Alkaline water electrolyzers (AWEs) and anion‐exchange membrane fuel cells (AEMFCs) have received increasing attention for their natural compatibility with earth‐abundant materials and are regarded ...as the cutting‐edge of hydrogen energy techniques and the research focuses. However, the commercialization of these devices remains in the sluggish hydrogen electrode reactions due to the requirement of cooperative adsorption of both hydrogen species and hydroxyl species. The research on synergistic alkaline hydrogen oxidation/evolution reaction (HOR/HER) electrocatalysts is still in its infancy. This review summarizes the recent progress and strategies in constructing synergistic active sites for advancing alkaline HOR/HER electrocatalysts. The fundamentals of alkaline HOR/HER are first introduced with both theoretical and experimental verifications to rationalizing the necessity of constructing synergistic active sites. Then, this review systemically dissects the functionality of different active sites in recently reported innovative HOR/HER catalysts and introduces the synergistic effects. Finally, some perspectives on the challenges and opportunities for the future design and synthesis of the synergistic HOR and HER electrocatalysts are proposed, intending to promote the application of hydrogen‐based energy conversion systems.
In this review, the recent progress and strategies in constructing synergistic active sites for advancing alkaline hydrogen oxidation/evolution reaction electrocatalysts are systematically summarized, aiming at promoting the commercialization of hydrogen‐based energy conversion systems.
The pro-inflammatory activation of microglia is a hallmark of Alzheimer’s disease (AD), and this process involves a switch from oxidative phosphorylation (OXPHOS) toward glycolysis. Here, we show how ...a positive feedback loop in microglia drives AD pathogenesis, and we demonstrate that inhibiting this cycle in microglia can ameliorate Aβ burden and cognitive deficits in an AD mouse model (5XFAD). After first detecting elevated histone lactylation in brain samples from both 5XFAD mice and individuals with AD, we observed that H4K12la levels are elevated in Aβ plaque-adjacent microglia. This lactate-dependent histone modification is enriched at the promoters of glycolytic genes and activates transcription, thereby increasing glycolytic activity. Ultimately, the glycolysis/H4K12la/PKM2 positive feedback loop exacerbates microglial dysfunction in AD. Pharmacologic inhibition of PKM2 attenuated microglial activation, and microglia-specific ablation of Pkm2 improved spatial learning and memory in AD mice. Thus, our study illustrates that disruption of the positive feedback loop may be a potential therapeutic approach for the treatment of AD.
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•Histone lactylation is elevated in the brains of 5XFAD model mice and AD patients•H4K12la activates transcription of glycolytic genes in AD microglia•A glycolysis/H4K12la/PKM2 positive feedback loop exacerbates microglial dysfunction•Interruption of this loop ameliorates microglial dysfunction and Aβ pathology
Pan et al. report a glycolysis/H4K12 lactylation/PKM2 positive feedback loop in microglia that drives the pathogenesis of Alzheimer’s disease (AD). They demonstrate that interruption of this loop by blocking PKM2 ameliorates Aβ pathology and improves spatial learning and memory in AD model mice.
Microbial secondary metabolites (MSMs) have played and continue to play a highly significant role in the drug discovery and development process. Genetically, MSM chemical structures are biologically ...synthesized by microbial gene clusters. Recently, however, the speed of new bioactive MSM discovery has been slowing down due to consistent employment of conventional cultivation and isolation procedure. In order to alleviate this challenge, a number of new approaches have been developed. The strategy of one strain many compounds (OSMAC) has been shown as a simple and powerful tool that can activate many silent biogenetic gene clusters in microorganisms to make more natural products. This review highlights important and successful examples using OSMAC approaches, which covers changing medium composition and cultivation status, co-cultivation with other strain(s), adding enzyme inhibitor(s) and MSM biosynthetic precursor(s). Available evidences had shown that variation of cultivation condition is the most effective way to produce more MSMs and facilitate the discovery of new therapeutic agents.
Ligand-controlled, palladium-catalyzed asymmetric 4+4 and 2+4 cycloaddition reactions of benzofuran-derived azadienes have been developed. Taking advantage of chiral P,N-ligand (S,R p)-PPFA, we ...obtained a variety of benzofuro2,3-c1,5 oxazocines in good yields with excellent enantioselectivities via 4+4 cycloaddition reactions. Employing chiral P,P-ligand (S)-Cl-MeO-BIPHEP, the chemo- and regioselectivities were switched to synthesize tetrahydropyran-fused spirocyclic compounds in good efficiency via 2+4 cycloaddition reactions.
This article addresses the safe stabilization problem of stochastic nonlinear time-delay systems. Based on the Krasovskii approach, we first propose a stochastic control Lyapunov-Krasovskii ...functional to guarantee the stabilization objective and a stochastic control barrier-Krasovskii functional to ensure the safety objective. Both functionals are developed, respectively, for each control objectives for the first time. Since the optimization problem is not easy to be resolved for stochastic time-delay systems, we derive a sliding mode-based approach to combine the proposed two functionals and to mediate stabilization and safety objectives, which allows to achieve the stabilization objective under the safety requirement. The proposed approach is illustrated via a numerical example.
