Loss of function of DJ‐1 (PARK7) is associated with autosomal recessive early‐onset Parkinson's disease (PD), one of the major age‐related neurological diseases. In this study, we extended former ...studies on DJ‐1 knockout mice by identifying subtle morphological and behavioural phenotypes. The DJ‐1 gene trap‐induced null mutants exhibit less dopamine‐producing neurons in the ventral tegmental area (VTA). They also exhibit slight changes in behaviour, i.e. diminished rearing behaviour and impairments in object recognition. Furthermore, we detected subtle phenotypes, which suggest that these animals compensate for the loss of DJ‐1. First, we found a significant upregulation of mitochondrial respiratory enzyme activities, a mechanism known to protect against oxidative stress. Second, a close to significant increase in c‐Jun N‐terminal kinase 1 phosphorylation in old DJ‐1‐deficient mice hints at a differential activation of neuronal cell survival pathways. Third, as no change in the density of tyrosine hydroxylase (TH)‐positive terminals in the striatum was observed, the remaining dopamine‐producing neurons likely compensate by increasing axonal sprouting. In summary, the present data suggest that DJ‐1 is implicated in major non‐motor symptoms of PD appearing in the early phases of the disease—such as subtle impairments in motivated behaviour and cognition—and that under basal conditions the loss of DJ‐1 is compensated
Using a conditioning paradigm, the olfactory sensitivity of three squirrel monkeys and three pigtail macaques for homologous series of aliphatic 2-ketones (2-butanone to 2-nonanone), symmetrical ...ketones (3-pentanone to 6-undecanone), and C7-ketones (2-heptanone to 4-heptanone) was assessed. In the majority of cases, the animals of both species significantly discriminated concentrations below 1 ppm from the odorless solvent, and with 2-nonanone and 5-nonanone the monkeys even demonstrated thresholds below 1 ppb. The results showed both primate species have a well-developed olfactory sensitivity for aliphatic ketones, and pigtail macaques generally perform better than squirrel monkeys in detecting members of this class of odorants. Further, in both species tested, we found a significant negative correlation between perceptibility in terms of olfactory detection thresholds and carbon-chain length of both the 2-ketones and the symmetrical ketones, but not between detection thresholds and position of the functional group with the C7-ketones. These findings lend further support to the growing body of evidence suggesting that between-species comparisons of the number of functional olfactory receptor genes or of neuroanatomical features are poor predictors of olfactory performance.
1. The present study was carried out to determine the effects of feeding ensiled alfalfa leaves (ALS) as an alternative protein source to laying hens under the terms of an organic diet. Due to the ...occurrence of unexpected negative health effects and undesirable egg yolk pigmentation in the test groups the trial was prematurely stopped and further analysis was conducted to evaluate the responsible substances.
2. Body weights of the test groups decreased significantly already in week 2 of the trial. Performance variables dropped. Olive green pigmented egg yolks were found in groups fed diets containing ALS. Severe comb necrosis occurred in the experimental group receiving the highest level of ALS (20%) combined with the option of free-range access and therefore natural light exposure.
3. The noxious agent found in ALS, blood serum and egg yolk was the photosensitising chlorophyll derivate pheophorbid a (PPBa), deriving from a strong depletion of chlorophyll contained in the alfalfa leaves. PPBa caused the olive-green pigmentation found in yolks and led to photosensitivity in groups with the highest level of ALS in the diet in combination with light exposure.
4. By aiming for high protein and amino acid levels, harvesting and processing have, unintentionally and initially unnoticed, led to a strong accumulation of phototoxic PPBa. From these results it is strongly advised not to include ensiled alfalfa leaves as a protein source in organic laying hen diets.
