Uridine phosphorylase-1 promotes cell viability and cell-cycle progression in human epidermal keratinocytes via the glycolytic pathway.

Glycolysis is vital for the excessive proliferation of keratinocytes in psoriasis, and uridine phosphorylase-1 (UPP1) functions as an enhancer of cancer cell proliferation. However, little is known about whether UPP1 promotes keratinocyte proliferation and accelerates psoriasis development. This study revealed that UPP1 facilitates cell viability and cell-cycle progression in human epidermal keratinocytes (HEKs) by modulating the glycolytic pathway. Bioinformatics analysis of UPP1 gene expression and its correlation with the Reactome revealed that UPP1 mRNA expression, cell-cycle progression, the interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway and glycolysis were positively associated with psoriasis. Cell proliferation, the cell cycle and glycolysis were evaluated after UPP1 was silenced or overexpressed. The results showed that UPP1 overexpression increased cell proliferation, cell-cycle progression and glycolysis, which was contrary to the effects of UPP1 silencing. However, the STAT3 inhibitor diminished UPP1 expression because STAT3 can bind to the UPP1 promoter. In conclusion, UPP1 was significantly activated by the IL-6/STAT3 pathway and could modulate glycolysis to regulate cell proliferation and cell-cycle progression in keratinocytes during the development of psoriasis.

Research on high sensitivity piezoresistive sensor based on structural design.

With the popularity of smart terminals, wearable electronic devices have shown great market prospects, especially high-sensitivity pressure sensors, which can monitor micro-stimuli and high-precision dynamic external stimuli, and will have an important impact on future functional development. Compressible flexible sensors have attracted wide attention due to their simple sensing mechanism and the advantages of light weight and convenience. Sensors with high sensitivity are very sensitive to pressure and can detect resistance/current changes under pressure, which has been widely studied. On this basis, this review focuses on analyzing the performance impact of device structure design strategies on high sensitivity pressure sensors. The design of structures can be divided into interface microstructures and three-dimensional framework structures. The preparation methods of various structures are introduced in detail, and the current research status and future development challenges are summarized.

Exploring the Relationship between Small Peptides and the T1R1/T1R3 Umami Taste Receptor for Umami Peptide Prediction: A Combined Approach.

Umami peptides are known for enhancing the taste experience by binding to oral umami T1R1 and T1R3 receptors. Among them, small peptides (composed of 2-4 amino acids) constitute nearly 40% of reported umami peptides. Given the diversity in amino acids and peptide sequences, umami small peptides possess tremendous untapped potential. By investigating 168,400 small peptides, we screened candidates binding to T1R1/T1R3 through molecular docking and molecular dynamics simulations, explored bonding types, amino acid characteristics, preferred binding sites, etc. Utilizing three-dimensional molecular descriptors, bonding information, and a back-propagation neural network, we developed a predictive model with 90.3% accuracy, identifying 24,539 potential umami peptides. Clustering revealed three classes with distinct logP (-2.66 ± 1.02, -3.52 ± 0.93, -2.44 ± 1.23) and asphericity (0.28 ± 0.12, 0.26 ± 0.11, 0.25 ± 0.11), indicating significant differences in shape and hydrophobicity (P < 0.05) among potential umami peptides binding to T1R1/T1R3. Following clustering, nine representative peptides (CQ, DP, NN, CSQ, DMC, TGS, DATE, HANR, and STAN) were synthesized and confirmed to possess umami taste through sensory evaluations and electronic tongue analyses. In summary, this study provides insights into exploring small peptide interactions with umami receptors, advancing umami peptide prediction models.

Bruceine A alleviates alcoholic liver disease by inhibiting AIM2 inflammasome activation via activating FXR.

