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1.
Commun Biol ; 7(1): 1236, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-39354050

RESUMEN

The integration of hippocampal oscillations during non-rapid eye movement (NREM) sleep is crucial for memory consolidation. However, how cardinal sleep oscillations bind across various subfields of the human hippocampus to promote information transfer and synaptic plasticity remains unclear. Using human intracranial recordings from 25 epilepsy patients, we find that hippocampal subfields, including DG/CA3, CA1, and SUB, all exhibit significant delta and spindle power during NREM sleep. The DG/CA3 displays strong coupling between delta and ripple oscillations with all the other hippocampal subfields. In contrast, the regions of CA1 and SUB exhibit more precise coordination, characterized by event-level triple coupling between delta, spindle, and ripple oscillations. Furthermore, we demonstrate that the synaptic plasticity within the hippocampal circuit, as indexed by delta-wave slope, is linearly modulated by spindle power. In contrast, ripples act as a binary switch that triggers a sudden increase in delta-wave slope. Overall, these results suggest that different subfields of the hippocampus regulate one another through diverse layers of sleep oscillation synchronization, collectively facilitating information processing and synaptic plasticity during NREM sleep.


Asunto(s)
Hipocampo , Plasticidad Neuronal , Humanos , Plasticidad Neuronal/fisiología , Masculino , Femenino , Adulto , Hipocampo/fisiología , Adulto Joven , Sueño/fisiología , Electroencefalografía , Persona de Mediana Edad , Fases del Sueño/fisiología , Epilepsia/fisiopatología , Sueño de Onda Lenta/fisiología
2.
J Neural Eng ; 2024 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-39423826

RESUMEN

OBJECTIVE: An electroencephalogram (EEG)-based brain-computer interface (BCI) is a direct communication pathway between the human brain and a computer. Most research so far studied more accurate BCIs, but much less attention has been paid to the ethics of BCIs. Aside from task-specific information, EEG signals also contain rich private information, e.g., user identity, emotion, disorders, etc., which should be protected. APPROACH: We show for the first time that adding user-wise perturbations can make identity information in EEG unlearnable. We propose four types of user-wise privacy-preserving perturbations, i.e., random noise, synthetic noise, error minimization noise, and error maximization noise. After adding the proposed perturbations to EEG training data, the user identity information in the data becomes unlearnable, while the BCI task information remains unaffected. MAIN RESULTS: Experiments on six EEG datasets using three neural network classifiers and various traditional machine learning models demonstrated the robustness and practicability of the proposed perturbations. SIGNIFICANCE: Our research shows the feasibility of hiding user identity information in EEG data without impacting the primary BCI task information.

3.
Antimicrob Agents Chemother ; : e0035724, 2024 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-39345183

RESUMEN

Isoniazid is an important first-line medicine to treat tuberculosis (TB). Isoniazid resistance increases the risk of poor treatment outcomes and development of multidrug resistance, and is driven primarily by mutations involving katG, encoding the prodrug-activating enzyme, rather than its validated target, InhA. The chemical tractability of InhA has fostered efforts to discover direct inhibitors of InhA (DIIs). In this study, we bridge the gap in understanding the potential contribution of DIIs to novel combination regimens and demonstrate a clear distinction of DIIs, like GSK693 and the newly described GSK138, from isoniazid, based on activity against clinical isolates and contribution to novel drug regimens. The results suggest that DIIs, specifically GSK138 and GSK693, could be promising partners in novel drug regimens, including those used against isoniazid-resistant TB, potentially enhancing their efficacy and/or preventing the selection of resistant mutants and supporting the continued exploration of InhA as a promising target for TB drug development.

