A systematic investigation of the protein kinases involved in NMDA receptor-dependent LTD: evidence for a role of GSK-3 but not other serine/threonine kinases

Background: The signalling mechanisms involved in the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression (LTD) in the hippocampus are poorly understood. Numerous studies have presented evidence both for and against a variety of second messengers systems being involved in LTD induction. Here we provide the first systematic investigation of the involvement of serine/threonine (ser/thr) protein kinases in NMDAR-LTD, using whole-cell recordings from CA1 pyramidal neurons. Results: Using a panel of 23 inhibitors individually loaded into the recorded neurons, we can discount the involvement of at least 57 kinases, including PKA, PKC, CaMKII, p38 MAPK and DYRK1A. However, we have been able to confirm a role for the ser/thr protein kinase, glycogen synthase kinase 3 (GSK-3). Conclusion: The present study is the first to investigate the role of 58 ser/thr protein kinases in LTD in the same study. Of these 58 protein kinases, we have found evidence for the involvement of only one, GSK-3, in LTD

Environmental change over the last millennium recorded in two contrasting crater lakes in western Uganda, eastern Africa (Lakes Kasenda and Wandakara)

The last millennium is a key period for understanding environmental change in eastern Africa, as there is clear evidence of marked fluctuations in climate (effective moisture) that place modern concern with future climate change in a proper context, both in terms of environmental and societal impacts and responses. Here, we compare sediment records from two small, nearby, closed crater lakes in western Uganda (Lake Kasenda and Lake Wandakara), spanning the last 700 (Wandakara) and 1200 years (Kasenda) respectively. Multiproxy analyses of chemical sedimentary parameters (including C/N ratios, δ13C of bulk organic matter and δ13C and δ18O of authigenic carbonates) and biotic remains (diatoms, aquatic macrofossils, chironomids) suggest that Kasenda has been sensitive to climate over much of this period, and has shown substantial fluctuations in conductivity, while Wandakara has a more muted response, likely due to the increasing dominance of human activity as a driver of change within the lake and catchment over the length of our record. Evidence from both records, however, supports the idea that lake levels were low from ∼AD 700–1000 AD, with increasing aridity from AD 1100–1600, and brief wet phases around AD 1000 and 1400. Wetter conditions are recorded in the 1700s, but drought returned by the end of the century and into the early 1800s, becoming wetter again from the mid-1800s. Comparison with other records across eastern Africa suggests that while some events are widespread (e.g. aridity beginning ∼ AD 1100), at other times there is a more complex spatial signature (e.g. in the 1200s to 1300s, and from the 1400s to 1600s). This study highlights the important role of catchment-specific factors (e.g. lakemorphometry, catchment size, and human impact) in modulating the sensitivity of proxies, and lake records, as indicators of environmental change, and potential hazards when regional inference is based on a single site or proxy

The shellfish enigma across the Mesolithic-Neolithic transition in southern Scandinavia

The well-known and widespread replacement of oysters (abundant during the Mesolithic period) by cockles and mussels in many Danish Stone Age shell middens ca. 5900 cal yrs BP coincides with the transition to agriculture in southern Scandinavia. This human resource shift is commonly believed to reflect changing resource availability, driven by environmental and/or climatic change at the Mesolithic-Neolithic transition rather than cultural choice. While several hypotheses have been proposed to explain the “Mesolithic-Neolithic oyster decline”, an explanation based on a sudden freshening of the inner Danish waters has received most attention. Here, for the first time, we test and refute this long-standing hypothesis that declining salinity explains the marked reduction in oysters identified within numerous shell middens across coastal Denmark at the Mesolithic-Neolithic transition using quantitative and qualitative salinity inference from several, independent proxies (diatoms, molluscs and foraminifera) from multiple Danish fjord sites. Alternatively, we attribute the oyster decline to other environmental causes (particularly changing sedimentation), ultimately driven by external climatic forcing. Critical application of such high-quality environmental archives can reinvigorate archaeological debates and can aid in understanding and managing environmental change in increasingly impacted coastal regions

