Nonequilibrium Corrections to the Spectra of Massless Neutrinos in the Early Universe

Distortion of the equilibrium spectra of cosmic neutrinos due to interaction with hotter electrons and positrons in the primeval cosmic plasma is considered. The set of integro-differential kinetic equations for neutrinos is accurately numerically solved. The relative corrections to neutrino energy densities are approximately 0.9% for $\nu_e$ and 0.4% for $\nu_\mu$ and $\nu_\tau$. This effect results in $1.4 \cdot 10^{-4}$ increase in the primordial $^4 He$ abundance.Comment: 28 pages including 6 figures. Latex

Novel diagnostic biomarkers and therapeutic options for neuroendocrine tumors

Neuroendocrine tumors (NETs) represent a heterogeneous group of rare, slow-growing neoplasms, originating from enterochromaffin cells. Their annual incidence has progressively increased, although it is not known whether this is a true increase in NET incidence, the result of increased use of (improved) diagnostic procedures, or a combination of both. While metastatic disease is frequently observed at diagnosis, survival in NET patients has increased, which may be related to the advances in diagnostic and therapeutic procedures. NETs require appropriate standardized diagnostic procedures to assure early diagnosis, monitor disease progression and guide an optimal treatment. Additionally, medical treatment options in NETs have significantly increased and improved in the last years. This thesis evaluates a number of novel diagnostic and therapeutic options for patients with NET. Chapter 1 provides a general overview about NETs, emphasizes the applicability and limitations of the current diagnostic biomarkers and summarizes some putative novel biomarkers in NETs. At the same time, this chapter describes current and novel therapeutic options for functioning a non-functioning NETs. The chapter introduces the main content of this thesis: novel diagnostic and therapeutic options for NETs. Chapter 1 ends with an overview of the main aims of this thesis. Chapter 2 comprehensively evaluates the expression of several components of the somatostatin/cortistatin and ghrelin systems in a large series of well-characterized typical and atypical lung carcinoids. To the best of our knowledge, this study represents the first systematic characterization of the components of these regulatory systems in samples from lung carcinoids (LCs), in which a comparison is made with adjacent non-tumor regions and normal lung tissue. In this study, we observed that the expression of somatostatin, of some receptor subtypes (SSTs), and of the ghrelin receptor GHSR gradually increases from normal to non-tumoral adjacent and tumor tissue. Moreover, the presence of the truncated isoforms SST5TMD4, In1-ghrelin and the ghrelin receptor GHSR1b are first reported in LCs. Higher expression levels of ghrelin-O-acyltransferase (GOAT) were observed in tumors with necrosis, which were tumors with a larger size and higher capacity of peritumoral invasion and distant metastasis. These data suggest that a dysregulation of ghrelin system may be involved in the development/progression of these tumors. Chapter 3 evaluates the expression of the somatostatin/cortistatin system components in gastroenteropancreatic- (GEP-) NETs. The observed overexpression of SST5 in tumor tissue compared to adjacent non-tumor and normal tissue, as well as its clinical relation with vascular and nerve invasion suggests the putative role of SST5 as a target for treating aggressive GEP-NETs. Furthermore, it emphasizes that the evaluation of SSTs profile in GEP-NETs may provide additional information for clinical decision making, including the use of second-generation somatostatin analogs (SSAs). The most novel and relevant finding of chapter 4 is the marked overexpression of GOAT in GEP-NET samples. Whereas the expression of this enzyme is almost absent in the corresponding normal tissues, it is present in adjacent non-tumoral tissue and notably overexpressed tumor tissues. Additionally, its overexpression was demonstrated using immunohistochemistry. Importantly, this enzyme was associated to larger tumors, especially in gastrointestinal-NETs. These findings, in combination with previous publications, suggest a putative role of GOAT as a diagnostic biomarker in GEP-NETs. Chapter 5 evaluates the effect of ketoconazole on proliferation, cell cycle, apoptosis and secretion of adrenocorticotropic hormone (ACTH) or serotonin and chromogranin in an ACTH-producing bronchial NET and a non-ACTH producing pancreatic NET cell line, respectively. Ketoconazole exerted a predominant pro-apoptotic or cytotoxic effect, depending on the cell line. Additionally, ketoconazole induced changes in the cell cycle progression, e.g. it increases G0/G1 phase in both cell lines and an arrest in G2/M phase in the pancreatic NET cell line. Furthermore, a non-previously reported inhibitory effect of the SSA pasireotide on serotonin secretion by pancreatic NET cells was reported, which is probably related to the predominant SST5 expression in this cell line. In chapter 6, a comprehensive characterization of two pancreatic NET models was performed using two- (2D; monolayer) and three- dimensional (3D; spheroids) culture systems in different medium conditions. According to our results, NET 3D spheroid cultures represent a promising method for evaluating cell proliferation and secretion in NET cell lines, even in serum-deprived conditions. A non-previously reported dynamic expression of SSTs and dopamine receptor (D2R) was observed during growth of both 2D and 3D cultures. The effects of the somatostatin analog octreotide, the dopamine agonist cabergoline and of two novel SSTs-D2R multi-receptor targeting drugs (BIM-065, BIM-23A760) were evaluated using both culture systems. Cabergoline and SSTs-D2R multi-receptor targeting drugs, but not octreotide, inhibited CgA and serotonin secretion, but not NET cell growth. This suggests that the effect of the SSTs-D2R multi-receptor targeting drugs on secretion is mediated by D2R, and may indicate a putative role of dopamine agonists for treating D2R expressing functioning NETs, including carcinoid syndrome. Chapter 7 shows the in vitro effects of the novel tryptophan hydoxylase inhibitor telotristat on pancreatic NET cells. Telotristat potently inhibited serotonin release in a dose-dependent manner at a clinically feasible concentration. Its combination with pasireotide, but not with octreotide, had an additive effect on serotonin secretion. In 3D cultured pancreatic NET cells, serotonin secretion was completely blocked by telotristat, whereas this drug did not influence cell growth. These data suggest that serotonin has no autocrine/paracrine effect on cell growth in this 3D PNET model. In chapter 8 decreased expression of SSTs was observed in tumor tissue of GEP-NET patients with type 2 diabetes, compared to non-diabetic GEP-NET patients. This decreased expression was not observed in type 2 diabetic patients that were treated with metformin. The in vitro experiments showed an antiproliferative effect of biguanides and statins in NET cell lines, with consequent increased apoptosis and decreased cell migration. Since metformin and statins are low cost commercially available drugs, with a large experience in their clinical use, they may represent putative options for adjuvant therapy in NETs. In Chapter 9, the results and conclusions of the studies included in this thesis, are discussed in relation to current and possible novel future diagnostic modalities, as well as therapeutic options for NET patients.The general aims of the studies presented in this thesis are: 1. To identify potential novel tissue biomarkers for lung carcinoids and GEP-NETs 2. To evaluate the antitumor effect of registered drugs (for other medical purposes) in NETs 3. To evaluate the effects of novel drugs on NET hormone release and cell proliferation Specifically, we studied the potential applicability of ghrelin and somatostatin systems as biomarkers in tissue samples of lung carcinoids and GEP-NETs. As registered drugs for other medical purposes, we evaluated the antitumor effects of ketoconazole, metformin and statins. Finally, somatostatin-dopamine receptor chimeras and telotristat were studied as novel drugs for hormone release and cell growth control

