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In chronic liver diseases, inflammation induces oxidative stress and thus may contribute to the progression of liver injury, fibrosis, and carcinogenesis. The KEAP1/NRF2 axis is a major regulator of cellular redox balance. In the present study, we investigated whether the KEAP1/NRF2 system is involved in liver disease progression in humans and mice. The clinical relevance of oxidative stress was investigated by liver RNA sequencing in a well-characterized cohort of patients with non-alcoholic fatty liver disease (n = 63) and correlated with histological and clinical parameters. For functional analysis, hepatocyte-specific Nemo knockout (NEMOΔhepa) mice were crossed with hepatocyte-specific Keap1 knockout (KEAP1Δhepa) mice. Immunohistochemical analysis of human liver sections showed increased oxidative stress and high NRF2 expression in patients with chronic liver disease. RNA sequencing of liver samples in a human pediatric NAFLD cohort revealed a significant increase of NRF2 activation correlating with the grade of inflammation, but not with the grade of steatosis, which could be confirmed in a second adult NASH cohort. In mice, microarray analysis revealed that Keap1 deletion induces NRF2 target genes involved in glutathione metabolism and xenobiotic stress (e.g. , Nqo1). Furthermore, deficiency of one of the most important antioxidants, glutathione (GSH), in NEMOΔhepa livers was rescued after deleting Keap1. As a consequence, NEMOΔhepa/KEAP1Δhepa livers showed reduced apoptosis compared to NEMOΔhepa livers as well as a dramatic downregulation of genes involved in cell cycle regulation and DNA replication. Consequently, NEMOΔhepa/KEAP1Δhepa compared to NEMOΔhepa livers displayed decreased fibrogenesis, lower tumor incidence, reduced tumor number, and decreased tumor size. NRF2 activation in patients with non-alcoholic steatohepatitis correlates with the grade of inflammation, but not steatosis. Functional analysis in mice demonstrated that NRF2 activation in chronic liver disease is protective by ameliorating fibrogenesis, initiation and progression of hepatocellular carcinogenesis. The KEAP1 (Kelch-like ECH-associated protein-1)/NRF2 (erythroid 2-related factor 2) axis has a major role in regulating cellular redox balance. Herein, we show that NRF2 activity correlates with the grade of inflammation in patients with non-alcoholic steatohepatitis. Functional studies in mice actually show that NRF2 activation, resulting from KEAP1 deletion, protects against fibrosis and cancer. • Patients with NAFLD display increased oxidative stress and high NRF2 activity. • NRF2 activation correlates with the grade of inflammation. • In mice, Keap1 deletion induces NRF2 target genes. • NRF2 activation downregulates genes involved in cell cycle regulation. • Consequently, Keap1 deletion reduces fibrosis and tumor development in mice. [ABSTRACT FROM AUTHOR]

Lévy walks are a property of random movements often observed among foraging animals (and humans), and they might confer some advantages for survival in an unpredictable environment, in comparison with Brownian walks. In animals with a nervous system, specific neurotransmitters associated with some psychological states could play a crucial role in controlling the occurrence of Lévy walks. We argue that incentive motivation, a dopamine-dependent process that in vertebrates makes rewards and their predictive conditioned stimuli attractive, has behavioral effects that may favor their occurrence: incentive motivation is higher when food is unpredictable and it strongly underpins foraging activity. An individual-based computer model is used to determine whether changes in incentive motivation can influence the probability that Lévy walks occur among foraging agents. Our results suggest that they are produced more often under an unpredictable than a predictable food access, and more often in strongly rather than weakly motivated foragers exposed to an unpredictable food access. Also, our motivational framework indicates that the occurrence of Lévy walks are correlated with, but not causally linked to, the number of food items consumed and the ability to store fat reserves. We conclude that Lévy walks can confer some advantages for survival in an unpredictable environment, provided that they appear in foragers with a high motivation to seek food. [ABSTRACT FROM AUTHOR]

Unpredictable rewards increase the vigor of responses in autoshaping (a Pavlovian conditioning procedure) and are preferred to predictable rewards in free-choice tasks involving fixed- versus variable-delay schedules. The significance those behavioral properties may have in field conditions is currently unknown. However, it is noticeable that when exposed to unpredictable food, small passerines – such as robins, titmice, and starlings – get fatter than when food is abundant. In functional terms, fattening is viewed as an evolutionary strategy acting against the risk of starvation when food is in short supply. But this functional view does not explain the causal mechanisms by which small passerines come to be fatter under food uncertainty. Here, it is suggested that one of these causal mechanisms is that involved in behavioral invigoration and preference for food uncertainty in the laboratory. Based on a psychological theory of motivational changes under food uncertainty, we developed an integrative computational model to test this idea. We show that, for functional (adaptive) reasons, the excitatory property of reward unpredictability can underlie the propensity of wild birds to forage longer and/or more intensively in an unpredictable environment, with the consequence that they can put on more fat reserves. [ABSTRACT FROM AUTHOR]

