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Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT.
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Within dynamic agroecosystems, microbes can act as key intermediaries, facilitating spatiotemporal communication among plants. Future research could categorize key plant genes involved in plant-microbe interactions into microbiome-shaping genes (Ms genes) and microbiome-responsive genes (Mr genes), potentially leading to the construction of spatiotemporal molecular networks with microbes as intermediaries.
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Thioesters make up an important class of bioactive compounds. Due to their chemoselectivity, they have been widely used in the synthesis of a wide range of complex bioactive molecules and natural products. At present, chemists have developed a variety of methods for the preparation of thioester compounds. However, these methods usually require the use of transition metal catalysis or harsh reaction conditions. The strategy of synthesizing thioester compounds via visible light-induced electron donor-acceptor (EDA) complex reactions avoids the problems associated with conventional methods through the development of photocatalysis. Here we report a sustainable method for thiocarbonylating aryl sulfonium salts via a visible light-induced EDA complex process without transition metals.
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Background: Diabetes mellitus (DM) is a chronic metabolic disease that poses serious threats to human physical and mental health worldwide. The PDZ domain-containing 8 (PDZD8) protein mediates mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) formation in mammals. We explored the role of PDZD8 in DM and investigated its potential mechanism of action. Methods: High-fat diet (HFD)- and streptozotocin-induced mouse DM and palmitic acid (PA)-induced insulin 1 (INS-1) cell models were constructed. PDZD8 expression was detected using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. MAM formation, interactions between voltage-dependent anion-selective channel 1 (VDAC1) and inositol 1,4,5-triphosphate receptor type 1 (IP3R1), pancreatic ß-cell apoptosis and proliferation were detected using transmission electron microscopy (TEM), proximity ligation assay (PLA), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunofluorescence staining, and Western blotting. The mitochondrial membrane potential, cell apoptosis, cytotoxicity, and subcellular Ca2+ localization in INS-1 cells were detected using a JC-1 probe, flow cytometry, and an lactate dehydrogenase kit. Results: PDZD8 expression was up-regulated in the islets of HFD mice and PA-treated pancreatic ß-cells. PDZD8 knockdown markedly shortened MAM perimeter, suppressed the expression of MAM-related proteins IP3R1, glucose-regulated protein 75 (GRP75), and VDAC1, inhibited the interaction between VDAC1 and IP3R1, alleviated mitochondrial dysfunction and ER stress, reduced the expression of ER stress-related proteins, and decreased apoptosis while increased proliferation of pancreatic ß-cells. Additionally, PDZD8 knockdown alleviated Ca2+ flow into the mitochondria and decreased cyclophilin D (Cypd) expression. Cypd overexpression alleviated the promoting effect of PDZD8 knockdown on the apoptosis of ß-cells. Conclusion: PDZD8 knockdown inhibited pancreatic ß-cell death in DM by alleviated ER-mitochondria contact and the flow of Ca2+ into the mitochondria.
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Inflammatory bowel disease (IBD) is a significant global health concern. The gut microbiota plays an essential role in the onset and development of IBD. Sanghuangporus (SH), a traditional Chinese medicinal mushroom, has excellent anti-inflammatory effects and is effective at modulating the gut microbiota. Despite these attributes, the specific anticolitic effects of SH and the mechanisms through which the gut microbiota mediates its benefits remain unclear. Herein, we demonstrated that polyphenol-rich extract from SH effectively alleviated the pathological symptoms of dextran sodium sulfate (DSS)-induced colitis in mice by modulating the gut microbiota. Treatment with SH distinctly enriched Alistipes, especially Alistipes onderdonkii, and its metabolite 5-hydroxyindole-3-acetic acid (5HIAA). Oral gavage of live A. onderdonkii or 5HIAA potently mitigated DSS-induced colitis in mice. Moreover, both 5HIAA and SH significantly activated the aromatic hydrocarbon receptor (AhR), and the administration of an AhR antagonist abrogated their protective effects against colitis. These results underscore the potent efficacy of SH in diminishing DSS-induced colitis through the promotion of A. onderdonkii and 5HIAA, ultimately activating AhR signaling. This study unveils potential avenues for developing therapeutic strategies for colitis based on the interplay between SH and the gut microbiota.
