Fluvial biofilms: a pertinent tool to assess β-blockers toxicity

Among increasingly used pharmaceutical products, β-blockers have been commonly reported at low concentrations in rivers and littoral waters of Europe and North America. Little is known about the toxicity of these chemicals in freshwater ecosystems while their presence may lead to chronic pollution. Hence, in this study the acute toxicity of 3 β-blockers: metoprolol, propranolol and atenolol on fluvial biofilms was assessed by using several biomarkers. Some were indicative of potential alterations in biofilm algae (photosynthetic efficiency), and others in biofilm bacteria (peptidase activity, bacterial mortality). Propranolol was the most toxic β-blocker, mostly affecting the algal photosynthetic process. The exposure to 531 μg/L of propranolol caused 85% of inhibition of photosynthesis after 24 h. Metoprolol was particularly toxic for bacteria. Though estimated No-Effect Concentrations (NEC) were similar to environmental concentrations, higher concentrations of the toxic (503 μg/L metoprolol) caused an increase of 50% in bacterial mortality. Atenolol was the least toxic of the three tested β-blockers. Effects superior to 50% were only observed at very high concentration (707 mg/L). Higher toxicity of metoprolol and propranolol might be due to better absorption within biofilms of these two chemicals. Since β-blockers are mainly found in mixtures in rivers, their differential toxicity could have potential relevant consequences on the interactions between algae and bacteria within river biofilms

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

Does bounded rationality lead to individual heterogeneity? The impact of the experimentation process and of memory constraints

In this paper we explore the effect of bounded rationality on the convergence of individual behavior toward equilibrium. In the context of a Cournot game with a unique and symmetric Nash equilibrium, firms are modeled as adaptive economic agents through a genetic algorithm. Computational experiments show that (1) there is remarkable heterogeneity across identical but boundedly rational agents; (2) such individual heterogeneity is not simply a consequence of the random elements contained in the genetic algorithm; (3) the more rational agents are in terms of memory abilities and pre-play evaluation of strategies, the less heterogeneous they are in their actions. At the limit case of full rationality, the outcome converges to the standard result of uniform individual behavior.

Grain size analyses in tin-lead glazes based on 2d-sections

A problem in the archaeometric classification of Catalan Renaissance pottery is the fact, thatthe clay supply of the pottery workshops was centrally organized by guilds, and thereforeusually all potters of a single production centre produced chemically similar ceramics.However, analysing the glazes of the ware usually a large number of inclusions in the glaze isfound, which reveal technological differences between single workshops. These inclusionshave been used by the potters in order to opacify the transparent glaze and to achieve a whitebackground for further decoration.In order to distinguish different technological preparation procedures of the single workshops,at a Scanning Electron Microscope the chemical composition of those inclusions as well astheir size in the two-dimensional cut is recorded. Based on the latter, a frequency distributionof the apparent diameters is estimated for each sample and type of inclusion.Following an approach by S.D. Wicksell (1925), it is principally possible to transform thedistributions of the apparent 2D-diameters back to those of the true three-dimensional bodies.The applicability of this approach and its practical problems are examined using differentways of kernel density estimation and Monte-Carlo tests of the methodology. Finally, it istested in how far the obtained frequency distributions can be used to classify the pottery

Vitamin E but not 17B-estradiol protect against vascular toxicity induced by B-amyloid wild type and the Dutch amyploid variant

Amyloid β-peptide (Aβ) fibril deposition on cerebral vessels produces cerebral amyloid angiopathy that appears in the majority of Alzheimer's disease patients. An early onset of a cerebral amyloid angiopathy variant called hereditary cerebral hemorrhage with amyloidosis of the Dutch type is caused by a point mutation in Aβ yielding AβGlu22→Gln. The present study addresses the effect of amyloid fibrils from both wild-type and mutated Aβ on vascular cells, as well as the putative protective role of antioxidants on amyloid angiopathy. For this purpose, we studied the cytotoxicity induced by Aβ1–40 Glu22→Gln and Aβ1–40 wild-type fibrils on human venule endothelial cells and rat aorta smooth muscle cells. We observed that AβGlu22→Gln fibrils are more toxic for vascular cells than the wild-type fibrils. We also evaluated the cytotoxicity of Aβ fibrils bound with acetylcholinesterase (AChE), a common component of amyloid deposits. Aβ1–40 wild-type–AChE fibrillar complexes, similar to neuronal cells, resulted in an increased toxicity on vascular cells. Previous reports showing that antioxidants are able to reduce the toxicity of Aβ fibrils on neuronal cells prompted us to test the effect of vitamin E, vitamin C, and 17β-estradiol on vascular damage induced by Aβwild-type and AβGlu22→Gln. Our data indicate that vitamin E attenuated significantly the Aβ-mediated cytotoxicity on vascular cells, although 17β-estradiol and vitamin C failed to inhibit the cytotoxicity induced by Aβ fibrils.

Spatial and temporal variation of natural toxicity in cnidarians, bryozoans and tunicates in Mediterranean caves

The natural toxicity of cnidarians, bryozoans and tunicates in two caves was assessed using the Microtox® technique in spring and autumn. One cave was located in the Cabrera Archipelago (Balearic Islands) and the other in the Medes Islands (Catalan littoral). The organisms analysed were good representatives of the coverage of each Phylum in the communities; however, these Phyla are less abundant than sponges which are the dominant group in these caves. Seventy-one percent of the species of cnidarians and bryozoans analysed were toxic in one of the caves, communities or seasons, which indicates the relevance of bioactive species in these groups. The tunicate Lissoclinum perforatum was the most toxic species. Although all three Phyla had some highly toxic species, a common pattern that related the caves, communities and seasons was not found. Seasonal variation of toxicity in cnidarians and bryozoans was higher in the Cabrera than in the Medes cave. Moreover, variation in toxicity either between communities or between seasons was a common trait for most cnidarians and bryozoans, whereas tunicates remained toxic throughout communities and seasons.

