We present a proof of concept with a methodological approach to formalize the logical reasoning necessary to infer reactions and molecular structures, abstracting molecular transformations based on previous biochemical knowledge., Graphical Abstract, Highlights • Combination of metabolite profiling and genome-scale metabolic networks analysis • New method to infer biochemical reactions and metabolites in promiscuous pathways • Red algal model for sterol and mycosporine-like amino acid biosynthesis pathways • Metabolic drift if pathway variation despite conserved initial and final metabolites, Bioinformatics; Genomics; Metabolomics

International audience; Based on long term investigations of the microstructure of various geomaterials as 14 different as sensitive low plastic clays from Eastern Canada, unsaturated compacted silt from 15 the Paris area, highly plastic compressible deep marine clay from the Gulf of Guinea, 16 compacted MX80 bentonite and the Callovo-Oxfordian claystone, considered as possible 17 barriers in deep geological radioactive waste disposal, two fundamentals and distinct nano 18 and micro mechanisms governing their macroscopic volume changes have been identified. In 19 low plastic structured clays and dry compacted soils, in which an aggregate microstructure has 20 been evidenced, the decrease in volume under mechanical compression result from the 21 collapse of inter-aggregates pores in an ordered manner, from the larger to the smaller, with 22 no effect on the intra-aggregate porosity. The soil skeleton can hence be modelled as an 23 elastic fragile porous matrix, affected by the ordered collapse of its pores. Things are different 24 in plastic soils, due to the significant reactivity of the montmorillonite minerals to changes in 25 water content that results in significant changes of the initial porous matrix. The ordered 26 adsorption of layers of water molecules in clay platelets with respect to the suction or stress 27 applied, evidenced long time ago in Soil science through X-ray diffraction techniques, appear 28 to be able to help better understanding various phenomena like the compression of plastic 29 compressible soils and the hydration of compacted bentonites. Interestingly, it also applies to 30 understand the effects of smectite minerals in the volume changes behaviour of the Callovo-31 Oxfordian claystone. These two mechanisms at nano and microscopic scales hence provide a 32 better understanding of the macroscopic volume changes of a large variety of natural and 33 compacted clayey soils and rocks. 34 Keywords: clayey soils and rocks; microstructure; montmorillonite; pore size distribution; 35 nano scale; water adsorption. 36 37 2

Background Severe Hurley stage 1 Hidradenitis suppurativa (HS1) is a difficult to treat form of the disease. Objective To assess the efficacy and tolerance of the oral combination of rifampin (10 mg/kg once daily) – moxifloxacin (400 mg once daily) – metronidazole (250 to 500 mg t.i.d) (RMoM) treatment strategy in severe HS1 patients. Methods Prospective, open-label, non-comparative cohort study in 28 consecutive patients. 19 patients were treated for 6 weeks by RMoM, followed by 4 weeks of RMo alone, then by cotrimoxazole after remission. Moxifloxacin was replaced by pristinamycin (1g t.i.d) in 9 cases because of contra-indications or intolerance. Primary endpoint was a Sartorius score of 0 (clinical remission, CR) at week 12. Results The median Sartorius score dropped from 14 to 0 (p= 6 x 10-6) at week 12, 75% of patients reaching CR. A low initial Sartorius score was a prognosis factor for CR (p = 0.049). Main side-effects were mild gastro-intestinal discomfort, mucosal candidiasis and asthenia. At one year of follow-up, the median [IQR] number of flares dropped from 21/year to 1 (p = 10-5). Limitations: small monocentric non-controlled study. Conclusion: complete and prolonged remission can be obtained in severe HS1 using targeted antimicrobial treatments.

This paper presents the measurement results of a MMIC power amplifiers (PA), based on InAlGaN/GaN HEMT technology, for Ka band applications. The three-stages MMIC is operating within a bandwidth of [25-31] GHz and demonstrate over this bandwidth a saturated output power of 40dBm. Each stage uses 8x50μm gate width HEMTs fabricated with a 0.I5μm gate length on 70μm thick SiC substrate.

