Rescue of severely affected dystrophin/utrophin-deficient mice through scAAV-U7snRNA-mediated exon skipping

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the dystrophin gene that result in the absence of functional protein. Antisense-mediated exon skipping is one of the most promising approaches for the treatment of DMD and recent clinical trials have demonstrated encouraging results. However, antisense oligonucleotide-mediated exon skipping for DMD still faces major hurdles such as extremely low efficacy in the cardiac muscle, poor cellular uptake and relatively rapid clearance from circulation, which means that repeated administrations are required to achieve some therapeutic efficacy. To overcome these limitations, we previously proposed the use of small nuclear RNAs (snRNAs), especially U7snRNA to shuttle the antisense sequences after vectorization into adeno-associated virus (AAV) vectors. In this study, we report for the first time the efficiency of the AAV-mediated exon skipping approach in the utrophin/dystrophin double-knockout (dKO) mouse which is a very severe and progressive mouse model of DMD. Following a single intravenous injection of scAAV9-U7ex23 in dKO mice, near-normal levels of dystrophin expression were restored in all muscles examined, including the heart. This resulted in a considerable improvement of their muscle function and dystrophic pathology as well as a remarkable extension of the dKO mice lifespan. These findings suggest great potential for AAV-U7 in systemic treatment of the DMD phenotype

Extending the reach of the Fire Effects Planning Framework by taking a critical approach to science delivery and application

The Fire Effects Planning Framework (FEPF), developed under JFSP project (99-1-3-16) “Wildland fuels management: evaluating and planning risks and benefits,” was formally completed in June 2004. FEPF is a logical framework that uses available data (e.g., local, LANDFIRE data) and existing software (e.g., GIS, Farsite, FlamMap, expert knowledge) to produce maps of probable fire effects during the pre-season or in advance of a fire front. The initial project included significant technology transfer activities. As that project concluded, however, we continued to receive requests for assistance from field managers (District, Forest and Regional Forest Service offices), international organizations (Interior West Fire Council), and national fire planning organizations (Fire Program Analysis). These requests sought more information about the tool, assistance with using it for hazardous fuels planning, and guidance for incorporating FEPF into regional training courses. To enable us to continue our outreach efforts, we initiated JFSP 05-4-1-20 “Extending the reach of the the Fire Effects Planning Framework by taking a critical approach to science delivery and application”. This funding allowed us to meet requests for assistance and participation while allowing us to identify and concentrate on the most valuable transfer mechanisms. Our goal was to observe how field managers think about and use the tool, learn who they think the primary audience is, and then revise our materials and activities accordingly. FEPF is the only analysis tool we know of that helps managers (land and fire) articulate probable ecologic effects of fire and integrate these into fire decision-making and assessment. The technology and data used by FEPF is widely available. The scientific basis for crosswalk determinations are grounded in best available science, transparent, and easily updated as new information becomes available. As the federal fire agencies move toward more comprehensive implementation of Appropriate Management Response, FEPF remains the only process that can quickly and consistently indicate areas and conditions where fire may be neutral, beneficial or harmful to natural resources of interest. Thus, it provides the only existing process to link emergency fire operations (from full suppression to wildland fire use) with land management plans, a requirement of federal oversight entities (e.g., OIG)

A novel sub-seabed CO\u3csub\u3e2\u3c/sub\u3e release experiment informing monitoring and impact assessment for geological carbon storage

© 2014 The Authors. Carbon capture and storage is a mitigation strategy that can be used to aid the reduction of anthropogenic CO2 emissions. This process aims to capture CO2 from large point-source emitters and transport it to a long-term storage site. For much of Europe, these deep storage sites are anticipated to be sited below the sea bed on continental shelves. A key operational requirement is an understanding of best practice of monitoring for potential leakage and of the environmental impact that could result from a diffusive leak from a storage complex. Here we describe a controlled CO2 release experiment beneath the seabed, which overcomes the limitations of laboratory simulations and natural analogues. The complex processes involved in setting up the experimental facility and ensuring its successful operation are discussed, including site selection, permissions, communications and facility construction. The experimental design and observational strategy are reviewed with respect to scientific outcomes along with lessons learnt in order to facilitate any similar future

The TAOS Project Stellar Variability I. Detection of Low-Amplitude delta Scuti Stars

We analyzed data accumulated during 2005 and 2006 by the Taiwan-American Occultation Survey (TAOS) in order to detect short-period variable stars (periods of <~ 1 hour) such as delta Scuti. TAOS is designed for the detection of stellar occultation by small-size Kuiper Belt Objects (KBOs) and is operating four 50cm telescopes at an effective cadence of 5Hz. The four telescopes simultaneously monitor the same patch of the sky in order to reduce false positives. To detect short-period variables, we used the Fast Fourier Transform algorithm (FFT) inasmuch as the data points in TAOS light-curves are evenly spaced. Using FFT, we found 41 short-period variables with amplitudes smaller than a few hundredths of a magnitude and periods of about an hour, which suggest that they are low-amplitude delta Scuti stars (LADS). The light-curves of TAOS delta Scuti stars are accessible online at the Time Series Center website (http://timemachine.iic.harvard.edu)Comment: Accepted for publication in A

