Regulation and Function of Activity-Dependent Homer in Synaptic Plasticity

Alterations in synaptic signaling and plasticity occur during the refinement of neural circuits over the course of development and the adult processes of learning and memory. Synaptic plasticity requires the rearrangement of protein complexes in the postsynaptic density (PSD), trafficking of receptors and ion channels and the synthesis of new proteins. Activity-induced short Homer proteins, Homer1a and Ania-3, are recruited to active excitatory synapses, where they act as dominant negative regulators of constitutively expressed, longer Homer isoforms. The expression of Homer1a and Ania-3 initiates critical processes of PSD remodeling, the modulation of glutamate receptor-mediated functions, and the regulation of calcium signaling. Together, available data support the view that Homer1a and Ania-3 are responsible for the selective, transient destabilization of postsynaptic signaling complexes to facilitate plasticity of the excitatory synapse. The interruption of activity-dependent Homer proteins disrupts disease-relevant processes and leads to memory impairments, reflecting their likely contribution to neurological disorders

Hippocampal Regulation of Postsynaptic Density Homer1 by Associative Learning

Genes involved in synaptic plasticity, particularly genes encoding postsynaptic density proteins, have been recurrently linked to psychiatric disorders including schizophrenia and autism. Postsynaptic density Homer1 proteins contribute to synaptic plasticity through the competing actions of short and long isoforms. The activity-induced expression of shortHomer1isoforms,Homer1aandAnia-3, is thought to be related to processes of learning and memory. However, the precise regulation ofHomer1aandAnia-3with different components of learning has not been investigated. Here, we used in situ hybridization to quantify short and longHomer1expression in the hippocampus following consolidation, retrieval, and extinction of associative fear memory, using contextual fear conditioning in rats.Homer1aandAnia-3, but not longHomer1, were regulated by contextual fear learning or novelty detection, although their precise patterns of expression in hippocampal subregions were dependent on the isoform. We also show for the first time that the two short Homer1 isoforms are regulated after the retrieval and extinction of contextual fear memory, albeit with distinct temporal and spatial profiles. These findings support a role of activity-induced Homer1 isoforms in learning and memory processes in discrete hippocampal subregions and suggest that Homer1a and Ania-3 may play separable roles in synaptic plasticity.</jats:p

Color Differences Highlight Concomitant Polymorphism of Chalcones

The meta- and para-nitro isomers of (E)-3′-dimethylamino-nitrochalcone (Gm8m and Gm8p) are shown to exhibit concomitant color polymorphism, with Gm8m appearing as yellow (P2_{1}/c) or orange (P1̅) crystals and Gm8p appearing as red (P2_{1}/n) or black (P2_{1}/c) crystals. Each of the polymorphs was characterized optically via UV–vis spectroscopy, and their thermal behavior was characterized via differential scanning calorimetry and low-temperature powder X-ray diffraction. To assess the effect of molecular configuration and crystal packing on the colors of crystals of the different polymorphs, time dependent density functional theory (ωB97x) calculations were carried out on isolated molecules, dimers, stacks, and small clusters cut from the crystal structures of the four polymorphs. The calculated color comes from several excitations and is affected by conformation and most intermolecular contacts within the crystal, with the color differences between polymorphs mainly being due to the differences in the π–π stacking. The visual differences between these related polymorphic systems make them particularly useful for studying polymorph behavior such as phase transitions and concomitant polymorph growth

Management of shoulder pain by UK general practitioners (GPs): a national survey

OBJECTIVES: Studies in Canada, the USA and Australia suggested low confidence among general practitioners (GPs) in diagnosing and managing shoulder pain, with frequent use of investigations. There are no comparable studies in the UK; our objective was to describe the diagnosis and management of shoulder pain by GPs in the UK. METHODS: A national survey of a random sample of 5000 UK GPs collected data on shoulder pain diagnosis and management using two clinical vignettes that described primary care presentations with rotator cuff tendinopathy (RCT) and adhesive capsulitis (AdhC). RESULTS: Seven hundred and fourteen (14.7%) responses were received. 56% and 83% of GPs were confident in their diagnosis of RCT and AdhC, respectively, and a wide range of investigations and management options were reported. For the RCT presentation, plain radiographs of the shoulder were most common (60%), followed by blood tests (42%) and ultrasound scans (USS) (38%). 19% of those who recommended a radiograph and 76% of those who recommended a USS did so 'to confirm the diagnosis'. For the AdhC presentation, the most common investigations were blood tests (60%), plain shoulder radiographs (58%) and USS (31%). More than two-thirds of those recommending a USS did so 'to confirm the diagnosis'. The most commonly recommended treatment for both presentations was physiotherapy (RCT 77%, AdhC 71%) followed by non-steroidal anti-inflammatory drugs (RCT 58%, AdhC 74%). 17% opted to refer the RCT to secondary care (most often musculoskeletal interface service), compared with 31% for the AdhC. CONCLUSIONS: This survey of GPs in the UK highlights reliance on radiographs and blood tests in the management of common shoulder pain presentations. GPs report referring more than 7 out of 10 patients with RCT and AdhC to physiotherapists. These findings need to be viewed in the context of low response to the survey and, therefore, potential non-response bias

