Methods for the efficient measurement of phased mission system reliability and component importance

An increasing number of systems operate over a number of consecutive time periods, in which their reliability structure and the consequences of failure differ, in order to perform some overall operation. Each distinct time period is known as a phase and the overall operation is known as a phased mission. Generally, a phased mission fails immediately if the system fails at any point and is considered a success only if all phases are completed without failure. The work presented in this thesis provides efficient methods for the prediction and optimisation of phased mission reliability. A number of techniques and methods for the analysis of phased mission reliability have been previously developed. Due to the component and system failure time dependencies introduced by the phases, the computational expense of these methods is high and this limits the size of the systems that can be analysed in reasonable time frames on modern computers. Two importance measures, which provide an index of the influence of each component on the system reliability, have also been previously developed. This is useful for the optimisation of the reliability of a phased mission, however a much larger number have been developed for non-phased missions and the different perspectives and functions they provide are advantageous. This thesis introduces new methods as well as improvements and extensions to existing methods for the analysis of both non-repairable and repairable systems with an emphasis on improved efficiency in the derivation of phase and mission reliability. New importance measures for phased missions are also presented, including interpretations of those currently available for non-phased missions. These provide a number of interpretations of component importance, allowing those most suitable in a given context to be employed and thus aiding in the optimisation of mission reliability. In addition, an extensive computer code has been produced that implements and tests the majority of the newly developed techniques and methods.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Preassociative aggregation functions

The classical property of associativity is very often considered in aggregation function theory and fuzzy logic. In this paper we provide axiomatizations of various classes of preassociative functions, where preassociativity is a generalization of associativity recently introduced by the authors. These axiomatizations are based on existing characterizations of some noteworthy classes of associative operations, such as the class of Acz\'elian semigroups and the class of t-norms.Comment: arXiv admin note: text overlap with arXiv:1309.730

A vision about lifelong learning and its barriers

Around 25 years ago, some researchers argued for moving towards innovative learning models characterized by being more personalized and where the students would have a more active role in deciding what to learn, when to learn and how to learn. Nowadays, there is a need for a flexible, efficient, universal and lifelong education. Lifelong learning is fully integrated into our society and, from the student point of view, it is very different from regular learning. Among these differences there is the maturity of students, the fact that the domains of interest are much broader, the way how learning occurs at different depths, the fact that the topics to study may be related both to work, family and leisure, and that students have little availability due to their necessity to conciliate home, work, leisure and learning. Lifelong learning requires personalized models that adapt to students'' needs and constraints, but lifelong learners keep suffering from models that are neither adapted to their necessities, nor to the needs of society. This paper reflects on the actual situation of lifelong learning, analyses some of the relevant literature and discusses the challenges to conceptualize, from a transdisciplinary point of view, innovative e-learning models that promote self-determination of students

Polyphosphate degradation by Nudt3-Zn²⁺ mediates oxidative stress response

Polyphosphate (polyP) is a polymer of hundreds of phosphate residues present in all organisms. In mammals, polyP is involved in crucial physiological processes, including coagulation, inflammation, and stress response. However, after decades of research, the metabolic enzymes are still unknown. Here, we purify and identify Nudt3, a NUDIX family member, as the enzyme responsible for polyP phosphatase activity in mammalian cells. We show that Nudt3 shifts its substrate specificity depending on the cation; specifically, Nudt3 is active on polyP when Zn2+ is present. Nudt3 has in vivo polyP phosphatase activity in human cells, and importantly, we show that cells with altered polyP levels by modifying Nudt3 protein amount present reduced viability upon oxidative stress and increased DNA damage, suggesting that polyP and Nudt3 play a role in oxidative stress protection. Finally, we show that Nudt3 is involved in the early stages of embryo development in zebrafish

Pharmacokinetic and exposure-response analysis of pertuzumab in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer

