Rational design of bimetallic MXene solid solution with High-Performance electrocatalytic N2 reduction.

Electrocatalytic N2 reduction reaction (eNRR) was an effective alternative method for green synthesis of NH3. By combining the first-principal Density functional theory (DFT) calculations and Monte Carlo (MC) simulation, we systematacially investigated 24 types equal-ratio bimetallic MXene solid solution, involving 88 different catalysts. Our focus was on the catalytic performance of these materials in eNRR. The computational result indicate that MoW(3Mo) has high stability, selectivity (93.8 % against the hydrogen evolution reaction (HER)) and activity (UL = -0.26 V), which is significantly better than that of monometal Mo2CO2 and W2CO2. This improvement in catalytic properties is attributed to the unique electronic structure (e.g. d-band center, charge) of bimetallic MXene solid solution. In explicit solvent conditions, the microenvironment of hydrogen bond in aqueous liquid thermodynamically promotes the catalytic property for eNRR and reduce the catalytic property of HER side reaction, but the kinetic barrier is also increased due to the effect of the hydrogen-bond microenvironment on proton migration. Overall, the obtained bimetallic MXene solid solution MoW(3Mo) exhibits excellent catalytic performance in eNRR.

Cooperatively interface role of surface atoms and aqueous media on single atom catalytic property for H2O2 synthesis.

Direct electrosynthesis of hydrogen peroxide (H2O2) from H2 and O2 is a promising alternative to currently industrial Riedl-Pfleiderer route. Utilizing a combination of density functional theory (DFT) and ab-initio-molecular dynamic simulation (AIMD), we presented an effective computational framework to identify the cooperative role of surface atoms(e.g. O, N and S) and aqueous media on catalytic performance of single-atom catalysts (SACs) supported Nb2C MXenes. Computational results shown that both Ni/Nb2CN2 and Co/Nb2CS2 have low overpotentials of 0.17 V and 0.20 V, and the barrier of 0.89 eV and 0.67 eV for 2e- ORR under gas phase, respectively, while in aqueous phase, hydrogen bond framework on the surface promotes the transfer of proton, resulting in the lower 2e- ORR overpotential (0.05 V) in Co/Nb2CS2 and lower barrier (almost 0.01 eV) for rate-determining step (RDS) in Ni/Nb2CN2. Electronically, we found that the less-electronegativity N and S relative to O more benefit to mediate the activation degree of O2 on SACs and thereby improve catalytic selectivity. Thus, it is concluded that both surface atom and aqueous medium synergistically promote catalytic property for H2O2 synthesis.

The synergetic effect of an aqua ligand and metal site on the performance of single-atom catalysts in H2O2 synthesis: a density functional theory study.

Studying the effect of the coordination field on the catalytic property is critical for the rational design of outstanding electrocatalysts for H2O2 synthesis. Herein, via density functional theory (DFT) calculations and ab initio molecular dynamic (AIMD) simulations, we built an effective computational framework to identify the synergetic effect of an aqua ligand and metal ion on the 2e- ORR catalytic performance under gas condition and aqua solvent. Specifically, the screening results of 29 single-atom catalysts (SACs), TM@C6N6 (TM = transition metal), indicated that Cu@C6N6 features excellent catalytic property with thermal stability, lowest 2e- ORR overpotential (0.02 V) and high selectivity of 99.99%. Once an aqua ligand binds with the Cu site, the activity is reduced to the overpotential of 0.42 V and the selectivity decreased slightly (99.98%) due to the reduction of the adsorption strength for the reaction intermediates. A combination of geometric structures and electronic properties revealed that such changes are correlated with the charge of the Cu site. Furthermore, based on molecular orbital theory, the essence of the high catalytic property deeply lies in the effect of the moderate electron back donation bond (dyz & dxz→) between Cu and O2. This work will provide a route to better design high-performance SACs for H2O2 synthesis effectively.

Collaboratively boosting charge transfer and CO2 chemisorption of SnO2 to selectively reduce CO2 to HCOOH.

In this study, we have facilely developed a SnO2-based electrocatalyst (SnO2-VO@N-C), which can combine together the favorable structure features of oxygen vacancies, porosity, and full-coating with N-doped carbon layers (N-C). Our experimental and theoretical calculation results indicated that with the facile engineering of oxygen vacancies and the full-coating of the N-doped carbon layer, the adsorption/activation of CO2 and charge transfer can be promoted in the CO2 reduction process, making SnO2-VO@N-C the electrocatalyst with improved activity and selectivity (FEHCOOH = 84%) toward the reduction of CO2 to HCOOH.

High-performance single-atom Ni catalyst loaded graphyne for H2O2 green synthesis in aqueous media.

