Corrigendum: Valenced action/inhibition learning in humans is modulated by a genetic variant linked to dopamine D2 receptor expression

Motivational salience plays an important role in shaping human behavior, but recent studies demonstrate that human performance is not uniformly improved by motivation. Instead, action has been shown to dominate valence in motivated tasks, and it is particularly difficult for humans to learn the inhibition of an action to obtain a reward, but the neural mechanism behind this behavioral specificity is yet unclear. In all mammals, including humans, the monoamine neurotransmitter dopamine is particularly important in the neural manifestation of appetitively motivated behavior, and the human dopamine system is subject to considerable genetic variability. The well-studied TaqIA restriction fragment length polymorphism (rs1800497) has previously been shown to affect striatal dopamine metabolism. In this study we investigated a potential effect of this genetic variation on motivated action/inhibition learning. Two independent cohorts consisting of 87 and 95 healthy participants, respectively, were tested using the previously described valenced go/no-go learning paradigm in which participants learned the reward-associated no-go condition significantly worse than all other conditions. This effect was modulated by the TaqIA polymorphism, with carriers of the A1 allele showing a diminished learning-related performance enhancement in the rewarded no-go condition compared to the A2 homozygotes. This result highlights a modulatory role for genetic variability of the dopaminergic system in individual learning differences of action-valence interaction

Investigating individual- and area-level socioeconomic gradients of pulse pressure among normotensive and hypertensive participants

Socioeconomic status is a strong predictor of cardiovascular disease. Pulse pressure, the difference between systolic and diastolic blood pressure, has been identified as an important predictor of cardiovascular risk even after accounting for absolute measures of blood pressure. However, little is known about the social determinants of pulse pressure. The aim of this study was to examine individual- and area-level socioeconomic gradients of pulse pressure in a sample of 2,789 Australian adults. Using data from the North West Adelaide Health Study we estimated the association between pulse pressure and three indices of socioeconomic status (education, income and employment status) at the area and individual level for hypertensive and normotensive participants, using Generalized Estimating Equations. In normotensive individuals, area-level education (estimate: −0.106; 95% CI: −0.172, −0.041) and individual-level income (estimate: −1.204; 95% CI: −2.357, −0.050) and employment status (estimate: −1.971; 95% CI: −2.894, −1.048) were significant predictors of pulse pressure, even after accounting for the use of medication and lifestyle behaviors. In hypertensive individuals, only individual-level measures of socioeconomic status were significant predictors of pulse pressure (education estimate: −2.618; 95% CI: −4.878, −0.357; income estimate: −1.683, 95% CI: −3.743, 0.377; employment estimate: −2.023; 95% CI: −3.721, −0.326). Further research is needed to better understand how individual- and area-level socioeconomic status influences pulse pressure in normotensive and hypertensive individuals.Lisa A. Matricciani, Catherine Paquet, Natasha J. Howard, Robert Adams, Neil T. Coffee, Anne W. Taylor and Mark Danie

Focal induction of ROS-release to trigger local vascular degeneration

Reactive oxygen species (ROS) play an important role in the process of cardiovascular degeneration. We evaluated the potential of a controlled, local induction of ROS-release by application of rose bengal (RB) and photo energy to induce atherosclerosis-like focal vascular degeneration in vivo. After injection of RB, rats fed with a pro-degenerative diet underwent focal irradiation of the abdominal aorta by a green laser (ROS group), while the controls received irradiation without RB. Aortic tissue was analyzed by histology and immunohistochemistry at 0, 2, 4, 8, 28 and 56 days (n = 5). The intimal surface topography was analyzed by scanning electron microscopy. In the ROS group, an initial thrombus formation had disappeared by day 8. Similarly, ROS-derived products displayed the highest concentrations at day 0. Relative matrix metalloproteinase (MMP) activity achieved a maximum after 8 days (ROS group vs. control group: 1.60 ± 0.11 vs. 0.98 ± 0.01; p < 0.001). After 28 days, no significant differences in any aspect were found between the ROS group and the controls. However, after 56 days, the aortic tissue of ROS animals exhibited relative mediapronounced thickening (ROS vs. control: 2.15 ± 0.19 vs. 0.87 ± 0.10; p < 0.001) with focal calcification and reduced expression of alpha smooth muscle actin (aSMA). The ROSreleasing application of RB and photo energy allowed for the induction of vascular degeneration in a rodent model. This protocol may be used for the focal induction of vascular disease without systemic side effects and can thereby elucidate the role of ROS in the multifactorial processes of vessel degeneration and atherogenesis