Purpose: To characterize the pharmacokinetics (PK) of pertuzumab and trastuzumab in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer in the randomized, double-blind, phase III JACOB study (NCT01774786), and to evaluate the appropriateness of the pertuzumab regimen in these patients. Methods: Patients received 840 mg intravenous pertuzumab or placebo plus trastuzumab q3w and chemotherapy. Pertuzumab and trastuzumab were administered until disease progression or unacceptable toxicity. Chemotherapy was administered for up to six cycles or disease progression or unacceptable toxicity. Serum concentrations of pertuzumab and trastuzumab were measured. Pertuzumab PK was characterized across treatment cycles. The impact of anti-drug antibodies (ADAs) on pertuzumab PK and the impact of pertuzumab on trastuzumab PK were assessed. An exploratory exposure-efficacy analysis was also conducted. Results: In total, 374 patients in the pertuzumab arm had evaluable PK data. The mean observed pertuzumab steady-state serum trough (minimum) concentration (C) ± standard deviation was 114 ± 51.8 μg/mL. The target pertuzumab C of ≥ 20 μg/mL was reached in 99.3% of patients at Cycle 5 (steady state) and beyond. Greater than 90% of patients were above the PK target right after the first pertuzumab dose. There was no apparent impact of ADAs on pertuzumab PK nor of pertuzumab on trastuzumab PK. There were no differences in overall survival across Cycle 1 pertuzumab (C) or Cycle 5 pertuzumab (C) exposure quartiles. Conclusions: Pertuzumab exposure in JACOB was consistent with prior studies in advanced gastric cancer and breast cancer. The 840 mg q3w dose allowed the majority of patients in JACOB to achieve target pertuzumab concentrations and appears to be an appropriate dose selectio

Wnt9a deficiency discloses a repressive role of Tcf7l2 on endocrine differentiation in the embryonic pancreas

Transcriptional and signaling networks establish complex cross-regulatory interactions that drive cellular differentiation during development. Using microarrays we identified the gene encoding the ligand Wnt9a as a candidate target of Neurogenin3, a basic helix-loop-helix transcription factor that functions as a master regulator of pancreatic endocrine differentiation. Here we show that Wnt9a is expressed in the embryonic pancreas and that its deficiency enhances activation of the endocrine transcriptional program and increases the number of endocrine cells at birth. We identify the gene encoding the endocrine transcription factor Nkx2-2 as one of the most upregulated genes in Wnt9a-ablated pancreases and associate its activation to reduced expression of the Wnt effector Tcf7l2. Accordingly, in vitro studies confirm that Tcf7l2 represses activation of Nkx2-2 by Neurogenin3 and inhibits Nkx2-2 expression in differentiated β-cells. Further, we report that Tcf7l2 protein levels decline upon initiation of endocrine differentiation in vivo, disclosing the downregulation of this factor in the developing endocrine compartment. These findings highlight the notion that modulation of signalling cues by lineage-promoting factors is pivotal for controlling differentiation programs

Gestión de la investigación en la Universidad Nacional de Cuyo (1949-2010)

La Universidad Nacional de Cuyo, desde su origen, consideró a la investigación como una de sus funciones básicas. En tal sentido este libro surge como una propuesta para sistematizar, preservar y difundir información institucional, relacionada a la gestión del área específica. La Secretaría de Ciencia, Técnica y Posgrado de esta Casa de Estudios, a fines de 2009, invitó a participar de la iniciativa a quienes fueron responsables de esta tarea y a investigadores interesados en la historia de la institución, los que aportaron información y el valor de su experiencia. En el desarrollo de la obra se puede verificar claramente la evolución de estructuras y la definición de políticas científicas desarrolladas en la UNCuyo, ligadas a momentos históricos, políticas nacionales, locales e institucionales. Del relato de cada autor se observa que: planificación, mecanismos y estrategias de promoción de la investigación manifiestan una continuidad de esfuerzos cuyo objeto es incentivar la producción del conocimiento y su transferencia a las aulas y al medio. De la compiladora de la obra: Patricia Pons, Licenciada en Ciencias De la Educación de la Pontificia Universidad Católica Argentina Santa María de los Buenos Aires; se encuentra en la etapa de finalización de sus estudios de Maestría en Gestión de la Ciencia, la Técnica y la Innovación de la Universidad Nacional de General Sarmiento; Directora General de Ciencia y Técnica de la Secretaría de Ciencia Técnica y Posgrado de la Universidad Nacional de Cuyo