A critical role of autophagy in antileukemia/lymphoma effects of APO866, an inhibitor of NAD biosynthesis.

APO866, an inhibitor of NAD biosynthesis, exhibits potent antitumor properties in various malignancies. Recently, it has been shown that APO866 induces apoptosis and autophagy in human hematological cancer cells, but the role of autophagy in APO866-induced cell death remains unclear. Here, we report studies on the molecular mechanisms underlying APO866-induced cell death with emphasis on autophagy. Treatment of leukemia and lymphoma cells with APO866 induced both autophagy, as evidenced by an increase in autophagosome formation and in SQSTM1/p62 degradation, but also increased caspase activation as revealed by CASP3/caspase 3 cleavage. As an underlying mechanism, APO866-mediated autophagy was found to deplete CAT/catalase, a reactive oxygen species (ROS) scavenger, thus promoting ROS production and cell death. Inhibition of autophagy by ATG5 or ATG7 silencing prevented CAT degradation, ROS production, caspase activation, and APO866-induced cell death. Finally, supplementation with exogenous CAT also abolished APO866 cytotoxic activity. Altogether, our results indicated that autophagy is essential for APO866 cytotoxic activity on cells from hematological malignancies and also indicate an autophagy-dependent CAT degradation, a novel mechanism for APO866-mediated cell killing. Autophagy-modulating approaches could be a new way to enhance the antitumor activity of APO866 and related agents

AE9, AP9 and SPM: New Models for Specifying the Trapped Energetic Particle and Space Plasma Environment

The radiation belts and plasma in the Earth’s magnetosphere pose hazards to satellite systems which restrict design and orbit options with a resultant impact on mission performance and cost. For decades the standard space environment specification used for spacecraft design has been provided by the NASA AE8 and AP8 trapped radiation belt models. There are well-known limitations on their performance, however, and the need for a new trapped radiation and plasma model has been recognized by the engineering community for some time. To address this challenge a new set of models, denoted AE9/AP9/SPM, for energetic electrons, energetic protons and space plasma has been developed. The new models offer significant improvements including more detailed spatial resolution and the quantification of uncertainty due to both space weather and instrument errors. Fundamental to the model design, construction and operation are a number of new data sets and a novel statistical approach which captures first order temporal and spatial correlations allowing for the Monte-Carlo estimation of flux thresholds for user-specified percentile levels (e.g., 50th and 95th) over the course of the mission. An overview of the model architecture, data reduction methods, statistics algorithms, user application and initial validation is presented in this paper.United States. Air Force (e contracts FA8718-05-C-0036, FA8718-10-C-001, FA8721-05-C-0002 and FA8802-09-C-0001)United States. National Aeronautics and Space Administration (grant NNG05GM22G

Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death.

Mitochondrial fusion and fission is a dynamic process critical for the maintenance of mitochondrial function and cell viability. During excitotoxicity neuronal mitochondria are fragmented, but the mechanism underlying this process is poorly understood. Here, we show that Mfn2 is the only member of the mitochondrial fusion/fission machinery whose expression is reduced in in vitro and in vivo models of excitotoxicity. Whereas in cortical primary cultures, Drp1 recruitment to mitochondria plays a primordial role in mitochondrial fragmentation in an early phase that can be reversed once the insult has ceased, Mfn2 downregulation intervenes in a delayed mitochondrial fragmentation phase that progresses even when the insult has ceased. Downregulation of Mfn2 causes mitochondrial dysfunction, altered calcium homeostasis, and enhanced Bax translocation to mitochondria, resulting in delayed neuronal death. We found that transcription factor MEF2 regulates basal Mfn2 expression in neurons and that excitotoxicity-dependent degradation of MEF2 causes Mfn2 downregulation. Thus, Mfn2 reduction is a late event in excitotoxicity and its targeting may help to reduce excitotoxic damage and increase the currently short therapeutic window in stroke

Plan de negocios para determinar la viabilidad econ?mica de una plataforma acad?mica digital que permita medir y reforzar el progreso escolar individual

