Monitoring demyelination and remyelination by magnetization transfer imaging in the mouse brain at 9.4 T

OBJECTIVE: The aim of this study was to assess quantitatively structural changes in myelin content occurring during demyelination and remyelination by magnetization transfer imaging (MTI). MATERIALS AND METHODS: In a reversible model of demyelination with no axonal loss, mice intoxicated by cuprizone were studied by MTI in vivo at 9.4 T. MRI data were compared to histopathological examinations. RESULTS: Data revealed that the magnetization transfer ratio (MTR) decreased significantly during demyelination and increased during remyelination with strong correlation to the myelin content (r = 0.79, P = 0.01). CONCLUSIONS: This study demonstrated that MTR is a sensitive and reproducible quantitative marker to assess myelin loss and repair. This may lead to in vivo monitoring of therapeutic strategies promoting remyelination.     

Transparent anodes for polymer photovoltaics: Oxygen permeability of PEDOT

The oxygen permeability of the transparent organic anode poly(3,4,-ethylene dioxythiophene) with paratoluenesulphonate as the anion (PEDOT:pTS) was determined to be (STP) , and is thus comparable in magnitude to the oxygen permeability of polyethyleneterephthalate (PET). The oxygen diffusion through bilayers of polyethylene (PE) and PEDOT:pTS and bilayers of PET and PEDOT:pTS was established. The bilayer structures were applied as the carrier substrate and the transparent anode in polymer-based photovoltaic devices employing a mixture of poly(1-methoxy-4-(2-ethylhexyloxy)-p-phenylenevinylene) (MEH-PPV) and [6,6]-phenyl-C₆₁-butanoicacidmethylester (PCBM) as the active layer and aluminium as the cathode. The oxygen permeability of the layers and the aluminium cathode was correlated with the lifetime of the solar cell devices. It was found that the performance of the devices with PET as the carrier substrate degraded more slowly due to the lower oxygen and water permeability, whereas devices using PE as the carrier substrate gave devices with a very short lifetime. It was found that PEDOT:pTS on its own is a not a significant barrier for oxygen in the context of photovoltaic devices where long lifetimes are anticipated. It is concluded that the large oxygen permeability of the barrier layers contribute to the short device lifetimes while other permeates such as water also contribute to device degradation.     

Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities

Melanoma is characterized by high glucose uptake, partially mediated through elevated pyruvate dehydrogenase kinase (PDK), making PDK a potential treatment target in melanoma. We aimed to reduce glucose uptake in melanoma cell lines through PDK inhibitors dichloroacetate (DCA) and AZD7545 and through PDK knockdown, to inhibit cell growth and potentially unveil metabolic co-vulnerabilities resulting from PDK inhibition. MeWo cells were most sensitive to DCA, while SK-MEL-2 was the least sensitive, with IC₅₀ values ranging from 13.3 to 27.0 mM. DCA strongly reduced PDH phosphorylation and increased the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio up to 6-fold. Knockdown of single PDK isoforms had similar effects on PDH phosphorylation and OCR:ECAR ratio as DCA but did not influence sensitivity to DCA. Growth inhibition by DCA was synergistic with the glutaminase inhibitor CB-839 (2- to 5-fold sensitization) and with diclofenac, known to inhibit monocarboxylate transporters (MCTs) (3- to 8-fold sensitization). CB-839 did not affect the OCR:ECAR response to DCA, whereas diclofenac strongly inhibited ECAR and further increased the OCR:ECAR ratio. We conclude that in melanoma cell lines, DCA reduces proliferation through reprogramming of cellular metabolism and synergizes with other metabolically targeted drugs.     

DspA/E-Triggered Non-Host Resistance against E. amylovora Depends on the Arabidopsis GLYCOLATE OXIDASE 2 Gene

DspA/E is a type three effector injected by the pathogenic bacterium Erwinia amylovora inside plant cells. In non-host Arabidopsis thaliana, DspA/E inhibits seed germination, root growth, de novo protein synthesis and triggers localized cell death. To better understand the mechanisms involved, we performed EMS mutagenesis on a transgenic line, 13-1-2, containing an inducible dspA/E gene. We identified three suppressor mutants, two of which belonged to the same complementation group. Both were resistant to the toxic effects of DspA/E. Metabolome analysis showed that the 13-1-2 line was depleted in metabolites of the TCA cycle and accumulated metabolites associated with cell death and defense. TCA cycle and cell-death associated metabolite levels were respectively increased and reduced in both suppressor mutants compared to the 13-1-2 line. Whole genome sequencing indicated that both suppressor mutants displayed missense mutations in conserved residues of Glycolate oxidase 2 (GOX2), a photorespiratory enzyme that we confirmed to be localized in the peroxisome. Leaf GOX activity increased in leaves infected with E. amylovora in a DspA/E-dependent manner. Moreover, the gox2-2 KO mutant was more sensitive to E. amylovora infection and displayed reduced JA-signaling. Our results point to a role for glycolate oxidase in type II non-host resistance and to the importance of central metabolic functions in controlling growth/defense balance.     

