99 research outputs found
Formal reliability analysis of redundant architectures
No full textReliability is a fundamental property for critical systems. A thorough evaluation of the reliability is required
by the certification procedures in various application domains, and it is important to support the exploration of the
space of the design solutions.
In this paper we propose a new, fully automated approach to the reliability analysis of complex redundant architectures. Given an abstract description of the architecture, the approach automatically extracts a fault tree and a symbolic
reliability function, i.e. a program mapping the probability of fault of the basic components to the probability that the
overall architecture deviates from the expected behavior.
The proposed approach heavily relies on formal methods, by representing the architecture blocks as Uninterpreted
Functions, and using the so-called miter construction to model the deviation from the nominal behavior. The extraction
of all the deviation conditions is reduced to an AllSMT problem, and we extract the reliability function by traversing
the Binary Decision Diagram corresponding to the quantified formula. Predicate abstraction is used to partition and
speed up the computation.
The approach has been implemented leveraging formal tools for model checking and safety assessment. A thorough
experimental evaluation demonstrates its generality and effectiveness of the proposed techniques
The structure of thin Lie algebras with characteristic two
No full text Thin Lie algebras are graded Lie algebras [Formula: see text] with dim Li ≤ 2 for all i, and satisfying a more stringent but natural narrowness condition modeled on an analogous condition for pro-p-groups. The two-dimensional homogeneous components of L, which include L1, are named diamonds. Infinite-dimensional thin Lie algebras with various diamond patterns have been produced, over fields of positive characteristic, as loop algebras of suitable finite-dimensional simple Lie algebras, of classical or of Cartan type depending on the location of the second diamond. The goal of this paper is a description of the initial structure of a thin Lie algebra, up to the second diamond. Specifically, if Lk is the second diamond of L, then the quotient L/Lk is a graded Lie algebras of maximal class. In odd characteristic p, the quotient L/Lk is known to be metabelian, and hence uniquely determined up to isomorphism by its dimension k, which ranges in an explicitly known set of possible values: 3, 5, a power of p, or one less than twice a power of p. However, the quotient L/Lk need not be metabelian in characteristic two. We describe here all the possibilities for L/Lk up to isomorphism. In particular, we prove that k + 1 equals a power of two. </jats:p
Small-molecule modulators of mitochondrial channels as chemotherapeutic agents
No full textIon channels residing in the inner (IMM) and outer (OMM) mitochondrial membranes are emerging as noteworthy pharmacological targets in oncology. While these aspects have not been investigated for all of them, a role in cancer growth and/or metastasis and/or drug resistance has been shown at least for the IMM-residing Ca2+ uniporter complex and K+- selective mtKV1.3, mtIKCa, mtSKCa and mtTASK-3, and for the OMM Voltage-Dependent Anion Channel (mitochondrial porin). A special case is that of the Mitochondrial Permeability Transition Pore, a large pore which forms in the IMM of severely stressed cells, and which may be exploited to precipitate the death of cancerous cells. Here we briefly discuss the oncological relevance of mitochondria and their channels, and summarize the methods that can be adopted to selectively target these intracellular organelles. We then present an updated list of known mitochondrial channels, and review the pharmacology of those with proven relevance for cancer
A software-defined coherent fiber optic sensor for manufacturing machine diagnostic
No full textA new approach to fiber optic sensing is proposed which combines the multi-parameter sensing capabilities of standard optical fibers with recent advances in demodulation schemes and digital signal processing (DSP) for coherent optical communication systems. A common HW that can fulfil multi-purpose monitoring requests is obtained, where the information related to a specific physical parameter is recovered through a proper tailoring of the DSP. The fiber optic sensor thus becomes Software-Defined by the customer specific requirements, proving a cost-effective and versatile diagnostic solution for the achievement of sustainable predictive maintenance strategies in the manufacturing industry
Quercetin Mitochondriotropic Derivatives Antagonize Nitrate Tolerance and Endothelial Dysfunction of Isolated Rat Aorta Rings
No full textChronic use of glyceryl trinitrate is limited by serious side effects, inter alia tolerance and endothelial dysfunction of coronary and resistance arteries. The natural flavonoid quercetin has been shown to counteract the development of glyceryl trinitrate tolerance in vitro. Two mitochondriotropic, 4-O-triphenylphosphoniumbutyl derivatives of quercetin (QTA-3BTPI and Q-3BTPI) were compared to quercetin for protection against glyceryl trinitrate-induced tolerance and endothelial dysfunction of isolated rat aorta rings. Both QTA-3BTPI and Q-3BTPI significantly counteracted the reduced vascular responsiveness to both glyceryl trinitrate and acetylcholine caused by prolonged exposure of the vessel to glyceryl trinitrate itself, their potency being much greater than that of quercetin. QTA-3BTPI, however, turned out to cause endothelial dysfunction per se. Since Q-3BTPI antagonized in vitro nitrate tolerance and endothelial dysfunction of vessels, this encourages assessing whether this effect is displayed also in vivo during long-term glyceryl trinitrate treatment
N-monosubstituted methoxy-oligo(ethylene glycol) carbamate ester prodrugs of resveratrol