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The advent of generative artificial intelligence (AI) technologies marks a transformative moment for the scientific sphere, unlocking novel avenues to elevate scientific writing's efficiency and quality, expedite insight discovery, and enhance code development processes. Essential to leveraging these advancements is prompt engineering, a method that enhances AI interaction efficiency and quality. Despite its benefits, effective application requires blending researchers' expertise with AI, avoiding overreliance. A balanced strategy of integrating AI with independent critical thinking ensures the advancement and quality of scientific research, leveraging innovation while maintaining research integrity.
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The increasing application of meta-omics approaches to investigate the structure, function, and intercellular interactions of microbial communities has led to a surge in available data. However, this abundance of human and environmental microbiome data has exposed new scalability challenges for existing bioinformatics tools. In response, we introduce Wekemo Bioincloud-a specialized platform for -omics studies. This platform offers a comprehensive analysis solution, specifically designed to alleviate the challenges of tool selection for users in the face of expanding data sets. As of now, Wekemo Bioincloud has been regularly equipped with 22 workflows and 65 visualization tools, establishing itself as a user-friendly and widely embraced platform for studying diverse data sets. Additionally, the platform enables the online modification of vector outputs, and the registration-independent personalized dashboard system ensures privacy and traceability. Wekemo Bioincloud is freely available at https://www.bioincloud.tech/.
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The vaginal microbiome plays an essential role in the reproductive health of human females. As infertility increases worldwide, understanding the roles that the vaginal microbiome may have in infertility and in vitro fertilization (IVF) treatment outcomes is critical. To determine the vaginal microbiome composition of 1411 individuals (1255 undergoing embryo transplantation) and their associations with reproductive outcomes, clinical and biochemical features are measured, and vaginal samples are 16S rRNA sequenced. Our results suggest that both too high and too low abundance of Lactobacillus is not beneficial for pregnancy; a moderate abundance is more beneficial. A moderate abundance of Lactobacillus crispatus and Lactobacillus iners (~80%) (with a pregnancy rate of I-B: 54.35% and III-B: 57.73%) is found beneficial for pregnancy outcomes compared with a higher abundance (>90%) of Lactobacillus (I-A: 44.81% and III-A: 51.06%, respectively). The community state type (CST) IV-B (contains a high to moderate relative abundance of Gardnerella vaginalis) shows a similar pregnant ratio (48.09%) with I-A and III-A, and the pregnant women in this CST have a higher abundance of Lactobacillus species. Metagenome analysis of 71 samples shows that nonpregnant women are detected with more antibiotic-resistance genes, and Proteobacteria and Firmicutes are the main hosts. The inherent differences within and between women in different infertility groups suggest that vaginal microbes might be used to detect infertility and potentially improve IVF outcomes.
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Venn diagrams serve as invaluable tools for visualizing set relationships due to their ease of interpretation. Widely applied across diverse disciplines such as metabolomics, genomics, transcriptomics, and proteomics, their utility is undeniable. However, the operational complexity has been compounded by the absence of standardized data formats and the need to switch between various platforms for generating different Venn diagrams. To address these challenges, we introduce the EVenn platform, a versatile tool offering a unified interface for efficient data exploration and visualization of diverse Venn diagrams. EVenn (http://www.ehbio.com/test/venn) streamlines the data upload process with a standardized format, enhancing the capabilities for multimodule analysis. This comprehensive protocol outlines various applications of EVenn, featuring representative results of multiple Venn diagrams, data uploads in the centralized data center, and step-by-step case demonstrations. Through these functionalities, EVenn emerges as a valuable and user-friendly tool for the in-depth exploration of multiomics data.
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Environmental-origin microbiota significantly influences Red Heart Qu (RH_Qu) stratification, but their microbial migration and metabolic mechanisms remain unclear. Using high-throughput sequencing and metabolomics, we divided the stratification of RH_Qu into three temperature-based stages. Phase I features rising temperatures, causing microbial proliferation and a two-layer division. Phase II, characterized by peak temperatures, sees the establishment of thermotolerant species like Bacillus, Thermoactinomyces, Rhodococcus, and Thermoascus, forming four distinct layers and markedly altering metabolite profiles. The Huo Quan (HQ), developing from the Pi Zhang (PZ), is driven by the tyrosine-melanin pathway and increased MRPs (Maillard reaction products). The Hong Xin evolves from the Rang, associated with the phenylalanine-coumarin pathway and QCs (Quinone Compounds) production. Phase III involves the stabilization of the microbial and metabolic profile as temperatures decline. These findings enhance our understanding of RH_Qu stratification and offer guidance for quality control in its fermentation process.
