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Host–pathogen interactions consist of an attack by the pathogen, frequently a defense by the host and possibly a counterdefense by the pathogen. Here, we present a game-theoretical approach to describe such interactions. We consider a game where the host and pathogen are players and can choose between the strategies of defense (or counterdefense) and no response. Specifically, they may or may not produce a toxin and an enzyme degrading the toxin, respectively. We consider that the host and pathogen must also incur a cost for toxin or enzyme production. We highlight both the sequential and non-sequential versions of the game and determine the Nash equilibria. Furthermore, we resolve a paradox occurring in that interplay. If the inactivating enzyme is very efficient, producing the toxin becomes useless, leading to the enzyme being no longer required. Then, the production of the defense becomes useful again. In game theory, such situations can be described by a generalized matching pennies game. As a novel result, we find under which conditions the defense cycle leads to a steady state or an oscillation. We obtain, for saturating dose–response kinetics and considering monotonic cost functions, "partial (counter)defense" strategies as pure Nash equilibria. This implies that producing a moderate amount of toxin and enzyme is the stable situation in this game. [ABSTRACT FROM AUTHOR]

Transmission of immune responses from one generation to the next represents a powerful adaptive mechanism to protect an organism's descendants. Parental infection by the natural C. elegans pathogen Pseudomonas vranovensis induces a protective response in progeny, but the bacterial cues and intergenerational signal driving this response were previously unknown. Here, we find that animals activate a protective stress response program upon exposure to P. vranovensis -derived cyanide and that a metabolic byproduct of cyanide detoxification, β-cyanoalanine, acts as an intergenerational signal to protect progeny from infection. Remarkably, this mechanism does not require direct parental infection; rather, exposure to pathogen-derived volatiles is sufficient to enhance the survival of the next generation, indicating that parental surveillance of environmental cues can activate a protective intergenerational response. Therefore, the mere perception of a pathogen-derived toxin, in this case cyanide, can protect an animal's progeny from future pathogenic challenges. [Display omitted] • Parental exposure to P. vranovensis volatiles protects progeny from infection • The cyanoalanine synthase CYSL-2 is required for this intergenerational response • Parental CYSL-2 detoxifies cyanide from P. vranovensis , producing β-cyanoalanine • β-cyanoalanine signals intergenerationally via MDT-15 to protect progeny Pathogen-derived cyanide in the environment is detected and detoxified by C. elegans parents, generating a byproduct that acts as an intergenerational signal to protect progeny from infection. [ABSTRACT FROM AUTHOR]

Cardiovascular-kidney-metabolic (CKM) syndrome is a systemic clinical condition characterized by pathological and physiological interactions among metabolic abnormalities, chronic kidney disease, and cardiovascular diseases, leading to multi-organ dysfunction and a higher incidence of cardiovascular endpoints. Traditional approaches to managing CKM syndrome risk are inadequate in these patients, necessitating strategies targeting specific CKM syndrome risk factors. Increasing evidence suggests that addressing uremic toxins and/or pathways induced by uremic toxins may reduce CKM syndrome risk and treat the disease. This review explores the interactions among heart, kidney, and metabolic pathways in the context of uremic toxins and underscores the significant role of uremic toxins as potential therapeutic targets in the pathophysiology of these diseases. Strategies aimed at regulating these uremic toxins offer potential avenues for reversing and managing CKM syndrome, providing new insights for its clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial toxin genes (ATGs) encode potent antimicrobial weapons in nature that rival antibiotics, significantly impacting microbial survival and offering potential benefits for human health. However, the drivers of their global diversity and biogeography remain unknown. Results: Here, we identified 4400 ATG clusters from 149 families by correlating 10,000 samples worldwide with over 200,000 microbial genome data. We demonstrated that global microbial communities universally encode complex and diverse ATGs, with widespread differences across various habitats. Most ATG clusters were rare within habitats but were shared among habitats. Compared with those in animal-associated habitats, ATG clusters in human-associated habitats exhibit greater diversity and a greater proportion of sharing with natural habitats. We generated a global atlas of ATG distribution, identifying anthropogenic factors as crucial in explaining ATG diversity hotspots. Conclusions: Our study provides baseline information on the global distribution of antimicrobial toxins by combining community samples, genome sequences, and environmental constraints. Our results highlight the natural environment as a reservoir of antimicrobial toxins, advance the understanding of the global distribution of these antimicrobial weapons, and aid their application in clinical, agricultural, and industrial fields. 7XT_CdqhdAdND4_ZwQEaMj Video Abstract [ABSTRACT FROM AUTHOR]

ABSTRACT: Introduction: Agriculture is the primary source of livelihood for about 58% of India's population. In recent years, there have been pressing public health and food safety concerns related to pesticide residues. Pesticides are a class of man-made environmental chemicals that can affect the body's development, growth, and hormone balance. Pregnant women are a particularly vulnerable group when it comes to pesticide exposure. Focusing on this population provides crucial data for designing protective interventions. Hence for formulating effective intervention strategy to combat this problem, proper quantification of the root cause was needed, hence the study was being conducted. Methods: Hospital-based, cross-sectional study was conducted among 151 pregnant mothers. The questionnaire was administered by the principal investigator in a simple local language. Chi-square test was done to find the association between socio-demographic variables and knowledge of pregnant mothers about fetal complications due to pesticide. Results: The overall knowledge about pesticide was through newspaper (44.3%) and social media (24.5%) whereas 84.1% believed pesticide has adverse effects on the fetus. It is shown that age <35 years, third trimester participants, educated participants, higher socio-economic status participants showed adequate knowledge about fetal complications due to pesticides. Conclusions: The study concluded that knowledge is adequate about pesticide exposure, but the practice is not. Safe pesticide practices during pregnancy are necessary to protect the developing fetus. [ABSTRACT FROM AUTHOR]

The evolution and maintenance of symbiotic systems remains a fascinating puzzle. While the coevolutionary dynamics of bipartite (host–symbiont) systems are well-studied, the dynamics of more complex systems have only recently garnered attention with increasing technological advances. We model a tripartite system inspired by the marine symbiotic relationship between the alga Bryopsis sp. its intracellular defensive bacterial symbiont " Candidatus Endobryopsis kahalalidifaciens," which produces a toxin that protects the alga against fish herbivores, and the sea-slug Elysia rufescens (Zan et al. 2019), which is not deterred by the toxin. We disentangle the role of selection on different actors within this system by investigating evolutionary scenarios where defense evolves as (i) a host-controlled trait that reduces algal reproductive ability; (ii) a symbiont-controlled trait that impacts symbiont transmission; and (iii) a trait jointly controlled by both host and symbiont. Optimal investment in defensive toxins varies based on the characteristics of the host, symbiont, and sea slug; and evolutionary trajectories are modulated by trade-off shape, i.e. a strongly decelerating trade-off between defense and symbiont transmission can drive symbiont diversification via evolutionary branching. Increasing slug herbivory reduces host investment in defense to favor reproduction, while symbiont investment in defense first declines and then increases as host density declines to the degree that horizontal symbiont transmission is no longer beneficial. Increasing vertical transmission selects for reduced defense by the host when it evolves as a jointly controlled trait, as a result of investment by the symbiont. Our theoretical exploration of the evolution of defensive symbiosis in scenarios involving interactions with multiple herbivores provides a first window into the origin and maintenance of the Bryopsis sp. system, and adds another piece to the puzzle of the evolution of symbiotic systems. [ABSTRACT FROM AUTHOR]