Cooperative self‐assembly (co‐assembly) of diblock copolymers (DBCs) and inorganic precursors that takes inspiration from the rich phase separation behavior of DBCs can enable the realization of a ...broad spectrum of functional nanostructures with the desired sizes. In a DBC assisted sol–gel chemistry approach with polystyrene‐block‐poly(ethylene oxide) and ZnO, hybrid films are formed with slot‐die coating. Pure DBC films are printed as control. In situ grazing‐incidence small‐angle X‐ray scattering measurements are performed to investigate the self‐assembly and co‐assembly process during the film formation. Combining complementary ex situ characterizations, several distinct regimes are differentiated to describe the morphological transformations from the initially solvent‐dispersed to the ultimately solidified films. The comparison of the assembly pathway evidences that the key step in the establishment of the pure DBC film is the coalescence of spherical micelles toward cylindrical domains. Due to the presence of the phase‐selective precursor, the formation of cylindrical aggregates in the solution is crucial for the structural development of the hybrid film. The pre‐existing cylinders in the ink impede the domain growth of the hybrid film during the subsequent drying process. The precursor reduces the degree of order, prevents crystallization of the PEO block, and introduces additional length scales in the hybrid films.
The complex film formation process during slot‐die coating of polystyrene‐block‐poly(ethylene oxide)/ZnO hybrid films is investigated with in situ X‐ray scattering. Both, cooperative self‐assembly and self‐assembly pathways during solution‐to‐film transition involve multistep structural transformations triggered by solvent evaporation.
Slot‐die coating is a powerful method for upscaling the production of organic solar cells (OSCs) with low energy consumption print processes at ambient conditions. Herein, chlorobenzene (CB) and ...chloroform (CF) are compared as host solvents for printing films of the neat novel fused‐ring unit based wide‐bandgap donor polymer (PDTBT2T‐FTBDT), the small molecule nonfullerene acceptor based on a fused ring with a benzothiadiazole core (BTP‐4F) as well as the respective PDTBT2T‐FTBDT:BTP‐4F blend films at room temperature in air. Using CF printing of the PDTBT2T‐FTBDT:BTP‐4F active layer, OSCs with a high power conversion efficiency of up to 13.2% are reached in ambient conditions. In comparison to CB printed blend films, the active layer printed out of CF has a superior morphology, a smoother film surface and a more pronounced face‐on orientation of the crystallites, which altogether result in an enhanced exciton dissociation, a superior charge transport, and suppressed nonradiative charge carrier recombination. Based on in situ studies of the slot‐die coating process of PDTBT2T‐FTBDT, BTP‐4F, and PDTBT2T‐FTBDT:BTP‐4F films, the details of the film formation kinetics are clarified, which cause the superior behavior for CF compared to CB printing due to balancing the aggregation and crystallization of donor and acceptor.
The printing of active layers for nonfullerene organic solar cells is studied at ambient conditions with in situ techniques to rationalize why the best performing devices are achieved with printing out of chloroform in terms of morphology and crystal structure.
Reports of tattoo-associated risks boosted the interest in tattoo pigment toxicity over the last decades. Nonetheless, the influence of tattoo pigments on skin homeostasis remains largely unknown. In ...vitro systems are not available to investigate the interactions between pigments and skin. Here, we established TatS, a reconstructed human full-thickness skin model with tattoo pigments incorporated into the dermis. We mixed the most frequently used tattoo pigments carbon black (0.02 mg/ml) and titanium dioxide (TiO
2
, 0.4 mg/ml) as well as the organic diazo compound Pigment Orange 13 (0.2 mg/ml) into the dermis. Tissue viability, morphology as well as cytokine release were used to characterize TatS. Effects of tattoo pigments were compared to monolayer cultures of human fibroblasts. The tissue architecture of TatS was comparable to native human skin. The epidermal layer was fully differentiated and the keratinocytes expressed occludin, filaggrin and e-cadherin. Staining of collagen IV confirmed the formation of the basement membrane. Tenascin C was expressed in the dermal layer of fibroblasts. Although transmission electron microscopy revealed the uptake of the tattoo pigments into fibroblasts, neither viability nor cytokine secretion was altered in TatS. In contrast, TiO
2
significantly decreased cell viability and increased interleukin-8 release in fibroblast monolayers. In conclusion, TatS emulates healed tattooed human skin and underlines the advantages of 3D systems over traditional 2D cell culture in tattoo pigment research. TatS is the first skin model that enables to test the effects of pigments in the dermis upon tattooing.
