Tfeb-Mediated Transcriptional Regulation of Autophagy Induces Autosis during Ischemia/Reperfusion in the Heart

Autosis is a unique form of cell death with characteristic morphological and biochemical features caused by dysregulated autophagy. Autosis is observed in the heart during the late phase of ischemia/reperfusion (I/R), when marked accumulation of autophagosomes is induced. We previously showed that the excessive accumulation of autophagosomes promotes autosis in cardiomyocytes. Although the inhibition of autophagic flux via the upregulation of Rubicon induces the accumulation of autophagosomes during I/R, it appears that additional mechanisms exacerbating autophagosome accumulation are required for the induction of autosis. Here, we show that Tfeb contributes to the induction of autosis during the late phase of I/R in the heart. During myocardial reperfusion, Tfeb is activated and translocated into the nucleus, which in turn upregulates genes involved in autophagy and lysosomal function. The overexpression of Tfeb enhanced cardiomyocyte death induced by a high dose of TAT-Beclin 1, an effect that was inhibited by the downregulation of Atg7. Conversely, the knockdown of Tfeb attenuated high-dose TAT-Beclin1-induced death in cardiomyocytes. Although the downregulation of Tfeb in the heart significantly decreased the number of autophagic vacuoles and inhibited autosis during I/R, the activation of Tfeb activity via 3,4-dimethoxychalcone, an activator of Tfeb, aggravated myocardial injury during I/R. These findings suggest that Tfeb promotes cardiomyocyte autosis during the late phase of reperfusion in the heart.

EXPRESS: Can arrows change the subjective perception of space? Exploring symbolic attention repulsion

The attention repulsion effect (ARE) refers to distortions in the perception of space for areas nearby the focus of attention. For instance, when attending to the right-hand side of the visual field, objects in central vision may appear as though they are shifted to the left. The phenomenon is likely caused by changes in visual cell functioning. To date, research on the ARE has almost exclusively used exogenous manipulations of attention. In contrast, research exploring endogenous attention repulsion has been mixed, and no research has explored the effects of non-predictive arrow cues on this phenomenon. This gap in the literature is unexpected, as symbolic attention appears to be a unique form of attentional orienting compared to endogenous and exogenous attention. Therefore, the current study explored the effects of symbolic orienting on spatial repulsion and compared it to an exogenously generated ARE. Across four experiments, both exogenous and symbolic orienting resulted in AREs; however, the magnitude of the symbolic ARE was smaller than the exogenous ARE. This difference in magnitude persisted, even after testing both phenomena using stimulus timing parameters known to produce optimal effects in traditional attentional cueing paradigms. Therefore, compared to symbolic attention, it appears that exogenous manipulations may tightly constrict attention resources on the cued location, in turn potentially influencing the functioning of visual cells for enhanced perceptual processing.

Another look at the Landau gauge three-gluon vertex

We revisit the computation of the three-gluon vertex in the Landau gauge using lattice QCD simulations with large physical volumes of ~ (6.5 fm)4 and ~ (8 fm) 4 and large statistical ensembles. For the kinematical configuration analysed, that is described by a unique form factor, an evaluation of the lattice artefacts is also performed. Particular attention is given to the low energy behavior of vertex and its connection with evidence (or lack of it) of infrared ghost dominance.

Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction

Human pathogenic trypanosomatid parasites harbor a unique form of peroxisomes termed glycosomes that are essential for parasite viability. We and others previously identified and characterized the essential Trypanosoma brucei ortholog TbPEX3, which is the membrane-docking factor for the cytosolic receptor PEX19 bound to the glycosomal membrane proteins. Knockdown of TbPEX3 expression leads to mislocalization of glycosomal membrane and matrix proteins, and subsequent cell death. As an early step in glycosome biogenesis, the PEX3–PEX19 interaction is an attractive drug target. We established a high-throughput assay for TbPEX3–TbPEX19 interaction and screened a compound library for small-molecule inhibitors. Hits from the screen were further validated using an in vitro ELISA assay. We identified three compounds, which exhibit significant trypanocidal activity but show no apparent toxicity to human cells. Furthermore, we show that these compounds lead to mislocalization of glycosomal proteins, which is toxic to the trypanosomes. Moreover, NMR-based experiments indicate that the inhibitors bind to PEX3. The inhibitors interfering with glycosomal biogenesis by targeting the TbPEX3–TbPEX19 interaction serve as starting points for further optimization and anti-trypanosomal drug development.

