Long term physiologic modification using rAAV in utero gene-therapy

BACKGROUND: Transfer of genes in utero via the amniotic fluid was shown previously with recombinant adeno-associated viruses (rAAV) to be highly efficient. Expression for over one year was demonstrated using reporter genes. In addition, it was shown previously that transgenes delivered by this method release protein into the general circulation. Given these results experiments were designed to test the hypothesis that in utero rAAV gene therapy could result in long term physiologic modification. METHODS: A rAAV recombinant expressing ciliary neurotrophic factor (cntf) and green fluorescent (gfp) in a polycistronic messenger was used to treat rat fetuses in utero. CNTF causes weight loss and decreased water consumption as a measurable physiologic effect. GFP was used as a marker of gene expression. RESULTS: In utero gene transfer with rAAV carrying human cntf and gfp resulted in long-term gene expression in rat. CNTF-specific physiologic effects of a decrease in weight and water intake were obtained. Expression of the GFP was documented in the treated animals at one year of age. CONCLUSION: Given this data, in utero gene therapy with rAAV into multipotential stem cells resulted in long term systemic physiologic modification of the treated animals by the transgene product. In utero rAAV gene therapy potentially could be used for gene replacement therapy in metabolic disorders

In utero recombinant adeno-associated virus gene transfer in mice, rats, and primates

BACKGROUND: Gene transfer into the amniotic fluid using recombinant adenovirus vectors was shown previously to result in high efficiency transfer of transgenes into the lungs and intestines. Adenovirus mediated in utero gene therapy, however, resulted in expression of the transgene for less than 30 days. Recombinant adenovirus associated viruses (rAAV) have the advantage of maintaining the viral genome in daughter cells thus providing for long-term expression of transgenes. METHODS: Recombinant AAV2 carrying green fluorescent protein (GFP) was introduced into the amniotic sac of fetal rodents and nonhuman primates. Transgene maintenance and expression was monitor. RESULTS: Gene transfer resulted in rapid uptake and long-term gene expression in mice, rats, and non-human primates. Expression and secretion of the reporter gene, GFP, was readily demonstrated within 72 hours post-therapy. In long-term studies in rats and nonhuman primates, maintenance of GFP DNA, protein expression, and reporter gene secretion was documented for over one year. CONCLUSIONS: Because only multipotential stem cells are present at the time of therapy, these data demonstrated that in utero gene transfer with AAV2 into stem cells resulted in long-term systemic expression of active transgene roducts. Thus, in utero gene transfer via the amniotic fluid may be useful in treatment of gene disorders

Drivers of 20th Century Sea-Level Change in Southern New Zealand Determined from Proxy and Instrumental Records

In this paper we present new proxy-based sea-level reconstructions for southern New Zealand spanning the last millennium. These palaeo sea-level records usefully complement sparse Southern Hemisphere proxy and tide-gauge sea-level datasets and, in combination with instrumental observations, can test hypotheses about the drivers of 20th century global sea-level change, including land-based ice melt and regional sterodynamics. We develop sea-level transfer functions from regional datasets of salt-marsh foraminifera to establish a new proxy-based sea-level record at Mokomoko Inlet, at the southern tip of the South Island, and to improve the previously published sea-level reconstruction at Pounawea, located about 110 km to the east. Chronologies are based on radiocarbon, radiocaesium, stable lead isotope and pollen analyses. Both records are in good agreement and show a rapid sea-level rise in the first half of the 20th century that peaked in the 1940s. Previously reported discrepancies between proxy-based sea-level records and tide-gauge records are partially reconciled by accounting for barystatic and sterodynamic components of regional sea-level rise. We conclude that the rapid sea-level rise during the mid-20th century along the coast of southern New Zealand was primarily driven by regional thermal expansion and ocean dynamics

RESOLVING UNCERTAINTIES IN FORAMINIFERA-BASED RELATIVE SEA-LEVEL RECONSTRUCTION : A CASE STUDY FROM SOUTHERN NEW ZEALAND

Since the pioneering work of David Scott and others in the 1970s and 1980s, foraminifera have been used to develop precise sea-level reconstructions from salt marshes around the world. In New Zealand, reconstructions feature rapid rates of sea-level rise during the early to mid-20th century. Here, we test whether infaunality, taphonomy, and sediment compaction influence these reconstructions. We find that surface (0–1 cm) and subsurface (3–4 cm) foraminiferal assemblages show a high degree of similarity. A landward shift in assemblage zones is consistent with recent sea-level rise and transgression. Changes associated with infaunality and taphonomy do not affect transfer function-based sea-level reconstructions. Applying a geotechnical modelling approach to the core from which sea-level changes were reconstructed, we demonstrate compaction is also negligible, resulting in maximum post-depositional lowering of 2.5 mm. We conclude that salt-marsh foraminifera are indeed highly accurate and precise indicators of past sea levels

