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Abstract Realization of stable and industrial-level H2O2 electroproduction still faces great challenge due large partly to the easy decomposition of H2O2. Herein, a two-dimensional dithiine-linked phthalocyaninato cobalt (CoPc)-based covalent organic framework (COF), CoPc-S-COF, was afforded from the reaction of hexadecafluorophthalocyaninato cobalt (II) with 1,2,4,5-benzenetetrathiol. Introduction of the sulfur atoms with large atomic radius and two lone-pairs of electrons in the C-S-C linking unit leads to an undulated layered structure and an increased electron density of the Co center for CoPc-S-COF according to a series of experiments in combination with theoretical calculations. The former structural effect allows the exposition of more Co sites to enhance the COF catalytic performance, while the latter electronic effect activates the 2e− oxygen reduction reaction (2e− ORR) but deactivates the H2O2 decomposition capability of the same Co center, as a total result enabling CoPc-S-COF to display good electrocatalytic H2O2 production performance with a remarkable H2O2 selectivity of >95% and a stable H2O2 production with a concentration of 0.48 wt% under a high current density of 125 mA cm−2 at an applied potential of ca. 0.67 V versus RHE for 20 h in a flow cell, representing the thus far reported best H2O2 synthesis COFs electrocatalysts.

Abstract Damage to lamellar keratinocytes, an essential cellular component of the epidermal layer of hoof tissue, can have a detrimental effect on hoof health and the overall production value of dairy cows. We isolated and cultured cow lamellar keratinocytes using the Dispase II and collagenase methods. We purified them by differential digestion and differential velocity adherent methods at each passaging and identified them by keratin 14 immunofluorescence. We established an in vitro model of inflammation in laminar keratinocytes using LPS and investigated whether chicoric acid protects against inflammatory responses by inhibiting the activation of the TLR4/MAPK/NF-κB signaling pathway. The results showed that cow lamellar keratinocytes were successfully isolated and cultured by Dispase II combined with the collagenase method. In the in vitro inflammation model established by LPS, the Chicoric acid decreased the concentration of inflammatory mediators (TNF-α, IL-1β, and IL-6), down-regulated the mRNA expression of TLR4 and MyD88 (P

Abstract Thick-coal-seam with complex structures and thick-hard roof in the initial mining phase pose various challenges, including a long weighting interval, strong rock pressure, poor top coal caving performance (TCCP), and significant coal loss. These problems directly affect the safety and efficiency of the mining operations. This study employs the principles of elastic thin plates and ellipsoidal bodies to unravel the formation mechanism of strong rock pressure in thick-hard roof and the influence of parting on the TCCP. In addition, a hydraulic fracturing technique is proposed for safe-efficient recovery during the initial mining phase. The reliability of this technique is verified through numerical simulations and field experiments. The research findings reveal the following. (1) The primary causes of strong rock pressure in the mining face are attributed to a long weighting interval and wide collapse range of the main roof, and the weighting interval is primarily influenced by the thickness and tensile strength of the main roof. (2)The key factor affecting the TCCP is the cantilever beam structure formed by the fracture of the thick-hard parting, as it intersects the ellipsoidal body during coal caving. The simultaneous fracturing of both the top coal and roof can reduce the weighting interval on the working face. This process effectively decreased the strength of the thick-hard parting within the top coal, while simultaneously enhancing its load strength and eliminating the cantilever structure resulting from the parting fracture. It not only reduces the first weighting intensity but also promotes the early and proper coal release, thereby enhancing the TCCP and ensuring safe-efficient mining during the initial mining phase. (3) Aiming at the difference in the strengths of the top coal and roof, a graded hydraulic fracturing technique and system were proposed. Fracturing boreholes with a diameter of 60 mm, spacing of 10 m, and height of 20.85 m, which can economically and effectively ensure the fracturing results. Field applications have demonstrated that fractured coal and rocks in fracturing areas exhibit well-developed fractures. During the initial mining phase, the weighting interval in the working face was reduced by 20 m, resulting in a decrease in the overburden pressure and 26.9% reduction in the lumpiness of the top coal. Additionally, the recovery rate increased by 31.19%.

