Notes

Onsager-regularized lattice Boltzmann strategy: A nonequilibrium thermodynamics-based regularized lattice Boltzmann method.
Four peptides with cytotoxic activity against BRIN-BD11 rat clonal β-cells were purified from the venom of the black-necked spitting cobra Naja nigricollis using reversed-phase HPLC. The peptides were identified as members of the three-finger superfamily of snake toxins by ESI-MS/MS sequencing of tryptic peptides. The most potent peptide (cytotoxin-1N) showed strong cytotoxic activity against three human tumor-derived cell lines (LC50 = 0.8 ± 0.2 μM for A549 non-small cell lung adenocarcinoma cells; LC50 = 7 ± 1 μM for MDA-MB-231 breast adenocarcinoma cells; and LC50 = 9 ± 1 μM for HT-29 colorectal adenocarcinoma cells). However, all the peptides were to varying degrees cytotoxic against HUVEC human umbilical vein endothelial cells (LC50 in the range 2-22 μM) and cytotoxin-2N was moderately hemolytic (LC50 = 45 ± 3 μM against mouse erythrocytes). The lack of differential activity against cells derived from non-neoplastic tissue limits their potential for development into anti-cancer agents. In addition, two proteins in the venom, identified as isoforms of phospholipase A2, effectively stimulated insulin release from BRIN-BD11 cells (an approximately 6-fold increase in rate compared with 5.6 mM glucose alone) at a concentration (1 μM) that was not cytotoxic to the cells suggesting possible application in therapy for Type 2 diabetes.The mouse digit abduction score (DAS) assay is commonly used to measure muscle flaccidity-inducing effects of botulinum neurotoxin (BoNT) in vivo. Adapting the assay to rats has been challenging, as injection of onabotulinumtoxinA (onaBoNT-A) into the gastrocnemius muscle, as performed in mice, or into the tibialis anterior leads to sub-optimal sensitivity of the test (Broide et al., 2013). To optimize the experimental design of the rat DAS assay, we evaluated the effects of research-grade, purified, native BoNT serotype A1 (BoNT-A) in three muscles the gastrocnemius lateralis, peronei, and extensor digitorum longus using female animals. Following injection, animals were tested daily for the digit abduction and body weight. BoNT-A caused dose-dependent inhibition of digit abduction when injected into the gastrocnemius lateralis or peronei. BoNT-A was six-fold more potent when injected into the peronei in comparison to the gastrocnemius lateralis. As injection of BoNT-A into the extensor digitorum longus muscle resulted in an all-or-none digit abduction response and therefore prevented calculation of the ED50, it was considered unsuitable for the rat DAS assay. At equipotent doses, peronei- and extensor digitorum longus-injected animals showed normal body weight gain, while those injected with BoNT-A into the gastrocnemius lateralis gained less weight in comparison to vehicle-treated controls. Thus, injecting the peronei muscles of female rats offers optimized conditions for evaluating the biological properties of BoNTs in the rat DAS assay; for assessing the potency, onset, and duration of action across natural and recombinant BoNT in a robust and reproducible manner.Domoic acid (DA), a neurotoxin produced by certain species within the diatom genus Pseudo-nitzschia, has caused numerous persistent harvest closures for razor clam Siliqua patula along the outer coast of Washington State (USA) over the last three decades. In comparison, bivalve harvest closures for DA have only occurred three times in Washington's largest inland estuary, Puget Sound, which has a variety of bivalve species excluding razor clam. While differing bloom dynamics in the two locations are responsible for much of the disparity in shellfish harvest closures, species-specific differences in DA depuration may affect the duration of harvest closures in the two regions. Toxin-producing Pseudo-nitzschia multiseries were fed to four species of bivalves, followed by measurement of tissue DA content over time to estimate depuration rate. Experimental species include razor clam and three species of intertidal Puget Sound bivalves soft-shell clam Mya arenaria, purple varnish clam Nuttallia obscurata and Manila clam Ruditapes philippinarum. Using an exponential decay model, DA depuration rates were estimated as 0.02·day-1 ±0.08 for razor clam, 0.10·day-1 ±0.07 for purple varnish clam, 0.37·day-1 ±0.03 for soft-shell clam, and 0.44·day-1 ±0.02 for Manila clam. Puget Sound species depurated DA between five and 22 times as fast as outer coast razor clam. Within Puget Sound species, slow DA depuration rates in purple varnish clam indicate that it may be a good sentinel organism for assessing beach-wide maximum DA concentrations in Puget Sound bivalves.The large box jellyfish Chironex fleckeri is found in northern Australian waters. A sting from this cubozoan species can kill within minutes. From clinical and animal studies, symptoms comprise severe pain, welts, scarring, hypotension, vasospasms, cardiac irregularities and cardiac arrest. At present, there is no cure and opioids are used to manage pain. Antivenom is available but controversy exists over its effectiveness. Experimental and combination therapies performed in vitro and in vivo have shown varied efficacy. These inconsistent results are likely a consequence of the different methods used to extract venom. Recent omics analysis has shed light on the systems of C. fleckeri venom action, including new toxin classes that use pore formation, cell membrane collapse and ion channel modulation. This review covers what is known on C. fleckeri pathomechanisms and highlights current gaps in knowledge. A more complete understanding of the mechanisms of C. fleckeri venom-induced pathology may lead