AXEL: A framework to deal with ambiguity in three-noun compounds

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University, 6/12/2010.Cognitive Linguistics has been widely used to deal with the ambiguity generated by words in combination. Although this domain offers many solutions to address this challenge, not all of them can be implemented in a computational environment. The Dynamic Construal of Meaning framework is argued to have this ability because it describes an intrinsic degree of association of meanings, which in turn, can be translated into computational programs. A limitation towards a computational approach, however, has been the lack of syntactic parameters. This research argues that this limitation could be overcome with the aid of the Generative Lexicon Theory (GLT). Specifically, this dissertation formulated possible means to marry the GLT and Cognitive Linguistics in a novel rapprochement between the two. This bond between opposing theories provided the means to design a computational template (the AXEL System) by realising syntax and semantics at software levels. An instance of the AXEL system was created using a Design Research approach. Planned iterations were involved in the development to improve artefact performance. Such iterations boosted performance-improving, which accounted for the degree of association of meanings in three-noun compounds. This dissertation delivered three major contributions on the brink of a so-called turning point in Computational Linguistics (CL). First, the AXEL system was used to disclose hidden lexical patterns on ambiguity. These patterns are difficult, if not impossible, to be identified without automatic techniques. This research claimed that these patterns can assist audiences of linguists to review lexical knowledge on a software-based viewpoint. Following linguistic awareness, the second result advocated for the adoption of improved resources by decreasing electronic space of Sense Enumerative Lexicons (SELs). The AXEL system deployed the generation of “at the moment of use” interpretations, optimising the way the space is needed for lexical storage. Finally, this research introduced a subsystem of metrics to characterise an ambiguous degree of association of three-noun compounds enabling ranking methods. Weighing methods delivered mechanisms of classification of meanings towards Word Sense Disambiguation (WSD). Overall these results attempted to tackle difficulties in understanding studies of Lexical Semantics via software tools

Design, Synthesis and Evaluation of 2,4- Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

Microtubules are highly dynamic polymers composed of α- and β- tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to β- tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well- known tubulin- depolymerizing agents that have close binding sites in the β- tubulin. In this study, we designed and synthesized a set of nine 2,4- diaminoquinazoline derivatives that could occupy both NZ and COL binding sites. The synthesized compounds were evaluated for their antiproliferative activities against five cancer cell lines (PC- 3, HCT- 15, MCF- 7, MDA- MB- 231, and SK- LU- 1), a noncancerous one (COS- 7), and peripheral blood mononuclear cells (PBMC). The effect of compounds 4- e and 4- i on tubulin organization and polymerization was analyzed on the SK- LU- 1 cell line by indirect immunofluorescence, western blotting, and tubulin polymerization assays. Our results demonstrated that both compounds exert their antiproliferative activity by inhibiting tubulin polymerization. Finally, a possible binding pose of 4- i in the NZ/COL binding site was determined by using molecular docking and molecular dynamics (MD) approaches. To our knowledge, this is the first report of non- N- substituted 2,4- diaminoquinazoline derivatives with the ability to inhibit tubulin polymerization.More is not always better: A set of nine 2,4- diaminoquinazoline derivatives were evaluated for their ability to inhibit tubulin polymerization by using immunofluorescence staining analysis, western blotting, tubulin polymerization assays, and molecular dynamics simulations. Our study provides valuable insights into the design of 2,4- diaminoquiazoline compounds as tubulin polymerization inhibitors for the treatment of lung and breast cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/3/cmdc202000185-sup-0001-misc_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/2/cmdc202000185_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163403/1/cmdc202000185.pd

Transcriptional and Microenvironmental Landscape of Macrophage Transition in Cancer: A Boolean Analysis

The balance between pro- and anti-inflammatory immune system responses is crucial to face and counteract complex diseases such as cancer. Macrophages are an essential population that contributes to this balance in collusion with the local tumor microenvironment. Cancer cells evade the attack of macrophages by liberating cytokines and enhancing the transition to the M2 phenotype with pro-tumoral functions. Despite this pernicious effect on immune systems, the M1 phenotype still exists in the environment and can eliminate tumor cells by liberating cytokines that recruit and activate the cytotoxic actions of TH1 effector cells. Here, we used a Boolean modeling approach to understand how the tumor microenvironment shapes macrophage behavior to enhance pro-tumoral functions. Our network reconstruction integrates experimental data and public information that let us study the polarization from monocytes to M1, M2a, M2b, M2c, and M2d subphenotypes. To analyze the dynamics of our model, we modeled macrophage polarization in different conditions and perturbations. Notably, our study identified new hybrid cell populations, undescribed before. Based on the in vivo macrophage behavior, we explained the hybrid macrophages’ role in the tumor microenvironment. The in silico model allowed us to postulate transcriptional factors that maintain the balance between macrophages with anti- and pro-tumoral functions. In our pursuit to maintain the balance of macrophage phenotypes to eliminate malignant tumor cells, we emulated a theoretical genetically modified macrophage by modifying the activation of NFκB and a loss of function in HIF1-α and discussed their phenotype implications. Overall, our theoretical approach is as a guide to design new experiments for unraveling the principles of the dual host-protective or -harmful antagonistic roles of transitional macrophages in tumor immunoediting and cancer cell fate decisions

