Danger signaling through the inflammasome acts as a master switch between tolerance and sensitization.

Efficient priming of adaptive immunity depends on danger signals provided by innate immune pathways. As an example, inflammasome-mediated activation of caspase-1 and IL-1beta is crucial for the development of reactive T cells targeting sensitizers like dinitrofluorobenzene (DNFB). Surprisingly, DNFB and dinitrothiocyanobenzene provide cross-reactive Ags yet drive opposing, sensitizing vs tolerizing, T cell responses. In this study, we show that, in mice, inflammasome-signaling levels can be modulated to turn dinitrothiocyanobenzene into a sensitizer and DNFB into a tolerizer, and that it correlates with the IL-6 and IL-12 secretion levels, affecting Th1, Th17, and regulatory T cell development. Hence, our data provide the first evidence that the inflammasome can define the type of adaptive immune response elicited by an Ag, and hint at new strategies to modulate T cell responses in vivo.

Switch-peptides: From conformational studies to Alzheimer's disease

Studies on designed peptides that exhibit high tendencies for medium-induced conformational transitions have recently attracted much attention because structural changes are considered as molecular key processes in degenerative diseases. The experimental access to these events has been limited so far mainly due to the intrinsic tendency of the involved polypeptides for self-association and aggregation, e.g. amyloid P plaque formation, thought to be at the origin of Alzheimer's disease. We have developed a new concept termed 'switch-peptides' which allows the controlled onset of polypeptide folding and misfolding in vitro and in vivo, starting from a soluble, non-toxic precursor molecule. As a major feature, the folding process is initiated by enzyme-triggered N,O-acyl migrations restoring the native peptide backbone in situ. As the folding is set off in the moment of creating the bioactive molecule ('in statu nascendi', ISN), our concept allows for the first time the investigation of the early steps of protein misfolding as relevant in degenerative diseases, opening new perspectives for the rational design of therapeutically relevant compounds.

Monitoring switch-type sensors and powering autonomous sensors via inductive coupling: application to removable seats in vehicles

Aquesta tesi explora la possibilitat de fer servir enllaços inductius per a una aplicació de l’automòbil on el cablejat entre la centraleta (ECU) i els sensors o detectors és difícil o impossible. S’han proposat dos mètodes: 1) el monitoratge de sensors commutats (dos possibles estats) via acoblament inductiu i 2) la transmissió mitjançant el mateix principi físic de la potència necessària per alimentar els sensors autònoms remots. La detecció d'ocupació i del cinturó de seguretat per a seients desmuntables pot ser implementada amb sistemes sense fils passius basats en circuits ressonants de tipus LC on l'estat dels sensors determina el valor del condensador i, per tant, la freqüència de ressonància. Els canvis en la freqüència són detectats per una bobina situada en el terra del vehicle. S’ha conseguit provar el sistema en un marge entre 0.5 cm i 3 cm. Els experiments s’han dut a terme fent servir un analitzador d’impedàncies connectat a una bobina primària i sensors comercials connectats a un circuit remot. La segona proposta consisteix en transmetre remotament la potència des d’una bobina situada en el terra del vehicle cap a un dispositiu autònom situat en el seient. Aquest dispositiu monitorarà l'estat dels detectors (d'ocupació i de cinturó) i transmetrà les dades mitjançant un transceptor comercial de radiofreqüència o pel mateix enllaç inductiu. S’han avaluat les bobines necessàries per a una freqüència de treball inferior a 150 kHz i s’ha estudiat quin és el regulador de tensió més apropiat per tal d’aconseguir una eficiència global màxima. Quatre tipus de reguladors de tensió s’han analitzat i comparat des del punt de vista de l’eficiència de potència. Els reguladors de tensió de tipus lineal shunt proporcionen una eficiència de potència millor que les altres alternatives, els lineals sèrie i els commutats buck o boost. Les eficiències aconseguides han estat al voltant del 40%, 25% i 10% per les bobines a distàncies 1cm, 1.5cm, i 2cm. Les proves experimentals han mostrat que els sensors autònoms han estat correctament alimentats fins a distàncies de 2.5cm.

