IF 4.2 2区化学

Molecules Pub Date : 2025-03-31 DOI: 10.3390/molecules30071545

Shunjie Li, Jian Chen

引用次数: 0

New Insights into the Metabolic Profile and Cytotoxic Activity of Kigelia africana Stem Bark.

IF 4.2 2区化学

Molecules Pub Date : 2025-03-20 DOI: 10.3390/molecules30061388

Dimitrina Zheleva-Dimitrova, Rositsa Mihaylova, Maria Nikolova, Nisha Singh, Spiro Konstantinov

{"title":"New Insights into the Metabolic Profile and Cytotoxic Activity of Kigelia africana Stem Bark.","authors":"Dimitrina Zheleva-Dimitrova, Rositsa Mihaylova, Maria Nikolova, Nisha Singh, Spiro Konstantinov","doi":"10.3390/molecules30061388","DOIUrl":"10.3390/molecules30061388","url":null,"abstract":"Ultra-high-performance liquid chromatography coupled to Orbitrap high-resolution mass spectrometry (UHPLC-HRMS) was recently employed in many fields to obtain a rapid characterization of plant extracts. Kigelia africana (family Bignoniaceae) is a quintessential African herbal medicinal plant with immense indigenous medicinal and non-medicinal applications. The aim of the present research was to obtain an in-depth metabolite profiling of the K. africana stem bark extract using UHPLC-HRMS and to conduct a preliminary screening of its anticancer activity against a panel of malignant human cell lines of different origin. The UHPLC-HRMS analysis revealed 63 secondary metabolites including phenolic acids, gallo- and ellagitannins, iridoids, naphthoquinones, and anthraquinones. A total of 34 of all annotated compounds are reported for the first time in K. africana stem bark. The studied profile was dominated by trimethylellagic acid, dimethylellagic acid isomers, and ellagic acid. In all tumor models, we established a pronounced inhibition of cell growth in a mostly dose-dependent manner, with IC50 values ranging near and well below (4-30 µg/mL) the lowest treatment concentration of 25 µg/mL. The established cytotoxicity profile of the K. africana extract, highly biased toward malignantly transformed but not normal cells, suggests specific modulation of defined molecular tumor targets. This study revealed K. africana stem bark as a new source of gallo- and ellagitannins, and highlighted the studied herbal drug as an antiproliferative agent with potential pharmaceutical application.","PeriodicalId":19041,"journal":{"name":"Molecules","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of Layer-by-Layer Magnetic Nanoparticles for Application to Radiotherapy of Pancreatic Cancer.

IF 4.2 2区化学

Molecules Pub Date : 2025-03-20 DOI: 10.3390/molecules30061382

Nobuyoshi Fukumitsu, Yoshitaka Matsumoto, Lili Chen, Yu Sugawara, Nanami Fujisawa, Eri Niiyama, Sosuke Ouchi, Emiho Oe, Takashi Saito, Mitsuhiro Ebara

{"title":"Development of Layer-by-Layer Magnetic Nanoparticles for Application to Radiotherapy of Pancreatic Cancer.","authors":"Nobuyoshi Fukumitsu, Yoshitaka Matsumoto, Lili Chen, Yu Sugawara, Nanami Fujisawa, Eri Niiyama, Sosuke Ouchi, Emiho Oe, Takashi Saito, Mitsuhiro Ebara","doi":"10.3390/molecules30061382","DOIUrl":"10.3390/molecules30061382","url":null,"abstract":"Pancreatic cancer is among the deadliest malignancies, with few treatment options for locally advanced, unresectable cases. Conventional therapies, such as chemoradiotherapy and hyperthermia, show promise but face challenges in improving outcomes. This study introduces a novel drug delivery system using gemcitabine (GEM)-loaded layer-by-layer magnetic nanoparticles (LBL MNPs) combined with alternating magnetic field (AMF) application and X-ray irradiation to enhance therapeutic efficacy. LBL MNPs were synthesized using optimized layering techniques to achieve superior drug loading and controlled release. Human pancreatic cancer cells (PANC-1) were treated with LBL MNPs alone, with AMF-induced hyperthermia, and in combination with X-rays. The results demonstrate that the 7-layer LBL MNPs exhibited optimal cytotoxicity, significantly reducing cell viability at concentrations of 30 µg/mL and higher. Combining 7-layer LBL MNPs with AMF increased cell death in a time- and concentration-dependent manner, achieving up to 98% inhibition of cell proliferation. The addition of X-rays to the regimen demonstrated a strong synergistic effect, resulting in a 13-fold increase in cell death compared to controls. These findings highlight the potential of this integrated approach to improve outcomes in patients with pancreatic cancer.","PeriodicalId":19041,"journal":{"name":"Molecules","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11946117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preparation and Characterization of Biocomposite Films with Enhanced Oxygen Barrier and Antioxidant Properties Based on Polylactide and Extracts from Coffee Silverskin.

