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Biotechnological Potential of Animal Venom and Toxins

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Animal Venoms".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 17716

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Special Issue Editors

Prof. Dr. Maria Elena De Lima

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Guest Editor

Faculdade Santa Casa de Belo Horizonte – Programa de Pós Graduação em Medicina e Biomedicina, Belo Horizonte, Brazil
Interests: toxins; biotechnology; spider venom; antimicrobial toxins; toxins and pain; anticancer toxins; toxins and therapeutic; arthropod toxins; animal venoms; toxin active in erectile function
Special Issues, Collections and Topics in MDPI journals

Dr. Christina Schroeder

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Guest Editor

Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
Interests: venom peptides; toxins; ion channels; peptide engineering; structural biology; pharmacology; pain; cancer
Special Issues, Collections and Topics in MDPI journals

Dr. Gerardo Corzo

E-Mail Website
Guest Editor

Instituto de Biotecnología, Av. Universidad 2001, Cuernavaca, Morelos 62210, Mexico
Interests: protein chemistry; protein expression; toxinology; venomous amimals

Special Issue Information

Dear Colleagues,

This special issue focused on the study of animal venoms and toxins, which comprise a plethora of bioactive molecules and, despite the extensive research in this field, as stated by Dr. A. Harvey “we are only scratching at the surface of the topic”. Most of the toxins from different venomous animals have not yet been discovered or studied. However, some of these molecules have become models for the development of drugs that are widely used, e.g. captopril, a synthetic antihypertensive compound that inhibits angiotensin converting enzyme and whose structure was inspired by a venom peptide from the snake Bothrops jararaca. Another example is the analgesic peptide omega-MVIIA from Conus magus, which became a potent analgesic drug. Other toxins have been used extensively as pharmacological tools allowing for the study of the structure and the activity of ion channels and other receptors, unveiling new active sites to be explored for medicines. Therefore, this Special Issue highlights works involving animal venoms and toxins with promising pharmacological and therapeutic activity, such as antimicrobials, anticancer, analgesics, active in blood coagulation, and others. We are very proud to build this issue with your participation, and show our progress and excellence on Toxicology, with new perspectives for biotechnology and health.

Prof. Dr. Maria Elena de Lima
Dr. Christina Schroeder
Dr. Gerardo Corzo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

toxins
biotechnology
antimicrobial toxins
toxins and pain
anticancer toxins
toxins and therapeutic
arthropod toxins
animal venoms
snake venoms
toxins and ionic channels

Published Papers (10 papers)

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Research

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15 pages, 2521 KiB

Open AccessArticle

PnPP-15, a Synthetic Peptide Derived from a Toxin from Phoneutria nigriventer Spider Venom, Alleviates Diabetic Neuropathic Pain and Acts Synergistically with Pregabalin in Mice

by Xavier Maia Mariano, Luana Caroline de Assis Ferreira, Camila Megale Almeida-Leite, Célio José de Castro Junior and Maria Elena de Lima

Toxins 2023, 15(9), 560; https://doi.org/10.3390/toxins15090560 - 07 Sep 2023

Viewed by 990

Abstract

Diabetic neuropathic pain is one of the complications that affect a wide variety of the diabetic population and is often difficult to treat. Only a small number of patients experience pain relief, which usually comes with onerous side effects and low levels of satisfaction. The search for new analgesic drugs is necessary, given the limitations that current drugs present. Combining drugs to treat neuropathic pain has been attracting interest to improve their efficacy compared to single-drug monotherapies while also reducing dose sizes to minimize side effects. The aim of our study was to verify the antinociceptive effect of a synthetic peptide, PnPP-15, alone and combined with pregabalin, in male Swiss diabetic mice using the von Frey method. PnPP-15 is a synthetic peptide derived from PnPP19, a peptide representing a discontinuous epitope of the primary structure of the toxin PnTx2-6 from the venom of the spider Phoneutria nigriventer. The antinociceptive activity of both compounds was dose-dependent and showed synergism, which was verified by isobolographic analysis. Treatment with PnPP-15 did not cause spontaneous or forced motor changes and did not cause any damage or signs of toxicity in the analyzed organs (pancreas, lung, heart, kidney, brain, or liver). In conclusion, PnPP-15 is a great candidate for an analgesic drug against neuropathic pain caused by diabetes and exerts a synergistic effect when combined with pregabalin, allowing for even more efficient treatment. Full article

(This article belongs to the Special Issue Biotechnological Potential of Animal Venom and Toxins)

