Estudis funcionals i de plegament dels dominis d'activació de les procarboxipeptidases

Els dominis d’activació (ADs) de les procarboxipeptidases de la subfamília A/B sempre han sorprès ja que representen una quarta part del proenzim. S’han realitzat alguns estudis per intentar descobrir-ne alguna possible funció alternativa, però no han estat fructífers. El descobriment de l’elevada velocitat de plegament del domini d’activació de la procarboxipeptidasa A2 humana, (ADA2h), emperò, va portar a proposar la possibilitat de que realitzessin una funció d’assistència al plegament del domini enzimàtic. Posteriorment, l’anàlisi del plegament d’ADA2h a pH baix va revelar la capacitat d’aquest domini per formar fibres amiloides, a més de demostrar que un increment de l’estabilitat proteica podia prevenir la formació d’aquests agregats. La profunda caracterització del plegament d’ADA2h va fer que aquesta proteïna fos un bon model amiloidogènic, de manera que es van proposar un seguit d’experiments que s’han desenvolupat en el present treball per tal de conèixer millor aquest procés. S’han dut a terme estudis cinètics d’agregació per tal de valorar la contribució dels diferents aminoàcids de la seqüència polipeptídica, utilitzant 29 variants puntuals d’ADA2h. Es va eliminar la contribució de l’estabilitat mitjançant la utilització d’urea, i per dicroïsme circular conjuntament amb un aparell de flux detingut, es van obtenir dues velocitats diferents, v1 i v2, que corresponen a la formació d’un intermediari i a la seva reorganització, respectivament. Experiments complementaris utilitzant espectroscòpia d’infraroig (IR) revelaren la reorganització de l’estat natiu (en aquest cas) per a donar la forma agregada. Les cinètiques d’IR van mostrar que ADA2h forma l’estructura _ típica de les fibres amiloides, previ desplegament les seves hèlixs-_. Finalment, s’han realitzat estudis de biocomputació per tal d’esbrinar possibles funcions alternatives dels ADs. Les superposicions estructurals semblen mostrar similaritat dels ADs amb dominis de reconeixement d’RNA (RRM). Aquesta hipòtesi s’ha comprovat experimentalment amb ADA4h, mostrant una dèbil, però existent, unió a RNA.

Privatization and competition in the delivery of local services: An empirical examination of the dual market hypothesis

This paper empirically analyses the hypothesis of the existence of a dual market for contracts in local services. Large firms that operate on a national basis control the contracts for delivery in the most populated and/or urban municipalities, whereas small firms that operate at a local level have the contracts in the least populated and/or rural municipalities. The dual market implies the high concentration and dominance of major firms in large municipalities, and local monopolies in the smaller ones. This market structure is harmful to competition for the market as the effective number of competitors is low across all municipalities. Thus, it damages the likelihood of obtaining cost savings from privatization.

Why do females mate with multiple males ? The sexually selected sperm hypothesis

One debated issues in evolutionary biology is, why in many species females mate with multiple males. Several hypotheses have been put forward, yet the benefits of multiple mating (here defined as mating with several males) remain unclear in many cases. The sperm sexual selection (SSS) hypothesis has been developed to account for the widespread occurrence of multiple mating in females. It argues that multiple mating by females may rapidly spread, when initially a small fraction of the females mate multiply, and if there is a heritable difference among males in one or several of the four characteristics: (1) the quantity of sperm they produce; (2) the success of their sperm in reaching and fertilizing an egg; (3) their ability to displace the sperm that females stored during previous mating; and (4) their ability to prevent any other male from subsequently introducing sperm (e.g., differential efficiency of mating plugs).

A New Test of the Real Interest Rate Parity Hypothesis: Bounds Approach and Structural Breaks

We test the real interest rate parity hypothesis using data for the G7 countries over the period 1970-2008. Our contribution is two-fold. First, we utilize the ARDL bounds approach of Pesaran et al. (2001) which allows us to overcome uncertainty about the order of integration of real interest rates. Second, we test for structural breaks in the underlying relationship using the multiple structural breaks test of Bai and Perron (1998, 2003). Our results indicate significant parameter instability and suggest that, despite the advances in economic and financial integration, real interest rate parity has not fully recovered from a breakdown in the 1980s.

Revisiting Shiller’s excess volatility hypothesis

One of the cornerstone of financial anomalies is that there exists money making opportunities. Shiller’s excess volatility theory is re-investigated from the perspective of a trading strategy where the present value is computed using a series of simple econometric models to forecast the present value. The results show that the excess volatility may not be exploited given the data available until time t. However, when learning is introduced empirically, the simple trading strategy may offer profits, but which are likely to disappear once transaction costs are considered.

