Effects of depressive symptoms and peripheral DAT methylation on neural reactivity to alcohol cues in alcoholism

In alcohol-dependent (AD) patients, alcohol cues induce strong activations in brain areas associated with alcohol craving and relapse, such as the nucleus accumbens (NAc) and amygdala. However, little is known about the influence of depressive symptoms, which are common in AD patients, on the brain’s reactivity to alcohol cues. The methylation state of the dopamine transporter gene (DAT) has been associated with alcohol dependence, craving and depression, but its influence on neural alcohol cue reactivity has not been tested. Here, we compared brain reactivity to alcohol cues in 38 AD patients and 17 healthy controls (HCs) using functional magnetic resonance imaging and assessed the influence of depressive symptoms and peripheral DAT methylation in these responses. We show that alcoholics with low Beck’s Depression Inventory scores (n=29) had higher cue-induced reactivity in NAc and amygdala than those with mild/moderate depression scores (n=9), though subjective perception of craving was higher in those with mild/moderate depression scores. We corroborated a higher DAT methylation in AD patients than HCs, and showed higher DAT methylation in AD patients with mild/moderate than low depression scores. Within the AD cohort, higher methylation predicted craving and, at trend level (P=0.095), relapse 1 year after abstinence. Finally, we show that amygdala cue reactivity correlated with craving and DAT methylation only in AD patients with low depression scores. These findings suggest that depressive symptoms and DAT methylation are associated with alcohol craving and associated brain processes in alcohol dependence, which may have important consequences for treatment. Moreover, peripheral DAT methylation may be a clinically relevant biomarker in AD patients

P11 promoter methylation predicts the antidepressant effect of electroconvulsive therapy

Although electroconvulsive therapy (ECT) is among the most effective treatment options for pharmacoresistant major depressive disorder (MDD), some patients still remain refractory to standard ECT practise. Thus, there is a need for markers reliably predicting ECT non/response. In our study, we have taken a novel translational approach for discovering potential biomarkers for the prediction of ECT response. Our hypothesis was that the promoter methylation of p11, a multifunctional protein involved in both depressive-like states and antidepressant treatment responses, is differently regulated in ECT responders vs. nonresponders and thus be a putative biomarker of ECT response. The chronic mild stress model of MDD was adapted with the aim to obtain rats that are resistant to conventional antidepressant drugs (citalopram). Subsequently, electroconvulsive stimulation (ECS) was used to select responders and nonresponders, and compare p11 expression and promoter methylation. In the rat experiments we found that the gene promoter methylation and expression of p11 significantly correlate with the antidepressant effect of ECS. Next, we investigated the predictive properties of p11 promoter methylation in two clinical cohorts of patients with pharmacoresistant MDD. In a proof-of-concept clinical trial in 11 patients with refractory MDD, higher p11 promoter methylation was found in responders to ECT. This finding was replicated in an independent sample of 65 patients with pharmacoresistant MDD. This translational study successfully validated the first biomarker reliably predicting the responsiveness to ECT. Prescreening of this biomarker could help to identify patients eligible for first-line ECT treatment and also help to develop novel antidepressant treatment procedures for depressed patients resistant to all currently approved antidepressant treatments.Peer reviewe

Tracing North Atlantic volcanism and seaway connectivity across the Paleocene–Eocene Thermal Maximum (PETM)