BACKGROUND: Alcoholic liver disease (ALD), a public health challenge worldwide caused by long-term persistent drinking, is life-threatening with minimal approved therapies. Hepatic steatosis accompanied by inflammation is an initial and inevitable stage in the complex progression of simple alcoholic liver injury to more severe liver diseases such as hepatitis, liver fibrosis, cirrhosis and liver cancer. PURPOSE: We aimed to identify the therapeutic role of Bruceine A (BA) in ALD whilst attempting to explore whether its protective effects depend specifically on the farnesoid X receptor (FXR). METHODS: Autodock was applied to detect the affinity between BA and FXR. Lieber-DeCarli liquid diet with 5 % ethanol (v/v) was adopted to establish the mouse ALD model. The lentivirus mediating FXR (LV-FXR) was injected into mice via the tail vein to establish FXR-overexpressed mice. FXR silencing or overexpression plasmids were transfected into AML-12 cells prior to ethanol stimulation. Quantitative real-time PCR, Western blotting and immunofluorescence assays were employed to determine the expression of related genes. We subjected liver sections to H&E and Oil Red O staining to evaluate the liver histological injury and the deposition of lipid droplets. RESULTS: BA significantly reduced body weight and liver-to-body weight ratios as well as biochemical indexes in mice. Ethanol-induced liver damage and lipid accumulation could be alleviated by BA treatment. BA bound to FXR by two hydrogen bonds. There was a positive correlation between BA administration and FXR expression. BA inhibited the expression of lipid synthesis genes and enhanced the expression of lipid metabolism genes by activating FXR, thus alleviating steatosis in ALD. Moreover, BA exerted an ameliorative effect against inflammation by inhibiting the activation of absent in melanoma 2 (AIM2) inflammasome by activating FXR. FXR overexpression possessed the ability to counter the accumulation of lipid and the activation of AIM2 inflammasome caused by ethanol. FXR deficiency exacerbated ethanol-induced liver steatosis and inflammation. The hepatoprotective effect of BA could be disrupted by FXR antagonist guggulsterone (GS) in vivo and FXR siRNA in vitro. CONCLUSION: BA alleviated alcoholic liver disease by inhibiting AIM2 inflammasome activation through an FXR-dependent mechanism. This study may potentially represent a new therapeutic approach for ALD.

Toxic Effects of Rare Earth Elements on Human Health: A Review.

Rare earth elements (REEs) are a new type of material resource which have attracted significant attention in recent years. REEs have emerged as essential metals in modern-day technology due to their unique functions. The long-term, large-scale mining and utilization of rare earths has caused serious environmental pollution and constitutes a global health issue, which has raised concerns regarding the safety of human health. However, the toxicity profile of suspended particulate matter in REEs in the environment, which interacts with the human body, remains largely unknown. Studies have shown that REEs can enter the human body through a variety of pathways, leading to a variety of organ and system dysfunctions through changes in genetics, epigenetics, and signaling pathways. Through an extensive literature search and critical analysis, we provide a comprehensive overview of the available evidence, identify knowledge gaps, and make recommendations for future research directions.