Introduction: The AB-type toxin AIP56 is a key virulence factor of Photobacterium damselae subsp. piscicida (Phdp), inducing apoptosis in fish immune cells. The discovery of AIP56-like and AIP56-related toxins in diverse organisms, including human-associated Vibrio strains, highlights the evolutionary conservation of this toxin family, suggesting that AIP56 and its homologs may share conserved receptors across species. These toxins have potential for biotechnological applications, such as therapeutic protein delivery and immune modulation. Methods: Herein, the cell specificity of AIP56 for immune cells was characterized. The tropism of AIP56 for cells of the sea bass, mouse and human immune system was analyzed by following toxin internalization by flow cytometry and arrival of the toxin in the cytosol by evaluating the cleavage of NF-kB p65 by western blotting. Results: Only a small population of sea bass neutrophils internalized AIP56, indicating that most of the neutrophilic destruction during Phdp infection and/or AIP56 intoxication does not result from the direct action of the toxin. Moreover, the cellular tropism of AIP56 for myeloid cells was observed in the three species, including its preference for macrophages. Further, mouse and human M0 and M2-like macrophages internalized more toxin than M1-like macrophages. Despite the limited interaction of lymphoid cells with AIP56, mouse B1-cells were able to internalize the toxin, possibly due to its myeloid features. Conclusion: AIP56 has tropism for sea bass, mouse and human myeloid cells, with greater affinity for macrophages. This points to an evolutionary conservation of its receptor(s) and mechanism of action across species, raising the possibility that AIP56-like and -related toxins may also play a role in pathogenesis. These findings are relevant for both pathogenicity and biomedical contexts. [ABSTRACT FROM AUTHOR]

Background: Antibody-drug conjugate (ADC) is an anticancer drug that links toxins to specifically targeted antibodies via linkers, offering the advantages of high target specificity and high cytotoxicity. However, complexity of its structural composition poses a greater difficulty for drug design studies. Objectives: Pharmacokinetic/pharmacodynamic (PK/PD) based consideration of ADCs has increasingly become a hot research topic for optimal drug design in recent years, providing possible ideas for obtaining ADCs with desirable properties. Methods: From the assessment of the ADC action process based on PK/PD, we introduce the main research strategies of ADCs. In addition, we investigated the strategies to solve the prominent problems of ADC in the clinic in recent years, and summarized and evaluated the specific ways to optimize various problems of ADC based on the PK/PD model from two perspectives of optimizing the structure and properties of the drugs themselves. Through the selection of target antigen, the optimization of the linker, the optimization of novel small molecule toxins as payload, the optimization of ADC, overcoming the multi-drug resistance of ADC, improving the ADC tumor penetration of ADC, surface modification of ADC and surface bystander effect of ADC provide a more comprehensive and accurate framework for designing new ADCs. Results: We've expounded comprehensively on applying pharmacokinetics or pharmacodynamics while designing ADC to obtain higher efficacy and fewer side effects. From the ADC's PK/PD property while coming into play in vivo and the PK/PD study strategy, to specific ADC optimization methods and recommendations based on PK/PD, it has been study-approved that the PK/PD properties exert a subtle role in the development of ADC, whether in preclinical trials or clinical promotion. Conclusion: The study of PK/PD unfolds the detailed mechanism of ADC action, making it easier to control related parameters in the process of designing ADC, limited efficacy and inevitable off-target toxicity remain a challenging bottleneck. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus, a common pathogen, is capable of producing a significant array of toxins and can develop biofilms or small colony variants (SCVs) to evade detection by the immune system and resist the effects of antibiotics. Its ability to persist for extended periods within host cells has led to increased research interest. This review examines the process of internalization of S. aureus, highlighting the impact of its toxins and adhesion factors on host cells. It elucidates the intricate interactions between them and the host cellular environment, thereby offering potential strategies for the treatment and prevention of S. aureus infections. [ABSTRACT FROM AUTHOR]

Tc toxins are pore-forming virulence factors of many pathogenic bacteria. Following pH-induced conformational changes, they perforate the target membrane like a syringe to translocate toxic enzymes into a cell. Although this complex transformation has been structurally well studied, the reaction pathway and the resulting temporal evolution have remained elusive. We used an integrated biophysical approach to monitor prepore-to-pore transition and found a reaction time of ~30 hours for a complete transition. We show two asynchronous general steps of the process, shell opening and channel ejection, with the overall reaction pathway being a slow multistep process involving three intermediates. Liposomes, an increasingly high pH, or receptors facilitate shell opening, which is directly correlated with an increased rate of the prepore-to-pore transition. Channel ejection is a near-instantaneous process which occurs with a transition time of <60 milliseconds. Understanding the mechanism of action of Tc toxins and unveiling modulators of the kinetics are key steps toward their application as biomedical devices or biopesticides. [ABSTRACT FROM AUTHOR]

Bongkrekic acid (BA) toxin, produced by Burkholderia gladioli pathovar cocovenenans bacteria, has been implicated in foodborne illness outbreaks. BA poisoning is associated with rice noodle consumption; hence, this study investigated B. cocovenenans growth and BA production in wet rice noodles comprising varying starch ratios, starch types, rice nutrients, and saccharides. Noodles with 100% rice flour had BA concentrations 47.7 times higher than that of 100% starch samples (30.53 ± 1.08 mg∙kg−1 vs 0.65 ± 0.03 mg∙kg−1). Moreover, protein powder and glucose significantly promoted BA production (P < 0.05). Corn starch with 120 μl∙100 ml−1 rice oil had a BA concentration of 0.23 ± 0.01 mg∙kg−1, which was 31% lower than those without rice oil. Acid-treated starch had a BA concentration 7.24 times higher than that of other natural starch and no BA was detected in acetate starch. Of the carbohydrates tested, only hexacarbon sugars stimulated BA production. Overall, the degree of carbohydrate hydrolysis critically influenced BA formation. Increasing the use of edible starch and reducing the amount of polysaccharides hydrolyzed into monosaccharides during production will mitigate the risk of B. cocovenenans -related food poisoning in rice noodles and starch products. Rice oil serves as a possible additive to hinder BA production. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are nanoparticle-sized vesicles secreted by nearly all cell types under normal physiological conditions. In toxicological research, EVs have emerged as a crucial link between public health and multi-omics approaches, offering insights into cellular responses to disease-causing injury agents such as environmental and biological toxins, contaminants, and drugs. Notably, EVs present a unique opportunity to deepen our understanding of the pathophysiology of envenomation by natural toxins. Recent advancements in isolating and purifying EV cargo, mass spectrometry techniques, and bioinformatics have positioned EVs as potential biomarkers that could elucidate biological signaling pathways and provide valuable information on the relationship between venomous toxins, their mechanisms of action, and the effectiveness of antivenoms. Additionally, EVs hold promise as proxies for various aspects of envenomation, including the toxin dosage, biological characterization, injury progression, and prognosis during therapeutic interventions. These aspects can be explored through multi-omics technology applied to EV contents from the plasma, saliva, or urine samples of envenomated individuals, offering a comprehensive integrative approach to understanding and managing envenomation cases. [ABSTRACT FROM AUTHOR]