The assembly of basement membranes (BMs) into tissue-specific morphoregulatory structures requires non-core BM components. Work in Drosophila indicates a principal role of collagen-binding matricellular glycoprotein SPARC (Secreted Protein, Acidic, Rich in Cysteine) in larval fat body BM assembly. We report that SPARC and collagen IV (Col(IV)) first colocalize in the trans-Golgi of hemocyte-like cell lines. Mutating the collagen-binding domains of Drosophila SPARC led to the loss of colocalization with Col(IV), a fibrotic-like BM, and 2nd instar larval lethality, indicating that SPARC binding to Col(IV) is essential for survival. Analysis of this mutant at 2nd instar reveals increased Col(IV) puncta within adipocytes, reflecting a disruption in the intracellular chaperone-like activity of SPARC. Removal of the disulfide bridge in the C-terminal EF-hand2 of SPARC, which is known to enhance Col(IV) binding, did not lead to larval lethality; however, a less intense fat body phenotype was observed. Additionally, both SPARC mutants exhibited altered fat body BM pore topography. Wing imaginal disc-derived SPARC did not localize within Col(IV)-rich matrices. This raises the possibility that SPARC interaction with Col(IV) requires initial intracellular interaction to colocalize at the BM or that wing-derived SPARC undergoes differential post-translational modifications that impacts its function. Collectively, these data provide evidence that the chaperone-like activity of SPARC on Col(IV) begins just prior to their co-secretion and demonstrate for the first time that the Col(IV) chaperone-like activity of SPARC is necessary for Drosophila development beyond the 2nd instar.

Aim: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (DMD) in clinical practice (NCT02369731). Here, we describe the initial demographic characteristics of the registry population. Patients & methods: Patients will be followed up from enrollment for ≥5 years or until study withdrawal. Results & conclusion: As of 9 July 2018, 213 DMD boys were enrolled from 11 countries. Mean (standard deviation) ages at first symptoms and at study treatment start were 2.7 (1.7) years and 9.8 (3.7) years, respectively. Corticosteroids were used by 190 patients (89.2%) before data cut-off. Mean (standard deviation) ataluren exposure was 639.0 (362.9) days. Six patients withdrew. STRIDE is the first drug registry for patients with DMD and represents the largest real-world registry of patients with nmDMD to date.

The assembly of basement membranes (BMs) into tissue-specific morphoregulatory structures requires non-core BM components. Work inDrosophilaindicates a principal role of collagen-binding matricellular glycoprotein SPARC (Secreted Protein, Acidic, Rich in Cysteine) in larval fat body BM assembly. We report that SPARC and collagen IV (Col(IV)) first colocalize in the trans-Golgi of hemocytes. Mutating the collagen-binding epitopes of SPARC leads to 2ndinstar larval lethality, indicating that SPARC binding to Col(IV) is essential for survival. Analysis of this mutant reveals increased Col(IV) puncta within adipocytes and intense perimeter Col(IV) staining surrounding the fat body as compared to wild-type larvae, reflecting a disruption in chaperone-like activity. In addition, Col(IV) in the wing imaginal disc was absent. Removal of the disulfide bridge in EF-hand2, which is known to enhance Col(IV) binding by SPARC, did not lead to larval lethality; however, a similar but less intense fat body phenotype was observed. Additionally, both SPARC mutants have altered fat body BM pore topography. Wing imaginal disc-derived SPARC did not localize within Col(IV)-rich matrices, indicating a distinct variant. Collectively, these data demonstrate the essential role of Col(IV) chaperone-like activity of SPARC toDrosophiladevelopment and indicate tissue-specific variants with differential functions.