DEAD-Box Helicase 17 circRNA (circDDX17) Reduces Sorafenib Resistance and Tumorigenesis in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver malignancy. Despite significant progress in HCC treatment, resistance to chemotherapy and tumor metastasis are the main reasons for the unsatisfactory prognosis of HCC. Circular RNAs (circRNAs) have been extensively documented to play a role in the development of various types of cancer. AIMS: Here, we investigated the role of DEAD-box helicase 17 circRNA (circDDX17) in HCC and its underlying molecular mechanisms. METHODS: Our research employed various techniques including reverse transcription-quantitative polymerase chain reaction (RT-qPCR), cell counting kit-8 (CCK-8), flow cytometry, dual luciferase reporter assay, RNA immunoprecipitation (RIP), and western blot analysis. Additionally, we conducted a tumor xenograft assay to investigate the in vivo function of circDDX17. RESULTS: Firstly, the expression of circDDX17 was downregulated in HCC tissues and cells. Through functional experiments, it was observed that the overexpression of circDDX17 enhanced the sensitivity of sorafenib, promoted apoptosis, and inhibited the process of epithelial-mesenchymal transition (EMT) in vitro. Additionally, in vivo studies revealed that circDDX17 reduced tumor growth and increased sorafenib sensitivity. Mechanically, circDDX17 competitively combined miR-21-5p to suppress PTEN expression and activate the PI3K/AKT pathway. Furthermore, our rescue assays demonstrated that circDDX17 act as a tumor suppressor by blocking sorafenib resistance and tumorigenesis, while the inhibitory effect caused by circDDX17 upregulation was neutralized when miR-21-5p was overexpressed, PTEN was silenced, or the PI3K/AKT pathway was activated. CONCLUSION: Our findings firstly confirmed that circDDX17 suppressed sorafenib resistance and HCC progression by regulating miR-21-5p/PTEN/PI3K/AKT pathway, which may provide novel biomarkers for the diagnosis, treatment and prognosis of HCC.

Pathways of soil organic carbon accumulation are related to microbial life history strategies in fertilized agroecosystems.

Although the formation, turnover, and accumulation of soil organic carbon (SOC) are driven by different fertilizer inputs and their subsequent microbial-mediated transformation, the relationship between changes in plant-derived and microbial-derived components and soil microbial life history strategies under different fertilization regimes has not been well explored. In this study, the changes in microbial necromass carbon (MNC), lignin phenols, and glomalin-related soil protein (GRSP), as well as soil microbial life history strategy were determined in a 16-year field experiment in response to different fertilization regimes, including a no-fertilizer control (C), conventional chemical NPK fertilization (NPK), and partial substitutions of the NPK in chemical fertilizers with a low (30 %) or high (60 %) level of straw (0.3S and 0.6S) or cattle manure (0.3M and 0.6M). The results showed that total lignin phenol content and its contribution to SOC were significantly increased by 88.7 % and 74.2 %, respectively, in high-level straw substitution treatment as compared to chemical fertilization. Both high-level straw and cattle manure substitution increased MNC and total GRSP contents, but did not alter their contributions to SOC compared to chemical fertilization. In fertilized treatments, the high-level cattle manure substitution had the lowest and highest bacterial and fungal K/r ratio, respectively. Bacterial K/r ratio was an important factor in predicting bacterial necromass carbon content and there was a significant negative correlation between them. The ratio of ectomycorrhizal to saprotrophic fungi and fungal diversity were important factors for predicting lignin phenol and GRSP contents, respectively. In addition, the SEMs modeling indicated that straw substitution directly affected lignin phenol and MNC accumulation, whereas cattle manure substitution indirectly affected MNC accumulation by affecting microbial life history strategies. In conclusions, agricultural residues inputs support the formation of a multiple carbon pool of SOC compared to chemical fertilization; and microbial life history strategy is an important driver of SOC formation and affects SOC accumulation and stability in agroecosystems.

Stearoyl-CoA desaturase 1 inhibition induces ER stress-mediated apoptosis in ovarian cancer cells.

Ovarian cancer is a leading cause of death among gynecologic tumors, often detected at advanced stages. Metabolic reprogramming and increased lipid biosynthesis are key factors driving cancer cell growth. Stearoyl-CoA desaturase 1 (SCD1) is a crucial enzyme involved in de novo lipid synthesis, producing mono-unsaturated fatty acids (MUFAs). Here, we aimed to investigate the expression and significance of SCD1 in epithelial ovarian cancer (EOC). Comparative analysis of normal ovarian surface epithelial (NOSE) tissues and cell lines revealed elevated SCD1 expression in EOC tissues and cells. Inhibition of SCD1 significantly reduced the proliferation of EOC cells and patient-derived organoids and induced apoptotic cell death. Interestingly, SCD1 inhibition did not affect the viability of non-cancer cells, indicating selective cytotoxicity against EOC cells. SCD1 inhibition on EOC cells induced endoplasmic reticulum (ER) stress by activating the unfolded protein response (UPR) sensors and resulted in apoptosis. The addition of exogenous oleic acid, a product of SCD1, rescued EOC cells from ER stress-mediated apoptosis induced by SCD1 inhibition, underscoring the importance of lipid desaturation for cancer cell survival. Taken together, our findings suggest that the inhibition of SCD1 is a promising biomarker as well as a novel therapeutic target for ovarian cancer by regulating ER stress and inducing cancer cell apoptosis.