Fusarium head blight, caused by Fusarium graminearum, continues to be one of the most important and devastating fungal diseases on cereal grains including wheat, barley, and oat crops. F. graminearum produces toxic secondary metabolites that include trichothecene type A and type B mycotoxins. There are many variants of these toxins that are produced, and in the early 2010s, a novel type A trichothecene mycotoxin known as 3ANX (7-α hydroxy,15-deacetylcalonectrin) and its deacetylated product NX (7-α hydroxy, 3,15-dideacetylcalonectrin) were identified in Minnesota, USA. In the current study, a total of 31,500 wheat spikes over a period of 6 years (2015–2020) within Manitoba, Canada, were screened for the F. graminearum pathogen, which accounted for 72.8% (2015), 98.3% (2016), 71.9% (2017), 74.4% (2018), 92.6% (2019), and 66.1% (2020) of isolations. A total of 303 F. graminearum isolates, confirmed through sequencing of the ribosomal intergenic spacer, were further investigated for variation in the gene Tri1, which was previously associated with the production of the NX toxin, as well as the accumulation of mycotoxins. A subset of these isolates, consisting of 73 isolates, which tested positive or negative for the NX-Tri1-F/R assay in this study, were cultured in vitro using rice media. Mycotoxins were quantified in these samples using mass spectrometry. Using the same rice culture, genomic DNA was isolated, and the Tri1 coding sequence along with its flanking regions (upstream and downstream of the Tri1 gene) was amplified and sequenced. Deoxynivalenol (DON) accumulated in 96% of the cultures from these isolates, while 3-acetyl deoxynivalenol (3ADON) and 3ANX mycotoxins accumulated in 66% and 63%, respectively. Nivalenol, 15-acetyl deoxynivalenol, and NX mycotoxins were detected in 62%, 36%, and 19% of samples, respectively. A significant correlation was observed between 3ADON and 3ANX (r2 = 0.87), as well as between DON and 3ANX (r2 = 0.89). This study highlights the first large identification of 3ANX- and NX-producing isolates of F. graminearum in Western Canada. In addition, it is the first identification of 15ADON chemotypes producing 3ANX in Western Canada and the first identification of 3ANX and NX-producing isolates in Manitoba, collected from wheat samples. [ABSTRACT FROM AUTHOR]

Rice (Oryza sativa L.) is the most important food in Vietnam. However, rice is often lost in post-harvest due to fungal growth and mycotoxins contamination. This study aimed to evaluate mycotoxin contamination in stored paddy rice collected in 2018, 2019, and 2022 in six provinces in Mekong Delta, Vietnam, using LC-MS/MS. The results revealed that 47% of the samples were contaminated with 12 types of mycotoxins. The prevalence of these mycotoxins was 30% (ZEN), 10% (FUS/MON), 6% (BEA/AFB2), 2–4% (AFG1, AFB1, AFG2), 2% (FB1), and 1% (OTA/AME/ENB). Among the provinces, stored paddy rice from Kien Giang had the highest contamination, followed by Ben Tre, Long An, An Giang, Dong Thap, and Can Tho. Remarkably, paddy rice collected in 2022 was usually contaminated with emerging mycotoxins with a higher incidence of co-occurrence ranging from 2–6% of the samples. Additionally, five stored paddy rice samples were contaminated with levels of AFB1, OTA, and ZEN exceeding Vietnamese regulatory limits for unprocessed rice. Our findings provide valuable insights into mycotoxin contamination across different years and growing regions in the Mekong Delta, Vietnam. This study could give essential information to stakeholders, including policy-makers or food safety authorities, etc., to inform strategies to mitigate these toxins in the near future and underscores the importance of monitoring rice production. [ABSTRACT FROM AUTHOR]

Nemertea is a phylum of bilaterally symmetrical, coelomate, unsegmented worms, also known as ribbon worms. Most species of the phylum Nemertea are marine predators that contain toxins in the single-celled glands of the proboscis and/or integument. Recent transcriptomic studies have shown that nemerteans from all taxonomic groups possess a wide range of putative protein and peptide toxins, while the proteomic data for these animals are highly limited. In this study, proteotranscriptomic analysis was used to investigate the major protein components of the poison of the nemertean Kulikovia alborostrata. We identified 146 transcripts of putative toxins in the transcriptome of K. alborostrata and five putative toxins among the secreted proteins and peptides of the mucus of the animal. The expression levels of cysteine-rich peptides found in the mucus with similarity to known toxins were evaluated in different parts of the body of the worm by quantitative real-time PCR. The high level of expression of investigated peptides in the integument indicate the protective function of these toxins. Overall, this supports the idea that the mucus of nemerteans is a valuable source of peptide and protein toxins. [ABSTRACT FROM AUTHOR]

Objectives The objective of thi s study was to identify and analyse the distribution characteristics, toxin genotyping and antimicrobial susceptibility of Clostridium perfringens and to investigate its resistance mechanisms and genetic characteristics. Methods The MICs of various antibiotics against C. perfringens were determined using the agar dilution method, and resistance genes and toxin genotypes were detected by PCR. Genetic relationships were analysed using MLST. WGS was conducted on the DNB system and PacBio platforms. Results Analysis of 36 strains of C. perfringens revealed that the major toxin types were types C and F, with 86.1% of the strains isolated from bile samples. Of these, 30.6% of the strains exhibited MDR, with resistance rates of 75.0%, 52.8% and 52.8% for penicillin, clindamycin and ampicillin, respectively; however, no resistance to metronidazole and carbapenems was observed. MLST analysis identified 29 STs, including 14 novel types. ST221 and ST498 were the dominant types. The WGS revealed that the most prevalent virulence factors are plc (100.0%), nagH (100.0%), colA (100.0%), nanJ (100.0%), entB (100%), nanH (97.0%), entA (97.0%) and nanI (90.9%). Among these factors, the primary determinants of tetracycline resistance are tetA (66.7%) and tetB (78.8%), which represent the most frequently detected antibiotic resistance genes. Conclusions This study indicates that the infection rate of C. perfringens is relatively high, with the majority of isolated strains exhibiting MDR. The observed high levels of antibiotic resistance, combined with the significant genetic diversity of these strains, suggest a potential public health risk. [ABSTRACT FROM AUTHOR]

Type VI secretion systems (T6SSs) are widespread bacterial protein secretion machines that inject toxic effector proteins into nearby cells, thus facilitating both bacterial competition and virulence. Pseudomonas aeruginosa encodes three evolutionarily distinct T6SSs that each export a unique repertoire of effectors. Owing to its genetic tractability, P. aeruginosa has served as a model organism for molecular studies of the T6SS. However, P. aeruginosa is also an opportunistic pathogen and ubiquitous environmental organism that thrives in a wide range of habitats. Consequently, studies of its T6SSs have provided insight into the role these systems play in the diverse lifestyles of this species. In this review, we discuss recent advances in understanding the regulation and toxin repertoire of each of the three P. aeruginosa T6SSs. We argue that these T6SSs serve distinct physiological functions; whereas one system is a dedicated defensive weapon for interbacterial antagonism, the other two T6SSs appear to function primarily during infection. We find support for this model in examining the signalling pathways that control the expression of each T6SS and co-ordinate the activity of these systems with other P. aeruginosa behaviours. Furthermore, we discuss the effector repertoires of each T6SS and connect the mechanisms by which these effectors kill target cells to the ecological conditions under which their respective systems are activated. Understanding the T6SSs of P. aeruginosa in the context of this organism's diverse lifestyles will provide insight into the physiological roles these secretion systems play in this remarkably adaptable bacterium. [ABSTRACT FROM AUTHOR]