A test of long memory hypothesis based on self-similarity

This paper develops a new test of true versus spurious long memory, based on log-periodogram estimation of the long memory parameter using skip-sampled data. A correction factor is derived to overcome the bias in this estimator due to aliasing. The procedure is designed to be used in the context of a conventional test of significance of the long memory parameter, and composite test procedure described that has the properties of known asymptotic size and consistency. The test is implemented using the bootstrap, with the distribution under the null hypothesis being approximated using a dependent-sample bootstrap technique to approximate short-run dependence following fractional differencing. The properties of the test are investigated in a set of Monte Carlo experiments. The procedure is illustrated by applications to exchange rate volatility and dividend growth series.

Revisiting Shiller’s excess volatility hypothesis

One of the cornerstone of financial anomalies is that there exists money making opportunities. Shiller’s excess volatility theory is re-investigated from the perspective of a trading strategy where the present value is computed using a series of simple econometric models to forecast the present value. The results show that the excess volatility may not be exploited given the data available until time t. However, when learning is introduced empirically, the simple trading strategy may offer profits, but which are likely to disappear once transaction costs are considered.

Revisiting the diacylglycerol-induced insulin resistance hypothesis.

Obesity is associated with skeletal muscle insulin resistance, which is a crucial step in the development of type 2 diabetes. Among the mechanisms by which obesity may lead to insulin resistance, lipotoxicity is one of the hypotheses being explored; others include inflammation or the oxidative stress hypotheses. This review focuses on the role of diacylglycerols (DAG), a family of lipid metabolites implicated in the pathogenesis of lipotoxicity and insulin resistance. While recent studies report contradictory results in humans with regard to the importance of DAG-induced insulin resistance in skeletal muscle, other current literature highlight a potential role for DAG as signalling molecules. This review will discuss possible hypotheses explaining these contradictory results and the need to explore further the role of DAG in human metabolism.

Immunocompetence and nestling survival in the house martin: the tasty chick hypothesis

In altricial birds post-fledging survival is usually positively related to nestling body mass. A large number of studies have shown that the latest hatched chick is the more likely to die, even if food is abundant. Here we suggest that ectoparasites may be a key factor in the evolution and the maintenance of the establishment of weight hierarchies within broods. We prepose the hypothesis that weight hierarchies within broods may be adaptive if the chick in poor condition is the one with the least efficient immune system within a nest. In this case parasites would preferentially feed on such a "tasty chick", because it would allow high reproductive rates for the parasites, without negatively affecting the survival of the other nestlings. This could prevent entire nest failure of the brood or allow the other chicks to grow more efficiently. This hypothesis was investigated in a colony of house martins Delichon urbica. We predicted that immunocompetence was positively correlated with body condition, and that nestlings dying before hedging should have lower immune responses when challenged with an antigen. T-cell immune response to an experimentally injected antigen was strongly positively related to body condition. Non-surviving chicks had low body condition and a weak immune response. The implications of these results are discussed in the context of the adaptive significance of hatching asynchrony.

Increased efflux of amyloid-β peptides through the blood-brain barrier by muscarinic acetylcholine receptor inhibition reduces pathological phenotypes in mouse models of brain amyloidosis.

The formation and accumulation of toxic amyloid-β peptides (Aβ) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL, and AβPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aβ peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Brain (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects.

Pre-hatching maternal effects and the tasty chick hypothesis

Question: Are maternal effects (i.e. maternal transfer of immune components to their offspring via the placenta or the egg) specifically directed to the offspring on which ectoparasites predictably aggregate? Organisms: The barn owl (Tyto alba) because late-hatched offspring are the main target of the ectoparasitic fly Carnus hemapterus. Hypothesis: Pre-hatching maternal effects enhance parasite resistance of late- compared with early-hatched nestlings. Search method: To disentangle the effect of natal from rearing ranks on parasite intensity, we exchanged hatchlings between nests to allocate early- and late-hatched hatchlings randomly in the within-brood age hierarchy. Result: After controlling for rearing ranks, cross-fostered late-hatched nestlings were less parasitized but lighter than cross-fostered early-hatched nestlings. Conclusion: Pre-hatching maternal effects increase parasite resistance of late-hatched offspring at a growth cost.

Omics meets hypothesis-driven research. Partnership for innovative discoveries in vascular biology and angiogenesis.

The emergence of omics technologies allowing the global analysis of a given biological or molecular system, rather than the study of its individual components, has revolutionized biomedical research, including cardiovascular medicine research in the past decade. These developments raised the prospect that classical, hypothesis-driven, single gene-based approaches may soon become obsolete. The experience accumulated so far, however, indicates that omic technologies only represent tools similar to those classically used by scientists in the past and nowadays, to make hypothesis and build models, with the main difference that they generate large amounts of unbiased information. Thus, omics and classical hypothesis-driven research are rather complementary approaches with the potential to effectively synergize to boost research in many fields, including cardiovascular medicine. In this article we discuss some general aspects of omics approaches, and review contributions in three areas of vascular biology, thrombosis and haemostasis, atherosclerosis and angiogenesis, in which omics approaches have already been applied (vasculomics).