Summary: In human neuroblastoma, amplification of the MYCN gene predicts poor prognosis and resistance to therapy. In a shRNA screen of genes that are highly expressed in MYCN-amplified tumors, we have identified AURKA as a gene that is required for the growth of MYCN-amplified neuroblastoma cells but largely dispensable for cells lacking amplified MYCN. Aurora A has a critical function in regulating turnover of the N-Myc protein. Degradation of N-Myc requires sequential phosphorylation by cyclin B/Cdk1 and Gsk3. N-Myc is therefore degraded during mitosis in response to low levels of PI3-kinase activity. Aurora A interacts with both N-Myc and the SCFFbxw7 ubiquitin ligase that ubiquitinates N-Myc and counteracts degradation of N-Myc, thereby uncoupling N-Myc stability from growth factor-dependent signals. [Copyright &y& Elsevier]

Abstract: The Biopsychology-Toolbox is a free, open-source Matlab-toolbox for the control of behavioral experiments. The major aim of the project was to provide a set of basic tools that allow programming novices to control basic hardware used for behavioral experimentation without limiting the power and flexibility of the underlying programming language. The modular design of the toolbox allows portation of parts as well as entire paradigms between different types of hardware. In addition to the toolbox, this project offers a platform for the exchange of functions, hardware solutions and complete behavioral paradigms. [Copyright &y& Elsevier]

CDK6 is an oncogenic kinase regulating the cell cycle. In this issue of Cancer Cell, Kollmann and colleagues demonstrate that CDK6 performs a kinase-independent transcriptional function in regulating expression of VEGF-A and p16INK4a. These observations link the cell cycle machinery and angiogenesis and reveal the presence of a fail-safe antiproliferative mechanism. [ABSTRACT FROM AUTHOR]

• Stress exposure has been shown to influence the use of different memory systems. • Compared to a control task, individuals in the stress conditions adopted a nondeclarative learning strategy more often. • Higher pre-stress cortisol levels favored the adoption of this non-declarative learning strategy. • The switch between learning strategies was moderated by common genetic variation of the mineralocorticoid receptor. Exposure to acute stress has been shown to result in a shift from declarative toward non-declarative learning, presumably mediated by brain mineralocorticoid receptors (MRs). In this study, we aimed to replicate and extend these findings by investigating the role of stress-associated cortisol secretion on learning behavior. Furthermore, we explored the influence of a well-characterized common single nucleotide polymorphism of the MR gene (rs2070951; minor allele frequency: 49.3%) previously shown to influence MR expression and HPA axis activity. Healthy males (n = 74) were exposed to the Trier Social Stress Test or a control condition prior to performing a probabilistic classification task (Weather Prediction Task). The use of a non-declarative learning strategy continuously increased over the course of the learning task after stress exposure, but leveled in the control condition. The shift toward a non-declarative strategy in the stress group was associated with better learning performance. Higher pre-stress cortisol levels favored the adoption of a non-declarative learning strategy. rs2070951 C/C-carriers in contrast to G-allele carriers exhibited a larger secretion of cortisol under stress. Furthermore, control participants homozygous for the C-allele adopted a non-declarative learning strategy less often than stressed participants, whereas the choice of strategy was independent of stress in G-allele carriers. The failure to switch strategies resulted in poorer performance, suggesting a beneficial effect of stress in dependence of MR variation. Consistent with previous findings, the results provide further support for cortisol as a driving force in coordinating the competition between multiple memory systems under stress. [ABSTRACT FROM AUTHOR]

Stress (or elevated cortisol concentration) typically impairs memory retrieval. The scenario model from Cheng et al. (2016) proposes that during retrieval, specifically during the construction of a scenario, only the gist is remembered, and missing information is substituted semantically. Since cortisol administration has been linked to reduced episodic memory retrieval, it remains to be explored if cortisol also impacts scenario construction. We have developed a new virtual reality-based paradigm that induced conflicts between episodic memory and semantic knowledge of the participants. In the current study, we investigated scenario construction in 60 participants with this virtual task during functional magnetic resonance imaging (fMRI). In addition, we administered 20 mg of hydrocortisone or placebo prior to retrieval. Cortisol was expected to lead to a stronger reliance on semantic information. This shift should be reflected in altered activations in medial temporal lobe regions. Cortisol-treated participants exhibited increased salivary cortisol concentrations relative to the placebo group. We found no group differences on the behavioral level. On the neural level, cortisol modulated hippocampal activity during retrieval of semantic responses. We will present further results of our currently ongoing analysis of the fMRI data. Our current findings illustrate for the first time the influence of cortisol on the interplay of episodic memory and semantic information and its underlying neural correlates. Results might help to mechanistically explain the reduced autobiographic memory specificity observed in patients with major depressive disorder. [ABSTRACT FROM AUTHOR]