Background: In uremic patients, the accumulation of gut-derived proteinbound uremic toxins (PBUTs) induces changes in the microenvironment of the patients, leading to changes in the elimination pattern of drugs. Aims: To assess ways in which PBUTs alter the CYP450 enzymes in hepatocytes as well as the possible effects of specific PBUTs on the metabolism and excretion of atorvastatin (ATV). Study Design: An experimental study. Methods: The experimental group was treated with long-term MHD for > 3 months, estimated-glomerular filtration rate (e-GFR) < 15 ml/ min, normal Alb level (35.0-55.0 g/l), and no urine; the control group was not treated with hemodialysis, e-GFR < 60 ml/min, normal Alb level, and normal urinary excretion function. A suitable UPLC-MS/MS method was developed for detecting the concentration of 4-hydroxy ATV. Fresh primary hepatocytes were isolated from rats, and the uptake of ATV was tested in the uremic serum (US) group, IS group, and HA group and compared with that in the normal serum group. The metabolic status of ATV in the US group, IS group, and HA group was compared with that in the ATV group. RLM were extracted, and the metabolic experiment of ATV was performed in a human CYP3A4 model. The influence of UTs on pregnane X receptor (PXR)/nuclear factor kappa B (NF-B) mRNA and the protein expression was also detected. Results: IS and HA inhibited the ATV metabolism to varying degrees, wherein IS was the most potent inhibitor, producing > 50% inhibition. Meanwhile, the protein expression of CYP3A4 was downregulated after incubation with US, IS, and HA (p < 0.01). The excretion of ATV was also inhibited by 59.24% and 71.95% after incubation with IS and HA, respectively. The effects of uremic toxins on PXR/NF-B mRNA and protein expression elucidated that PBUTs can inhibit ATV uptake and metabolism by exerting inhibitory effects on CYP3A4 through the PXR/ NF-B signaling pathway. Conclusion: ATV metabolism could be significantly altered in the presence of uremic toxins, suggesting a downregulated effect on the ATV uptake, possibly through Oatp1b1, and also on the activity of CYP3A4 through the PXR/NF-B signaling pathway. [ABSTRACT FROM AUTHOR]

Acute Hepatopancreatic Necrosis Disease (AHPND) represents a significant challenge in the field of shrimp aquaculture. This disease is primarily caused by Vibrio parahaemolyticus strains harbouring the pVA1 plasmid encoding the PirAvp and PirBvp toxins. To combat this epidemic and mitigate its devastating consequences, it is crucial to identify and characterize the receptors responsible for the binding of these pathogenic toxins. Our studied discovered that Penaeus vannamei's Serine protease inhibitor 3 (PvSerpin3) derived from shrimp hepatopancreatic tissues could bind to recombinant PirAvp, confirming its role as a novel PirAvp‐binding protein (PABP). Through comprehensive computational methods, we revealed two truncated PirAvp–binding proteins derived from PvSerpin3 called Serpin3(13) and Serpin3(22), which had higher affinity to PirAvp than the full‐length PvSerpin3. The PABP genes were amplified from a cDNA library that was reversed from total RNA extracted from shrimp, cloned and expressed in Escherichia coli. Three PABP inclusion bodies were refolded to obtain the soluble form, and the recovery efficacy was found to be 100% for Serpin3 and Serpin3(13), while Serpin3(22) had a recovery efficacy of roundly 50%. Co‐Immunoprecipitation (co‐IP) and dot blot assays substantiated the interaction of these recombinant PABPs with both recombinant PirAvp and VPAHPND (XN89)‐producing natural toxins. [ABSTRACT FROM AUTHOR]

Natural toxins present an ongoing risk for human exposure that requires a rapid and accurate diagnosis for proper response. In this study, a qualitative liquid chromatography–high-resolution mass spectrometry (LC–HRMS) method was developed and validated for the detection of a large, diverse selection of natural toxins. Data-dependent acquisition was performed to identify compounds with an in-house mass spectral library of 129 hazardous toxins that originate from plants, animals, and fungi. All 129 compounds were spiked into human urine, extracted, and evaluated for spectral library matching. Of these, 92 toxins met the quality criteria and underwent validation in urine matrix based on American National Standards Institute guidelines. A generalized workflow for method expansion was developed and enables the rapid addition of relevant compounds to the established method. This LC–HRMS method achieves efficient detection of natural toxins in urine, and the created workflow can rapidly increase compound coverage via method expansion. [ABSTRACT FROM AUTHOR]

Simple Summary: The soil bacterium Bacillus thuringiensis (Bt) produces protein crystals during sporulation. Cry toxins, a major component of these protein crystals, are insecticidal proteins with pore-forming activity. Cry toxins are environmentally friendly biopesticides used to create Bt-incorporating genetically modified crops (BT-GMCs) that confer resistance to insect pests. However, public acceptance of BT-GMCs is lacking. A major concern over BT-GMCs is the allergenicity of Cry toxins. Specifically, the pore-forming activity of Cry toxins may directly induce intestinal mast cells to release histamine. In this study, three lepidopteran-specific Cry toxins, Cry1Aa, Cy1Ab, and Cry1Ac, were treated with simulated digestive fluids under different conditions. Cry1A toxins exhibited differing sensitivity to simulated digestive fluids, and digests of Cry1A toxins contained the α4–α5 helical hairpin of domain I, which is thought to be the transmembrane domain. To determine whether Cry1A toxins directly induce histamine release, intact and digested Cry1A toxins were applied to RBL-2H3 cultured rat mast cells. However, no histamine secretion from these mast cells was detected, even when samples were analyzed using HPLC. The results of our study provide important data supporting the safety of Cry1A toxins and potentially BT-GMCs, and reducing anxiety over their safety should help increase public acceptance. Public acceptance of genetically modified crops engineered with Bacillus thuringiensis (Bt) insecticidal protein genes (BT-GMCs), which confer resistance to various lepidopteran insect pests, is generally lacking. As a major concern over BT-GMCs is the allergenicity of insecticidal proteins, alleviating safety concerns should help increase public acceptance. In this study, three lepidopteran-specific Bt toxins, Cry1Aa, Cy1Ab, and Cry1Ac, were treated with simulated digestive fluids under various conditions. Western blotting using antiserum raised against individual segments (α-helices of domain I and β-sheets of domains II and III) of Cry1Aa showed that digestion produces a variety of polypeptides. In particular, the transmembrane α4–α5 of domain I, which may retain the ability to form pores, was the most resistant to digestion. Intact Cry1A toxins and these digests were then applied to RBL-2H3 cultured rat mast cells to determine whether the toxins directly induce histamine release. However, fluorescence microscopy revealed no specific binding of Cry1A toxins to RBL-2H3 cultured rat mast cells. In addition, neither the OPA method nor HPLC analysis detected significant histamine release from mast cells treated with Cry1A toxins and these digests. Our results provide important data supporting the safety of Cry1A toxins and potentially BT-GMCs. [ABSTRACT FROM AUTHOR]