Risk thresholds for alcohol consumption : combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Background Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. Methods We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12.5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5.6 years [5th-95th percentile 1.04-13.5]) from 71 011 participants from 37 studies. Findings In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5.4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1.14, 95% CI, 1.10-1.17), coronary disease excluding myocardial infarction (1.06, 1.00-1.11), heart failure (1.09, 1.03-1.15), fatal hypertensive disease (1.24, 1.15-1.33); and fatal aortic aneurysm (1.15, 1.03-1.28). By contrast, increased alcohol consumption was loglinearly associated with a lower risk of myocardial infarction (HR 0.94, 0.91-0.97). In comparison to those who reported drinking >0-100-200-350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. Interpretation In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. Copyright (C) The Author(s). Published by Elsevier Ltd.Peer reviewe

Invited review : the spectrum of age‐related small vessel diseases : potential overlap and interactions of amyloid and nonamyloid vasculopathies

Deep perforator arteriopathy (DPA) and cerebral amyloid angiopathy (CAA) are the commonest known cerebral small vessel diseases (CSVD), which cause ischaemic stroke, intracebral haemorrhage (ICH) and vascular cognitive impairment (VCI). While thus far mainly considered as separate entities, we here propose that DPA and CAA share similarities, overlap and interact, so that ‘pure’ DPA or CAA are extremes along a continuum of age-related small vessel pathologies. We suggest blood-brain barrier (BBB) breakdown, endothelial damage and impaired perivascular β-amyloid (Aβ) drainage are hallmark common mechanisms connecting DPA and CAA. We also suggest a need for new biomarkers (e.g. high-resolution imaging) to deepen understanding of the complex relationships between DPA and CAA.Projekt DEAL 201

Local snowmelt and temperature – but not regional sea‐ice – explain variation in spring phenology in coastal Arctic tundra

The Arctic is undergoing dramatic environmental change with rapidly rising surface temperatures, accelerating sea‐ice decline and changing snow regimes, all of which influence tundra plant phenology. Despite these changes, no globally consistent direction of trends in spring phenology has been reported across the Arctic. While spring has advanced at some sites, spring has delayed or not changed at other sites, highlighting substantial unexplained variation. Here, we test the relative importance of local temperatures, local snowmelt date and regional spring drop in sea‐ice extent as controls of variation in spring phenology across different sites and species. Trends in long‐term time‐series of spring leaf out and flowering (average span: 18 years) were highly variable for the 14 tundra species monitored at our four study sites on the Arctic coasts of Alaska, Canada and Greenland, ranging from advances of 10.06 days per decade to delays of 1.67 days per decade. Spring temperatures and the day of spring drop in sea‐ice extent advanced at all sites (average 1 °C per decade and 21 days per decade respectively), but only those sites with advances in snowmelt (average 5 days advance per decade) also had advancing phenology. Variation in spring plant phenology was best explained by snowmelt date (mean effect: 0.45 days advance in phenology per day advance snowmelt) and, to a lesser extent, by mean spring temperature (mean effect: 2.39 days advance in phenology per °C). In contrast to previous studies examining sea ice and phenology at different spatial scales, regional spring drop in sea‐ice extent did not predict spring phenology for any species or site in our analysis. Our findings highlight that tundra vegetation responses to global change are more complex than a direct response to warming and emphasize the importance of snowmelt as a local driver of tundra spring phenology

Genetic variation of the RASGRF1 regulatory region affects human hippocampus-dependent memory