Abstract While aging and stress are both known to affect cognitive functions, little is known on whether and how age modulates stress effects on executive functions and their neural correlates. The current study investigated the effect of acute stress on response inhibition and error processing and their underlying cortical processes in younger and older healthy men, using EEG. Forty-nine participants (30 young) were stressed with the Trier Social Stress Test (16 young, 9 older) or underwent a friendly control procedure (14 young, 10 older) and subsequently performed a Go/No-Go task with two levels of task difficulty while performance (reaction time, error rate), stimulus-locked (N2, P3) and response-locked (Ne, Pe) ERPs were measured. Previous results on age-related cognitive deficits were replicated, with slower responses and reduced and delayed N2 and P3 components, as well as reduced Ne and Pe components in older participants. Independent of age, acute stress improved response inhibition, reflected in higher accuracy for compatible trials and enhanced inhibition-related components (N2, P3 and N2d, P3d of the difference waves No-Go minus Go), and improved error processing, reflected in enhanced error-related components (Ne, Pe and Ne_d, Pe_d of the difference waves error minus correct trial). Our findings indicate that acute stress leads to a reallocation of cognitive resources, strengthening inhibition and error processing in young and older healthy men to a similar degree. Neural generators of the analyzed ERPs are mainly part of the salience network, which is upregulated immediately after stress. This offers an explanation as to why response inhibition, in contrast to other executive functions, improves after acute stress. Highlights • Acute stress improves response inhibition accuracy in healthy men. • Acute stress enhanced the neural correlates of response inhibition, N2 and P3. • Acute stress enhanced error processing reflected by enhanced Ne and Pe amplitudes. • This beneficial stress effects may result from activation of the saliency network. • These beneficial stress effects were independently of age. [ABSTRACT FROM AUTHOR]

Background fMRI experiments on olfaction offer new insights into the complex, but in contrast to other sensory systems, less studied cognition of odors. To perform these experiments is still a challenge. New method To address the challenge posed by MR settings, an olfactometer design is presented including specific improvements to the limited number of already existing olfactometers. Innovative features such as pneumatically controlled pinch valves, useable in the scanner and providing exact stimulus timing as well as a 3D-printed nasal mask inlet for common sleep laboratory masks that can be used for lateral divided stimulus presentation are introduced. To ensure a fully automated and mobile system, the use of a flexible and easily-adapted Matlab-Code and a portable adaptable container system are presented. Results The functional efficiency of these features are proven by results of an fMRI study as well as testing temporal resolution and concentration stability with a mass spectrometer. Comparison with existing methods The 24-channel olfactometer design presented here provides an inexpensive alternative to the currently available olfactometers including the achievement of fast onset times, lateral divided stimulus presentation and high flexibility and adaptability to different scientific questions. Conclusion The olfactometer design presented in this paper can be seen as a realistic and feasible solution to overcome the challenges of presenting olfactory stimuli within the MR setting. [ABSTRACT FROM AUTHOR]

Abstract: Studies in patients with an isolated, congenital agenesis of the corpus callosum have documented potentials and limits of brain plasticity. Literature suggests that early reorganization mechanisms can compensate for the absence of the corpus callosum in unisensory tasks that involve interhemispheric transfer. It is unknown, however, how the congenitally acallosal brain processes multisensory information, which presumably requires interhemispheric transfer of modality-specific input. Therefore, we tested five patients with total and one patient with partial agenesis of the corpus callosum in a visuotactile interference task (the “crossmodal congruency task”) with uncrossed and crossed hands and compared their performance to that of 31 healthy controls. We found that congruency effects followed the hands in space not only in healthy, but also in congenitally acallosal individuals. Remarkably, this was also true when patients’ hands crossed the vertical visual meridian and stimuli were presented at the same hand. These results suggest that callosal connectivity is not required for remapping of visuotactile space. We conclude that early brain plasticity allows for compensation of the developmental absence of the corpus callosum in a visuotactile interference task. [Copyright &y& Elsevier]

Summary Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in numerous human tumors. To identify means of interfering with cyclins/CDKs, we performed nine genome-wide screens for human microRNAs (miRNAs) directly regulating cell-cycle proteins. We uncovered a distinct class of miRNAs that target nearly all cyclins/CDKs, which are very effective in inhibiting cancer cell proliferation. By profiling the response of over 120 human cancer cell lines, we derived an expression-based algorithm that can predict the response of tumors to cell-cycle-targeting miRNAs. Using systemic administration of nanoparticle-formulated miRNAs, we inhibited tumor progression in seven mouse xenograft models, including three treatment-refractory patient-derived tumors, without affecting normal tissues. Our results highlight the utility of using cell-cycle-targeting miRNAs for treatment of refractory cancer types. [ABSTRACT FROM AUTHOR]