99 pubs · 5,558 cites · h-index 30
Retrospective analysis identifies key adverse prognostic factors in older patients, suggesting implications for treatment and monitoring strategies.
Objective: To evaluate the prognostic performance of six scoring systems in predicting outcomes of first-line chemo-immunotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC), aiming to guide individualized treatment. Methods: This single-center retrospective study included 197 ES-SCLC patients treated with first-line chemo-immunotherapy. Clinical and laboratory data were collected, including baseline characteristics, treatment responses, and survival outcomes. The prognostic impact of six scoring systems (RHM, MDACC, MDACC+NLR, MDA-ICI, LIPI, GRIm) was assessed using univariate and multivariate Cox regression analyses for progression-free survival (PFS) and overall survival (OS). Kaplan-Meier analysis was conducted for risk stratification. Results: By the last follow-up (October 15, 2024), the median follow-up was 12 months, with 113 deaths (57.3%). The objective response rate was 75.6%. ECOG ≥1, lung metastasis, and liver metastasis were independent predictors of poorer PFS and OS. Among the scoring systems, only MDACC+NLR effectively stratified patients: low-risk patients had significantly longer PFS and OS (both p = 0.02). MDACC alone did not distinguish PFS among risk groups (p = 0.17) but showed significant OS differences (p = 0.02). Other systems (RHM, MDA-ICI, LIPI, GRIm) lacked significant discriminatory ability for both PFS and OS (all p > 0.05). Conclusion: ECOG ≥1, lung metastasis, and liver metastasis are adverse prognostic factors for ES-SCLC patients receiving first-line chemo-immunotherapy. The MDACC+NLR scoring system provides superior predictive value for treatment outcomes and survival, supporting its potential utility for clinical risk stratification.
Small-molecule drugs play a critical role in cancer therapy by selectively targeting key signaling pathways that drive tumor growth. While deep learning models have advanced drug discovery, there remains a lack of generative frameworks for de novo covalent molecule design using a fragment-based approach. To address this, we propose MOFF (MOlecule generation with Functional Fragments), a reinforcement learning framework for molecule generation. MOFF is specifically designed to generate both covalent and noncovalent compounds based on functional fragments. The model leverages docking scores as reward functions and is trained using the Soft Actor-Critic algorithm. We evaluate MOFF through case studies targeting Bruton’s tyrosine kinase (BTK) and the epidermal growth factor receptor (EGFR), demonstrating that MOFF can generate ligand-like molecules with favorable docking scores and drug-like properties, compared to baseline models and ChEMBL compounds. As a computational validation, molecular dynamics (MD) simulations were conducted on selected top-scoring molecules to assess potential binding stability. These results highlight MOFF as a flexible and extensible framework for fragment-based molecule generation, with the potential to support downstream applications.
The activation of glycogen synthase kinase 3β (GSK-3β) and the deterioration of spatial memory represent prominent pathological and clinical manifestations of Alzheimer's disease (AD). Nevertheless, the precise intrinsic mechanisms linking these pathological features remain poorly elucidated. In this study, we identified significant upregulation of GSK-3β activity in inhibitory interneurons within the hippocampal dentate gyrus (DG) of 3×Tg-AD mice. Subsequent investigations demonstrated that targeted overexpression of GSK-3β in these interneurons triggered aberrant activation of neural stem cells (NSCs), culminating in apoptotic cell death and consequent deficits in adult hippocampal neurogenesis (AHN). Utilizing in vivo fiber-optic recording techniques, we further established that GSK-3β overexpression in DG inhibitory interneurons elicited hyperactivation of excitatory neurons, thereby disrupting the excitation-inhibition (E/I) balance within the DG circuitry. Notably, these pathological alterations were ameliorated through chemogenetic suppression of excitatory neuronal activity. Mechanistically, we determined that impaired GABAergic transmission, characterized by reduced GABA release in the DG region, underlies these observed effects. Pharmacological intervention with GABA receptor agonists effectively rescued AHN impairment and attenuated spatial cognitive deficits. Collectively, these findings demonstrate that GSK-3β overexpression in GABAergic interneurons compromises AHN and promotes NSC apoptosis via disruption of GABAergic signaling, while pharmacological potentiation of GABAergic transmission exerts neuroprotective effects. This study elucidates a previously unrecognized mechanism contributing to AHN impairment in AD and identifies a promising therapeutic target for pro-neurogenic strategies.
