Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia.

Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material.The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders

Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes.

Strong epidemiologic evidence suggests an association between Alzheimer disease (AD) and type 2 diabetes. To determine if amyloid beta (Abeta) and hyperphosphorylated tau occurs in type 2 diabetes, pancreas tissues from 21 autopsy cases (10 type 2 diabetes and 11 controls) were analyzed. APP and tau mRNAs were identified in human pancreas and in cultured insulinoma beta cells (INS-1) by RT-PCR. Prominent APP and tau bands were detected by Western blotting in pancreatic extracts. Aggregated Abeta, hyperphosphorylated tau, ubiquitin, apolipoprotein E, apolipoprotein(a), IB1/JIP-1 and JNK1 were detected in Langerhans islets in type 2 diabetic patients. Abeta was co-localized with amylin in islet amyloid deposits. In situ beta sheet formation of islet amyloid deposits was shown by infrared microspectroscopy (SIRMS). LPS increased APP in non-neuronal cells as well. We conclude that Abeta deposits and hyperphosphorylated tau are also associated with type 2 diabetes, highlighting common pathogenetic features in neurodegenerative disorders, including AD and type 2 diabetes and suggesting that Abeta deposits and hyperphosphorylated tau may also occur in other organs than the brain

A Theory of Cheap Control in Embodied Systems

We present a framework for designing cheap control architectures for embodied agents. Our derivation is guided by the classical problem of universal approximation, whereby we explore the possibility of exploiting the agent's embodiment for a new and more efficient universal approximation of behaviors generated by sensorimotor control. This embodied universal approximation is compared with the classical non-embodied universal approximation. To exemplify our approach, we present a detailed quantitative case study for policy models defined in terms of conditional restricted Boltzmann machines. In contrast to non-embodied universal approximation, which requires an exponential number of parameters, in the embodied setting we are able to generate all possible behaviors with a drastically smaller model, thus obtaining cheap universal approximation. We test and corroborate the theory experimentally with a six-legged walking machine. The experiments show that the sufficient controller complexity predicted by our theory is tight, which means that the theory has direct practical implications. Keywords: cheap design, embodiment, sensorimotor loop, universal approximation, conditional restricted Boltzmann machineComment: 27 pages, 10 figure

IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson's disease

To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we investigate the function of IFN-γ and TNF-α in experimental models of Parkinson's disease and analyze their relation with local glial cell activation. It was found that IFN-γ and TNF-α remained higher over the years in the serum and CNS of chronic Parkinsonian macaques than in untreated animals, accompanied by sustained glial activation (microglia and astroglia) in the substantia nigra pars compacta. Importantly, Parkinsonian monkeys showed persistent and increasing levels of IFN-γR signaling in both microglial and astroglial cells. In addition, experiments performed in IFN-γ and TNF-α KO mice treated with MPTP revealed that, even before dopaminergic cell death can be observed, the presence of IFN-γ and TNF-α is crucial for microglial and astroglial activation, and, together, they have an important synergistic role. Both cytokines were necessary for the full level of activation to be attained in both microglial and astroglial cells. These results demonstrate that IFN-γ signaling, together with the contribution of TNF-α, have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism

Moving Stories: Agency, Emotion and Practical Rationality

What is it to be an agent? One influential line of thought, endorsed by G. E. M. Anscombe and David Velleman, among others, holds that agency depends on practical rationality—the ability to act for reasons, rather than being merely moved by causes. Over the past 25 years, Velleman has argued compellingly for a distinctive view of agency and the practical rationality with which he associates it. On Velleman’s conception, being an agent consists in having the capacity to be motivated by a drive to act for reasons. Your bodily movements qualify as genuine actions insofar as they are motivated in part by your desire to behave in a way that makes sense to yourself. However, there are at least two distinct ways of spelling out what this drive towards self-intelligibility consists in, both present in Velleman’s work. It might consist in a drive towards intelligibility in causal-psychological terms: roughly, a drive to maximize the rational coherence of your psychological states. Alternatively, it might consist in a drive towards narrative intelligibility: a drive to make your ongoing activity conform to a recognizable narrative structure, where that structure is understood emotionally. Velleman originally saw these options as basically equivalent, but later came to prioritize the drive towards causal-psychological intelligibility over that towards narrative intelligibility. I argue that this gets things the wrong way round—we should instead understand our capacities to render ourselves intelligible in causal-psychological terms as built upon a bedrock of emotionally suffused narrative understanding. In doing so, we resolve several problems for Velleman’s view, and pave the way for an embodied, embedded and affective account of practical rationality and agency. According to the picture that emerges, practical rationality is essential to agency, narrative understanding is essential to practical rationality, and the rhythms and structures patterning the ebb and flow of our emotional lives are essential to narrative understanding

Philosophy of Hope

The philosophy of hope centers on two interlocking sets of questions. The first concerns the nature of hope. Specific questions here include how to analyze hope, how hope motivates us, and whether there is only one type of hope. The second set concerns the value of hope. Key questions here include whether and when it is good to hope and whether there is a virtue of hope. Philosophers of hope tend to proceed from the first set of questions to the second. This is a natural approach, for one might expect that you must develop a basic understanding of what hope is before you can determine its value. The structure of this chapter thus follows this approach. But readers should not be misled: there is in fact a good deal of feedback between the two sets of questions. A theory of hope is more plausible to the extent that it fits well with plausible ideas about the value of hope. So the movement from hope’s nature to its value is one of emphasis rather than a strict, step-wise process

A Cost-Effectiveness Analysis of “Test” versus “Treat” Patients Hospitalized with Suspected Influenza in Hong Kong

BACKGROUND: Seasonal and 2009 H1N1 influenza viruses may cause severe diseases and result in excess hospitalization and mortality in the older and younger adults, respectively. Early antiviral treatment may improve clinical outcomes. We examined potential outcomes and costs of test-guided versus empirical treatment in patients hospitalized for suspected influenza in Hong Kong. METHODS: We designed a decision tree to simulate potential outcomes of four management strategies in adults hospitalized for severe respiratory infection suspected of influenza: "immunofluorescence-assay" (IFA) or "polymerase-chain-reaction" (PCR)-guided oseltamivir treatment, "empirical treatment plus PCR" and "empirical treatment alone". Model inputs were derived from literature. The average prevalence (11%) of influenza in 2010-2011 (58% being 2009 H1N1) among cases of respiratory infections was used in the base-case analysis. Primary outcome simulated was cost per quality-adjusted life-year (QALY) expected (ICER) from the Hong Kong healthcare providers' perspective. RESULTS: In base-case analysis, "empirical treatment alone" was shown to be the most cost-effective strategy and dominated the other three options. Sensitivity analyses showed that "PCR-guided treatment" would dominate "empirical treatment alone" when the daily cost of oseltamivir exceeded USD18, or when influenza prevalence was <2.5% and the predominant circulating viruses were not 2009 H1N1. Using USD50,000 as the threshold of willingness-to-pay, "empirical treatment alone" and "PCR-guided treatment" were cost-effective 97% and 3% of time, respectively, in 10,000 Monte-Carlo simulations. CONCLUSIONS: During influenza epidemics, empirical antiviral treatment appears to be a cost-effective strategy in managing patients hospitalized with severe respiratory infection suspected of influenza, from the perspective of healthcare providers in Hong Kong