to novel treatments and possibly, the discovery of novel cell pathways, novel drug scaffolds and novel drug targets for human disease.In comparison with other animal venoms, fish venoms remain relatively understudied. This is especially true for that of the lesser Echiichthys vipera and greater weever fish Trachinus draco which, apart from the isolation of their unique venom cytolysins, trachinine and dracotoxin, respectively, remain relatively uncharacterised. Envenomation reports mainly include mild symptoms consisting of nociception and inflammation. ARS853 However, like most fish venoms, if the venom becomes systemic it causes cardiorespiratory and blood pressure changes. Although T. draco venom has not been studied since the 1990's, recent studies on E. vipera venom have discovered novel cytotoxic components on human cancer cells, but due to the scarcity of research on the molecular make-up of the venom, the molecule(s) causing this cytotoxicity remains unknown. This review analyses past studies on E. vipera and T. draco venom, the methods used in the , the venom constituents characterised, the reported symptoms of envenomation and compares these findings with those from other venomous Scorpaeniformes.An outbreak of acute febrile syndrome associated with coagulopathy and severe pancytopenia occurred in cattle grazing in paddocks with high infestation by Adiantopsis chlorophylla. The administration of the plant to a calf reproduced the same signs and lesions seen in spontaneous cases. Similar syndromes are caused by ptaquiloside from bracken fern. Traces of the ptaquiloside-like molecule caudatoside were detected together with 0.03-0.24 mg/g of it's degradation product pterosin A, in dry fronds of the plant. In conclusion, A. chlorophylla is a cause of hemorrhagic diathesis in cattle.New strategies are needed to mitigate the mycotoxin deoxynivalenol (DON) in feed and food products. Microbial DNA fragments were generated from a library of DON-tolerant microorganisms. These fragments were screened in DON-sensitive yeast strains for their ability to modify or transport DON. Fragments were cloned into a PCR8/TOPO vector, and recombined into the yeast vector, pYES-DEST52. Resulting yeast transformants were screened in the presence of 100 ppm DON. Transformants that were able to grow in the presence of DON were plated on a selective medium, and the cloned microbial DNA fragments were sequenced. BLAST queries of one microbial DNA fragment (4D) showed a high degree of similarity to an ABC transporter. A series of screening and inhibition assays were conducted with a transport inhibitor (propanol), to test the hypothesis that 4D is a mycotoxin transporter. DON concentrations did not change for yeast transformants expressing 4D. The ability of yeast transformants expressing 4D to transport DON was inhibited by the addition of propanol. Moreover, yeast transformants expressing a known efflux pump (PDR5) showed similar trends in propanol transport inhibition compared to 4D. Future work should consider mycotoxin transporters such as 4D to the development of transgenic plants to limit DON accumulation in seeds.Isocoma pluriflora and Isocoma acradenia are toxic plants that contain the putative toxin tremetone. It is common for I. pluriflora to poison livestock in the southwestern United States. I. acradenia has been suspected of poisoning livestock but its toxicity has not been confirmed by association with clinical poisonings or experimental studies. Jersey calves dosed with I. pluriflora and I. acradenia for nine days developed "trembles" characterized by skeletal muscle degeneration and necrosis and large increases in serum creatine kinase activity. This is the first report of I. acradenia toxicity in an animal model. This study also demonstrates that I. pluriflora remains toxic even though tremetone concentrations in the plant were low due to storage of the plant for over five years. Thus, supporting recent research which indicates that another toxin in the plant may be responsible for, or at least contributes to causing "trembles" in livestock.A large outbreak of liver toxicity in dairy cows that were consuming swede (rutabaga, Brassica napus ssp. napobrassica) crops in Southland and Otago, New Zealand in 2014 prompted the search for the toxin(s) responsible for brassica-associated liver disease (BALD). Analysis of swede plant material showed that the ultra-dominant glucosinolate was progoitrin. The two nitrile derivatives of progoitrin, 1-cyano-2-hydroxy-3-butene (CHB, also known as crambene) and 1-cyano-2-hydroxy-3,4-epithiobutane (CHEB), were custom-synthesised. In this pilot trial, individual progoitrin nitriles were administered by gavage to rats in order to establish a "subtoxic" dose, i.e. the dose where apparently clinically normal rats show liver injury based on altered serum biochemical indicators and histological lesions. We found that consecutive daily doses of 1 mmol/kg CHB produced severe pancreatic and mild liver histological lesions in the absence of notable biochemical changes in clinically normal rats. No evidence of a cumulative ns and ulcers in the squamous portion of the stomach. These stomach lesions, as well as the renal lesions, appear identical to those caused by another epithionitrile, 1-cyano-3,4-epithiobutane, derived from gluconapin, which was a minor glucosinolate in the swedes. Because of the fact that cyanide can be released with the metabolism of some nitriles, we analysed cyanide in the livers of treated rats. The liver of a rat dosed with 1 mmol/kg of 3-butenenitrile contained 0.5 μg/g of cyanide. The hypothesis that BALD is due to nitrile toxicity requires further testing.
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