Selective neurodegeneration induced in rotation-mediated aggregate cell cultures by a transient switch to stationary culture conditions: a potential model to study ischemia-related pathogenic mechanisms.

Aggregating brain cell cultures at an advanced maturational stage (20-21 days in vitro) were subjected for 1-3 h to anaerobic (hypoxic) and/or stationary (ischemic) conditions. After restoration of the normal culture conditions, cell loss was estimated by measuring the release of lactate dehydrogenase as well as the irreversible decrease of cell type-specific enzyme activities, total protein and DNA content. Ischemia for 2 h induced significant neuronal cell death. Hypoxia combined with ischemia affected both neuronal and glial cells to different degrees (GABAergic neurons>cholinergic neurons>astrocytes). Hypoxic and ischemic conditions greatly stimulated the uptake of 2-deoxy-D-glucose, indicating increased glucose consumption. Furthermore, glucose restriction (5.5 mM instead of 25 mM) dramatically increased the susceptibility of neuronal and glial cells to hypoxic and ischemic conditions. Glucose media concentrations below 2 mM caused selective neuronal cell death in otherwise normal culture conditions. GABAergic neurons showed a particularly high sensitivity to glucose restriction, hypoxia, and ischemia. The pattern of ischemia-induced changes in vitro showed many similarities to in vivo findings, suggesting that aggregating brain cell cultures provide a useful in vitro model to study pathogenic mechanisms related to brain ischemia.

Rhumatologie. Une nouvelle option thérapeutique dans la prise en charge de l'inflammation chronique en rhumatologie: les inhibiteurs des janus kinases [A new therapeutical option for chronic inflammation in rheumatology: janus kinases inhibitors (JAK)].

In the last 15 years, the therapeutical options for the treatment of chronic inflammatory diseases in rheumatology have increased a lot. Nevertheless, some patients do not respond or respond partially to the current therapies--including to the biologics therapy. Tofacitinib (Xeljanz) is now on the Swiss market. It inhibits the JAK pathway. Tofacitinib--as monotherapy or with methotrexate--improves the control of rheumatoid arthritis (RA). In a comparative study, tofacitinib was as effective as adalimumab. Further, tofacitinib reduced structural damages in RA and is considered as an alternative, in case of non-response, to anti-TNF and probably to other biologics therapy. The side effects are upper respiratory tract and opportunist infections and tuberculosis. Blood count, lipids, kidney function, liver tests, CK and blood pressure have to be monitored.

On the goodness of fit of Kirk's formula for spread option prices

In this paper we investigate the goodness of fit of the Kirk's approximation formula for spread option prices in the correlated lognormal framework. Towards this end, we use the Malliavin calculus techniques to find an expression for the short-time implied volatility skew of options with random strikes. In particular, we obtain that this skew is very pronounced in the case of spread options with extremely high correlations, which cannot be reproduced by a constant volatility approximation as in the Kirk's formula. This fact agrees with the empirical evidence. Numerical examples are given.

Tailored thoracomyoplasty as a valid treatment option for chronic post-lobectomy empyema

Background: Chronic post-lobectomy empyema is rare but may require space obliteration for infection control. We report our experience by using a tailored thoracomyoplasty for this specific indication with respect to infection control and functional outcome. Patients and Methods: We retrospectively analysed 17 patients (11 men, 6 women) with chronic post-lobectomy empyema and treated by thoracomyoplasty in our institution between 2000 and 2011. All patients underwent an initial treatment attempt by use of chest tube drainage and antibiotics except those with suspicion of pleural aspergillosis (n=6). In 5 patients, bronchus stump insufficiency was identified at preoperative bronchoscopy. A tailored thoracoplasty was combined with a serratus anterior - rhomboid myoplasty which also served to close a broncho-pleural fistula, if present. The first rib was resected in 11/17 patients. Results: The 90-day mortality was 11.7%. Thoracomyoplasty was successful in all surviving patients with respect to infection control, space obliteration and definitive closure of broncho-pleural fistula, irrespective of the type of infection, the presence of a broncho-pleural fistula and whether a 1st rib resection was performed . Post-lobectomy pulmonary function testing before and after thoracoplasty revealed a mean predicted FEV1 of 63.0±8.5% and 51.5±4.2% (p=0.01), and a mean predicted DLCO of 59.8±11.6% and 54.5±12.5%, respectively. Postoperative shoulder girdle dysfunction and scoliosis were prevented in patients willing to undergo intense physiotherapy. Conclusions: Tailored thoracomyoplasty represents a valid option for patients with chronic post-lobectomy empyema without requiring a preceding open window thoracostomy. Space obliteration and infection control was equally obtained with and without first rib resection.