No full textResveratrol is a natural polyphenol with many interesting biological activities. Its pharmacological exploitation in vivo is, however, hindered by its rapid elimination via phase II conjugative metabolism at the intestinal and, most importantly, hepatic levels. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, hydrolysis, and in vivo pharmacokinetic behavior of resveratrol prodrugs in which the OH groups are engaged in an N-monosubstituted carbamate ester linkage. As promoiety, methoxy-oligo(ethylene glycol) groups (m-OEG) (CH3–[OCH2CH2]n–) of defined chain length (n = 3, 4, 6) were used. These are expected to modulate the chemico-physical properties of the resulting derivatives, much like longer poly(ethylene glycol) (PEG) chains, while retaining a relatively low MW and, thus, a favorable drug loading capacity. Intragastric administration to rats resulted in the appearance in the bloodstream of the prodrug and of the products of its partial hydrolysis, confirming protection from first-pass metabolism during absorption
Strategies to target bioactive molecules to subcellular compartments. Focus on natural compounds
No full textAn agonist of the cxcr4 receptor accelerates the recovery from the peripheral neuroparalysis induced by taipan snake envenomation
No full textEnvenomation by snakes is a major neglected human disease. Hospitalization and use of animal-derived antivenom are the primary therapeutic supports currently available. There is consensus that additional, not expensive, treatments that can be delivered even long after the snake bite are needed. We recently showed that the drug dubbed NUCC-390 shortens the time of recovery from the neuroparalysis caused by traumatic or toxic degeneration of peripheral motor neurons. These syndromes are characterized by the activation of a pro-regenerative molecular axis, consisting of the CXCR4 receptor expressed at the damaged site in neuronal axons and by the release of its ligand CXCL12α, produced by surrounding Schwann cells. This intercellular signaling axis promotes axonal growth and functional recovery from paralysis. NUCC-390 is an agonist of CXCR4 acting similarly to CXCL12α. Here, we have tested its efficacy in a murine model of neuroparalytic envenoming by a Pap-uan Taipan (Oxyuranus scutellatus) where a degeneration of the motor axon terminals caused by the presynaptic PLA2 toxin Taipoxin, contained in the venom, occurs. Using imaging of the neuromuscular junction and electrophysiological analysis, we found that NUCC-390 administration after injection of either the purified neuroparalytic Taipoxin or the whole Taipan venom, significantly accelerates the recovery from paralysis. These results indicate that NUCC-390, which is non-toxic in mice, should be considered for trials in humans to test its efficacy in accelerating the recovery from the peripheral neuroparalysis induced by Taipans. NUCC-390 should be tested as well in the envenomation by other snakes that cause neuroparalytic syndromes in humans. NUCC-390 could become an additional treatment, common to many snake envenomings, that can be delivered after the bite to reduce death by respiratory deficits and to shorten and improve functional recovery
Regioselective O-Derivatization of Quercetin via Ester Intermediates. An Improved Synthesis of Rhamnetin and Development of a New Mitochondriotropic Derivative
No full textThe regioselective synthesis of several quercetin (3,3’,4’,5,7-pentahydroxy flavone) tetraesters bearing a single free OH on 5-C was achieved in good yield by proper choice of reaction conditions using common esterification procedures. Tetracetylated quercetin with the free OH on 7-C was selectively obtained instead via imidazole-promoted deacylation of the corresponding pentaester. Unambiguous structural characterization of the two isomeric tetraacetyl quercetin derivatives was obtained by combined HSQC and HMBC 2D-NMR analysis. These molecules can be used as starting materials for the regioselective synthesis of other derivatives. High yield syntheses of the natural polyphenol rhamnetin (7-O-methylquercetin) and of the new mitochondriotropic compound 7-(4-triphenylphosphoniumbutyl) quercetin iodide are reported as examples
Acetal Derivatives as Prodrugs of Resveratrol.
No full textThe pharmacological exploitation of resveratrol is hindered by rapid phase-II conjugative metabolism in enterocytes and hepatocytes. One approach to the solution of this problem relies on prodrugs. We report the synthesis and characterization as well as the assessment of in vivo absorption and metabolism of a set of prodrugs of resveratrol in which the OH groups are engaged in the formal (−OCH2OR) or the more labile acetal (−OCH(CH3)OR) linkages. As carrier group (R) of the prodrug, we have used short ethyleneglycol oligomers (OEG) capped by a terminal methoxy group: −O–(CH2CH2O)n–CH3 (n = 0, 1, 2, 3, 4, 6). These moieties are expected to exhibit, to a degree, the favorable properties of longer polyethyleneglycol (PEG) chains, while their relatively small size makes for a more favorable drug loading capacity. After administration of formal-based prodrugs to rats by oral gavage, significant concentrations of derivatives were measured in blood samples over several hours, in all cases except for n = 0. Absorption was maximal for n = 4. Complete deprotection to give resveratrol and its metabolites was however too slow to be of practical use. Administration of the acetal prodrug carrying tetrameric OEG chains resulted instead in the protracted presence of resveratrol metabolites in blood, consistent with a progressive regeneration of the parent molecule from the prodrug after its absorption. The results suggest that prodrugs of polyphenols based on the acetal bond and short ethyleneglycol oligomers of homogeneous size may be a convenient tool for the systemic delivery of the unconjugated parent compound
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