Abstract. There is a temporal correlation between the peak activity of the North Atlantic Igneous Province (NAIP) and the Paleocene–Eocene Thermal Maximum (PETM), suggesting that the NAIP may have initiated and/or prolonged this extreme warming event. However, corroborating a causal relationship is hampered by a scarcity of expanded sedimentary records that contain both climatic and volcanic proxies. One locality hosting such a record is the island of Fur in Denmark, where an expanded pre- to post-PETM succession containing hundreds of NAIP ash layers is exceptionally well preserved. We compiled a range of environmental proxies, including mercury (Hg) anomalies, paleotemperature proxies, and lithium (Li) and osmium (Os) isotopes, to trace NAIP activity, hydrological changes, weathering, and seawater connectivity across this interval. Volcanic proxies suggest that NAIP activity was elevated before the PETM and appears to have peaked during the body of the δ13C excursion but decreased considerably during the PETM recovery. This suggests that the acme in NAIP activity, dominated by flood basalt volcanism and thermogenic degassing from contact metamorphism, was likely confined to just ∼ 200 kyr (ca. 56.0–55.8 Ma). The hundreds of thick (> 1 cm) basaltic ashes in the post-PETM strata likely represent a change from effusive to explosive activity, rather than an increase in NAIP activity. Detrital δ7Li values and clay abundances suggest that volcanic ash production increased the basaltic reactive surface area, likely enhancing silicate weathering and atmospheric carbon sequestration in the early Eocene. Signals in lipid biomarkers and Os isotopes, traditionally used to trace paleotemperature and weathering changes, are used here to track seaway connectivity. These proxies indicate that the North Sea was rapidly cut off from the North Atlantic in under 12 kyr during the PETM recovery due to NAIP thermal uplift. Our findings reinforce the hypothesis that the emplacement of the NAIP had a profound and complex impact on Paleocene–Eocene climate, both directly through volcanic and thermogenic degassing and indirectly by driving regional uplift and changing seaway connectivity

Effects of redox variability and early diagenesis on marine sedimentary Hg records

Volcanism is a dominant natural source of mercury (Hg) to the atmosphere, biosphere, ocean and sediments. In recent years, sedimentary Hg contents have emerged as a tool to reconstruct volcanic activity, and particularly activity of (subaerially emplaced) large igneous provinces in geological deep time. More specifically, Hg has shown potential as a useful proxy to illuminate the previously elusive impact of such large-scale volcanism on marine and terrestrial paleo-environments. While Hg is now widely applied as volcanism tracer, non-volcanic factors controlling sedimentary Hg content are generally not well constrained. Part of this uncertainty stems from our inability to directly observe a natural unperturbed “steady-state” environment as a baseline, as the modern Hg cycle is heavily influenced by anthropogenic activity. Here we focus on the effects of ambient redox conditions in the water column and shallow sediments (early diagenesis), quantify their influence on the geological Hg record and thereby contribute to constraining their potential impact on the use of Hg as a proxy for deep-time volcanic activity. Constraining these factors is of critical importance for the application of Hg as such a proxy. Many periods in the geological past for which records have been generated, such as the Mesozoic Oceanic Anoxic Events, are marked by a variety of high-amplitude environmental perturbations, including widespread deoxygenation and deposition of organic-rich sediments. We estimate the impact of redox changes and early diagenesis on the geological Hg record using a suite of (sub)recent–Pleistocene and Upper Cretaceous sediments representing oxic to euxinic marine conditions. Our sample set includes a transect through an oxygen minimum zone and cores that record transient shifts in oxygenation state, as well as post-depositional effects – all unrelated to volcanism, to the best of our knowledge. We find substantial alterations to the Hg record and the total organic carbon and total sulfur content, which are typically assumed to be the most common carrier phases of Hg in marine sediments. Moreover, these biases can lead to signal alteration on a par with those interpreted to result from volcanic activity. Geochemical modifications are ubiquitous and their potential magnitude implies that the factors leading to biases in the geological record warrant careful consideration before interpretation. Factors of particular concern to proxy application are (1) the disproportionate loss of organic carbon and sulfur relative to Hg during oxidation that strongly modulates normalized Hg records, (2) the evasion of Hg in anoxic and mildly euxinic sediments and (3) sharp focusing of Hg during post-depositional oxidation of organic matter. We suggest that paired analyses of additional redox-sensitive trace elements such as molybdenum, and organic-matter characteristics, particularly the type of organic matter, could provide first-order constraints on the role that redox and diagenetic changes played in shaping the Hg record as part of checking the attribution of enrichments to volcanic activity

The DeepMIP contribution to PMIP4: methodologies for selection, compilation and analysis of latest Paleocene and early Eocene climate proxy data, incorporating version 0.1 of the DeepMIP database

