Interactive Learning-Based Realizability for Heyting Arithmetic with EM1

We apply to the semantics of Arithmetic the idea of ``finite approximation'' used to provide computational interpretations of Herbrand's Theorem, and we interpret classical proofs as constructive proofs (with constructive rules for $\vee, \exists$) over a suitable structure \StructureN for the language of natural numbers and maps of G\"odel's system \SystemT. We introduce a new Realizability semantics we call ``Interactive learning-based Realizability'', for Heyting Arithmetic plus \EM_1 (Excluded middle axiom restricted to $\Sigma^0_1$ formulas). Individuals of \StructureN evolve with time, and realizers may ``interact'' with them, by influencing their evolution. We build our semantics over Avigad's fixed point result, but the same semantics may be defined over different constructive interpretations of classical arithmetic (Berardi and de' Liguoro use continuations). Our notion of realizability extends intuitionistic realizability and differs from it only in the atomic case: we interpret atomic realizers as ``learning agents''

Preciseness of Subtyping on Intersection and Union Types

Abstract. The notion of subtyping has gained an important role both in theoretical and applicative domains: in lambda and concurrent calculi as well as in programming languages. The soundness and the complete-ness, together referred to as the preciseness of subtyping, can be consid-ered from two different points of view: denotational and operational. The former preciseness is based on the denotation of a type which is a math-ematical object that describes the meaning of the type in accordance with the denotations of other expressions from the language. The latter preciseness has been recently developed with respect to type safety, i.e. the safe replacement of a term of a smaller type when a term of a bigger type is expected. We propose a technique for formalising and proving operational pre-ciseness of the subtyping relation in the setting of a concurrent lambda calculus with intersection and union types. The key feature is the link between typings and the operational semantics. We then prove sound-ness and completeness getting that the subtyping relation of this calculus enjoys both denotational and operational preciseness.

Presence of fluoroquinolones and sulfonamides in urban sewage sludge and their degradation as a result of composting

The concentrations of some widely used pharmaceuticals, namely fluoroquinolones (ciprofloxacin C17H18FN3O3, norfloxacin C16H18FN3O3 and ofloxacin C18H20FN3O4) and sulfonamides (sulfadimethoxine C12H14N4O4S and sulfamethoxazole C10H11N3O3S ) were determined in urban sewage sludge utilized for making compost. The levels of degradation of these pharmaceuticals resulting from sludge treatment were assessed. The concentrations of the studied pharmaceuticals sufficiently varied both in sewage sludge and in compost and due to this phenomenon the possible danger resulting from the presence of pharmaceuticals in sewage sludge, used for composting, can not be ignored. The concentrations of the studied pharmaceuticals were lower in compost, if compared to the relevant concentrations in sewage sludge. The highest pharmaceutical concentration in sewage sludge - 426 μg/kg - was detected in the case of ciprofloxacin. The highest concentrations present in compost were 22 μg/kg of norfloxacin and 20 μg/kg of ciprofloxacin. Results show that before using the sewage sludge for making compost or before using the compost a fertilizer for food plants, they should be carefully tested against the content of commonly used pharmaceuticals

Delayed toxicity of three fluoroquinolones and their mixtures after neonatal or embryonic exposure, in Daphnia magna

Fluoroquinolones (FQs) are antibacterial drugs, used both in human and veterinary medicine, that are currently considered as emerging micropollutants. This study investigated the delayed toxic effects of enrofloxacin (ENR), flumequine (FLU), levofloxacin (LEV) and their binary mixtures in D. magna. For this purpose, a 10-day follow-up in pure medium was added to the standard D. magna immobilization test. During this follow-up, phenotypic alterations were evidenced, which were related to scarce or zeroed egg production and early mortality. Consequently, the EC50 s recalculated at the end of the follow-up were always remarkably lower than those obtained after the 48 h immobilization test: ENR 3.13 vs. 16.72 mg L 121; FLU 7.18 vs. 25.35 mg L 121; LEV 15.11 vs. > 40 mg L 121. To analyse the possible interactions within the binary mixtures, the method of nonlinear additive isoboles was applied. The three compounds showed invariably to follow the principle of concentration addition. Furthermore, as previous experiments showed toxicity of FLU and ENR after embryonic exposure of D. magna at a concentration of 2 mg L 121, an additional two embryonic tests were conducted with identical design: one with 2 mg L 121 LEV and the other with a ternary mixture containing 0.66 mg L 121 of each of the three FQs. The embryos were exposed for three days in vitro to the drug solutions and were then reconducted to pure medium for 21 days observation. Both the tests ended-up with only non-significant effects on growth and reproduction, confirming the lower toxicity of LEV, when compared to ENR and FLU, and the absence of any evident synergistic interaction among the three FQs. Overall, these studies have shown two relevant features related to the toxicity of the three FQs: (1) they give rise to delayed toxic effects in D. magna that are undetectable by the standard immobilization test; (2) their interaction in mixtures follow the principle of Concentration Addition. Both these indications concern the Environmental Risk Assessment of FQs and may be of interest to regulatory authorities

