Loss of Hierarchical Imprinting Regulation at the Prader-Willi/Angelman Syndrome Locus in Human iPSCs

The human chr15q11-q13 imprinted cluster is linked to several disorders, including Prader-Willi (PWS) and Angelman (AS) syndromes. Recently, disease modeling approaches based on induced pluripotent stem cells (iPSCs) have been used to study these syndromes. A concern regarding the use of these cells for imprinted disease modeling is the numerous imprinting defects found in many iPSCs. Here, by reprogramming skin fibroblasts from a control and AS individuals, we generated several iPSC lines and addressed the stability of imprinting status across the PWS/AS domain. We focused on three important regulatory DNA elements which are all differentially methylated regions (DMRs), methylated on the maternal allele: the PWS imprinting center (PWS-IC), which is a germline DMR and the somatic NDN and MKRN3 DMRs, hierarchically controlled by PWS-IC. Normal PWS-IC methylation pattern was maintained in most iPSC lines; however, loss of maternal methylation in one out of five control iPSC lines resulted in a monoallelic to biallelic switch for many imprinted genes in this domain. Surprisingly, MKRN3 DMR was found aberrantly hypermethylated in all control and AS iPSCs, regardless of the methylation status of the PWS-IC master regulator. This suggests a loss of hierarchical control of imprinting at PWS/AS region. We confirmed these results in established iPSC lines derived using different reprogramming procedures. Overall, we show that hierarchy of imprinting control in donor cells might not apply to iPSCs, accounting for their spectrum of imprinting alterations. Such differences in imprinting regulation should be taken into consideration for the use of iPSCs in disease modeling.info:eu-repo/semantics/publishedVersio

Real-time Artificial Intelligence for Accelerator Control: A Study at the Fermilab Booster

We describe a method for precisely regulating the gradient magnet power supply at the Fermilab Booster accelerator complex using a neural network trained via reinforcement learning. We demonstrate preliminary results by training a surrogate machine-learning model on real accelerator data to emulate the Booster environment, and using this surrogate model in turn to train the neural network for its regulation task. We additionally show how the neural networks to be deployed for control purposes may be compiled to execute on field-programmable gate arrays. This capability is important for operational stability in complicated environments such as an accelerator facility.Comment: 16 pages, 10 figures. Submitted to Physical Review Accelerators and Beams. For associated dataset and data sheet see http://doi.org/10.5281/zenodo.408898

Athletic Races Represent Complex Systems, and Pacing Behavior Should Be Viewed as an Emergent Phenomenon

Pacing is the manner in which effort is distributed over the duration of an exercise bout, and is an important determinant of the extent to which individual potential is realized during athletic races. Observed pacing behaviors are thought to result from complex decision-making processes, and several models have been proposed that may explain the manner in which these decisions are made. In this article we argue that examination of individual factors implicated in the regulation of pacing is unlikely to allow full understanding of the events leading to pacing and performance. Rather than utilizing such a reductionist approach, it is suggested that athletic races be viewed as complex systems, and that pacing behavior is an emergent phenomenon that cannot be fully understood through study of components of the system in isolation. We describe and discuss known and potential interactions between determinants of pacing during races, and conclude with a call for the development of novel research methodologies that may further understanding of the manner in which observed behaviors emerge

Impairment of Adenosinergic System in Rett syndrome: Novel Therapeutic Target to Boost BDNF Signalling

Rett syndrome (RTT; OMIM#312750) is mainly caused by mutations in the X-linked MECP2 gene (methyl-CpG-binding protein 2 gene; OMIM*300005), which leads to impairments in the brain-derived neurotrophic factor (BDNF) signalling. The boost of BDNF mediated effects would be a significant breakthrough but it has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine, an endogenous neuromodulator, may accomplish that role since through A2AR it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the adenosinergic and BDNF signalling in RTT and explored whether A2AR activation could boost BDNF actions. For this study, the RTT animal model, the Mecp2 knockout (Mecp2-/y) (B6.129P2 (C)-Mecp2tm1.1Bird/J) mouse was used. Whenever possible, parallel data was also obtained from post-mortem brain samples from one RTT patient. Ex vivo extracellular recordings of field excitatory post-synaptic potentials in CA1 hippocampal area were performed to evaluate synaptic transmission and long-term potentiation (LTP). RT-PCR was used to assess mRNA levels and Western Blot or radioligand binding assays were performed to evaluate protein levels. Changes in cortical and hippocampal adenosine content were assessed by liquid chromatography with diode array detection (LC/DAD). Hippocampal ex vivo experiments revealed that the facilitatory actions of BDNF upon LTP is absent in Mecp2-/y mice and that TrkB full-length (TrkB-FL) receptor levels are significantly decreased. Extracts of the hippocampus and cortex of Mecp2-/y mice revealed less adenosine amount as well as less A2AR protein levels when compared to WT littermates, which may partially explain the deficits in adenosinergic tonus in these animals. Remarkably, the lack of BDNF effect on hippocampal LTP in Mecp2-/y mice was overcome by selective activation of A2AR with CGS21680. Overall, in Mecp2-/y mice there is an impairment on adenosinergic system and BDNF signalling. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting A2AR as a therapeutic target in this devastating pathology.info:eu-repo/semantics/publishedVersio

