Investigation of the in vitro toxicological properties of the synthetic cannabimimetic drug CP-47,497-C8

Cannabicyclohexanol (CP-47,497-C8) is a representative of a group of cannabimimetic cyclohexylphenols which is added to herbal mixtures as a cannabis substitute since 2008. Although in the beginning CP-47,497-C8 was the main ingredient of “Spice” and similar products, it was partly replaced by aminoalkylindole-type cannabinoid receptor agonists like JWH-018, JWH-073 or JWH-250, but never completely disappeared from the market. Since information on its toxicological properties is scarce, we investigated the effects of the drug in human derived cell lines. The cytotoxic effects were studied in a panel of assays (SRB, XTT, LDHe and NR tests) in a buccal derived (TR146) and a liver derived (HepG2) cell line. The strongest effects were seen in the two former assays at levels ≥ 7.5 μM indicating that the compound interferes with protein synthesis and causes membrane damage. In additional comet assays, DNA damage was detected at levels ≥ 10 μM. Experiments with lesion specific enzymes showed that these effects are not due to oxidative damage of DNA bases. The negative findings obtained in Salmonella/microsome assays and the positive results of micronucleus tests with the cell lines indicate that the compound does not cause gene mutations but acts on the chromosomal level. In contrast to other synthetic cannabinoids, no indication for estrogenic/antiestrogenic properties was seen in a luciferase assay with bone marrow derived U2-OS cells. In conclusion, our findings show that the drug has only weak cytotoxic properties. However, the induction of chromosomal damage indicates that it may cause adverse effects in users due to its impact on the stability of the genetic material.     

Ancient plant DNA reveals High Arctic greening during the Last Interglacial

Summer warming is driving a greening trend across the Arctic, with the potential for large-scale amplification of climate change due to vegetation-related feedbacks [Pearson et al., Nat. Clim. Chang. (3), 673–677 (2013)]. Because observational records are sparse and temporally limited, past episodes of Arctic warming can help elucidate the magnitude of vegetation response to temperature change. The Last Interglacial ([LIG], 129,000 to 116,000 y ago) was the most recent episode of Arctic warming on par with predicted 21st century temperature change [Otto-Bliesner et al., Philos. Trans. A Math. Phys. Eng. Sci. (371), 20130097 (2013) and Post et al., Sci. Adv. (5), eaaw9883 (2019)]. However, high-latitude terrestrial records from this period are rare, so LIG vegetation distributions are incompletely known. Pollen-based vegetation reconstructions can be biased by long-distance pollen transport, further obscuring the paleoenvironmental record. Here, we present a LIG vegetation record based on ancient DNA in lake sediment and compare it with fossil pollen. Comprehensive plant community reconstructions through the last and current interglacial (the Holocene) on Baffin Island, Arctic Canada, reveal coherent climate-driven community shifts across both interglacials. Peak LIG warmth featured a ∼400-km northward range shift of dwarf birch, a key woody shrub that is again expanding northward. Greening of the High Arctic—documented here by multiple proxies—likely represented a strong positive feedback on high-latitude LIG warming. Authenticated ancient DNA from this lake sediment also extends the useful preservation window for the technique and highlights the utility of combining traditional and molecular approaches for gleaning paleoenvironmental insights to better anticipate a warmer future.

The Arctic is greening as shrub biomass increases and vegetation ranges shift north in response to summer warming (1, 2). This process—one of the clearest terrestrial manifestations of climate change thus far—has major implications both for local ecosystems and for global energy balance and biogeochemical systems (3–5). In particular, taller shrubs darken otherwise snow-covered surfaces, contributing to the albedo feedback (6, 7), and enhanced evapotranspiration is expected to result in a positive greenhouse feedback (8). Shrub cover also impacts soil thermal regime, which may impact permafrost vulnerability (9–11). Because feedbacks related to Arctic greening are complex and potentially large in magnitude, estimating the extent and rate of northward shrub migration is a vital component of predicting future warming.Past warm periods serve as valuable analogs for understanding the extent of Arctic greening under well-constrained climate conditions. The Last Interglacial (LIG; Marine Isotope Stage [MIS] 5e, 129 to 116 ka [thousands of years before present]) was ∼1 °C warmer than the preindustrial period globally, but the Arctic experienced amplified warming due to higher summer insolation anomalies and positive feedbacks at high latitudes (12, 13). The Eastern Canadian Arctic and Greenland, in particular, were likely ∼4 to 8 °C warmer in summer than present (Fig. 1) (14–18). LIG sediment records from this region thus provide an archive of the vegetation response to Arctic warming at levels comparable to predicted 21^st-century climate change (19).Open in a separate windowFig. 1.Map of Baffin Island and Lake CF8 study area. The symbols represent maximum LIG temperature anomalies based on terrestrial proxy records (shape indicates proxy type) from Baffin Island and Greenland (see SI Appendix, Table S1 for metadata). The shaded regions indicate Arctic bioclimate subzones delineations (29), including modern Betula range in subzones D and E. We note that a small outlier population of Betula occurs east of the D/E boundary on Baffin Island (not captured by vegetation map resolution) (38).While most High Arctic lake basins were scraped clean by ice sheet erosion during the last glaciation and thus only contain postglacial sediments, lakes with small, low-relief catchments within regions of cold-based, slow-flowing ice were protected from erosion. Several such sites have been discovered on eastern Baffin Island, Arctic Canada and contain stratified records of multiple interglacials (20–22). Previous work from Lake CF8 on northeastern Baffin Island (Fig. 1 and SI Appendix, Fig. S1) demonstrates that its sediment record spans at least three interglacials (∼200 ka), including a substantially warmer-than-present LIG as indicated by chironomids, diatoms, and geochemical proxies (15, 23).We targeted the multi-interglacial record from Lake CF8 to assess the vegetation response to pronounced warmth during the LIG and moderate warmth during the Holocene. Pollen produced by some key shrubs and trees, including Betula (birch), is efficiently wind-transported and thus present in lake sediments far north of their ranges (24, 25). We therefore analyzed both sedimentary ancient DNA (sedaDNA), which is sourced locally from within the lake catchment and does not include pollen-derived DNA (26), and fossil pollen to generate a robust vegetation record spanning the last ∼130 ka. Taken together, DNA-inferred plant communities and pollen-inferred July air temperatures provide insight into Arctic plant range shifts under strong summer warming.     