Balancing biosafety with multifunctionality remains a critical challenge in biopatch development, impeding clinical translation. This study introduces a minimally invasive myocardial patch fabricated entirely from FDA‐approved components, integrating piezoelectric property and a sustained release of miRNA agomir. Briefly, the piezoelectric small intestinal submucosa (SIS) serves as the matrix for the in situ growth of β‐cyclodextrin metal‐organic framework (β‐CD‐MOF). Cholesterol‐modified miR‐210 Agomir is efficiently loaded into cyclodextrin cavities through host‐guest interactions. Flexibility and water‐triggered adhesion properties, bestowed by a poly (sodium thioctate) (PST) coating on the rim, allow the dry SIS‐Patch to fold into a catheter‐deliverable tube for minimally invasive implantation. In rat myocardial infarction models, the Ago‐Patch achieved sustained miR‐210 Agomir release, effectively downregulating target gene expression. Simultaneously, the piezoelectric SIS converts mechanical energy in vivo into electrical pulses, activating related signaling pathway. Synergistic gene‐electrical therapy improved cardiac function, increasing ejection fraction by 14.0% and fractional shortening by 10.4%, while attenuating left ventricular remodeling and fibrosis. The Ago‐Patch's dual‐action mechanism offers a safe, multifunctional solution for cardiac repair.
Purpose The assimilation of external knowledge by gatekeepers plays a pivotal role in rejuvenating corporate knowledge, thus fostering organizational success. This study aims to delve into the function of gatekeepers in disseminating knowledge and enhancing knowledge transfer performance through a motivational lens. It investigates whether gatekeepers inherently disseminate knowledge or if certain motivations drive their actions. Particularly, this research centers on the influence of autonomous motivation (intrinsic acceptance) and controlled motivation (external pressure) on knowledge transfer performance, asserting that understanding both motivations is crucial for grasping the intricacies of the behavior-performance nexus. Design/methodology/approach A structured questionnaire survey was used to select a total of 24 firms of three different sizes, large, medium and small, in the provinces of Hunan, Guangdong, Shandong and Zhejiang, China, to conduct a survey of knowledge gatekeepers, and 321 valid questionnaires were finally obtained. The study analyzed the proposed hypotheses through structural equation modeling. Findings The controlled motivation of gatekeepers negatively affects knowledge transfer performance, while autonomous motivation has a positive impact. Additionally, this study unveils that work effort serves as a mediator in the correlation between motivation for knowledge dissemination and knowledge transfer performance. Furthermore, the capability for knowledge transfer positively moderates the link between work effort and knowledge transfer performance. Remarkably, the mediating effect of work effort becomes more pronounced when gatekeepers possess higher knowledge transfer capability. Originality/value This research contributes to the knowledge gatekeeping theory and the literature on knowledge transfer by examining the connection between knowledge gatekeepers’ motivation to disseminate knowledge and knowledge transfer performance. It challenges the conventional belief that gatekeepers consistently share knowledge and provides new perspectives on the mechanisms linking motivation and performance. By doing so, this study helps organizations boost employees’ job autonomy and improve knowledge transfer performance.
The distribution of electrical potentials and current in exogenous electrostimulation has significant impacts on its effectiveness in promoting tissue repair. However, there is still a lack of a flexible, implantable power source capable of generating customizable patterned electric fields for in situ electrostimulation(electrical stimulation). Herein, this study reports a fuel cell patch (FCP) that can provide in situ electrostimulation and a hypoxic microenvironment to promote tissue repair synergistically. Stable and highly efficient PtNi nanochains and PtNi nanocages electrocatalysts with anti‐interference properties catalyze glucose oxidation and oxygen reduction respectively in an encapsulation‐free fuel cell. The laser‐induced graphene (LIG) electrode loaded with PtNi electrocatalysts is transferred to the surface of a flexible chitosan hydrogel. The resulting flexible FCP can adapt to tissues with different morphologies, firmly adhere to prevent suturing, and provide potent electrostimulation (0.403 V, 51.55 µW cm −2 ). Additionally, it consumes oxygen in situ to create a hypoxic microenvironment, increasing the expression of hypoxia‐inducible factor‐1α (HIF‐1α). Based on the different pattern requirements of exogenous electrostimulation during the repair of various types of tissue, an axial FCP for peripheral nerves and a flower‐patterned FCP for myocardial tissue are constructed and transplanted into animals, showing significant tissue repair in both models.
