Mass spectrometry and n-in-one analytics in early drug discovery: Combinatorial chemistry libraries, lipophilicity and absorption screening

This thesis describes current and past n-in-one methods and presents three early experimental studies using mass spectrometry and the triple quadrupole instrument on the application of n-in-one in drug discovery. N-in-one strategy pools and mix samples in drug discovery prior to measurement or analysis. This allows the most promising compounds to be rapidly identified and then analysed. Nowadays properties of drugs are characterised earlier and in parallel with pharmacological efficacy. Studies presented here use in vitro methods as caco-2 cells and immobilized artificial membrane chromatography for drug absorption and lipophilicity measurements. The high sensitivity and selectivity of liquid chromatography mass spectrometry are especially important for new analytical methods using n-in-one. In the first study, the fragmentation patterns of ten nitrophenoxy benzoate compounds, serial homology, were characterised and the presence of the compounds was determined in a combinatorial library. The influence of one or two nitro substituents and the alkyl chain length of methyl to pentyl on collision-induced fragmentation was studied, and interesting structurefragmentation relationships were detected. Two nitro group compounds increased fragmentation compared to one nitro group, whereas less fragmentation was noted in molecules with a longer alkyl chain. The most abundant product ions were nitrophenoxy ions, which were also tested in the precursor ion screening of the combinatorial library. In the second study, the immobilized artificial membrane chromatographic method was transferred from ultraviolet detection to mass spectrometric analysis and a new method was developed. Mass spectra were scanned and the chromatographic retention of compounds was analysed using extract ion chromatograms. When changing detectors and buffers and including n-in-one in the method, the results showed good correlation. Finally, the results demonstrated that mass spectrometric detection with gradient elution can provide a rapid and convenient n-in-one method for ranking the lipophilic properties of several structurally diverse compounds simultaneously. In the final study, a new method was developed for caco-2 samples. Compounds were separated by liquid chromatography and quantified by selected reaction monitoring using mass spectrometry. This method was used for caco-2 samples, where absorption of ten chemically and physiologically different compounds was screened using both single and nin- one approaches. These three studies used mass spectrometry for compound identification, method transfer and quantitation in the area of mixture analysis. Different mass spectrometric scanning modes for the triple quadrupole instrument were used in each method. Early drug discovery with n-in-one is area where mass spectrometric analysis, its possibilities and proper use, is especially important.

Use and access to ICT in students of public secondary schools in Chihuahua City, Mexico: inclusion in teaching and digital literacy

This paper addresses the issue of the digital divide in students of public secondary schools at Chihuahua City, Mexico. It seeks to identify potential inequality of opportunities with regards to subjects’ access to information, knowledge and education through the ICT (internet, mobile telephony, broadband and television). The study takes three schools as investigative stage, using the survey as a data collection instrument, identifying patterns of behavior regarding: general knowledge of them, access to computer equipment and internet, and characterization of their use. Other aspects of analysis are the identification of the educational level of parents and access to technology resources available for academic and non-academic purposes in various application areas (home, school and social environment). The proposal concludes, that it is through the recollection of alternatives suggested by the teachers themselves to incorporate ICT for teaching purposes in a systematic and planned fashion, whose greatest reflection manifests in better digital literacy indicators.

[Le podium du marathon de Boston, 19/4/20, de gauche à droite, Peter] Trivoulidas, Arthur Roth [et Carl] Linder : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 59159

Fairview school photograph, ca. 1940

Fairview School was built in 1919 in Louth Township, Lincoln County, Ont. The school remained in operation until 1979 when it was purchased for a church, the Fairview-Louth Community church, which later became Southridge Community church. Currently, the building is occupied by the Niagara Korean Presbyterian Church.

A new approach to the classification of mammographic masses and normal breast tissue

A new approach to mammographic mass detection is presented in this paper. Although different algorithms have been proposed for such a task, most of them are application dependent. In contrast, our approach makes use of a kindred topic in computer vision adapted to our particular problem. In this sense, we translate the eigenfaces approach for face detection/classification problems to a mass detection. Two different databases were used to show the robustness of the approach. The first one consisted on a set of 160 regions of interest (RoIs) extracted from the MIAS database, being 40 of them with confirmed masses and the rest normal tissue. The second set of RoIs was extracted from the DDSM database, and contained 196 RoIs containing masses and 392 with normal, but suspicious regions. Initial results demonstrate the feasibility of using such approach with performances comparable to other algorithms, with the advantage of being a more general, simple and cost-effective approach

Análisis de la instrumentalización de las organizaciones internacionales por parte de los estados para construir su identidad de rol. Un estudio a partir de la experiencia de Francia entre 1940 y 1946 en el marco de los primeros años de la ONU

Analisis de la transformación de la identidad de rol francesa durante la segunda guerra mundial y la importancia de la fundación de la onu para la reconstrucción de dicha identidad.