This is the final version of the article. Available from European Geosciences Union via the DOI in this record.Data availability. The data referenced in this manuscript are provided as Supplement Data Files 1 to 8. In the final version, these files will form DeepMIP database version 0.1 and will be accessible online via a citable DOI reference.The early Eocene (56 to 48 million years ago) is inferred to have been the most recent time that Earth's atmospheric CO2 concentrations exceeded 1000 ppm. Global mean temperatures were also substantially warmer than those of the present day. As such, the study of early Eocene climate provides insight into how a super-warm Earth system behaves and offers an opportunity to evaluate climate models under conditions of high greenhouse gas forcing. The Deep Time Model Intercomparison Project (DeepMIP) is a systematic model–model and model–data intercomparison of three early Paleogene time slices: latest Paleocene, Paleocene–Eocene thermal maximum (PETM) and early Eocene climatic optimum (EECO). A previous article outlined the model experimental design for climate model simulations. In this article, we outline the methodologies to be used for the compilation and analysis of climate proxy data, primarily proxies for temperature and CO2. This paper establishes the protocols for a concerted and coordinated effort to compile the climate proxy records across a wide geographic range. The resulting climate “atlas” will be used to constrain and evaluate climate models for the three selected time intervals and provide insights into the mechanisms that control these warm climate states. We provide version 0.1 of this database, in anticipation that this will be expanded in subsequent publications.Natural Environment Research Council (NERC)GNS Science Global Change through Time ProgrammeNational Science Foundation (NSF)KU Leuve

Volcanism and carbon cycle perturbations in the High Arctic during the Late Jurassic – Early Cretaceous

This is the final version. Available on open access from Elsevier via the DOI in this recordLarge perturbations in the global carbon cycle recorded as carbon-isotope (δ13C) excursions (CIEs) in both organic carbon and carbonate records have been linked to volcanism during the emplacement of Large Igneous Provinces (LIPs). This link is based primarily on the purported temporal coincidence between CIEs and LIP emplacement. Mercury (Hg) concentration in sedimentary rocks has been used as a regional to global tracer of large-scale volcanic activity, yet few studies have been undertaken on Upper Jurassic – Lower Cretaceous sediments from Boreal localities compared to those for Tethyan (northern mid-latitude) successions. This has limited our understanding of the regional-to-global spatial impact of volcanic activity during this period. This study examines the Hg record as a proxy for volcanism, and the δ13C records from organic matter (δ13Corg) of CIEs from the uppermost Jurassic to Lower Cretaceous (Callovian – Aptian) successions from Axel Heiberg and Spitsbergen in the Canadian Arctic and Svalbard archipelagos, respectively. This interval includes three regional- to global CIEs. These sections show no significant variation in the ratio of Hg to total organic carbon (TOC) across the Boreal-wide Volgian negative CIE (Volgian Isotopic Carbon Excursion, “VOICE”), which has not been associated with LIP volcanism. The examined successions spanning this interval all show some influence from changing environmental or post-burial parameters, however, which could have (partially) overprinted a volcanic signal. Despite some problems in stratigraphically constraining the Weissert Event, increased Hg/TOC ratios are observed across this interval, which may be partially driven by volcanism associated with the emplacement of the Paraná-Etendeka Traps. A spike in Hg/TOC is observed immediately prior to the negative peak of the Aptian Oceanic Anoxic Event (OAE1a) CIE, supporting recent evidence of a pulse of High Arctic Large Igneous Province (HALIP) volcanic activity preceding this oceanic anoxic event

Why Does the Giant Panda Eat Bamboo? A Comparative Analysis of Appetite-Reward-Related Genes among Mammals

Background: The giant panda has an interesting bamboo diet unlike the other species in the order of Carnivora. The umami taste receptor gene T1R1 has been identified as a pseudogene during its genome sequencing project and confirmed using a different giant panda sample. The estimated mutation time for this gene is about 4.2 Myr. Such mutation coincided with the giant panda’s dietary change and also reinforced its herbivorous life style. However, as this gene is preserved in herbivores such as cow and horse, we need to look for other reasons behind the giant panda’s diet switch. Methodology/Principal Findings: Since taste is part of the reward properties of food related to its energy and nutrition contents, we did a systematic analysis on those genes involved in the appetite-reward system for the giant panda. We extracted the giant panda sequence information for those genes and compared with the human sequence first and then with seven other species including chimpanzee, mouse, rat, dog, cat, horse, and cow. Orthologs in panda were further analyzed based on the coding region, Kozak consensus sequence, and potential microRNA binding of those genes. Conclusions/Significance: Our results revealed an interesting dopamine metabolic involvement in the panda’s food choice