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Liver fibrosis is an urgent clinical problem without effective therapies. Here we conducted a high-content screening on a natural Euphorbiaceae diterpenoid library to identify a potent anti-liver fibrosis lead, 12-deoxyphorbol 13-palmitate (DP). Leveraging a photo-affinity labeling approach, apolipoprotein L2 (APOL2), an endoplasmic reticulum (ER)-rich protein, was identified as the direct target of DP. Mechanistically, APOL2 is induced in activated hepatic stellate cells upon transforming growth factor-β1 (TGF-β1) stimulation, which then binds to sarcoplasmic/ER calcium ATPase 2 (SERCA2) to trigger ER stress and elevate its downstream protein kinase R-like ER kinase (PERK)–hairy and enhancer of split 1 (HES1) axis, ultimately promoting liver fibrosis. As a result, targeting APOL2 by DP or ablation of APOL2significantly impairs APOL2–SERCA2–PERK–HES1 signaling and mitigates fibrosis progression. Our findings not only define APOL2 as a novel therapeutic target for liver fibrosis but also highlight DP as a promising lead for treatment of this symptom.

Dynamic hydrogels are emerging as advanced materials for engineering tissue-like environments that mimic cellular microenvironments. We introduce a diselenide-cross-linked hydrogel system with light-responsive properties, designed for precise control of tumor organoid growth and light-initiated radical inactivation, particularly for dendritic cell (DC) vaccines. Diselenide exchange enables stress relaxation and hydrogel remodeling, while recombination and quenching of seleno radicals (Se•) reduce cross-linking density, leading to controlled degradation. We demonstrate a 2D to 3D growth strategy, where tumor cells inoculate on the hydrogel surface, expand, and gradually form spherical organoids within the 3D hydrogel. These tumor organoids show significantly higher drug resistance compared to 2D-cultured cells. High-density light irradiation enhances diselenide exchange, inducing hydrogel degradation, tumor cell death, and release of functional antigens. This system serves as a dynamic platform for tumor organoid culture and antigen release, offering significantly advanced approaches for in vitro tumor modeling and immunological research. Our findings position diselenide-cross-linked hydrogels as versatile materials for precision cellular engineering, with broad applications in cancer research and beyond.

Ru–N/C catalysts demonstrate good catalytic performance toward the reductive amination of furfural (FAL) to furfurylamine (FAM). However, its underlying catalytic mechanism remains unclear at the molecular level. In this study, a single-atom Ru1–N3/C surface was modeled, which can simultaneously activate NH3and H2to an appropriate level. Over Ru1–N3/C, the catalytic mechanisms for the reductive amination of FAL to FAM, as well as the dimerization of FAM to difurfurylamine (DFAM), have been investigated theoretically in methanol solution at the GGA-PBE/DNP level. Molecular dynamic simulation results indicate the preferential adsorption of NH3over Ru1–N3/C. The preferential activation of NH3facilitates the formation of furfurylimine (FIM). However, the prior activation of H2leads to the formation of furfuryl alcohol (FOL), which hinders the production of FAM. The Ru–N–C group in the amination of FAL with FIM as an intermediate enhances the C–O bond cleavage more efficiently due to the nucleophilicity of the N atom. Lower temperatures are crucial for preserving FAM formation, whereas FAM undergoes dimerization with increasing temperature elevating kinetically. The current research results should provide some theoretical insights for designing highly selective catalytic systems toward the reductive amination of aldehydes/ketones.

• The Bi 12 O 17 Br 2 nanotubes with average diameter of 5 nm were embedded inside the ZIF-67-derived hollow porous carbon materials. • The abundant confined spaces of porous carbon ensured more CO 2 molecules participate in the photoreduction reaction. • The tight interfacial contact between the Bi 12 O 17 Br 2 and porous carbon boosted the charge separation and transfer. • The composites displayed 2.95 times higher CO yield than that of the pure Bi 12 O 17 Br 2. Increasing the utilization efficiency of photogenerated electrons is highly recognized as one of the efficient approaches to boost the photocatalytic CO 2 conversion efficiency. Herein, ZIF-67-derived porous carbon (PC) material was employed for the construction of PC@ultrafine Bi 12 O 17 Br 2 nanotubes (PC@BOB NTs) composites through a facile solvothermal synthesis in order to optimize the use of excited electrons in the BOB NTs. Photoelectrochemical characterization results revealed that the introduction of PC material achieved a faster charge separation rate in the PC@BOB composites, ensuring more photogenerated electrons participate in the CO 2 adsorption and activation process. Moreover, the pore structures of ZIF-67-derived PC material provided abundant confined spaces for the enrichment of CO 2 molecules. After 5 h of Xenon lamp irradiation, PC@BOB composites exhibited obviously increased photocatalytic CO 2 reduction activity in the pure water. When the addition amount of PC was 5 wt%, the PC@BOB-2 composite showed the highest CO evolution rate of 359.70 µmol/g, which was 2.95 times higher than that of the pure BOB NTs. This work provides some independent insights into the applications of Metal-Organic Framework (MOF)-derived hierarchical porous structures to strengthen the CO 2 enrichment, as well as the excited charge utilization efficiency, thus achieving a high solar-to-fuel conversion efficiency. [ABSTRACT FROM AUTHOR]