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Bactérias , Microbiota , Bactérias/metabolismo , Bactérias/genética , Bactérias/classificação , Bactérias/isolamento & purificação , Fermentação , Metabolômica , Temperatura , Alimentos Fermentados/análise , Alimentos Fermentados/microbiologiaRESUMO
BACKGROUND: The global dissemination of the multidrug resistance efflux pump gene cluster tmexCD-toprJ has greatly weakened the effects of multiple antibiotics, including tigecycline. However, the potential origin and transmission mechanisms of the gene cluster remain unclear. METHODS: Here, we concluded a comprehensive bioinformatics analysis on integrated 73,498 bacterial genomes, including Pseudomonas spp., Klebsiella spp., Aeromonas spp., Proteus spp., and Citrobacter spp., along with 1,152 long-read metagenomic datasets to trace the origin and propagation of tmexCD-toprJ. RESULTS: Our results demonstrated that tmexCD-toprJ was predominantly found in Pseudomonas aeruginosa sourced from human hosts in Asian countries and North American countries. Phylogenetic and genomic feature analyses showed that tmexCD-toprJ was likely evolved from mexCD-oprJ of some special clones of P. aeruginosa. Furthermore, metagenomic analysis confirmed that P. aeruginosa is the only potential ancestral bacterium for tmexCD-toprJ. A putative mobile genetic structure harboring tmexCD-toprJ, int-int-hp-hp-tnfxB-tmexCD-toprJ, was the predominant genetic context of tmexCD-toprJ across various bacterial genera, suggesting that the two integrase genes play a pivotal role in the horizontal transmission of tmexCD-toprJ. CONCLUSIONS: Based on these findings, it is almost certain that the tmexCD-toprJ gene cluster was derived from P. aeruginosa and further spread to other bacteria.
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Antibacterianos , Genoma Bacteriano , Metagenômica , Família Multigênica , Filogenia , Pseudomonas aeruginosa , Tigeciclina , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/efeitos dos fármacos , Tigeciclina/farmacologia , Antibacterianos/farmacologia , Humanos , Farmacorresistência Bacteriana Múltipla/genética , Genômica , Proteínas de Bactérias/genética , Biologia Computacional , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana/genéticaRESUMO
This study delves into the effects of curdlan integration and thermal sterilization on the rheological properties, structure, and quality attributes of concentrated rice starch gel. Acting as a heat-set polysaccharide, curdlan established a dual-network gel structure with rice starch gel, displaying strong interactions with rice starch, as confirmed by confocal laser scanning microscopy and Fourier-transform infrared spectroscopy. The addition of curdlan expedited the gel formation of rice starch, yielding a denser gel structure. Consequently, this enhanced G', solid-like behavior, textural properties, and cooking quality while reducing frequency-dependence. Given the cooling-induced gelation behavior of pure rice starch, thermal treatment disrupted inter-chain hydrogen bonding, compromising the structural integrity of the gel. This disruption manifested in a softer texture and diminished mechanical properties and cooking quality. Notably, this decline in mechanical properties and cooking quality of rice starch gel was markedly ameliorated with the incorporation of curdlan, particularly at a content of ≥1.0 %. Compared with pure RS, 1.0 % CD inclusion showed a reduction in cooking breakage rate by 30.69 % and an increase in hardness by 38.04 %. This work provides valuable insights for the advancement of fresh starch gel-based foods that exhibit exceptional quality and an extended shelf life.
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Géis , Oryza , Reologia , Amido , beta-Glucanas , Oryza/química , beta-Glucanas/química , Amido/química , Géis/química , Esterilização/métodos , Temperatura Alta , Espectroscopia de Infravermelho com Transformada de Fourier , Culinária/métodosRESUMO
Nanomedicines that combine reactive oxygen species (ROS)-responsive polyprodrug and photodynamic therapy have shown great potential for improving treatment efficacy. However, the consumption of ROS by overexpressed glutathione in tumor cells is a major obstacle for achieving effective ROS amplification and prodrug activation. Herein, we report a polyprodrug-based nanoparticle that can realize ROS amplification and cascaded drug release. The nanoparticle can respond to the high level of hydrogen peroxide in tumor microenvironment, achieving self-destruction and release of quinone methide. The quinone methide depletes intracellular glutathione and thus decreases the antioxidant capacity of cancer cells. Under laser irradiation, a large amount of ROS will be generated to induce cell damage and prodrug activation. Therefore, the glutathione-depleting polyprodrug nanoparticles can efficiently inhibit tumor growth by enhanced photodynamic therapy and cascaded locoregional chemotherapy.