IF 4.2 2区化学

Molecules Pub Date : 2025-03-20 DOI: 10.3390/molecules30061383

Argyri-Ioanna Petaloti, Adamantini Paraskevopoulou, Dimitris S Achilias

{"title":"Preparation and Characterization of Biocomposite Films with Enhanced Oxygen Barrier and Antioxidant Properties Based on Polylactide and Extracts from Coffee Silverskin.","authors":"Argyri-Ioanna Petaloti, Adamantini Paraskevopoulou, Dimitris S Achilias","doi":"10.3390/molecules30061383","DOIUrl":"10.3390/molecules30061383","url":null,"abstract":"In the food packaging industry, significant efforts have been dedicated to addressing the pressing market demand for environmentally friendly and sustainable products. Biocomposite films based on compostable and biobased polymers represent a sustainable alternative to conventional packaging materials, offering biodegradability and enhanced functional properties. Additionally, there is growing interest in utilizing waste materials from agriculture and the food industry. This study focuses on the development of multifunctional eco-sustainable biocomposite films by combining poly(lactic acid) (PLA) as a biopolymeric matrix and extracts derived from coffee silverskin (CS), a significant agro-industrial waste byproduct of the coffee roasting process. Extracts of coffee silverskin were obtained via extraction with several solvents. Several properties of the prepared biocomposites were measured using techniques such as scanning electron microscopy (SEM), infrared spectroscopy (FTIR, ATR), differential scanning calorimetry (DSC), and oxygen and water vapor permeability, together with mechanical and physico-chemical characterization and measurements of water content, film solubility, and degree of swelling. The results demonstrate that optimized formulations of PLA/CS biocomposite films exhibit enhanced oxygen barrier properties, reduced permeability, and significant antioxidant activity. These findings underscore the potential for agro-waste valorization in creating eco-friendly food packaging solutions.","PeriodicalId":19041,"journal":{"name":"Molecules","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Polythiophene/Ti₃C₂T_X MXene Composites for Effective Removal of Diverse Organic Dyes via Complementary Activity of Adsorption and Photodegradation.

IF 4.2 2区化学

Molecules Pub Date : 2025-03-20 DOI: 10.3390/molecules30061393

Young-Hwan Bae, Seongin Hong, Jin-Seo Noh

{"title":"Polythiophene/Ti3C2TX MXene Composites for Effective Removal of Diverse Organic Dyes via Complementary Activity of Adsorption and Photodegradation.","authors":"Young-Hwan Bae, Seongin Hong, Jin-Seo Noh","doi":"10.3390/molecules30061393","DOIUrl":"10.3390/molecules30061393","url":null,"abstract":"This study presents an effective method to remove organic dyes from wastewater, using a composite of few-layered porous (FLP) Ti3C2Tx MXene and polythiophene (PTh) nanospheres. The FLP MXene, which was pre-synthesized by a series of intercalation, heat-induced TiO2 formation, and its selective etching, was combined with PTh nanospheres via a simple solution method. The composite effectively removed various organic dyes, but its efficiency was altered depending on the type of dye. Particularly, the removal efficiency of methylene blue reached 91.3% and 97.8% after irradiation for 10 min and 1 h, respectively. The high dye removal efficiency was attributed to the large surface area (32.01 m2/g) of the composite, strong electrostatic interaction between the composite and dye molecules, and active photodegradation process. The strong electrostatic interaction and large surface area could facilitate the adsorption of dye molecules, while photocatalytic activity further enhance dye removal under light. These results are indicative that the PTh/FLP MXene composite may be a promising material for environmental remediation through synergistic processes of adsorption and photocatalysis.","PeriodicalId":19041,"journal":{"name":"Molecules","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Potential of Bio-Sourced Oligogalacturonides in Crop Protection.