Biomacromolecules, such as proteins, nucleic acids and polysaccharides, are widely distributed in the human body, and some of them have been recognized as the targets of drugs for disease theranostics. Drugs typically act on targets in two ways: non-covalent bond and covalent bond. Non-covalent bond-based drugs have some disadvantages, such as structural instability and environmental sensitivity. Covalent interactions between drugs and targets have a longer action time, higher affinity and controllability than non-covalent interactions of conventional drugs. With the development of artificial intelligence, covalent drugs have received more attention and have been developed rapidly in pharmaceutical research in recent years. From the perspective of covalent drugs, this review summarizes the design methods and the effects of covalent drugs. Finally, we discuss the application of covalent peptide drugs and expect to provide a new reference for cancer treatment.

Background and aims: Knowledge of how intrinsic capacity (IC) shape functional ability (FA) trajectories in later life remains unclear. We investigated the changes in IC and their impact on 5-years FA trajectories in the Chinese older population. Methods: A total of 1640 older adults from the Rugao Longitudinal Ageing Study were included and analyzed. FA was assessed by The Lawton Instrumental Activities of Daily Living Scale (IADLs). We used cognition, psychology, locomotion, sensory capacity, and vitality to capture the multiple domains of IC according to the ICOPE method. The IC was derived retrospectively from variables collected before this was described by WHO. Results: At baseline, a higher IC was associated with higher IADLs (β= 0.98, 95% CI 0.90, 1.06, P< 0.001). Individuals with declines in IC between wave1 and wave2 experienced a faster decline in IADLs over time (β= − 0.28, 95% CI − 0.40, − 0.16, P< 0.001) after considering covariates. One or more impairment IC scores at baseline strongly predicted death (HR = 1.20, 95% CI 1.11, 1.30, P< 0.001). In addition, according to the IC scores at baseline, we stratify IC in low, middle, and high, compared with those in the high IC score, those in the low were associated with a 2.56-fold (95% CI 1.64, 4.01, P< 0.001) higher risk of mortality, after adjustment for variables. Conclusion: Changes in IC shape FA trajectories. IC impairment is associated with an increased risk of death. Assessing intrinsic capacity would facilitate early identification of older adults at high risk of adverse outcomes and prompt targeted interventions.

Three-phase contactor is an important switching device in a power distribution system. In contactors, unavoidable tolerances create differences in three-phase contact overtravel. The separation of the contacts at different times produces three-phase asynchronous arcs. On the basis of the magnetohydrodynamic (MHD) simulation model, the arc behavior of the synchronous arc and the asynchronous arc are analyzed. An experimental platform based on phase control technology is built. The volt-ampere characteristics and high-speed photography of synchronous and asynchronous arcs are acquired. The influence of phase and actuator speed on the asynchronous arc is analyzed. The experimental and simulation results show that the asynchronous arc makes the three-phase arc more uneven. The higher the lagging phase voltage, the more obvious the unevenness. Increasing the actuator speed can effectively reduce the adverse effects of asynchronous arc.