Discrepancies between the [O III] and [S III] temperatures in H II regions

Context. Analysis of published [O iii] and [S iii] temperatures measurements of emission line objects consisting of Hii galaxies, giant extragalactic Hii regions, Galactic Hii regions, and Hii regions from the Magellanic Clouds reveal that the [O iii] temperatures are higher than the corresponding values from [S iii] in most objects with gas metallicities in excess of 0.2 solar. For the coolest nebulae (the highest metallicities), the [O iii] temperature excess can reach ∼3000 K. Aims. We look for an explanation for these temperature differences and explore the parameter space of models with the aim of reproducing the observed trend of T O iii > T S iii in Hii regions with temperatures below 14 000 K. Methods. Using standard photoionization models, we varied the ionization parameter, the hardness of the ionizing continuum, and the gas metallicities in order to characterize how models behave with respect to the observations. We introduced temperature inhomogeneities and varied their mean squared amplitude t 2. We explored the possibility of inhomogeneities in abundances by combining two models of widely different metallicity. We calculated models that consider the possibility of a non-Maxwell-Boltzmann energy distribution (a κ-distribution) for the electron energies. We also considered shock heating within the photoionized nebula. Results. Simple photoionization calculations yield nearly equal [O iii] and [S iii] temperatures in the domain of interest. Hence these models fail to reproduce the [O iii] temperature excess. Models that consider temperature inhomogeneities, as measured by the mean squared amplitude t 2, also fail in the regime where T O iii < 14 000 K. Three options remain that can reproduce the observed excess in T O iii temperatures: (1) large metallicity inhomogeneities in the nebula; a (2) κ-distribution for the electron energies; and (3) shock waves that propagate in the photoionized plasma at velocities ∼60 km s -1. Conclusions. The observed nebular temperatures are not reproduced by varying the input parameters in the pure photoionization case nor by assuming local temperature inhomogeneities. We find that (1) metallicity inhomogeneities of the nebular gas; (2) shock waves of velocities 60 km s -1 propagating in a photoionized plasma; and (3) an electron energy distribution given by a κ-distribution are successful in reproducing the observed excess in the [O iii] temperatures. However, shock models require proper 3D hydrodynamical simulations to become a fully developed alternative while models with metallicity inhomogeneities appear to fail in metal-poor nebulae, since they result in T rec O++ T O iii T rec O++ ≳ TO iii.Facultad de Ciencias Astronómicas y Geofísica

Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase

Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we tested giardial arginine deiminase (GlADI) as a target against giardiasis. GlADI belongs to an essential pathway in Giardia for the synthesis of ATP, which is absent in humans. In silico docking with six thiol-reactive compounds was performed; four of which are approved drugs for humans. Recombinant GlADI was used in enzyme inhibition assays, and computational in silico predictions and spectroscopic studies were applied to follow the enzyme’s structural disturbance and identify possible effective drugs. Inhibition by modification of cysteines was corroborated using Ellman’s method. The efficacy of these drugs on parasite viability was assayed on Giardia trophozoites, along with the inhibition of the endogenous GlADI. The most potent drug against GlADI was assayed on Giardia encystment. The tested drugs inhibited the recombinant GlADI by modifying its cysteines and, potentially, by altering its 3D structure. Only rabeprazole and omeprazole decreased trophozoite survival by inhibiting endogenous GlADI, while rabeprazole also decreased the Giardia encystment rate. These findings demonstrate the potential of GlADI as a target against giardiasis

Construcción de medidor de potencia óptica de alta exactitud para fibras ópticas

En este trabajo se describe el diseño y la implementación de un medidor de potencia óptica – MPO – para uso en el área de fibras ópticas de telecomunicaciones. El dispositivo opera en el intervalo de longitud de onda de 950 nm a 1 650 nm usando un fotodiodo de arseniuro de indio-galio – InGaAs – y su respuesta en potencia fue linealizada de 0.07 mW a 0.70 mW. El ingreso de haz de luz se realiza por medio de fibra óptica de telecomunicaciones y la medición está basada en un fotodiodo estabilizado en temperatura, amplificador de transimpedancia, amplificación de tensión, conversión digital y comunicación inalámbrica de datos operada por microcontrolador. El prototipo descrito fue probado como referencia de medición de potencia acoplada a fibra en condiciones de laboratorio de metrología con incertidumbre de medición inferior a 2.2% para las longitudes de onda de 1 310 nm, 1 550 nm y 1 625 nm

Boolean modeling reveals that cyclic attractors in macrophage polarization serve as reservoirs of states to balance external perturbations from the tumor microenvironment