The project aims to develop a predictive model for assessing the effects of environmental toxins on lily pollen tube growth. By integrating principles from biology, mathematics, and game theory, the project will simulate asymmetric polar growth patterns of pollen tubes in response to chemical stressors and determine the ecotoxicological impacts of new chemicals or emerging materials. To address this, this study first proposes a game-theoretical method for balancing various efficacy under multiple-considerations. Additionally, considering that different conditional impacts result from varying factors, this study also presents several asymmetric generalizations relative to the factors and its behavior. Concurrently, several axiomatic processes are utilized to demonstrate the mathematical correctness and practicality for these measuring methods. [ABSTRACT FROM AUTHOR]

Animal venoms are a focus of research due to the hazards they represent and to their relationship to evolution and ecology, pharmacology, biodiscovery, and biotechnology. Venoms have evolved multiple times in Lepidoptera, mostly as defensive adaptations that protect the larval life stages. While venoms are always produced in structures derived from cuticle and setae, they are diverse in their composition and bioactivity, reflecting their multiple evolutionary origins. The most common result of envenomation by lepidopterans is pain and inflammation, but envenomation by some species causes fatal hemorrhagic syndromes or chronic inflammatory conditions in humans or veterinary pathologies such as equine amnionitis and fetal loss. The handful of lepidopteran venom toxins that have been characterized includes coagulotoxins from Lonomia obliqua (Saturniidae) and pain-causing cecropin-like peptides from Doratifera vulnerans (Limacodidae). However, our knowledge of lepidopteran venoms remains comparatively poor, with further studies required to yield a clear picture of the evolution, composition, and function of venoms produced by Lepidoptera. [ABSTRACT FROM AUTHOR]

Botulinum neurotoxins (BoNTs), including serotypes A and E, are potent biotoxins known to cause human poisoning. In addition to the critical protective antigen found in the full BoNT molecule, the receptor binding domain (Hc domain), BoNTs also harbour another essential protective antigen—the light chain‐translocation domain (L‐HN domain). Leveraging these pivotal protective antigens, we genetically engineered a series of inactivated chimeric molecules incorporating L‐HN and Hc domains of BoNT/A and E. The structure of these chimeric molecules, mirror BoNT/A and E, but are devoid of enzyme activity. Experimental findings demonstrated that a lead candidate mEL‐HN‐mAHc harnessing the inactivated protease LCHN/E with the mutated gangliosides binding site Hc/A (mE‐mA) elicited robust immune protection against BoNT/A and E simultaneously in a mouse model, requiring low immune dosages and minimal immunisations. Moreover, mE‐mA exhibited high protective efficacy against BoNT/A and E in guinea pigs and New Zealand white rabbits, resulting in elevated neutralising antibody titres. Furthermore, mE‐mA proved to be a more stable and safer vaccine compared to formaldehyde‐inactivated toxoid. Our data underscore the genetically engineered mE‐mA as a highly effective bivalent vaccine against BoNT/A and E, paving the way for the development of polyvalent vaccines against biotoxins. [ABSTRACT FROM AUTHOR]

Background: The Public Health Agency of Canada oversees the Human Pathogens and Toxins Act and Human Pathogens and Toxins Regulations, and monitors human pathogen and toxin incidents in licensed facilities to minimize exposure impact at the individual and population level. Objective: To provide an overview of confirmed laboratory exposure incidents in Canada in 2023. Methods: Confirmed exposure incident reports in 2023 were analyzed using R 4.2.2, Microsoft Excel and SAS. Results: In 2023, 207 incident reports were received, including 63 confirmed exposure incidents that affected 85 individuals. The academic sector accounted for 50.8% (n=32) of the reported confirmed exposure incidents. Microbiology (n=33; 52.4%) was the predominant activity being performed, with the most common occurrence types being sharps-related (n=22; 27.2%) and procedure-related (n=16; 19.8%). Human interaction (n=36; 57.1%) and standard operating procedures (n=24; 38.1%) were the most frequent root causes cited, with corrective actions often directly addressing these causes. Most of the 85 affected individuals were technicians/technologists (n=55; 64.7%) and had a median of 11 years of laboratory experience. Sixty-seven human pathogens and toxins (HPTs) were implicated in the confirmed exposure incidents, with bacteria (n=36; 53.7%) being the most common biological agent type. The median time between the incident and the reporting date was six days. Conclusion: The number of confirmed exposure incidents increased in 2023 compared to 2022. Microbiology was most often the activity being performed at the time of exposure, and occurrence-types, root causes and HPTs implicated in 2023 mirrored those cited in 2022. [ABSTRACT FROM AUTHOR]

Glomerella cingulata is a pathogenic fungus that can cause apple Glomerella leaf spot (GLS), a new and destructive apple disease in China. Phytotoxins are important factors closely related to the disease process, but there is still no report on the phytotoxins of G. cingulata. The aim of this study was to rapidly identify the phytotoxins of this pathogen using a strategy of HRMS‐based preliminary qualification, followed by targeted structure confirmation and also investigation of phytotoxicity characteristics. First, the crude toxin sample was directly analyzed by the UPLC‐HRMS and GC‐MS, and the data were processed to screen for possible phytotoxic compounds using MS library and the phytotoxicity‐related literature. The reference standards of credible phytotoxic compounds were then subjected to targeted structure validation (signal comparison between standards and compounds in crude toxin via HPLC‐DAD, UPLC‐MS/MS, and GC‐MS), and also the phytotoxicity assay. The results confirmed six phytotoxins produced by G. cingulata, namely 5‐hydroxymethyl‐2‐furancarboxylic acid (HMFCA), 2,5‐bis(hydroxymethyl)furan (BHMF), 2‐furoic acid (FA), 2,3‐butanediol, trans‐aconitic acid (TAA), and cis‐aconitic acid (CAA). Of these, HMFCA and TAA exhibited greater phytotoxicity. Main characteristics: All of them were non‐host‐selective toxins, and toxins were synergistically phytotoxic to the host when mixed. BHMF, HMFCA, FA, TAA, and CAA could be commonly produced by all tested strains, and their phytotoxicity can be significantly inhibited or even eliminated at high temperatures or high pH. The elucidation of the phytotoxins of G. cingulata in this work could provide information on the pathogenesis and control of apple GLS. [ABSTRACT FROM AUTHOR]