Dynamic roles of social presence and individual differences in social TV platforms

These days, many individuals engage in a unique form of TV viewing that includes a simultaneous act of watching television content and talking about it with others in a mediated environment. This phenomenon is commonly referred to as social TV viewing. Responding to the popularity of this form of TV viewing behavior, the present study examines the individual differences of the social TV viewing experience, particularly with regard to different communication platforms (e.g. private vs. public). Based on the data collected from an online survey, primary findings indicate that extroverted and lonely individuals have different social TV viewing experiences such as preferences for a particular type of platforms for social TV viewing. Further, social presence plays an important role in the understanding of social TV enjoyment in private and public platforms.

Interpopulational variation in human brain size: implications for hominin cognitive phylogeny

Throughout the hominin lineage brain size is believed to have increased threefold – increase which, it is argued by some researchers, results in the enhanced brain power that distinguishes humans from any other living being. However, as we demonstrate in this article this supposed increase is the result of comparing the species mean of contemporary humans with other great apes and fossil hominins. This method obscures both interpopulational variation among modern humans, and the fact that the putative increases in the mean are the result of an increase in the upper limit in some populations, which has the result of obscuring the relative stasis in the lower limit over the last 600k years. For example, populations such as Aboriginal Australians have a range that is more different from Danes than it is from that of Asian H. erectus over the last 600ka. Yet Aboriginal Australians, whose unique anatomy seems to be related to the climatic conditions of Australia, possess all of the socio-cognitive traits characteristic of all other modern-day populations – yet they seemed not to have undergone increase in brain size to the degree that many other populations have. In this instance brain size seems to be unrelated to cognition. In this article we present a statistical analysis of interpopulational variation in contemporary humans and why such an analysis is crucial for our understanding of hominin cognitive, social and technological evolution. We also suggest how such variation may add to our understanding of hominin ontogeny or life history. Additionally, we develop a model based on humanity’s unique form of embodied social cognition that results from our upright bipedal posture and hand morphology. This model is then used to explain the results of our statistical analysis and the possible factors underpinning the human emergence.

Religious Disagreement Is Not Unique

Chapter 4 addresses the fact that in discussions of religious disagreement, some epistemologists have suggested that religious disagreement is distinctive. More specifically, they have argued that religious disagreement has certain features which make it possible for theists to resist conciliatory arguments that they must adjust their religious beliefs in response to finding that peers disagree with them. The chapter considers what its author takes to be the two most prominent features which are claimed to make religious disagreement distinct: religious evidence and evaluative standards in religious contexts. It argues that these two features fail to distinguish religious disagreement in the ways they have been taken to. However, it shows that the view that religious disagreement is not a unique form of disagreement makes religious disagreement less, rather than more, worrisome to the theist who would prefer to rationally remain steadfast in her religious beliefs.

Managing Prisons Through Extended Solitary Confinement: A Necessary Approach or a Signal of Prison System Failure?

In contemporary American corrections, extended solitary confinement (ESM) as a management tool has emerged as a strategy for avowedly controlling the most violent individuals and, in so doing, creating a safer prison system. We theorize that the emergence of this unique form of housing may also be viewed as a signal of prison system failure. To advance this argument, we identify how different theoretical perspectives can be used to anticipate the effects of ESM on prison system violence and order and then investigate the plausibility of this account by grounding it in analysis of qualitative data from a study of one state’s prison system. The analysis suggests theoretical and empirical warrant for both views of ESM—as an effective tool and as a symptom of system failure. Implications of the study research and policy are discussed.