A compact 20-pass thin-disk multipass amplifier stable against thermal lensing effects and delivering 330 mJ pulses with M2<1.17\bf{M^2 < 1.17}

We report on an Yb:YAG thin-disk multipass amplifier delivering 50 ns long pulses at a central wavelength of 1030 nm with an energy of 330 mJ at a repetition rate of 100 Hz. The beam quality factor at the maximum energy was measured to be $\text{M}^2 = 1.17$. The small signal gain is 20, and the gain at 330 mJ was measured to be 6.9. The 20-pass amplifier is designed as a concatenation of stable resonator segments in which the beam is alternately Fourier transformed and relay-imaged back to the disk by a 4f-imaging optical scheme stage. The Fourier transform propagation makes the output beam robust against spherical phase front distortions, while the 4f-stage is used to compensate the thermal lens of the thin-disk and to reduce the footprint of the amplifier

The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs

Background: Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti).Methodology/principal findings: Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them-entinostat, TH65, and TH92 -had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed.Conclusion, significance: The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave the way to understanding the roles of HDACs in these parasites.Fil: Vaca, Hugo Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente; ArgentinaFil: Celentano, Ana M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología; ArgentinaFil: Toscanini, María Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Heimburg, Tino. No especifíca;Fil: Ghazy, Ehab. No especifíca;Fil: Zeyen, Patrik. No especifíca;Fil: Hauser, Alexander Thomas. Albert Ludwigs University of Freiburg; AlemaniaFil: Oliveira, Guilherme. Instituto Tecnológico Vale.; BrasilFil: Elissondo, María Celina. Universidad Nacional de Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Producción, Sanidad y Ambiente; ArgentinaFil: Jung, Manfred. Albert Ludwigs University of Freiburg; AlemaniaFil: Sippl, Wolfgang. No especifíca;Fil: Camicia, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Rosenzvit, Mara Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentin

Tempered mlo broad-spectrum resistance to barley powdery mildew in an Ethiopian landrace

Recessive mutations in the Mlo gene confer broad spectrum resistance in barley (Hordeum vulgare) to powdery mildew (Blumeria graminis f. sp. hordei), a widespread and damaging disease. However, all alleles discovered to date also display deleterious pleiotropic effects, including the naturally occurring mlo-11 mutant which is widely deployed in Europe. Recessive resistance was discovered in Eth295, an Ethiopian landrace, which was developmentally controlled and quantitative without spontaneous cell wall appositions or extensive necrosis and loss of photosynthetic tissue. This resistance is determined by two copies of the mlo-11 repeat units, that occur upstream to the wild-type Mlo gene, compared to 11-12 in commonly grown cultivars and was designated mlo-11 (cnv2). mlo-11 repeat unit copy number-dependent DNA methylation corresponded with cytological and macroscopic phenotypic differences between copy number variants. Sequence data indicated mlo-11 (cnv2) formed via recombination between progenitor mlo-11 repeat units and the 3' end of an adjacent stowaway MITE containing region. mlo-11 (cnv2) is the only example of a moderated mlo variant discovered to date and may have arisen by natural selection against the deleterious effects of the progenitor mlo-11 repeat unit configuration

Cation Exchange in Smectites as a New Approach to Mineral Carbonation

Mineral carbonation of alkaline mine residues is a carbon dioxide removal (CDR) strategy that can be employed by the mining industry. Here, we describe the mineralogy and reactivity of processed kimberlites and kimberlite ore from Venetia (South Africa) and Gahcho Kué (Canada) diamond mines, which are smectite-rich (2.3–44.1 wt.%). Whereas, serpentines, olivines, hydrotalcites and brucite have been traditionally used for mineral carbonation, little is known about the reactivity of smectites to CO2. The smectite from both mines is distributed as a fine-matrix and is saponite, Mx/mm+Mg3(AlxSi4−x)O10(OH)2·nH2O, where the layer charge deficiency is balanced by labile, hydrated interlayer cations (Mm+). A positive correlation between cation exchange capacity and saponite content indicates that smectite is the most reactive phase within these ultramafic rocks and that it can be used as a source of labile Mg2+ and Ca2+ for carbonation reactions. Our work shows that smectites provide the fast reactivity of kimberlite to CO2 in the absence of the highly reactive mineral brucite [Mg(OH)2]. It opens up the possibility of using other, previously inaccessible rock types for mineral carbonation including tailings from smectite-rich sediment-hosted metal deposits and oil sands tailings. We present a decision tree for accelerated mineral carbonation at mines based on this revised understanding of mineralogical controls on carbonation potential

Sodium fast reactor safety and licensing research plan. Volume II.