Cyclic attractors generated from Boolean models may explain the adaptability of a cell in response to a dynamical complex tumor microenvironment. In contrast to this idea, we postulate that cyclic attractors in certain cases could be a systemic mechanism to face the perturbations coming from the environment. To justify our conjecture, we present a dynamic analysis of a highly curated transcriptional regulatory network of macrophages constrained into a cancer microenvironment. We observed that when M1-associated transcription factors (STAT1 or NF-κB) are perturbed and the microenvironment balances to a hyper-inflammation condition, cycle attractors activate genes whose signals counteract this effect implicated in tissue damage. The same behavior happens when the M2-associated transcription factors are disturbed (STAT3 or STAT6); cycle attractors will prevent a hyper-regulation scenario implicated in providing a suitable environment for tumor growth. Therefore, here we propose that cyclic macrophage phenotypes can serve as a reservoir for balancing the phenotypes when a specific phenotype-based transcription factor is perturbed in the regulatory network of macrophages. We consider that cyclic attractors should not be simply ignored, but it is necessary to carefully evaluate their biological importance. In this work, we suggest one conjecture: the cyclic attractors can serve as a reservoir to balance the inflammatory/regulatory response of the network under external perturbations

Detection of the delayed condensation effect and determination of its impact on the accuracy of gas adsorption pore size distributions

Macroscopic, highly disordered, mesoporous materials present a continuing challenge for accurate pore structure characterization. The typical macroscopic variation in local average pore space descriptors means that methods capable of delivering statistically representative characterizations are required. Gas adsorption is a representative but indirect method, normally requiring assumptions about the correct model for data analysis. In this work we present a novel method to both expand the range, and obtain greater accuracy, for the information obtained from the main boundary adsorption isotherms by using a combination of data obtained for two adsorptives, namely nitrogen and argon, both before and after mercury porosimetry. The method makes use of the fact that nitrogen and argon apparently ‘see’ a different pore geometry following mercury entrapment, with argon, relatively, ‘ignoring’ new metal surfaces produced by mercury porosimetry. The new method permits the study of network and pore–pore co-operative effects during adsorption that substantially affect the accuracy of the characteristic parameters, such as modal pore size, obtained for disordered materials. These effects have been explicitly quantified, for a typical sol-gel silica catalyst support material as a case study. The technique allowed the large discrepancies between modal pore sizes obtained from standard gas adsorption and mercury thermoporometry methods to be attributed to the network-based delayed condensation effect, rather than spinodal adsorption. Once the network-based delayed condensation effect had been accounted for, the simple cylindrical pore model and macroscopic thermodynamic Kelvin-Cohan equation were then found sufficient to accurately describe adsorption in the material studied, rather than needing a more complex microscopic theory. Hence, for disordered mesoporous solids, a proper account of inter-pore interactions is more important than that of intra-pore adsorbate density distribution, to obtain accurate pore size distributions

Discrepancies between the [O III] and [S III] temperatures in H II regions

Context. Analysis of published [O iii] and [S iii] temperatures measurements of emission line objects consisting of Hii galaxies, giant extragalactic Hii regions, Galactic Hii regions, and Hii regions from the Magellanic Clouds reveal that the [O iii] temperatures are higher than the corresponding values from [S iii] in most objects with gas metallicities in excess of 0.2 solar. For the coolest nebulae (the highest metallicities), the [O iii] temperature excess can reach ∼3000 K. Aims. We look for an explanation for these temperature differences and explore the parameter space of models with the aim of reproducing the observed trend of T O iii > T S iii in Hii regions with temperatures below 14 000 K. Methods. Using standard photoionization models, we varied the ionization parameter, the hardness of the ionizing continuum, and the gas metallicities in order to characterize how models behave with respect to the observations. We introduced temperature inhomogeneities and varied their mean squared amplitude t 2. We explored the possibility of inhomogeneities in abundances by combining two models of widely different metallicity. We calculated models that consider the possibility of a non-Maxwell-Boltzmann energy distribution (a κ-distribution) for the electron energies. We also considered shock heating within the photoionized nebula. Results. Simple photoionization calculations yield nearly equal [O iii] and [S iii] temperatures in the domain of interest. Hence these models fail to reproduce the [O iii] temperature excess. Models that consider temperature inhomogeneities, as measured by the mean squared amplitude t 2, also fail in the regime where T O iii < 14 000 K. Three options remain that can reproduce the observed excess in T O iii temperatures: (1) large metallicity inhomogeneities in the nebula; a (2) κ-distribution for the electron energies; and (3) shock waves that propagate in the photoionized plasma at velocities ∼60 km s -1. Conclusions. The observed nebular temperatures are not reproduced by varying the input parameters in the pure photoionization case nor by assuming local temperature inhomogeneities. We find that (1) metallicity inhomogeneities of the nebular gas; (2) shock waves of velocities 60 km s -1 propagating in a photoionized plasma; and (3) an electron energy distribution given by a κ-distribution are successful in reproducing the observed excess in the [O iii] temperatures. However, shock models require proper 3D hydrodynamical simulations to become a fully developed alternative while models with metallicity inhomogeneities appear to fail in metal-poor nebulae, since they result in T rec O++ T O iii T rec O++ ≳ TO iii.Facultad de Ciencias Astronómicas y Geofísica