Due to its intrinsic properties and the possible lattice match to GaN, InAlN is expected to allow the fabrication of optimal high electron mobility transistors for high power and high frequency applications. However, the crystal quality of InAlN nearly lattice-matched to GaN degrades when the layer thickness is increased, and this is a strong limitation for the fabrication of devices in which thick barriers need to be used. In this work, we have carried out a detailed theoretical investigation of the behavior of indium atoms in the alloy. It is clearly shown that in the presence of nitrogen vacancies, which are common defects in these materials, indium nitride clusters will present excess formation energy up to diameters around 1.4 nm. In parallel, Z-contrast TEM observations close to the InAlN/GaN interface show that 2–5 nm size indium rich areas form and are systematically connected to the vertical degradation channels. This is at variance with published results, which concluded that the observed degradation was exclusively either due to the underlying threading dislocations or due to a characteristic three-dimensional growth mode.

The effects of temperature on the water transport properties of intact and damaged Opalinus (OPA) clay are investigated by using a recently developed hollow cylinder triaxial cell [Monfared (Int J Rock Mech Min Sci 48:637–649, 2011b)] that allows full saturation and drainage conditions in low-permeability clays and shales. The volumetric response of saturated OPA clay sample during a drained heating test shows an irreversible contraction after a temperature threshold. The permeability tests which are performed before and after the heating test show that the induced irreversible sample contraction by thermal loading reduces the permeability of OPA clay sample. In order to study the effect of temperature on the permeability of a damaged sample of OPA clay, the permeability tests are performed on a saturated sample previously sheared by a standard drained triaxial loading. The test results show no significant effect of shear-type damage on the permeability of the sample at 25 °C and 80 °C. The experimental results presented in this paper show the crucial role of the thermally induced strains on sample permeability. Thermo-elastic dilation leads to a slight increase of the permeability, whereas thermoplastic contraction leads to a reduction.

Brentuximab vedotin (BV) is an antibody–drug conjugate (ADC) composed of a CD30-directed monoclonal antibody covalently linked to the anti-microtubule agent monomethyl auristatin E (MMAE). Binding ...

International audience; Mixtures made up of bentonite powder and pellets are a possible candidate for making sealing plugs used in deep radioactive waste disposal due to their low permeability, high swelling capacity, favourable properties with respect to radionuclide retention and operational advantages in terms of placement in situ, which is much easier than that of pre-compacted bricks of bentonite/sand mixture. It is therefore essential to better understand their hydro-mechanical behaviour to optimize the design of the repository. In this context, the French Institute for Radiation Protection and Nuclear Safety (IRSN) has launched the SEALEX project (SEALing performance EXperiments) in which this work has been conducted. Once the initially heterogeneous unsaturated powder/pellet (80/20) MX80 bentonite mixture is put in place, these sealing materials will be subject to coupled hydro-mechanical loadings: hydration due to the infiltration of pore water from the natural barrier and mechanical confinement resulting from the engineered barriers. The present work focuses on the different scales of the material: at the macroscopic scale, it is characterised by a heterogeneous distribution of pellets and powder of bentonite; at the microscopic scale, it is studied by several techniques (MIP, μ-CT observations and SEM). From MIP results, a typical bimodal distribution was found for both pellet and powder. From μ-CT and SEM observations, a heterogeneity was revealed in the internal structure of the pellet: heterogeneous density distribution of the clay minerals and presence of several high density elements.