The upregulated autophagy fuels the activation of hepatic stellate cells (HSCs) to promote hepatic fibrosis. However, the lack of specific inhibitors targeting autophagy and high requirements for cell targeting impede the application of antifibrotic therapy that targets autophagy. RNA interference (RNAi)-based short interfering RNA (siRNA) provides an approach to specifically inhibit autophagy. The therapeutic potential of siRNA, however, is far from being exploited due to the lack of safe and effective delivery vehicles. The cytoplasmic delivery of siRNA is essential for RNAi, and the intracellular trafficking pathway of vehicles determines the fate of siRNA. Unfortunately, the lysosomal degradation pathway, the intracellular fate of most gene vehicles, impedes RNAi efficiency. Inspired by the trafficking pathway of some viruses infecting cells, KDEL-grafted chondroitin sulfate (CK) was designed to alter the intracellular delivery fate of siRNA. The well-designed CD44–Golgi–ER trafficking pathway of CK was realized by triple cascade targeting including (1) CD44 targeting mediated by chondroitin sulfate, (2) Golgi apparatus targeting mediated by the caveolin-mediated endocytic pathway, and (3) endoplasmic reticulum (ER) targeting mediated by coat protein I (COP I) vesicles. CK was adsorbed on the complex of cationic liposomes (Lip) encapsulating siRNA targeting autophagy-related gene 7 (siATG7) to afford Lip/siATG7/CK. Lip/siATG7/CK functions as a drifting boat that follows the CD44–Golgi–ER flow and travels downstream to its destination (ER), bypassing the lysosomal degradation pathway and endowing HSCs with excellent RNAi efficiency. The efficient downregulation of ATG7 leads to an excellent antifibrotic effect both in vitro and in vivo.

Raptor, a regulatory-associated protein of mTOR, has been genetically proved to be an important regulator in lipogenesis. However, its druggable potential is rarely investigated, largely due to the lack of an inhibitor. In this study, the antiadipogenic screening of a daphnane diterpenoid library followed by target fishing led to the identification of a Raptor inhibitor, 1c(5/7/6 carbon ring with orthoester and chlorine functionalities). Pharmacodynamic studies verified that 1cis a potent and tolerable antiadipogenic agent in vitro and in vivo. Mechanistic studies revealed that the targeting of Raptor by 1ccould block the formation of mTORC1 and then downregulate the downstream S6K1- and 4E-BP1-mediated C/EBPs/PPARγ signaling, eventually retarding adipocyte cell differentiation at the early stage. These findings suggest that Raptor can be explored as a novel therapeutic target for obesity and its related complications, and 1cas the first Raptor inhibitor may provide a new therapeutic option for these conditions.

Although the Co–N–C catalyst exhibits good catalytic performance toward the hydrogenation of 5-hydroxymethylfurfural (HMF) with formic acid (FA) as the H source, its catalytic mechansim is still unclear at the molecular level, including competitive hydrogenation of the aldehyde (−CHO) group and hydrogenolysis of the hydroxymethyl (−CH2OH) group. Here, a single-atom Co-N3/C surface was modeled as a Co–N–C catalyst with an armchair model of activated carbon support. Over Co-N3/C, the catalytic mechanism for the hydrogenation/hydrogenolysis of HMF with FA has been theoretically investigated in 1,4-dioxane solution at the GGA-PBE/DNP level. The hydrogenation product, i.e., 2,5-dihydroxymethylfuran (DHMF), should be predominant, whereas the hydrogenolysis products, i.e., 5-methylfurfuryl alcohol (5-MFA), 5-methylfurfural (5-MF), and 2,5-dimethylfuran (DMF), should be minor. The rate-determining steps are concerned with the cleavage of the C–H bond in the FA moiety through an intermolecular H-shift. For the crucial transition states, compared with the Co–C group in the hydrogenolysis of the −CH2OH group, the Co–O–C group in the hydrogenation of the −CHO group can more efficiently promote the cleavage of the C–H bond in the FA moiety, which stems from the electrophilic properties of aldehyde oxygen. Kinetically, Co-N3/C boosts the hydrogenation of the −CHO group to a −CH2OH group and selectively hampers the hydrogenolysis of the −CH2OH group to a −CH3group.

Biscroyunoid A (1), a 19-nor-clerodane diterpenoid dimer featuring a unique C-16–C-12′ linkage and containing an unusual 4,7-dihydro-5H-spiro[benzofuran-6,1′-cyclohexane] motif, together with its biosynthetic precursor, croyunoid A (2), were isolated from Croton yunnanensis. Their structures were determined by spectroscopic, computational, and single-crystal X-ray diffraction methods. Compound 1exerted an antihepatic fibrosis effect in LX-2 cells via inhibition of TGFβ-Smad2/3 signaling.