Injectable hydrogels (IHs) have garnered significant attention in biomedical applications due to their minimally invasive nature, adaptability, and high degree of customization. However, traditional design methods of IHs have limitations in addressing complex clinical needs, such as precise regulation of the gelation time and mechanical strength within a wide window. Hyperbranched polymers (HBPs), due to their unique highly branched structures and abundant functional sites, can be easily prepared and functionalized to enable decoupled modulation of mechanical properties of IHs and address the clinical challenges of IHs. Our research group developed a library of HBPs via a dynamically controllable polymerization method and built a series of adjustable, controllable, and responsive IHs based on the resulting HBPs. The prepared IHs fed by HBPs demonstrate an adjustable gelation process, a wide-range tuning of mechanical properties, and responsiveness on demand, which show the capabilities in the various biomedical applications. In this review, we summarize the role of HBPs in the gelation process, mechanical properties, self-healing ability, and responsiveness of IHs. However, achieving IHs through HBPs and extending them to a broad range of biomedical applications are still in its infancy. This review provides an overview of IHs fabricated by a variety of multifunctional HBPs, and their biomedical applications in diverse fields are also presented. Meanwhile, we point out the future development of IHs based on HBPs and their potential challenges.
Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel-catalyzed asymmetric syn-hydrometalative 4-exo-trig cyclization of 1,4-alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl-containing rigid (spiro)carbocycle skeletons in good yields with high enantioselectivities (up to 84 % yield and 98.5 : 1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spiro molecules. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni-H species, with carbonyl-directed hydrometalation as the key for regioselective control. This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynes and represents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres.
Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel‐catalyzed asymmetric syn ‐hydrometalative 4‐ exo ‐ trig cyclization of 1,4‐alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl‐containing rigid (spiro)carbocycle skeletons in good yields with high enantioselectivities (up to 84 % yield and 98.5 : 1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spiro molecules. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni−H species, with carbonyl‐directed hydrometalation as the key for regioselective control. This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynes and represents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres.
A pioneering pink cultivar of Auricularia cornea, first commercially cultivated in 2022, lacks genomic data, hindering research in genetic breeding, gene discovery, and product development. Here, we report the de novo assembly of the pink A. cornea Fen-A1 genome and provide a detailed functional annotation. The genome is 73.17 Mb in size, contains 86 scaffolds (N50 ∼ 5.49 Mb), 59.09% GC content and encodes 19,120 predicted genes with a BUSCO completeness of 92.60%. Comparative genomic analysis reveals the phylogenetic relatedness of Fen-A1 and remarkable gene family dynamics. Putative genes were found mapped to 3 antibiotic-related, 36 light-dependent and 25 terpene metabolites. In addition, 789 CAZymes genes were classified, revealing the dynamics of quality loss due to postharvest refrigeration. Overall, our work is the first report on a pink A. cornea genome and provides a comprehensive insight into its complex functions.
Comprehensive Summary The azepine ring is a prominent structural scaffold in biologically significant molecules. In this study, we present a Ni(II)‐catalyzed asymmetric difunctionalization of alkynes, involving intermolecular regioselective arylation and intramolecular nitrile addition, enabling the synthesis of enantioenriched azepine derivatives. This reaction simultaneously installs an all‐carbon quaternary stereocenter and introduces an unprotected imine functionality, showing great promise for subsequent transformations. The reaction exhibits good tolerance toward various functional groups, resulting in high yields and enantioselectivities. The synthetic utility of this methodology is further demonstrated through gram‐scale synthesis and product derivatization. This research offers an efficient approach to the synthesis of seven‐membered nitrogen heterocycles.
Although substantial efforts have been made using graph neural networks (GNNs) for artificial intelligence (AI)-driven drug discovery, effective molecular representation learning remains an open challenge, especially in the case of insufficient labeled molecules. Recent studies suggest that big GNN models pre-trained by self-supervised learning on unlabeled datasets enable better transfer performance in downstream molecular property prediction tasks. However, the approaches in these studies require multiple complex self-supervised tasks and large-scale datasets , which are time-consuming, computationally expensive and difficult to pre-train end-to-end. Here, we design a simple yet effective self-supervised strategy to simultaneously learn local and global information about molecules, and further propose a novel bi-branch masked graph transformer autoencoder (BatmanNet) to learn molecular representations. BatmanNet features two tailored complementary and asymmetric graph autoencoders to reconstruct the missing nodes and edges, respectively, from a masked molecular graph. With this design, BatmanNet can effectively capture the underlying structure and semantic information of molecules, thus improving the performance of molecular representation. BatmanNet achieves state-of-the-art results for multiple drug discovery tasks, including molecular properties prediction, drug-drug interaction and drug-target interaction, on 13 benchmark datasets, demonstrating its great potential and superiority in molecular representation learning.
