Millennial-scale climatic cycles in the Early Pliocene pollen record of Ptolemais, northern Greece

Early Pliocene lacustrine sediments from the Ptolemais Basin, northern Greece, exhibit a climatically induced cyclicity, which can be correlated with the orbital cycle of precession. Superimposed on precession-controlled cycles, palynological time-series data reveal a higher-order climatic cyclicity with periodicities of ∼10, ∼2.5, and ∼1.5 ka. These millennial-scale vegetation changes are likely to reflect changes of the soil-moisture gradient on mountain slopes, caused by fluctuations in orographic winter-precipitation. Such fluctuations corroborate the concept of a NAO-like North Atlantic climatic teleconnection during Early Pliocene times. The periodicities are similar to those of climate oscillations inferred from Quaternary records. The occurrence of millennial-scale cyclicity in a time interval when the Northern Hemisphere was essentially ice-free, implies an ultimate forcing mechanism that operated independently of changes in the thermohaline circulation in the Atlantic Ocean. The cycles are likely to be related to long-period variations in solar activity.     

Laboratory scale enclosure: concept, construction and operation

A laboratory scale enclosure (LSE) was devised for studyingthe seston dynamics in shallow, wind-mixed lakes. The LSE isa continuous flow system suitable for mass balance studies oflake water columns, and for cultivation of phytoplankton speciesas a reference for potential growth at the lake's light andmixing regime. The construction of the LSE is described in detail.Results are given on the operation with water from Lake Loosdrecht(The Netherlands). The coefficient of vertical mixing in theLSE was variable from 7.6 to 25.6 cm² s^–1, i.e. similarto values reported for shallow, wind-exposed lakes. On average,the vertical light attenuation and the spectral changes withdepth in the LSE agreed well with the in situ underwater lightclimate. Mass balances for phosphorus and oxygen could be accuratelyestablished, while the loss of paniculate matter due to settlingand wall growth was insignificant. The LSE may also be appliedas an incubator for primary production measurements in a ‘natural’light gradient and allowed prolonged continuous cultivationof Prochlorothrix hollandica.     

Modulatory Effects of the Piccolo Genotype on Emotional Memory in Health and Depression

Major depressive disorder (MDD) has been associated with biased memory formation for mood-congruent information, which may be related to altered monoamine levels. The piccolo (PCLO) gene, involved in monoaminergic neurotransmission, has previously been linked to depression in a genome-wide association study. Here, we investigated the role of the PCLO risk allele on functional magnetic resonance imaging (MRI) correlates of emotional memory in a sample of 89 MDD patients (64 PCLO risk allele carriers) and 29 healthy controls (18 PCLO risk allele carriers). During negative word encoding, risk allele carriers showed significant lower activity relative to non-risk allele carriers in the insula, and trend-wise in the anterior cingulate cortex and inferior frontal gyrus. Moreover, depressed risk allele carriers showed significant lower activity relative to non-risk allele carriers in the striatum, an effect which was absent in healthy controls. Finally, amygdalar response during processing new positive words vs. known words was blunted in healthy PCLO+ carriers and in MDD patients irrespective of genotype, which may indicate that signalling of salient novel information does not occur to the same extent in PCLO+ carriers and MDD patients. The PCLO risk allele may increase vulnerability for MDD by modulating local brain function with regard to responsiveness to salient stimuli (i.e. insula) and processing novel negative information. Also, depression-specific effects of PCLO on dorsal striatal activation during negative word encoding and the absence of amygdalar salience signalling for novel positive information further suggest a role of PCLO in symptom maintenance in MDD.     

Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children

Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day– 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect.     

Protein Kinase C Activation Upregulates Intercellular Adhesion of α-Catenin–negative Human Colon Cancer Cell Variants via Induction of Desmosomes

The α-catenin molecule links E-cadherin/ β-catenin or E-cadherin/plakoglobin complexes to the actin cytoskeleton. We studied several invasive human colon carcinoma cell lines lacking α-catenin. They showed a solitary and rounded morphotype that correlated with increased invasiveness. These round cell variants acquired a more normal epithelial phenotype upon transfection with an α-catenin expression plasmid, but also upon treatment with the protein kinase C (PKC) activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Video registrations showed that the cells started to establish elaborated intercellular junctions within 30 min after addition of TPA. Interestingly, this normalizing TPA effect was not associated with α-catenin induction. Classical and confocal immunofluorescence showed only minor TPA-induced changes in E-cadherin staining. In contrast, desmosomal and tight junctional proteins were dramatically rearranged, with a conversion from cytoplasmic clusters to obvious concentration at cell–cell contacts and exposition at the exterior cell surface. Electron microscopical observations revealed the TPA-induced appearance of typical desmosomal plaques. TPA-restored cell–cell adhesion was E-cadherin dependent as demonstrated by a blocking antibody in a cell aggregation assay. Addition of an antibody against the extracellular part of desmoglein-2 blocked the TPA effect, too. Remarkably, the combination of anti–E-cadherin and anti-desmoglein antibodies synergistically inhibited the TPA effect.

Our studies show that it is possible to bypass the need for normal α-catenin expression to establish tight intercellular adhesion by epithelial cells. Apparently, the underlying mechanism comprises upregulation of desmosomes and tight junctions by activation of the PKC signaling pathway, whereas E-cadherin remains essential for basic cell–cell adhesion, even in the absence of α-catenin.

     

The Chimpanzee''s service economy: Food for grooming

Evidence is presented that the reciprocal exchange of social services among chimpanzees (Pan troglodytes) rests on cognitive abilities that allow current behavior to be contingent upon a history of interaction. Food sharing within a captive colony of chimpanzees was studied by means of 200 food trials, conducted on separate daus over a 3-year period, in which 6,972 approaches occurred among the nine adults in the colony. The success rate of each adult, A, to obtain food from another adult, B, was compared with grooming interactions between A and B in the 2 hours prior to each food trial. The tendency of B to share with A was higher if A had groomed B than if A had not done so. The exchange was partner-specific, i.e., the effect of previous grooming on the behavior of food possessors was limited to the grooming partner. Grooming did not affect subsequent sharing by the groomer, only by the groomee. The effect of grooming was greatest for pairs of adults who rarely groomed. Nevertheless, the effect was general: 31 dyadic directions showed an increase in sharing following grooming, and only 11 a decrease. Food possessors actively resisted approaches by individuals who had not groomed them. After food trials there was a significant reduction of grooming by previous possessors towards those individuals with whom they had shared.