ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation.

Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both in vitro and in vivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD.

Strong effect-correlated electrochemical CO2 reduction.

Electrochemical CO2 reduction (ECR) holds great potential to alleviate the greenhouse effect and our dependence on fossil fuels by integrating renewable energy for the electrosynthesis of high-value fuels from CO2. However, the high thermodynamic energy barrier, sluggish reaction kinetics, inadequate CO2 conversion rate, poor selectivity for the target product, and rapid electrocatalyst degradation severely limit its further industrial-scale application. Although numerous strategies have been proposed to enhance ECR performances from various perspectives, scattered studies fail to comprehensively elucidate the underlying effect-performance relationships toward ECR. Thus, this review presents a comparative summary and a deep discussion with respect to the effects strongly-correlated with ECR, including intrinsic effects of materials caused by various sizes, shapes, compositions, defects, interfaces, and ligands; structure-induced effects derived from diverse confinements, strains, and fields; electrolyte effects introduced by different solutes, solvents, cations, and anions; and environment effects induced by distinct ionomers, pressures, temperatures, gas impurities, and flow rates, with an emphasis on elaborating how these effects shape ECR electrocatalytic activities and selectivity and the underlying mechanisms. In addition, the challenges and prospects behind different effects resulting from various factors are suggested to inspire more attention towards high-throughput theoretical calculations and in situ/operando techniques to unlock the essence of enhanced ECR performance and realize its ultimate application.

Emerging Nanomaterials toward Uranium Extraction from Seawater: Recent Advances and Perspectives.

Nuclear energy holds great potential to facilitate the global energy transition and alleviate the increasing environmental issues due to its high energy density, stable energy output, and carbon-free emission merits. Despite being limited by the insufficient terrestrial uranium reserves, uranium extraction from seawater (UES) can offset the gap. However, the low uranium concentration, the complicated uranium speciation, the competitive metal ions, and the inevitable marine interference remarkably affect the kinetics, capacity, selectivity, and sustainability of UES materials. To date, massive efforts have been made with varying degrees of success to pursue a desirable UES performance on various nanomaterials. Nevertheless, comprehensive and systematic coverage and discussion on the emerging UES materials presenting the fast-growing progress of this field is still lacking. This review thus challenges this position and emphatically focuses on this topic covering the current mainstream UES technologies with the emerging UES materials. Specifically, this review elucidates the causality between the physiochemical properties of UES materials induced by the intellectual design strategies and the UES performances and further dissects the relationships of materials-properties-activities and the corresponding mechanisms in depth. This review is envisaged to inspire innovative ideas and bring technical solutions for developing technically and economically viable UES materials.

Vitexin enhances radiosensitivity of mouse subcutaneous xenograft glioma by affecting the miR-17-5p/miR-130b-3p/PTEN/HIF-1α pathway.

PURPOSE: Vitexin can cooperate with hyperbaric oxygen to sensitize the radiotherapy of glioma by inhibiting the hypoxia-inducible factor (HIF)-1α. However, whether vitexin has a direct radiosensitization and how it affects the HIF-1α expression remain unclear. This study investigated these issues. METHODS: The SU3 cells-inoculated nude mice were divided into control, radiation, and vitexin + radiation groups. The vitexin + radiation-treated mice were intraperitoneally injected with 75 mg/kg vitexin daily for 21 days. On the 3rd, 10th, and 17th days during the vitexin treatment, the radiation-treated mice were locally irradiated with 10 Gy, respectively. In vitro, the microRNA (miR)-17-5p or miR-130b-3p mimics-transfected SU3 cells were used to examine the effects of vitexin plus radiation on expression of miR-17-5p- or miR-130b-3p-induced radioresistance-related pathway proteins. The effects of vitexin on miR-17-5p and miR-130b-3p expression in SU3 cells were also evaluated. RESULTS: Compared with the radiation group, the tumor volume, tumor weight, and expression of HIF-1α, vascular endothelial growth factor, and glucose transporter-1/3 proteins, miR-17-5p, and miR-130b-3p in tumor tissues in the vitexin + radiation group decreased, whereas the expression of phosphatase and tensin homolog (PTEN) protein increased. After treatment of miR-17-5p or miR-130b-3p mimics-transfected SU3 cells with vitexin plus radiation, the PTEN protein expression also increased, the HIF-1α protein expression decreased correspondingly. Moreover, vitexin decreased the miR-17-5p and miR-130b-3p expression in SU3 cells. CONCLUSION: Vitexin can enhance the radiosensitivity of glioma, and its mechanism may partly be related to the attenuation of HIF-1α pathway after lowering the inhibitory effect of miR-17-5p and miR-130b-3p on PTEN.