The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP) rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT) and the logical memory section of the Wechsler Memory Scale (WMS). Two sub-cohorts additionally participated in functional magnetic resonance imaging (fMRI) studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage-dependent manner, with carriers of the T allele (i.e., the myopia risk allele) showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus-dependent memory and, along with the previous association with myopia, point toward pleitropic effects of RASGRF1 genetic variations on complex neural function in humans.Peer Reviewe

Report from the new technology testing cruise in Sognefjorden in February 2024

During a five days survey with G.O. Sars in February 2024, we simultaneously collected data with marine robotics and standard sampling. The main goals of the test survey were to 1) assess data types and quality of data when sampling with robotics and evaluate what we gain/loose when using autonomous sampling as compared to standard sampling from a vessel, and 2) evaluate the suitability of autonomous sampling. During the survey we ran three gliders from two manufacturers and with diverging sensors. In addition, we deployed and recovered a vertically profiling CTD-drone. We also collected in situ data with CTD, nets and Multinet. The results show that gliders indeed are promising, but there are challenges associated with a rapid implementation of gliders in the monitoring program with the aim of reducing the ordinary surveys with research vessels. These challenges include build-up of institutional competence on the new technology, but also the functionality/ease of use of the gliders. Glider leakages are a concern. Different glider types work better for different applications. The small simple Hefring Oceanscout dealt a lot better with the strong currents in the fjord, but its small size also prevents integration of larger sensors. These can be integrated in the larger Slocum glider, but they affect the efficiency of the glider behaviour and robustness. Further work includes testing mobility offshore and developing routines for deployment/recovery of gliders using smaller boats close to the coast, as this would prevent use of research vessels for glider activity. Further work also includes building more experience with using gliders during longer missions. The short data sets from the fjord deployments also highlight the need to develop data processing routines and tools, largely based on existing correction and processing protocols.Report from the new technology testing cruise in Sognefjorden in February 2024publishedVersio

Abnormal Wnt and PI3Kinase Signaling in the Malformed Intestine of lama5 Deficient Mice

Laminins are major constituents of basement membranes and are essential for tissue homeostasis. Laminin-511 is highly expressed in the intestine and its absence causes severe malformation of the intestine and embryonic lethality. To understand the mechanistic role of laminin-511 in tissue homeostasis, we used RNA profiling of embryonic intestinal tissue of lama5 knockout mice and identified a lama5 specific gene expression signature. By combining cell culture experiments with mediated knockdown approaches, we provide a mechanistic link between laminin α5 gene deficiency and the physiological phenotype. We show that laminin α5 plays a crucial role in both epithelial and mesenchymal cell behavior by inhibiting Wnt and activating PI3K signaling. We conclude that conflicting signals are elicited in the absence of lama5, which alter cell adhesion, migration as well as epithelial and muscle differentiation. Conversely, adhesion to laminin-511 may serve as a potent regulator of known interconnected PI3K/Akt and Wnt signaling pathways. Thus deregulated adhesion to laminin-511 may be instrumental in diseases such as human pathologies of the gut where laminin-511 is abnormally expressed as it is shown here

Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection.

Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands the capacity of memory CD8+ T cells to produce IFN-γ. Whether acetate modulates memory CD8+ T cell metabolism and function during pathogen re-encounter remains unexplored. Here we show that at sites of infection, high acetate concentrations are being reached, yet memory CD8+ T cells shut down the acetate assimilating enzymes ACSS1 and ACSS2. Acetate, being thus largely excluded from incorporation into cellular metabolic pathways, now had different effects, namely (1) directly activating glutaminase, thereby augmenting glutaminolysis, cellular respiration, and survival, and (2) suppressing TCR-triggered calcium flux, and consequently cell activation and effector cell function. In vivo, high acetate abundance at sites of infection improved pathogen clearance while reducing immunopathology. This indicates that, during different stages of the immune response, the same metabolite-acetate-induces distinct immunometabolic programs within the same cell type