Maternal psychological distress in primary care and association with child behavioural outcomes at age three

Observational studies indicate children whose mothers have poor mental health are at increased risk of socio-emotional behavioural difficulties, but it is unknown whether these outcomes vary by the mothers’ mental health recognition and treatment status. To examine this question, we analysed linked longitudinal primary care and research data from 1078 women enrolled in the Born in Bradford cohort. A latent class analysis of treatment status and self-reported distress broadly categorised women as (a) not having a common mental disorder (CMD) that persisted through pregnancy and the first 2 years after delivery (N = 756, 70.1 %), (b) treated for CMD (N = 67, 6.2 %), or (c) untreated (N = 255, 23.7 %). Compared to children of mothers without CMD, 3-year-old children with mothers classified as having untreated CMD had higher standardised factor scores on the Strengths and Difficulties Questionnaire (d = 0.32), as did children with mothers classified as having treated CMD (d = 0.27). Results were only slightly attenuated in adjusted analyses. Children of mothers with CMD may be at risk for socio-emotional and behavioural difficulties. The development of effective treatments for CMD needs to be balanced by greater attempts to identify and treat women. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00787-015-0777-2) contains supplementary material, which is available to authorized users

Blueberry Advisory Committee Extension Report

The 1986 edition of the Blueberry Advisory Committee Extension Reports was prepared for the Maine Blueberry Commission and the University of Maine Blueberry Advisory Committee by researchers with the Maine Agricultural Experiment Station and Maine Cooperative Extension Service at the University of Maine, Orono. Projects in this report include: 1. Fertility Levels 2. Insect and Disease Fact Sheets 3. Development of Insect ID Information for Growers 4. Effect of Pruning Practices an Blueberry Insect Abundance 5. Control of Blueberry Maggot (Alternatives to Guthion) 6. Economic Thresholds and Control of Secondary Blueberry Pests 7. Chemical Control of Mummyberry Disease 8. Chemical Control of Botrytis Bloom Blight 9. Effects of Late Summer Fungicide Applications 10. Mowing vs. Burning - Comparisons of Disease Incidence 11. Long-term Effects of N and NPK Fertilizer on Plant Growth and Yield 12. Effect of Several Mulches on Frost Heaving, Soil Moisture, Soil Temperature and Rhizome Development 13. Interaction of Fertility and Pruning Practices on Soil 14. Effect of Block Freezing on Physical Characterization and Sugar Migration on Lowbush Blueberries 15. Demonstration of the Rota-Cone Vacuum Drying Process on Lowbush Blueberries 16. Production of a Blueberry Gelatin 17. Isolation and Characterization of Blueberry Pectin 18. The Effect of pH, Chemicals and Holding time-temperature on the color of Blueberry Puree 19. Effect of Hexazinone on Species Distribution in Lowbush Blueberry Fields 20. Evaluation of Postemergent Herbicides for Grass Control 21. Evaluation of Sulfonyl urea and lmidazoline compounds for Bunchberry Control 22. Use of Mechanical wiper with glyphosate or dicamba for control of dogbane 23. Hand-wiper Applications of Herbicides on Woody Weeds 24. Dogbane Control with 2% Glyphosate 25. Low Volume Solution of Asulam for Bracken Fern Control 26. Integrated Weed Management 27. 1986 Annual Report to the Maine Lowbush Blueberry Commissio

Search for transient optical counterparts to high-energy IceCube neutrinos with Pan-STARRS1

In order to identify the sources of the observed diffuse high-energy neutrino flux, it is crucial to discover their electromagnetic counterparts. IceCube began releasing alerts for single high-energy ($E > 60$ TeV) neutrino detections with sky localisation regions of order 1 deg radius in 2016. We used Pan-STARRS1 to follow-up five of these alerts during 2016-2017 to search for any optical transients that may be related to the neutrinos. Typically 10-20 faint ($m < 22.5$ mag) extragalactic transients are found within the Pan-STARRS1 footprints and are generally consistent with being unrelated field supernovae (SNe) and AGN. We looked for unusual properties of the detected transients, such as temporal coincidence of explosion epoch with the IceCube timestamp. We found only one transient that had properties worthy of a specific follow-up. In the Pan-STARRS1 imaging for IceCube-160427A (probability to be of astrophysical origin of $\sim$50 %), we found a SN PS16cgx, located at 10.0' from the nominal IceCube direction. Spectroscopic observations of PS16cgx showed that it was an H-poor SN at z = 0.2895. The spectra and light curve resemble some high-energy Type Ic SNe, raising the possibility of a jet driven SN with an explosion epoch temporally coincident with the neutrino detection. However, distinguishing Type Ia and Type Ic SNe at this redshift is notoriously difficult. Based on all available data we conclude that the transient is more likely to be a Type Ia with relatively weak SiII absorption and a fairly normal rest-frame r-band light curve. If, as predicted, there is no high-energy neutrino emission from Type Ia SNe, then PS16cgx must be a random coincidence, and unrelated to the IceCube-160427A. We find no other plausible optical transient for any of the five IceCube events observed down to a 5$\sigma$ limiting magnitude of $m \sim 22$ mag, between 1 day and 25 days after detection.Comment: 20 pages, 6 figures, accepted to A&

Coordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas

We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far