169,849 research outputs found
Adjoint expansions in local Lévy models
No full textWe propose a novel method for the analytical approximation in local volatility models with Lévy
jumps. The main result is an expansion of the characteristic function in a local Lévy model, which
is worked out in the Fourier space by considering the adjoint formulation of the pricing problem.
Combined with standard Fourier methods, our result provides efficient and accurate pricing
formulae. In the case of Gaussian jumps, we also derive an explicit approximation of the
transition density of the underlying process by a heat kernel expansion: the approximation is
obtained in two ways, using PIDE techniques and working in the Fourier space. Numerical tests
confirm the effectiveness of the method
Dall’inventario del cardinale Pietro Vidoni: parati e baldacchini nel palazzetto di San Marcello in via del Corso
No full textIl testo analizza la disposizione dei parati e tessuti d'arredo nell'appartamento romano del cardinale cremonese Pietro Vidoni (Cremona, 1610 - Roma, 1681). Dalla trascrizione dell'inventario topografico dei beni mobili del cardinale, redatto poco dopo la sua morte, e dall'analisi di altri materiali documentari, è stato possibile identificare il palazzo di residenza con il palazzetto adiacente alla chiesa di San Marcello in via del Corso, noto come palazzo Salviati Mellini. Gli arredi presenti nelle sale dei tre appartamenti del palazzo sono descritti e analizzati in relazione alla presenza di parati, di numerosi baldacchini cardinalizi, di tappeti e corami, talvolta posti rapporto con la simbologia dei colori associata alla carica cardinalizia
Novel Drugs Targeting the c-Ring of the F1FO-ATP Synthase
No full textIncreasing evidence highlights the role of the ATP synthase/hydrolase, also known as F1FO-complex, as key molecular and enzymatic switch between cell life and death, thus increasing the enzyme attractiveness as drug target in pharmacology. Being inhibition of ATP production usually linked to antiproliferative properties, drugs targeting the enzyme complex have been mainly considered to fight pathogen parasites and cancer. In recent years, a number of natural macrolides, produced by bacterial fermentation and structurally related to the classical enzyme inhibitor oligomycin, have been shown to bind to the membrane-embedded FO sector and to inhibit the enzyme complex by an oligomycin-like mechanism, namely by interacting with the c-ring. Other than natural macrolide antibiotics, which display variegated inhibition power on different F1FO-complexes, synthetic compounds from the diarylquinoline and organotin families also target the c-ring and strongly inhibit the enzyme. Bioinformatic insights address drug design to target FO subunits. Additionally, the possible modulation of the drug inhibition power, by amino acid substitutions or post-translational modifications of c-subunits, adds further interest to the target. The present survey on compounds targeting the c-ring and bi-directionally blocking the transmembrane proton flux which drives ATP synthesis/hydrolysis, discloses new therapeutic options to fight cancer and infections sustained by therapeutically recalcitrant microorganisms. Additionally, c-ring targeting compounds may constitute new tools to eradicate undesired biofilms and to address at the molecular level the therapy of mammalian diseases linked to mitochondrial dysfunctions. In summary, studies on the only partially known molecular interactions within the c-ring of the F1FO-complex may renew hope to counteract mammalian diseases
The c-Ring of the F1FO-ATP Synthase: Facts and Perspectives
No full textThe F1FO-ATP synthase is the only enzyme in nature endowed with bi-functional catalytic mechanism of synthesis and hydrolysis of ATP. The enzyme functions, not only confined to energy transduction, are tied to three intrinsic features of the annular arrangement of c subunits which constitutes the so-called c-ring, the core of the membrane-embedded FO domain: (i) the c-ring constitution is linked to the number of ions (H+ or Na+) channeled across the membrane during the dissipation of the transmembrane electrochemical gradient, which in turn determines the species-specific bioenergetic cost of ATP, the “molecular currency unit” of energy transfer in all living beings; (ii) the c-ring is increasingly involved in the mitochondrial permeability transition, an event linked to cell death and to most mitochondrial dysfunctions; (iii) the c subunit species-specific amino acid sequence and susceptibility to post-translational modifications can address antibacterial drug design according to the model of enzyme inhibitors which target the c subunits. Therefore, the simple c-ring structure not only allows the F1FO-ATP synthase to perform the two opposite tasks of molecular machine of cell life and death, but it also amplifies the enzyme’s potential role as a drug target
Characterization of a CYP3A-like activity in the digestive gland of Mytilus galloprovincialis-inhibition by 17alfa ethynylestradiol
No full textCYP3A enzyme is a toxicologically relevant end-point; interactions between xenobiotics (e.g. pharmaceuticals and xenoestrogens) and CYP3A may compromise both the clearance of xenobiotics and endogenous molecules (e.g. steroid hormones), as they share common routes of metabolism through CYP3A enzymes. The purpose of this work was to better characterize CYP3A-like enzyme in microsomal fractions isolated from the digestive gland of mussels Mytilus galloprovincialis by using 7benzyloxy-4-trifluoromethylcoumarin as a substrate. The higher Km value in mussels collected from Barcelona harbor with respect to that collected from Ebro delta indicated lower affinity of the enzyme in polluted specimens. 17 alfa-ethynylestradiol (EE2)acted as mixed inhibitor of CYP3A activity. The study contributes to the better knowledge of CYP3A-like activity in mussels and shows potential interference between EE2 and possibly other pollutants, and CYP3A function
