Rate of exposure of a sentinel species, invasive American mink (Neovison vison) in Scotland, to anticoagulant rodenticides

Anticoagulant rodenticides (ARs) are highly toxic compounds that are exclusively used for the control of rodent pests. Despite their defined use, they are nonetheless found in a large number of non-target species indicating widespread penetration of wildlife. Attempts to quantify the scale of problem are complicated by non-random sampling of individuals tested for AR contamination. The American mink (Neovison vison) is a wide ranging, non-native, generalist predator that is subject to wide scale control efforts in the UK. Exposure to eight ARs was determined in 99 mink trapped in NE Scotland, most of which were of known age. A high percentage (79%) of the animals had detectable residues of at least one AR, and more than 50% of the positive animals had two or more ARs. The most frequently detected compound was bromadiolone (75% of all animals tested), followed by difenacoum (53% of all mink), coumatetralyl (22%) and brodifacoum (9%). The probability of mink exposure to ARs increased by 4.5% per month of life, and was 1.7 times higher for mink caught in areas with a high, as opposed to a low, density of farms. The number of AR compounds acquired also increased with age and with farm density. No evidence was found for sexual differences in the concentration and number of ARs. The wide niche and dietary overlap of mink with several native carnivore species, and the fact that American mink are culled for conservation throughout Europe, suggest that this species may act as a sentinel species, and the application of these data to other native carnivores is discussed

Molecular Analysis of the Interaction of Bordetella pertussis Adenylyl Cyclase with Fluorescent Nucleotides

The calmodulin (CaM)-dependent adenylyl cyclase (AC) toxin from Bordetella pertussis (CyaA) substantially contributes to the pathogenesis of whooping cough. Thus, potent and selective CyaA inhibitors may be valuable drugs for prophylaxis of this disease. We examined the interactions of fluorescent 2',3'-N-methylanthraniloyl (MANT)-, anthraniloyl- and trinitrophenyl (TNP)-substituted nucleotides with CyaA. Compared with mammalian AC isoforms and Bacillus anthracis AC toxin edema factor, nucleotides inhibited catalysis by CyaA less potently. Introduction of the MANT substituent resulted in 5- to 170-fold increased potency of nucleotides. Ki values of 3'MANT-2'd- ATP and 2'MANT-3'd-ATP in the AC activity assay using Mn2+ were 220 and 340 nM, respectively. Natural nucleoside 5'- triphosphates, guanine-, hypoxanthine- and pyrimidine-MANTand TNP nucleotides and d(i)-MANT nucleotides inhibited CyaA, too. MANT nucleotide binding to CyaA generated fluorescence resonance energy transfer (FRET) from tryptophans Trp69 and Trp242 and multiple tyrosine residues, yielding K(d) values of 300 nM for 3MANT-2d-ATP and 400 nM for 2'MANT-3'd-ATP. Fluorescence experiments and docking approaches indicate that the MANT- and TNP groups interact with Phe306. Increases of FRET and direct fluorescence with MANT nucleotides were strictly CaM-dependent, whereas TNP nucleotide fluorescence upon binding to CyaA increased in the absence of CaM and was actually reduced by CaM. In contrast to lowaffinity MANT nucleotides, even low-affinity TNP nucleotides generated strong fluorescence increases upon binding to CyaA. We conclude that the catalytic site of CyaA possesses substantial conformational freedom to accommodate structurally diverse ligands and that certain ligands bind to CyaA even in the absence of CaM, facilitating future inhibitor design

Anthraniloyl-derived nucleotides as potent and selective adenylyl cyclase inhibitors

Mammals express nine membranous adenylyl cyclases (AC 1-9) for the catalysis of the important second messenger cAMP in the intracellular signaling pathway. Inhibitors of AC1 and AC5 may be useful drugs for neuroprotection, heart failure and longevity. 2�,3�-O-(N-Methylanthraniloyl) (MANT)-substituted nucleotides are competitive AC inhibitors and were synthesized with different nucleobases in high purity after reversed phase HPLC separation. MANT-nucleotides were tested for their inhibitory potency at recombinant AC1, 2, and 5 expressed by a Sf9 insect cell system. In our primary investigations MANT-ITP was identified as the most potent AC1 and 5 inhibitor known so far with Ki values of 1 - 3 nM. Interestingly, bis-substituted MANT-nucleotides were discovered as side products in the regular synthesis of MANT-nucleotides. The synthesis of new mono- and bis-substituted anthraniloyl-group derived purine nucleotides was expanded. The anthraniloyl moiety differ by halogens of chlorine and bromine and acetylated amino group in 5 position of the phenyl ring system. Moreover, substitution at the amino function of the ANT-group lead to propyl derivatives. The immobile and aerobic bacterium Bordetella pertussis secretes the key virulence factor, the adenylyl cyclase toxin CyaA. Overall, 32 compounds were prepared to compare 16 pairs of mono- and bis-substituted (M)ANT-nucleotides for their potencies at inhibiting CyaA and membranous ACs (mAC). For the first time we found inhibitors combining high inhibition potency for CyaA toxin with selectivity towards mammalian ACs. Bis-substituted halogen anthraniloyl-derived purine nucleotides inhibited CyaA in the nanomolar range in a competitive manner (Ki = 13 - 20 nM). Moreover, bis-substituted halogen anthraniloyl-derived nucleotides of adenine displayed not only high affinity to the bacterial AC, but also revealed high selectivity by 50- to 150-fold depending on the chosen mAC 1, 2 or 5. The modeling study demonstrate an impression for the obvious alignment of the (M)ANT-nucleotide binding mode to CyaA. The docking of bis-substituted halogen anthraniloyl derivatives exposed additional hydrophobic interactions between enzyme and inhibitor causing higher potency for this class of compounds. Bis-substituted (M)ANT-nucleotides offered the advantage of excellent signal to noise ratio in fluorescence spectroscopy, compared to mono-substituted (M)ANT-nucleotides, with applications in HTS for assessment of non-fluorescent inhibitor potencies

Stigmatisierung von Patienten mit Schizophrenie durch Pflegekräfte: Welche Folgen hat Stigmatisierung von Patienten/Patientinnen mit Schizophrenie durch die Pflegekraft für die Pflege und den Patienten/die Patientin? Welche Maßnahmen gibt es, um den möglichen Folgen der Stigmatisierung vorzubeugen?

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Magnetic Nanobeads as Support for Zinc(II)–Cyclen Complexes: Selective and Reversible Extraction of Riboflavin

Fishing for riboflavin: Highly magnetic polymer-coated Fe/C nanoparticles are used as supports for zinc(II)–cyclen complexes. Quantitative and reversible extraction of riboflavin (vitamin B2) from aqueous solutions and a vitamin dietary supplement is achieved retaining high efficacy for six consecutive cycles. Applying an external magnetic field readily recycles the nanobeads