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The human brain shows functional and structural hemispheric asymmetries for various cognitive functions such as language. One of the most replicated findings in behavioural laterality research is the so-called right ear advantage in the dichotic listening task, which is observed in 60 different languages and language families. However, it could not be replicated for whistle languages. Previous research on whistled Turkish has shown the absence of asymmetry on the behavioural level. Therefore, the current study focuses on the investigation of asymmetric electrophysiological processes to map the auditory processing as well as the comprehension of spoken versus whistled syllables. Electrophysiological recordings captured during dichotic listening were obtained from 117 participants consisting of proficient Spanish whistlers and two control groups from two different language families. The design of the study intended to generate potential novel insights into whistle languages’ unique neural aspects. While the right-ear advantage was replicated, an unexpected tendency towards faster right-hemispheric involvement was observed. Most importantly, the left hemisphere turned out to play a crucial function in the perception, processing, and comprehension of whistled syllables in Spanish whistlers. In light of its potential clinical value, future research in this field leveraging modern multimodal fusion approaches is needed to further elucidate the neuronal mechanisms underlying the functional and structural asymmetries of this communication method.

We investigated the modulation of neural and behavioral responses to moral dilemmas by the physical presence of a close friend. We argue that the presence of a close other not only changes the moral response but also the process of decision-making, something that can only be discovered by combining insights from social and cognitive psychology. Our participants rated the acceptability of sacrificing ingroup members to save outgroup members and vice versa while being alone or in the presence of a close other. We obtained behavioral and functional MRI data from a within-participant functional MRI study (N = 17, native Dutch women). The behavioral data replicated classical identity theory with regard to higher acceptability to sacrifice the outgroup (vs. the ingroup) but did not show any differences when deciding alone or in the presence of the friend. The imaging results did not reveal main and interaction effects in our hypothesized brain areas. Exploratory analysis however revealed an interaction effect in a region previously found to be related to guilt and shame (superior frontal gyrus), such that reactions to the sacrifice of the outgroup evoked increased activation when being together with a close other. (PsycInfo Database Record (c) 2020 APA, all rights reserved)

Perceptual decision making involves choices between alternatives based on sensory information. Studies in primates and rodents revealed a stochastic perceptual evidence accumulation process that, after reaching threshold, results in action execution. Birds represent a cognitively highly successful vertebrate class that has been evolving independent from mammals for more than 300 million years. The present study investigated whether perceptual decision making in pigeons shows behavioral and computational dynamics comparable to those in mammals and rodents. Using a novel "pigeon helmet" with liquid shutter displays that controls visual input to individual eyes/hemispheres with precise timing, we indeed revealed highly similar dynamics of perceptual decision making. Thus, both mammals and birds seem to share this core cognitive process that possibly represents a fundamental constituent of decision making throughout vertebrates. Interestingly, in our experiments we additionally discovered that both avian hemispheres start independent sensory accumulation processes without any major interhemispheric exchange. Because birds lack a corpus callosum and have only a small anterior commissure, they seem to be forced to decide on motor responses based on unihemispheric decisions under conditions of time pressure. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Green plants exposed to abiotic or biotic stress release C-5 and C-6 unsaturated oxygenated hydrocarbons called Green Leaf Volatiles (GLVs). GLVs partition into tropospheric waters and react to form secondary organic aerosol (SOA). We explored the kinetics of aqueous-phase reactions of 1-penten-3-ol (PENTOL), (Z)-2-hexen-1-ol (HEXOL), and (E)-2-hexen-1-al (HEXAL) with SO4•–, •OH, and NO3•. At 298 K, the rate constants for reactions of PENTOL, HEXOL, and HEXAL with SO4•– were, respectively, (9.4 ± 1.0) × 108 L mol–1 s–1, (2.5 ± 0.3) × 109 L mol–1 s–1, and (4.8 ± 0.2) × 108 L mol–1 s–1; with •OH – (6.3 ± 0.1) × 109 L mol–1 s–1, (6.7 ± 0.3) × 109 L mol–1 s–1, and (4.8 ± 0.3) × 109 L mol–1 s–1; and with NO3• – (1.5 ± 0.15) × 108 L mol–1 s–1, (8.4 ± 2.3) × 108 L mol–1 s–1, and (3.0 ± 0.7) × 107 L mol–1 s–1. The rate constants increased weakly with temperatures ranging from 278 to 318 K. The diffusional limitations of the rate constants appeared significant only for the GLV–•OH reactions. The aqueous-phase reactions appeared negligible in deliquescent aerosol and haze water but not in clouds and rains. The atmospheric lifetimes of GLVs decreased from many days to hours with increasing liquid water content and radicals’ concentration., Green leaf volatiles emitted by plants under biotic and abiotic stress react with atmospheric oxidants in the gas and water phases to influence air quality.

