Inhibitory Regulation of Dendritic Activity in vivo

The spatiotemporal control of neuronal excitability is fundamental to the inhibitory process. We now have a wealth of information about the active dendritic properties of cortical neurons including axonally generated sodium action potentials as well as local sodium spikelets generated in the dendrites, calcium plateau spikes, and NMDA spikes. All of these events have been shown to be highly modified by the spatiotemporal pattern of nearby inhibitory input which can drastically change the output firing mode of the neuron. This means that particular populations of interneurons embedded in the neocortical microcircuitry can more precisely control pyramidal cell output than has previously been thought. Furthermore, the output of any given neuron tends to feed back onto inhibitory circuits making the resultant network activity further dependent on inhibition. Network activity is therefore ultimately governed by the subcellular microcircuitry of the cortex and it is impossible to ignore the subcompartmentalization of inhibitory influence at the neuronal level in order to understand its effects at the network level. In this article, we summarize the inhibitory circuits that have been shown so far to act on specific dendritic compartments in vivo

Molecular Mechanisms Linking Diabetes with Increased Risk of Thrombosis

This review will provide an overview of what is currently known about mechanisms linking poor glycaemic control with increased thrombotic risk. The leading causes of death in people with diabetes are strokes and cardiovascular disease. Significant morbidity is associated with an increased risk of thrombosis, resulting in myocardial infarction, ischaemic stroke, and peripheral vascular disease, along with the sequelae of these events, including loss of functional ability, heart failure, and amputations. While the increased platelet activity, pro-coagulability, and endothelial dysfunction directly impact this risk, the molecular mechanisms linking poor glycaemic control with increased thrombotic risk remain unclear. This review highlights the complex mechanisms underlying thrombosis prevalence in individuals with diabetes and hyperglycaemia. Post-translational modifications, such as O-GlcNAcylation, play a crucial role in controlling protein function in diabetes. However, the role of O-GlcNAcylation remains poorly understood due to its intricate regulation and the potential involvement of multiple variables. Further research is needed to determine the precise impact of O-GlcNAcylation on specific disease processes

The role of health impact assessment in Phase V of the Healthy Cities European Network

Health impact assessment (HIA) is a prospective decision-making aid tool that aims to improve the quality of policies, programmes or projects through recommendations that promote health. It identifies how and through which pathways a decision can impact a wide range of health determinants and seeks to define the distribution of effects within populations, thereby raising the issue of equity. HIA was introduced to the WHO European Healthy Cities Network as one of its four core themes during the Phase IV (2004-08). Here we present an evaluation of the use of HIA during Phase V (2009-13), where HIA was linked with the overarching theme of health and health equity in all local policies and a requirement regarding capacity building. The evaluation was based on 10 case studies contributed by 9 Healthy Cities in five countries (France, Hungary, Italy, Spain and the UK). A Realist Evaluation framework was used to collect and aggregate data obtained through three methods: an HIA factors analysis, a case-study template analysis using Nvivo software and a detailed questionnaire. The main conclusion is that HIA significantly helps promote Health in All Policies (HiAP) and sustainability in Healthy Cities. It is recommended that all Healthy City candidates to Phase VI (2014-18) of the WHO Healthy Cities European Network effectively adopt HIA and HiA

Contributions to 21st century projections of extreme sea-level change around the UK

We provide a synthesis of results of a recent government-funded initiative to make projections of 21st century change in extreme sea levels around the coast of the United Kingdom. We compare four factors that influence future coastal flood risk: (i) time-mean sea-level (MSL) rise; (ii) changes in storm surge activity; (iii) changes in the offshore wave climate; (iv) changes in tidal amplitude arising from the increase in MSL. Our projections are dominated by the effects of MSL rise, which is typically more than five times larger than any of the other contributions. MSL is projected to rise by about 53 to 115 centimetres at the mouth of the Thames and 30 to 90 centimetres at Edinburgh (5th to 95th percentiles at 2100 relative to 1981–2000 average). Surge model projections disagree on the sign of future changes. Typical simulated changes are around +/−7 centimetres. Because of the disagreement, our best estimate is of no change from this contribution, although we cannot rule out changes of either sign. Wave model projections suggest a decrease in significant wave height of the order of 7 centimetres over the 21st century. However, the limited sample size and uncertainty in projections of changes in atmospheric circulation means that we cannot be confident about the sign of future changes in wave climate. MSL rise may induce changes in tidal amplitude of more than 15 centimetres over the 21st century for the Bristol Channel. However, models disagree on the sign of change there. Elsewhere, our projected tidal amplitude changes are mostly less than 7 centimetres. Whilst changes in MSL dominate, we have shown the potential for all processes considered here to make non-negligible contributions over the 21st century

