Predicting the subsurface

Britain is blessed with a magnificent variety of landscapes, much of it the result of the diverse range of rock types that form our small island, and the different ways in which they respond to weathering and erosion. Nowhere is this clearer than when enjoying a walk along many of the paths that snake around our coastline; dramatic colour changes in the cliffs, steep climbs and descents between headlands and bays all reflect changes in the underlying geology. Sometimes the connection is obvious, such as the contrast between the low, sandy and muddy cliffs that tumble into the sea along the coast of Essex, and the rugged white cliffs on the south coast of England. These natural features, which we take for granted, have a significant impact on how we live and move about our island

Influence of the TARP γ8-selective negative allosteric modulator JNJ-55511118 on AMPA receptor gating and channel conductance

AMPARs mediate excitatory signaling in the brain and are therapeutic targets for the treatment of diverse neurological disorders. The receptors interact with a variety of auxiliary subunits, including the transmembrane AMPAR regulatory proteins (TARPs). The TARPs influence AMPAR biosynthesis and trafficking and enhance receptor responses by slowing desensitization and deactivation and increasing single-channel conductance. TARP γ8 has an expression pattern that is distinct from other TARPs, being enriched in the hippocampus. Recently, several compounds have been identified that selectivity inhibit γ8-containing AMPARs. One such inhibitor, JNJ-55511118, has shown considerable promise for the treatment of epilepsy. However, key details of its mechanism of action are still lacking. Here, using patch-clamp electrophysiological recording from heterologously expressed AMPARs, we show that JNJ-55511118 inhibits peak currents of γ8-containing AMPARs by decreasing their single-channel conductance. The drug also modifies hallmark features of AMPAR pharmacology, including the TARP-dependent actions of intracellular polyamines and the partial agonist kainate. Moreover, we find that JNJ-5551118 reduces the influence of γ8 on all biophysical measures, aside from its effect on the recovery from desensitization. The drug is also effective when applied intracellularly, suggesting it may access its binding site from within the membrane. Additionally, we find that AMPARs incorporating TARP γ2 mutated to contain the JNJ-55511118 binding site, exhibit greater block than seen with AMPARs containing γ8, potentially reflecting differences in TARP stoichiometry. Taken together, our data provide new insight into the mechanism by which γ8-selective drugs inhibit AMPARs

Speleothem U-series constraints on scarp retreat rates and landscape evolution: an example from the Severn valley and Cotswold Hills gull-caves, UK

Modelling landscape evolution requires quantitative estimates of erosional processes. Dating erosional landscape features such as escarpments is usually difficult because of the lack of datable deposits. Some escarpments and valley margins are associated with the formation of mass-movement caves, sometimes known as ‘gull’ or ‘crevice’ caves, which are typically restricted to within 0.5 km of the valley margin or scarp edge. As in other caves, these mass-movement cavities may host speleothems. As gull-caves develop only after valley incision, uranium-series dating of speleothems within them can provide a minimum age for the timing of valley excavation and scarp formation. Here we present data from several gull-caves in the Cotswold Hills, which form the eastern flank of the Severn valley in southern England. U-series ages from these gull-caves yield estimates for both the minimum age of the Cotswold escarpment and the maximum scarp retreat rate. This is combined with data from geological modelling to propose a model for the evolution of the Severn valley and the Cotswold Hills. The data suggest that the location of the escarpment and regional topography is determined not by valley widening and scarp retreat, but by the in situ generation of relief by differential erosion

Enhanced functional detection of synaptic calcium-permeable AMPA receptors using intracellular NASPM

Calcium-permeable AMPA-type glutamate receptors (CP-AMPARs) contribute to many forms of synaptic plasticity and pathology. They can be distinguished from GluA2-containing calcium-impermeable AMPARs by the inward rectification of their currents, which reflects voltage-dependent channel block by intracellular spermine. However, the efficacy of this weakly permeant blocker is differentially altered by the presence of AMPAR auxiliary subunits - including transmembrane AMPAR regulatory proteins, cornichons and GSG1L - which are widely expressed in neurons and glia. This complicates the interpretation of rectification as a measure of CP-AMPAR expression. Here we show that inclusion of the spider toxin analogue 1‑naphthylacetyl spermine (NASPM) in the intracellular solution results in complete block of GluA1-mediated outward currents irrespective of the type of associated auxiliary subunit. In neurons from GluA2-knockout mice expressing only CP-AMPARs, intracellular NASPM, unlike spermine, completely blocks outward synaptic currents. Thus, our results identify a functional measure of CP-AMPARs, that is unaffected by their auxiliary subunit content

Molecular mechanisms contributing to TARP regulation of channel conductance and polyamine block of calcium-permeable AMPA receptors.