Isoprene epoxydiols are well-known intermediates of the isoprene oxidation in the gas phase under pristine conditions. According to their Henry’s Law constants, they are well water-soluble and will...

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.

Stimuli of different modalities can acquire an affective value via evaluative conditioning. This process describes a shift in perceived affective quality of a neutral stimulus towards the hedonics of an associated affective stimulus. The olfactory system, as compared to other modalities, might be especially prone to attributing affective value to an odor due to its close neuroanatomical connectivity with brain regions processing emotion. In the present study, we investigated whether perceived affective quality of odors is more sensitive to evaluative conditioning than that of sounds. For this purpose, 48 healthy participants (50% male) rated unfamiliar and emotionally neutral odors and sounds before and after pairing with either aversive or neutral pictures. Our results show a stronger decrease in odor valence and stronger increases in arousal and dominance ratings for odors paired with aversive compared to neutral pictures. For sounds, ratings of valence, arousal, and dominance were independent of picture emotionality. Odors appear to be more sensitive to evaluative conditioning than sounds. Our findings extend existing modality comparisons mainly focusing on characteristics of odor-associated memories by specifically looking at affective quality of the odor itself in associative learning. Perceived affective quality of a stimulus goes along with the tendency to approach or avoid this stimulus. For odors, it is especially prone to change into an aversive direction. This may have implications for food and fragrance choices but also for the understanding of clinical conditions in which odors become highly aversive, such as post-traumatic stress disorder.

In situations where the left and right brain sides receive conflicting information that leads to incompatible response options, the brain requires efficient problem-solving mechanisms. This problem is particularly significant in lateralized brains, in which the hemispheres differ in encoding strategies or attention focus and hence, consider different information for decision-making. Meta-control, in which one hemisphere dominates ambiguous decisions, can be a mechanism that ensures fast behavioral reactions. We therefore confronted pigeons with a task in which two stimulus classes were brought into conflict. To this end, we trained pigeons simultaneously on two categories (cats or dogs) whereby each hemisphere learnt only one of the categories respectively. After learning, the birds were confronted with stimulus pairs that combined a picture with a cat (positive for one hemisphere) and a picture with a dog (positive for the other hemisphere). Pecking responses indicated the hemisphere dominating response selection. Pigeons displayed individual meta-control despite equal categorization performances of both brain hemispheres. This means that hemispheric dominance only emerged in interhemispheric conflict situations. The analysis of response latencies indicate that conflict decisions relied on intrahemispheric processes. Interhemispheric components played a role for more complex decisions. This flexibility could be a crucial building block for the evolutionary success of a lateralized brain.

Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Therapies targeting molecular pathways altered in BC had significantly enhanced treatment options for BC over the last decades, which ultimately improved the lives of millions of women worldwide. Among various molecular pathways accruing substantial interest for the development of targeted therapies are cyclin-dependent kinases (CDKs)—in particular, the two closely related members CDK4 and CDK6. CDK4/6 inhibitors indirectly trigger the dephosphorylation of retinoblastoma tumor suppressor protein by blocking CDK4/6, thereby blocking the cell cycle transition from the G1 to S phase. Although the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib gained FDA approval for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC as they significantly improved progression-free survival (PFS) in randomized clinical trials, regrettably, some patients showed resistance to these therapies. Though multiple molecular pathways could be mechanistically responsible for CDK4/6 inhibitor therapy resistance, one of the most predominant ones seems to be the fibroblast growth factor receptor (FGFR) pathway. FGFRs are involved in many aspects of cancer formation, such as cell proliferation, differentiation, and growth. Importantly, FGFRs are frequently mutated in BC, and their overexpression and/or hyperactivation correlates with CDK4/6 inhibitor resistance and shortened PFS in BC. Intriguingly, the inhibition of aberrant FGFR activity is capable of reversing the resistance to CDK4/6 inhibitors. This review summarizes the molecular background of FGFR signaling and discusses the role of aberrant FGFR signaling during cancer development in general and during the development of CDK4/6 inhibitor resistance in BC in particular, together with other possible mechanisms for resistance to CDK4/6 inhibitors. Subsequently, future directions on novel therapeutic strategies targeting FGFR signaling to overcome such resistance during BC treatment will be further debated.

Background & Aims 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. Methods 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. Results 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. Conclusions 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. Lay summary 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.

Animal-fMRI is a powerful method to understand neural mechanisms of cognition, but it remains a major challenge to scan actively participating small animals under low-stress conditions. Here, we present an event-related functional MRI platform in awake pigeons using single-shot RARE fMRI to investigate the neural fundaments for visually-guided decision making. We established a head-fixated Go/NoGo paradigm, which the animals quickly learned under low-stress conditions. The animals were motivated by water reward and behavior was assessed by logging mandibulations during the fMRI experiment with close to zero motion artifacts over hundreds of repeats. To achieve optimal results, we characterized the species-specific hemodynamic response function. As a proof-of-principle, we run a color discrimination task and discovered differential neural networks for Go-, NoGo-, and response execution-phases. Our findings open the door to visualize the neural fundaments of perceptual and cognitive functions in birds—a vertebrate class of which some clades are cognitively on par with primates., Functional magnetic resonance imaging (fMRI) is a powerful method to understand neural mechanisms of cognition but imaging of small animals can be challenging. The authors present an event-related fMRI platform to visualize the neural fundaments of perceptual and cognitive functions in awake birds.

© 2020 Elsevier Inc. The cyclin-dependent kinase 1 (Cdk1) drives cell division. To uncover additional functions of Cdk1, we generated knockin mice expressing an analog-sensitive version of Cdk1 in place of wild-type Cdk1. In our study, we focused on embryonic stem cells (ESCs), because this cell type displays particularly high Cdk1 activity. We found that in ESCs, a large fraction of Cdk1 substrates is localized on chromatin. Cdk1 phosphorylates many proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. Consistent with these findings, inhibition of Cdk1 altered histone-modification status of ESCs. High levels of Cdk1 in ESCs phosphorylate and partially inactivate Dot1l, the H3K79 methyltransferase responsible for placing activating marks on gene bodies. Decrease of Cdk1 activity during ESC differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ESCs.

