2,016 research outputs found
Assessing long-distance RNA sequence connectivity via RNA-templated DNA-DNA ligation
Many RNAs, including pre-mRNAs and long non-coding RNAs, can be thousands of nucleotides long and undergo complex post-transcriptional processing. Multiple sites of alternative splicing within a single gene exponentially increase the number of possible spliced isoforms, with most human genes currently estimated to express at least ten. To understand the mechanisms underlying these complex isoform expression patterns, methods are needed that faithfully maintain long-range exon connectivity information in individual RNA molecules. In this study, we describe SeqZip, a methodology that uses RNA-templated DNA-DNA ligation to retain and compress connectivity between distant sequences within single RNA molecules. Using this assay, we test proposed coordination between distant sites of alternative exon utilization in mouse Fn1, and we characterize the extraordinary exon diversity of Drosophila melanogaster Dscam1
4-Year Results from the RAPID-PsA Phase 3 Randomised Placebo-Controlled Trial of Certolizumab Pegol in Psoriatic Arthritis
Objective: To report the efficacy, patient-reported, radiographic and safety outcomes of 4 years\u27 certolizumab pegol (CZP) treatment in patients with psoriatic arthritis (PsA). Methods: RAPID-PsA (NCT01087788) was double-blind and placebo-controlled to Week 24, dose-blind to Week 48 and open-label (OL) to Week 216. Patients were randomised 1:1:1 to either placebo or CZP 200 mg every 2 weeks (Q2W) or 400 mg every 4 weeks (Q4W) (following 400 mg at Weeks 0/2/4). Patients randomised to CZP continued their assigned dose in the OL period. Patients randomised to placebo were re-randomised to CZP 200 mg Q2W or 400 mg Q4W (post-loading dose) at Week 16 (early escape) or after the double-blind phase. We present observed and imputed data; missing values were imputed using non-responder imputation (NRI) for categorical and last observation carried forward (LOCF) for continuous measures. Results: 409 patients were randomised; 20% (54/273) of Week 0 patients randomised to CZP had prior anti-tumour necrosis factor (TNF) exposure; 67% (183/273) completed 216 weeks. By Week 48, 60.4% of patients achieved Disease Activity Index for Psoriatic Arthritis low disease activity or remission, which was maintained; 66.3% achieved these outcomes at Week 216 (NRI). At Weeks 48 and 216, 39.2% of patients achieved minimal disease activity (NRI). 75% reduction in Psoriasis Area and Severity Index responses were 65% and 52% at Weeks 48 and 216 (NRI). Total resolution rates for enthesitis, dactylitis and nail psoriasis, at 4 years, were 71%, 81% and 65%, respectively (LOCF). Structural damage progression was low over 4 years\u27 treatment. No new safety signals were identified after Week 96. Conclusions: CZP efficacy in treating PsA was maintained over 4 years, in patients both with and without prior anti-TNF exposure, with no new safety signals identified
Measurement of gut permeability using fluorescent tracer agent technology
Abstract The healthy gut restricts macromolecular and bacterial movement across tight junctions, while increased intestinal permeability accompanies many intestinal disorders. Dual sugar absorption tests, which measure intestinal permeability in humans, present challenges. Therefore, we asked if enterally administered fluorescent tracers could ascertain mucosal integrity, because transcutaneous measurement of differentially absorbed molecules could enable specimen-free evaluation of permeability. We induced small bowel injury in rats using high- (15 mg/kg), intermediate- (10 mg/kg), and low- (5 mg/kg) dose indomethacin. Then, we compared urinary ratios of enterally administered fluorescent tracers MB-402 and MB-301 to urinary ratios of sugar tracers lactulose and rhamnose. We also tested the ability of transcutaneous sensors to measure the ratios of absorbed fluorophores. Urinary fluorophore and sugar ratios reflect gut injury in an indomethacin dose dependent manner. The fluorophores generated smooth curvilinear ratio trajectories with wide dynamic ranges. The more chaotic sugar ratios had narrower dynamic ranges. Fluorophore ratios measured through the skin distinguished indomethacin-challenged from same day control rats. Enterally administered fluorophores can identify intestinal injury in a rat model. Fluorophore ratios are measureable through the skin, obviating drawbacks of dual sugar absorption tests. Pending validation, this technology should be considered for human use
Geochemical evidence of the seasonality, affinity and pigmenation of Solenopora jurassica
Solenopora jurassica is a fossil calcareous alga that functioned as an important reef-building organism during the Palaeozoic. It is of significant palaeobiological interest due to its distinctive but poorly understood pink and white banding. Though widely accepted as an alga there is still debate over its taxonomic affinity, with recent work arguing that it should be reclassified as a chaetetid sponge. The banding is thought to be seasonal, but there is no conclusive evidence for this. Other recent work has, however demonstrated the presence of a unique organic boron-containing pink/red pigment in the pink bands of S. jurassica. We present new geochemical evidence concerning the seasonality and pigmentation of S. jurassica. Seasonal growth cycles are demonstrated by X-ray radiography, which shows differences in calcite density, and by varying δ13C composition of the bands. Temperature variation in the bands is difficult to constrain accurately due to conflicting patterns arising from Mg/Ca molar ratios and δ18O data. Fluctuating chlorine levels indicate increased salinity in the white bands, when combined with the isotope data this suggests more suggestive of marine conditions during formation of the white band and a greater freshwater component (lower chlorinity) during pink band precipitation (δ18O). Increased photosynthesis is inferred within the pink bands in comparison to the white, based on δ13C. Pyrolysis Gas Chromatography Mass Spectrometry (Py-GCMS) and Fourier Transform Infrared Spectroscopy (FTIR) show the presence of tetramethyl pyrrole, protein moieties and carboxylic acid groups, suggestive of the presence of the red algal pigment phycoerythrin. This is consistent with the pink colour of S. jurassica. As phycoerythrin is only known to occur in algae and cyanobacteria, and no biomarker evidence of bacteria or sponges was detected we conclude S. jurassica is most likely an alga. Pigment analysis may be a reliable classification method for fossil algae