Sources, sinks and subsidies : terrestrial carbon storage in mid-latitude fjords

This work was supported by the Natural Environment Research Council (Grant Number: NE/L501852/1) with additional support from the NERC Life Science Mass Spectrometry Facility (CEH_L_098_11_2015) and the NERC Geophysical Equipment Facility (NGGFSC Minor Loan 1031).Fjords are recognized as globally important sites for the burial and long-term storage of carbon (C) within sediments. The proximity of fjords to the terrestrial environment in combination with their geomorphology and hydrography results in the fjordic sediments being subsidized with organic carbon (OC) from the terrestrial environment. It has been well documented that terrestrial OC (OCterr) is an important component of coastal sediments, yet our understanding of the quantity of OCterr stored in these sediments remains poorly constrained. Utilizing Bayesian isotopic sediment fingerprinting techniques to the surface sediments of Loch Sunart, we estimate that 42.0 ± 10.1% of the OC is terrestrial in origin. Through combining these outputs with sedimentary OC stock estimates, we have calculated that the surface sediments (0–15 cm) hold 0.1 megaton (Mt) OCterr and estimate that the postglacial sediment held within the fjord contains 3.96 Mt OCterr. When these totals are compared to the quantity of OC stored in the adjacent terrestrial environment, it is clear that the fjord's catchment stores a greater amount of OCterr in the form of vegetation and soil. Though when normalized for area the results suggest that the marine sediments are a more effective long-term store of OCterr than the adjacent terrestrial environment. This striking result highlights the importance of the terrestrial environment as a source of OC to the coastal ocean and that the OCterr subsidy to the marine sediments is a significant mechanism for the long-term storage of OC in coastal marine sediments.Publisher PDFPeer reviewe

Physical activity for people living with dementia: carer outcomes and side effects from the perspectives of professionals and family carers

Adherence to physical activity is challenging for people living with dementia, and largely dependent on carers' involvement. Carers are likely to support physical activity based on their perceived balance between benefits and potential side effects of such intervention for both patients and themselves. Professionals also have a role in terms of optimising such interventions not only for people with dementia but also their carers.publishe

RNAMotifScan: automatic identification of RNA structural motifs using secondary structural alignment

Recent studies have shown that RNA structural motifs play essential roles in RNA folding and interaction with other molecules. Computational identification and analysis of RNA structural motifs remains a challenging task. Existing motif identification methods based on 3D structure may not properly compare motifs with high structural variations. Other structural motif identification methods consider only nested canonical base-pairing structures and cannot be used to identify complex RNA structural motifs that often consist of various non-canonical base pairs due to uncommon hydrogen bond interactions. In this article, we present a novel RNA structural alignment method for RNA structural motif identification, RNAMotifScan, which takes into consideration the isosteric (both canonical and non-canonical) base pairs and multi-pairings in RNA structural motifs. The utility and accuracy of RNAMotifScan is demonstrated by searching for kink-turn, C-loop, sarcin-ricin, reverse kink-turn and E-loop motifs against a 23S rRNA (PDBid: 1S72), which is well characterized for the occurrences of these motifs. Finally, we search these motifs against the RNA structures in the entire Protein Data Bank and the abundances of them are estimated. RNAMotifScan is freely available at our supplementary website (http://genome.ucf.edu/RNAMotifScan)

Long-range transport of airborne microbes over the global tropical and subtropical ocean

The atmosphere plays a fundamental role in the transport of microbes across the planet but it is often neglected as a microbial habitat. Although the ocean represents two thirds of the Earth’s surface, there is little information on the atmospheric microbial load over the open ocean. Here we provide a global estimate of microbial loads and air-sea exchanges over the tropical and subtropical oceans based on the data collected along the Malaspina 2010 Circumnavigation Expedition. Total loads of airborne prokaryotes and eukaryotes were estimated at 2.2 × 1021 and 2.1 × 1021 cells, respectively. Overall 33–68% of these microorganisms could be traced to a marine origin, being transported thousands of kilometres before re-entering the ocean. Moreover, our results show a substantial load of terrestrial microbes transported over the oceans, with abundances declining exponentially with distance from land and indicate that islands may act as stepping stones facilitating the transoceanic transport of terrestrial microbes.En prens