Acute Hepatopancreatic Necrosis Disease (AHPND) represents a significant challenge in the field of shrimp aquaculture. This disease is primarily caused by Vibrio parahaemolyticus strains harbouring the pVA1 plasmid encoding the PirAvp and PirBvp toxins. To combat this epidemic and mitigate its devastating consequences, it is crucial to identify and characterize the receptors responsible for the binding of these pathogenic toxins. Our studied discovered that Penaeus vannamei's Serine protease inhibitor 3 (PvSerpin3) derived from shrimp hepatopancreatic tissues could bind to recombinant PirAvp, confirming its role as a novel PirAvp‐binding protein (PABP). Through comprehensive computational methods, we revealed two truncated PirAvp–binding proteins derived from PvSerpin3 called Serpin3(13) and Serpin3(22), which had higher affinity to PirAvp than the full‐length PvSerpin3. The PABP genes were amplified from a cDNA library that was reversed from total RNA extracted from shrimp, cloned and expressed in Escherichia coli. Three PABP inclusion bodies were refolded to obtain the soluble form, and the recovery efficacy was found to be 100% for Serpin3 and Serpin3(13), while Serpin3(22) had a recovery efficacy of roundly 50%. Co‐Immunoprecipitation (co‐IP) and dot blot assays substantiated the interaction of these recombinant PABPs with both recombinant PirAvp and VPAHPND (XN89)‐producing natural toxins. [ABSTRACT FROM AUTHOR]

Background Although cnidarians are mostly marine organisms, the occurrence of freshwater jellyfish frequently arouses the interest of ecologists, due to their sudden and unusual appearances in natural and artificial water bodies around the world. Methods This study describes a series of cases compatible with cnidarian envenomation that occurred coincidentally in time and space with the presence of Craspedacusta sowerbii Lankester, 1880 jellyfish in the province of Misiones (El Saltito stream) in January 2022. A year later, its presence was confirmed in another watercourse of this province (Cazador stream). Based on these findings, its possible toxicological consequences in humans were evaluated by characterizing the jellyfish extract using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and enzymatic/toxic activities. Results We revealed the presence of proteolytic enzymes and cytolytic toxin(s), which—by means of activating the inflammatory cascade—could explain the stinging skin lesions observed in the suspected cases described. Conclusions In addition to recording for the first time the occurrence of this cnidarian in northeastern Argentina, this work provides, for the first time, a toxinological explanation for the clinical observations after contact with the most widespread freshwater jellyfish species in the world, giving support to health professionals in the diagnosis and management of such accidents/envenomation. [ABSTRACT FROM AUTHOR]

Poisoning is a major problem all over the world, though the type of poison and the associated morbidity and mortality varies from place to place and changes over a period of time. A retrospective study of 154 cases of poisoning received in the casualty of G.C.S. Medical College, Hospital and Research Centre, Ahmedabad during a span of last 3 years (Jan 2021 to Dec 2023) was done to know the demographic profile and pattern of acute poisoning in the region. Knowing the pattern of poisoning cases in a region helps in suggesting proper earliest preventive measures and also in early management of cases. Out of total cases majority of the cases were male (36 %), unmarried (54.5 %), and most commonly affected age group was 31 to 40 years (19.5 %). Household poisoning cases (21.43 %) were the most common type of poisoning. Majority of the cases intentionally consumed poison(56.50 %). Oral ingestion was the most common route of exposure (94.8 %). [ABSTRACT FROM AUTHOR]

Understanding the origins of novel, complex phenotypes is a major goal in evolutionary biology. Poison frogs of the family Dendrobatidae have evolved the novel ability to acquire alkaloids from their diet for chemical defense at least three times. However, taxon sampling for alkaloids has been biased towards colorful species, without similar attention paid to inconspicuous ones that are often assumed to be undefended. As a result, our understanding of how chemical defense evolved in this group is incomplete. Here, we provide new data showing that, in contrast to previous studies, species from each undefended poison frog clade have measurable yet low amounts of alkaloids. We confirm that undefended dendrobatids regularly consume mites and ants, which are known sources of alkaloids. Thus, our data suggest that diet is insufficient to explain the defended phenotype. Our data support the existence of a phenotypic intermediate between toxin consumption and sequestration -- passive accumulation -- that differs from sequestration in that it involves no derived forms of transport and storage mechanisms yet results in low levels of toxin accumulation. We discuss the concept of passive accumulation and its potential role in the origin of chemical defenses in poison frogs and other toxin-sequestering organisms. In light of ideas from pharmacokinetics, we incorporate new and old data from poison frogs into an evolutionary model that could help explain the origins of acquired chemical defenses in animals and provide insight into the molecular processes that govern the fate of ingested toxins. [ABSTRACT FROM AUTHOR]

Aflatoxins are the most potent hepatocarcinogens of all biologically produced toxins found to date. Contaminated food and commodities are one of the most serious problems due to an irreversible damage to health. Taking advantage of biological methods to improve food safety, an aflatoxin B1 (AFB1) bioremoval study was conducted to investigate the potential of arrested fungal cells on magnetic nanoparticles. The favourable results on the degradation of AFB1 indicate a reasonable influence of the carriers on the fungal cells and the degradation process. The efficacy of degradation of AFB1 by free and immobilised fungal cells on four different magnetic nanoparticles (Fe3O4) was investigated. The degradation rate by HPLC analysis exhibited 54.97% for the free cell study, 85.85% for Fe3O4@MTMS@cell, 95.07% for Fe3O4@TEOS@cell, 84.48% for Fe3O4@SiO2-NH2@cell and 96.52% for Fe3O4@BCD@cell for the 3 μg/ml AFB1. The degradation with Fe3O4@ BCD@cell showed remarkable results even for 5 μg/ml AFB1 resulting 93.42%. [ABSTRACT FROM AUTHOR]

Botulinum neurotoxins (BoNTs), ricin, and many other biological toxins are called AB toxins possessing heterogeneous A and B subunits. We propose herein a quick and safe sensing approach to AB toxins based on their unique quaternary structures. The proposed approach utilizes IgG antibodies against their A-subunits in combination with those human cell-membrane glycolipids that act as the natural ligands of B-subunits. In practice, an IgG antibody against the A-subunit of a target toxin is selected from commercially available sources and immobilized on the surface of Au nanoparticles to constitute a multivalent IgG/Au nanoconjugate. The derived IgG/Au conjugate is used in the pretreatment process of test samples for deactivating biological toxins in the form of a ternary toxin/antibody/Au complex. This process is implemented in advance to reduce the risk of handling biological toxins in laboratory work. On the other hand, the human glycolipid is immobilized on a tiny glass plate and used as a biosensor chip. The biosensor chip is set in the chamber of a flow sensing system using localized surface plasmon resonance (LSPR) spectrometry available in portable size at relatively low cost. In principle, the LSPR sensing system enables us to perform a rapid and selective detection for different kinds of biological toxins if the human glycolipid is correctly selected and installed in the sensing system. In the present LSPR sensing approach, a target AB toxin may have been deactivated during the pretreatment process. The test sample containing the deactivated AB toxin becomes a real target to be analyzed by the sensing system. In the present, we describe the concept of employing the commercially available IgG antibody in the pretreatment process followed by a typical procedure for converting it into the multivalent antibody/Au nanoconjugate and its preliminary applications in the LSPR detection of a ricin homologue (RCA120) and BoNTs in different serotypes. The tested LSPR sensing approach has worked very well for the ricin homologue and certain serotypes of botulinum neurotoxins like BoNT/A, indicating that the prior deactivation process at their A-domains causes no significant damage to the function of their B-domains with respect to determining the host cell-membrane glycolipid. The experimental results also indicated that LSPR responses from these pretreated AB toxins are significantly amplified. That is obviously thanks to the presence of Au nanoparticles in the multivalent IgG/Au nanoconjugate. We suggest in conclusion that the proposed LSPR sensing approach will provide us with a safe and useful tool for the study of biological AB toxins based on their unique quaternary protein structures. [ABSTRACT FROM AUTHOR]

