Measures and Limits of Models of Fixation Selection

Models of fixation selection are a central tool in the quest to understand how the human mind selects relevant information. Using this tool in the evaluation of competing claims often requires comparing different models' relative performance in predicting eye movements. However, studies use a wide variety of performance measures with markedly different properties, which makes a comparison difficult. We make three main contributions to this line of research: First we argue for a set of desirable properties, review commonly used measures, and conclude that no single measure unites all desirable properties. However the area under the ROC curve (a classification measure) and the KL-divergence (a distance measure of probability distributions) combine many desirable properties and allow a meaningful comparison of critical model performance. We give an analytical proof of the linearity of the ROC measure with respect to averaging over subjects and demonstrate an appropriate correction of entropy-based measures like KL-divergence for small sample sizes in the context of eye-tracking data. Second, we provide a lower bound and an upper bound of these measures, based on image-independent properties of fixation data and between subject consistency respectively. Based on these bounds it is possible to give a reference frame to judge the predictive power of a model of fixation selection . We provide open-source python code to compute the reference frame. Third, we show that the upper, between subject consistency bound holds only for models that predict averages of subject populations. Departing from this we show that incorporating subject-specific viewing behavior can generate predictions which surpass that upper bound. Taken together, these findings lay out the required information that allow a well-founded judgment of the quality of any model of fixation selection and should therefore be reported when a new model is introduced

Vitamin C:from nutrition to oxygen sensing and epigenetics

Abstract Vitamin C is unbeatable — at least when it comes to sales. Of all the vitamin preparations, those containing vitamin C sell best. This is surprising because vitamin C deficiency is extremely rare. Nevertheless, there is still controversy about whether the additional intake of vitamin C supplements is essential for our health. In this context, the possible additional benefit is in most cases merely reduced to the known effect as an antioxidant. However, new findings in recent years on the mechanisms of oxygen-sensing and epigenetic control underpin the multifaceted role of vitamin C in a biological context and have therefore renewed interest in it. In the present article, therefore, known facts are linked to these new key data. In addition, available clinical data on vitamin C use of cancer therapy are summarized

Metabolic zonation of the liver:the oxygen gradient revisited

Abstract The liver has a multitude of functions which are necessary to maintain whole body homeostasis. This requires that various metabolic pathways can run in parallel in the most efficient manner and that futile cycles are kept to a minimum. To a large extent this is achieved due to a functional specialization of the liver parenchyma known as metabolic zonation which is often lost in liver diseases. Although this phenomenon is known for about 40 years, the underlying regulatory pathways are not yet fully elucidated. The physiologically occurring oxygen gradient was considered to be crucial for the appearance of zonation; however, a number of reports during the last decade indicating that β-catenin signaling, and the hedgehog (Hh) pathway contribute to metabolic zonation may have shifted this view. In the current review we connect these new observations with the concept that the oxygen gradient within the liver acinus is a regulator of zonation. This is underlined by a number of facts showing that the β-catenin and the Hh pathway can be modulated by the hypoxia signaling system and the hypoxia-inducible transcription factors (HIFs). Altogether, we provide a view by which the dynamic interplay between all these pathways can drive liver zonation and thus contribute to its physiological function

Liver zonation in health and disease:hypoxia and hypoxia-inducible transcription factors as concert masters

Abstract The liver and its zonation contribute to whole body homeostasis. Acute and chronic, not always liver, diseases impair proper metabolic zonation. Various underlying pathways, such as β-catenin, hedgehog signaling, and the Hippo pathway, along with the physiologically occurring oxygen gradient, appear to be contributors. Interestingly, hypoxia and hypoxia-inducible transcription factors can orchestrate those pathways. In the current review, we connect novel findings of liver zonation in health and disease and provide a view about the dynamic interplay between these different pathways and cell-types to drive liver zonation and systemic homeostasis

Cellular redox compartments

Abstract Although initially considered as harmful, reactive oxygen species (ROS) are now also recognized as important signaling molecules affecting various cellular processes. For example, they contribute to the response to hormones, growth factors, or hypoxia, and defense reactions against mechanical or chemical stress. Therefore, different ROS-generating, ROS-utilizing, and ROS-degrading systems in different intracellular compartments play an important role. On the one hand, this leads to a functional specialization wherein proteins, which participate in a specific ROS-regulated pathway in one compartment, may have another ROS-unrelated specific function in another compartment. On the other hand, this also adds a layer of protection by keeping unwanted side reactions to a minimum. Accordingly, the intracellular communication between different cellular compartments is an important mechanism to achieve proper responses and adaptations at the cellular level

Reactive oxygen species and fibrosis:further evidence of a significant liaison

Abstract Age-related diseases such as obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease and cardiomyopathy are frequently associated with fibrosis. Work within the last decade has improved our understanding of the pathophysiological mechanisms contributing to fibrosis development. In particular, oxidative stress and the antioxidant system appear to be crucial modulators of processes such as transforming growth factor-β1 (TGF-β1) signalling, metabolic homeostasis and chronic low-grade inflammation, all of which play important roles in fibrosis development and persistence. In the current review, we discuss the connections between reactive oxygen species, antioxidant enzymes and TGF-β1 signalling, together with functional consequences, reflecting a concept of redox-fibrosis that can be targeted in future therapies

Hypoxia-inducible factor prolyl 4-hydroxylases and metabolism

Abstract Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs, also known as PHDs or EglNs) are enzymes that act as cellular oxygen sensors. Inhibition of HIF-P4Hs leads to stabilization of hypoxia-inducible transcription factors (HIFs), which initiates a gene expression program that allows organisms to cope with low oxygen levels and restore tissue oxygenation. This involves, for example, upregulation of erythropoiesis and angiogenesis, modulation of inflammatory responses, and reprogramming of metabolism. Currently, several pharmacological HIF-P4H inhibitors are in clinical trials mainly for renal anemia. However, recent data suggest that HIF-P4H inhibitors could also be considered to treat metabolic disorders. Here, we discuss the potential of targeting HIF-P4Hs and the HIF pathway for the treatment of obesity, metabolic syndrome, atherosclerosis, and fatty liver diseases (FLDs)

Mitochondria, mitophagy, and the role of deubiquitinases as novel therapeutic targets in liver pathology

Abstract Liver diseases such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) have increased over the past few decades due to the absence or ineffective therapeutics. Recently, it has been shown that inappropriate regulation of hepatic mitophagy is linked to the pathogenesis of the above-mentioned liver diseases. As mitophagy maintains cellular homeostasis by removing damaged and nonfunctional mitochondria from the cell, the proper function of the molecules involved are of utmost importance. Thereby, mitochondrial E3 ubiquitin ligases as well as several deubiquitinases (DUBs) appear to play a unique role for the degradation of mitochondrial proteins and for proper execution of the mitophagy process by either adding or removing ubiquitin chains from target proteins. Therefore, these enzymes could be considered as valuable liver disease biomarkers and also as novel targets for therapy. In this review, we focus on the role of different DUBs on mitophagy and their contribution to NAFLD, NASH, alcohol-related liver disease, and especially HCC