Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.

Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy

The descriptive content of names as predicate modifiers

In this paper I argue that descriptive content associated with a proper name can serve as a truth-conditionally relevant adjunct and be an additional contribution of the name to the truth-conditions. Definite descriptions the so-and-so associated by speakers with a proper name can be used as qualifying prepositional phrases as so-and-so, so sentences containing a proper name NN is doing something could be understood as NN is doing something as NN (which means as so-and-so). Used as an adjunct, the descriptive content of a proper name expresses the additional circumstances of an action (a manner, reason, goal, time or purpose) and constitute a part of a predicate. I argue that qualifying prepositional phrases should be analyzed as predicate modifiers and propose a formal representation of modified predicates. The additional truth-conditional relevance of the descriptive content of a proper name helps to explain the phenomenon of the substitution failure of coreferential names in simple sentences

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

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

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field