Modelled glacier response to centennial temperature and precipitation trends on the Antarctic Peninsula

The northern Antarctic Peninsula is currently undergoing rapid atmospheric warming. Increased glacier-surface melt during the twentieth century has contributed to ice-shelf collapse and the widespread acceleration, thinning and recession of glaciers. Therefore, glaciers peripheral to the Antarctic Ice Sheet currently make a large contribution to eustatic sea-level rise, but future melting may be offset by increased precipitation. Here we assess glacier-climate relationships both during the past and into the future, using ice-core and geological data and glacier and climate numerical model simulations. Focusing on Glacier IJR45 on James Ross Island, northeast Antarctic Peninsula, our modelling experiments show that this representative glacier is most sensitive to temperature change, not precipitation change. We determine that its most recent expansion occurred during the late Holocene a Little Ice Age' and not during the warmer mid-Holocene, as previously proposed. Simulations using a range of future Intergovernmental Panel on Climate Change climate scenarios indicate that future increases in precipitation are unlikely to offset atmospheric-warming-induced melt of peripheral Antarctic Peninsula glaciers

Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function.

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this record Data Availability: Transcriptomic data from RNA sequencing is available from the Gene Expression Omnibus (GEO) with identifier GSE199428. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (80) partner repository with the dataset identifier PXD032742.Large-scale genomic studies of schizophrenia implicate genes involved in the epigenetic regulation of transcription by histone methylation and genes encoding components of the synapse. However, the interactions between these pathways in conferring risk to psychiatric illness are unknown. Loss-of-function (LoF) mutations in the gene encoding histone methyltransferase, SETD1A, confer substantial risk to schizophrenia. Among several roles, SETD1A is thought to be involved in the development and function of neuronal circuits. Here, we employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins. Using large-scale patient genomics data, we observed no enrichment for genetic association with schizophrenia within differentially expressed transcripts or proteins, suggesting they derive from a distinct mechanism of risk from that implicated by genomic studies. This study highlights biological pathways through which SETD1A loss-of-function may confer risk to schizophrenia. Further work is required to determine whether the effects observed in this model reflect human pathology.Medical Research CouncilWellcome Trus

Ocean acidification through the lens of ecological theory

Ocean acidification, chemical changes to the carbonate system of seawater, is emerging as a key environmental challenge accompanying global warming and other human-induced perturbations. Considerable research seeks to define the scope and character of potential outcomes from this phenomenon, but a crucial impediment persists. Ecological theory, despite its power and utility, has been only peripherally applied to the problem. Here we sketch in broad strokes several areas where fundamental principles of ecology have the capacity to generate insight into ocean acidification's consequences. We focus on conceptual models that, when considered in the context of acidification, yield explicit predictions regarding a spectrum of population- and community-level effects, from narrowing of species ranges and shifts in patterns of demographic connectivity, to modified consumer–resource relationships, to ascendance of weedy taxa and loss of species diversity. Although our coverage represents only a small fraction of the breadth of possible insights achievable from the application of theory, our hope is that this initial foray will spur expanded efforts to blend experiments with theoretical approaches. The result promises to be a deeper and more nuanced understanding of ocean acidification and the ecological changes it portends

Predicting consumer biomass, size-structure, production, catch potential, responses to fishing and associated uncertainties in the world's marine ecosystems