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15 pages, 2627 KiB

Open AccessCommunication

Identification and Venom Characterization of Two Scorpions from the State of Chihuahua Mexico: Chihuahuanus coahuliae and Chihuahuanus crassimannus

by Carolina Alvarado-Gonzalez, Herlinda Clement, Lourdes Ballinas-Casarrubias, Angelica Escarcega-Avila, Ivan Arenas-Sosa, Karla Sofia Lopez-Contreras, Fernando Zamudio, Gerardo Corzo and Gerardo Pavel Espino-Solis

Toxins 2023, 15(7), 416; https://doi.org/10.3390/toxins15070416 - 27 Jun 2023

Viewed by 1099

Abstract

Chihuahua is the largest state in Mexico. The ecosystem of this region is composed of large area of bushes, forests, and grasslands, which allows for a specific diversity of fauna; among them are interesting species of non-lethal scorpions. Most of the Chihuahuan scorpions have been previously morphologically and molecularly described; however, this manuscript could be the first to describe the composition of those venoms. This work aimed at the collection of two scorpion species from the region of Jiménez (Southwest of the State of Chihuahua), which belong to the species Chihuahuanus cohauilae and Chihuahuanus crassimanus; the two species were taxonomically and molecularly identified using a 16S DNA marker. Reverse-phase high-performance liquid chromatography (RP-HPLC) of C. coahuilae and C. crassimanus venoms allowed the identification of three fractions lethal to mice. Additionally, three fractions of each scorpion displayed an effect on house crickets. In the end, three new fractions from the venom of C. coahuilae were positive for antimicrobial activity, although none from C. crassimanus venom displayed growth inhibition. Despite being a preliminary study, the venom biochemical analysis of these two uncharacterized scorpion species opens the opportunity to find new molecules with potential applications in the biomedical and biotechnological fields. Full article

(This article belongs to the Special Issue Biotechnological Potential of Animal Venom and Toxins)

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20 pages, 4481 KiB

Open AccessArticle

Chimeric Peptides from Californiconus californicus and Heterodontus francisci with Antigen-Binding Capacity: A Conotoxin Scaffold to Create Non-Natural Antibodies (NoNaBodies)

by Salvador Dueñas, Teresa Escalante, Jahaziel Gasperin-Bulbarela, Johanna Bernáldez-Sarabia, Karla Cervantes-Luévano, Samanta Jiménez, Noemí Sánchez-Campos, Olivia Cabanillas-Bernal, Blanca J. Valdovinos-Navarro, Angélica Álvarez-Lee, Marco A. De León-Nava and Alexei F. Licea-Navarro

Toxins 2023, 15(4), 269; https://doi.org/10.3390/toxins15040269 - 04 Apr 2023

Cited by 2 | Viewed by 1627

Abstract

Research into various proteins capable of blocking metabolic pathways has improved the detection and treatment of multiple pathologies associated with the malfunction and overexpression of different metabolites. However, antigen-binding proteins have limitations. To overcome the disadvantages of the available antigen-binding proteins, the present investigation aims to provide chimeric antigen-binding peptides by binding a complementarity-determining region 3 (CDR3) of variable domains of new antigen receptors (VNARs) with a conotoxin. Six non-natural antibodies (NoNaBodies) were obtained from the complexes of conotoxin cal14.1a with six CDR3s from the VNARs of Heterodontus francisci and two NoNaBodies from the VNARs of other shark species. The peptides cal_P98Y vs. vascular endothelial growth factor 165 (VEGF₁₆₅), cal_T10 vs. transforming growth factor beta (TGF-β), and cal_CV043 vs. carcinoembryonic antigen (CEA) showed in-silico and in vitro recognition capacity. Likewise, cal_P98Y and cal_CV043 demonstrated the capacity to neutralize the antigens for which they were designed. Full article

(This article belongs to the Special Issue Biotechnological Potential of Animal Venom and Toxins)

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17 pages, 5255 KiB

Open AccessArticle

Monoclonal-Based Antivenomics Reveals Conserved Neutralizing Epitopes in Type I PLA₂ Molecules from Coral Snakes

by Carlos Corrêa-Netto, Marcelo A. Strauch, Marcos Monteiro-Machado, Ricardo Teixeira-Araújo, Juliana Guzzo Fonseca, Moema Leitão-Araújo, Maria Lúcia Machado-Alves, Libia Sanz, Juan J. Calvete, Paulo A. Melo and Russolina Benedeta Zingali