Discovery of Compounds That Selectively Repress the Amyloidogenic Processing of the Amyloid Precursor Protein: Design,Synthesis and Pharmacological Evaluation of Diphenylpyrazoles

The rationale to define the biological and molecular parameters derived from structure–activity relationships (SAR) is mandatory for the lead selection of small drug compounds. Several series of small molecules have been synthesized based on a computer-assisted pharmacophore design derived from two series of compounds whose scaffold originates from chloroquine or amodiaquine. All compounds share similar biological activities. In vivo, Alzheimer’s disease-related pathological lesions are reduced, consisting of amyloid deposition and neurofibrillary degeneration, which restore and reduce cognitive-associated impairments and neuroinflammation, respectively. Screening election was performed using a cell-based assay to measure the repression of Aβ_1–x peptide production, the increased stability of APP metabolites, and modulation of the ratio of autophagy markers. These screening parameters enabled us to select compounds as potent non-competitive β-secretase modulators, associated with various levels of lysosomotropic or autophagy modulatory activities. Structure–activity relationship analyses enabled us to define that (1) selectively reducing the production of Aβ_1–x, and (2) little Aβ_x–40/42 modification together with (3) a decreased ratio of p62/(LC3-I/LC3-II) enabled the selection of non-competitive β-secretase modulators. Increased stability of CTFα and AICD precluded the selection of compounds with lysosomotropic activity whereas cell toxicity was associated with the sole p62 enhanced expression shown to be driven by the loss of nitrogen moieties. These SAR parameters are herein proposed with thresholds that enable the selection of potent anti-Alzheimer drugs for which further investigation is necessary to determine the basic mechanism underlying their mode of action.     

Identification of Adipose Tissue as a Reservoir of Macrophages after Acute Myocardial Infarction

Medullary and extra-medullary hematopoiesis has been shown to govern inflammatory cell infiltration and subsequently cardiac remodeling and function after acute myocardial infarction (MI). Emerging evidence positions adipose tissue (AT) as an alternative source of immune cell production. We, therefore, hypothesized that AT could act as a reservoir of inflammatory cells that participate in cardiac homeostasis after MI. To reveal the distinct role of inflammatory cells derived from AT or bone marrow (BM), chimeric mice were generated using standard repopulation assays. We showed that AMI increased the number of AT-derived macrophages in the cardiac tissue. These macrophages exhibit pro-inflammatory characteristics and their specific depletion improved cardiac function as well as decreased infarct size and interstitial fibrosis. We then reasoned that the alteration of AT-immune compartment in type 2 diabetes could, thus, contribute to defects in cardiac remodeling. However, in these conditions, myeloid cells recruited in the infarcted heart mainly originate from the BM, and AT was no longer used as a myeloid cell reservoir. Altogether, we showed here that a subpopulation of cardiac inflammatory macrophages emerges from myeloid cells of AT origin and plays a detrimental role in cardiac remodeling and function after MI. Diabetes abrogates the ability of AT-derived myeloid cells to populate the infarcted heart.     

Statistical learning for wind power: A modeling and stability study towards forecasting

We focus on wind power modeling using machine learning techniques. We show on real data provided by the wind energy company Maïa Eolis that parametric models even following closely the physical equation relating wind production to wind speed are outperformed by intelligent learning algorithms. In particular, the CART‐Bagging algorithm gives very stable and promising results. Besides, as a step towards forecast, we quantify the impact of using deteriorated wind measures on the performances. We show also on this application that the default methodology to select a subset of predictors provided in the standard random forest package can be refined, especially when there exists among the predictors one variable, which has a major impact.     

Sex Bias in Differentiated Thyroid Cancer

Differentiated thyroid cancers are more frequent in women than in men. These different frequencies may depend on differences in patient’s behavior and in thyroid investigations. However, an impact on sexual hormones is likely, although this has been insufficiently elucidated. Estrogens may increase the production of mutagenic molecules in the thyroid cell and favor the proliferation and invasion of tumoral cells by regulating both the thyrocyte enzymatic machinery and the inflammatory process associated with tumor growth. On the other hand, the worse prognosis of thyroid cancer associated with the male gender is poorly explained.     

Magnetization transfer characteristics in atherosclerotic plaque components assessed by adapted binomial preparation pulses

Increasing the contrast between atheromatous plaque components is a major issue in cardiovascular MRI research. It would allow one to identify unstable plaque by differentiating the lipid core associated with vulnerability, from the fibrous cap, considered as a factor of stability. T₂ and diffusion-weighted imaging have already provided satisfying results. Magnetization transfer (MT) between restricted protons H_r and free-water protons H_f could achieve a different contrast related to collagen and lipoprotein macromolecules present in the fibrous cap and lipid core, respectively. The purpose of this work was to evaluate in vitro the MT effect produced by adapted T₂-selective 1-3-3-1 binomial pulses on isolated samples of atheromatous arteries at 3 T. A method based on simulation was used in order to improve the MT specificity: it is shown that 50% 1-3-3-1 pulses (the percentage indicating the level of H_r saturation) allow an estimation of T_2r, the H_r T₂. Using this technique, magnetization transfer was observed for the first time in atherosclerotic plaque components, an effect more pronounced for the fibrous cap and media than for the lipid core and advantitia. The T_2r estimation gave values ranging from 20 to 25 μs for the four samples. This preliminary study provides a basis for establishing an MT imaging sequence of atheromatous arteries, by using 50% 1-3-3-1 pulses calibrated for saturating protons with a 20 μs T₂. This MT protocol should be further compared to T₂ and diffusion-weighted imaging.