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Precipitation and land use in terms of livestock grazing have been identified as two of the most important drivers structuring the vegetation composition of semi-arid and arid savannas. Savanna research on the impact of these drivers has widely applied the so-called plant functional type (PFT) approach, grouping the vegetation into two or three broad types (here called meta-PFTs): woody plants and grasses, which are sometimes divided into perennial and annual grasses. However, little is known about the response of functional traits within these coarse types towards water availability or livestock grazing. In this study, we extended an existing eco-hydrological savanna vegetation model to capture trait diversity within the three broad meta-PFTs to assess the effects of both grazing and mean annual precipitation (MAP) on trait composition along a gradient of both drivers. Our results show a complex pattern of trait responses to grazing and aridity. The response differs for the three meta-PFTs. From our findings, we derive that trait responses to grazing and aridity for perennial grasses are similar, as suggested by the convergence model for grazing and aridity. However, we also see that this only holds for simulations below a MAP of 500 mm. This combined with the finding that trait response differs between the three meta-PFTs leads to the conclusion that there is no single, universal trait or set of traits determining the response to grazing and aridity. We finally discuss how simulation models including trait variability within meta-PFTs are necessary to understand ecosystem responses to environmental drivers, both locally and globally and how this perspective will help to extend conceptual frameworks of other ecosystems to savanna research.
Due to the low cutaneous bioavailability of tacrolimus (TAC), penetration enhancers are used to improve its penetration into the skin. However, poor loading capacity, non-biodegradability, toxicity, and in some cases inefficient skin penetration are challenging issues that hamper their applications for the dermal TAC delivery. Here we present poly(lactide-co-glycerol) (PLG) as a water soluble, biodegradable, and biocompatible TAC-carrier with high loading capacity (14.5% w/w for TAC) and high drug delivery efficiencies into the skin. PLG was synthesized by cationic ring-opening copolymerization of a mixture of glycidol and lactide and showed 35 nm and 300 nm average sizes in aqueous solutions before and after loading of TAC, respectively. Delivery experiments on human skin, quantified by fluorescence microscopy and LC-MS/MS, showed a high ability for PLG to deposit Nile red and TAC into the stratum corneum and viable epidermis of skin in comparison with Protopic (R) (0.03% w/w, TAC ointment). The cutaneous distribution profile of delivered TAC proved that 80%, 16%, and 4% of the cutaneous drug level was deposited in the stratum corneum, viable epidermis, and upper dermis, respectively. TAC delivered by PLG was able to efficiently decrease the IL-2 and TSLP expressions in human skin models. Taking advantage of the excellent physicochemical and biological properties of PLG, it can be used for efficient dermal TAC delivery and potential treatment of inflammatory skin diseases.
Objectives: Severe pneumonia may evoke acute lung injury, and sphingosine-1-phosphate is involved in the regulation of vascular permeability and immune responses. However, the role of sphingosine-1-phosphate and the sphingosine-1-phosphate producing sphingosine kinase 1 in pneumonia remains elusive. We examined the role of the sphingosine-1-phosphate system in regulating pulmonary vascular barrier function in bacterial pneumonia. Design: Controlled, in vitro, ex vivo, and in vivo laboratory study. Subjects: Female wild-type and SphK1-deficient mice, 8-10 weeks old. Human postmortem lung tissue, human blood-derived macrophages, and pulmonary microvascular endothelial cells. Interventions: Wild-type and SphK1-deficient mice were infected with Streptococcus pneumoniae. Pulmonary sphingosine-1-phosphate levels, messenger RNA expression, and permeability as well as lung morphology were analyzed. Human blood-derived macrophages and human pulmonary microvascular endothelial cells were infected with S. pneumoniae. Transcellular electrical resistance of human pulmonary microvascular endothelial cell monolayers was examined. Further, permeability of murine isolated perfused lungs was determined following exposition to sphingosine-1-phosphate and pneumolysin. Measurements and Main Results: Following S. pneumoniae infection, murine pulmonary sphingosine-1-phosphate levels and sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 expression were increased. Pneumonia-induced lung hyperpermeability was reduced in SphK1(-/-) mice compared with wild-type mice. Expression of sphingosine kinase 1 in macrophages recruited to inflamed lung areas in pneumonia was observed in murine and human lungs. S. pneumoniae induced the sphingosine kinase 1/sphingosine-1-phosphate system in blood-derived macrophages and enhanced sphingosine-1-phosphate receptor 2 expression in human pulmonary microvascular endothelial cell in vitro. In isolated mouse lungs, pneumolysin-induced hyperpermeability was dose dependently and synergistically increased by sphingosine-1-phosphate. This sphingosine-1-phosphate-induced increase was reduced by inhibition of sphingosine-1-phosphate receptor 2 or its downstream effector Rho-kinase. Conclusions: Our data suggest that targeting the sphingosine kinase 1-/sphingosine-1-phosphate-/sphingosine-1-phosphate receptor 2-signaling pathway in the lung may provide a novel therapeutic perspective in pneumococcal pneumonia for prevention of acute lung injury.