The asynchrony of the multi-break dc relay has an important influence on its arcing characteristics. Through the experimental test platform, the arc characteristics of the single bridge-type contact and the double bridge-type contacts are compared. Arc images are acquired through high-speed photography. On the basis of asynchronous action, the influence of action speed and overtravel difference on arcing characteristics is analyzed. A multi-breakpoint asynchronous arc model is established to study the nonlinear relationship between overtravel difference and arc duration. The distribution characteristics of the double-bridge arc are analyzed. Experiments and simulations show that the double bridge-type contacts have better arc-extinguishing characteristics. Increasing breaking speed is conducive to reducing arc energy difference between fractures. When the overtravel difference is small, the bridge $B$ (bridge with larger overtravel) arc can enter the diffusion state, and the arc voltage of bridge $B$ is higher. Reducing the overtravel difference can effectively reduce the arc duration.

Both covalent organic frameworks (COFs) and polyoxometalates (POMs) show excellent properties and application potential in many fields, thus receiving widespread attention. In recent years, COF–POM hybrid materials were prepared by combining COFs and POMs through physical or chemical methods. COF–POM hybrids have shown high performance in many fields, such as catalysis, sensing, energy storage, and biomedicine. In this review, we introduced the preparation strategy and application of COF–POM hybrids in detail. We believe that the combination of COFs and POMs will provide more abundant functions and broad application prospects.

In order to overcome the problems of long response time and small number of manageable indicators existing in traditional construction project schedule management methods, a new construction schedule management method based on BIM model is designed in this paper. The construction progress data acquisition and decoding module circuit is set to complete the construction progress data acquisition, and the K-means algorithm is used to preprocess the construction progress data. First, the construction project progress is decomposed; then, the large-scale construction project is divided into different progress management levels by the WBS analysis method; a functional information module is established; the construction project progress data is imported into the BIM model; and finally, the BIM information function management of the method is realised. The experimental results show that the proposed method has low response time and multiple schedule management indicators, and the shortest response time of the proposed method is only 1.1 s.

X-rays play an extremely significant role in medical diagnosis, safety testing, scientific research, and other practical applications. However, as the main sources of radioactive pollution, the hazard of X-rays to human health and the environment has been a major concern. Herein, the explored perovskite scintillator of Cs2Zr1–xPbxCl6in this work exhibits an ultrahigh radioluminescence intensity owing to the enhanced X-ray absorption for the introduction of Pb2+ions. The Cs2Zr1–xPbxCl6crystals are demonstrated as efficient scintillators with a self-trapped exciton emission and extremely high steady-state light yield (∼101,944 photons meV–1). This fascinating scintillator provides a convenient visual tool for X-ray detection even for an indoor lighting environment, reaching a low detection limit of ∼14.2 nGy·s–1, which is about 1/387 of the typical medical imaging dose (5.5 μGy·s–1). Moreover, X-ray imaging with a high resolution of 16.6 lp·mm–1is achieved with the as-explored Cs2Zr1–xPbxCl6scintillator film. Herein, the Cs2Zr1–xPbxCl6scintillator provides a feasible strategy for X-ray monitoring in the field of biomedicine, high-energy physics, national security, and other applications.

Protein therapy has been considered to be one of the most direct and safe ways to regulate cell function and treat tumors. However, safe and effective intracellular delivery of protein drugs is still a key challenge. Herein, we developed a tannic acid-assisted biomineralization strategy for the encapsulation and intracellular delivery of protein drugs. RNase A and glucose oxidase (GOD) were choose as the protein drug model. RNase A, GOD, TA, and Mn2+are mixed in one pot to attain RG@MT, and CaCO3coating is subsequently carried out to construct RG@MT@C through biomineralization. Once RG@MT@C is endocytosed, the acidic environment of the lysosome will dissolve the protective layer of CaCO3and produce plenty of CO2to cause lysosome bursting, ensuring the lysosome escape of the RG@MT@C and thus releasing the generated TA-Mn2+, RNase A, and GOD into the cytoplasm. The released substances would activate starvation therapy, chemodynamic therapy, and protein therapy pathways to ensure a high performance of cancer therapy. Due to simple preparation, low toxicity, and controlled release in the tumor microenvironment, we expect it can realize efficient and nondestructive delivery of protein drugs and meet the needs for precise, high performance of synergistically antitumor therapy in biomedical applications.