Caracterización de un modelo de gestión del conocimiento aplicable a las funciones universitarias de investigación y extensión: caso Universidad CES

Existen en la actualidad múltiples modelos de gestión de conocimiento y medición del capital humano, los cuales son aplicados en las organizaciones, pero ninguno de éstos ha sido diseñado para Instituciones de Educación Superior. En este trabajo se hace un recuento de algunos de los modelos de gestión del conocimiento y capital intelectual más destacados como el Modelo de conversión del conocimiento de Nonaka y Takeuchi, el Modelo de GC de Arthur Andersen, el Cuadro de Mando Integral de Kaplan y Norton, entre otros, pero es a partir del Modelo Organizacional Estrella de Galbraith que se presenta una propuesta teórica para caracterizar un modelo de gestión del conocimiento aplicable a las funciones universitarias de investigación y extensión en la Universidad CES – Medellín, Colombia, a través de una investigación cualitativa en donde, a partir de la correlación entre la teoría general de la GC, particularmente de los modelos y el análisis de las características de la Universidad CES, así como la revisión sistemática, el grupo focal y el análisis documental se propone el Modelo Hexagonal de GC.

Las leyes unilaterales de preferencias comerciales adoptadas por Estados Unidos como medio de presión política para la creación y consolidación de un bloque regional

Conocer los condicionamientos incluidos a los compromisos adquiridos para la negociación del ALCA o del TLC y todo lo relacionado con las regulaciones OMC plus que implícitamente deben aprobar y cumplir los Estados perdiendo en casos potestad

Caracterización de la competencia entre dos organizaciones del sector de seguros en Colombia

En la permanente búsqueda de mejores condiciones que las organizaciones realizan con el propósito de dar respuesta a los cambios del entorno y la complejidad de la interacción con las organizaciones del mismo sector, se encuentra necesario identificar las características que les permiten a estas, sobrevivir, mantenerse en el mercado o crecer en él. En este orden de ideas, en este documento se desarrolla la caracterización de la forma como dos organizaciones importantes y líderes del sector asegurador en Colombia: Seguros Bolívar y Suramericana de Seguros, compiten, desde el punto de vista comercial, con el propósito de identificar como esto influye en cada organización. La investigación se centró en explicar a partir de los autores revisados y analizados con respecto al concepto de la competencia, en particular, la forma como se enfrenta la organización al entorno tanto interno como externo, la influencia de cada organización según su estructura, su importancia, la disponibilidad de los recursos necesarios para desarrollar sus actividades, el impacto y las implicaciones organizacionales a partir de la forma cómo se enfrenta el entorno. Para lo anterior y con base a la revisión conceptual, se realizó la recolección de datos y cifras tanto de las organizaciones como del sector al cual pertenecen, adicionalmente se realizaron entrevistas tanto estructuradas como semi estructuradas al área de ventas, debido a que es el área de las organizaciones encargada de generar estrategias de ventas, posicionar productos en el mercado, identificar el perfil del consumidor, conocer y comprender el mercado y la competencia. Lo anterior con el fin de caracterizar a las organizaciones analizadas, determinando cómo responden a la competencia y al entorno, para finalmente establecer cuáles son los comportamientos recurrentes, similares y diferentes entre ellas. Por lo tanto, los resultados obtenidos en la investigación permiten establecer si dos empresas con estructuras, tamaño y participación en el mercado similares compiten de igual forma y que implicación tiene esto en el comportamiento organizacional.

Target mass corrections revisited

We propose a new implementation of target mass corrections to nucleon structure functions which, unlike existing treatments, has the correct kinematic threshold behavior at finite Q(2) in the x -> 1 limit. We illustrate the differences between the new approach and existing prescriptions by considering specific examples for the F-2 and F-L structure functions, and discuss the broader implications of our results, which call into question the notion of universal parton distribution at finite Q(2).

Evidence for a new boson in the search for the Standard Model Higgs particle decaying to four leptons at CMS

One of the main targets of the CMS experiment is to search for the Standard Model Higgs boson. The 4-lepton channel (from the Higgs decay h->ZZ->4l, l = e,mu) is one of the most promising. The analysis is based on the identification of two opposite-sign, same-flavor lepton pairs: leptons are required to be isolated and to come from the same primary vertex. The Higgs would be statistically revealed by the presence of a resonance peak in the 4-lepton invariant mass distribution. The 4-lepton analysis at CMS is presented, spanning on its most important aspects: lepton identification, variables of isolation, impact parameter, kinematics, event selection, background control and statistical analysis of results. The search leads to an evidence for a signal presence with a statistical significance of more than four standard deviations. The excess of data, with respect to the background-only predictions, indicates the presence of a new boson, with a mass of about 126 GeV/c2 , decaying to two Z bosons, whose characteristics are compatible with the SM Higgs ones.

