•The formation of CrTaO4 after a short incubation period decreased the oxidation kinetics of Ta-containing alloys.•Activation energies for scale growth comparable to those of Cr2O3 and CrTaO4 forming ...Ni-based superalloys were found.•The oxygen inward diffusion was found to be rate determining in CrTaO4 forming alloys.•In Nb-containing alloys, the formation of Nb2O5 caused a porous oxide scale as well as severe oxide spallation.•Ti had a positive effect on the high-temperature oxidation behaviour because it supports the formation of protective CrTaO4.
The high-temperature oxidation mechanism of a series of refractory high entropy alloys: TaMoCrTiAl, NbMoCrTiAl, NbMoCrAl and TaMoCrAl at 1000 °C in air was studied. A complex protective oxide layer consisting of Al2O3, Cr2O3 and CrTaO4 oxides was observed for the quinary Ta-containing alloy. The formation of CrTaO4 in this alloy after a short incubation period decreased the oxidation kinetics from a parabolic to a quartic rate law. Ti was found to support the formation of CrTaO4. In the Nb-containing alloys, the formation of different Nb2O5 polytypes near the metal/oxide interface caused a highly porous oxide scale and severe oxide spallation.
Miller-Dieker syndrome (MDS) is caused by a heterozygous deletion of chromosome 17p13.3 involving the genes LIS1 and YWHAE (coding for 14.3.3ε) and leads to malformations during cortical development. ...Here, we used patient-specific forebrain-type organoids to investigate pathological changes associated with MDS. Patient-derived organoids are significantly reduced in size, a change accompanied by a switch from symmetric to asymmetric cell division of ventricular zone radial glia cells (vRGCs). Alterations in microtubule network organization in vRGCs and a disruption of cortical niche architecture, including altered expression of cell adhesion molecules, are also observed. These phenotypic changes lead to a non-cell-autonomous disturbance of the N-cadherin/β-catenin signaling axis. Reinstalling active β-catenin signaling rescues division modes and ameliorates growth defects. Our data define the role of LIS1 and 14.3.3ε in maintaining the cortical niche and highlight the utility of organoid-based systems for modeling complex cell-cell interactions in vitro.
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•Homogeneous forebrain-type organoids reflect early cortical development in vitro•MDS-derived organoids show reduced expansion rate caused by premature neurogenesis•MDS-derived organoids exhibit alterations in cortical niche architecture•Niche disruption leads to a non-cell-autonomous disturbance of β-catenin signaling
Using Miller-Dieker-syndrome-specific iPSC-derived forebrain-type organoid cultures, Iefremova et al. find that a disturbance of cortical niche signaling leads to alterations in N-cadherin/β-catenin signaling that result in a non-cell-autonomous expansion defect of ventricular zone radial glia cells.
Neural stem cell (NSC) transplantation represents an unexplored approach for treating neurodegenerative disorders associated with cognitive decline such as Alzheimer disease (AD). Here, we used aged ...triple transgenic mice (3xTg-AD) that express pathogenic forms of amyloid precursor protein, presenilin, and tau to investigate the effect of neural stem cell transplantation on AD-related neuropathology and cognitive dysfunction. Interestingly, despite widespread and established Ass plaque and neurofibrillary tangle pathology, hippocampal neural stem cell transplantation rescues the spatial learning and memory deficits in aged 3xTg-AD mice. Remarkably, cognitive function is improved without altering Ass or tau pathology. Instead, the mechanism underlying the improved cognition involves a robust enhancement of hippocampal synaptic density, mediated by brain-derived neurotrophic factor (BDNF). Gain-of-function studies show that recombinant BDNF mimics the beneficial effects of NSC transplantation. Furthermore, loss-of-function studies show that depletion of NSC-derived BDNF fails to improve cognition or restore hippocampal synaptic density. Taken together, our findings demonstrate that neural stem cells can ameliorate complex behavioral deficits associated with widespread Alzheimer disease pathology via BDNF.
Refractory high entropy alloys (RHEA) are considered as novel promising high‐temperature materials for structural applications at ultrahigh temperatures primarily due to their attractive mechanical ...properties. By contrast, the oxidation behavior of RHEA has raised concern owing to pest oxidation, significant weight changes, scale spallation, or even complete oxidation at elevated temperatures. Herein, the currently available literature on high‐temperature oxidation behavior of RHEA is reviewed with respect to alloy composition, mass changes, corrosion products, and scale constitution. While many RHEA indeed suffer from poor oxidation resistance similar to that of pure refractory metals, some RHEA exhibit very good protectiveness, which is attributed to the formation of either well‐known protective scales such as α‐Al2O3 or rarely encountered complex oxides such as CrTaO4. Thermodynamic and kinetic aspects of oxide formation and growth are discussed to understand the oxidation mechanisms typical of RHEA. Further research directions with respect to additional in‐depth studies elucidating the oxidation mechanisms as well as the further consequent improvement of the oxidation resistance of RHEA are developed from the current intermediate stage of research in the field.