The electrochemical synthesis of hydrogen peroxide (H2O2) provides a greener and more efficient method compared with classic catalysts containing toxic metals. Herein, we used first-principles density functional theory (DFT) calculations to investigate 174 different single-atom catalysts with graphyne substrates, and conducted a three-step screening strategy to identify the optimal noble metal-free single atom catalyst. It is found that a single Ni atom loaded on γ-graphyne with carbon vacancies (Ni@V-γ-GY) displayed remarkable thermodynamic stability, excellent selectivity, and high activity with an ultralow overpotential of 0.03 V. Furthermore, based on ab-initio molecular dynamic and DFT calculations under the H2O solvent, it was revealed that the catalytic performance for H2O2 synthesis in aqueous phase was much better than that in gas phase condition, shedding light on the hydrogen bond network being beneficial to accelerate the transfer of protons for H2O2 synthesis.

FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway.

Presbycusis is the cumulative effect of aging on hearing. Recent studies have shown that common mitochondrial gene deletions are closely related to deafness caused by degenerative changes in the auditory system, and some of these nuclear factors are proposed to participate in the regulation of mitochondrial function. However, the detailed mechanisms involved in age-related degeneration of the auditory systems have not yet been fully elucidated. In this study, we found that FOXG1 plays an important role in the auditory degeneration process through regulation of macroautophagy/autophagy. Inhibition of FOXG1 decreased the autophagy activity and led to the accumulation of reactive oxygen species and subsequent apoptosis of cochlear hair cells. Recent clinical studies have found that aspirin plays important roles in the prevention and treatment of various diseases by regulating autophagy and mitochondria function. In this study, we found that aspirin increased the expression of FOXG1, which further activated autophagy and reduced the production of reactive oxygen species and inhibited apoptosis, and thus promoted the survival of mimetic aging HCs and HC-like OC-1 cells. This study demonstrates the regulatory function of the FOXG1 transcription factor through the autophagy pathway during hair cell degeneration in presbycusis, and it provides a new molecular approach for the treatment of age-related hearing loss.Abbreviations: AHL: age-related hearing loss; baf: bafilomycin A1; CD: common deletion; D-gal: D-galactose; GO: glucose oxidase; HC: hair cells; mtDNA: mitochondrial DNA; RAP: rapamycin; ROS: reactive oxygen species; TMRE: tetramethylrhodamine, ethyl ester.

Treatment With Calcineurin Inhibitor FK506 Attenuates Noise-Induced Hearing Loss.

Attenuation of noise-induced hair cell loss and noise-induced hearing loss (NIHL) by treatment with FK506 (tacrolimus), a calcineurin (CaN/PP2B) inhibitor used clinically as an immunosuppressant, has been previously reported, but the downstream mechanisms of FK506-attenuated NIHL remain unknown. Here we showed that CaN immunolabeling in outer hair cells (OHCs) and nuclear factor of activated T-cells isoform c4 (NFATc4/NFAT3) in OHC nuclei are significantly increased after moderate noise exposure in adult CBA/J mice. Consequently, treatment with FK506 significantly reduces moderate-noise-induced loss of OHCs and NIHL. Furthermore, induction of reactive oxygen species (ROS) by moderate noise was significantly diminished by treatment with FK506. In agreement with our previous finding that autophagy marker microtubule-associated protein light chain 3B (LC3B) does not change in OHCs under conditions of moderate-noise-induced permanent threshold shifts, treatment with FK506 increases LC3B immunolabeling in OHCs after exposure to moderate noise. Additionally, prevention of NIHL by treatment with FK506 was partially abolished by pretreatment with LC3B small interfering RNA. Taken together, these results indicate that attenuation of moderate-noise-induced OHC loss and hearing loss by FK506 treatment occurs not only via inhibition of CaN activity but also through inhibition of ROS and activation of autophagy.

Apralogs: Apramycin 5-O-Glycosides and Ethers with Improved Antibacterial Activity and Ribosomal Selectivity and Reduced Susceptibility to the Aminoacyltranserferase (3)-IV Resistance Determinant.

Apramycin is a structurally unique member of the 2-deoxystreptamine class of aminoglycoside antibiotics characterized by a monosubstituted 2-deoxystreptamine ring that carries an unusual bicyclic eight-carbon dialdose moiety. Because of its unusual structure, apramycin is not susceptible to the most prevalent mechanisms of aminoglycoside resistance including the aminoglycoside-modifying enzymes and the ribosomal methyltransferases whose widespread presence severely compromises all aminoglycosides in current clinical practice. These attributes coupled with minimal ototoxocity in animal models combine to make apramycin an excellent starting point for the development of next-generation aminoglycoside antibiotics for the treatment of multidrug-resistant bacterial infections, particularly the ESKAPE pathogens. With this in mind, we describe the design, synthesis, and evaluation of three series of apramycin derivatives, all functionalized at the 5-position, with the goals of increasing the antibacterial potency without sacrificing selectivity between bacterial and eukaryotic ribosomes and of overcoming the rare aminoglycoside acetyltransferase (3)-IV class of aminoglycoside-modifying enzymes that constitutes the only documented mechanism of antimicrobial resistance to apramycin. We show that several apramycin-5-O-ß-d-ribofuranosides, 5-O-ß-d-eryrthofuranosides, and even simple 5-O-aminoalkyl ethers are effective in this respect through the use of cell-free translation assays with wild-type bacterial and humanized bacterial ribosomes and of extensive antibacterial assays with wild-type and resistant Gram negative bacteria carrying either single or multiple resistance determinants. Ex vivo studies with mouse cochlear explants confirm the low levels of ototoxicity predicted on the basis of selectivity at the target level, while the mouse thigh infection model was used to demonstrate the superiority of an apramycin-5-O-glycoside in reducing the bacterial burden in vivo.