Drivers of 20th century sea-level change in southern New Zealand determined from proxy and instrumental records

In this paper we present new proxy-based sea-level reconstructions for southern New Zealand spanning the last millennium. These palaeo sea-level records usefully complement sparse Southern Hemisphere proxy and tide-gauge sea-level datasets and, in combination with instrumental observations, can test hypotheses about the drivers of 20th century global sea-level change, including land-based ice melt and regional sterodynamics. We develop sea-level transfer functions from regional datasets of salt-marsh foraminifera to establish a new proxy-based sea-level record at Mokomoko Inlet, at the southern tip of the South Island, and to improve the previously published sea-level reconstruction at Pounawea, located about 110 km to the east. Chronologies are based on radiocarbon, radiocaesium, stable lead isotope and pollen analyses. Both records are in good agreement and show a rapid sea-level rise in the first half of the 20th century that peaked in the 1940s. Previously reported discrepancies between proxy-based sea-level records and tide-gauge records are partially reconciled by accounting for barystatic and sterodynamic components of regional sea-level rise. We conclude that the rapid sea-level rise during the mid-20th century along the coast of southern New Zealand was primarily driven by regional thermal expansion and ocean dynamics

Corrigendum to “Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy” [Neuromuscular Disorders, Vol. 30 (6) 2020, 492-502] (Neuromuscular Disorders (2020) 30(6) (492–502), (S0960896620301188), (10.1016/j.nmd.2020.05.002))

This article reported on the results from a phase 2 trial of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619). The manuscript also provided results on two secondary endpoints for magnetic resonance imaging (MRI), muscle volume and muscle volume index. The authors regret that, following publication of the results and in preparation for a separate publication on MRI results from this trial, the MRI images were reviewed and segmentation errors were identified. As a result, the team worked to (1) Perform a rigorous quality inspection of all analysed data; (2) Identify cases where there were incorrect segmentations; (3) correct segmentation errors; (4) Re-analyse all data with correct segmentation. Using the updated MRI data, the MMRM analysis showed there was a change in the significance of secondary endpoints evaluating Thigh Muscle Volume and Muscle Volume Index. No significant differences between treatment groups in muscle volume measures were found in the original analysis. These results have not altered the overall interpretation of the study results but do necessitate revisions to the article. These data confirm that the trial design and execution adequately tested the hypothesis that myostatin inhibition would slow or delay the loss of function in patients with Duchenne muscular dystrophy (DMD). The increase in muscle volume observed by MRI in patients with DMD treated with domagrozumab is in accordance with mechanism of action for domagrozumab, which targets myostatin, a negative regulator of muscle growth. The increase in muscle volume did not lead to a clinical benefit in patients with DMD. The primary endpoint (4 stair climb) did not meet statistical significance, nor did the other functional tests. The study was terminated due to lack of efficacy. Full details of the needed revisions are as follows: 1. In the results section 3.6 (page 8, second paragraph), we reported no significant differences in mean percent change from baseline between domagrozumab and placebo for both muscle volume and muscle volume index. This paragraph was replaced with the following text: “There was a significant difference between domagrozumab and placebo in the mean percent change from baseline in thigh muscle volume at Week 17 (difference 2.945%, P=0.0087) and Week 49 (differences 4.087%, P=0.0298), and in muscle volume index at Week 33 (difference 2.612%, P=0.0376) and Week 49 (differences3.208%, P=0.0411).” 2. In the discussion (page 9), the following sentence, “Although neither muscle volume nor muscle volume index measures were statistically significant in this study, they are both consistent with a potential anabolic effect.” was replaced with, “The increase in muscle volume observed on MRI in patients with DMD treated with domagrozumab, is in accordance with mechanism of action for this compound which targets myostatin, a negative regulator of muscle growth. However, the increase in muscle volume did not lead to a clinical benefit (improved function) in patients with DMD.” 3. In view of the correction to the Results section, this is now reflected in the abstract which has changed to read: “There were no significant between-group differences in secondary clinical endpoints, except for the thigh muscle volume and muscle volume index measures (P\u3c0.05).” The authors would like to apologise for any inconvenience caused

The Multi-Object, Fiber-Fed Spectrographs for SDSS and the Baryon Oscillation Spectroscopic Survey

