Thyroid Disorders in Patients Treated with Dimethyl Fumarate for Multiple Sclerosis: A Retrospective Observational Study.

Dimethyl fumarate (DMF), a drug used for the treatment of multiple sclerosis (MS) and psoriasis, has been shown to activate the Keap1/Nrf2 antioxidant response. Nrf2 exerts pleiotropic roles in the thyroid gland; among others, single nucleotide polymorphisms (SNPs) in the gene encoding Nrf2 modulate the risk of Hashimoto's thyroiditis (HT), suggesting that pharmacological activation of Nrf2 might also be protective. However, a patient with acute exacerbation of HT after starting DMF for MS was recently reported, raising questions about the thyroidal safety of Nrf2 activators. In a retrospective observational study, we investigated the prevalence and incidence of thyroid disorders (TD) among 163 patients with MS treated with DMF. Only 7/163 patients (4.3%) were diagnosed with functional TD; most (5/163, 3.0%) were diagnosed before DMF treatment. Functional TD were diagnosed under or after DMF in only 2 patients (1.2%). Under DMF, one patient developed transient mild hypothyroidism with negative thyroid autoantibodies. After DMF discontinuation, another patient developed hyperthyroidism due to Graves' disease. No patient developed thyroid structural disease under or after DMF. The very low incidence of functional TD indicates an overall very good thyroid tolerance of DMF, arguing against screening for TD in MS patients considered for or treated with DMF, and supporting the further study of Nrf2 activators for the prevention and treatment of TD

Osteocytes Specific GSK3 Inhibition Affects In Vitro Osteogenic Differentiation.

Osteocytes, the most important regulators of bone processes, are producers of molecules (usually proteins) that act as signals in order to communicate with nearby cells. These factors control cell division (proliferation), differentiation, and survival. Substantial evidence showed different signaling pathways activated by osteocytes and involved in osteoblast differentiation, in particular in the last decade, when the Wingless-related integration site (WNT) pathway assumed a critical large importance. WNT activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism, making GSK3 a potential therapeutic target for bone diseases. In our study, we hypothesized an important role of the osteocyte MLO-Y4 conditioned medium in controlling the differentiation process of osteoblast cell line 2T3. We found an effect of diminished differentiation capability of 2T3 upon conditioning with medium from murine long bone osteocyte-Y4 cells (MLO-Y4) pre-treated with GSK3 inhibitor CHIR2201. The novel observations of this study provide knowledge about the inhibition of GSK3 in MLO-Y4 cells. This strategy could be used as a plausible target in osteocytes in order to regulate bone resorption mediated by a loss of osteoblasts activity through a paracrine loop

Growth factors and mechano-regulated reciprocal crosstalk with extracellular matrix tune the keratocyte–fibroblast/myofibroblast transition

Improper healing of the cornea after injury, infections or surgery can lead to corneal scar formation, which is associated with the transition of resident corneal keratocytes into activated fibroblasts and myofibroblasts (K–F/M). Myofibroblasts can create an extracellular matrix (ECM) niche in which fibrosis is promoted and perpetuated, resulting in progressive tissue opacification and vision loss. As a reversion back to quiescent keratocytes is essential to restore corneal transparency after injury, we characterized how growth factors with demonstrated profibrotic effects (PDGF, FGF, FBS, TGFβ1) induce the K–F/M transition, and whether their withdrawal can revert it. Indeed, the upregulated expression of αSMA and the associated changes in cytoskeletal architecture correlated with increases in cell contractility, fibronectin (Fn) and collagen matrix density and Fn fiber strain, as revealed by 2D cell culture, nanopillar cellular force mapping and a FRET-labeled Fn tension probe. Substrate mechanosensing drove a more complete K–F/M transition reversal following growth factor withdrawal on nanopillar arrays than on planar glass substrates. Using decellularized ECM scaffolds, we demonstrated that the K–F/M transition was inhibited in keratocytes reseeded onto myofibroblast-assembled, and/or collagen-1-rich ECM. This supports the presence of a myofibroblast-derived ECM niche that contains cues favoring tissue homeostasis rather than fibrosis

L'innovation technologique face au changement climatique : quelle est la position de la France ?

Cet article propose une analyse statistique du positionnement et de la performance de la France en matière de technologies de lutte contre le réchauffement climatique. La méthodologie s'appuie sur une base de données décrivant l'ensemble des dépôts de brevets entre 1980 et 2008 dans 17 classes technologiques couvrant un large spectre de technologies liées au climat. Avec 5,2% des inventions brevetées en moyenne en 2008 dans les technologies étudiées, la France est en moyenne au 5ème rang mondial dans un classement dominé par les Etats-Unis, le Japon, la Corée du Sud et l'Allemagne. 20% des dépôts de brevet en France proviennent du secteur public, contre 10% dans les autres pays industrialisés. Plus de la moitié des inventions "climat" françaises sont protégés dans des pays étrangers, soit 1,5 fois plus que la moyenne mondiale. L'analyse par domaine technologique met en évidence un positionnement faible de la France dans les énergies renouvelables, dans lesquelles l'innovation est pourtant la plus dynamique au niveau mondial. En revanche, son positionnement est fort dans des secteurs comme le nucléaire (même si elle n'arrive qu'au troisième rang derrière le Japon et les Etats-Unis), la capture et séquestration du carbone (CSC), l'isolation, le ciment, le chauffage, l'hydraulique et les véhicules électriques et hybrides, où elle tire parti de la présence et du potentiel innovant des grandes firmes françaises d'envergure internationale (Air Liquide, Alstom, Areva, Electricité de France, Lafarge, PSA Peugeot Citroën, Renault, Saint-Gobain, Schlumberger) et des organismes publics de recherche scientifique (CNRS, Commissariat à l'Energie Atomique, Institut Français du Pétrole)

Systematically Developing a Web-Based Tailored Intervention Promoting HPV-Vaccination Acceptability Among Mothers of Invited Girls Using Intervention Mapping.

