Targeting the hypoxia pathway in malignant plasma cells by using 17-allylamino-17-demethoxygeldanamycin

Multiple myeloma (MM) is characterized as a clonal expansion of malignant plasma cells in the bone marrow, which is often associated with pancytopenia and osteolytic bone disease. Interestingly, myeloma-infiltrated bone marrow is considered to be hypoxic, providing selection pressure for a developing tumour. Since HSP90 was shown to participate in stabilization of the subunit of the key transcription factor HIF-1, which controls the hypoxic response, the aim of this study was to investigate the influence of a HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), on MM cells cultured under low oxygenation conditions. We confirmed that 17-AAG inhibits hypoxic induction of the HIF-1 target genes in malignant plasma cells and demonstrate the concentration range of severe hypoxia-specific cytotoxicity. Next, we selected the malignant plasma cells under severe hypoxia/re-oxygenation culture conditions in the presence or absence of 17-AAG and subsequently, the cells which survived were further expanded and analyzed. Interestingly, we have noticed significant changes in the survival and the response to anti-MM drugs between the parental cell lines and those selected in cyclic severe hypoxia in the presence and absence of 17-AAG. Importantly, we also observed that the lack of oxygen itself, irrespectively of HIF-1 inhibition, is the main/pivotal factor driving the selection process in the experiments presented here

LA JUSTICIA TRANSICIONAL EN COLOMBIA DESDE LOS ESTÁNDARES INTERNACIONALES DE PROTECCIÓN DE DERECHOS HUMANOS

The present scholarly-scientific work deals with the juridical-procedural and substantial tools that would allow us to overcome the current state of internal armed conflict, as well as the possible normative collision in the construction of a stable and lasting peace, with the objective of providing the bases necessary to resolve possible tensions between the national and international legal system in the framework of a process of transition that allows the realization of a peace agreement.The research method used is the logical deductive of study and documentary analysis of secondary sources, specifically legal norms, jurisprudence, national and foreign doctrine on the subjects. The results are the reflections on the elements provided by International Human Rights Law, International Humanitarian Law, experiences of the internal Colombian, foreign, and comparative order to ensure a stable and lasting peace under international and national law, without ignoring the rights of victims to truth, justice and reparation.La presente labor académico-científica versa sobre las herramientas jurídico-procesales y sustanciales que nos permitirían superar el estado de conflicto armado interno actual, así como la posible colisión normativa en la construcción de una paz estable y duradera, con el objetivo de brindar las bases necesarias para darle solución a las eventuales tensiones entre el ordenamiento jurídico nacional y el internacional en el marco de un proceso de transición que permita la materialización de un acuerdo de paz. El método de investigación utilizado es el lógico deductivo de estudio y análisis documental de fuentes secundarias, concretamente normas jurídicas, jurisprudencia, doctrina nacional y foránea sobre los temas. El resultado son las reflexiones sobre los elementos que brindan el Derecho Internacional de los Derechos Humanos, el Derecho Internacional Humanitario, las experiencias del orden colombiano interno, extranjeras, y el ordenamiento comparado, para asegurar una paz estable y duradera conforme al derecho internacional y nacional, sin desconocer los derechos de las víctimas a la verdad, la justicia y la reparación

Post-modernism's use and abuse of Nietzsche

I focus on Nietzsche's architectural metaphor of self-construction in arguing for the claim that postmodern readings of Nietzsche misunderstand his various attacks on dogmatic philosophy as paving the way for acceptance of a self characterized by fundamental disunity. Nietzsche's attack on essentialist dogmatic metaphysics is a call to engage in a purposive self-creation under a unifying will, a will that possesses the strength to reinterpret history as a pathway to "the problem that we are". Nietzsche agrees with the postmodernists that unity is not a pre-given, however he would disavow their rejection of unity as a goal. Where the postmodernists celebrate "the death of the subject" Nietzsche rejects this valorization of disunity as a form of Nihilism and prescribes the creation of a genuine unified subjectivity to those few capable of such a goal. Postmodernists are nearer Nietzsche's idea of the Last Man than his idea of the Overman.Articl

EFEITOS DO NÚMERO DE EXEMPLARES SOBRE AQUISIÇÃO E GENERALIDADE DE DESEMPENHO EM CRIANÇAS DIAGNOSTICADAS COM TRANSTORNO DO ESPECTRO DO AUTISMO (TEA)

