Research最新文献

Intervening in the microbial environment holds promise for enhancing antitumor efficacy by reshaping the tumor microenvironment, yet few strategies have been reported. In a study led by Zou and coworkers, oral hydrogels are introduced to regulate the microbiota balance in the intestines and tumors, triggering an antitumor immune response. This work presents a microbiota-targeted drug delivery system that demonstrates notable efficacy in colon targeting and colon retention for the treatment of colorectal cancer. This represents a significant clinical advancement in treating colorectal cancer, which is particularly vulnerable to microbial infiltration.

Cognitive dysfunction stands as a prevalent and consequential non-motor manifestation in Parkinson's disease (PD). Although dysfunction of the olfactory system has been recognized as an important predictor of cognitive decline, the exact mechanism by which aberrant olfactory circuits contribute to cognitive dysfunction in PD is unclear. Here, we provide the first evidence for abnormal functional connectivity across olfactory bulb (OB) and piriform cortex (PC) or entorhinal cortex (EC) by clinical fMRI, and dysfunction of neural coherence in the olfactory system in PD mice. Moreover, we discovered that 2 subpopulations of mitral/tufted (M/T) cells in OB projecting to anterior PC (aPC) and EC precisely mediated the process of cognitive memory respectively by neural coherence at specific frequencies in mice. In addition, the transcriptomic profiling analysis and functional genetic regulation analysis further revealed that biorientation defective 1 (Bod1) may play a pivotal role in encoding OB^M/T-mediated cognitive function. We also verified that a new deep brain stimulation protocol in OB ameliorated the cognitive function of Bod1-deficient mice and PD mice. Together, aberrant coherent activity in the olfactory system can serve as a biomarker for assessing cognitive function and provide a candidate therapeutic target for the treatment of PD.

Game theory problems are widely applied in many research areas such as computer science and finance, with the key issue being how to quickly make decisions. Here, we present a novel quantum algorithm for game theory problems based on a continuous quantum walk. Our algorithm exhibits quantum advantage compared to classical game algorithms. Furthermore, we exploit the analogy between the wave function of the Schrödinger equation and the voltage in Kirchhoff's law to effectively translate the design of quantum game trees into classical circuit networks. We have theoretically simulated the quantum game trees and experimentally validated the quantum functionality speedup on classical circuit networks. Due to the robust scalability and stability inherent in classical circuit networks, quantum game trees implemented within this framework hold promise for addressing more intricate application scenarios.

Advanced sensing devices based on metasurfaces have emerged as a revolutionary platform for innovative label-free biosensors, holding promise for early diagnostics and the detection of low-concentration analytes. Here, we developed a chip-based ultrasensitive terahertz (THz) metasensor, leveraging a quasi-bound state in the continuum (q-BIC) to address the challenges associated with intricate operations in trace biochemical detection. The metasensor design features an open-ring resonator metasurface, which supports magnetic dipole q-BIC combining functionalized gold nanoparticles (AuNPs) bound with a specific antibody. The substantial enhancement in THz-analyte interactions, facilitated by the potent near-field enhancement enabled by the q-BICs, results in a substantial boost in biosensor sensitivity by up to 560 GHz/refractive index units. This methodology allows for the detection of conjugated antibody-AuNPs for cardiac troponin I at concentrations as low as 0.5 pg/ml. These discoveries deliver valuable insight for AuNP-based trace biomolecule sensing and pave the path for the development of chip-scale biosensors with profound light-matter interactions.

Activation of mitochondrial function and heat production in adipose tissue by the modification of dietary fat is a promising strategy against obesity. However, as an important source of lipids for ketogenic and daily diets, the function of fats extracted from different adipose tissue sites was largely unknown. In this study, we illustrated the function of fats extracted from adipose tissues with different "beigeing" properties in the ketogenic diet and identified lipid profiles of fats that facilitate energy expenditure. We found that the anti-obesity effect of ketogenic diets was potentiated by using "beigeing" fat [porcine subcutaneous adipose tissue (SAT)] as a major energy-providing ingredient. Through lipidomic analyses, phosphatidylserine (PS) was identified as a functional lipid activating thermogenesis in adipose tissue. Moreover, in vivo studies showed that PS induces adipose tissue thermogenesis and alleviates diet-induced obesity in mice. In vitro studies showed that PS promotes UCP1 expression and lipolysis of adipocytes. Mechanistically, PS promoted mitochondrial function in adipocytes via the ADCY3-cAMP-PKA-PGC1α pathway. In addition, PS-PGC1a binding may affect the stability of the PGC1α protein, which further augments PS-induced thermogenesis. These results demonstrated the efficacy of dietary SAT fats in diminishing lipid accumulation and the underlying molecular mechanism of PS in enhancing UCP1 expression and mitochondrial function. Thus, our findings suggest that as dietary fat, "beigeing" fat provides more beneficial lipids that contribute to the improvement of mitochondrial function, including PS, which may become a novel, nonpharmacological therapy to increase energy expenditure and counteract obesity and its related diseases.

Understanding protein corona composition is essential for evaluating their potential applications in biomedicine. Relative protein abundance (RPA), accounting for the total proteins in the corona, is an important parameter for describing the protein corona. For the first time, we comprehensively predicted the RPA of multiple proteins on the protein corona. First, we used multiple machine learning algorithms to predict whether a protein adsorbs to a nanoparticle, which is dichotomous prediction. Then, we selected the top 3 performing machine learning algorithms in dichotomous prediction to predict the specific value of RPA, which is regression prediction. Meanwhile, we analyzed the advantages and disadvantages of different machine learning algorithms for RPA prediction through interpretable analysis. Finally, we mined important features about the RPA prediction, which provided effective suggestions for the preliminary design of protein corona. The service for the prediction of RPA is available at http://www.bioai-lab.com/PC_ML.