Expert panels comprised of subject matter experts identified at the U.S. National Laboratories (SNL, ANL, INL, ORNL, LBL, and BNL), universities (University of Wisconsin and Ohio State University), international agencies (IRSN, CEA, JAEA, KAERI, and JRC-IE) and private consultation companies (Radiation Effects Consulting) were assembled to perform a gap analysis for sodium fast reactor licensing. Expert-opinion elicitation was performed to qualitatively assess the current state of sodium fast reactor technologies. Five independent gap analyses were performed resulting in the following topical reports: (1) Accident Initiators and Sequences (i.e., Initiators/Sequences Technology Gap Analysis), (2) Sodium Technology Phenomena (i.e., Advanced Burner Reactor Sodium Technology Gap Analysis), (3) Fuels and Materials (i.e., Sodium Fast Reactor Fuels and Materials: Research Needs), (4) Source Term Characterization (i.e., Advanced Sodium Fast Reactor Accident Source Terms: Research Needs), and (5) Computer Codes and Models (i.e., Sodium Fast Reactor Gaps Analysis of Computer Codes and Models for Accident Analysis and Reactor Safety). Volume II of the Sodium Research Plan consolidates the five gap analysis reports produced by each expert panel, wherein the importance of the identified phenomena and necessities of further experimental research and code development were addressed. The findings from these five reports comprised the basis for the analysis in Sodium Fast Reactor Research Plan Volume I

Microglial-specific depletion of TAK1 is neuroprotective in the acute phase after ischemic stroke

Abstract: Transforming growth factor-β-activated kinase 1 (TAK1) is upregulated after cerebral ischemia and contributes to an aggravation of brain injury. TAK1 acts as a key regulator of NF-ΚB and the MAP kinases JNK and p38 and modulates post-ischemic neuroinflammation and apoptosis. Microglia are the main TAK1-expressing immunocompetent cells of the brain. However, little is known about the function and regulation of microglial TAK1 after cerebral ischemia. Tamoxifen-dependent conditiona ldepletion of TAK1 in microglial cells was induced in Cx3cr1creER-Tak1fl/fl mice. The creER-negative Tak1fl/fl mice and vehicle treated(corn oil) mice served as control groups. A transient intraluminal middle cerebral artery occlusion of 30 min followed by6 h and 72 h of reperfusion was performed in male mice. Oxygen-glucose-deprivation (OGD) was performed with primary cortical glial cell cultures to examine the effect of microglial-specific and general (5Z-7-Oxozeaenol) TAK1 inhibition after different reperfusion times (1 h, 6 h, and 72 h). Cx3cr1creER-Tak1fl/fl mice showed reduced infarct sizes and improved neurological outcomes compared to the control group. The mRNA and protein levels of pro-inflammatory Il1b/IL-1β and Tnf/TNF-α in theperi-infarct zones of microglial-specific TAK1-depleted mice were significantly reduced. Furthermore, TAK1 depletion in vitroled to reduced cell death rates after OGD. Moreover, hypoxia-mediated activation of TAK1 and its downstream signalling proteins, JNK and p38, were dampened by microglial TAK1 depletion. In contrast, 5Z-7-Oxozeaenol-induced pharmacological inhibition of TAK1 completely diminished MAPK-signalling including the kinases JNK and p38 in all cells. Microglial TAK1depletion abrogates post-ischemic neuroinflammation and apoptosis in the acute phase, hence might be considered as a potential target in the treatment of cerebral hypoxia

Upscaling of geological properties in a world-class carbonate geothermal system in France: From core scale to 3D regional reservoir dimensions

International audienceThe greater Paris area has some 12 million inhabitants and 48 heating network production units that exploit the heat capacity of a 1.5 km deep aquifer, the Bathonian limestone. This is one of the most productive aquifers in the world for district heating, with an annual output of about 1.7 TWh of energy. The current challenge for Paris is to triple the number of heating networks using geothermal energy so as to reduce dependence on fossil fuels (40% in 2020 in France). As no detailed geothermal reservoir model is available, drilling involves geological risk. A recent well, drilled at Grigny (20 km south of Paris), turned out to be a failure in transmissibility because the bed of permeable limestones it tapped into was very thin (meter-scale). The main aim of this study is to create a digital database and a 3D geological model of this aquifer to minimize geological risks and optimize the location of future geothermal operations around Paris. By compiling data from 168 wells, a high-resolution 3D geological model of 360 km3 size is constructed (about 40 km x 50 km x 0.2 km), made up of 12.2 million cells and displaying sedimentary facies, sequence stratigraphy, porosity (Φ) and permeability (k). About 20% of the oolitic and bioclastic facies are of good reservoir quality (Φ > 13% and k > 350 mD), especially in two targeted, high-quality reservoir sequences. These facies of interest probably correspond to giant dunes and a shoal/barrier prograding from east to west. In these facies, permeable zones are generally 4 m thick and form patches of 1600 m x 1100 m, on average, elongated perpendicular to the depositional slope. 2D and 3D maps of temperature, salinity, porosity, transmissivity, and permeability allow us to understand the areas of interest for geothermal exploration, as demonstrated around Grigny. This model helps us to apprehend better the heterogeneous character of the reservoir for geothermal prospection and to reduce the risk of future doublets during well implantation. Detailed local models may be extracted to anticipate better the implantation of new doublets in areas with already densely spaced existing wells