Naturally occurring protein toxins can derive from bacteria, fungi, plants, and animal venom. Traditionally, toxins are known for their destructive effects on host cells. Despite, and sometimes even because of, these harmful effects, toxins have been used for medical benefits. The prerequisite for the development of toxin-based medications or treatments against toxins is thorough knowledge about the toxin and its underlying mechanism of action. Thus, the toxin of interest must be synthesized. Traditional cell-based production requires high laboratory safety standards and often results in a low total protein yield due to the toxin's harmful, cytotoxic nature. These drawbacks can be circumvented by using cell-free protein synthesis (CFPS), a highly adaptable platform technology relying on cell lysates rather than living cells. This review discusses the current advances in cell-free synthesis of protein toxins as well as their uses and applications for pharmaceutical and diagnostic purposes. [ABSTRACT FROM AUTHOR]

Aflatoxins are foodborne toxins that occur naturally in various crops because of fungal contamination, particularly from two strains, namely Aspergillus flavus and Aspergillus parasiticus. Given their adverse properties, which are teratogenic, mutagenic, and carcinogenic, aflatoxins present a significant public health concern. Consequently, efforts are underway to inactivate aflatoxins and inhibit the growth of these fungi to prevent toxin formation. Since chemical treatments for food products are undesirable or even restricted in some countries, alternative approaches are also implemented. This study investigated gamma-ray (γ-ray) irradiation as a potential method for reducing aflatoxin levels. Specifically, solutions of aflatoxins B1, B2, G1, and G2 were irradiated with doses of 1, 2, 4, and 8 kGy using a cobalt-60 irradiation source. Following γ-irradiation, a notable reduction in aflatoxin levels was observed, particularly for types B1 and G1, which process higher toxicity. This finding suggests γ-irradiation as a feasible method for aflatoxin deactivation. Additionally, as a proof of concept, almond samples spiked with aflatoxins and A. flavus were irradiated. The results showed a decrease in both aflatoxin levels and microbial load in these samples. Overall, these findings indicate that γ-irradiation is a promising approach to aflatoxin reduction, microbial decontamination, and the potential extension of almonds' shelf life. [ABSTRACT FROM AUTHOR]

Bacillus thuringiensis (Bt) bacteria produce different pore forming toxins with insecticidal activity, including Cry and Vip3 proteins. While both Cry and Vip3 cause insect death by forming pores in susceptible lepidopteran larval midgut cells, their mechanisms of action differ. The Vip3Aa protoxin adopts a tetramer-structure, where each monomer has five distinct domains. Upon proteolytic activation, the Vip3 tetramer undergoes a large conformational change forming a syringe like structure that is ready for membrane insertion and pore formation. Here we show that Vip3Aa protoxin had low binding to Spodoptera frugiperda brush border membrane vesicles (BBMV) unlike the activated toxin that bound specifically in a concentration dependent way, suggesting that a structural change upon Vip3Aa proteolytic activation is required for efficient receptor binding. Consistently, the Vip3Aa protoxin showed no toxicity to Sf9 cells compared to the activated toxin. In contrast, Cry1Fa protoxin and its activated toxin, were both highly toxic to Sf9 cells. To identify the region of Vip3 involved in binding to BBMV proteins, different overlapping peptides from Vip3Aa covering domains III, IV and V were expressed, and binding analysis were performed against BBMV, showing that domain III is the primary binding domain. Additionally, domains III, IV and V amino acid residues that become exposed upon activation of Vip3Aa were identified. Mutagenesis of these exposed residues revealed three amino acids (K385, K526 and V529) located in two structural adjacent loops, domain III loop β5-β6 and loop α11-β16 that connects domains III and IV, that are crucial for binding to the midguts of S. frugiperda larvae and for toxicity. Our results demonstrate that proteolytic activation of Vip3Aa exposes a receptor binding region essential for its toxicity. Author summary: To exert toxicity, Vip3 tetrameric protoxins are activated by larval gut proteases facilitating the formation of lytic pores that destroy the midgut epithelium cells killing the susceptible larvae. Here, we demonstrate that the proteolytic activation of Vip3Aa protoxin is necessary for triggering receptor binding. Binding analysis of Vip3Aa protoxin and activated toxin to S. frugiperda midguts and toxicity assays against Sf9 cells, confirmed that proteolytic activation is necessary for an efficient binding to the insect midgut membranes and for toxicity. The analysis of residues from domains III, IV and V, that become exposed after Vip3Aa activation by proteolysis, allowed us to identify a structural binding epitope which plays an important role in receptor binding and toxicity. Our results indicate that the structural change that Vip3Aa undergoes after activation by larval midgut proteases, besides being important for membrane insertion and pore formation, also triggers receptor binding important for toxicity. [ABSTRACT FROM AUTHOR]

Bacteria use the type VI secretion system (T6SS) to secrete toxins into pro- and eukaryotic cells via machinery consisting of a contractile sheath and a rigid tube. Rearrangement hotspot (Rhs) proteins represent one of the most common T6SS effectors. The Rhs C-terminal toxin domain displays great functional diversity, while the Rhs core is characterized by YD repeats. We elucidate the Rhs core structures of PAAR- and VgrG-linked Rhs proteins from Salmonella bongori and Advenella mimigardefordensis , respectively. The Rhs core forms a large shell of β-sheets with a negatively charged interior and encloses a large volume. The S. bongori Rhs toxin does not lead to ordered density in the Rhs shell, suggesting the toxin is unfolded. Together with bioinformatics analysis showing that Rhs toxins predominantly act intracellularly, this suggests that the Rhs core functions two-fold, as a safety feature for the producer cell and as delivery mechanism for the toxin. [Display omitted] • PAAR- and VgrG-linked Rhs form large, negatively charged shells • Rhs toxins function predominantly intracellularly, in contrast to non-Rhs toxins • TMDs, prePAAR motifs, and VIRs are not consistently present in Rhs effectors Kielkopf et al. elucidate the structures of two bacterial T6SS-associated Rhs proteins. Rhs cores form large, negatively charged shells that encapsulate unfolded or molten globule toxin domains. Their bioinformatic analyses show that Rhs toxins predominantly act intracellularly and that TMDs, prePAAR motifs, and VIRs are not consistently present in Rhs effectors. [ABSTRACT FROM AUTHOR]

Venom is a metabolically expensive secretion used sparingly in a variety of ecological contexts, most notably predation and defence. Accordingly, few animals employ their toxins from a distance, and venom-squirting behaviour is only known from select taxa. In scorpions, species belonging to two genera are known to spray venom when threatened, and previous work in Parabuthus transvaalicus shows that venom delivery depends on perceived levels of threat. Here, I describe Tityus (Tityus) achilles sp. nov. , a new species of buthid scorpion from Cundinamarca, Colombia. Remarkably, this species is capable of venom spraying, a first for both the genus and the South American continent. Using frame-by-frame video analysis and ballistic equations, I show that T. (Tityus) achilles sp. nov. employs not one, but two types of airborne defences with dramatic differences in reach and venom expenditure. Further, the new species uses an unusually large reserve of prevenom-like secretion for spraying, as opposed to the costly venom used by other spraying scorpions. In light of these key specializations, I propose that toxungen spraying convergently evolved in response to different selection pressures, laying the groundwork for future investigation. [ABSTRACT FROM AUTHOR]