Visible-Light-Driven Z-Type Pg-C3N4/Nitrogen Doped Biochar/BiVO4 Photo-Catalysts for the Degradation of Norfloxacin.

Antibiotics cannot be effectively removed by traditional wastewater treatment processes, and have become widespread pollutants in various environments. In this study, a Z-type heterojunction photo-catalyst Pg-C3N4 (PCN)/Nitrogen doped biochar (N-Biochar)/BiVO4 (NCBN) for the degradation of norfloxacin (NOR) was prepared by the hydrothermal method. The specific surface area of the NCBN (42.88 m2/g) was further improved compared to BiVO4 (4.528 m2/g). The photo-catalytic performance of the catalyst was investigated, and the N-Biochar acted as a charge transfer channel to promote carrier separation and form Z-type heterojunctions. Moreover, the NCBN exhibited excellent performance (92.5%) in removing NOR, which maintained 70% degradation after four cycles. The main active substance of the NCBN was •O2-, and the possible degradation pathways are provided. This work will provide a theoretical basis for the construction of heterojunction photo-catalysts.

Population Genetic Analyses and Trichothecene Genotype Profiling of Fusarium pseudograminearum Causing Wheat Crown Rot in Henan, China.

In China, Fusarium pseudograminearum has emerged as a major pathogen causing Fusarium crown rot (FCR) and caused significant losses. Studies on the pathogen's properties, especially its mating type and trichothecene chemotypes, are critical with respect to disease epidemiology and food/feed safety. There are currently few available reports on these issues. This study investigated the species composition, mating type idiomorphs, and trichothecene genotypes of Fusarium spp. causing FCR in Henan, China. A significant shift in F. pseudograminearum-induced FCR was found in the present study. Of the 144 purified strains, 143 were F. pseudograminearum, whereas only 1 Fusarium graminearum was identified. Moreover, a significant trichothecene-producing capability of F. pseudograminearum strains from Henan was observed in this work. Among the 143 F. pseudograminearum strains identified, F. pseudograminearum with a 15ADON genotype was found to be predominant (133 isolates), accounting for 92.36% of all strains, followed by F. pseudograminearum with a 3ADON genotype, whereas only one NIV genotype strain was detected. Overall, a relatively well-balanced 1:1 ratio of the F. pseudograminearum population was found in Henan. To the best of our knowledge, this is the first study that has examined the Fusarium populations responsible for FCR across the Henan wheat-growing region.

Evolution of renewable energy laws and policies in China.

This study employs Latent Dirichlet Allocation (LDA) topic modelling methodology to analyze documents related to renewable energy laws and policies at the central level in China. The objective is to investigate the development and evolution of renewable energy policies in China and to gain insights into the national-level attitudes towards renewable energy development. The study consists of two phases: initially, renewable energy policy documents undergo keyword analysis using word clouds and keyword co-occurrence network analysis to elucidate the focal areas and their interconnections within the legal and policy texts. Subsequently, after determining the optimal number of topics for modelling based on topic perplexity and consistency results, the text undergoes data cleaning to isolate words with practical significance. These words are then incorporated into the LDA topic model to analyze the distribution and content of potential topics within the policies. Lastly, by linearly segmenting the time frame, changes in topic intensity over time are visually examined using heat maps. The findings indicate that energy policies have consistently prioritized "development" and emphasized the significance of "new energy" in renewable energy policies. Moreover, as renewable energy has progressed, governments and policymakers have come to acknowledge the importance of comprehensive energy planning, transitioning to clean energy sources, and regulating the electricity market. This growing awareness has led to efforts to strengthen policy and regulatory measures to foster renewable energy's sustainable development and utilization. In summary, this study highlights the effectiveness of the LDA topic model in analyzing renewable energy policies, advancing its adoption and furthering research in the field.