Considering the importance of generality, one of the seven dimensions of Applied Behavior Analysis, the goal of the present study was to compare the acquisition and the generalization degree of tact and intraverbal repertoires when trained with single exemplar antecedent stimulus versus multiple-exemplar antecedent stimuli, with two children diagnosed with Autism Spectrum Disorder (ASD). The children’s parents were taught on how to implement these repertoires via Discrete Trial Teaching (DTT). The effect of the introduction of the intervention was evaluated by a non-concurrent multiple baseline design between participants. The effect of each experimental condition was evaluated by comparing data from “single exemplar” versus “multiple exemplar” conditions throughout training. Then, for a given repertoire (tact, for example), some relations were taught with multiple exemplars while others, with only one exemplar. On the generalization phase, performance accuracy in all discriminations was measured with new exemplars/antecedent stimuli. For Guto and Manuel it was necessary, on average, 25.5 and 15 trials, respectively, to teach the relations with three exemplars, and 17 and 22 trials to teach with one exemplar. During the generalization phase, the average accuracy in the relations with three exemplars was 83.5% and 100% for Guto and Manuel, respectively; with one exemplar, the averages were 74 and 61%. The data showed that the multiple-exemplar presentation during training of verbal repertoires resulted in higher generalization degree without increasing training difficulty. The present study encourages multiple-exemplar training in applied context.Keywords: generalization, multiple exemplars, verbal repertoires.Considerando a importância da generalidade, uma das sete dimensões da Análise do Comportamento Aplicada, o objetivo do presente estudo foi comparar a aquisição e o grau de generalização de repertórios verbais de tacto e intraverbais quando treinados com exemplar único de estímulo antecedente e com múltiplos exemplares de antecedentes, com duas crianças diagnosticadas com Transtorno do Espectro do Autismo (TEA). Os pais das crianças foram ensinados a implementar o ensino de tacto e intraverbal via tentativas discretas (DTT). O efeito da introdução da intervenção foi avaliado por meio do delineamento de linha de base múltipla não concorrente entre participantes. O efeito de cada uma das condições experimentais foi avaliado pela comparação intrassujeito de dados entre as condições “exemplar único” versus “múltiplos exemplares” ao longo do tratamento. Assim, para uma mesma habilidade (tacto, por exemplo), algumas relações foram ensinadas com múltiplos exemplares de estímulos e outras, com exemplar único. Na fase de generalização, foi aferida a precisão de desempenho para todas as relações com novos estímulos antecedentes/exemplares. Para Guto e Manuel foram necessárias, em média, 25,5 e 15 tentativas, respectivamente, para ensinar as relações com três exemplares, e 17 e 22 tentativas para ensinar com um exemplar. Durante a fase de generalização, a precisão média nas relações com três exemplares foi 83,5% e 100% para Guto e Manuel, respectivamente; com um exemplar, as médias foram 74 e 61%. Os dados mostram que a apresentação de múltiplos exemplares no treino de repertórios verbais proporcionou maior grau de generalização e não acarretou maior dificuldade de treino. Pelo presente estudo, encoraja-se o uso de múltiplos exemplares de estímulos em treino de repertório discriminativo em contexto aplicado.Palavras-chave: generalização, múltiplos exemplares, repertórios verbais

Information Asymmetries between Parents and Educators in German Childcare Institutions

Economic theory predicts market failure in the market for early childhood education and care (ECEC) due to information asymmetries. We empirically investigate information asymmetries between parents and ECEC professionals in Germany, making use of a unique extension of the German Socio-Economic Panel Study (SOEP). It allows us to compare quality perceptions by parents and pedagogic staff of 734 ECEC institutions which were attended by children in SOEP households. Parents and staff were asked to rate the same quality measures. We detect considerable information asymmetries between these groups which differ across quality measures but little by parental socio-economic background or center characteristics. Our findings imply that information is not readily available to parents, an issue that should be addressed by policy-makers

Inductive Theorem Proving by Program Specialisation: Generating proofs for

Abstract. In this paper we discuss the similarities between program specialisation and inductive theorem proving, and then show how program specialisation can be used to perform inductive theorem proving. We then study this relationship in more detail for a particular class of problems (verifying infinite state Petri nets) in order to establish a clear link between program specialisation and inductive theorem proving. In particular, we use the program specialiser ecce to generate specifications, hypotheses and proof scripts in the theory format of the proof assistant Isabelle. Then, in many cases, Isabelle can automatically execute these proof scripts and thereby verify the soundness of ecce’s verification process and of the correspondence between program specialisation and inductive theorem proving.

LA JUSTICIA TRANSICIONAL EN COLOMBIA DESDE LOS ESTÁNDARES INTERNACIONALES DE PROTECCIÓN DE DERECHOS HUMANOS

The present scholarly-scientific work deals with the juridical-procedural and substantial tools that would allow us to overcome the current state of internal armed conflict, as well as the possible normative collision in the construction of a stable and lasting peace, with the objective of providing the bases necessary to resolve possible tensions between the national and international legal system in the framework of a process of transition that allows the realization of a peace agreement.The research method used is the logical deductive of study and documentary analysis of secondary sources, specifically legal norms, jurisprudence, national and foreign doctrine on the subjects. The results are the reflections on the elements provided by International Human Rights Law, International Humanitarian Law, experiences of the internal Colombian, foreign, and comparative order to ensure a stable and lasting peace under international and national law, without ignoring the rights of victims to truth, justice and reparation.La presente labor académico-científica versa sobre las herramientas jurídico-procesales y sustanciales que nos permitirían superar el estado de conflicto armado interno actual, así como la posible colisión normativa en la construcción de una paz estable y duradera, con el objetivo de brindar las bases necesarias para darle solución a las eventuales tensiones entre el ordenamiento jurídico nacional y el internacional en el marco de un proceso de transición que permita la materialización de un acuerdo de paz. El método de investigación utilizado es el lógico deductivo de estudio y análisis documental de fuentes secundarias, concretamente normas jurídicas, jurisprudencia, doctrina nacional y foránea sobre los temas. El resultado son las reflexiones sobre los elementos que brindan el Derecho Internacional de los Derechos Humanos, el Derecho Internacional Humanitario, las experiencias del orden colombiano interno, extranjeras, y el ordenamiento comparado, para asegurar una paz estable y duradera conforme al derecho internacional y nacional, sin desconocer los derechos de las víctimas a la verdad, la justicia y la reparación