Toxins 2023, 15(1), 15; https://doi.org/10.3390/toxins15010015 - 26 Dec 2022

Viewed by 1309

Abstract

For over a century, polyclonal antibodies have been used to treat snakebite envenoming and are still considered by the WHO as the only scientifically validated treatment for snakebites. Nevertheless, moderate innovations have been introduced to this immunotherapy. New strategies and approaches to understanding how antibodies recognize and neutralize snake toxins represent a challenge for next-generation antivenoms. The neurotoxic activity of Micrurus venom is mainly due to two distinct protein families, three-finger toxins (3FTx) and phospholipases A₂ (PLA₂). Structural conservation among protein family members may represent an opportunity to generate neutralizing monoclonal antibodies (mAbs) against family-conserved epitopes. In this work, we sought to produce a set of monoclonal antibodies against the most toxic components of M. altirostris venom. To this end, the crude venom was fractionated, and its major toxic proteins were identified and used to generate a panel of five mAbs. The specificity of these mAbs was characterized by ELISA and antivenomics approaches. Two of the generated mAbs recognized PLA₂ epitopes. They inhibited PLA₂ catalytic activity and showed paraspecific neutralization against the myotoxicity from the lethal effect of Micrurus and Naja venoms’ PLA_2s. Epitope conservation among venom PLA₂ molecules suggests the possibility of generating pan-PLA₂ neutralizing antibodies. Full article

(This article belongs to the Special Issue Biotechnological Potential of Animal Venom and Toxins)

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13 pages, 1899 KiB

Open AccessArticle

Cationic PLGA Nanoparticle Formulations as Biocompatible Immunoadjuvant for Serum Production and Immune Response against Bothrops jararaca Venom

by Emanuell dos Santos-Silva, Manoela Torres-Rêgo, Fiamma Gláucia-Silva, Renata Carvalho Feitosa, Ariane Ferreira Lacerda, Hugo Alexandre de Oliveira Rocha, Matheus de Freitas Fernandes-Pedrosa and Arnóbio Antônio da Silva-Júnior

Toxins 2022, 14(12), 888; https://doi.org/10.3390/toxins14120888 - 19 Dec 2022

Cited by 1 | Viewed by 1661

Abstract

Snakebite envenoming represents a worldwide public health issue. Suitable technologies have been investigated for encapsulated recombinant or native proteins capable of inducing an effective and long-lasting adaptive immune response. Nanoparticles are colloidal dispersions that have been used as drug delivery systems for bioactive biological compounds. Venom-loaded nanoparticles modulate the protein release and activate the immune response to produce specific antibodies. In this study, biocompatible cationic nanoparticles with Bothrops jararaca venom were prepared to be used as a novel immunoadjuvant that shows a similar or improved immune response in antibody production when compared to a conventional immunoadjuvant (aluminum hydroxide). We prepared stable, small-sized and spherical particles with high Bothrops jararaca venom protein association efficiency. The high protein loading efficiency, electrophoresis, and zeta potential results demonstrated that Bothrops jararaca venom is adsorbed on the particle surface, which remained as a stable colloidal dispersion over 6 weeks. The slow protein release occurred and followed parabolic diffusion release kinetics. The in vivo studies demonstrated that venom-loaded nanoparticles were able to produce an immune response similar to that of aluminum hydroxide. The cationic nanoparticles (CNp) as carriers of bioactive molecules, were successfully developed and demonstrated to be a promising immunoadjuvant. Full article

(This article belongs to the Special Issue Biotechnological Potential of Animal Venom and Toxins)

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16 pages, 3098 KiB

Open AccessArticle

µ-Conotoxins Targeting the Human Voltage-Gated Sodium Channel Subtype Na_V1.7

by Kirsten L. McMahon, Hue N. T. Tran, Jennifer R. Deuis, David J. Craik, Irina Vetter and Christina I. Schroeder