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Antineoplásicos , Glutationa , Nanopartículas , Fotoquimioterapia , Pró-Fármacos , Espécies Reativas de Oxigênio , Glutationa/metabolismo , Glutationa/química , Nanopartículas/química , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Humanos , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Animais , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/administração & dosagem , Camundongos , Ensaios de Seleção de Medicamentos Antitumorais , Tamanho da Partícula , Peróxido de Hidrogênio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Propriedades de Superfície , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Microambiente Tumoral/efeitos dos fármacos , IndolquinonasRESUMO
In this work, an effective strategy for the large-scale fabrication of highly porous CuO/Cu2O/Cu/carbon (P-Cu-C) has been established. Cu-cross-linked aerogels were first continuously prepared using a continuous flow mode to form uniform beads, which were transformed into P-Cu-C with a subsequent pyrolysis process. Various pyrolysis temperatures were used to form a series of P-Cu-C including P-Cu-C-250, P-Cu-C-200, P-Cu-C-350, and P-Cu-C-450 to investigate suitable pyrolysis conversion processes. The obtained P-Cu-C series were utilized as anodes of lithium-ion batteries, in which P-Cu-C-250 exhibited a higher reversible gravimetric capacity, excellent rate capability, and superior cycle stability. The enhanced behavior of P-Cu-C-250 was benefitted from the synergistic interaction between uniformly dispersed CuO, Cu2O, Cu nanoparticles, and highly graphitized carbon with a large surface area and highly porous structure. More importantly, the preparation of P-Cu-C-250 could be scaled up by taking advantage of the continuous flow synthesis mode, which may provide pilot- or industrial-scale applications. The large-scale fabrication proposed here may give a universal method to fabricate highly porous metal oxide-carbon anode materials for electrochemical energy conversion and storage applications. Porous CuO/Cu2O/Cu/carbon derived from Cu-crosslinked aerogels was used as Li-ion battery anode materials, exhibiting a high reversible areal capacity, large gravimetric capacity, superior cycling performance, and excellent rate capacity. A continuous preparation method is established to ensure the product scaled up.
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Ischemic stroke (IS), primarily caused by cerebrovascular obstruction, results in severe neurological deficits and has emerged as a leading cause of death and disability worldwide. Recently, there has been increasing exploration of the neuroprotective properties of the inert gas argon. Argon has exhibited impressive neuroprotection in many in vivo and ex vivo experiments without signs of adverse effects, coupled with the advantages of being inexpensive and easily available. However, the efficient administration strategy and underlying mechanisms of neuroprotection by argon in IS are still unclear. This review summarizes current research on the neuroprotective effects of argon in IS with the goal to provide effective guidance for argon application and to elucidate the potential mechanisms of argon neuroprotection. Early and appropriate argon administration at as high a concentration as possible offers favorable neuroprotection in IS. Argon inhalation has been shown to provide some long-term protection benefits. Argon provides the anti-oxidative stress, anti-inflammatory and anti-apoptotic cytoprotective effects mainly around Toll-like receptor 2/4 (TLR2/4), mediated by extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor kappa-B (NF-ĸB) and B-cell leukemia/lymphoma 2 (Bcl-2). Therefore, argon holds significant promise as a novel clinical neuroprotective gas agent for ischemic stroke after further researches to identify the optimal application strategy and elucidate the underlying mechanism.
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Argônio , AVC Isquêmico , Fármacos Neuroprotetores , Argônio/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Animais , Humanos , AVC Isquêmico/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Neuroproteção/fisiologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismoRESUMO
In meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase I. The conserved meiosis-specific kinetochore protein meikin (Moa1 in fission yeast) associates with polo-like kinase: Plo1 and regulates both mono-orientation and cohesion protection. Although the phosphorylation of Rec8-S450 by Plo1 associated with Moa1 plays a key role in cohesion protection, how Moa1-Plo1 regulates mono-orientation remains elusive. Here, we identify Plo1 phosphorylation sites in the cohesin subunits, Rec8 and Psm3. The non-phosphorylatable mutations at these sites showed specific defects in mono-orientation. These results enabled the genetic dissection of meikin functions at the centromeres.