ZIF-8 functionalized S-tapered fiber-optic sensor for polystyrene nanoplastics detection by electrostatic adsorption.

Microplastic (MP) residues in marine have become an increasingly serious environmental pollution issue, and in recent years the detection of MPs in marine started to attract worldwide research interests. Optical-fiber-based environmental sensors have been extensively employed for their several merits such as high sensitivity, pressure resistance, compactness and ease of constructing communication networks. However, fiber-optic refractive index sensors are not specifically developed for distinguishing MPs from other inorganic particles suspended in water. In this paper, an metal-organic framework (MOF) ZIF-8 functionalized S-tapered fiber (STF) sensor is proposed for specific detection of polystyrene nanoplastics (PSNPs) in aqueous environment. ZIF-8 coordination nanoporous polymers with different film thickness were immobilized over the surface of the fabricated STF structure based on self-growth technique and yielding a large surface area over the sensor surface. High sensitivity detection can be achieved by converting the concentration perturbation of PSNPs into evanescent waves over the ZIF-8 functionalized STF surface through the strong electrostatic adsorption effect and π-π stacking, while the fabricated sensor is insensitive to gravels with silica as the primary component in water. It is found that the proposed detector with 18 film layers achieves a sensitivity up to 114.1353nm/%(w/v) for the PSNPs concentration range of 0.01 %(w/v) to 0.08 %(w/v).

A parametric design framework for the mass customization of bicycle helmet.

Cluster analysis of 3D head shapes plays a crucial role in the mass customization design of products related to the head. Head shapes exhibit variations across different races, and designing helmets exclusively for Chinese individuals cannot solely rely on or reference foreign head models. Currently, research on cluster analysis of Chinese head shapes is limited, especially concerning shape variances. To address this, we developed an improved k-medoids algorithm and integrated Cluster Validity Index as an assessment metric. This enabled us to cluster 339 Chinese young males aged 18 to 30 into 7 groups based on their head shapes. By comparing our improved algorithm to the traditional k-medoids method, we affirmed its superiority in achieving higher sample participation rates and reducing inter-cluster sample disparities. To simplify the helmet design and editing process, and to improve the efficiency of mass customization, we have developed a parametric modeling program for bicycle helmets based on the head shape clustering results. Results from the Helmet Fit Index and stress simulation analysis demonstrate that our approach significantly enhances helmet fit and wearer comfort.

Outline and background for the EU-OS solubility prediction challenge.

In June 2022, EU-OS came to the decision to make public a solubility data set of 100+K compounds obtained from several of the EU-OS proprietary screening compound collections. Leveraging on the interest of SLAS for screening scientific development it was decided to launch a joint EUOS-SLAS competition within the chemoinformatics and machine learning (ML) communities. The competition was open to real world computation experts, for the best, most predictive, classification model of compound solubility. The aim of the competition was multiple: from a practical side, the winning model should then serve as a cornerstone for future solubility predictions having used the largest training set so far publicly available. From a higher project perspective, the intent was to focus the energies and experiences, even if professionally not precisely coming from Pharma R&D; to address the issue of how to predict compound solubility. Here we report how the competition was ideated and the practical aspects of conducting it within the Kaggle framework, leveraging of the versatility and the open-source nature of this data science platform. Consideration on results and challenges encountered have been also examined.

Circ-Bptf Ameliorates Learning and Memory Impairments via the miR-138-5p/p62 Axis in APP/PS1 Mice.