Recently, we proposed a small molecular inducing ligand strategy to assemble proteins into highly-ordered structures via dual non-covalent interactions, i.e. carbohydrate-protein interaction and dimerization of Rhodamine B. Using this approach, artificial protein microtubules were successfully constructed. In this study, we find that these microtubules exhibit a perfect CO2 responsiveness; assembly and disassembly of these microtubules were nicely controlled by the alternative passage of CO2 and N-2. Upon the injection of CO2, a negative net-charged SBA turns into a neutral or positive net-charged SBA, which elongated, to some extent, the effective distance between SBA and Rhodamine B, resulting in the disassociation of the Rhodamine B dimer. Further experimental and simulation results reveal that the CO2-responsive mechanism differs from that of solubility change of the previously reported CO2-responsive synthetic materials.
Alkaline igneous rocks are relatively rare in settings of tectonic convergence and little is known about their petrogenesis in these settings. This study aims to contribute to a better understanding of the formation of alkaline igneous rocks by an investigation of the Tezhsar volcano-intrusive alkaline ring complex (TAC) in the Armenian Lesser Caucasus, which is located between the converging Eurasian and Arabian plates. We present new petrological, geochemical and Sr Nd isotope data for the TAC to constrain magma genesis and magma source characteristics. Moreover, we provide a new Ar-40/Ar-39 age of 41.0 +/- 0.5 Ma on amphibole from a nepheline syenite that is integrated into the regional context of ongoing regional convergence and widespread magmatism. The TAC is spatially concentric and measures similar to 10 km in diameter representing the relatively shallow plumbing system of a major stratovolcano juxtaposed by ring faulting with its extrusive products. The plutonic units comprise syenites and nepheline syenites, whereas the extrusive units are dominated by trachytic-phonolitic rocks. The characteristic feature of the TAC is the development of pseudomorphs after leucite in all types of the volcanic, subvolcanic and intrusive alkaline rocks. Whole-rock major element data show a metaluminous (Alkalinity Index = 0-0.1), alkalic and silica-undersaturated (Feldspathoid Silica-Saturation Index <0) character of the TAC. The general trace element enrichment and strong fractionation of REEs (La-N/Yb-N up to 70) indicate a relatively enriched magma source and small degrees of partial melting. All TAC rocks show a negative Nb Ta anomalies typical of subduction zone settings. The initial 87Sr/85Sr ratios (0.704-0.705) and positive sNd values (+3 to +5) indicate an isotopically depleted upper mantle and lack of significant crustal influence, which in turn suggests the TAC magma has formed via differentiation from lithospheric mantle melts.