4.
Artículo en Inglés | MEDLINE | ID: mdl-39255189

RESUMEN

Training an accurate classifier for EEG-based brain-computer interface (BCI) requires EEG data from a large number of users, whereas protecting their data privacy is a critical consideration. Federated learning (FL) is a promising solution to this challenge. This paper proposes Federated classification with local Batch-specific batch normalization and Sharpness-aware minimization (FedBS) for privacy protection in EEG-based motor imagery (MI) classification. FedBS utilizes local batch-specific batch normalization to reduce data discrepancies among different clients, and sharpness-aware minimization optimizer in local training to improve model generalization. Experiments on three public MI datasets using three popular deep learning models demonstrated that FedBS outperformed six state-of-the-art FL approaches. Remarkably, it also outperformed centralized training, which does not consider privacy protection at all. In summary, FedBS protects user EEG data privacy, enabling multiple BCI users to participate in large-scale machine learning model training, which in turn improves the BCI decoding accuracy.


Asunto(s)
Algoritmos , Interfaces Cerebro-Computador , Aprendizaje Profundo , Electroencefalografía , Imaginación , Aprendizaje Automático , Humanos , Imaginación/fisiología , Seguridad Computacional , Privacidad
5.
Environ Pollut ; 362: 125024, 2024 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-39322107

RESUMEN

In the Guangdong-Hong Kong-Macao Greater Bay Area (GBA), microplastic pollution in urban rivers is a prominent problem due to the developed economy and high industrial intensity. Using the Xiaohai River, Hanxi River and Dongguan Canal in Dongguan City, an important node city in the GBA, as an example, microplastic characteristics, drivers and ecological risks in the surface water of three rivers were investigated. Results showed that the average abundance of rivers in the wet period (1646.22 ± 154.73 items/m3) was 4.7 times higher than that in the dry period (351.09 ± 34.2 items/m3). Microplastics were mainly in the form of fragments and fibers, with a size range of 30-500 µm, and appeared transparent with white color. The microplastic polymer types PE, PP, PET and PA accounted for more than 70%. There are large differences in the characteristics of microplastic pollution during different hydrological periods. Redundancy analysis showed that the distribution of plastics, chemical materials, packaging and printing industries along the rivers dominated the differences in microplastic abundance. The electronic information industry contributed most to the composition of microplastic polymer types. The polymer hazard index, pollution load index, and potential ecological risk index for rivers indicate a medium-high risk classification or higher. Therefore, the industrial layout along the urban rivers should be rationalized, the disposal of microplastics in wastewater should be increased, and the use of green plastic products should be promoted. This study provides support for the management of microplastic pollution in urban surface water in the GBA.

6.
Nat Commun ; 15(1): 6907, 2024 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-39134536

RESUMEN

Photoelectrochemical (PEC) cell is an ideal platform for organic transformation because of its green benefits and minimal energy consumption. As an emerging methodology, the reaction types of photoelectrocatalytic organic synthesis (PECOS) are limited to simple oxidation and C-H activation at current stage. Metal catalysis for the construction of C(sp2)-N bonds has not been touched yet in PECOS. We introduce here a PEC method that successfully engages Ni catalysis for the mild production of aniline derivatives. Experimental and computational investigations elucidate that the addition of photoanode-generated amine radical to Ni catalyst avoids the sluggish nucleophilic attack, enabling the reaction to proceed at an ultra-low potential (-0.4 V vs. Ag/AgNO3) and preventing the overoxidation of products in conventional electrochemical synthesis. This synergistic catalysis strategy exhibits good functional group tolerance and wide substrate scope on both aryl halides and amines, by which some important natural products and pharmaceutical chemicals have been successfully modified.