International audience; Americium is a strong contributor to the long term radiotoxicity of high activity nuclear waste.Transmutation by irradiation in nuclear reactors of long-lived nuclides like $^{241}$Am is therefore an option for the reduction of radiotoxicity and heat production of waste packages to be stored in a repository. The MARINE irradiation experiment is the latest of a series of European experiments on americium transmutation (e.g. EFTTRA-T4, EFTTRA-T4bis, HELIOS, MARIOS, SPHERE) performed in the High Flux Reactor (HFR). The MARINE experiment is developed and carried out in the framework of the collaborative research project PELGRIMM of the EURATOM 7th Framework Programme (FP7). During the past years of experimental works in the field of transmutation and tests of innovative nuclear fuels, the release or trapping of helium as well as swelling have been shown to be the key issues for the design of such kind of fuel both as drivers and even more for Am-bearing blanket targets (due to the higher Am contents). The main objective of the MARINE experiment is to study the in-pile behaviour of uranium oxide fuel containing 13% of americium and to compare the behaviour of sphere-pac versus pellet fuel, in particular the role of microstructure and temperature on fission gas release and He on fuel swelling.The MARINE experiment will be irradiated in 2016 in the HFR in Petten (The Netherlands) and is expected to be completed in spring 2017. This paper discusses the rationale and objective of the MARINE experiment and provides a generaldescription of its design for which some innovative features have been adopted.

Mechanisms related to the induction of phlorotannin biosynthesis in marine brown algae remain poorly known. Several studies undertaken on fucoid species have shown that phlorotannins accumulate in the algae for several days or weeks after being exposed to grazing, and this is measured by direct quantification of soluble phenolic compounds. In order to investigate earlier inducible responses involved in phlorotannin metabolism, Fucus vesiculosus was studied between 6 and 72 h of grazing by the sea snail Littorina littorea. In this study, the quantification of soluble phenolic compounds was complemented by a Quantitative real-time PCR (qRT-PCR) approach applied on genes that are potentially involved in either the phlorotannin metabolism or stress responses. Soluble phlorotannin levels remained stable during the kinetics and increased significantly only after 12 h in the presence of grazers, compared to the control, before decreasing to the initial steady state for the rest of the kinetics. Under grazing conditions, the expression of vbpo, cyp450 and ast6 genes was upregulated, respectively, at 6 h, 12 h and 24 h, and cyp450 gene was downregulated after 72 h. Interestingly, the pksIII gene involved in the synthesis of phloroglucinol was overexpressed under grazing conditions after 24 h and 72 h. This study supports the hypothesis that phlorotannins are able to provide an inducible chemical defense under grazing activity, which is regulated at different stages of the stress response.

The objective of this work was to study the development of polypropylene (PP) foams with low density ( We have shown that the branched structure of polymer chains can be defined on the basis of a rheological criterion. It defines the notion of fractal behavior (coupling of relaxation modes), which polymer chains must have for nonlinear behavior (strain hardening). This criterion has been defined by analogy with the sol-gel transition, tan δ = 1. Finally, in terms of modeling and simulation, the plasticizing effect of CO2 was modeled from the experimental rheological behavior of the PP plasticized with synthetic oil. A theoretical power law was derived and was then introduced in the mass balance equations to predict the cell growth during depressurization.

We propose a novel model approach for temperature evaluation in the channel region of a InAlN/AlN/gallium nitride high electron mobility transistor (HEMT) due to self-heating effects. The heat transfer in a HEMT device has been investigated experimentally by the nearby temperature sensor and compared by theoretical models solved by both numerical and analytical methods. The average temperature of the channel area of almost 160 °C for dissipated power of 2 W was determined using the drain-source current variation analysis. The electrical and thermal behavioral numerical model under quasi-static conditions have been used to describe the HEMT device. In contrast, the one-dimensional thermal model for analytical evaluation has been proposed as an alternative approach. Surprisingly, the experimental results verified not only the validity of precise numerical simulation but also the simplified analytical model that makes it a reliable tool even for complex electronic devices.

The purpose of this paper is to combine a classical 1D twin-screw extrusion model with machine learning techniques to obtain accurate predictions of a complex system despite few data. Systems involving reactive polyethylene oligomer dispersed in situ in a polypropylene matrix by reactive twin-screw extrusion are studied for this purpose. The twin-screw extrusion simulation software LUDOVIC is used and machine learning techniques dealing with low data limit are used as a correction of the simulation. This research was funded by the French ANR through the DataBEST project.