Fingolimod (FTY720) is not protective in the subacute MPTP mouse model of Parkinson's disease and does not lead to a sustainable increase of brain-derived neurotrophic factor

Parkinson's disease (PD) is characterized by the loss of midbrain dopaminergic neurons and aggregates of α‐synuclein termed Lewy bodies. Fingolimod (FTY720) is an agonist of sphingosine‐1 phosphate receptors and an approved oral treatment for multiple sclerosis. Fingolimod elevates brain‐derived neurotrophic factor (BDNF), an important neurotrophic factor for dopaminergic neurons. BDNF and fingolimod are beneficial in several animal models of PD. In order to validate the therapeutic potential of fingolimod for the treatment of PD, we tested its effect in the subacute MPTP mouse model of PD. MPTP or vehicle was applied i.p. in doses of 30 mg/kg MPTP on five consecutive days. In order to recapitulate the combination of dopamine loss and α‐synuclein aggregates found in PD, MPTP was first administered in Thy1‐A30P‐α‐synuclein transgenic mice. Fingolimod was administered i.p. at a dose of 0.1 mg/kg every second day. Nigrostriatal degeneration was assayed by stereologically counting the number of dopaminergic neurons in the substantia nigra pars compacta, by analysing the concentration of catecholamines and the density of dopaminergic fibres in the striatum. MPTP administration produced a robust nigrostriatal degeneration, comparable to previous studies. Unexpectedly, we found no difference between mice with and without fingolimod treatment, neither at baseline, nor at 14 or 90 days after MPTP. Also, we found no effect of fingolimod in the subacute MPTP mouse model when we used wildtype mice instead of α‐synuclein transgenic mice, and no effect with an increased dose of 1 mg/kg fingolimod administered every day. In order to explain these findings, we analysed BDNF regulation by fingolimod. We did find an increase of BDNF protein after a single injection of fingolimod 0.1 or 1.0 mg/kg, but not after multiple injections, indicating that the BDNF response to fingolimod is unsustainable over time. Taken together we did not observe a neuroprotective effect of fingolimod in the subacute MPTP mouse model of PD. We discuss possible explanations for this discrepancy with previous findings and conclude fingolimod might be beneficial for the nonmotor symptoms of PD

Hydrogeological study in the Kalaa Khasba plain (Northwestern Tunisia). Contribution of well logging and electrical prospecting

International audienceThe protection of groundwater through the rationalization of its exploitation is crucial in water resources management. However, this rationalization needs a good knowledge of the aquifer system. The present study aimed at the characterization of the Mio-Plio-Quaternary aquifer in Kalaa Khasba plain (northwestern Tunisia) using 250 vertical electrical soundings (VES) and 41 water boreholes. First, well logs consisting of gamma ray, resistivity and spontaneous polarization logs were analyzed to define reservoir layers and follow their lateral evolution in different directions via several correlations. Second, VES data were qualitatively and quantitatively interpreted. Qualitatively, apparent resistivity maps were established for different AB spacings. Quantitatively, theoretical master curves, auxiliary point charts and software were used to determine layer thicknesses and true resistivities. The obtained models were correlated to the lithological columns restored from well logs in the form of geoelectrical cross sections and a three-dimensional representation, the analysis of which elucidated the aquifer geometry. The comparisons and correlations of lithological columns to their corresponding well logs highlighted that the substratum of Mio-Plio-Quaternary deposits near the plain borders consists of Eocene or Cretaceous limestones with marly intercalations. Further, they showed that in most of the boreholes, these deposits contain three lithological units: two clayey units separated by a coarse one which presented its greatest thicknesses (81 and 97 m) in the central part of the plain. The apparent resistivity maps clearly highlighted the richness of this zone in water reservoirs through relatively high resistivity values (15–40 Ωm) for different AB spacings. The geo-electrical cross sections and three-dimensional representation indicated that successive normal faults generated the gradual downwarping of the Eocene and Cretaceous series and the thickening of the Mio-Plio-Quaternary filling within the Kalaa Khasba plain. Moreover, they revealed notable variations in the depth (8–125 m), thickness (28 to > 90 m) and resistivity (15–55 Ωm) of the coarse unit corresponding to the Kalaa Khasba aquifer