Early recovery of microvascular perfusion induced by t-PA in combination with abciximab or eptifibatide during postischemic reperfusion

BACKGROUND: GPIIb/IIIa inhibitors abciximab and eptifibatide have been shown to inhibit platelet aggregation in ischemic heart disease. Our aim was to test the efficacy of abiciximab (Reo Pro) or eptifibatide (Integrilin) alone or in combination with plasminogen activator (t-PA) in an experimental model of ischemia reperfusion (I/R) in hamster cheek pouch microcirculation visualized by fluorescence microscopy. Hamsters were treated with saline, or abiciximab or eptifibatide or these drugs combined with t-PA infused intravenously 10 minutes before ischemia and through reperfusion. We measured the microvessel diameter changes, the arteriolar red blood cell (RBC) velocity, the increase in permeability, the perfused capillary length (PCL), and the platelet and leukocyte adhesion on microvessels. RESULTS: I/R elicited large increases in the platelet and leukocyte adhesion and a decrease in microvascular perfusion. These responses were significantly attenuated by abiciximab or eptifibatide (PCL:70 and 65% at 5–10 mins of reperfusion and 85 and 87% at 30 mins of reperfusion, respectively, p < 0.001) while t-PA combined with abiciximab or eptifibatide, was more effective and microvascular perfusion recovered immediately after postischemic reperfusion. CONCLUSIONS: Platelets are crucial in I/R injury, as shown by the treatment with abicixmab or eptifibatide, which decreased platelet aggregation in microvessels, and also decreased leukocyte adhesion in venules. Arterial vasoconstriction, decreased arterial RBC velocity and alterations in the endothelial barrier with increased permeability delayed the complete restoration of blood flow, while t-PA combined with inhibition of platelet aggregation speeded up the capillary perfusion after reperfusion

Towards establishing Lepton Flavour Universality violation in Bˉ→Kˉ∗ℓ+ℓ−\bar{B}\to \bar{K}^*\ell^+\ell^- decays

Rare semileptonic $b \to s \ell^+ \ell^-$ transitions provide some of the most promising frameworks to search for new physics effects. Recent analyses of these decays have indicated an anomalous behaviour in measurements of angular distributions of the decay $B^0\to K^*\mu^+\mu^-$ and lepton-flavour-universality observables. Unambiguously establishing if these deviations have a common nature is of paramount importance in order to understand the observed pattern. We propose a novel approach to independently and complementary probe this hypothesis by performing a simultaneous amplitude analysis of $\bar{B}^0 \to \bar{K}^{*0} \mu^+\mu^-$ and $\bar{B}^0 \to \bar{K}^{*0} e^+e^-$ decays. This method enables the direct determination of observables that encode potential non-equal couplings of muons and electrons, and are found to be insensitive to nonperturbative QCD effects. If current hints of new physics are confirmed, our approach could allow an early discovery of physics beyond the standard model with LHCb run II data sets.Comment: 6 pages, 7 figures. Matching the journal versio

Reproducing the assembly of massive galaxies within the hierarchical cosmogony

In order to gain insight into the physical mechanisms leading to the formation of stars and their assembly in galaxies, we compare the predictions of the MOdel for the Rise of GAlaxies aNd Active nuclei (MORGANA) to the properties of K- and 850 micron-selected galaxies (such as number counts, redshift distributions and luminosity functions) by combining MORGANA with the spectrophotometric model GRASIL. We find that it is possible to reproduce the K- and 850 micron-band datasets at the same time and with a standard Salpeter IMF, and ascribe this success to our improved modeling of cooling in DM halos. We then predict that massively star-forming discs are common at z~2 and dominate the star-formation rate, but most of them merge with other galaxies within ~100 Myr. Our preferred model produces an overabundance of bright galaxies at z<1; this overabundance might be connected to the build-up of the diffuse stellar component in galaxy clusters, as suggested by Monaco et al. (2006), but a naive implementation of the mechanism suggested in that paper does not produce a sufficient slow-down of the evolution of these objects. Moreover, our model over-predicts the number of 10^{10}-10^{11} M_sun galaxies at z~1; this is a common behavior of theoretical models as shown by Fontana et al. (2006). These findings show that, while the overall build-up of the stellar mass is correctly reproduced by galaxy formation models, the ``downsizing'' trend of galaxies is not fully reproduced yet. This hints to some missing feedback mechanism in order to reproduce at the same time the formation of both the massive and the small galaxies.Comment: 14 pages; 11 figures; accepted for publication by MNRA