7.
Sci China Life Sci ; 67(11): 2444-2458, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39136860

RESUMEN

Autotetraploid Carassius auratus is a stable hereditary autotetraploid fish resulting from the hybridization of Carassius auratus red var. (RCC, ♀) × Megalobrama amblycephala (BSB, ♂), containing four sets of RCC chromosomes. However, the molecular mechanism underlying the determination of sex in this species remains largely unknown. Currently, there lacks a full understanding of the molecular mechanisms governing sex determination and specific molecular markers to differentiate sex in this species. In this study, 25,801,677 SNPs (Single-nucleotide polymorphism) and 6,210,306 Indels (insertion-deletion) were obtained from whole-genome resequencing of 100 individuals (including 50 female and 50 male). Further identification confirmed the candidate chromosomes as Chr46B, with the sex-determining region located at Chr46B: 22,500,000-22,800,000 bp. Based on the male-specific insertion (26 bp) within the candidate sex-determining region, a pair of sex-specific molecular markers has been identified. In addition, based on the screening of candidate sex-determining region genes and RT-qPCR validation analysis, ADAM10, AQP9 and tc1a were identified as candidate sex-determining genes. These findings provide a robust foundation for investigating sex determination mechanisms in fish, the evolution of sex chromosomes, and the development of monosex populations.


Asunto(s)
Carpa Dorada , Polimorfismo de Nucleótido Simple , Procesos de Determinación del Sexo , Tetraploidía , Animales , Femenino , Masculino , Carpa Dorada/genética , Procesos de Determinación del Sexo/genética , Mutación INDEL , Marcadores Genéticos , Proteínas de Peces/genética , Secuenciación Completa del Genoma/métodos
8.
Angew Chem Int Ed Engl ; 63(41): e202408901, 2024 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-39017961

RESUMEN

Photoelectrochemistry (PEC) is burgeoning as an innovative solution to organic synthesis. However, the current PEC systems suffer from limited reaction types and unsatisfactory performances. Herein, we employ efficient BiVO4 photoanodes with tailored deposition layers for customizing two PEC approaches toward C-N and C-P bond formation. Our process proceeds under mild reaction conditions, deploying easily available substrates and ultra-low potentials. Beyond photocatalysis and electrocatalysis, customized PEC offers high efficiency, good functional group tolerance, and substantial applicability for decorating drug molecules, highlighting its promising potential to enrich the synthetic toolbox for broader organic chemistry of practical applications.

9.
ACS Macro Lett ; 13(8): 1037-1042, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39078044

RESUMEN

Catalyst-free, volatile organic solvent (VOC)-free synthesis of biobased cross-linked polymers is an important sustainable feature in polyesterification. To date, these polyesters have been extensively studied for their fundamental sustainability across various uses. The ultimate potential sustainability for these materials, however, is constrained to static structural parts due to their intractable rigid three-dimensional (3D) network. Here, we reveal intrinsic dynamic exchangeable bonds within this type of cross-linked semicrystalline network, poly(1,8-octanediol-co-1,12-docanedioate-co-citrate) (PODDC), enabling permanent shape reconfigurability. Annealing at slightly above melting-transition temperature (Tm) allows for shape reconfigurability up to nine times, comparable in performance to the existing bond-exchange systems. No reagents are involved from synthesis to shape reconfiguration, suggesting an exciting feature exhibited by this sustainable cross-linked material without the need for further chemical modification. We further extend this benefit of reconfigurability to enable flexible shape design in a smart shape-memory polymer (SMP), showing it as one of its potential applications. After its applications, it can undergo hydrolytic degradation. We envision that such multifaceted sustainability for the material will attract interest in environmentally friendly applications such as fabricating external part of soft robots and shape-morphing devices with reduced environmental impact.

10.
Adv Sci (Weinh) ; 11(34): e2404094, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38973354

RESUMEN

Nonlinear nanophotonic devices have shown great potential for on-chip information processing, quantum source, 3D microfabrication, greatly promoting the developments of integrated optics, quantum science, nanoscience and technologies, etc. To promote the applications of nonlinear nanodevices, improving the nonlinear efficiency, expanding the spectra region of nonlinear response and reducing device thickness are three key issues. Herein, this study focuses on the nonlinear effect of third-harmonic generation (THG), and present a thin Si meta-sructure to improve the THG efficiency in the ultraviolet (UV) region. The measured THG efficiency is up to 10-5 at an emission wavelength of 309 nm. Also, the THG nanosystem is only 100 nm in thickness, which is two-five times thinner than previous all-dielectric nanosystems applied in THG studies. These findings not only present a powerful thin meta-structure with highly efficient THG emission in UV region, but also provide a constructive avenue for further understanding the light-matter interactions at subwavelength scales, guiding the design and fabricating of advanced photonic devices in future.