A cascade three-component iodoazidation of para-quinone methides to construct spiro4.5deca-6,9-dien-8-ones under mild conditions has been developed. The chemoselective 1,6-addition of azide radical ...triggered a regioselective 5-exo-dig cyclization/radical coupling sequence, enabling C–N, C–C, and C–I bond formations in a one-pot procedure with high efficiency.
Genetic variants conferring risk for schizophrenia (SCZ) have been extensively studied, but the role of posttranscriptional mechanisms in SCZ is not well studied. Here we performed the first ...genome-wide microRNA (miRNA) expression profiling in serum-derived exosome from 49 first-episode, drug-free SCZ patients and 46 controls and identified miRNAs and co-regulated modules that were perturbed in SCZ. Putative targets of these SCZ-affected miRNAs were enriched strongly for genes that have been implicated in protein glycosylation and were also related to neurotransmitter receptor and dendrite (spine) development. We validated several differentially expressed blood exosomal miRNAs in 100 SCZ patients as compared with 100 controls by quantitative reverse transcription-polymerase chain reaction. The potential regulatory relationships between several SCZ-affected miRNAs and their putative target genes were also validated. These include hsa-miR-206, which is the most upregulated miRNA in the blood exosomes of SCZ patients and that previously reported to regulate brain-derived neurotrophic factor expression, which we showed reduced mRNA and protein levels in the blood of SCZ patients. In addition, we found 11 miRNAs in blood exosomes from the miRNA sequence data that can be used to classify samples from SCZ patients and control subjects with close to 90% accuracy in the training samples, and approximately 75% accuracy in the testing samples. Our findings support a role for exosomal miRNA dysregulation in SCZ pathophysiology and provide a rich data set and framework for future analyses of miRNAs in the disease, and our data also suggest that blood exosomal miRNAs are promising biomarkers for SCZ.
Nonequilibrium processes of small systems such as molecular machines are ubiquitous in biology, chemistry, and physics but are often challenging to comprehend. In the past two decades, several exact ...thermodynamic relations of nonequilibrium processes, collectively known as fluctuation theorems, have been discovered and provided critical insights. These fluctuation theorems are generalizations of the second law and can be unified by a differential fluctuation theorem. Here we perform the first experimental test of the differential fluctuation theorem using an optically levitated nanosphere in both underdamped and overdamped regimes and in both spatial and velocity spaces. We also test several theorems that can be obtained from it directly, including a generalized Jarzynski equality that is valid for arbitrary initial states, and the Hummer-Szabo relation. Our study experimentally verifies these fundamental theorems and initiates the experimental study of stochastic energetics with the instantaneous velocity measurement.
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l-Tryptophan (Trp) metabolites and related neurotransmitters play crucial roles in physiological functions, and their imbalances are implicated in the pathology of depression, Alzheimer's disease and ...other diseases. Measurement of Trp metabolites and related neurotransmitters possesses a great potential to elucidate the disease mechanisms and evaluate the outcomes of therapeutic interventions. A simple, rapid, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous determination of Trp, l-kynurenine (Kyn), kynurenic acid (Kyna), 3-hydroxykynurenine (3-HK), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine (NE), l-glutamic acid (Glu), γ-aminobutyric acid (GABA) and acetylcholine (ACh) in mice serum and the brain tissues in a single chromatographic run. Samples were spiked with the internal standard, mixed with trifluoroacetic acid to precipitate protein and analyzed by LC-MS/MS. Chromatographic separation was achieved using a Restek Ultra Aqueous C18 column in combination with a gradient elution within 8 min. Mass spectrometric detection was performed using multiple reaction monitoring with electrospray ionization source in positive mode. The method exhibited good selectivity and correlation coefficient values for the calibration curves of each analyte were >0.99. The limit of detection and quantification ranged from 0.96 to 24.48 nmol/L and 3.42 to 244.82 nmol/L, respectively. The intra- and inter-day precision were ≤13.92%. All analytes were stable in prepared samples at room temperature in the autosampler for 24 h. This method was successfully applied to the analysis of biological samples from control and chronic mild stress (CMS) induced depression mice. It was found that Kyn and 3-HK pathways were enhanced by CMS, while the levels of Trp, Kyna, 5-HIAA, Glu, GABA and ACh were significantly reduced. The changes in 5-HT and NE levels were not uniform in the periphery and the brain. This method can therefore be applied to analyze Trp metabolites and related neurotransmitters levels to monitor disease states, study the mechanisms and outcomes of therapeutic interventions.
•Simultaneous quantification of tryptophan metabolites and related neurotransmitters•The validated method shows high selectivity, sensitivity and precision.•Analytes were successfully detected in control and chronic mild stress mice.
Spurred on by recent advances in materials chemistry and drug delivery, a new stimuli-responsive theranostic hybrid platform, based on mechanized monodisperse nano metal-organic frameworks (NMOFs) ...gated by carboxylatopillar5arene (CP5) switches with bio-friendly pH-triggered cargo release capabilities, has been constructed for the first time. This nanoscale smart cargo delivery system showed pH- and/or competitive binding agent-triggered controlled cargo release with negligible premature release, large pore sizes for drug encapsulation, low cytotoxicity, good biodegradability and biocompatibility, and potential application in cell imaging, which offers a new tool in targeted drug delivery and the controlled release of therapeutic agents.
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