Toxins 2022, 14(9), 600; https://doi.org/10.3390/toxins14090600 - 30 Aug 2022

Cited by 5 | Viewed by 1930

Abstract

µ-Conotoxins are small, potent, peptide voltage-gated sodium (Na_V) channel inhibitors characterised by a conserved cysteine framework. Despite promising in vivo studies indicating analgesic potential of these compounds, selectivity towards the therapeutically relevant subtype Na_V1.7 has so far been limited. We recently identified a novel µ-conotoxin, SxIIIC, which potently inhibits human Na_V1.7 (hNa_V1.7). SxIIIC has high sequence homology with other µ-conotoxins, including SmIIIA and KIIIA, yet shows different Na_V channel selectivity for mammalian subtypes. Here, we evaluated and compared the inhibitory potency of µ-conotoxins SxIIIC, SmIIIA and KIIIA at hNa_V channels by whole-cell patch-clamp electrophysiology and discovered that these three closely related µ-conotoxins display unique selectivity profiles with significant variations in inhibitory potency at hNa_V1.7. Analysis of other µ-conotoxins at hNa_V1.7 shows that only a limited number are capable of inhibition at this subtype and that differences between the number of residues in loop 3 appear to influence the ability of µ-conotoxins to inhibit hNa_V1.7. Through mutagenesis studies, we confirmed that charged residues in this region also affect the selectivity for hNa_V1.4. Comparison of µ-conotoxin NMR solution structures identified differences that may contribute to the variance in hNa_V1.7 inhibition and validated the role of the loop 1 extension in SxIIIC for improving potency at hNa_V1.7, when compared to KIIIA. This work could assist in designing µ-conotoxin derivatives specific for hNa_V1.7. Full article

(This article belongs to the Special Issue Biotechnological Potential of Animal Venom and Toxins)

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18 pages, 2071 KiB

Open AccessArticle

Crotoxin B: Heterologous Expression, Protein Folding, Immunogenic Properties, and Irregular Presence in Crotalid Venoms

by Miguel Angel Mejía-Sánchez, Herlinda Clement, Ligia Luz Corrales-García, Timoteo Olamendi-Portugal, Alejandro Carbajal and Gerardo Corzo

Toxins 2022, 14(6), 382; https://doi.org/10.3390/toxins14060382 - 31 May 2022

Cited by 6 | Viewed by 2294

Abstract

Crotoxin complex CA/CB and crotamine are the main toxins associated with Crotalus envenomation besides the enzymatic activities of phospholipases (PLA₂) and proteases. The neutralization at least of the crotoxin complex by neutralizing the subunit B could be a key in the production process of antivenoms against crotalids. Therefore, in this work, a Crotoxin B was recombinantly expressed to evaluate its capacity as an immunogen and its ability to produce neutralizing antibodies against crotalid venoms. A Crotoxin B transcript from Crotalus tzabcan was cloned into a pCR^®2.1-TOPO vector (Invitrogen, Waltham, MA, USA) and subsequently expressed heterologously in bacteria. HisrCrotoxin B was extracted from inclusion bodies and refolded in vitro. The secondary structure of HisrCrotoxin B was comparable to the secondary structure of the native Crotoxin B, and it has PLA₂ activity as the native Crotoxin B. HisrCrotoxin B was used to immunize rabbits, and the obtained antibodies partially inhibited the activity of PLA₂ from C. tzabcan. The anti-HisrCrotoxin B antibodies neutralized the native Crotoxin B and the whole venoms from C. tzabcan, C. s. salvini, and C. mictlantecuhtli. Additionally, anti-HisrCrotoxin B antibodies recognized native Crotoxin B from different Crotalus species, and they could discriminate venom in species with high or low levels of or absence of Crotoxin B. Full article

(This article belongs to the Special Issue Biotechnological Potential of Animal Venom and Toxins)

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Review

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17 pages, 557 KiB

Open AccessReview

Therapeutic Prospection of Animal Venoms-Derived Antimicrobial Peptides against Infections by Multidrug-Resistant Acinetobacter baumannii: A Systematic Review of Pre-Clinical Studies

by William Gustavo Lima and Maria Elena de Lima

Toxins 2023, 15(4), 268; https://doi.org/10.3390/toxins15040268 - 03 Apr 2023

Cited by 2 | Viewed by 1526

Abstract

Infections caused by multidrug-resistant Acinetobacter baumannii (MDR-Ab) have become a public health emergency. Due to the small therapeutic arsenal available to treat these infections, health agencies have highlighted the importance of developing new antimicrobials against MDR-Ab. In this context, antimicrobial peptides (AMPs) stand out, and animal venoms are a rich source of these compounds. Here, we aimed to summarize the current knowledge on the use of animal venom-derived AMPs in the treatment of MDR-Ab infections in vivo. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The eight studies included in this review identified the antibacterial activity of eleven different AMPs against MDR-Ab. Most of the studied AMPs originated from arthropod venoms. In addition, all AMPs are positively charged and rich in lysine residues. In vivo assays showed that the use of these compounds reduces MDR-Ab-induced lethality and bacterial load in invasive (bacteremia and pneumonia) and superficial (wounds) infection models. Moreover, animal venom-derived AMPs have pleiotropic effects, such as pro-healing, anti-inflammatory, and antioxidant activities, that help treat infections. Animal venom-derived AMPs are a potential source of prototype molecules for the development of new therapeutic agents against MDR-Ab. Full article