11.
Front Plant Sci ; 15: 1390069, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38828216

RESUMEN

Root rot is a major disease that causes decline of alfalfa production, and Fusarium is a major pathogen associated with root rot. In this study, 13 Fusarium isolates were obtained from alfalfa with root rot in Gansu Province, the major alfalfa production region in China. The isolates were characterized by molecular genotyping (ITS, TEF 1-α and RPB2 fragments) and identified as six species, which included the F. acuminatum, F. incarnatum, F. oxysporum, F. proliferatum, F. redolens, and F. solani. We found that their morphology varied significantly at both the macro- and micro-levels, even for those from the same species. We developed a low cost and fast pathogenicity test and revealed that all isolates were pathogenic to alfalfa with typical root rot symptoms such as leaf yellowing and brown lesions on the root and stem. However, the virulence of the isolates differed. We also found that the conidia of all isolates germinated as early as 24 hours post inoculation (hpi), while hyphae colonized the root extensively and invaded the xylem vessel by 48 hpi. Together our results reveal that different virulent Fusarium isolates use a similar invasion strategy in alfalfa. This natural plant-fungus pathosystem is intriguing and warrants further examination, particularly with regard to efforts aimed at mitigating the impact of multiple similar vascular pathogens on infected alfalfa plants.

12.
J Am Chem Soc ; 146(23): 16039-16051, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38832517

RESUMEN

Efficient methane photooxidation to formic acid (HCOOH) has emerged as a sustainable approach to simultaneously generate value-added chemicals and harness renewable energy. However, the persistent challenge lies in achieving a high yield and selectivity for HCOOH formation, primarily due to the complexities associated with modulating intermediate conversion and desorption after methane activation. In this study, we employ first-principles calculations as a comprehensive guiding tool and discover that by precisely controlling the O2 activation process on noble metal cocatalysts and the adsorption strength of carbon-containing intermediates on metal oxide supports, one can finely tune the selectivity of methane photooxidation products. Specifically, a bifunctional catalyst comprising Pd nanoparticles and monoclinic WO3 (Pd/WO3) would possess optimal O2 activation kinetics and an intermediate oxidation/desorption barrier, thereby promoting HCOOH formation. As evidenced by experiments, the Pd/WO3 catalyst achieves an exceptional HCOOH yield of 4.67 mmol gcat-1 h-1 with a high selectivity of 62% under full-spectrum light irradiation at room temperature using molecular O2. Notably, these results significantly outperform the state-of-the-art photocatalytic systems operated under identical condition.

13.
bioRxiv ; 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38826442

RESUMEN

Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs). As examples, we demonstrate that SABER hydrogels can prolong the release of five BA-containing small-molecule drugs as well as BA-modified insulin and antibodies. Pharmacokinetic studies revealed that SABER hydrogels extended the therapeutic effect of ganfeborole from days to weeks, preventing Mycobacterium tuberculosis growth better than repeated oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for six days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation.