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Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Cinetocoros , Fosforilação , Coesinas , Meiose , Centrômero , Schizosaccharomyces/genética , Proteínas Serina-Treonina Quinases , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Ciclo Celular/genéticaRESUMO
Metagenomic binning is an essential technique for genome-resolved characterization of uncultured microorganisms in various ecosystems but hampered by the low efficiency of binning tools in adequately recovering metagenome-assembled genomes (MAGs). Here, we introduce BASALT (Binning Across a Series of Assemblies Toolkit) for binning and refinement of short- and long-read sequencing data. BASALT employs multiple binners with multiple thresholds to produce initial bins, then utilizes neural networks to identify core sequences to remove redundant bins and refine non-redundant bins. Using the same assemblies generated from Critical Assessment of Metagenome Interpretation (CAMI) datasets, BASALT produces up to twice as many MAGs as VAMB, DASTool, or metaWRAP. Processing assemblies from a lake sediment dataset, BASALT produces ~30% more MAGs than metaWRAP, including 21 unique class-level prokaryotic lineages. Functional annotations reveal that BASALT can retrieve 47.6% more non-redundant opening-reading frames than metaWRAP. These results highlight the robust handling of metagenomic sequencing data of BASALT.
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Ecossistema , Metagenoma , Silicatos , Metagenoma/genética , Metagenômica/métodosRESUMO
China, the world's largest consumer and producer of pork in the world, is attracting increasing attention due to the environmental impacts of its pig production. Previous studies seldom comprehensively compare the environmental impacts of the pig production system with different models, resulting in different intensities of environmental impacts. We aim to comprehensively evaluate Chinese pig production with different breeding models and explore a more sustainable way for pig production. We use life cycle assessment (LCA) to evaluate and compare environmental impacts of pig production system with four main breeding models in China from 1998 to 2020: domestic breeding, small-scale breeding, medium-scale breeding, and large-scale breeding. The life cycle encompasses fertilizer production, feed production, feed processing, pig raising, waste treatment, and slaughtering. The impact categories including energy consumption (EN), global warming (GWP), acidification (AP), eutrophication (EU), water use (WD), and land occupation (LO) are expressed with "100 kg live weight of fattening pig at farm gate." The results show that driven by governmental support, growing meat demand, and cost advantage, the scale breeding especially large-scale breeding simultaneously yielded greater net economic benefit and less environmental impact compared to other breeding models especially the domestic breeding. Due to mineral fertilizer application, feed production contributed over 50% of the total environmental impacts. Notably, the composition of feeds exerted significant influence on the environmental impacts arising from fertilizer production and feed processing. Furthermore, attributable to the substantial use of electricity and heat, as well as the concomitant emissions, pig raising contributed the largest GWP, while ranking second in terms of AP and EU. Notably, waste management constituted the third-largest EU, AP, and WD. In addition to promote scale breeding, we put forth several sustainable measures encompassing feed composition, cultivation practices, fertilizer utilization, and waste management for consideration.
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Conservação dos Recursos Naturais , Fertilizantes , Animais , Suínos , Fazendas , Aquecimento Global , ChinaRESUMO
Machine learning has been increasingly used to retrieve chlorophyll-a (Chl-a) in optically variable waters. However, without the guidance of physical principles or expert knowledge, machine learning may produce biased mapping relationships, or waste considerable time searching for physically infeasible hyperparameter domains. In addition, most Chl-a retrieval models cannot evaluate retrieval uncertainty when ground observations are not available, and the retrieval uncertainty is crucial for understanding the model limitations and evaluating the reliability of retrieval results. In this study, we developed a novel knowledge-guided mixture density network to retrieve Chl-a in optically variable inland waters based on Sentinel-3 Ocean and Land Color Instrument (OLCI) imagery. The proposed method embedded prior knowledge derived from spectral shape classification into the mixture density network. Compared to another deterministic model, the knowledge-guided mixture density network outputted the conditional distribution of Chl-a given an input spectrum, enabling us to estimate the optimal retrieval and the associated uncertainty. The proposed method showed favorable correspondence with the field Chl-a, with root mean square error (RMSE) of 6.56 µg/L, and mean absolute percentage error (MAPE) of 43.64 %. Calibrated against Sentinel-3 OLCI spectrum, the proposed method also performed well when applied to field spectrum (RMSE = 4.58 µg/L, MAPE = 72.70 %), suggesting its effectiveness and good generalization. The proposed method provided the standard deviation of each estimated Chl-a, which enabled us to inspect the reliability of the estimated results and understand the model limitations. Overall, the proposed method improved the Chl-a retrieval in terms of model accuracy and uncertainty evaluation, providing a more comprehensive Chl-a observation of inland waters.