Relaxing benevolence: on the undesirability of socialist calculation when planners are human

The Austrian calculation argument suggests that inability to engage in economic calculation worsened outcomes in socialist states. We suggest that this is hardly the case. When Austrian assumptions of benevolence are relaxed, inability to engage in economic calculation prevents the non-benevolent planner from fully extracting all available surplus from the citizenry. Consequently, when planners are non-benevolent, calculation ceases to be a relevant argument against the desirability of central planning; its normative force reverses absent benevolent planners

Land use planning for high pressure pipelines : ground hazards from dissolution of soluble rocks

The overall permeability of each geological unit has been interpreted to produce an index of the vulnerability of groundwater occurring in Glasgow, and provides a broad-based view of both the vulnerability of groundwater and the location of the more permeable aquifers in Glasgow. The data used to interpret the groundwater vulnerability index are derived from the 1:50 000 DigMap bedrock and superficial geology coverage. The GIS and associated maps should not therefore be used at scales larger than 1:50 000. Locations of thick clays have been interpreted and drawn based on BGS borehole records. Information on water boreholes is derived from the British Geological Survey Scottish Water Borehole database

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

Protection mechanisms in the resurrection plant Xerophyta viscosa (Baker): both sucrose and raffinose family oligosaccharides (RFOs) accumulate in leaves in response to water deficit

Changes in water-soluble carbohydrates were examined in the leaves of the resurrection plant Xerophyta viscosa under conditions of water deficit. Sucrose and raffinose family oligosaccharides (RFOs), particularly raffinose, increased under these conditions, with the highest concentrations evident at 5% relative water content [RWC; 23.5 mg g−1 dry weight (DW) and 17.7 mg g−1 DW, respectively]. Importantly, these effects were reversible, with concentrations returning to levels comparable with that of the full turgor state 7 d after water deficit conditions were alleviated, providing evidence that both sucrose and RFOs may play a protective role in desiccated leaf tissue of X. viscosa. Further, because the sucrose-to-raffinose mass ratio of 1.3:1 observed in the dehydrated state was very low, compared with published data for other resurrection plants (always >5), it is suggested that, in X. viscosa leaves, RFOs serve the dual purpose of stress protection and carbon storage. XvGolS, a gene encoding a galactinol synthase enzyme responsible for the first catalytic step in RFO biosynthesis, was cloned and functionally expressed. In leaf tissue exposed to water deficit, XvGolS transcript levels were shown to increase at 19% RWC. GolS activity in planta could not be correlated with RFO accumulation, but a negative correlation was observed between RFO accumulation and myo-inositol depletion, during water deficit stress. This correlation was reversed after rehydration, suggesting that during water deficit myo-inositol is channelled into RFO synthesis, but during the rehydration process it is channelled to metabolic pathways related to the repair of desiccation-induced damag

A systematic review comparing the evidence for kidney function outcomes between oral antidiabetic drugs for type 2 diabetes.

Background: The development of kidney disease is a serious complication among people with type 2 diabetes mellitus, associated with substantially increased morbidity and mortality.  We aimed to summarise the current evidence for the relationship between treatments for type 2 diabetes and long-term kidney outcomes, by conducting a systematic search and review of relevant studies. Methods: We searched Medline, Embase and Web of Science, between 1st January 1980 and 15th May 2018 for published clinical trials and observational studies comparing two or more classes of oral therapy for type 2 diabetes. We included people receiving oral antidiabetic drugs. Studies were eligible that; (i) compared two or more classes of oral therapy for type 2 diabetes; (ii) reported kidney outcomes as primary or secondary outcomes; (iii) included more than 100 participants; and (iv) followed up participants for 48 weeks or more. Kidney-related outcome measures included were Incidence of chronic kidney disease, reduced eGFR, increased creatinine, 'micro' and 'macro' albuminuria. Results: We identified 15 eligible studies, seven of which were randomised controlled trials and eight were observational studies. Reporting of specific renal outcomes varied widely. Due to variability of comparisons and outcomes meta-analysis was not possible. The majority of comparisons between treatment with metformin or sulfonylurea indicated that metformin was associated with better renal outcomes. Little evidence was available for recently introduced treatments or commonly prescribed combination therapies. Conclusions: Comparative evidence for the effect of treatments for type 2 diabetes on renal outcomes, either as monotherapy or in combination is sparse

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

Synapse-specific expression of calcium-permeable AMPA receptors in neocortical layer 5

In the hippocampus, calcium‐permeable AMPA receptors have been found in a restricted subset of neuronal types that inhibit other neurons, although their localization in the neocortex is less well understood. In the present study, we looked for calcium‐permeable AMPA receptors in two distinct populations of neocortical inhibitory neurons: basket cells and Martinotti cells. We found them in the former but not in the latter. Furthermore, in basket cells, these receptors were associated with particularly fast responses. Computer modelling predicted (and experiments verified) that fast calcium‐permeable AMPA receptors enable basket cells to respond rapidly, such that they promptly inhibit neighbouring cells and shut down activity. The results obtained in the present study help our understanding of pathologies such as stroke and epilepsy that have been associated with disordered regulation of calcium‐permeable AMPA receptors

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

Frontal fibrosing alopecia in men: an association with leave-on facial cosmetics and sunscreens

SCOPUS: le.jinfo:eu-repo/semantics/publishe

BGS karst report series. C7, karst in the Chalk of the South Downs.