Enhanced topical delivery of dexamethasone by beta-cyclodextrin decorated thermoresponsive nanogels
(2018)
Highly hydrophilic, responsive nanogels are attractive as potential systems for the topical delivery of bioactives encapsulated in their three-dimensional polymeric scaffold. Yet, these drug carrier systems suffer from drawbacks for efficient delivery of hydrophobic drugs. Addressing this, β-cyclodextrin (βCD) could be successfully introduced into the drug carrier systems by exploiting its unique affinity toward dexamethasone (DXM) as well as its role as topical penetration enhancer. The properties of βCD could be combined with those of thermoresponsive nanogels (tNGs) based on dendritic polyglycerol (dPG) as a crosslinker and linear thermoresponsive polyglycerol (tPG) inducing responsiveness to temperature changes. Electron paramagnetic resonance (EPR) studies localized the drug within the hydrophobic cavity of βCD by differences in its mobility and environmental polarity. In fact, the fabricated carriers combining a particulate delivery system with a conventional penetration enhancer, resulted in an efficient delivery of DXM to the epidermis and the dermis of human skin ex vivo (enhancement compared to commercial DXM cream: ∼2.5 fold in epidermis, ∼30 fold in dermis). Furthermore, DXM encapsulated in βCD tNGs applied to skin equivalents downregulated the expression of proinflammatory thymic stromal lymphopoietin (TSLP) and outperformed a commercially available DXM cream.
Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1(tmEx1) mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.
The Northern Zagros Suture Zone (NZSZ), formed as a result of the collision between Arabian and Sanandaj-Sirjan microplate, is considered as part of the Zagros orogenic belt. NZSZ is marked by two allochthonous thrust sheets in upward stacking order: lower and upper allochthon. The Bulfat complex is a part of the upper allochthon or "Ophiolite-bearing terrane" of Albian-Cenomenion age (97-105 Ma). Voluminous highly sheared serpentinites associated with ophiolites occur within this upper allochthon. In addition, the Gemo-Qandil Group is characterized by gabbroic to dioritic Bulfat intrusion with a crystallization age spanning from similar to 45 to similar to 40 Ma, as well as extensive metapelites with contact to the Walash-Naupurdam metavolcanic rocks. Due to the deformation in the Sanandaj-Sirjan Zone along the eastern side of the Iraqi segment of NZSZ, the Gemo-Qandil Group was regionally metamorphosed during late Cretaceous (similar to 80 Ma). This tectono-compressional dynamics ultimately caused an oscillatory deformation against Arabian continental margin deposits as well. During these events, gabbro-diorite intrusion with high-grade contact metamorphic aureoles occurred near Bulfat. Thus, there is an overlap between regional and contact metamorphic conditions in the area. The earlier metamorphic characteristic can be seen only in places where the latter contact influence was insignificant. Generally, this can only observed at a distance of more than 2.5 km from the contact. According to petrographic details and field observations, the thermally metamorphosed metapelitic units of the metasediment have been completely assimilated, with only some streaks of biotite and relicts of initial foliation. They strongly resemble amphibolite-grade slices from the regional metamorphic rocks in the region. Metapelitic samples far from the intrusion give similar biotite cooling ages as the intrusive rocks. Thus, they may be affected by the same thermal event. Ar-40/Ar-39 dating of biotite in metapelite rocks of Bulfat by step-wise heating with laser gave average weighted isotopic ages of 34.78 +/- 0.06 Ma. This is interpreted as crystallization/recrystallization age of biotite possibly representing the time of cooling and uplift history of the Bulfat intrusion. Cooling and exhumation rates for the Bulfat gabbro-diorite rocks were estimated as similar to 400 A degrees C/Ma and similar to 3.3 mm/year respectively. According to petrographic details, field observations and Ar/Ar dating concerning the contact metamorphism near Bulfat due to the gabbro-diorite intrusion, no significant deformation is visible during exhumation processes after the Paleogene tectono-thermal event, indicating that isotopic ages of 34.78 +/- 0.06 Ma could mark the timing of termination of the island arc activity in the Ophiolite-bearing terrane (upper allochthon).