IF 4.2 2区化学

Molecules Pub Date : 2025-03-20 DOI: 10.3390/molecules30061392

Camille Carton, Maryline Magnin-Robert, Béatrice Randoux, Corinne Pau-Roblot, Anissa Lounès-Hadj Sahraoui

{"title":"Potential of Bio-Sourced Oligogalacturonides in Crop Protection.","authors":"Camille Carton, Maryline Magnin-Robert, Béatrice Randoux, Corinne Pau-Roblot, Anissa Lounès-Hadj Sahraoui","doi":"10.3390/molecules30061392","DOIUrl":"10.3390/molecules30061392","url":null,"abstract":"During plant development or interactions with pathogens, modifications of the plant cell wall occur. Among the enzymes involved, pectinases, particularly polygalacturonases (PGases), play a crucial role in the controlled hydrolysis of cell wall polysaccharides, leading to the formation of oligogalacturonides (OGs). These pectin-derived fragments act as key elicitors of plant defense responses, stimulating innate immunity and enhancing resistance to pathogens by modulating the expression of genes involved in immune responses and inducing the production of defense compounds. OGs are of particular interest for plant protection as a natural alternative to conventional phytosanitary products as they can be obtained through chemical, thermal, or enzymatic degradation of plant biomass. In a sustainable approach, agricultural by-products rich in pectin, such as citrus peels, apple pomace, or sugar beet pulp, offer an eco-friendly and cost-effective alternative for OG production. Thus, the current review aims to (i) update the state of the art about the different methods used to produce OGs, (ii) explore the potential of OGs as bio-based biocontrol molecules, and (iii) examine the relevance of new pectin sources for OG production.","PeriodicalId":19041,"journal":{"name":"Molecules","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11946057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Proteomic Analysis of Platelet Extracellular Vesicles in Diabetic Patients by nanoLC-MALDI-MS/MS and nanoLC-TIMS-MS/MS.

IF 4.2 2区化学

Molecules Pub Date : 2025-03-20 DOI: 10.3390/molecules30061384

Joanna Kasprzyk-Pochopień, Agnieszka Kamińska, Przemysław Mielczarek, Radosław Porada, Ewa Stępień, Wojciech Piekoszewski

{"title":"The Proteomic Analysis of Platelet Extracellular Vesicles in Diabetic Patients by nanoLC-MALDI-MS/MS and nanoLC-TIMS-MS/MS.","authors":"Joanna Kasprzyk-Pochopień, Agnieszka Kamińska, Przemysław Mielczarek, Radosław Porada, Ewa Stępień, Wojciech Piekoszewski","doi":"10.3390/molecules30061384","DOIUrl":"10.3390/molecules30061384","url":null,"abstract":"Platelet extracellular vesicles (PEVs) are emerging as key biomarkers in diabetes mellitus (DM), reflecting altered platelet function and coagulation pathways. This study compares two proteomic techniques-nanoLC-MALDI-MS/MS and nanoLC-TIMS-MS/MS-for analyzing PEVs in diabetic patients, to assess their potential for biomarker discovery. PEVs were isolated from platelet-rich plasma and characterized using tunable resistive pulse sensing (TRPS), Fourier-transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). Proteomic analyses identified significant differences in protein expression between diabetic and non-diabetic individuals, with nanoLC-TIMS-MS/MS demonstrating superior sensitivity by detecting 97% more unique proteins than nanoLC-MALDI-MS/MS. Key differentially expressed proteins included apolipoproteins and oxidative stress markers, which may contribute to platelet dysfunction and cardiovascular complications in DM. Sex-specific variations in protein expression were also observed, highlighting potential differences in disease progression between male and female patients. The integration of advanced proteomic methodologies provides novel insights into the role of PEVs in diabetes pathophysiology, underscoring their diagnostic and therapeutic potential. These findings pave the way for improved biomarker-based strategies for early detection and monitoring of diabetic complications.","PeriodicalId":19041,"journal":{"name":"Molecules","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting the CXCR4/CXCL12 Axis in Cancer Therapy: Analysis of Recent Advances in the Development of Potential Anticancer Agents.

IF 4.2 2区化学

Molecules Pub Date : 2025-03-20 DOI: 10.3390/molecules30061380

Gerardina Smaldone, Francesca Di Matteo, Roberta Castelluccio, Valeria Napolitano, Maria Rosaria Miranda, Michele Manfra, Pietro Campiglia, Vincenzo Vestuto