The construction of TRIGA-TRAP and direct high-precision Penning trap mass measurements on rare-earth elements and americium

Nuclear masses are an important quantity to study nuclear structure since they reflect the sum of all nucleonic interactions. Many experimental possibilities exist to precisely measure masses, out of which the Penning trap is the tool to reach the highest precision. Moreover, absolute mass measurements can be performed using carbon, the atomic-mass standard, as a reference. The new double-Penning trap mass spectrometer TRIGA-TRAP has been installed and commissioned within this thesis work, which is the very first experimental setup of this kind located at a nuclear reactor. New technical developments have been carried out such as a reliable non-resonant laser ablation ion source for the production of carbon cluster ions and are still continued, like a non-destructive ion detection technique for single-ion measurements. Neutron-rich fission products will be available by the reactor that are important for nuclear astrophysics, especially the r-process. Prior to the on-line coupling to the reactor, TRIGA-TRAP already performed off-line mass measurements on stable and long-lived isotopes and will continue this program. The main focus within this thesis was on certain rare-earth nuclides in the well-established region of deformation around N~90. Another field of interest are mass measurements on actinoids to test mass models and to provide direct links to the mass standard. Within this thesis, the mass of 241-Am could be measured directly for the first time.

Wild immunology: converging on the real world

Recently, the Centre for Immunity, Infection and Evolution sponsored a one-day symposium entitled "Wild Immunology." The CIIE is a new Wellcome Trust-funded initiative with the remit to connect evolutionary biology and ecology with research in immunology and infectious diseases in order to gain an interdisciplinary perspective on challenges to global health. The central question of the symposium was, "Why should we try to understand infection and immunity in wild systems?" Specifically, how does the immune response operate in the wild and how do multiple coinfections and commensalism affect immune responses and host health in these wild systems? The symposium brought together a broad program of speakers, ranging from laboratory immunologists to infectious disease ecologists, working on wild birds, unmanaged animals, wild and laboratory rodents, and on questions ranging from the dynamics of coinfection to how commensal bacteria affect the development of the immune system. The meeting on wild immunology, organized by Amy Pedersen, Simon Babayan, and Rick Maizels, was held at the University of Edinburgh on 30 June 2011.

Transforming growth factor-beta inhibits the expression of clock genes

Disturbances of sleep-wake rhythms are an important problem in Alzheimer's disease (AD). Circadian rhythms are regulated by clock genes. Transforming growth factor-beta (TGF-β) is overexpressed in neurons in AD and is the only cytokine that is increased in cerebrospinal fluid (CSF). Our data show that TGF-β2 inhibits the expression of the clock genes Period (Per)1, Per2, and Rev-erbα, and of the clock-controlled genes D-site albumin promoter binding protein (Dbp) and thyrotroph embryonic factor (Tef). However, our results showed that TGF-β2 did not alter the expression of brain and muscle Arnt-like protein-1 (Bmal1). The concentrations of TGF-β2 in the CSF of 2 of 16 AD patients and of 1 of 7 patients with mild cognitive impairment were in the dose range required to suppress the expression of clock genes. TGF-β2-induced dysregulation of clock genes may alter neuronal pathways, which may be causally related to abnormal sleep-wake rhythms in AD patients.

Cytokines and pregnancy in rheumatic disease

Cytokines are important mediators involved in the successful outcome of pregnancy. The concept of pregnancy as biased toward a Th2 immune response states that Th1 type cytokines are associated with pregnancy failure and that Th2 cytokines are protective and counteract pregnancy-related disorders. Studies at the level of the maternal-fetal interface, in the maternal circulation and in cells of peripheral blood have shown that the Th2 concept of pregnancy is an oversimplification. Both Th1 and Th2 type cytokines play a role at different stages of pregnancy and are adapted to the localization and function of cells and tissues. The changes of local and systemic cytokine patterns during pregnancy correspond to neuroendocrine changes with hormones as powerful modulators of cytokine expression. Several autoimmune disorders show a modulation of disease activity during and after pregnancy. In rheumatic diseases with a predominance of a Th1 immune response, a shift to a Th2 type immune response during pregnancy has been regarded as beneficial. Studies of pregnant patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have shown a cytokine expression similar to that found in healthy pregnant women. Significant differences were present only for a few cytokines and seemed related to the activity of the underlying disease. Interestingly, a gestational increase of cytokine inhibitors interleukin 1 receptor antagonist (IL-1ra) and soluble tumor necrosis factor receptor (sTNFR) in the circulation corresponded to low disease activity in RA. The influence of hormones and cytokines on autoimmune disease is an issue for further study.