Achieving high-performance luminescence for underwater bonding remains a significant challenge in materials science. This study addresses this issue by synthesizing a luminescent material based on an aggregation-induced emission (AIE) monomer and copolymerizing it with lipoic acid (LA) to create an AIE supramolecular polymer. The resulting copolymer exhibits strong fluorescence under ultraviolet (UV) irradiation at 365 nm due to the AIE of TPEE and enables underwater adhesion. The P(LA-TPEE) polymer demonstrates potential for digital encryption and decryption of quick response (QR) codes underwater. Furthermore, it can dissolve well in anhydrous ethanol, producing an environment-friendly and super waterproof adhesive. Most notably, the P(LA-TPEE) solution can be sprayed on human skin, creating an invisible tattoo that only became visible under UV light due to the hydrogen bond (H-bond) and π-π structures. This smart tattoo can be quickly wiped away with alcohol, avoiding the painful and harmful process of tattoo removal. It can also be repeatedly applied to draw the preferred tattoo pattern. This AIE supramolecular polymer shows great potential in underwater adhesion and repair, underwater message encryption, and non-toxic and painless invisible tattooing. Overall, this study provides a valuable approach for material design in the future.
Based on the marine natural products piperafizine B, X334 and our previously reported compound 4m, fourteen novel 3,6-diunsaturated 2,5-diketopiperazine (2,5-DPK) derivatives (1-2, 4-6, 8-16), together with two known ones (3 and 7), were designed and synthesized as anticancer agents against cell lines A549 and Hela. The MTT assay results showed that the derivatives 6, 8-12 and 15 had moderate to good anticancer capacities with the IC50 values ranging from 0.7 to 8.9 μM. Among them, compound 11 with naphthalen-1-ylmethylene and 2-methoxybenzylidene functions at the 3- and 6-positions of 2,5-DPK ring, respectively, displayed good inhibitory activities to both cancer cells A549 (IC50 = 1.2 μM) and Hela (IC50 = 0.7 μM). It could also induce apoptosis and obviously block the cell cycle progression at G2/M phase in both cells at 1.0 μM. The electron withdrawing functions might not be favorable for the derivatives with high anticancer activities. Additionally, compared to piperafizine B and X334, these semi-N-alkylated derivatives have high liposolubilities (> 1.0 mg•mL-1). Compound 11 can be further developed aiming to the discovery of novel anticancer candidate.
Nitrocellulose membranes (NCM) have broad application prospects in the field of organic wastewater treatment. In this research, acid orange 8 was used as the target pollutant, and the effects of factors, such as concentration, light intensity, anions, and cations, on the photodegradation of acid orange 8 were investigated under simulated sunlight by NCM. The results showed that the degradation rate constant of acid orange 8 in the NCM system was 1.94 × 10−3 min−1, which was 27.3 times that in the pure water. The photodegradation rate increases with decreasing concentration in the range of 20–120 μmol/L for acid orange 8. The photodegradation rate increased with increasing NCM area. The degradation effect of acid orange 8 increased with the increase of light intensity. Acidic conditions were favorable for the degradation of acid orange 8. The optimal conditions for photodegradation of acid orange 8 were the solution concentration of 20 μmol/L, membrane area of 17.35 cm2, light intensity of 481 μmol/(m2s), and pH value of 3.0. The effect of different components in water on the photodegradation of acid orange 8 was different. Ca2+, Mg2+, and NO3− could promote the photodegradation of acid orange 8, while CO32- could inhibit the photodegradation. The effect of degrading acid orange 8 by NCM under light conditions is obvious, which can provide a new method for the removal of acid orange 8 in wastewater.