14.
Nat Commun ; 15(1): 4679, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38824163

RESUMEN

Tungsten trioxide (WO3) has been recognized as the most promising photocatalyst for highly selective oxidation of methane (CH4) to formaldehyde (HCHO), but the origin of catalytic activity and the reaction manner remain controversial. Here, we take {001} and {110} facets dominated WO3 as the model photocatalysts. Distinctly, {001} facet can readily achieve 100% selectivity of HCHO via the active site mechanism whereas {110} facet hardly guarantees a high selectivity of HCHO along with many intermediate products via the radical way. In situ diffuse reflectance infrared Fourier transform spectroscopy, electron paramagnetic resonance and theoretical calculations confirm that the competitive chemical adsorption between CH4 and H2O and the different CH4 activation routes on WO3 surface are responsible for diverse CH4 oxidation pathways. The microscopic mechanism elucidation provides the guidance for designing high performance photocatalysts for selective CH4 oxidation.

15.
Angew Chem Int Ed Engl ; 63(29): e202405593, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38716660

RESUMEN

For zinc-metal batteries, the instable chemistry at Zn/electrolyte interphasial region results in severe hydrogen evolution reaction (HER) and dendrite growth, significantly impairing Zn anode reversibility. Moreover, an often-overlooked aspect is this instability can be further exacerbated by the interaction with dissolved cathode species in full batteries. Here, inspired by sustained-release drug technology, an indium-chelated resin protective layer (Chelex-In), incorporating a sustained-release mechanism for indium, is developed on Zn surface, stabilizing the anode/electrolyte interphase to ensure reversible Zn plating/stripping performance throughout the entire lifespan of Zn//V2O5 batteries. The sustained-release indium onto Zn electrode promotes a persistent anticatalytic effect against HER and fosters uniform heterogeneous Zn nucleation. Meanwhile, on the electrolyte side, the residual resin matrix with immobilized iminodiacetates anions can also repel detrimental anions (SO4 2- and polyoxovanadate ions dissolved from V2O5 cathode) outside the electric double layer. This dual synergetic regulation on both electrode and electrolyte sides culminates a more stable interphasial environment, effectively enhancing Zn anode reversibility in practical high-areal-capacity full battery systems. Consequently, the bio-inspired Chelex-In protective layer enables an ultralong lifespan of Zn anode over 2800 h, which is also successfully demonstrated in ultrahigh areal capacity Zn//V2O5 full batteries (4.79 mAh cm-2).

16.
Neural Netw ; 176: 106351, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38713969

RESUMEN

A brain-computer interface (BCI) enables direct communication between the human brain and external devices. Electroencephalography (EEG) based BCIs are currently the most popular for able-bodied users. To increase user-friendliness, usually a small amount of user-specific EEG data are used for calibration, which may not be enough to develop a pure data-driven decoding model. To cope with this typical calibration data shortage challenge in EEG-based BCIs, this paper proposes a parameter-free channel reflection (CR) data augmentation approach that incorporates prior knowledge on the channel distributions of different BCI paradigms in data augmentation. Experiments on eight public EEG datasets across four different BCI paradigms (motor imagery, steady-state visual evoked potential, P300, and seizure classifications) using different decoding algorithms demonstrated that: (1) CR is effective, i.e., it can noticeably improve the classification accuracy; (2) CR is robust, i.e., it consistently outperforms existing data augmentation approaches in the literature; and, (3) CR is flexible, i.e., it can be combined with other data augmentation approaches to further improve the performance. We suggest that data augmentation approaches like CR should be an essential step in EEG-based BCIs. Our code is available online.


Asunto(s)
Interfaces Cerebro-Computador , Electroencefalografía , Electroencefalografía/métodos , Humanos , Algoritmos , Encéfalo/fisiología , Potenciales Evocados Visuales/fisiología , Potenciales Relacionados con Evento P300/fisiología , Procesamiento de Señales Asistido por Computador , Imaginación/fisiología
17.
Angew Chem Int Ed Engl ; 63(24): e202404658, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38573117

