Shelf Edge Tide Correlated Eddies Along the Southeastern United States

High frequency radar observations in the Southeastern United States have revealed sequences of small short‐lived cyclonic eddies along the shoreward edge of the Gulf Stream, that spin up as the local tide turns alongshelf antiparallel to the Stream. Eddies propagate equatorward along the shelf edge, sometimes progressing shoreward before dissipating one to three hours later. They are distinctly different from Gulf Stream meander eddies, which propagate poleward. In this article, radar and mooring data are used to establish three important aspects of these neweddies: they represent an instability process operating at a previously unidentified frequency, scale, and cross‐Stream position; they contribute to shoreward momentum fluxes,defining a link between Gulf Stream and outer shelf subtidal variability and illustrating a mechanism to justify locally large horizontal eddy viscosity estimates; and they transport properties across the shelf edge, importing nutrients onto the shelf and transferring heat between the Gulf Stream and the coastal ocean

SDI-118, a novel procognitive SV2A modulator: First-in-human randomized controlled trial including PET/fMRI assessment of target engagement

Background: Current treatments for progressive neurodegenerative disorders characterized by cognitive impairment either have limited efficacy or are lacking altogether. SDI-118 is a small molecule which modulates the activity of synaptic vesicle glycoprotein 2A (SV2A) in the brain and shows cognitive enhancing effects in a range of animal models of cognitive deficit.Methods: This first-in-human study evaluated safety, tolerability, and pharmacokinetics/pharmacodynamics of SDI-118 in single ascending oral doses up to 80 mg administered to 32 healthy male subjects. Brain target occupancy was measured in eight subjects using positron emission tomography with PET-ligand [11C]-UCB-J. Food effect was assessed in seven subjects. Mood state was regularly evaluated using standardized questionnaires, and resting state fMRI data were analyzed as exploratory objectives.Key Results: At all doses tested, SDI-118 was well tolerated and appeared safe. Adverse events were mainly dizziness, hypersomnia, and somnolence. All were mild in intensity and increased in frequency with increasing administered dose. No dose-limiting adverse reactions were observed at any dose. SDI-118 displayed a linear pharmacokinetic profile with no significant food effect. Brain penetration and target engagement were demonstrated by a dose-proportional SV2A occupancy.Conclusion: Single oral doses of SDI-118 up to 80 mg were very well tolerated in healthy male subjects. Dose-proportional SV2A occupancy in the brain was demonstrated with brain imaging. Adverse effects in humans mainly occurred in higher dose ranges, with high occupancy levels, and were all mild and self-limiting. These data support further clinical exploration of the compound in patients with cognitive disorders.Clinical Trial Registration:https://clinicaltrials.gov/, identifier NCT0548619

The unpredictable nature of internal tides on continental shelves

Author Posting. © American Meteorological Society, 2012. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 42 (2012): 1981–2000, doi:10.1175/JPO-D-12-028.1.Packets of nonlinear internal waves (NLIWs) in a small area of the Mid-Atlantic Bight were 10 times more energetic during a local neap tide than during the preceding spring tide. This counterintuitive result cannot be explained if the waves are generated near the shelf break by the local barotropic tide since changes in shelfbreak stratification explain only a small fraction of the variability in barotropic to baroclinic conversion. Instead, this study suggests that the occurrence of strong NLIWs was caused by the shoaling of distantly generated internal tides with amplitudes that are uncorrelated with the local spring-neap cycle. An extensive set of moored observations show that NLIWs are correlated with the internal tide but uncorrelated with barotropic tide. Using harmonic analysis of a 40-day record, this study associates steady-phase motions at the shelf break with waves generated by the local barotropic tide and variable-phase motions with the shoaling of distantly generated internal tides. The dual sources of internal tide energy (local or remote) mean that shelf internal tides and NLIWs will be predictable with a local model only if the locally generated internal tides are significantly stronger than shoaling internal tides. Since the depth-integrated internal tide energy in the open ocean can greatly exceed that on the shelf, it is likely that shoaling internal tides control the energetics on shelves that are directly exposed to the open ocean.This research was supported by ONR Grants N00014-05-1-0271, N00014-08-1-0991, N00014-04- 1-0146, and N00014-11-1-0194.2013-05-0

Computational Characterization of 3′ Splice Variants in the GFAP Isoform Family

Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) protein specific to central nervous system (CNS) astrocytes. It has been the subject of intense interest due to its association with neurodegenerative diseases, and because of growing evidence that IF proteins not only modulate cellular structure, but also cellular function. Moreover, GFAP has a family of splicing isoforms apparently more complex than that of other CNS IF proteins, consistent with it possessing a range of functional and structural roles. The gene consists of 9 exons, and to date all isoforms associated with 3′ end splicing have been identified from modifications within intron 7, resulting in the generation of exon 7a (GFAPδ/ε) and 7b (GFAPκ). To better understand the nature and functional significance of variation in this region, we used a Bayesian multiple change-point approach to identify conserved regions. This is the first successful application of this method to a single gene – it has previously only been used in whole-genome analyses. We identified several highly or moderately conserved regions throughout the intron 7/7a/7b regions, including untranslated regions and regulatory features, consistent with the biology of GFAP. Several putative unconfirmed features were also identified, including a possible new isoform. We then integrated multiple computational analyses on both the DNA and protein sequences from the mouse, rat and human, showing that the major isoform, GFAPα, has highly conserved structure and features across the three species, whereas the minor isoforms GFAPδ/ε and GFAPκ have low conservation of structure and features at the distal 3′ end, both relative to each other and relative to GFAPα. The overall picture suggests distinct and tightly regulated functions for the 3′ end isoforms, consistent with complex astrocyte biology. The results illustrate a computational approach for characterising splicing isoform families, using both DNA and protein sequences

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Straight Outta Compton

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