Immune checkpoint therapy, such as programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blockade, has achieved remarkable results in treating various tumors. However, most cancer patients show a low response rate to PD-1/PD-L1 blockade, especially those with microsatellite stable/mismatch repair-proficient colorectal cancer subtypes, which indicates an urgent need for new approaches to augment the efficacy of PD-1/PD-L1 blockade. Cholesterol metabolism, which involves generating multifunctional metabolites and essential membrane components, is also instrumental in tumor development. In recent years, inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine proteinase that regulates cholesterol metabolism, has been demonstrated to be a method enhancing the antitumor effect of PD-1/PD-L1 blockade to some extent. Mechanistically, PCSK9 inhibition can maintain the recycling of major histocompatibility protein class I, promote low-density lipoprotein receptor-mediated T-cell receptor recycling and signaling, and modulate the tumor microenvironment (TME) by affecting the infiltration and exclusion of immune cells. These mechanisms increase the quantity and enhance the antineoplastic effect of cytotoxic T lymphocyte, the main functional immune cells involved in anti-PD-1/PD-L1 immunotherapy, in the TME. Therefore, combining PCSK9 inhibition therapy with anti-PD-1/PD-L1 immunotherapy may provide a novel option for improving antitumor effects and may constitute a promising research direction. This review concentrates on the relationship between PCSK9 and cholesterol metabolism, systematically discusses how PCSK9 inhibition potentiates PD-1/PD-L1 blockade for cancer treatment, and highlights the research directions in this field.

Hydrologic reconstructions from North America are largely unknown for the Middle Miocene. Examination of fungal palynomorph assemblages coupled with traditional plant-based palynology permits delineation of local, as opposed to regional, climate signals and provides a baseline for study of ancient fungas. Here, the Fungi in a Warmer World project presents paleoecology and paleoclimatology of 351 fungal morphotypes from 3 sites in the United States: the Clarkia Konservat-Lagerstätte site (Idaho), the Alum Bluff site (Florida), and the Bouie River site (Mississippi). Of these, 83 fungi are identified as extant taxa and 41 are newly reported from the Miocene. Combining new plant-based paleoclimatic reconstructions with funga-based paleoclimate reconstructions, we demonstrate cooling and hydrologic changes from the Miocene climate optimum to the Serravallian. In the southeastern United States, this is comparable to that reconstructed with pollen and paleobotany alone. In the northwestern United States, cooling is greater than indicated by other reconstructions and hydrology shifts seasonally, from no dry season to a dry summer season. Our results demonstrate the utility of fossil fungi as paleoecologic and paleoclimatic proxies and that warmer than modern geological time intervals do not match the "wet gets wetter, dry gets drier" paradigm. Instead, both plants and fungi show an invigorated hydrological cycle across mid-latitude North America.

Background: The nasopharyngeal brush sampling can effectively collect samples from the nasopharynx. The blind brush sampling does not require the guidance of endoscopy, which is favorable for implementation and dissemination in the community. This study explored methylation markers for nasopharyngeal carcinoma (NPC) at both Epstein-Barr virus (EBV) and its host genome levels, aiming to construct a blind brushing diagnostic method. Methods: EBV DNA capture and methylation sequencing and GEO Illumina 450K methylation array data were used respectively for the discovery of EBV and host methylation markers. The diagnostic method was built in training cohort (n = 347) and validated in an independent validation cohort (n = 155). Results: A total of 1 EBV methylation marker (BILF2) and 6 host methylation markers (ITGA4, IMPA2, ITPKB, PI9, AMIGO2, and VAV3) were identified. Both EBV and host methylation markers were almost exclusively detected in NPC samples, with negligible detection in control samples. In validation cohort, the diagnostic method that included only the EBV BILF2 marker showed a sensitivity and specificity of 80.22% and 98.44%, respectively. When combining the EBV-derived marker BILF2 with the host-derived marker IMPA2, the diagnostic method's sensitivity increased to 84.62%, while the specificity remained unchanged (IDI = 4.4%, P = 0.0419). Conclusion: Overall, the blind nasopharyngeal brushing diagnostic method, combining EBV and host methylation markers, showed great potential in NPC detection and could promote its application in nonclinical screening of NPC.

Microneedles have shown considerable potential in treating ocular diseases, yet enhancing their architecture and functionality to improve therapeutic efficacy poses marked challenges. Here, inspired by the antioxidant strategy of blueberries and the wet adhesive mechanism of clingfish, we construct hierarchical and multifunctional microneedles. These microneedles possess both wet adhesive and antioxidant properties, making them highly effective for ocular wound healing. Constructed using polyacrylic acid-N-hydroxysuccinimide-based hydrogel with hexagonal structures, these generated microneedles ensure strong adhesion in wet environments. Furthermore, by incorporating proanthocyanidins (pAc) into the tips, the microneedle is imparted with excellent competence to scavenge reactive oxygen species (ROS). In the rat model of ocular alkali burns, the designed microneedle not only exhibited robust adhesion and desirable antioxidant properties in the moist ocular environment but also facilitated sustained drug release and effective treatment. These results suggest that our bioinspired microneedles with multifunctional properties offer substantial advancement over conventional approaches, positioning them as promising candidates for versatile wound healing applications.