Abstract To investigate the vibration isolation effect of composite vibration isolation walls on surface vibrations in suburban railway deep tunnels under various influencing factors, an integrated numerical model of the train was initially developed. This model solved the wheel-rail interaction force and was applied to a three-dimensional volume coupling model of the track soil. Subsequently, the model's reliability was validated through comparison with measured data. Afterward, the vibration isolation effects of various types of EPS material vibration isolation walls were examined, with a focus on exploring the impact of thickness, material proportion, and relative positioning of the materials within the vibration isolation wall composed of EPS material and concrete. Research indicates that with an increase in the burial depth of a single material vibration isolation wall, its effective vibration isolation frequency range gradually widens. When the burial depth of the vibration isolation wall exceeds the tunnel burial depth, the vibration isolation effect is optimal. Composite vibration isolation walls, with thicknesses smaller than single-material vibration isolation walls, exhibit superior vibration isolation effects compared to their single-material counterparts. The effective vibration isolation frequency band of composite vibration isolation walls differs from that of single-material vibration isolation walls. Using the optimal-size vibration isolation wall of a single material as a composite vibration isolation wall enhances the vibration isolation effect of peak acceleration in the frequency domain by 16.58% and peak velocity by 16.95%. Moreover, frequency domain peak displacement experiences a 30.73% improvement in the vibration isolation effect.

Abstract Idiopathic fertility disorders are associated with mutations in various genes. Here, we report that coiled-coil glutamate-rich protein 1 (CCER1), a germline-specific and intrinsically disordered protein (IDP), mediates postmeiotic spermatid differentiation. In contrast, CCER1 deficiency results in defective sperm chromatin compaction and infertility in mice. CCER1 increases transition protein (Tnp1/2) and protamine (Prm1/2) transcription and mediates multiple histone epigenetic modifications during the histone-to-protamine (HTP) transition. Immiscible with heterochromatin in the nucleus, CCER1 self-assembles into a polymer droplet and forms a liquid-liquid phase-separated condensate in the nucleus. Notably, we identified loss-of-function (LoF) variants of human CCER1 (hCCER1) in five patients with nonobstructive azoospermia (NOA) that were absent in 2713 fertile controls. The mutants led to premature termination or frameshift in CCER1 translation, and disrupted condensates in vitro. In conclusion, we propose that nuclear CCER1 is a phase-separated condensate that links histone epigenetic modifications, HTP transitions, chromatin condensation, and male fertility.

Abstract Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein we report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in 36 NAFLD patients (NCT04140123). There were three cohorts. Each cohort included twelve patients, nine of whom received ZSP1601 50 mg once daily, 50 mg twice daily, or 100 mg twice daily, and three of whom received matching placebos for 28 days. The primary outcomes were the safety and tolerability of ZSP1601. A total of 27 (27/36, 75%) patients experienced at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild to moderate. There was no Serious Adverse Event. Diarrhea, transiently elevated creatinine and adaptive headache were frequently reported adverse drug reaction. We conclude that ZSP1601 is well-tolerated and safe, showing effective improvement in liver chemistries, liver fat content and fibrosis in patients with NAFLD.

Abstract Cinnamon aqueous extract’s active substance base remains unclear and its mechanisms, mainly the therapeutic target of anti-Alzheimer’s disease (AD)-related GABAergic synaptic dysfunction, remain unclear. Here, 30 chemical components were identified in the aqueous extract of cinnamon using LC/MS; secondly, we explored the brain-targeting components of the aqueous extract of cinnamon, and 17 components had a good absorption due to the blood–brain barrier (BBB) limitation; thirdly, further clustering analysis of active ingredient targets by network pharmacology showed that the GABA pathway with GABRG2 as the core target was significantly enriched; then, we used prominent protein–protein interactions (PPI), relying on a protein-metabolite network, and identified the GABRA1, GABRB2 and GABRA5 as the closest targets to GABRG2; finally, the affinity between the target and its cognate active compound was predicted by molecular docking. In general, we screened five components, methyl cinnamate, propyl cinnamate, ( +)-procyanidin B2, procyanidin B1, and myristicin as the brain synapse-targeting active substances of cinnamon using a systematic strategy, and identified GABRA1, GABRB2, GABRA5 and GABRG2 as core therapeutic targets of cinnamon against Alzheimer's disease-related GABAergic synaptic dysfunction. Exploring the mechanism of cinnamon’ activities through multi-components and multiple targets strategies promise to reduce the threat of single- target and symptom-based drug discovery failure.