We present the design and performance of the multi-object fiber spectrographs for the Sloan Digital Sky Survey (SDSS) and their upgrade for the Baryon Oscillation Spectroscopic Survey (BOSS). Originally commissioned in Fall 1999 on the 2.5-m aperture Sloan Telescope at Apache Point Observatory, the spectrographs produced more than 1.5 million spectra for the SDSS and SDSS-II surveys, enabling a wide variety of Galactic and extra-galactic science including the first observation of baryon acoustic oscillations in 2005. The spectrographs were upgraded in 2009 and are currently in use for BOSS, the flagship survey of the third-generation SDSS-III project. BOSS will measure redshifts of 1.35 million massive galaxies to redshift 0.7 and Lyman-alpha absorption of 160,000 high redshift quasars over 10,000 square degrees of sky, making percent level measurements of the absolute cosmic distance scale of the Universe and placing tight constraints on the equation of state of dark energy. The twin multi-object fiber spectrographs utilize a simple optical layout with reflective collimators, gratings, all-refractive cameras, and state-of-the-art CCD detectors to produce hundreds of spectra simultaneously in two channels over a bandpass covering the near ultraviolet to the near infrared, with a resolving power R = \lambda/FWHM ~ 2000. Building on proven heritage, the spectrographs were upgraded for BOSS with volume-phase holographic gratings and modern CCD detectors, improving the peak throughput by nearly a factor of two, extending the bandpass to cover 360 < \lambda < 1000 nm, and increasing the number of fibers from 640 to 1000 per exposure. In this paper we describe the original SDSS spectrograph design and the upgrades implemented for BOSS, and document the predicted and measured performances.Comment: 43 pages, 42 figures, revised according to referee report and accepted by AJ. Provides background for the instrument responsible for SDSS and BOSS spectra. 4th in a series of survey technical papers released in Summer 2012, including arXiv:1207.7137 (DR9), arXiv:1207.7326 (Spectral Classification), and arXiv:1208.0022 (BOSS Overview

The subtropical nutrient spiral

Author Posting. © American Geophysical Union, 2003. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 17 (2003): 1110, doi:10.1029/2003GB002085.We present an extended series of observations and more comprehensive analysis of a tracer-based measure of new production in the Sargasso Sea near Bermuda using the 3He flux gauge technique. The estimated annually averaged nitrate flux of 0.84 ± 0.26 mol m−2 yr−1 constitutes only that nitrate physically transported to the euphotic zone, not nitrogen from biological sources (e.g., nitrogen fixation or zooplankton migration). We show that the flux estimate is quantitatively consistent with other observations, including decade timescale evolution of the 3H + 3He inventory in the main thermocline and export production estimates. However, we argue that the flux cannot be supplied in the long term by local diapycnal or isopycnal processes. These considerations lead us to propose a three-dimensional pathway whereby nutrients remineralized within the main thermocline are returned to the seasonally accessible layers within the subtropical gyre. We describe this mechanism, which we call “the nutrient spiral,” as a sequence of steps where (1) nutrient-rich thermocline waters are entrained into the Gulf Stream, (2) enhanced diapycnal mixing moves nutrients upward onto lighter densities, (3) detrainment and enhanced isopycnal mixing injects these waters into the seasonally accessible layer of the gyre recirculation region, and (4) the nutrients become available to biota via eddy heaving and wintertime convection. The spiral is closed when nutrients are utilized, exported, and then remineralized within the thermocline. We present evidence regarding the characteristics of the spiral and discuss some implications of its operation within the biogeochemical cycle of the subtropical ocean.This work was supported by grants from the National Science Foundation (OCE-0221247) and NSF/ONR NOPP (N000140210370)

The Eighth Data Release of the Sloan Digital Sky Survey: First Data from SDSS-III

The Sloan Digital Sky Survey (SDSS) started a new phase in August 2008, with new instrumentation and new surveys focused on Galactic structure and chemical evolution, measurements of the baryon oscillation feature in the clustering of galaxies and the quasar Ly alpha forest, and a radial velocity search for planets around ~8000 stars. This paper describes the first data release of SDSS-III (and the eighth counting from the beginning of the SDSS). The release includes five-band imaging of roughly 5200 deg^2 in the Southern Galactic Cap, bringing the total footprint of the SDSS imaging to 14,555 deg^2, or over a third of the Celestial Sphere. All the imaging data have been reprocessed with an improved sky-subtraction algorithm and a final, self-consistent photometric recalibration and flat-field determination. This release also includes all data from the second phase of the Sloan Extension for Galactic Understanding and Evolution (SEGUE-2), consisting of spectroscopy of approximately 118,000 stars at both high and low Galactic latitudes. All the more than half a million stellar spectra obtained with the SDSS spectrograph have been reprocessed through an improved stellar parameters pipeline, which has better determination of metallicity for high metallicity stars.Comment: Astrophysical Journal Supplements, in press (minor updates from submitted version