Alzheimer's disease (AD) is a common age-associated progressive neurodegenerative disorder that is implicated in the aberrant regulation of numerous circular RNAs (circRNAs). Here, we reported that circ-Bptf, a conserved circRNA derived from the Bptf gene, showed an age-dependent decrease in the hippocampus of APP/PS1 mice. Overexpression of circ-Bptf significantly reversed dendritic spine loss and learning and memory impairment in APP/PS1 mice. Moreover, we found that circ-Bptf was predominantly localized to the cytoplasm and upregulated p62 expression by binding to miR-138-5p. Furthermore, the miR-138-5p mimics reversed the decreased expression of p62 induced by the silencing of circ-Bptf. Together, our findings suggested that circ-Bptf ameliorated learning and memory impairments via the miR-138-5p/p62 axis in APP/PS1 mice. It may act as a potential player in AD pathogenesis and therapy.

Synthesis and Characterization of 6-Ti-Substituted Polyoxomolybdate with High Catalytic Activity for Sulfide Oxidation.

A 6-Ti-substituted polyoxometalate, (NH4)5Cs7Na3H2[Cs@(Ti2GeMo10O39)3]·34H2O (1), was synthesized by reacting (NH4)6Mo7O24·4H2O, GeO2, and TiOSO4 through the conventional aqueous method. Polyanion 1a is composed of three {Ti2GeMo10} segments linked by Ti-O-Ti linkages and shows a trefoil-shaped structure. Furthermore, one Cs+ cation is encapsulated in the cavity of 1a. Notably, it possesses the highest number of Ti centers among the reported polyoxomolybdates. In addition, serving as a high-efficiency heterogeneous catalyst, 1 enables the conversion of methyl phenyl sulfide within 20 min, yielding 96.4% of the corresponding sulfoxide with good recyclability.

Mitochondrial fission enhances IL-6-induced metastatic potential in ovarian cancer via ERK1/2 activation.

Ovarian cancer is a lethal gynecologic cancer mostly diagnosed in an advanced stage with an accumulation of ascites. Interleukin-6 (IL-6), a pro-inflammatory cytokine is highly elevated in malignant ascites and plays a pleiotropic role in cancer progression. Mitochondria are dynamic organelles that undergo fission and fusion in response to external stimuli and dysregulation in their dynamics has been implicated in cancer progression and metastasis. Here, we investigate the effect of IL-6 on mitochondrial dynamics in ovarian cancer cells (OVCs) and its impact on metastatic potential. Treatment with IL-6 on ovarian cancer cell lines (SKOV3 and PA-1) led to an elevation in the metastatic potential of OVCs. Interestingly, a positive association was observed between dynamin-related protein 1 (Drp1), a regulator of mitochondrial fission, and IL-6R in metastatic ovarian cancer tissues. Additionally, IL-6 treatment on OVCs was linked to the activation of Drp1, with a notable increase in the ratio of the inhibitory form p-Drp1(S637) to the active form p-Drp1(S616), indicating enhanced mitochondrial fission. Moreover, IL-6 treatment triggered the activation of ERK1/2, and inhibiting ERK1/2 mitigated IL-6-induced mitochondrial fission. Suppressing mitochondrial fission through siRNA transfection and a pharmacological inhibitor reduced the IL-6-induced migration and invasion of OVCs. This was further supported by 3D invasion assays using patient-derived spheroids. Altogether, our study suggests the role of mitochondrial fission in the metastatic potential of OVCs induced by IL-6. The inhibition of mitochondrial fission could be a potential therapeutic approach to suppress the metastasis of ovarian cancer.

Tracing back primed resistance in cancer via sister cells.