On the term structure of Interbank interest rates: Jump-diffusion processes and option pricing

In this paper we study the dynamic behavior of the term structureof Interbank interest rates and the pricing of options on interest ratesensitive securities. We posit a generalized single factor model withjumps to take into account external influences in the market. Daily datais used to test for jump effects. Qualitative examination of the linkagebetween Monetary Authorities' interventions and jumps are studied. Pricingresults suggests a systematic underpricing in bonds and call options ifthe jumps component is not included. However, the pricing of put optionson bonds presents indeterminacies.

Option pricing under stochastic volatility and stochastic interest rate in the Spanish case

Among the underlying assumptions of the Black-Scholes option pricingmodel, those of a fixed volatility of the underlying asset and of aconstantshort-term riskless interest rate, cause the largest empirical biases. Onlyrecently has attention been paid to the simultaneous effects of thestochasticnature of both variables on the pricing of options. This paper has tried toestimate the effects of a stochastic volatility and a stochastic interestrate inthe Spanish option market. A discrete approach was used. Symmetricand asymmetricGARCH models were tried. The presence of in-the-mean and seasonalityeffectswas allowed. The stochastic processes of the MIBOR90, a Spanishshort-terminterest rate, from March 19, 1990 to May 31, 1994 and of the volatilityofthe returns of the most important Spanish stock index (IBEX-35) fromOctober1, 1987 to January 20, 1994, were estimated. These estimators wereused onpricing Call options on the stock index, from November 30, 1993 to May30, 1994.Hull-White and Amin-Ng pricing formulas were used. These prices werecomparedwith actual prices and with those derived from the Black-Scholesformula,trying to detect the biases reported previously in the literature. Whereasthe conditional variance of the MIBOR90 interest rate seemed to be freeofARCH effects, an asymmetric GARCH with in-the-mean and seasonalityeffectsand some evidence of persistence in variance (IEGARCH(1,2)-M-S) wasfoundto be the model that best represent the behavior of the stochasticvolatilityof the IBEX-35 stock returns. All the biases reported previously in theliterature were found. All the formulas overpriced the options inNear-the-Moneycase and underpriced the options otherwise. Furthermore, in most optiontrading, Black-Scholes overpriced the options and, because of thetime-to-maturityeffect, implied volatility computed from the Black-Scholes formula,underestimatedthe actual volatility.

A generalization of Hull and White formula and applications to option pricing approximation

By means of Malliavin Calculus we see that the classical Hull and White formulafor option pricing can be extended to the case where the noise driving thevolatility process is correlated with the noise driving the stock prices. Thisextension will allow us to construct option pricing approximation formulas.Numerical examples are presented.

Multiple prisoner's dilemma games with (out) an outside option: An experimental study

Experiments in which subjects play simultaneously several finite prisoner's dilemma supergames with and without an outside optionreveal that: (i) subjects use probabilistic start and endeffect behaviour, (ii) the freedom to choose whether to play the prisoner's dilemma game enhances cooperation, (iii) if the payoff for simultaneous defection is negative, subjects' tendency to avoid losses leads them to cooperate; while this tendency makes them stick to mutual defection if its payoff is positive.

A decomposition formula for option prices in the Heston model and applications to option pricing approximation

By means of classical Itô's calculus we decompose option prices asthe sum of the classical Black-Scholes formula with volatility parameterequal to the root-mean-square future average volatility plus a term dueby correlation and a term due to the volatility of the volatility. Thisdecomposition allows us to develop first and second-order approximationformulas for option prices and implied volatilities in the Heston volatilityframework, as well as to study their accuracy. Numerical examples aregiven.