In vitro comparison of aldicarb oxidation in various food-producing animal species

Aldicarb (ALD) metabolism was studied in vitro using hepatic microsomes from chickens, rabbits, sheep and pigs. The microsomal activities of mono-ooxygenase enzymes (flavin-containing and cytochrome P-450-dependent mixed function oxygenases) were compared by measuring the quantity of the 2 oxidized metabolites, ALD sulfoxide and ALD sulfone, produced during 60 min of incubation. Pig microsomes produced the greatest quantity of ALD sulfoxide and the lowest quantity of ALD sulfone; the latter being produced in greater quantities in sheep than in chickens and rabbits. Aldicarb and its metabolites were degraded fastest in rabbits, probably by hydrolytic reactions. These in vitro results, which are consistent both with the levels of cytochrome P450 found in hepatic microsomes and previous in vivo data on ALD kinetics in pigs, rabbits and chickens, indicate that preliminary in vitro studies can limit the necessary use of animals for drug metabolism experiments.[...

Toxicity of individual and binary mixtures of perfluoroalkyl compounds in freshwater algae Raphidocelis subcapitata

Introduction: Per- and polyfluoroalkyl substances (PFAS) are environmental pollutants of increasing scientific interest. Widely used for several commercial and industrial applications, they are potentially harmful to the environment and biota. Following the ban of legacy PFAS such as perfluorooctanoic sulfonic acid (PFOS), several next-generation substitutes have been developed and introduced in the industry (1). Our study investigated the effects of one PFAS monitored by EFSA and two next-generation substitute compounds, either individually or in binary mixtures, in the unicellular algae model of ecotoxicology Raphidocelis subcapitata. Materials and Methods: Algal toxicity tests for perfluorononanoic acid (PFNA), PFOS, perfluorobutanesulfonic acid (PFBS) and perfluorobutanoic acid (PFBA) were executed using the US-EPA 96h Acute Toxicity Test (2), with minor modifications. Each compound was dissolved in Bold’s Basal Medium (1.0 g/L) and serial dilutions were made using a dilution factor of 2.0. Binary mixtures were set up according to the individually obtained concentration inhibiting the algal growth by 50% (EC 50 ), with the highest concentration represented by the sum of each EC 50 and using a dilution factor of 2.0. Results: Data obtained (four replicates) allowed us to determine the EC 50 for each tested PFAS and the type of interaction (additive effect, synergism or antagonism) in PFAS binary mixtures. PFBA was the most toxic PFAS (EC50 30.3 mg/L), followed by PFOS (47.3 mg/L), PFNA (90.5 mg/L) and PFBS (105.8 mg/L). The EC 50 of binary mixtures were 57.0 mg/L (PFOS-PFBS), 44.5 mg/L (PFOS-PFBA), 116.6 mg/L (PFNA-PFBA), 221.5 mg/L (PFNA-PFBS) and 121.4 mg/L (PFBA-PFBS). Discussion: Overall, PFAS toxicity (e.g., trend to bioaccumulation) is directly proportional to the carboxyl chain length; moreover, it increases with the presence of the sulfonate functional group at the end of the carboxyl chain (3). Our study highlights the highest toxicity of PFBA (a short-chain perfluoroalkyl substitute) on the freshwater algae R. subcapitata. Among the binary mixtures, PFOS-PFBS and PFOS-PFBA combinations were proved additive. However, antagonism was observed in the PFNA-PFBA, the PFNA-PFBS, and the PFBA-BFBS mixtures. We hypothesize this might be due to competition for the same molecular targets. Further studies are needed to shed a light on molecular mechanisms involved in PFAS uptake and toxicity in this ecotoxicology model species