{"title":"Targeting the CXCR4/CXCL12 Axis in Cancer Therapy: Analysis of Recent Advances in the Development of Potential Anticancer Agents.","authors":"Gerardina Smaldone, Francesca Di Matteo, Roberta Castelluccio, Valeria Napolitano, Maria Rosaria Miranda, Michele Manfra, Pietro Campiglia, Vincenzo Vestuto","doi":"10.3390/molecules30061380","DOIUrl":"10.3390/molecules30061380","url":null,"abstract":"Cancer, a leading cause of premature death, arises from genetic and epigenetic mutations that transform normal cells into tumor cells, enabling them to proliferate, evade cell death, and stimulate angiogenesis. Recent evidence indicates that chemokines are essential in tumor development, activating receptors that promote proliferation, invasion, and metastasis. The CXCR4/CXCL12 signaling pathway is gaining attention as a promising target for cancer therapy. CXCR4, a chemokine receptor, is often overexpressed in various types of cancer, including kidney, lung, brain, prostate, breast, pancreas, ovarian, and melanomas. When it binds to its endogenous ligand, CXCL12, it promotes cell survival, proliferation, and migration, crucial mechanisms for the retention of hematopoietic stem cells in the bone marrow and the movement of lymphocytes. The extensive expression of CXCR4 in cancer, coupled with the constant presence of CXCL12 in various organs, drives the activation of this axis, which in turn facilitates angiogenesis, tumor progression, and metastasis. Given the detrimental role of the CXCR4/CXCL12 axis, the search for drugs acting selectively against this protein represents an open challenge. This review aims to summarize the recent advancements in the design and development of CXCR4 antagonists as potential anticancer agents.","PeriodicalId":19041,"journal":{"name":"Molecules","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome.

IF 4.2 2区化学

Molecules Pub Date : 2025-03-20 DOI: 10.3390/molecules30061386

Hagen Sülzen, Pavla Fajtova, Anthony J O'Donoghue, Jan Silhan, Evzen Boura

{"title":"Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome.","authors":"Hagen Sülzen, Pavla Fajtova, Anthony J O'Donoghue, Jan Silhan, Evzen Boura","doi":"10.3390/molecules30061386","DOIUrl":"10.3390/molecules30061386","url":null,"abstract":"The 20S proteasome, a critical component of the ubiquitin-proteasome system, plays a central role in regulating protein degradation in eukaryotic cells. Marizomib (MZB), also known as salinosporamide A, is a natural γ-lactam-β-lactone compound derived from Salinispora tropica and is a potent 20S proteasome covalent inhibitor with demonstrated anticancer properties. Its broad-spectrum inhibition of all three proteasome subunits and its ability to cross the blood-brain barrier has made it a promising therapeutic candidate for glioblastoma. In addition to this, MZB also demonstrates significant inhibition against the 20S proteasome of Trichomonas vaginalis (Tv20S), a protozoan parasite, suggesting its potential for parasitic treatments. Here, we present the cryo-EM structure of the human 20S proteasome in complex with MZB at 2.55 Å resolution. This structure reveals the binding mode of MZB to all six catalytic subunits within the two β-rings of the 20S proteasome, providing a detailed molecular understanding of its irreversible inhibitory mechanism. These findings enhance the therapeutic potential of MZB for both cancer and parasitic diseases at the molecular level and highlight marine-derived natural products in targeting the proteasome for therapeutic applications.","PeriodicalId":19041,"journal":{"name":"Molecules","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11946101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Effect of the Ratio of Butylene Succinate and Dilinoleic Diol in Their Copolyester (PBS-DLS) on the Physicochemical Properties and Biofilm Formation.

IF 4.2 2区化学

Molecules Pub Date : 2025-03-20 DOI: 10.3390/molecules30061387

Szymon Macieja, Agnieszka Piegat, Małgorzata Mizielińska, Nina Stefaniak, Mirosława El Fray, Artur Bartkowiak, Magdalena Zdanowicz

{"title":"The Effect of the Ratio of Butylene Succinate and Dilinoleic Diol in Their Copolyester (PBS-DLS) on the Physicochemical Properties and Biofilm Formation.","authors":"Szymon Macieja, Agnieszka Piegat, Małgorzata Mizielińska, Nina Stefaniak, Mirosława El Fray, Artur Bartkowiak, Magdalena Zdanowicz","doi":"10.3390/molecules30061387","DOIUrl":"10.3390/molecules30061387","url":null,"abstract":"Biofilm-forming microorganisms pose a severe threat in the food and medical industries, among others. In this paper, the research materials were poly(butylene succinate-dilinoleic succinate) (PBS-DLS) copolymers with variable hard and soft segment weight ratios (90:10, 70:30, and 50:50). Polymeric films were prepared by the solvent casting method. Selected physicochemical properties and the tendency to form biofilm on the polymer surface were investigated. As the amount of DLS soft segments in the polymer matrix increased, changes in the FTIR-ATR spectra (signal intensity), surface (SEM), and phase transition (DSC) were observed. The higher the content of the DLS segment, the lower the transition temperatures and the smoother the film's surface. These factors resulted in a significant reduction in the amount of biofilm formed on the material's surface and a decrease in the metabolic activity of microorganisms present in the biofilm and SEM micrographs. The obtained PBS-DLS films have great potential in the food and medical packaging industries.","PeriodicalId":19041,"journal":{"name":"Molecules","volume":"30 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11944411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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