Advances of non-precious-metal catalysts for alkaline water electrolysis are reviewed, highlighting operando techniques and theoretical calculations in their development.
Two nucleotide substitutions in the human FGFR2 gene (C755G or C758G) are responsible for virtually all sporadic cases of Apert syndrome. This condition is 100 -1,000 times more common than genomic mutation frequency data predict. Here, we report on the C758G de novo Apert syndrome mutation. Using data on older donors, we show that spontaneous mutations are not uniformly distributed throughout normal testes. Instead, we find foci where C758G mutation frequencies are 3-4 orders of magnitude greater than the remaining tissue. We conclude this nucleotide site is not a mutation hot spot even after accounting for possible LuriaDelbruck ''mutation jackpots.'' An alternative explanation for such foci involving positive selection acting on adult self-renewing Ap spermatogonia experiencing the rare mutation could not be rejected. Further, the two youngest individuals studied (19 and 23 years old) had lower mutation frequencies and smaller foci at both mutation sites compared with the older individuals. This implies that the mutation frequency of foci increases as adults age, and thus selection could explain the paternal age effect for Apert syndrome and other genetic conditions. Our results, now including the analysis of two mutations in the same set of testes, suggest that positive selection can increase the relative frequency of premeiotic germ cells carrying such mutations, although individuals who inherit them have reduced fitness. In addition, we compared the anatomical distribution of C758G mutation foci with both new and old data on the C755G mutation in the same testis and found their positions were not correlated with one another.Apert syndrome ͉ paternal age ͉ positive selection ͉ spermatogonia ͉ testis
Multiple endocrine neoplasia type 2B (MEN2B) is a highly aggressive thyroid cancer syndrome. Since almost all sporadic cases are caused by the same nucleotide substitution in the RET proto-oncogene, the calculated disease incidence is 100–200 times greater than would be expected based on the genome average mutation frequency. In order to determine whether this increased incidence is due to an elevated mutation rate at this position (true mutation hot spot) or a selective advantage conferred on mutated spermatogonial stem cells, we studied the spatial distribution of the mutation in 14 human testes. In donors aged 36–68, mutations were clustered with small regions of each testis having mutation frequencies several orders of magnitude greater than the rest of the testis. In donors aged 19–23 mutations were almost non-existent, demonstrating that clusters in middle-aged donors grew during adulthood. Computational analysis showed that germline selection is the only plausible explanation. Testes of men aged 75–80 were heterogeneous with some like middle-aged and others like younger testes. Incorporating data on age-dependent death of spermatogonial stem cells explains the results from all age groups. Germline selection also explains MEN2B's male mutation bias and paternal age effect. Our discovery focuses attention on MEN2B as a model for understanding the genetic and biochemical basis of germline selection. Since RET function in mouse spermatogonial stem cells has been extensively studied, we are able to suggest that the MEN2B mutation provides a selective advantage by altering the PI3K/AKT and SFK signaling pathways. Mutations that are preferred in the germline but reduce the fitness of offspring increase the population's mutational load. Our approach is useful for studying other disease mutations with similar characteristics and could uncover additional germline selection pathways or identify true mutation hot spots.
development of sustainable energy conversion and storage technologies. [1] Nowadays, the electrolysis of oxygen reduction reaction (ORR), oxygen evolution reaction (OER), hydrogen evolution reaction (HER), and carbon dioxide reduction reaction (CO 2 RR) is being extensively researched. [2] The conversion efficiencies of these electrochemical reactions are critical to the performance of sustainable energy devices, including fuel cells, metal-air batteries, and electrolyzers. [3] Particularly, ORR is the cathode reaction of fuel cells which are characterized by a higher energy efficiency than that of conventional combustion engines. [4] ORR and OER occur at the gas electrode of a rechargeable metal-air battery. [5] In the production of electro-fuels (e.g., H 2 or CO), HER and CO 2 RR serve as the cathode reactions in electrolyzers with H 2 O and CO 2 as the reactants, respectively. [6] The development of high-performance electrocatalysts is critical for the mass adoption of those sustainable energy applications. [7] Carbon-supported nonprecious metals (C@NPMs) have recently attracted significant attention for the promotion of the above-mentioned reactions during electrolysis owing to their low cost and potentially high activity. [8] Carbon frameworks can be easily modified and can take the form of various nanostructures, such as 1D carbon nanotubes (CNTs), [9] 2D graphene, [10] and 3D porous carbons. [11] The coupling of nonprecious metals with carbons can mitigate the corrosion issues of these metals under harsh electrolysis conditions (e.g., strong alkaline/acidic electrolytes and oxidative potentials), and reduce agglomeration by enhancing the dispersion of the metal moieties. [12] In addition, the coupling can promote charge transfer between the carbon and the metal components, thereby tuning the electronic structure for catalysis. [13] Thus, the carbon support not only works as a conductive substrate but also interacts electronically with the metal species, modifying the electronic/ electrochemical properties of the composite. [14] The catalytic properties of C@NPMs can be further optimized by introducing heteroatom dopants, engineering topological defects, modulating metal size, tuning the carbon shell, and coupling multimetals. [15] Owing to the tremendous efforts of the research community in this field, C@NPMs have seen significant advancements. For instance, Fe or Co coupled with N-doped carbon, i.e., FeNC and CoNC are one of the most promising ORR electrocatalysts to replace precious Pt in both acidic and alkaline electrolytes. [16] The development of sustainable energy conversion and storage devices, such as fuel cells, metal-air batteries, and electrolyzers is highly dependent on the catalytic oxygen reduction reaction (ORR), oxygen evolution reaction (OER), hydrogen evolution reaction (HER), and carbon dioxide reduction reaction (CO 2 RR). Carbon-supported nonprecious metals (C@NPMs) with variable metal sizes (single atom, cluster, and nanoparticle) are attracting significant interest for catalyzin...