(This article belongs to the Special Issue Biotechnological Potential of Animal Venom and Toxins)

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17 pages, 1392 KiB

Open AccessReview

Challenges and Opportunities in Clinical Diagnostic Routine of Envenomation Using Blood Plasma Proteomics

by Joeliton dos Santos Cavalcante, Denis Emanuel Garcia de Almeida, Micael Saggion Moraes, Sophia Ribeiro Santos, Pedro Moriel Pincinato, Pedro Marques Riciopo, Laís Lacerda B. de Oliveira, Wuelton Marcelo Monteiro and Rui Seabra Ferreira-Junior

Toxins 2023, 15(3), 180; https://doi.org/10.3390/toxins15030180 - 27 Feb 2023

Cited by 2 | Viewed by 2441

Abstract

Specific and sensitive tools for the diagnosis and monitoring of accidents by venomous animals are urgently needed. Several diagnostic and monitoring assays have been developed; however, they have not yet reached the clinic. This has resulted in late diagnoses, which represents one of the main causes of progression from mild to severe disease. Human blood is a protein-rich biological fluid that is routinely collected in hospital settings for diagnostic purposes, which can translate research progress from the laboratory to the clinic. Although it is a limited view, blood plasma proteins provide information about the clinical picture of envenomation. Proteome disturbances in response to envenomation by venomous animals have been identified, allowing mass spectrometry (MS)-based plasma proteomics to emerge as a tool in a range of clinical diagnostics and disease management that can be applied to cases of venomous animal envenomation. Here, we provide a review of the state of the art on routine laboratory diagnoses of envenomation by snakes, scorpions, bees, and spiders, as well as a review of the diagnostic methods and the challenges encountered. We present the state of the art on clinical proteomics as the standardization of procedures to be performed within and between research laboratories, favoring a more excellent peptide coverage of candidate proteins for biomarkers. Therefore, the selection of a sample type and method of preparation should be very specific and based on the discovery of biomarkers in specific approaches. However, the sample collection protocol (e.g., collection tube type) and the processing procedure of the sample (e.g., clotting temperature, time allowed for clotting, and anticoagulant used) are equally important to eliminate any bias. Full article

(This article belongs to the Special Issue Biotechnological Potential of Animal Venom and Toxins)

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16 pages, 1200 KiB

Open AccessReview

Antimicrobial Compounds from Skin Secretions of Species That Belong to the Bufonidae Family

by Rodrigo Ibarra-Vega, Alan Roberto Galván-Hernández, Hermenegildo Salazar-Monge, Rocio Zataraín-Palacios, Patricia Elizabeth García-Villalvazo, Diana Itzel Zavalza-Galvez, Laura Leticia Valdez-Velazquez and Juana María Jiménez-Vargas

Toxins 2023, 15(2), 145; https://doi.org/10.3390/toxins15020145 - 10 Feb 2023

Cited by 1 | Viewed by 1642

Abstract

Skin secretions of toads are a complex mixture of molecules. The substances secreted comprise more than 80 different compounds that show diverse pharmacological activities. The compounds secreted through skin pores and parotid glands are of particular interest because they help toads to endure in habitats full of pathogenic microbes, i.e., bacteria, fungi, viruses, and protozoa, due to their content of components such as bufadienolides, alkaloids, and antimicrobial peptides. We carried out an extensive literature review of relevant articles published until November 2022 in ACS Publications, Google Scholar, PubMed, and ScienceDirect. It was centered on research addressing the biological characterization of the compounds identified in the species of genera Atelopus, Bufo, Duttaphrynus, Melanophryniscus, Peltopryne, Phrynoidis, Rhaebo, and Rhinella, with antibacterial, antifungal, antiviral, and antiparasitic activities; as well as studies performed with analogous compounds and skin secretions of toads that also showed these activities. This review shows that the compounds in the secretions of toads could be candidates for new drugs to treat infectious diseases or be used to develop new molecules with better properties from existing ones. Some compounds in this review showed activity against microorganisms of medical interest such as Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Coronavirus varieties, HIV, Trypanosoma cruzi, Leishmania chagasi, Plasmodium falciparum, and against different kinds of fungi that affect plants of economic interest. Full article

(This article belongs to the Special Issue Biotechnological Potential of Animal Venom and Toxins)

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