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The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome is an important regulator of inflammation and immune ...responses. Histone deacetylase 6 (HDAC6) has been implicated in the assembly and activation of the NLRP3 inflammasome in mouse cells, however, the role in human immune cells remains poorly understood. Here, we investigated the effect of HDAC6 deficiency on NLRP3-mediated interleukin (IL)-1β release using proteolysis targeting chimeras (PROTAC) technology. We designed an HDAC6 PROTAC (A6) composed of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and the E3 ligase ligand thalidomide and a control PROTAC (non-degrading control, nc-A6) that binds to HDAC6 but lacks the ability to induce HDAC6 degradation. A6 but not nc-A6 reduced HDAC6 levels in THP-1 macrophages without affecting cell viability. PROTAC A6 and nc-A6 significantly reduced the release of IL-1β in a concentration-dependent manner, suggesting that HDAC6 deficiency is not necessary for inhibition of NLRP3 inflammasome-mediated IL-1β release. We found that inhibition of the catalytic domain with HDAC inhibitor SAHA or the specific HDAC6 inhibitor tubastatin A is sufficient to reduce IL-1β release indicating that the enzymatic activity of HDAC6 is critical for NLRP3 inflammasome function. Mechanistically, the observed effects of HDAC6 inhibition on NLRP3-mediated inflammatory responses could be attributed to its interaction with Toll-like receptor (TLR) signaling. Tubastatin A did not affect IL-1β levels when added after TLR-mediated priming. Collectively, our findings indicate that HDAC6 inhibitors show potent anti-inflammatory activity and suppress IL-1β release by human macrophages, independent of NLRP3 assembly and activation.
Scalable thin‐film deposition methods are increasingly important for hybrid lead halide perovskite thin films. Understanding the structure evolution during non‐equilibrium processes helps to find ...suitable materials and processing parameters to produce films with well‐performing optoelectronic properties. Here, spin‐cast and slot‐die coated bilayers of lead iodide (PbI2) and methylammonium iodide (MAI) are investigated by in situ grazing‐incidence wide‐angle X‐ray scattering during the thermal annealing process, which converts the bilayer into methylammonium lead iodide (MAPI). Photoluminescence (PL) and UV/Vis measurements show increasing crystallinity during the annealing process and a slight PL red‐shift of the spin‐cast film, attributed to crystallite coalescence that is not prominent for the slot‐die coated film. The disintegration of the solvent‐precursor complex (MA)2(Pb3I8) ⋅ 2 DMSO and conversion into perovskite are followed in situ and differences in the morphology and time evolution are observed. In both, spin‐cast and slot‐die coated thin‐films, the isotropic orientation is dominant, however, in the slot‐die coated films, the perovskite crystallites have an additional face‐on orientation ((110) parallel to substrate) that is not detected in spin‐cast films. An Avrami model is applied for the perovskite crystal growth that indicates reduced dimensionality of the growth for the printed thin films.
In this work in situ morphology analysis during the MAPI perovskite annealing process of spin‐cast and slot‐die coated thin films is coupled with optical measurements that show a slightly larger bandgap for spin‐cast films. Morphology is probed by in situ GIWAXS and reveals an additional face‐on crystallite orientation in the slot‐die coated films that grow stronger during the annealing.
For efficient pain reduction in severe skin wounds, topical opioids may be a new option – given that wound healing is not impaired and the vehicle allows for slow opioid release, since long intervals ...of painful wound dressing changes are intended. We investigated the influence of opioids on the wound healing process via in vitro models, migration assay and scratch test. In fact, morphine, hydromorphone, fentanyl and buprenorphine increased the number of migrated HaCaT cells (spontaneously transformed keratinocytes) twofold. In the scratch test, morphine accelerated the closure of a monolayer wound (scratch). As possible slow release application forms are nanoparticulate systems like solid lipid nanoparticles (SLN) and dendritic core-multishell (CMS) nanotransporters, we evaluated the effect of unloaded nanoparticles on HaCaT cell migration, too. CMS nanotransporters did not inhibit migration, SLN even enhanced it (twofold). Applying morphine plus unloaded nanoparticles reduced morphine effects possibly due to uptake into CMS nanotransporters and adsorption to the surface of SLN. In contrast to SLN, TGF-β1 was taken up by CMS nanotransporters, too. Both nanoparticles are tolerable by skin and eye as derived from Episkin-SM
TM skin irritation test and HET-CAM assay. No acute toxic effects were observed either. In conclusion, opioids as well as the investigated nanoparticulate carriers conform the essential conditions for topical pain reduction.
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