Introduction Numerous green leaf volatiles (GLVs) are released into the atmosphere due to the stress, cell damage or wounding. Fog forming over vegetation takes up these compounds, promoting their aqueous-phase oxidation to less volatile compounds. The droplets eventually dry out, leaving behind the secondary organic aerosol (SOA). These pathways are still poorly recognized as potentially novel routes for the formation of atmospheric SOA. Kinetic investigations of GLVs in the gas phase have already been reported by Shalamzari et. al. 2014, Davis et. al. 2011 and many others, while there is no kinetic data on the aqueous phase reactions of selected C6 and C5 GLVs. In the present study, we focussed on the kinetic studies of GLVs with the hydroxyl, sulfate and nitrate radicals as a possible source of aqueous SOA.Experimental method The rate constants of reactions of GLVs with atmospherically relevant radicals were studied using a laser flash photolysis-laser long path absorption (LFP-LLPA). Kinetic investigations of GLVs with hydroxyl radicals were performed using competition kinetics, where H2O2 (2 x 10-4 mol L-1) was used as a radical precursor and KSCN (2 x 10-5 mol L-1) as a reference compound. The method is similar to that introduced by Behar, et al. 1972. Kinetic measurements of sulfate and nitrate radicals with GLVs, were done using a direct flash photolysis method, where sodium persulfate (5 x 10-4 mol L-1) was the precursor in the generation of SO4•ꟷ and sodium nitrate (1 x 10-1 mol L-1) and sodium sulfate (3 x 10-2 mol L-1) were the precursor for the generation of nitrate radicals.Conclusions In the present study, we explored the kinetics of aqueous-phase reactions of three GLVs- 1-penten-3-ol, cis-2-hexen-1-ol and 2-E-hexenal - with atmospheric radicals SO4•ꟷ, •OH and NO3•. The second-order rate constants were determined for a temperature range of 278 K to 318 K. A weak temperature dependence was observed for the aqueous-phase kinetics of all three GLVs with selected atmospherically relevant radicals. To explain the weak temperature dependence of aqueous-phase reaction of GLVs with atmospheric radicals, rate constants were investigated for the diffusion limitation. The atmospheric significance of the aqueous-phase reaction was evaluated, by calculating aqueous-phase lifetime and their relative rate to the gas phase reactions with respective radicals, which clearly demonstrated their importance above the gas-phase reactions in tropospheric aqueous-phase. The present work is a part of the bigger research project on the aqueous-phase reactions of a series of atmospherically relevant GLVs whereas a next step oxidation products in the aqueous-phase are being investigated at a present stage. This project is supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 711859 and by financial resources for science in the years 2017-2021 awarded by the Polish Ministry of Science and Higher Education for the implementation of an international co-financed project. The research project was also partially supported by funding under Project CREATE of European Union’s H2020 and ERASMUS PLUS staff mobility programme.

Organosulfates (OSs), also referred to as organic sulfate esters, are well-known and ubiquitous constituents of atmospheric aerosol particles. Commonly, they are assumed to form upon mixing of air masses of biogenic and anthropogenic origin, that is, through multiphase reactions between organic compounds and acidic sulfate particles. However, in contrast to this simplified picture, recent studies suggest that OSs may also originate from purely anthropogenic precursors or even directly from biomass and fossil fuel burning. Moreover, besides classical OS formation pathways, several alternative routes have been discovered, suggesting that OS formation possibly occurs through a wider variety of formation mechanisms in the atmosphere than initially expected. During the past decade, OSs have reached a constantly growing attention within the atmospheric science community with evermore studies reporting on large numbers of OS species in ambient aerosol. Nonetheless, estimates on OS concentrations and implications on atmospheric physicochemical processes are still connected to large uncertainties, calling for combined field, laboratory, and modeling studies. In this Critical Review, we summarize the current state of knowledge in atmospheric OS research, discuss unresolved questions, and outline future research needs, also in view of reductions of anthropogenic sulfur dioxide (SO2) emissions. Particularly, we focus on (1) field measurements of OSs and measurement techniques, (2) formation pathways of OSs and their atmospheric relevance, (3) transformation, reactivity, and fate of OSs in atmospheric particles, and (4) modeling efforts of OS formation and their global abundance.

This study presents strategies to render triple-negative breast cancers sensitive to CDK4/6 inhibitors., Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor–positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies.

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.