Identification and map-based cloning of an EMS-induced mutation in wheat gene TaSP1 related to spike architecture.

KEY MESSAGE: A candidate gene TaSP1 related to spike shape was cloned, and the gene-specific marker was developed to efficiently track the superior haplotype in common wheat. Spike shape, an important factor that affects wheat grain yield, is mainly defined by spike length (SPL), spikelet number (SPN), and compactness. Zhoumai32 mutant 1160 (ZM1160), a mutant obtained from ethyl methane sulfonate (EMS) treatment of hexaploid wheat variety Zhoumai32, was used to identify and clone the candidate gene that conditioned the spike shape. Genetic analysis of an F2 population derived from a cross of ZM1160 and Bainong207 suggested that the compact spike shape in ZM1160 was controlled by a single recessive gene, and therefore, the mutated gene was designated as Tasp1. With polymorphic markers identified through bulked segregant analysis (BSA), the gene was mapped to a 2.65-cM interval flanked by markers YZU0852 and MIS46239 on chromosome 7D, corresponding to a 0.42-Mb physical interval of Chinese spring (CS) reference sequences (RefSeq v1.0). To fine map TaSP1, 15 and seven recombinants were, respectively, screened from 1599 and 1903 F3 plants derived from the heterozygous F2 plants. Finally, TaSP1 was delimited to a 21.9 Kb (4,870,562 to 4,892,493 bp) Xmis48123-Xmis48104 interval. Only one high-confidence gene TraesCS7D02G010200 was annotated in this region, which encodes an unknown protein with a putative vWA domain. Quantitative reverse transcription PCR (qRT-PCR) analysis showed that TraesCS7D02G010200 was mainly expressed in the spike. Haplotype analysis of 655 wheat cultivars using the candidate gene-specific marker Xg010200p2 identified a superior haplotype TaSP1b with longer spike and more spikelet number. TaSP1 is beneficial to the improvement in wheat spike shape.

The tRNA discriminator base defines the mutual orthogonality of two distinct pyrrolysyl-tRNA synthetase/tRNAPyl pairs in the same organism.

Site-specific incorporation of distinct non-canonical amino acids into proteins via genetic code expansion requires mutually orthogonal aminoacyl-tRNA synthetase/tRNA pairs. Pyrrolysyl-tRNA synthetase (PylRS)/tRNAPyl pairs are ideal for genetic code expansion and have been extensively engineered for developing mutually orthogonal pairs. Here, we identify two novel wild-type PylRS/tRNAPyl pairs simultaneously present in the deep-rooted extremely halophilic euryarchaeal methanogen Candidatus Methanohalarchaeum thermophilum HMET1, and show that both pairs are functional in the model halophilic archaeon Haloferax volcanii. These pairs consist of two different PylRS enzymes and two distinct tRNAs with dissimilar discriminator bases. Surprisingly, these two PylRS/tRNAPyl pairs display mutual orthogonality enabled by two unique features, the A73 discriminator base of tRNAPyl2 and a shorter motif 2 loop in PylRS2. In vivo translation experiments show that tRNAPyl2 charging by PylRS2 is defined by the enzyme's shortened motif 2 loop. Finally, we demonstrate that the two HMET1 PylRS/tRNAPyl pairs can simultaneously decode UAG and UAA codons for incorporation of two distinct noncanonical amino acids into protein. This example of a single base change in a tRNA leading to additional coding capacity suggests that the growth of the genetic code is not yet limited by the number of identity elements fitting into the tRNA structure.

Application of association rules and simulated annealing algorithms in optimizing traditional Chinese medicine placement schemes.

BACKGROUND AND AIM: China has used traditional Chinese medicine (TCM) to treat diseases for more than 2000 years. Traditionally, TCMs in medicine cabinets are arranged alphabetically or on the basis of experience, but this arrangement greatly affects dispensing efficiency. However, owing to the unique properties and qualities of TCM, very few automatic approaches or systems have specifically addressed TCM dispensing problems. Therefore, it is necessary to establish a method of optimizing the traditional Chinese medicine placement scheme (TCMPS) via computer algorithms to improve the work efficiency of pharmacists. METHODS: A prescription dataset from a hospital in 2022 was obtained, and the association rule algorithm (ARA) was used to calculate the frequency of use for each type of TCM and the associations between different types of TCMs. On the basis of these association and frequency data, the optimal TCMPS was calculated using the simulated annealing algorithm (SAA) and then verified using the prescription dataset from 2023. RESULTS: A total of 10,601 prescriptions were collected in 2022, involving 360 different TCMs, and each prescription contained an average of 9.485 TCMs, with Danggui (3628) being the most frequently used. When the threshold of support was set to 0.05 and the confidence was set to 0.8, 78 couplet medicines used in orthopedics clinics were found through ARA. When the threshold value of support was set to 0, the confidence was set to 0, and the rule length was 2, a total of 129,240 rules were obtained, indicating support between all pairwise TCMs. The TCMPS, calculated using SAA, had a correlation sum of 14.183 and a distance sum of 3.292. The TCMPS was verified using a prescription dataset from 2023 and theoretically improved the dispensing efficiency of pharmacists by approximately 50%. CONCLUSIONS: In this study, the ARA and SAA were successfully applied to pharmacies for the first time, and the optimal TCMPS was calculated. This approach not only significantly improves the dispensing efficiency of pharmacists and reduces patient waiting time but also enhances the quality of medical services and patient satisfaction, and provides a valuable reference for the development of smart medicine.