RESUMEN

Efficiently converting methane into valuable chemicals via photocatalysis under mild condition represents a sustainable route to energy storage and value-added manufacture. Despite continued interest in this area, the achievements have been overshadowed by the absence of standardized protocols for conducting photocatalytic methane oxidation experiments as well as evaluating the corresponding performance. In this review, we present a structured solution aimed at addressing these challenges. Firstly, we introduce the norms underlying reactor design and outline various configurations in the gas-solid and gas-solid-liquid reaction systems. This discussion helps choosing the suitable reactors for methane conversion experiments. Subsequently, we offer a comprehensive step-by-step protocol applicable to diverse methane-conversion reactions. Emphasizing meticulous verification and accurate quantification of the products, this protocol highlights the significance of mitigating contamination sources and selecting appropriate detection methods. Lastly, we propose the standardized performance metrics crucial for evaluating photocatalytic methane conversion. By defining these metrics, the community could obtain the consensus of assessing the performance across different studies. Moving forward, the future of photocatalytic methane conversion necessitates further refinement of stringent experimental standards and evaluation criteria. Moreover, development of scalable reactor is essential to facilitate the transition from laboratory proof-of-concept to potentially industrial production.

18.
Light Sci Appl ; 13(1): 98, 2024 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-38678015

RESUMEN

Due to its unbounded and orthogonal modes, the orbital angular momentum (OAM) is regarded as a key optical degree of freedom (DoF) for future information processing with ultra-high capacity and speed. Although the manipulation of OAM based on metasurfaces has brought about great achievements in various fields, such manipulation currently remains at single-DoF level, which means the multiplexed manipulation of OAM with other optical DoFs is still lacking, greatly hampering the application of OAM beams and advancement of metasurfaces. In order to overcome this challenge, we propose the idea of multiplexed coherent pixel (MCP) for metasurfaces. This approach enables the manipulation of arbitrary complex-amplitude under incident lights of both plane and OAM waves, on the basis of which we have realized the multiplexed DoF control of OAM and wavelength. As a result, the MCP method expands the types of incident lights which can be simultaneously responded by metasurfaces, enriches the information processing capability of metasurfaces, and creates applications of information encryption and OAM demultiplexer. Our findings not only provide means for the design of high-security and high-capacity metasurfaces, but also raise the control and application level of OAM, offering great potential for multifunctional nanophotonic devices in the future.

19.
bioRxiv ; 2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38496644

RESUMEN

A significant challenge in the development of long-acting injectable drug formulations, especially for anti-infective agents, is delivering an efficacious dose within a tolerable injection volume. Co-administration of the extracellular matrix-degrading enzyme hyaluronidase can increase maximum tolerable injection volumes but is untested for this benefit with long-acting injectable formulations. One concern is that hyaluronidase could potentially alter the tissue response surrounding an injection depot, a response known to be important for drug release kinetics of long-acting injectable formulations. The objective of this pilot study was to evaluate the impact of co-administration of hyaluronidase on the drug release kinetics, pharmacokinetic profiles, and injection site histopathology of the long-acting injectable paliperidone palmitate for up to four weeks following intramuscular injection in mouse and rat models. In both species, co-administration of hyaluronidase increased paliperidone plasma exposures the first week after injection but did not negate the overall long-acting release nature of the formulation. Hyaluronidase-associated modification of the injection site depot was observed in mice but not in rats. These findings suggest that further investigation of hyaluronidase with long-acting injectable agents is warranted.

20.
Heliyon ; 10(5): e27217, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38449612

RESUMEN

Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner. Furthermore, trilobolide-6-O-isobutyrate stimulates the production of reactive oxygen species, leading to oxidative stress and initiation of apoptosis via the activation of the mitochondrial pathway. Data from xenograft tumor assays in nude mice confirms that TBB inhibits tumor growth, and that there are no obvious toxic effects or side effects in vivo. Mechanistically, trilobolide-6-O-isobutyrate exerts antitumor effects by inhibiting STAT3 transcriptional activation, reducing PCNA and Bcl-2 expression, and increasing P21 expression. These findings emphasizes the potential of trilobolide-6-O-isobutyrate as a promising therapeutic candidate for the treatment of CCA.

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