Existential neuroscience: effects of mortality salience on the neurocognitive processing of attractive opposite-sex faces

Being reminded of the inherently finite nature of human existence has been demonstrated to elicit strivings for sexual reproduction and the formation and maintenance of intimate relationships. Recently, it has been proposed that the perception of potential mating partners is influenced by mortality salience. Using functional magnetic resonance imaging, we investigated the neurocognitive processing of attractive opposite-sex faces after priming with death-related words for heterosexual men and women. Significant modulations of behavioral and neural responses were found when participants were requested to decide whether they would like to meet the presented person. Men were more in favor of meeting attractive women after being primed with death-related words compared to a no-prime condition. Increased neural activation could be found under mortality salience in the left anterior insula and the adjacent lateral prefrontal cortex (lPFC) for both men and women. As previously suggested, we believe that the lPFC activation reflects an approach-motivated defense mechanism to overcome concerns that are induced by being reminded of death and dying. Our results provide insight on a neurocognitive level that approach motivation in general, and mating motivation in particular is modulated by mortality salience.     

Selective increase of in vivo firing frequencies in DA SN neurons after proteasome inhibition in the ventral midbrain

The impairment of protein degradation via the ubiquitin‐proteasome system (UPS) is present in sporadic Parkinson's disease (PD), and might play a key role in selective degeneration of vulnerable dopamine (DA) neurons in the substantia nigra pars compacta (SN). Further evidence for a causal role of dysfunctional UPS in familial PD comes from mutations in parkin, which results in a loss of function of an E3‐ubiquitin‐ligase. In a mouse model, genetic inactivation of an essential component of the 26S proteasome lead to widespread neuronal degeneration including DA midbrain neurons and the formation of alpha‐synuclein‐positive inclusion bodies, another hallmark of PD. Studies using pharmacological UPS inhibition in vivo had more mixed results, varying from extensive degeneration to no loss of DA SN neurons. However, it is currently unknown whether UPS impairment will affect the neurophysiological functions of DA midbrain neurons. To answer this question, we infused a selective proteasome inhibitor into the ventral midbrain in vivo and recorded single DA midbrain neurons 2 weeks after the proteasome challenge. We found a selective increase in the mean in vivo firing frequencies of identified DA SN neurons in anesthetized mice, while those in the ventral tegmental area (VTA) were unaffected. Our results demonstrate that a single‐hit UPS inhibition is sufficient to induce a stable and selective hyperexcitability phenotype in surviving DA SN neurons in vivo. This might imply that UPS dysfunction sensitizes DA SN neurons by enhancing ‘stressful pacemaking’.     

The Impact of Inpatient Multimodal Treatment or Family-Based Treatment on Six-Month Weight Outcomes in Youth with Anorexia Nervosa: A Naturalistic,Cross-Continental Comparison

In the USA, family-based treatment (FBT) with inpatient medical stabilization as needed is the leading evidence-based treatment for youth with anorexia nervosa (AN). In continental Europe, typically inpatient multimodal treatment targeting weight recovery followed by outpatient care (IMT) is standard care, if prior outpatient treatment was not sufficient. Our aim was to compare weekly weight gain and hospital days over six months for adolescents receiving FBT (USA) versus IMT (Germany) using naturalistic treatment data. To yield similar subgroups of youth aged 12–18 years, inclusion criteria were a percent median BMI (%mBMI) between 70–85 and the restrictive AN subtype. Weight gain and hospital days were compared, adjusted further in a multiple linear regression analysis (MLRA) for baseline group differences. Samples differed on baseline %mBMI (FBT [n = 71], 90.5 ± 12.8; IMT [n = 29], 78.3 ± 9.1, p < 0.05). In subgroups with comparable baseline %mBMI, the weekly weight gain over 6 months was similar (FBT [n = 21]: 0.35 ± 0.18 kg/week; IMT [n = 20]: 0.30 ± 0.18, p = 0.390, p = 0.166 after MLRA), but achieved fewer hospital days in FBT (FBT [n = 7]: 4 ± 6 days, IMT [n = 20]: 121 ± 42 days, p < 0.0001 before and after MLRA). FBT may be effective for a subgroup of adolescents with AN currently receiving IMT, but head-to-head studies in the same healthcare system are needed.