Exploring non-genetic evolution of cell states during cancer treatments has become attainable by recent advances in lineage-tracing methods. However, transcriptional changes that drive cells into resistant fates may be subtle, necessitating high resolution analysis. Here, we present ReSisTrace that uses shared transcriptomic features of sister cells to predict the states priming treatment resistance. Applying ReSisTrace in ovarian cancer cells perturbed with olaparib, carboplatin or natural killer (NK) cells reveals pre-resistant phenotypes defined by proteostatic and mRNA surveillance features, reflecting traits enriched in the upcoming subclonal selection. Furthermore, we show that DNA repair deficiency renders cells susceptible to both DNA damaging agents and NK killing in a context-dependent manner. Finally, we leverage the obtained pre-resistance profiles to predict and validate small molecules driving cells to sensitive states prior to treatment. In summary, ReSisTrace resolves pre-existing transcriptional features of treatment vulnerability, facilitating both molecular patient stratification and discovery of synergistic pre-sensitizing therapies.

Automatic Detection of 30 Fundus Diseases Using Ultra-Widefield Fluorescein Angiography with Deep Experts Aggregation.

INTRODUCTION: Inaccurate, untimely diagnoses of fundus diseases leads to vision-threatening complications and even blindness. We built a deep learning platform (DLP) for automatic detection of 30 fundus diseases using ultra-widefield fluorescein angiography (UWFFA) with deep experts aggregation. METHODS: This retrospective and cross-sectional database study included a total of 61,609 UWFFA images dating from 2016 to 2021, involving more than 3364 subjects in multiple centers across China. All subjects were divided into 30 different groups. The state-of-the-art convolutional neural network architecture, ConvNeXt, was chosen as the backbone to train and test the receiver operating characteristic curve (ROC) of the proposed system on test data and external test date. We compared the classification performance of the proposed system with that of ophthalmologists, including two retinal specialists. RESULTS: We built a DLP to analyze UWFFA, which can detect up to 30 fundus diseases, with a frequency-weighted average area under the receiver operating characteristic curve (AUC) of 0.940 in the primary test dataset and 0.954 in the external multi-hospital test dataset. The tool shows comparable accuracy with retina specialists in diagnosis and evaluation. CONCLUSIONS: This is the first study on a large-scale UWFFA dataset for multi-retina disease classification. We believe that our UWFFA DLP advances the diagnosis by artificial intelligence (AI) in various retinal diseases and would contribute to labor-saving and precision medicine especially in remote areas.

Klebicin E, a pore-forming bacteriocin of Klebsiella pneumoniae, exploits the porin OmpC and the Ton system for translocation.

Bacteriocins, which have narrow-spectrum activity and limited adverse effects, are promising alternatives to antibiotics. In this study, we identified klebicin E (KlebE), a small bacteriocin derived from Klebsiella pneumoniae. KlebE exhibited strong efficacy against multidrug-resistant K. pneumoniae isolates and conferred a significant growth advantage to the producing strain during intraspecies competition. A giant unilamellar vesicle leakage assay demonstrated the unique membrane permeabilization effect of KlebE, suggesting that it is a pore-forming toxin. In addition to a C-terminal toxic domain, KlebE also has a disordered N-terminal domain and a globular central domain. Pulldown assays and soft agar overlay experiments revealed the essential role of the outer membrane porin OmpC and the Ton system in KlebE recognition and cytotoxicity. Strong binding between KlebE and both OmpC and TonB was observed. The TonB-box, a crucial component of the toxin-TonB interaction, was identified as the 7-amino acid sequence (E3ETLTVV9) located in the N-terminal region. Further studies showed that a region near the bottom of the central domain of KlebE plays a primary role in recognizing OmpC, with eight residues surrounding this region identified as essential for KlebE toxicity. Finally, based on the discrepancies in OmpC sequences between the KlebE-resistant and sensitive strains, it was found that the 91st residue of OmpC, an aspartic acid residue, is a key determinant of KlebE toxicity. The identification and characterization of this toxin will facilitate the development of bacteriocin-based therapies targeting multidrug-resistant K. pneumoniae infections.