Applicazione delle strutture sandwich per la realizzazione di furgonature isotermiche autoportanti
No full textA Therapeutic Role for the F1FO-ATP Synthase
No full textRecently, the F1FO-ATP synthase, due to its dual role of life enzyme as main adenosine triphosphate (ATP) maker and of death enzyme, as ATP dissipator and putative structural component of the mitochondrial permeability transition pore (mPTP), which triggers cell death, has been increasingly considered as a drug target. Accordingly, the enzyme offers new strategies to counteract the increased antibiotic resistance. The challenge is to find or synthesize compounds able to discriminate between prokaryotic and mitochondrial F1FO-ATP synthase, exploiting subtle structural differences to kill pathogens without affecting the host. From this perspective, the eukaryotic enzyme could also be made refractory to macrolide antibiotics by chemically produced posttranslational modifications. Moreover, because the mitochondrial F1FO-ATPase activity stimulated by Ca2+ instead of by the natural modulator Mg2+ is most likely involved in mPTP formation, effectors preferentially targeting the Ca2+-activated enzyme may modulate the mPTP. If the enzyme involvement in the mPTP is confirmed, Ca2+-ATPase inhibitors may counteract conditions featured by an increased mPTP activity, such as neurodegenerative and cardiovascular diseases and physiological aging. Conversely, mPTP opening could be pharmacologically stimulated to selectively kill unwanted cells. On the basis of recent literature and promising lab findings, the action mechanism of F1 and FO inhibitors is considered. These molecules may act as enzyme modifiers and constitute new drugs to kill pathogens, improve compromised enzyme functions, and limit the deathly enzyme role in pathologies. The enzyme offers a wide spectrum of therapeutic strategies to fight at the molecular level diseases whose treatment is still insufficient or merely symptomatic
Applicazione delle strutture sandwich per la realizzazione di furgonature isotermiche autoportanti
No full textThiol oxidation of mitochondrial FO-c subunits: a way to switch off antimicrobial drug targets of the mitochondrial ATP synthase
No full textA primary goal in antimicrobial drug design is to find molecules which inhibit key proteins in bacteria without affecting mammalian homologues. To this aim, structural differences between eukaryotic and prokaryotic enzyme proteins involved in life processes are widely exploited. The membrane-bound enzyme complex ATP synthase synthesizes the energy currency molecule of the cell. Due to its bioenergetic role, it represents “the enzyme of life” of all living beings. The enzyme complex has the unique bi-functional property of exploiting either the electrochemical transmembrane gradient to make ATP or, conversely, the free energy of ATP hydrolysis to build an electrochemical gradient across the membrane. The catalytic mechanism of ATP synthesis/hydrolysis, based on the coupling between the two rotary sectors FO and F1 is shared by eukaryotes and prokaryotes. However slight structural differences distinguish prokaryotic ATP synthases, embedded in cell membrane, from eukaryotic ones localized in the mitochondrial inner membrane. In spite of its fundamental task in living organisms, up to now the ATP synthase has been poorly exploited as target in antibacterial therapy, mainly due to harmful effects on patients. Recent advances shoulder the use of drugs targeting the ATP synthase to fight mycobacteria and treat human tuberculosis. Macrolide antibiotics and other antimicrobial drugs specifically bind to the c-ring of the membrane-embedded FO domain, thus blocking ion translocation through FO which is essential for both ATP synthesis and ATP hydrolysis. Our findings show that, once bound to the ATP synthase, probably through different binding sites on a common binding region on FO, the macrolide antibiotics oligomycin, venturicidin and bafilomycin behave as enzyme inhibitors. Interestingly, the c subunits of mitochondrial ATP synthase contain conserved cysteine residues which are absent in bacteria. We pointed out that when these crucial cysteine thiols are oxidized, the common drug binding site of the enzyme is somehow destabilized, thus weakening the enzyme-drug interactions and making the ATP synthase insensitive to drug inhibition. On these bases we hypothesize that the selective oxidation of these cysteine thiols can be exploited to desensitize the mitochondrial ATP synthase to drugs which target FO and maintain their inhibitory potency on bacterial ATP synthases. According to our hypothesis, this strategy could represent an intriguing tool to prevent adverse effects of antimicrobial drugs in mammals, thus enhancing the number of natural and synthetic compounds which can be used in therapy. To this aim studies should be addressed to the identification and formulation of compounds and/or treatments able to selectively oxidize the crucial cysteine thiols of c-subunits without affecting the overall functionality of the mitochondrial ATP synthase and other thiol containing proteins
- …