Designing simple, efficient, and environmentally friendly methods to construct high-efficient photocatalysts is an important strategy to promote the further development of the field of photocatalysis. Herein, flower-like carbon quantum dots (CQDs)/BiOBr composite photocatalysts have been prepared via in-situ synthesis by mechanical ball milling in the existence of ionic liquid. The CQDs/BiOBr composites exhibit higher photo-degradation performance for tetracycline (TC) than BiOBr monomer and the commercial Bi2O3under visible light irradiation. For comparison, the different Br sources and synthetic methods are chosen to prepare BiOBr and CQDs/BiOBr composites. Photocatalysts prepared by ball milling and ionic liquid present significantly enhanced photocatalytic performance for removing TC. In addition, the introduction of CQDs could distinctly enhance the photocatalytic performances of pure BiOBr. The reason is that CQDs as electron acceptor effectively separate electrons and holes and inhibit their recombination. The intermediates during photocatalytic degradation were tested using liquid chromatography-mass spectrometry (LC-MS) and possible degradation pathways were given. During degradation, •OH, O2·-and h+were identified to be the main active species based on electron spin resonance (ESR) spectra and free radical trapping experiments. A possible mechanism of CQDs/BiOBr with enhanced photocatalytic performances was further proposed.

Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a small Euphorbiaceaediterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types. The most active compound 6, a lathyrane diterpenoid (5/11/3 ring system), dose-dependently activated hPXR with a high selectivity, and significantly upregulated the expression of hPXR downstream genes CYP3A4and UGT1A1. In LCA-induced cholestasis mouse model, administration of compound 6(50 mg· kg−1. d−1, ip) for 7 days significantly suppressed liver necrosis and decreased serum levels of AST, ALT, Tbili, ALP, and TBA, ameliorating LCA-induced cholestatic liver injury. We further revealed that compound 6exerted its anti-cholestatic efficacy via activation of PXR pathway, accelerating the detoxification of toxic BAs and promoting liver regeneration. These results suggest that lathyrane diterpenoids may serve as a promising scaffold for future development of anti-cholestasis drugs.

Crotonianoids A–C (1–3), three unusual tigliane diterpenoids, were isolated from the seeds of Croton tiglium. Compound 1is a 13,14:13,15-diseco-tigliane featuring a unique spiro[bicyclo[5.3.0]decane-2,5′-2′(3′H,4′H)-furanone] core; 2is a 13,15-seco-tigliane incorporating a rare peroxide bridge between C-13 and C-15; and 3is the first example of a phorbol ester with a 10R-configuration. Their structures were determined by spectroscopic, computational, and X-ray diffraction methods. Compounds 1and 2markedly inhibited the growth and survival of prostate cancer cell C4–2B at micromolar concentrations and induced cell apoptosis. Mechanistic study revealed that 1and 2could suppress androgen receptor (AR) signaling pathway by promoting the degradation of AR protein.

In this work, a T2–T1switchable superparamagnetic iron oxide nanoprobe with a pH/H2O2dual response was obtained using a microemulsion method. This novel method for the controllable assembly of small iron clusters followed by their independent modification was reported, which could not be prepared by common synthetic methods. The size of the assembled nanoprobe was uniform and controllable, with a stable T2magnetic resonance imaging (MRI) signal under a single condition. When the nanoprobe was exposed to the tumor environment, the higher H+and H2O2concentrations at the tumor site could dissociate the nanoprobe and redisperse into small iron clusters. When this occurred, the T2MRI signal was converted into a T1MRI signal, achieving specific detection of tumors by a pH/H2O2dual-response T2–T1MRI.

Cell adhesion and migration play essential roles in tissue development and maintenance, and abnormal cell migration is involved in life-threatening diseases, including vascular disease, tumor formation, and metastasis. The advances in hydrogel-based 3D cell culture development facilitated the investigation of cell motility behavior, including cell-cell and cell-matrix adhesion and cell migration in a microenvironment more related to in vivosituations. Establishing advanced methods for these in vitrostudies is thus necessary. Photo-sensitive proteins show advantages in remote and non-invasive regulation of hydrogels’ properties, and thus are of great potential in regulating 3D cultured cells’ behavior. In the presented study, we engineered photocleavable protein(PhoCl)-decorated hydrogels to regulate cell adhesion and migration of MDA-MB-231. The integrin-binding motif RGD was fused to the PhoCl and was decorated on the hydrogel. After being exposed to light at 405 nm, the PhoCl was cleaved and the RGD motif was released, resulting in detachment of the binding cells. The regulatory effect of the light illumination showed a time-dependent and cell density-dependent manner. Furthermore, the elimination of RGD by patterned light exposure completely suspended the cell migration to the corresponding region, suggesting a controllable regulation of the cell migration direction.