AT-MFCGA: An Adaptive Transfer-guided Multifactorial Cellular Genetic Algorithm for Evolutionary Multitasking

Transfer Optimization is an incipient research area dedicated to solving multiple optimization tasks simultaneously. Among the different approaches that can address this problem effectively, Evolutionary Multitasking resorts to concepts from Evolutionary Computation to solve multiple problems within a single search process. In this paper we introduce a novel adaptive metaheuristic algorithm to deal with Evolutionary Multitasking environments coined as Adaptive Transfer-guided Multifactorial Cellular Genetic Algorithm (AT-MFCGA). AT-MFCGA relies on cellular automata to implement mechanisms in order to exchange knowledge among the optimization problems under consideration. Furthermore, our approach is able to explain by itself the synergies among tasks that were encountered and exploited during the search, which helps us to understand interactions between related optimization tasks. A comprehensive experimental setup is designed to assess and compare the performance of AT-MFCGA to that of other renowned Evolutionary Multitasking alternatives (MFEA and MFEA-II). Experiments comprise 11 multitasking scenarios composed of 20 instances of 4 combinatorial optimization problems, yielding the largest discrete multitasking environment solved to date. Results are conclusive in regard to the superior quality of solutions provided by AT-MFCGA with respect to the rest of the methods, which are complemented by a quantitative examination of the genetic transferability among tasks throughout the search process

Lambda^0 polarization as a probe for production of deconfined matter in ultra-relativistic heavy-ion collisions

We study the polarization change of Lambda^0's produced in ultra-relativistic heavy-ion collisions with respect to the polarization observed in proton-proton collisions as a signal for the formation of a Quark-Gluon Plasma (QGP). Assuming that, when the density of participants in the collision is larger than the critical density for QGP formation, the Lambda^0 production mechanism changes from recombination type processes to the coalescence of free valence quarks, we find that the Lambda^0 polarization depends on the relative contribution of each process to the total number of Lambda^0's produced in the collision. To describe the polarization of Lambda^0's in nuclear collisions for densities below the critical density for the QGP formation, we use the DeGrand-Miettinen model corrected for the effects introduced by multiple scattering of the produced Lambda^0 within the nuclear environment.Comment: 9 pages, 6 figures, uses ReVTeX and epsfig.st

Nonlocal Equation of State in Anisotropic Static Fluid Spheres in General Relativity