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Efficacy and Safety of Antioxidant Treatment With α-Lipoic Acid Over 4 Years in Diabetic Polyneuropathy
Objective: To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN). Research Design and Methods: In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]–Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs). Results: Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%). Conclusions: Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible
Seasonal calibration of the end-cretaceous Chicxulub impact event
The end-Cretaceous Chicxulub impact triggered Earth’s last mass-extinction, extinguishing ~ 75% of species diversity and facilitating a global ecological shift to mammal-dominated biomes. Temporal details of the impact event on a fine scale (hour-to-day), important to understanding the early trajectory of mass-extinction, have largely eluded previous studies. This study employs histological and histo-isotopic analyses of fossil fish that were coeval with a unique impact-triggered mass-death assemblage from the Cretaceous-Paleogene (KPg) boundary in North Dakota (USA). Patterns of growth history, including periodicity of ẟ18O and ẟ13C and growth band morphology, plus corroborating data from fish ontogeny and seasonal insect behavior, reveal that the impact occurred during boreal Spring/Summer, shortly after the spawning season for fish and most continental taxa. The severity and taxonomic symmetry of response to global natural hazards are influenced by the season during which they occur, suggesting that post-impact perturbations could have exerted a selective force that was exacerbated by seasonal timing. Data from this study can also provide vital hindsight into patterns of extant biotic response to global-scale hazards that are relevant to both current and future biomes
BLAST: The Mass Function, Lifetimes, and Properties of Intermediate Mass Cores from a 50 Square Degree Submillimeter Galactic Survey in Vela (l = ~265)
We present first results from an unbiased 50 deg^2 submillimeter Galactic
survey at 250, 350, and 500 micron from the 2006 flight of the Balloon-borne
Large Aperture Submillimeter Telescope (BLAST). The map has resolution ranging
from 36 arcsec to 60 arcsec in the three submillimeter bands spanning the
thermal emission peak of cold starless cores. We determine the temperature,
luminosity, and mass of more than one thousand compact sources in a range of
evolutionary stages and an unbiased statistical characterization of the
population. From comparison with C^(18)O data, we find the dust opacity per gas
mass, kappa r = 0.16 cm^2 g^(-1) at 250 micron, for cold clumps. We find that
2% of the mass of the molecular gas over this diverse region is in cores colder
than 14 K, and that the mass function for these cold cores is consistent with a
power law with index alpha = -3.22 +/- 0.14 over the mass range 14 M_sun < M <
80 M_sun. Additionally, we infer a mass-dependent cold core lifetime of t_c(M)
= 4E6 (M/20 M_sun)^(-0.9) years - longer than what has been found in previous
surveys of either low or high mass cores, and significantly longer than free
fall or likely turbulent decay times. This implies some form of non-thermal
support for cold cores during this early stage of star formation.Comment: Accepted for publication in the Astrophysical Journal. Maps available
at http://blastexperiment.info
A Cautionary Tale: MARVELS Brown Dwarf Candidate Reveals Itself To Be A Very Long Period, Highly Eccentric Spectroscopic Stellar Binary
We report the discovery of a highly eccentric, double-lined spectroscopic
binary star system (TYC 3010-1494-1), comprising two solar-type stars that we
had initially identified as a single star with a brown dwarf companion. At the
moderate resolving power of the MARVELS spectrograph and the spectrographs used
for subsequent radial-velocity (RV) measurements (R ~ <30,000), this particular
stellar binary mimics a single-lined binary with an RV signal that would be
induced by a brown dwarf companion (Msin(i)~50 M_Jup) to a solar-type primary.
At least three properties of this system allow it to masquerade as a single
star with a very low-mass companion: its large eccentricity (e~0.8), its
relatively long period (P~238 days), and the approximately perpendicular
orientation of the semi-major axis with respect to the line of sight (omega~189
degrees). As a result of these properties, for ~95% of the orbit the two sets
of stellar spectral lines are completely blended, and the RV measurements based
on centroiding on the apparently single-lined spectrum is very well fit by an
orbit solution indicative of a brown dwarf companion on a more circular orbit
(e~0.3). Only during the ~5% of the orbit near periastron passage does the
true, double-lined nature and large RV amplitude of ~15 km/s reveal itself. The
discovery of this binary system is an important lesson for RV surveys searching
for substellar companions; at a given resolution and observing cadence, a
survey will be susceptible to these kinds of astrophysical false positives for
a range of orbital parameters. Finally, for surveys like MARVELS that lack the
resolution for a useful line bisector analysis, it is imperative to monitor the
peak of the cross-correlation function for suspicious changes in width or
shape, so that such false positives can be flagged during the candidate vetting
process.Comment: 16 pages, 11 figures, 6 table
Corrigendum to "Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology" [Clin. Neurophysiol. 132(2) (2021) 666-682].
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