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

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

Finite Minds and Open Minds

One of the most persistent complaints about Peter Klein’s infinitism involves the finite mind objection: given that we are finite, how can we ever handle an infinite series of reasons? Klein’s answer has been that we need not actually produce an infinite series; it is enough that such a series be available to us. In this paper a different reply is presented through the reconstruction of epistemic justification as a trade-off. In acting as responsible agents, we are striking a balance between the number of reasons that we can handle and the level of precision that we want our beliefs to have. If we are unable or unwilling to manage a large number of reasons, then we have to pay the price in terms of justificatory inexactitude and thereby of accepting relatively untrustworthy beliefs. As well as being intuitively attractive, this idea of a trade-off is warranted by the mathematics of epistemic justification, understood as involving probabilistic relations

Free Will & Empirical Arguments for Epiphenomenalism

While philosophers have worried about mental causation for centuries, worries about the causal relevance of conscious phenomena are also increasingly featuring in neuroscientific literature. Neuroscientists have regarded the threat of epiphenomenalism as interesting primarily because they have supposed that it entails free will scepticism. However, the steps that get us from a premise about the causal irrelevance of conscious phenomena to a conclusion about free will are not entirely clear. In fact, if we examine popular philosophical accounts of free will, we find, for the most part, nothing to suggest that free will is inconsistent with the presence of unconscious neural precursors to choices. It is only if we adopt highly non-naturalistic assumptions about the mind (e.g. if we embrace Cartesian dualism and locate free choice in the non-physical realm) that it seems plausible to suppose that the neuroscientific data generates a threat to free will

Benign Infinity

According to infinitism, all justification comes from an infinite series of reasons. Peter Klein defends infinitism as the correct solution to the regress problem by rejecting two alternative solutions: foundationalism and coherentism. I focus on Klein's argument against foundationalism, which relies on the premise that there is no justification without meta-justification. This premise is incompatible with dogmatic foundationalism as defended by Michael Huemer and Time Pryor. It does not, however, conflict with non-dogmatic foundationalism. Whereas dogmatic foundationalism rejects the need for any form of meta-justification, non-dogmatic foundationalism merely rejects Laurence BonJour's claim that meta-justification must come from beliefs. Unlike its dogmatic counterpart, non-dogmatic foundationalism can allow for basic beliefs to receive meta-justification from non-doxastic sources such as experiences and memories. Construed thus, non-dogmatic foundationalism is compatible with Klein's principle that there is no justification without meta-justification. I conclude that Klein's rejection of foundationalism. fails. Nevertheless, I agree with Klein that when in response to a skeptical challenge we engage in the activity of defending our beliefs, the number of reasons we can give is at least in principle infinite. I argue that this type of infinity is benign because, when we continue to give reasons, we will eventually merely repeat previously stated reasons. Consequently, I reject Klein's claim that the more reasons we give the more we increase the justification of our beliefs

Alternatives and responsibility: an asymmetrical approach

En este trabajo defiendo una visión asimétrica sobre la relación entre las posibilidades alternativas y la responsabilidad moral, según la cual se requiere tener posibilidades alternativas para ser culpable por lo que uno decide o hace, pero no para ser laudable por ello. Defiendo la no necesidad de alternativas para ser laudable a través de un examen de lo que yo llamo “ejemplos Lutero”. Mi defensa de la necesidad de alternativas para ser culpable procede en cambio mediante un análisis de los llamados “casos Frankfurt”. En ambos casos, mis argumentos se basan en la afirmación según la cual, en las adscripciones de responsabilidad moral, la cuestión principal no es si el agente podría haber hecho algo distinto, sino si debería haber hecho lo que hizo, de modo que la primera pregunta solo se vuelve apremiante cuando la respuesta a la segunda es negativa. Así, pues, en lo que se refiere a la responsabilidad moral, el concepto de obligación o deber moral es previo al de posibilidades alternativas.In this paper, I defend an asymmetrical view concerning the relationship between alternative possibilities and moral responsibility, according to which alternative possibilities are required for being blameworthy, but not praiseworthy, for what one decides or does. I defend the non-necessity of alternatives for praiseworthiness through an examination of what I call ‘Luther’ examples. My defence of the necessity of alternatives for blameworthiness proceeds instead through an analysis of so-called ‘Frankfurt’ examples. In both cases, my arguments rest on the contention that, in ascriptions of moral responsibility, the primary question is not whether the agent could have done otherwise, but whether she should have done what she did, so that the former question only becomes pressing when the answer to the latter is negative. Concerning moral responsibility, then, the concept of moral obligation or duty is prior to that of alternative possibilities

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

Single-Step Production of a Recyclable Nanobiocatalyst for Organophosphate Pesticides Biodegradation Using Functionalized Bacterial Magnetosomes

Enzymes are versatile catalysts in laboratories and on an industrial scale; improving their immobilization would be beneficial to broadening their applicability and ensuring their (re)use. Lipid-coated nano-magnets produced by magnetotactic bacteria are suitable for a universally applicable single-step method of enzyme immobilization. By genetically functionalizing the membrane surrounding these magnetite particles with a phosphohydrolase, we engineered an easy-to-purify, robust and recyclable biocatalyst to degrade ethyl-paraoxon, a commonly used pesticide. For this, we genetically fused the opd gene from Flavobacterium sp. ATCC 27551 encoding a paraoxonase to mamC, an abundant protein of the magnetosome membrane in Magnetospirillum magneticum AMB-1. The MamC protein acts as an anchor for the paraoxonase to the magnetosome surface, thus producing magnetic nanoparticles displaying phosphohydrolase activity. Magnetosomes functionalized with Opd were easily recovered from genetically modified AMB-1 cells: after cellular disruption with a French press, the magnetic nanoparticles are purified using a commercially available magnetic separation system. The catalytic properties of the immobilized Opd were measured on ethyl-paraoxon hydrolysis: they are comparable with the purified enzyme, with Km (and kcat) values of 58 µM (and 178 s−1) and 43 µM (and 314 s−1) for the immobilized and purified enzyme respectively. The Opd, a metalloenzyme requiring a zinc cofactor, is thus properly matured in AMB-1. The recycling of the functionalized magnetosomes was investigated and their catalytic activity proved to be stable over repeated use for pesticide degradation. In this study, we demonstrate the easy production of functionalized magnetic nanoparticles with suitably genetically modified magnetotactic bacteria that are efficient as a reusable nanobiocatalyst for pesticides bioremediation in contaminated effluents