Tip-like Fe-N4 Sites Induced Surface Microenvironments Regulation Boosts the Oxygen Reduction Reaction.

Single atom catalysts with defined local structures and favorable surface microenvironments are significant for overcoming slow kinetics and accelerating O2 electroreduction. Here, enriched tip-like FeN4 sites (T-Fe SAC) on spherical carbon surfaces were developed to investigate the change in surface microenvironments and catalysis behavior. Finite element method (FEM) simulations, together with experiments, indicate the strong local electric field of the tip-like FeN4 and the more denser interfacial water layer, thereby enhancing the kinetics of the proton-coupled electron transfer process. In situ spectroelectrochemical studies and the density functional theory (DFT) calculation results indicate the pathway transition on the tip-like FeN4 sites, promoting the dissociation of O-O bond via side-on adsorption model. The adsorbed OH* can be facilely released on the curved surface and accelerate the oxygen reduction reaction (ORR) kinetics. The obtained T-Fe SAC nanoreactor exhibits excellent ORR activities (E1/2 =0.91 V vs. RHE) and remarkable stability, exceeding those of flat FeN4 and Pt/C. This work clarified the in-depth insights into the origin of catalytic activity of tip-like FeN4 sites and held great promise in industrial catalysis, electrochemical energy storage, and many other fields.

Integrated "Two-in-One" Strategy for High-Rate Electrocatalytic CO2 Reduction to Formate.

The electrochemical CO2 reduction reaction (ECR) is a promising pathway to producing valuable chemicals and fuels. Despite extensive studies reported, improving CO2 adsorption for local CO2 enrichment or water dissociation to generate sufficient H* is still not enough to achieve industrial-relevant current densities. Herein, we report a "two-in-one" catalyst, defective Bi nanosheets modified by CrOx (Bi-CrOx), to simultaneously promote CO2 adsorption and water dissociation, thereby enhancing the activity and selectivity of ECR to formate. The Bi-CrOx exhibits an excellent Faradic efficiency (≈ 100 %) in a wide potential range from ‒0.4 to ‒0.9 V. In addition, it achieves a remarkable formate partial current density of 687 mA cm‒2 at a moderate potential of ‒0.9 V without iR compensation, the highest value at ‒0.9 V reported so far. Control experiments and theoretical simulations revealed that the defective Bi facilitates CO2 adsorption/activation while the CrOx accounts for enhancing the protonation process via accelerating H2O dissociation. This work presents a pathway to boosting formate production through tuning CO2 and H2O species at the same time.

Update of the Pyrrolysyl-tRNA Synthetase/tRNAPyl Pair and Derivatives for Genetic Code Expansion.

The cotranslational incorporation of pyrrolysine (Pyl), the 22nd proteinogenic amino acid, into proteins in response to the UAG stop codon represents an outstanding example of natural genetic code expansion. Genetic encoding of Pyl is conducted by the pyrrolysyl-tRNA synthetase (PylRS) and its cognate tRNA, tRNAPyl. Owing to the high tolerance of PylRS toward diverse amino acid substrates and great orthogonality in various model organisms, the PylRS/tRNAPyl-derived pairs are ideal for genetic code expansion to insert noncanonical amino acids (ncAAs) into proteins of interest. Since the discovery of cellular components involved in the biosynthesis and genetic encoding of Pyl, synthetic biologists have been enthusiastic about engineering PylRS/tRNAPyl-derived pairs to rewrite the genetic code of living cells. Recently, considerable progress has been made in understanding the molecular phylogeny, biochemical properties, and structural features of the PylRS/tRNAPyl pair, guiding its further engineering and optimization. In this review, we cover the basic and updated knowledge of the PylRS/tRNAPyl pair's unique characteristics that make it an outstanding tool for reprogramming the genetic code. In addition, we summarize the recent efforts to create efficient and (mutually) orthogonal PylRS/tRNAPyl-derived pairs for incorporation of diverse ncAAs by genome mining, rational design, and advanced directed evolution methods.