This review summarizes the current stage of high‐temperature oxidation behavior of refractory high entropy alloys (RHEA)—candidates for demanding high‐temperature structural applications. Despite the intrinsic poor oxidation resistance of refractory metals, some RHEA exhibit oxidation protectiveness. The different oxidation modes, mechanisms, and future research directions aiming at the consequent enhancement of corrosion resistance of RHEA are highlighted.
DNA methylation plays a critical role during development, particularly in repressing retrotransposons. The mammalian methylation landscape is dependent on the combined activities of the canonical ...maintenance enzyme Dnmt1 and the de novo Dnmts, 3a and 3b. Here, we demonstrate that Dnmt1 displays de novo methylation activity in vitro and in vivo with specific retrotransposon targeting. We used whole-genome bisulfite and long-read Nanopore sequencing in genetically engineered methylation-depleted mouse embryonic stem cells to provide an in-depth assessment and quantification of this activity. Utilizing additional knockout lines and molecular characterization, we show that the de novo methylation activity of Dnmt1 depends on Uhrf1, and its genomic recruitment overlaps with regions that enrich for Uhrf1, Trim28 and H3K9 trimethylation. Our data demonstrate that Dnmt1 can catalyze DNA methylation in both a de novo and maintenance context, especially at retrotransposons, where this mechanism may provide additional stability for long-term repression and epigenetic propagation throughout development.
Forced expression of proneural transcription factors has been shown to direct neuronal conversion of fibroblasts. Because neurons are postmitotic, conversion efficiencies are an important parameter ...for this process. We present a minimalist approach combining two-factor neuronal programming with small molecule-based inhibition of glycogen synthase kinase-3β and SMAD signaling, which converts postnatal human fibroblasts into functional neuron-like cells with yields up to >200% and neuronal purities up to >80%.
•The protectiveness of refractory metal-based alloys can be realized if alloys contain required concentrations of Cr and Ta.•The oxide CrTaO4 reliably protects the refractory equatomic high entropy ...alloy Ta-Mo-Cr-Ti-Al by formation of a CrTaO4 scale.•CrTaO4 scale forms in a wide temperature range from 500 °C to 1500 °C exhibiting low growth rates.•CrTaO4 possesses high adhesive properties.•Wide stability range of the stoichiometric composition that suppresses the formation of other (non-protective) oxides.
Poor oxidation resistance represents one of the main shortcomings of refractory metal based alloys. This work shows an innovative way to intrinsically protect such materials. Our approach relies on the alloying with Cr and Ta allowing the formation of CrTaO4. The CrTaO4 scale formed on the novel refractory equiatomic high entropy alloy Ta-Mo-Cr-Ti-Al reveals a unique combination of the following properties: (i) easy formation in a wide temperature range from 500 °C to 1500 °C, (ii) excellent adherence after cooling, (iii) low growth rates, and (iv) wide stability range of the stoichiometric composition that suppresses the formation of non-protective oxides.
During nervous system development, early neuroepithelial stem (NES) cells with a highly polarized morphology and responsiveness to regionalizing morphogens give rise to radial glia (RG) cells, which ...generate region‐specific neurons. Recently, stable neural cell populations reminiscent of NES cells have been obtained from pluripotent stem cells and the fetal human hindbrain. Here, we explore whether these cell populations, similar to their in vivo counterparts, can give rise to neural stem (NS) cells with RG‐like properties and whether region‐specific NS cells can be generated from NES cells with different regional identities. In vivo RG cells are thought to form from NES cells with the onset of neurogenesis. Therefore, we cultured NES cells temporarily in differentiating conditions. Upon reinitiation of growth factor treatment, cells were found to enter a developmental stage reflecting major characteristics of RG‐like NS cells. These NES cell‐derived NS cells exhibited a very similar morphology and marker expression as primary NS cells generated from human fetal tissue, indicating that conversion of NES cells into NS cells recapitulates the developmental progression of early NES cells into RG cells observed in vivo. Importantly, NS cells generated from NES cells with different regional identities exhibited stable region‐specific transcription factor expression and generated neurons appropriate for their positional identity. Stem Cells 2019;37:1429–1440
In vivo, neuroepithelial stem cells of the neural tube give rise to radial glia cells of the fetal brain. Stably expandable neuroepithelial stem (NES) cells can be derived from pluripotent stem cells and directly from early‐stage human fetal brain tissue. Later‐stage human fetal brain tissue gives rise to radial glia‐like neural stem (NS) cells. Results of this study showed that radial glia‐like NS cells can be directly generated from in vitro expanded NES cells.
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