Staphylococcus lugdunensis infective endocarditis. Description of 10 cases and analysis of native valve, prosthetic valve and pacemaker lead endocarditis clinical profiles

bolism. Surgery was needed in 51% of cases and mortality was 42%. Prosthetic valve endocarditis (nine of 60, 13%) predominated in the aortic position and was associated with abscess formation, required surgery, and high mortality (78%). Pacemaker lead IE (seven of 69, 10%) is associated with a better prognosis when antibiotic treatment is combined with surgery. Conclusions:S lugdunensis IE is an uncommon cause of IE, involving mainly native left sided valves, and it is characterised by an aggressive clinical course. Mortality in left sided native valve IE is high but the prognosis has improved in recent years. Surgery has improved survival in left sided IE and, therefore, early surgery should always be considered. Prosthetic valve S lugdunensis IE carries an ominous prognosis.

MiR-SNPs as markers of toxicity and clinical outcome in Hodgkin Lymphoma patients

Background: In recent years, microRNA (miRNA) pathways have emerged as a crucial system for the regulation of tumorogenesis. miR-SNPs are a novel class of single nucleotide polymorphisms that can affect miRNA pathways. Design and Methods: We analyzed eight miR-SNPs by allelic discrimination in 141 patients with Hodgkin lymphoma and correlated the results with treatment-related toxicity, response, disease-free survival (DFS) and overall survival (OS). Results: The KRT81 (rs3660) GG genotype was associated with an increased risk of neurological toxicity (P=0.016), while patients with XPO5 (rs11077) AA or CC genotypes had a higher rate of bleomycin-associated pulmonary toxicity (P=0.048). Both miR-SNPs emerged as independent factors in the multivariate analysis. The XPO5 AA and CC genotypes were also associated with a lower response rate (P=0.036). XPO5 (P=0.039) and TRBP (rs784567) (P=0.022) genotypes emerged as prognostic markers for DFS, and XPO5 was also associated with OS (P=0.033). In the multivariate analysis, only XPO5 emerged as an independent prognostic factor for DFS (HR: 2.622; 95%CI 1.039-6.620; P=0.041). Given the influence of XPO5 and TRBP as individual markers, we then investigated the combined effect of these miR-SNPs. Patients with both the XPO5 AA/CC and TRBP TT/TC genotypes had the shortest DFS (P=0.008) and OS (P=0.008). Conclusion: miR-SNPs can add useful prognostic information on treatment-related toxicity and clinical outcome in Hodgkin lymphoma and can be used to identify patients likely to be chemoresistant or to relapse.

Place illusion and plausibility can lead to realistic behaviour in immersive virtual environments

In this paper address we the question as to why participants tend to respond realistically to situations and events portrayed within an Immersive Virtual Reality (IVR) system. The idea is put forward, based on experience of a large number of experimental studies, that there are two orthogonal components that contribute to this realistic response. The first is"being there", often called"presence", the qualia of having a sensation of being in a real place. We call this Place Illusion (PI). Second, Plausibility Illusion (Psi) refers to the illusion that the scenario being depicted is actually occurring. In the case of both PI and Psi the participant knows for sure that that they are not"there" and that the events are not occurring. PI is constrained by the sensorimotor contingencies afforded by the virtual reality system. Psi is determined by the extent to which the system can produce events that directly relate to the participant, and the overall credibility of the scenario being depicted in comparison with expectations. We argue that when both PI and Psi occur, participants will respond realistically to the virtual reality.

Toxicity of allyl esters in insect cell lines and in Spodoptera littoralis larvae

We investigated the effects of five allyl esters, two aromatic (allyl cinnamate and allyl 2-furoate) and three aliphatic (allyl hexanoate, allyl heptanoate, and allyl octanoate) in established insect cell lines derived from different species and tissues. We studied embryonic cells of the fruit fly Drosophila melanogaster (S2) (Diptera) and the beet armyworm Spodoptera exigua (Se4) (Lepidoptera), fat body cells of the Colorado potato beetle Leptinotarsa decemlineata (CPB) (Coleoptera), ovarian cells of the silkmoth Bombyx mori (Bm5), and midgut cells of the spruce budworm Choristoneura fumiferana (CF203) (Lepidoptera). Cytotoxicity was determined with use of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and trypan blue. In addition, we tested the entomotoxic action of allyl cinnamate against the cotton leafworm Spodoptera littoralis .The median (50%) cytotoxic concentrations (EC50s) of the five allyl esters in the MTT bioassays ranged between 0.25 and 27 mM with significant differences among allyl esters (P = 0.0012), cell lines (P < 0.0001), and the allyl estercell line interaction (P < 0.0001). Allyl cinnamate was the most active product, and CF203 the most sensitive cell line. In the trypan blue bioassays, cytotoxicity was produced rapidly and followed the same trend observed in the MTT bioassay. In first instars of S. littoralis, allyl cinnamate killed all larvae at 0.25% in the diet after 1 day, while this happened in third instars after 5 days. The LC50 in first instars was 0.08%. In addition, larval weight gain was reduced (P < 0.05) after 1 day of feeding on diet with 0.05%. In conclusion, the data provide evidence of the significant but differential cytotoxicity among allyl esters in insect cells of different species and tissues. Midgut cells show high sensitivity, indicating the insect midgut as a primary target tissue. Allyl cinnamate caused rapid toxic effects in S. littoralis larvae at low concentrations, suggesting further potential for use in pest control.