δ18O-inferred salinity from Littorina littorea (L.) gastropods in a Danish shell midden at the Mesolithic–Neolithic transition

Norsminde Fjord has received extensive geoarchaeological investigation, hosting one of the classic Stone Age shell midden sites in Denmark, and one of the best examples of the widespread oyster decline at the Mesolithic–Neolithic transition. Here, intra-shell δ18O (and δ13C) analyses from the common periwinkle Littorina littorea (L.) are used to infer inter-annual environmental changes at the Mesolithic–Neolithic transition (four from each period). This study utilises a modern δ18O L. littorea-salinity training set previously developed for the Limfjord, Denmark to quantify winter salinity. δ18O values range between +1.6% and +4.0% in the late Mesolithic and ‒6.3% to +2.0% in the early Neolithic. Using maximum δ18O values, winter salinity at the known temperature of growth cessation in L. littorea (i.e. +3.7 ± 1°C) for the first annual cycle of each shell ranges between 25.5 and 26.8 psu (standard deviation (SD): 0.56) for the late Mesolithic, with an average salinity of 26.1 psu. Early-Neolithic shells range between 19.4 and 28.2 psu (SD: 4.59) with an average salinity of 23.7 psu. No statistically significant change in salinity occurs between the late Mesolithic and early Neolithic. This result supports recent diatom/mollusc-based inferences that salinity was not the sole cause of the oyster decline, although some evidence is presented here for more variable seasonal salinity conditions in the early Neolithic, which (along sedimentary change and temperature deterioration) might have increased stress on oyster populations in some years. It is recommended here that for robust palaeoenvironmental inferences, where possible, multiple specimens should be used from the same time period in conjunction with multiproxy data

Glycogen Synthase Kinase (GSK) 3β phosphorylates and protects nuclear myosin 1c from proteasome-mediated degradation to activate rDNA transcription in early G1 cells

Nuclear myosin 1c (NM1) mediates RNA polymerase I (pol I) transcription activation and cell cycle progression by facilitating PCAF-mediated H3K9 acetylation, but the molecular mechanism by which NM1 is regulated remains unclear. Here, we report that at early G1 the glycogen synthase kinase (GSK) 3β phosphorylates and stabilizes NM1, allowing for NM1 association with the chromatin. Genomic analysis by ChIP-Seq showed that this mechanism occurs on the rDNA as active GSK3β selectively occupies the gene. ChIP assays and transmission electron microscopy in GSK3β-/- mouse embryonic fibroblasts indicated that at G1 rRNA synthesis is suppressed due to decreased H3K9 acetylation leading to a chromatin state incompatible with transcription. We found that GSK3β directly phosphorylates the endogenous NM1 on a single serine residue (Ser-1020) located within the NM1 C-terminus. In G1 this phosphorylation event stabilizes NM1 and prevents NM1 polyubiquitination by the E3 ligase UBR5 and proteasome-mediated degradation. We conclude that GSK3β-mediated phosphorylation of NM1 is required for pol I transcription activation

Co-prescription of medication for bipolar disorder and diabetes mellitus : a nationwide population based study with focus on gender differences

BackgroundStudies have shown a correlation between bipolar disorder and diabetes mellitus. It is unclear if this correlation is a part of common pathophysiological pathways, or if medication for bipolar disorder has negative effects on blood sugar regulation.MethodsThe Norwegian prescription database was analyzed. Prescriptions for lithium, lamotrigine, carbamazepine and valproate were used as proxies for bipolar disorder. Prescriptions for insulin and oral anti-diabetic agents were used as proxies for diabetes mellitus. We explored the association between medication for bipolar disorder and diabetes medication by logistic regressionResultsWe found a strong association between concomitant use of medication to treat diabetes mellitus and mood stabilizers for the treatment of bipolar disorder. Females had a 30% higher risk compared to men of being treated for both disorders. Persons using oral anti-diabetic agents had higher odds of receiving valproate than either lithium or lamotrigine. Use of insulin as monotherapy seemed to have lower odds than oral anti-diabetic agents of co-prescription of mood stabilizers, compared to the general population.ConclusionsThis study showed a strong association between the use of mood stabilizers and anti-diabetic agents. The association was stronger among women than men