Background: Currently, the eHealth field calls for detailed descriptions of theory-based interventions in order to support improved design of such interventions. This article aims to provide a systematic description of the design rationale behind an interactive web-based tailored intervention promoting HPV-vaccination acceptability. Methods: The 6-step Intervention Mapping (IM) protocol was used to describe the design rationale. After the needs assessment in Step 1, intervention objectives were formulated in Step 2. In Step 3, we translated theoretical methods into practical applications, which were integrated into a coherent intervention in Step 4. In Step 5, we anticipated future implementation and adoption, and finally, an evaluation plan was generated in Step 6. Results: Walking through the various steps of IM resulted in a detailed description of the intervention. The needs assessment indicated HPV-vaccination uptake remaining lower than expected. Mothers play the most important role in decision-making about their daughter's immunization. However, they generally feel ambivalent after they made their decisions, and their decisions are based on rather unstable grounds. Therefore, intervention objectives were to improve HPV-vaccination uptake and informed decision-making, and to decrease decisional conflict among mothers of invited girls. Computer-tailoring was chosen as the main method; virtual assistants were chosen as a practical application to deliver interactive tailored feedback. To maximize compatibility with the needs of the target group, a user-centered design strategy by means of focus groups and online experiments was applied. In these, prototypes were tested and sequentially refined. Finally, efficacy, effectiveness, and acceptability of the intervention were tested in a randomized controlled trial. Results showed a significant positive effect of the intervention on informed decision-making, decisional conflict, and nearly all determinants of HPV-vaccination uptake (P < 0.001). Mothers evaluated the intervention as highly positive. Discussion: Using IM led to an innovative effective intervention for promoting HPV-vaccination acceptability. The intervention maps will aid in interpreting the results of our evaluation studies. Moreover, it will ease the comparison of design rationales across interventions, and may provide leads for the development of other eHealth interventions. This paper adds to the plea for systematic reporting of design rationales constituting the process of developing interventions

Microscale heterogeneity of the spatial distribution of organic matter can promote bacterial biodiversity in soils: Insights from computer simulations

There is still no satisfactory understanding of the factors that enable soil microbial populations to be as highly biodiverse as they are. The present article explores in silico the hypothesis that the heterogeneous distribution of soil organic matter, in addition to the spatial connectivity of the soil moisture, might account for the observed microbial biodiversity in soils. A multi-species, individual-based, pore-scale model is developed and parameterized with data from 3 Arthrobacter sp. strains, known to be, respectively, competitive, versatile, and poorly competitive. In the simulations, bacteria of each strain are distributed in a 3D computed tomography (CT) image of a real soil and three water saturation levels (100, 50, and 25%) and spatial heterogeneity levels (high, intermediate, and low) in the distribution of the soil organic matter are considered. High and intermediate heterogeneity levels assume, respectively, an amount of particulate organic matter (POM) distributed in a single (high heterogeneity) or in four (intermediate heterogeneity) randomly placed fragments. POM is hydrolyzed at a constant rate following a first-order kinetic, and continuously delivers dissolved organic carbon (DOC) into the liquid phase, where it is then taken up by bacteria. The low heterogeneity level assumes that the food source is available from the start as DOC. Unlike the relative abundances of the 3 strains, the total bacterial biomass and respiration are similar under the high and intermediate resource heterogeneity schemes. The key result of the simulations is that spatial heterogeneity in the distribution of organic matter influences the maintenance of bacterial biodiversity. The least competing strain, which does not reach noticeable growth for the low and intermediate spatial heterogeneities of resource distribution, can grow appreciably and even become more abundant than the other strains in the absence of direct competition, if the placement of the resource is favorable. For geodesic distances exceeding 5 mm, microbial colonies cannot grow. These conclusions are conditioned by assumptions made in the model, yet they suggest that microscale factors need to be considered to better understand the root causes of the high biodiversity of soils

Complete genome sequence of the dairy isolate Streptococcus macedonicus ACA-DC 198

Within the Streptococcus genus, only Streptococcus thermophilus is considered to be non-pathogenic due to its adaptation to the milk environment. Streptococcus macedonicus is also an intriguing streptococcal species since its most frequent source of isolation to date is fermented foods, mainly of dairy origin. Sequencing of S. macedonicus ACA-DC 198 genome was performed using a combination of 454 GS FLX pyrosequencing and HiSeq 2000 Illumina sequencing. The hybrid assembly between 454 and HiSeq2000 data (>200x coverage) resulted in one continuous genomic scaffold of 2,130,034 bp and a plasmid of 12,728 bp. The genome assembly was validated against a NheI optical map of the S. macedonicus genome. Sequences were annotated with the BaSys and the RAST pipelines and manually curated using Kodon. Final corrections were made based on the quality assessment of the annotation using GenePRIMP. We found 2,192 protein-coding genes on the chromosome, 192 of which were identified as potential pseudogenes, indicating an ongoing genome decay process. This hypothesis is also supported by the approximately 220 kb-smaller genome size of S. macedonicus compared to the S. gallolyticus genomes, despite the high level of gene synteny between the two species. Such a reductive evolutionary process is common for lactic acid bacteria domesticated to the food environment, which in the case of S. thermophilus was also accompanied by the loss of pathogenicity traits. With our in silico analysis we attempt to investigate whether S. macedonicus shows traits that would support its adaptation to the dairy environment at the genomic level