Celtis choseniana is the traditional plant used at Korea as a herbal medicine to ameliorate inflammatory responses. Although Celtis choseniana has been traditionally used as a herbal medicine at Korea, no systemic research has been conducted on its anti-inflammatory activity. Therefore, the present study explored an anti-inflammatory effect and its underlying molecular mechanism using Celtis choseniana methanol extract (Cc-ME) in macrophage-mediated inflammatory responses. In vitro anti-inflammatory activity of Cc-ME was evaluated using RAW264.7 cells and peritoneal macrophages stimulated by lipopolysaccharide (LPS), pam3CSK4 (Pam3), or poly(I:C). In vivo anti-inflammatory activity of Cc-ME was investigated using acute inflammatory disease mouse models, such as LPS-induced peritonitis and HCl/EtOH-induced gastritis. The molecular mechanism of Cc-ME-mediated anti-inflammatory activity was examined by Western blot analysis and immunoprecipitation using whole cell and nuclear fraction prepared from the LPS-stimulated RAW264.7 cells and HEK293 cells. Cc-ME inhibited NO production and mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and tumor necrosis factor-alpha (TNF-α) in the RAW264.7 cells and peritoneal macrophages induced by LPS, pam3, or poly(I:C) without cytotoxicity. High-performance liquid chromatography (HPLC) analysis showed that Cc-ME contained anti-inflammatory flavonoids quercetin, luteolin, and kaempferol. Among those, the content of luteolin, which showed an inhibitory effect on NO production, was highest. Cc-ME suppressed the NF-κB signaling pathway by targeting Src and interrupting molecular interactions between Src and p85, its downstream kinase. Moreover, Cc-ME ameliorated the morphological finding of peritonitis and gastritis in the mouse disease models. Therefore, these results suggest that Cc-ME exerted in vitro and in vivo anti-inflammatory activity in LPS-stimulated macrophages and mouse models of acute inflammatory diseases. This anti-inflammatory activity of Cc-ME was dominantly mediated by targeting Src in NF-κB signaling pathway during macrophage-mediated inflammatory responses.
The effects of impurities, Mn or Al, on interface and grain boundary electromigration (EM) in Cu damascene lines were investigated. The addition of Mn or Al solute caused a reduction in diffusivity at the Cu/dielectric cap interface and the EM activation energies for both Cu-alloys were found to increase by about 0.2 eV as compared to pure Cu. Mn mitigated and Al enhanced Cu grain boundary diffusion; however, no significant mitigation in Cu grain boundary diffusion was observed in low Mn concentration samples. The activation energies for Cu grain boundary diffusion were found to be 0.74 ± 0.05 eV and 0.77 ± 0.05 eV for 1.5 μm wide polycrystalline lines with pure Cu and Cu (0.5 at. % Mn) seeds, respectively. The effective charge number in Cu grain boundaries Z*GB was estimated from drift velocity and was found to be about −0.4. A significant enhancement in EM lifetimes for Cu(Al) or low Mn concentration bamboo-polycrystalline and near-bamboo grain structures was observed but not for polycrystalline-only alloy lines. These results indicated that the existence of bamboo grains in bamboo-polycrystalline lines played a critical role in slowing down the EM-induced void growth rate. The bamboo grains act as Cu diffusion blocking boundaries for grain boundary mass flow, thus generating a mechanical stress-induced back flow counterbalancing the EM force, which is the equality known as the “Blech short length effect.”
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