Stabilisation of β-Catenin Downstream of T Cell Receptor Signalling

The role of TCF/β-catenin signalling in T cell development is well established, but important roles in mature T cells have only recently come to light.Here we have investigated the signalling pathways that are involved in the regulation of β-catenin in primary human T cells. We demonstrate that β-catenin expression is upregulated rapidly after T cell receptor (TCR) stimulation and that this involves protein stabilisation rather than an increase in mRNA levels. Similar to events in Wnt signalling, the increase in β-catenin coincides with an inhibition of GSK3, the kinase that is required for β-catenin degradation. β-catenin stabilisation in T cells can also be induced by the activation of PKC with phorbol esters and is blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K) and phospholipase C (PKC). Upon TCR signalling, β-catenin accumulates in the nucleus and, parallel to this, the ratio of TCF1 isoforms is shifted in favour of the longer β-catenin binding isoforms. However, phosphorylated β-catenin, which is believed to be inactive, can also be detected and the expression of Wnt target genes Axin2 and dickkopf is down regulated.These data show that in mature human T cells, TCR signalling via PI3K and PKC can result in the stabilisation of β-catenin, allowing β-catenin to migrate to the nucleus. They further highlight important differences between β-catenin activities in TCR and Wnt signalling

Lithium Impacts on the Amplitude and Period of the Molecular Circadian Clockwork

Lithium salt has been widely used in treatment of Bipolar Disorder, a mental disturbance associated with circadian rhythm disruptions. Lithium mildly but consistently lengthens circadian period of behavioural rhythms in multiple organisms. To systematically address the impacts of lithium on circadian pacemaking and the underlying mechanisms, we measured locomotor activity in mice in vivo following chronic lithium treatment, and also tracked clock protein dynamics (PER2::Luciferase) in vitro in lithium-treated tissue slices/cells. Lithium lengthens period of both the locomotor activity rhythms, as well as the molecular oscillations in the suprachiasmatic nucleus, lung tissues and fibroblast cells. In addition, we also identified significantly elevated PER2::LUC expression and oscillation amplitude in both central and peripheral pacemakers. Elevation of PER2::LUC by lithium was not associated with changes in protein stabilities of PER2, but instead with increased transcription of Per2 gene. Although lithium and GSK3 inhibition showed opposing effects on clock period, they acted in a similar fashion to up-regulate PER2 expression and oscillation amplitude. Collectively, our data have identified a novel amplitude-enhancing effect of lithium on the PER2 protein rhythms in the central and peripheral circadian clockwork, which may involve a GSK3-mediated signalling pathway. These findings may advance our understanding of the therapeutic actions of lithium in Bipolar Disorder or other psychiatric diseases that involve circadian rhythm disruptions

Diel surface temperature range scales with lake size

Ecological and biogeochemical processes in lakes are strongly dependent upon water temperature. Long-term surface warming of many lakes is unequivocal, but little is known about the comparative magnitude of temperature variation at Diel timescales, due to a lack of appropriately resolved data. Here we quantify the pattern and magnitude of Diel temperature variability of surface waters using high-frequency data from 100 lakes. We show that the near-surface Diel temperature range can be substantial in summer relative to long-term change and, for lakes smaller than 3 km2, increases sharply and predictably with decreasing lake area. Most small lakes included in this study experience average summer Diel ranges in their near-surface temperatures of between 4 and 7°C. Large Diel temperature fluctuations in the majority of lakes undoubtedly influence their structure, function and role in biogeochemical cycles, but the full implications remain largely unexplored