Cochlear Surface Preparation in the Adult Mouse.

Auditory processing in the cochlea depends on the integrity of the mechanosensory hair cells. Over a lifetime, hearing loss can be acquired from numerous etiologies such as exposure to excessive noise, the use of ototoxic medications, bacterial or viral ear infections, head injuries, and the aging process. Loss of sensory hair cells is a common pathological feature of the varieties of acquired hearing loss. Additionally, the inner hair cell synapse can be damaged by mild insults. Therefore, surface preparations of cochlear epithelia, in combination with immunolabeling techniques and confocal imagery, are a very useful tool for the investigation of cochlear pathologies, including losses of ribbon synapses and sensory hair cells, changes in protein levels in hair cells and supporting cells, hair cell regeneration, and determination of report gene expression (i.e., GFP) for verification of successful transduction and identification of transduced cell types. The cochlea, a bony spiral-shaped structure in the inner ear, holds the auditory sensory end organ, the organ of Corti (OC). Sensory hair cells and surrounding supporting cells in the OC are contained in the cochlear duct and rest on the basilar membrane, organized in a tonotopic fashion with high-frequency detection occurring in the base and low-frequency in the apex. With the availability of molecular and genetic information and the ability to manipulate genes by knockout and knock-in techniques, mice have been widely used in biological research, including in hearing science. However, the adult mouse cochlea is miniscule, and the cochlear epithelium is encapsulated in a bony labyrinth, making microdissection difficult. Although dissection techniques have been developed and used in many laboratories, this modified microdissection method using cell and tissue adhesive is easier and more convenient. It can be used in all types of adult mouse cochleae following decalcification.

Self-assemblies of TTF derivatives programmed by alkyl chains and functional groups.

Tetrathiafulvalenes (TTFs) are a class of important functional materials whose intermolecular interaction, which will contribute to constructing a supramolecular structure, still needs further understanding. In this study, the self-assembly behavior and structure of a series of TTFs bearing different alkyl chains and substituents were investigated by scanning tunneling microscopy (STM) in combination with density functional theory (DFT) calculations. Contrary to previous reports, herein, a series of benzoic acid-functionalized TTFs (CnTTFCOOH) and pyridine-functionalized TTFs (CnTTFN) with different lengths of alkyl chains have been substituted on the sulfur atom, where n is equal to 8, 10, 14, or 16. Due to the weak intra- and intermolecular interactions, CnTTFN (n = 8 and 10) molecules cannot be observed during STM scanning. For other cases, various self-assembled monolayers with different nanostructures were observed depending on different substituents. The results reveal that the alkyl chains and functional groups on the TTF skeleton synergistically affect the molecular self-assembly process, which results from the synergism of van der Waals, hydrogen bonding, and SS interactions. These results not only help to explain the relationship between structures and properties, but also help to design better molecular structures for various fields.

Polymer-KLAK Peptide Conjugates Induce Cancer Cell Death through Synergistic Effects of Mitochondria Damage and Autophagy Blockage.

Nanoscaled polymer-peptide conjugates (PPCs) containing both functional peptides and synthetic polymer comprise a new family of biomaterials that can circumvent the limitation of peptides alone. Our previous work showed that PPCs with the therapeutic peptide KLAK, especially PPCs with shorter PEG spacers and a higher degree of polymerization, exhibit enhanced antitumor effects through disrupting mitochondrial membranes. However, as PPCs have a spherical nanostructure (45-60 nm), this may have other effects besides the conjugated therapeutic peptide KLAK itself when they enter cancer cells. In this research, we compared the proteome differences of U87 cells treated with KLAK, polymer, and their conjugates (P-KLAK) through quantitative proteomics technology. The result reveals that proteins involved in oxidative stress response and the Nrf2/ARE pathway were significantly up-regulated after P-KLAK treatment. Moreover, the overexpression of sequestosome 1, a protein substrate that is selectively incorporated into the formation of autophagosome and degraded by autophagy, is found in our study and has not been reported previously in the study of KLAK toxicity. Additional experiments suggest that upon endocytosis, P-KLAK causes lysosome impairment and results in autophagosomes accumulation. Hence, P-KLAK might induce U87 cell death by autophagy blockage due to lysosome impairment as well as mitochondria damage synergistically.

A General Strategy for Facile Synthesis and In Situ Screening of Self-Assembled Polymer-Peptide Nanomaterials.

A universal strategy for efficient, mild, and purification-free synthesis and in situ screening of functional polymer-peptide nanomaterials is described. More than 1000 polymer-peptide conjugates (PPCs) with various chemical structures, compositions, and therapeutic efficacy are created. According to this strategy, the structure-function relationship of the PPCs is revealed, and the antitumor efficacies of the top performing PPCs are evaluated in vivo.