Pain is a frequent and disturbing symptom among hemodialysis patients. Protein-bound uremic toxins (PBUTs) are related to cardiovascular and overall mortality, and they are difficult to remove with current hemodialysis treatments. The PBUT displacers, such as furosemide, tryptophan, or ibuprofen, may be promising new strategies for improving their clearance. This study aims to compare ibuprofen versus other analgesic drugs in PBUT removal. A prospective study was carried out in 23 patients. Patients underwent four dialysis sessions with routine dialysis parameters, except for analgesic drugs administered (lysine acetylsalicylic acid, acetaminophen, dexketoprofen, and ibuprofen). The reduction ratios (RRs) of a wide range of molecular weight molecules were assessed, including total p-cresyl sulfate and total indoxyl-sulfate. There were no complications related to the administered drug, and pain was controlled independently of the drug. There were no differences in the RR of small-size and medium-sized molecules between all four study treatments. However, indoxyl sulfate and p-cresyl sulfate RRs when ibuprofen was administered were significantly higher than lysine acetylsalicylic acid, acetaminophen, and dexketoprofen treatments. In conclusion, patients with pain may benefit from treatment with ibuprofen instead of lysine acetylsalicylic acid, paracetamol, or dexketoprofen, since in addition to improving pain, it increases the removal of PBUTs. [ABSTRACT FROM AUTHOR]

Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer. The aim of this paper is to review the chemistry, biosynthetic, and synthetic pathways of mycolactone A/B to help develop an understanding of the mode of action of these polyketides as well as their therapeutic potential. The synthetic work has largely been driven by the desire to afford researchers enough (≥100 mg) of the pure toxins for systematic biological studies toward understanding their very high biological activities. The review focuses on pioneering studies of Kishi which elaborate first-, second-, and third-generation approaches to the synthesis of mycolactones A/B. The three generations focused on the construction of the key intermediates required for the mycolactone synthesis. Synthesis of the first generation involves assignment of the relative and absolute stereochemistry of the mycolactones A and B. This was accomplished by employing a linear series of 17 chemical steps (1.3% overall yield) using the mycolactone core. The second generation significantly improved the first generation in three ways: (1) by optimizing the selection of protecting groups; (2) by removing needless protecting group adjustments; and (3) by enhancing the stereoselectivity and overall synthetic efficiency. Though the synthetic route to the mycolactone core was longer than the first generation, the overall yield was significantly higher (8.8%). The third-generation total synthesis was specifically aimed at an efficient, scalable, stereoselective, and shorter synthesis of mycolactone. The synthesis of the mycolactone core was achieved in 14 linear chemical steps with 19% overall yield. Furthermore, a modular synthetic approach where diverse analogues of mycolactone A/B were synthesized via a cascade of catalytic and/or asymmetric reactions as well as several Pd-catalyzed key steps coupled with hydroboration reactions were reviewed. In addition, the review discusses how mycolactone is employed in the diagnosis of Buruli ulcer with emphasis on detection methods of mass spectrometry, immunological assays, RNA aptamer techniques, and fluorescent-thin layer chromatography (f-TLC) methods as diagnostic tools. We examined studies of the structure–activity relationship (SAR) of various analogues of mycolactone. The paper highlights the multiple biological consequences associated with mycolactone such as skin ulceration, host immunomodulation, and analgesia. These effects are attributed to various proposed mechanisms of actions including Wiskott–Aldrich Syndrome protein (WASP)/neural Wiskott–Aldrich Syndrome protein (N-WASP) inhibition, Sec61 translocon inhibition, angiotensin II type 2 receptor (AT2R) inhibition, and inhibition of mTOR. The possible application of novel mycolactone analogues produced based on SAR investigations as therapeutic agents for the treatment of inflammatory disorders and inflammatory pain are discussed. Additionally, their therapeutic potential as anti-viral and anti-cancer agents have also been addressed. [ABSTRACT FROM AUTHOR]

Harmful algal blooms (HABs) formed by toxic microalgae have seriously threatened marine ecosystems and food safety and security in recent years. Among them, Karenia selliformis has attracted the attention of scientists and society due to its acute and rapid neurotoxicity in mice. Herein, the growth and gymnodimine A (GYM-A) production of K. selliformis were investigated in diverse culture systems with different surface-to-volume (S/V) ratios and nitrogen/phosphorus concentrations. The results showed that the specific growth rates (μ), maximal cell yields, and GYM-A production levels of K. selliformis increased with higher S/V, but no significant differences were observed under different culture volumes with the same S/V, which indicated that light penetration and gas exchange in the seawater culture systems actually influenced the growth and GYM-A production of K. selliformis. The maximum cell density and photosynthetic efficiency of K. selliformis decreased under nitrogen (N) and phosphorus (P) deficiency, suggesting that the growth of K. selliformis was significantly inhibited by the deficiency in N or P. Both N and P limitation conditions, especially P deficiency, promoted the cellular GYM-A quotas of K. selliformis. In this study, a scientific basis is provided for understanding the effects of culture systems and nutrient concentrations on the growth and toxin production of K. selliformis. [ABSTRACT FROM AUTHOR]

Advances in synthetic peptide methodologies have enabled the development of macromolecules mimicking protein properties and have found applications in various fields, particularly in immunology. Furthermore, Sequential Oligopeptide Carriers (SOCn and CPSOC) have been designed as multi-functional core molecules, to which multiple bio-cargos can be anchored, allowing the construction of high molecular weight molecules (>3000 Da) capable of inducing a strong immune response. This study presents the design and synthesis of the Ac-[K-Aib-C(3,9-Acm; 6,12-SSNC(Acm)QENSDK)]4-NH2 peptide conjugate of branched architecture. The peptide epitope S128SNCQENSDK137 belongs to the V. berus basic phospholipase A2, a member of the European viper species' most lethal protein families. The peptide epitope was synthesized according to the SPPS Fmoc/tBu strategy and characterized by HR-ESI-MS and NMR experiments, while the conjugate was purified by RP-HPLC and characterized by HR-ESI-MS. [ABSTRACT FROM AUTHOR]

Neuromuscular junction (NMJ) disorders represent a heterogenous group of acquired and congenital disorders that present in variable and distinctive ways. The diagnosis is typically reached through a combination of clinical, serological, pharmacological and electrophysiological evaluation. While the diagnosis can be fairly straightforward in some cases, the overlap with other neurological disorders can make diagnosis challenging, particularly in pure ocular presentations and in seronegative patients. The over-reliance on serological tests and electrophysiological evaluation in isolation can lead to misdiagnosis. In this article, we provide an overview of the NMJ disorders, discuss red flags for the key differential diagnoses (mimics) and report the atypical ways in which NMJ disorders may present (chameleons). [ABSTRACT FROM AUTHOR]