Many properties of fast synaptic transmission in the brain are influenced by transmembrane AMPAR regulatory proteins (TARPs) that modulate the pharmacology and gating of AMPA-type glutamate receptors (AMPARs). Although much is known about TARP influence on AMPAR pharmacology and kinetics through their modulation of the extracellular ligand-binding domain (LBD), less is known about their regulation of the ion channel region. TARP-induced modifications in AMPAR channel behavior include increased single-channel conductance and weakened block of calcium-permeable AMPARs (CP-AMPARs) by endogenous intracellular polyamines. To investigate how TARPs modify ion flux and channel block, we examined the action of γ-2 (stargazin) on GluA1 and GluA4 CP-AMPARs. First, we compared the permeation of organic cations of different sizes. We found that γ-2 increased the permeability of several cations but not the estimated AMPAR pore size, suggesting that TARP-induced relief of polyamine block does not reflect altered pore diameter. Second, to determine whether residues in the TARP intracellular C-tail regulate polyamine block and channel conductance, we examined various γ-2 C-tail mutants. We identified the membrane proximal region of the C terminus as crucial for full TARP-attenuation of polyamine block, whereas complete deletion of the C-tail markedly enhanced the TARP-induced increase in channel conductance; thus, the TARP C-tail influences ion permeation. Third, we identified a site in the pore-lining region of the AMPAR, close to its Q/R site, that is crucial in determining the TARP-induced changes in single-channel conductance. This conserved residue represents a site of TARP action, independent of the AMPAR LBD

Synapse Type-Dependent Expression of Calcium-Permeable AMPA Receptors

Calcium-permeable (CP) AMPA-type glutamate receptors (AMPARs) are known to mediate synaptic plasticity in several different interneuron (IN) types. Recent evidence suggests that CP-AMPARs are synapse-specifically expressed at excitatory connections onto a subset of IN types in hippocampus and neocortex. For example, CP-AMPARs are found at connections from pyramidal cells (PCs) to basket cells (BCs), but not to Martinotti cells (MCs). This synapse type-specific expression of CP-AMPARs suggests that synaptic dynamics as well as learning rules are differentially implemented in local circuits and has important implications not just in health but also in disease states such as epilepsy

Nutritional practices to manage menstrual cycle related symptoms: A systematic review

Certain nutritional practices may reduce menstrual-related symptoms, but there is no current consensus on what foods/supplements are sufficiently evidenced to warrant promotion to reduce menstrual symptoms of naturally menstruating individuals. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two online databases were searched for published experimental studies that investigated the effects of foods/supplements on menstrual-related symptoms in eumenorrheic women. Extracted data and study characteristics were tabulated and grouped based on food/supplement intervention and dosage compared to UK dietary reference values (DRVs) and safe upper limits. In total, 28 studies and 21 different foods/supplement interventions were included in the review. None of the studies reported a negative effect on symptoms, 23 reported a positive effect and 5 had no effect. Eighteen different ways of measuring menstrual-related symptoms were described across the studies. The results indicate a lack of consistency in studies to confidently provide information to eumenorrheic, naturally menstruating women regarding the use of foods/supplements to reduce menstrual symptoms. Determination of menstrual-related symptoms varied along with dose and duration of food or supplements provided. These data provide some evidence for the use of vitamin D, calcium, zinc and curcumin to reduce menstrual related symptoms of non-hormonal contraceptive users, on an individual basis, however further investigation is required prior to implementation with a focus on robust protocols to determine and measure changes in menstrual symptoms, with interventions adhering to DRVs and safe upper limits

The lithostratigraphical context of the English Chalk Rock (Turonian)

Correlations of borehole geophysical logs in the middle and upper Turonian Chalk Group are used to consider recent proposals for a revision in understanding of a unit of hardgrounds (Chalk Rock) and associated stratigraphy developed across parts of southern England. Along the northern edge of the London and Wessex basins, geophysical logs reveal a laterally continuous framework of correlatable inflection patterns in the New Pit Chalk, with the package of sediment immediately below the Chalk Rock showing a trend of lateral thinning and increasingly condensed sedimentation westwards into areas where the oldest of the Chalk Rock Hardgrounds (Ogbourne Hardground) is present. However, apart from local absence of the Glynde Marls Complex near the top of the New Pit Chalk, there is no evidence for the presence of a major erosion event. This questions recent interpretations of microcrinoid data, reportedly showing that the Ogbourne Hardground lithifies a stratigraphical level in the lower part of the New Pit Chalk, with the middle and upper parts of this unit corresponding with a hiatus and related short-lived globally significant sea level fall. Macrofossil biostratigraphy supports the geophysical log interpretations, with evidence of both younger and older parts of the New Pit Chalk below the Ogbourne Hardground. The data are consistent with the Ogbourne Hardground in Wiltshire and Berkshire representing a highly condensed equivalent of thickened nodular chalk fabrics at the base of the Lewes Nodular Chalk in the eastern Chilterns