Slowly rotating black hole solutions in Horndeski gravity

We study black hole solutions at first order in the Hartle-Thorne slow-rotation approximation in Horndeski gravity theories. We derive the equations of motion including also cases where the scalar depends linearly on time. In the Hartle-Thorne formalism, all first-order rotational corrections are described by a single frame-dragging function. We show that the frame-dragging function is exactly the same as in general relativity for all known black hole solutions in shift symmetric Horndeski theories, with the exception of theories with a linear coupling to the Gauss-Bonnet invariant. Our results extend previous no-hair theorems for a broad class of Horndeski gravity theories.Comment: Fixed more typos found in proof. Matches version published in PR

Role of leptin receptors in the development of obesity

The focus of this dissertation was leptin and the leptin receptor, and the role of these genes (OB and OB-R) in the development of obesity and type 2 diabetes in humans and Psammomys obesus, a polygenic rodent model of obesity and type 2 diabetes. Studies in humans showed that circulating leptin concentrations were positively associated with adiposity, and independently associated with circulating insulin and triglyceride concentrations. Analysis of two leptin receptor sequence polymorphisms in a Caucasian Australian population and a population of Nauruan males, with very high prevalence rates of obesity, showed no associations between sequence variation within the OB-R gene and obesity- or diabetes-related phenotypic measures. In addition, these two OB-R polymorphisms were not associated with longitudinal changes in body mass or composition in either of the populations examined. A unique analysis of the effects of multiple gene defects in the Nauruan population, demonstrated that the presence of sequence alterations in both the OB and OB-R genes were associated with insulin resistance. Psammomys obesus is regarded as an excellent rodent model in which to study the development of obesity and type 2 diabetes in humans. Examination of circulating leptin concentrations in Psammomys revealed that, as in humans, leptin concentrations were associated with adiposity, and independently associated with circulating insulin concentrations. This animal model was utilised to examine expression of OB-R, and the regulation of expression of this gene after dietary manipulation. OB-R is known to have several isoforms, and in particular, OB-RA and OB-RB gene expression were examined. OB-RB is the main signalling isoform of the leptin receptors. It has a long intracellular domain and has previously been shown to play an important role in energy balance and body weight regulation in rodents and humans. OB-RA is a much shorter isoform of OB-R, and although it lacks the long intracellular domain necessary to activate the JAK/STAT pathway, OB-RA is also capable of signalling, although to a lesser degree than OB-RB. OB-RA is found to be expressed almost ubiquitously throughout the body, and this isoform may be involved in transport of leptin into the cell, although its role remains unclear. OB-RA and OB-RB were both found to be expressed in a large number of tissues in Psammomys obesus. Interestingly, obese Psammomys were found to have lower levels of expression of OB-RA and OB-RB in the hypothalamus, compared to lean animals. This finding raises the possibility that decreased leptin signalling in the brain of obese, hyperleptinemic Psammomys obesus may contribute to the leptin resistance previously described in this animal model. However, the primary defect is unclear, as alternatively, increased circulating leptin concentrations may lead to down-regulation of leptin receptors. The effect of fasting on leptin concentrations and gene expression of OB-RA and OB-RB was also examined. A 24-hour fast resulted in no change in body weight, but a reduction in circulating leptin concentrations, and an increase in hypothalamic OB-RB gene expression in lean Psammomys. In obese animals, fasting again did not alter body weight, but resulted in an increase in both circulating leptin concentrations and hypothalamic OB-RB gene expression. In the liver, fasting resulted in a large increase in OB-RA gene expression in both lean and obese animals. These results highlighted the fact that regulation of leptin receptor gene expression in polygenic models of obesity and type 2 diabetes is complex, and not solely under the control of circulating leptin concentrations. Sucrose-feeding is an established method of inducing obesity and type 2 diabetes in rodents, and this experimental paradigm was utilised to examine the effects of longer term perturbations of energy balance on the leptin signalling pathway in Psammomys obesus. Addition of a 5% sucrose solution to the diet of lean and obese Psammomys resulted in increased body weight in both groups of animals, however only obese Psammomys showed increased fat mass and the development of type 2 diabetes. The changes in body mass and composition with sucrose-feeding were accompanied by decreased circulating leptin concentrations in both groups of animals, as well as a range of changes in leptin receptor gene expression. Sucrose-feeding increased hypothalamic OB-RB gene expression in obese Psammomys only, while in the liver there was evidence of a reduction in OB-RA and OB-RB gene expression in both lean and obese animals. The direct effects of sucrose on the leptin signalling pathway are unclear, however it is possible to speculate that the effect of sucrose to decrease leptin concentrations may have been involved in the exacerbation of obesity and the development of type 2 diabetes in obese Psammomys, From these studies, it appears that sequence variation in the OB and OB-R genes is unlikely to be a major factor in the etiology of obesity in human populations. The ability to examine regulation of expression of these genes in Psammomys obesus, however, has demonstrated that the effects of nutritional modifications on leptin receptor gene expression need closer attention. The role of the OB and OB-R genes in metabolism and the development of type 2 diabetes also warrants further examination, with particular attention on the differential effects of dietary modifications on leptin receptor gene expression across a range of tissues