Substituted phenols are known to readily react with the hydroxyl radical (OH˙), which is the most powerful atmospheric oxidant and is also most often used in advanced oxidation processes (AOP) for wastewater treatment. We report temperature-dependent (278.15–318.15 K) second order kinetic rate constants for the aqueous-phase reactions of OH˙ with phenol and four substituted phenols: catechol, phloroglucinol, pyrogallol and 3-methylcatechol, with the last two measured for the first time. The constructed Hammett plots for mono- and di-substituted phenols have the potential to be further applied for predicting the reaction rate constants of other substituted phenols at 298.15 K. This will significantly facilitate the optimization of AOP and improve the predictive capabilities of atmospheric multiphase models in the future. Moreover, an advancement in the understanding of the underlying mechanism, i.e. OH˙ addition to the aromatic ring is made by theoretical calculations at the M06-2X level. We demonstrate that the position of substituents on the aromatic ring is important for the [OH–phenol]˙ adduct formation, which is supported by the experiment and theoretical calculations. Adjacent and nonadjacent electron donor/acceptor substituents differently impact the interplay between the activation energy and entropy. We also show that explicit solvation has to be accounted for in theoretical models in order to explicitly describe the formation of the transition state.

In this work we present a technique of incorporation of semiconductor CdTe nanocrystals (NCs) into metal oxide matrices prepared by inorganic sol-gel method. As the matrices, we chose alumina and aluminum tin oxide, which are optically transparent in the visible region. Among them the first is electrically insulating, while the second is conductive and thus can be used in optoelectronic devices. We found optimal synthetic parameters allowing us to maintain optical properties of the NCs in both matrices even after heating up to 150°C in air. Therefore, in our approach we overcame a common problem of degradation of the optical properties of semiconductor NCs in oxide matrices as a result of the incorporation and subsequent interaction with the matrix. The resulting materials were characterized in detail from the point of view of their optical and structural properties. Based on the results obtained, we suggest the formation mechanism of these materials. Semiconductor NCs embedded in robust and optically transparent metal oxides offer promising applications in optical switching, optical filtering, waveguides, light emitting diodes, and solar concentrators.

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.

Renewal describes the recovery of an extinguished response if the contexts of extinction and recall differ, highlighting the context dependency of extinction. Studies demonstrated dopaminergic (DA) signalling to be important for context-related extinction learning with and without a fear component. In a previous study in humans, administration of the dopamine D2/D3 antagonist tiapride prior to extinction impaired extinction learning in a novel, but not a familiar context, without affecting renewal. In a further study, context processing during initial acquisition of associations was shown to be related to renewal. In this human fMRI study we investigated the potential role of DA signalling during this initial conditioning for the learning process and for renewal. While tiapride, administered prior to the start of learning, did not affect initial acquisition and renewal, extinction learning in a novel context was impaired, associated with reduced BOLD activation in vmPFC, left iFG and ACC – regions mediating response inhibition and selection from competing options using contextual information. Thus, different timepoints of administration of tiapride (before initial conditioning or extinction) had largely similar effects upon extinction and renewal. In addition, retrieval of previously acquired associations was impaired, pointing towards weaker association forming during acquisition. Conceivably, effects of the DA blockade are associated with the challenge present in the respective task rather than the administration timepoint: the cognitive flexibility required for forming a new inhibitory association that includes a novel element clearly requires DA processing, while initial forming of associations, or of inhibitory associations without a new element, apparently rely less on the proper function of the DA system.

MicroRNAs (miRNAs) have been known to affect various biological processes by repressing expression of specific genes. Here we describe an essential function of the miR-34/449 family during differentiation of epithelial cells. We found that miR-34/449 suppresses the cell-cycle machinery in vivo and promotes cell-cycle exit, thereby allowing epithelial cell differentiation. Constitutive ablation of all six members of this miRNA family causes derepression of multiple cell cycle-promoting proteins, thereby preventing epithelial cells from exiting the cell cycle and entering a quiescent state. As a result, formation of motile multicilia is strongly inhibited in several tissues such as the respiratory epithelium and the fallopian tube. Consequently, mice lacking miR-34/449 display infertility as well as severe chronic airway disease leading to postnatal death. These results demonstrate that miRNA-mediated repression of the cell cycle is required to allow epithelial cell differentiation.