This report documents the evidence for karst and rapid groundwater flow in the Chalk of the South Downs area in Southern England. It is part of the BGS karst report series on those karst aquifers in England in which cave development is limited – principally the Upper Cretaceous Chalk and the Jurassic and Permian limestones. The series is the main output of the NERC funded Knowledge Exchange fellowship “Karst knowledge exchange to improve protection of groundwater resources”. The term “karst” applies to rocks that are soluble. In classic karst there are extensive caves and large scale surface karst landforms such as dolines, shafts, stream/river sinks, and springs. In the past, the Chalk and the Jurassic and Permian limestones of England were not considered karstic because they have limited cave development, and because karst features are usually small and have not been well documented. However, permeability in these aquifers is determined by their soluble nature and groundwater flow is predominantly through small-scale karstic solutional features. These reports provide data and information on karst in each area. Karst data are compiled from the British Geological Survey databases on karst, springs, and transmissivity; reports and peer reviewed papers; from geological mapping, and through knowledge exchange with the Environment Agency, universities, water companies and consultants. This report shows that in the C7 karst knowledge exchange area, the South Downs area of the Chalk, there is extensive evidence for karst development with dry valleys, caves, stream sinks, dolines, dissolution pipes, and springs present. Short caves have been recorded in the area, and the longest known Chalk cave in England (~350 m) is in this area at Beachy Head. Observations of coastal cliffs have been particularly important in demonstrating that caves and conduits can occur even beneath interfluves and in the absence of obvious surface karst. Coastal sections also provide evidence for pervasive stratigraphical influence on subsurface karst with distinct stratigraphical horizons (particularly sheet and semi-tabular flints, marl seams and hardgrounds) being important for conduit development. In the Beachy Head area, the Seven Sisters Flint, the Belle Tout Marls, the Shoreham Marls, the Navigation Marl, and the Hope Gap sheet flint all host cave and conduit systems. Locally, many stream sinks occur in association with the Chalk-Palaeogene margin, particularly in the west of the area. Stream sinks are less common or absent in the eastern parts of the area where the Palaeogene cover is absent, although major rivers cross the Chalk and their contribution to point recharge via losses to the aquifer was not established during this work. Soakaways and SUDs with high infiltration rates into the Chalk have also not been identified. Dolines also occur in the area, although many recorded surface depressions are likely to be pits of anthropogenic origin. Dissolution pipes are extremely common, especially where the Chalk is overlain by thin unconsolidated superficial deposits, and in some cases can be 10s of metres deep and/or wide. There are many springs in the area, which would have formed the natural outlets for the karstic solutional networks, although little is known about the discharge of most springs and how this has changed in response to groundwater abstraction. Five large springs are identified, the largest being the Bedhampton and Havant complex with a discharge of ~ 600-1900 l.s-1. Evidence from 22 tracer test connections demonstrate very rapid groundwater flow, with velocities ranging from 0.2 to 12.3 km/day over distances of up to 6.6 km; and tracer recoveries ranging from 0.1 to 100 %. Other evidence of karst comes from hydrogeological studies including investigations of transmissivity and pumping tests, water level data from observation boreholes, downhole imaging and borehole logs, groundwater quality, inflows during tunnel construction, saline intrusion, and groundwater flooding. There is considerable evidence for karst and rapid groundwater flow at groundwater abstractions throughout the South Downs area. Karst is clearly important in enabling rapid recharge and providing some rapid flowpaths through the unsaturated zone, especially via stream sinks but also via solutional fissures with no surface expression. However, there appears to be a higher degree of protection from surface pollutants than in highly karstic aquifers, perhaps due to fewer and smaller stream sinks and the potential for more attenuation in the unsaturated zone. Saturated zone networks of solutional fissures and conduits appear to be very common, and there is evidence to suggest that they extend over distances of several kilometres suggesting that karst specific approaches to Source Protection Zone delineation are likely to be useful. Consideration of the karstic processes that result in the enhanced permeability of the aquifer through the development of solutional fissures and conduits is key to understanding the hydrogeology of this area; and improved understanding of rapid flow in both the unsaturated and saturated zones is important for groundwater protection and management of water resources. This report presents an overview of the current conceptual understanding of karst in the Chalk in the South Downs and provides a basis for further investigations of karst in this area to enable improved management and protection of groundwater resources