Existing estimates of fish and consumer biomass in the world’s oceans are disparate. This creates uncertainty about the roles of fish and other consumers in biogeochemical cycles and ecosystem processes, the extent of human and environmental impacts and fishery potential. We develop and use a size-based macroecological model to assess the effects of parameter uncertainty on predicted consumer biomass, production and distribution. Resulting uncertainty is large (e.g. median global biomass 4.9 billion tonnes for consumers weighing 1 g to 1000 kg; 50% uncertainty intervals of 2 to 10.4 billion tonnes; 90% uncertainty intervals of 0.3 to 26.1 billion tonnes) and driven primarily by uncertainty in trophic transfer efficiency and its relationship with predator-prey body mass ratios. Even the upper uncertainty intervals for global predictions of consumer biomass demonstrate the remarkable scarcity of marine consumers, with less than one part in 30 million by volume of the global oceans comprising tissue of macroscopic animals. Thus the apparently high densities of marine life seen in surface and coastal waters and frequently visited abundance hotspots will likely give many in society a false impression of the abundance of marine animals. Unexploited baseline biomass predictions from the simple macroecological model were used to calibrate a more complex size- and trait-based model to estimate fisheries yield and impacts. Yields are highly dependent on baseline biomass and fisheries selectivity. Predicted global sustainable fisheries yield increases ≈4 fold when smaller individuals (< 20 cm from species of maximum mass < 1kg) are targeted in all oceans, but the predicted yields would rarely be accessible in practice and this fishing strategy leads to the collapse of larger species if fishing mortality rates on different size classes cannot be decoupled. Our analyses show that models with minimal parameter demands that are based on a few established ecological principles can support equitable analysis and comparison of diverse ecosystems. The analyses provide insights into the effects of parameter uncertainty on global biomass and production estimates, which have yet to be achieved with complex models, and will therefore help to highlight priorities for future research and data collection. However, the focus on simple model structures and global processes means that non-phytoplankton primary production and several groups, structures and processes of ecological and conservation interest are not represented. Consequently, our simple models become increasingly less useful than more complex alternatives when addressing questions about food web structure and function, biodiversity, resilience and human impacts at smaller scales and for areas closer to coasts

Radiation-induced malignancies following radiotherapy for breast cancer

With advances in diagnosis and treatment, breast cancer is becoming an increasingly survivable disease resulting in a large population of long-term survivors. Factors affecting the quality of life of such patients include the consequences of breast cancer treatment, which may have involved radiotherapy. In this study, we compare the incidence of second primary cancers in women who received breast radiotherapy with that in those who did not (non-radiotherapy). All women studied received surgery for their first breast cancer. Second cancers of the lung, colon, oesophagus and thyroid gland, malignant melanomas, myeloid leukaemias and second primary breast cancers were studied. Comparing radiotherapy and non-radiotherapy cohorts, elevated relative risks (RR) were observed for lung cancer at 10-14 years and 15 or more (15+) years after initial breast cancer diagnosis (RR 1.62, 95% confidence interval [CI] 1.05-2.54 and RR 1.49, 95% CI 1.05-2.14, respectively), and for myeloid leukaemia at 1-5 years (RR 2.99, 95% CI 1.13-9.33), for second breast cancer at 5-10 years (RR 1.34, 95% CI 1.10-1.63) and 15+ years (RR 1.26, 95% CI 1.00-1.59) and oesophageal cancer at 15+ years (RR 2.19, 95% CI 1.10-4.62)

Decaying Dark Matter in Supersymmetric Model and Cosmic-Ray Observations

We study cosmic-rays in decaying dark matter scenario, assuming that the dark matter is the lightest superparticle and it decays through a R-parity violating operator. We calculate the fluxes of cosmic-rays from the decay of the dark matter and those from the standard astrophysical phenomena in the same propagation model using the GALPROP package. We reevaluate the preferred parameters characterizing standard astrophysical cosmic-ray sources with taking account of the effects of dark matter decay. We show that, if energetic leptons are produced by the decay of the dark matter, the fluxes of cosmic-ray positron and electron can be in good agreements with both PAMELA and Fermi-LAT data in wide parameter region. It is also discussed that, in the case where sizable number of hadrons are also produced by the decay of the dark matter, the mass of the dark matter is constrained to be less than 200-300 GeV in order to avoid the overproduction of anti-proton. We also show that the cosmic gamma-ray flux can be consistent with the results of Fermi-LAT observation if the mass of the dark matter is smaller than nearly 4 TeV.Comment: 24 pages, 5 figure