We show that it is possible to obtain credible static anisotropic spherically symmetric matter configurations starting from known density profiles and satisfying a nonlocal equation of state. These particular types of equation of state describe, at a given point, the components of the corresponding energy-momentum tensor not only as a function at that point, but as a functional throughout the enclosed configuration. To establish the physical plausibility of the proposed family of solutions satisfying nonlocal equation of state, we study the constraints imposed by the junction and energy conditions on these bounded matter distributions. We also show that it is possible to obtain physically plausible static anisotropic spherically symmetric matter configurations, having nonlocal equations of state\textit{,}concerning the particular cases where the radial pressure vanishes and, other where the tangential pressures vanishes. The later very particular type of relativistic sphere with vanishing tangential stresses is inspired by some of the models proposed to describe extremely magnetized neutron stars (magnetars) during the transverse quantum collapse.Comment: 21 pages, 1 figure, minor changes in the text, references added, two new solutions studie

Recent Developments in OCL and Textual Modelling

The panel session of the 16th OCL workshop featured a lightning talk session for discussing recent developments and open questions in the area of OCL and textual modelling. During this session, the OCL community discussed, stimulated through short presentations by OCL experts, tool support, potential future extensions, and suggested initiatives to make the textual modelling community even more successful. This collaborative paper, to which each OCL expert contributed one section, summarises the discussions as well as describes the recent developments and open questions presented in the lightning talks

Fifteen years controlling unwanted thoughts: A systematic review of the thought control ability questionnaire (TCAQ)

Thought control ability is a vulnerability factor implicated in the etiology and maintenance of emotional disorders. This manuscript aims to systematically review the use and psychometric performance of the Thought Control Ability Questionnaire (TCAQ), designed to assess people's ability to control unwanted thoughts. Three electronic databases were searched for papers administering the TCAQ published in indexed peer-reviewed journals. Data (participants characteristics, country, study design, etc.) were extracted from the results for qualitative synthesis. The TCAQ's content validity, dimensionality, internal consistency, test-retest reliability, convergent/divergent validity, floor/ceiling effects, and interpretability were summarized. Two reviewers independently screened articles and assessed quality taking COSMIN criteria into account. Finally, the review included 17 papers. The TCAQ has been administered to healthy individuals, students, and adult patients, in six languages from nine countries. We found that the TCAQ, and its shorter versions, demonstrate robust reliability and adequate content validity. Of interest is the TCAQ's capacity to predict performance in diverse experimental tasks focused on thought control. The TCAQ unidimensionality has been supported in exploratory and confirmatory factor analyses. Regarding construct validity, the TCAQ is significantly related to a wide range of psychopathological measures of anxiety, worry, depression, obsessive-compulsive symptoms, etc. However, as only a few of the included studies had a longitudinal design, we are unable to draw firm conclusions about the measure's temporal stability. Moreover, psychometric aspects such as factorial invariance across different samples have not been analyzed. Despite these limitations, based on available psychometric evidence we can recommend using the TCAQ for measuring perceived control of unwanted thoughts

Intermediate inflation in Gauss-Bonnet braneworld

In this article we study an intermediate inflationary universe models using the Gauss-Bonnet brane. General conditions required for these models to be realizable are derived and discussed. We use recent astronomical observations to constraint the parameters appearing in the model.Comment: 16 pages, 2 figures, accepted for publication in European Physical Journal

Test results for the V0 detector in ALICE

ALIC

Effect of the Tryptophan Hydroxylase Inhibitor Telotristat on Growth and Serotonin Secretion in 2D and 3D Cultured Pancreatic Neuroendocrine Tumor Cells

Serotonin, a biologically active amine, is related to carcinoid syndrome in functioning neuroendocrine tumors (NETs). Telotristat ethyl is a novel inhibitor of the tryptophan hydroxylase (TPH), a key enzyme in the production of serotonin. While its use in patients with carcinoid syndrome and uncontrolled diarrhea under somatostatin analogs (SSAs) has been recently approved, in vitro data evaluating its effectiveness are lacking. For this reason, we aimed to evaluate the effect of telotristat as monotherapy, and in combination with SSAs, on proliferation and secretion in a NET cell line model. The human pancreatic NET cell lines BON-1/QGP-1 were used as 2D and 3D cultured models; somatostatin receptor and TPH mRNA expression, as well as the potential autocrine effect of serotonin on tumor cell proliferation using a 3D culture system were evaluated. Telotristat decreased serotonin production in a dose-dependent manner at a clinically feasible concentration, without affecting cell proliferation. Its combination with pasireotide, but not with octreotide, had an additive inhibitory effect on serotonin secretion. The effect of telotristat was slightly less potent, when BON-1 cells were co-treated with octreotide. Octreotide and pasireotide had no effect on the expression of TPH. Telotristat did not have an effect on mRNA expression of somatostatin receptor subtypes. Finally, we showed that serotonin did not have an autocrine effect on NET cell proliferation on the 3D cell model. These results suggest that telotristat is an effective drug for serotonin inhibition, but the effectiveness of its combination with SST2 (somatostatin receptor subtype 2)-preferring SSA should be evaluated in more detail