General procedure for the synthesis of pyridinium salts.All reactions were run on the multi-gram scale, using the following general procedure. 1-Benzyl-4-(3-nitrophenyl)-pyridinium bromide (3a).Benzyl bromide (1.6 g, 9.4 mmol) was added to a solution of 4-(3-nitrophenyl)-pyridine 2a (1.6 g, 8.0 mmol) in acetone (20 mL).The resulting mixture was stirred at 60 °C for 10 h.The mixture was then cooled to 0 °C, and stirred for 20 minutes after petroleum ether (10 mL) was added.The mixture was filtrated to give white solid product 3a (2.5 g, 84%), which was ove1-dried and pure enough to use in the next step.mp 266-268 °C; 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.36 (d, J = 6.8 Hz, 2H), 8.83 (s, 1H), 8.69 (d, J = 6.8 Hz, 2H), 8.50 -8.47 (m, 2H), 7.94 (t, J = 8.0 Hz, 1H), 7.61 -7.59 (m, 2H), 7.48 -7.44 (m, 3H), 5.91 (s, 2H); 13 C NMR (125 MHz, DMSO-d 6 ) δ 152.9, 148.5, 145.1,
Lysosomes, the main digestive compartment of live cells, are the most acidic organelles (pH 3.8-6.6) with the highest viscosity (47-190 cP at 25 °C). Lysosomal viscosity can reflect the status and function of the lysosomes, and abnormal lysosomal viscosity is responsible for the dysfunction of lysosomes, which is closely related to multiple diseases. In this work, a new GFP (green fluorescent protein) fluorophore-based probe (Lys-V) was designed and synthesized for mapping lysosomal viscosity in live cells. The increasing viscosity can restrict the two C[double bond, length as m-dash]C twisting double bonds between phenol and imidazolidinone, causing the fluorescence emission of Lys-V to enhance with increasing viscosity, and there is an excellent linear relationship between log FI (515 nm) and log viscosity. Notably, fluorescence of Lys-V is quite stable in different pH solvents at the same viscosity, demonstrating that Lys-V is suitable for quantifying viscosity over a wide pH range (from 4 to 10). Because of its ideal water solubility, low cytotoxicity and weak basic amino morpholine substituents, Lys-V can be utilized for lysosome labelling in live cells. Significantly, the dynamic viscosity changes in lysosomes under dexamethasone stimulus could also be captured by Lys-V. Our results will allow Lys-V to become a new chemical tool for detecting lysosomal viscosity in live cells as well as unveiling the underlying mechanism of lysosome behaviour during various biological processes, which is beneficial for studying lysosome-related diseases as well as the exploration of lysosome-related pharmacology.
The development of a suitable fluorescent probe for the specific labeling and imaging of lysosomes through the direct visual fluorescent signal is extremely important for understanding the dysfunction of lysosomes, which might induce various pathologies, including neurodegenerative diseases, cancer, and Alzheimer's disease. Herein, a new carbon dot-based fluorescent probe (CDs-PEI-ML) was designed and synthesized for highly selective imaging of lysosomes in live cells. In this probe, PEI (polyethylenimine) is introduced to improve water solubility and provide abundant amine groups for the as-prepared CDs-PEI, and the morpholine group (ML) serves as a targeting unit for lysosomes. More importantly, passivation with PEI could dramatically increase the fluorescence quantum yield of CDs-PEI-ML as well as their stability in fluorescence emission under different excitation wavelength. Consequently, experimental data demonstrated that the target probe CDs-PEI-ML has low cytotoxicity and excellent photostability. Additionally, further live cell imaging experiment indicated that CDs-PEI-ML is a highly selective fluorescent probe for lysosomes. We speculate the mechanism for selective staining of lysosomes that CDs-PEI-ML was initially taken up by lysosomes through the endocytic pathway and then accumulated in acidic lysosomes. It is notable that there was less diffusion of CDs-PEI-ML into cytoplasm, which could be ascribed to the presence of lysosome target group morpholine on surface of CDs-PEI-ML. The blue emission wavelength combined with the high photo stability and ability of long-lasting cell imaging makes CDs-PEI-ML become an alternative fluorescent probe for multicolor labeling and long-term tracking of lysosomes in live cells and the potential application in super-resolution imaging. To best of our knowledge, there are still limited carbon dots-based fluorescent probes that have been studied for specific lysosomal imaging in live cells. The concept of surface functionality of carbon dots will also pave a new avenue for developing carbon dots-based fluorescent probes for subcellular labeling.
Recently, carbon dots (CDs) have been playing an increasingly important role in industrial production and biomedical field because of their excellent properties. As such, finding an efficient method to quickly synthesize a large scale of relatively high purity CDs is of great interest. Herein, a facile and novel microwave method has been applied to prepare nitrogen doped CDs (N-doped CDs) within 8 min using L-glutamic acid as the sole reaction precursor in the solid phase condition. The as-prepared N-doped CDs with an average size of 1.64 nm are well dispersed in aqueous solution. The photoluminescence of N-doped CDs is pH-sensitive and excitation-dependent. The N-doped CDs show a strong blue fluorescence with relatively high fluorescent quantum yield of 41.2%, which remains stable even under high ionic strength. Since the surface is rich in oxygen-containing functional groups, N-doped CDs can be applied to selectively detect Fe(3+) with the limit of detection of 10(-5) M. In addition, they are also used for cellular bioimaging because of their high fluorescent intensity and nearly zero cytotoxicity. The solid-phase microwave method seems to be an effective strategy to rapidly obtain high quality N-doped CDs and expands their applications in ion detection and cellular bioimaging.