Quantifying simulator discrepancy in discrete-time dynamical simulators

When making predictions with complex simulators it can be important to quantify the various sources of uncertainty. Errors in the structural specification of the simulator, for example due to missing processes or incorrect mathematical specification, can be a major source of uncertainty, but are often ignored. We introduce a methodology for inferring the discrepancy between the simulator and the system in discrete-time dynamical simulators. We assume a structural form for the discrepancy function, and show how to infer the maximum likelihood parameter estimates using a particle filter embedded within a Monte Carlo expectation maximization (MCEM) algorithm. We illustrate the method on a conceptual rainfall runoff simulator (logSPM) used to model the Abercrombie catchment in Australia. We assess the simulator and discrepancy model on the basis of their predictive performance using proper scoring rules

FMRP and CYFIP1 at the synapse and their role in psychiatric vulnerability

There is increasing awareness of the role genetic risk variants have in mediating vulnerability to psychiatric disorders such as schizophrenia and autism. Many of these risk variants encode synaptic proteins, influencing biological pathways of the postsynaptic density and, ultimately, synaptic plasticity. Fragile X Mental Retardation 1 (FMR1) and Cytoplasmic FRMP-Interacting Protein (CYFIP1) contain two such examples of highly penetrant risk variants and encode synaptic proteins with shared functional significance. In this Review, we will discuss the biological actions of FMRP and CYFIP1, including their regulation of i) protein translation and specifically FMRP targets, ii) dendritic and spine morphology and iii) forms of synaptic plasticity such as long-term depression. We draw upon a range of preclinical studies that have used genetic dosage models of FMR1 and CYFIP1 to determine their biological function. In parallel, we discuss how clinical studies of Fragile X Syndrome or 15q11.2 deletion patients have informed our understanding of FMRP and CYFIP1 proteins, and highlight the latest psychiatric genomic findings that continue to implicate FMRP and CYFIP1. Lastly, we assess the current limitations in our understanding of FMRP and CYFIP1 biology and how they must be addressed before mechanism-led therapeutic strategies can be developed for psychiatric disorders

Profiles of SUMO and ubiquitin conjugation in an Alzheimer's disease model

► Global levels of ubiquitinated proteins increased in the hippocampus of Tg2576 mice. ► No global changes in either SUMO-1 or SUMO-2/3 conjugation in any brain regions analysed. ► SUMO conjugating and deconjugating enzymes, UBC9 and SENP-1, unaltered in Tg2576 mice. ► Total levels of AMPA and kainate receptors were also unaffected in Tg2576 mice. ► Posttranslational modification by ubiquitin may play a role in Alzheimer's disease

Quantifying simulator discrepancy in discrete-time dynamical simulators

When making predictions with complex simulators it can be important to quantify the various sources of uncertainty. Errors in the structural specification of the simulator, for example due to missing processes or incorrect mathematical specification, can be a major source of uncertainty, but are often ignored. We introduce a methodology for inferring the discrepancy between the simulator and the system in discrete-time dynamical simulators. We assume a structural form for the discrepancy function, and show how to infer the maximum likelihood parameter estimates using a particle filter embedded within a Monte Carlo expectation maximization (MCEM) algorithm. We illustrate the method on a conceptual rainfall runoff simulator (logSPM) used to model the Abercrombie catchment in Australia. We assess the simulator and discrepancy model on the basis of their predictive performance using proper scoring rules

Commentary: Analysis of SUMO1-conjugation at synapses

[no abstract

Winter-to-summer transition of Arctic sea ice breakup and floe size distribution in the Beaufort Sea

Breakup of the near-continuous winter sea ice into discrete summer ice floes is an important transition that dictates the evolution and fate of the marginal ice zone (MIZ) of the Arctic Ocean. During the winter of 2014, more than 50 autonomous drifting buoys were deployed in four separate clusters on the sea ice in the Beaufort Sea, as part of the Office of Naval Research MIZ program. These systems measured the ocean-ice-atmosphere properties at their location whilst the sea ice parameters in the surrounding area of these buoy clusters were continuously monitored by satellite TerraSAR-X Synthetic Aperture Radar. This approach provided a unique Lagrangian view of the winter-to-summer transition of sea ice breakup and floe size distribution at each cluster between March and August. The results show the critical timings of a) temporary breakup of winter sea ice coinciding with strong wind events and b) spring breakup (during surface melt, melt ponding and drainage) leading to distinctive summer ice floes. Importantly our results suggest that summer sea ice floe distribution is potentially affected by the state of winter sea ice, including the composition and fracturing (caused by deformation events) of winter sea ice, and that substantial mid-summer breakup of sea ice floes is likely linked to the timing of thermodynamic melt of sea ice in the area. As the rate of deformation and thermodynamic melt of sea ice has been increasing in the MIZ in the Beaufort Sea, our results suggest that these elevated factors would promote faster and more enhanced breakup of sea ice, leading to a higher melt rate of sea ice and thus a more rapid advance of the summer MIZ

Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2

The endosome-associated cargo adaptor sorting nexin-27 (SNX27) is linked to various neuropathologies through sorting of integral proteins to the synaptic surface, most notably AMPA receptors. To provide a broader view of SNX27-associated pathologies, we performed proteomics in rat primary neurons to identify SNX27-dependent cargoes, and identified proteins linked to excitotoxicity, epilepsy, intellectual disabilities, and working memory deficits. Focusing on the synaptic adhesion molecule LRFN2, we established that SNX27 binds to LRFN2 and regulates its endosomal sorting. Furthermore, LRFN2 associates with AMPA receptors and knockdown of LRFN2 results in decreased surface AMPA receptor expression, reduced synaptic activity, and attenuated hippocampal long-term potentiation. Overall, our study provides an additional mechanism by which SNX27 can control AMPA receptor-mediated synaptic transmission and plasticity indirectly through the sorting of LRFN2 and offers molecular insight into the perturbed function of SNX27 and LRFN2 in a range of neurological conditions