Sex Differences in Myelin Deficits and Neuroinflammatory Responses to Adolescent Drinking in Rats

Alcohol binge drinking during adolescence is associated with higher risk of developing alcohol use disorders later in life. Alcohol can lead to decreased white matter volume, myelin damage, and neuroinflammation in animal models of adolescent binge alcohol exposure. These deficits in turn are associated with cognitive disfunctions that are long-lasting and could contribute to alcohol abuse and alcoholism later in life. Importantly, human males are more likely to develop alcohol use disorders than females, thus the mechanisms underlying this might be different between the sexes. Understanding how alcohol impacts the developing adolescent brain can help us identify molecular and cellular pathways to target for therapeutic intervention. Here we sought to determine whether males and females are affected differently by voluntary alcohol drinking using an operant self-administration paradigm, and whether this level of alcohol exposure is enough to elicit similar inflammatory responses as those seen in chronic models of binge alcohol exposure. We found that alcohol had a negative impact on myelin microstructure in both males and females, however, overall myelinated fiber density was significantly reduced only in males, suggesting impaired remyelination. Similarly, males appeared to have a more robust inflammatory response than females, as indicated by upregulation of the gene that encodes for Toll-like receptor 4 (Tlr4) after alcohol drinking. While females did have an inflammatory response to alcohol, there was no change in the levels of Tlr4, and this was not due to differing circulating levels of pubertal hormones, as ovariectomized females also exhibited a similar attenuated response to alcohol. Taken together, this suggests that males might be more vulnerable to the effects of alcohol pre-pubertally, partly due to a more robust inflammatory response to alcohol, possibly related to sex differences in innate and adaptive immunity

Diseño de una planta de fabricación del polímero ácido poliláctico

Treballs Finals de Màster d'Enginyeria Química, Facultat de Química, Universitat de Barcelona. Curs: 2019-2020. Tutor:José María Gutiérrez GonzálezOver the last decades, plastic demand has grown increasingly at a level such that it is unavoidable for current society. Plastics versatility and unique properties makes them suitable for all kind of industries, which currently suppose a threat to both environment and human health at every stage, right from their production to their end-of-life scenario. Bioplastics stand out in this way as a greener solution able to reduce carbon footprint, with high recycling value and complete biodegradability or compostability. In this regard, polylactic acid constitutes a biodegradable and bio-based bioplastic which is gaining attention in the recent years, as it possesses the potential to replace conventional fossil-based plastics in food packaging and other applications. Continuous research and development in this field has made possible the polylactic acid mass production at a competitive cost, promising a sustainable future and overcoming the accumulation of plastic waste in landfills. The purpose of this project is the development of the Master’s Degree Final Project with which it is intended to apply for the Master Degree in Chemical Engineering by the “Universidad de Barcelona” The project is focused on the design of a plant for polylactic acid polymer manufacture from lactic acid solutions. Based on a comparison among different polylactic acid market players and the increasing demand reflected in the market analysis, the plant has a fixed annual production capacity of 60,000 tonnes and operates 330 days per year. A selection of the most adequate synthesis of the manufacturing process, according to product necessities, is conducted through a bibliographic research. By means of mass and energy balances, stream flows and operating conditions of each equipment are determined in order to carry out the basic design of the plant, in which the main design parameters and dimensions are detailed. A falling film evaporator type of reactor is selected for the condensation polymerization of lactic acid into polylactic acid of low molecular weight, as it provides the advantages required to optimize the polymer production due to its high surface area to volumetric hold up ratio, which reduces evaporation residence time. A detailed design of this equipment, based on heat transfer and mechanical design, is carried out and reflected in the equipment lay-out. As a final point, the control system of the plant is studied in order to supress the influence of external disturbances, ensuring the stability of the chemical process and the optimization of the process performance. The control system stands for the discussion of the control philosophy and the establishment of the control loops of the plant, described through a P&I diagram which includes the engineering details of the equipment as well as instruments, piping, valves and fittings