Pollen extracts and constituent sugars increase growth of a trypanosomatid parasite of bumble bees

ABSTRACT Phytochemicals produced by plants, including at flowers, function in protection against plant diseases, and have a long history of use against trypanosomatid infection. Floral nectar and pollen, the sole food sources for many species of insect pollinators, contain phytochemicals that have been shown to reduce trypanosomatid infection in bumble and honey bees when fed as isolated compounds. Nectar and pollen, however, consist of phytochemical mixtures, which can have greater antimicrobial activity than do single compounds. This study tested the hypothesis that pollen extracts would inhibit parasite growth. Extracts of six different pollens were tested for direct inhibitory activity against cell cultures of the bumble bee trypanosomatid gut parasite Crithidia bombi. Surprisingly, pollen extracts increased parasite growth rather than inhibiting it. Pollen extracts contained high concentrations of sugars, mainly the monosaccharides glucose and fructose. Experimental manipulations of growth media showed that supplemental monosaccharides (glucose and fructose) increased maximum cell density, while a common floral phytochemical (caffeic acid) with inhibitory activity against other trypanosomatids had only weak inhibitory effects on Crithidia bombi. These results indicate that, although pollen is essential for bees and other pollinators, pollen may promote growth of intestinal parasites that are uninhibited by pollen phytochemicals and, as a result, can benefit from the nutrients that pollen provides

A Generative Deep Learning Approach to Stochastic Downscaling of Precipitation Forecasts

Despite continuous improvements, precipitation forecasts are still not as accurate and reliable as those of other meteorological variables. A major contributing factor to this is that several key processes affecting precipitation distribution and intensity occur below the resolved scale of global weather models. Generative adversarial networks (GANs) have been demonstrated by the computer vision community to be successful at super-resolution problems, i.e., learning to add fine-scale structure to coarse images. Leinonen et al. (2020) previously applied a GAN to produce ensembles of reconstructed high-resolution atmospheric fields, given coarsened input data. In this paper, we demonstrate this approach can be extended to the more challenging problem of increasing the accuracy and resolution of comparatively low-resolution input from a weather forecasting model, using high-resolution radar measurements as a "ground truth". The neural network must learn to add resolution and structure whilst accounting for non-negligible forecast error. We show that GANs and VAE-GANs can match the statistical properties of state-of-the-art pointwise post-processing methods whilst creating high-resolution, spatially coherent precipitation maps. Our model compares favourably to the best existing downscaling methods in both pixel-wise and pooled CRPS scores, power spectrum information and rank histograms (used to assess calibration). We test our models and show that they perform in a range of scenarios, including heavy rainfall.Comment: Submitted to JAMES 4/4/2

NMDA spikes enhance action potential generation during sensory input

Recent evidence in vitro suggests that the tuft dendrites of pyramidal neurons are capable of evoking local NMDA receptor–dependent electrogenesis, so-called NMDA spikes. However, it has so far proved difficult to demonstrate their existence in vivo. Moreover, it is not clear whether NMDA spikes are relevant to the output of pyramidal neurons. We found that local NMDA spikes occurred in tuft dendrites of layer 2/3 pyramidal neurons both spontaneously and following sensory input, and had a large influence on the number of output action potentials. Using two-photon activation of an intracellular caged NMDA receptor antagonist (tc-MK801), we found that isolated NMDA spikes typically occurred in multiple branches simultaneously and that sensory stimulation substantially increased their probability. Our results demonstrate that NMDA receptors have a vital role in coupling the tuft region of the layer 2/3 pyramidal neuron to the cell body, enhancing the effectiveness of layer 1 input