Interesados en cambiar la realidad de la Educaci?n B?sica Regular del Per?, debido a que nuestro pa?s ocupa uno de los ultimos lugares en resultados de evaluaciones internacionales. Las instituciones Educativas se han visto en la necesidad de implementar o contratar servicios que le permitan contar con indicadores eficientes de progreso acad?mico, le permitan mejorar el aprendizaje estudiantil y por ende la calidad educativa. En ese sentido el presente trabajo tiene por objetivo evaluar la viabilidad econ?mica de una plataforma acad?mica digital que permita medir y reforzar el progreso escolar con indicadores basados en inteligencia artificial. La propuesta tiene como mercado objetivo los colegios particulares con pensiones superiores a los 300 soles mensuales y pertenecientes a los Niveles Socioecon?micos A y B de Lima provincia y el Nivel Socioecon?mico C de Lima moderna. Se estima que el proyecto requerir? una inversi?n inicial de 134,028 soles para el cual se ha considerado un financiado equivalente al 50% obteniendo como resultado dentro del an?lisis econ?mico un VAN de S/ 367,663 y una TIR de 39% para un horizonte de 5 a?os con lo que concluimos la viabilidad de nuestra propuesta de negocio. As? mismo considerando la incertidumbre generada por la pandemia se ha realizado an?lisis de escenarios adicionales los cuales validaron y robustecieron nuestra propuesta

Does Non-Moral Ignorance Exculpate? Situational Awareness and Attributions of Blame and Forgiveness

In this paper, we set out to test empirically an idea that many philosophers find intuitive, namely that non-moral ignorance can exculpate. Many philosophers find it intuitive that moral agents are responsible only if they know the particular facts surrounding their action. Our results show that whether moral agents are aware of the facts surrounding their action does have an effect on people’s attributions of blame, regardless of the consequences or side effects of the agent’s actions. In general, it was more likely that a situationally aware agent will be blamed for failing to perform the obligatory action than a situationally unaware agent. We also tested attributions of forgiveness in addition to attributions of blame. In general, it was less likely that a situationally aware agent will be forgiven for failing to perform the obligatory action than a situationally unaware agent. When the agent is situationally unaware, it is more likely that the agent will be forgiven than blamed. We argue that these results provide some empirical support for the hypothesis that there is something intuitive about the idea that non-moral ignorance can exculpate

Spontaneous Voice Gender Imitation Abilities in Adult Speakers

Background The frequency components of the human voice play a major role in signalling the gender of the speaker. A voice imitation study was conducted to investigate individuals' ability to make behavioural adjustments to fundamental frequency (F0), and formants (Fi) in order to manipulate their expression of voice gender. Methodology/Principal Findings Thirty-two native British-English adult speakers were asked to read out loud different types of text (words, sentence, passage) using their normal voice and then while sounding as ‘masculine’ and ‘feminine’ as possible. Overall, the results show that both men and women raised their F0 and Fi when feminising their voice, and lowered their F0 and Fi when masculinising their voice. Conclusions/Significance These observations suggest that adult speakers are capable of spontaneous glottal and vocal tract length adjustments to express masculinity and femininity in their voice. These results point to a “gender code”, where speakers make a conventionalized use of the existing sex dimorphism to vary the expression of their gender and gender-related attributes

The JNK Inhibitor XG-102 Protects against TNBS-Induced Colitis

The c-Jun N-terminal kinase (JNK)-inhibiting peptide D-JNKI-1, syn. XG-102 was tested for its therapeutic potential in acute inflammatory bowel disease (IBD) in mice. Rectal instillation of the chemical irritant trinitrobenzene sulfonic acid (TNBS) provoked a dramatic acute inflammation in the colon of 7–9 weeks old mice. Coincident subcutaneous application of 100 µg/kg XG-102 significantly reduced the loss of body weight, rectal bleeding and diarrhoea. After 72 h, the end of the study, the colon was removed and immuno-histochemically analysed. XG-102 significantly reduced (i) pathological changes such as ulceration or crypt deformation, (ii) immune cell pathology such as infiltration and presence of CD3- and CD68-positive cells, (iii) the production of tumor necrosis factor (TNF)-α in colon tissue cultures from TNBS-treated mice, (iv) expression of Bim, Bax, FasL, p53, and activation of caspase 3, (v) complexation of JNK2 and Bim, and (vi) expression and activation of the JNK substrate and transcription factor c-Jun. A single application of subcutaneous XG-102 was at least as effective or even better depending on the outcome parameter as the daily oral application of sulfasalazine used for treatment of IBD