934 research outputs found
Quantification of Plasma and Urine Thymidine and 2'-Deoxyuridine by LC-MS/MS for the Pharmacodynamic Evaluation of Erythrocyte Encapsulated Thymidine Phosphorylase in Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disorder caused by mutations in TYMP, leading to a deficiency in thymidine phosphorylase and a subsequent systemic accumulation of thymidine and 2'-deoxyuridine. Erythrocyte-encapsulated thymidine phosphorylase (EE-TP) is under clinical development as an enzyme replacement therapy for MNGIE. Bioanalytical methods were developed according to regulatory guidelines for the quantification of thymidine and 2'-deoxyuridine in plasma and urine using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for supporting the pharmacodynamic evaluation of EE-TP. Samples were deproteinized with 5% perchloric acid (v/v) and the supernatants analyzed using a Hypercarb column (30 à 2.1 mm, 3 ”m), with mobile phases of 0.1% formic acid in methanol and 0.1% formic acid in deionized water. Detection was conducted using an ion-spray interface running in positive mode. Isotopically labelled thymidine and 2'-deoxyuridine were used as internal standards. Calibration curves for both metabolites showed linearity (r > 0.99) in the concentration ranges of 10-10,000 ng/mL for plasma, and 1-50 ”g/mL for urine, with method analytical performances within the acceptable criteria for quality control samples. The plasma method was successfully applied to the diagnosis of two patients with MNGIE and the quantification of plasma metabolites in three patients treated with EE-TP
An apparently normal gamma-ray burst with an unusually low luminosity
Much of progress in gamma-ray bursts has come from the studies of distant
events (redshift z~1). The brightest GRBs are the most collimated events and
seen across the Universe due to their brilliance. It has long been suspected
that nearest (and most common) events have been missed because they are not so
collimated or under-energetic or both. Here we report soft gamma-ray
observations of GRB 031203, the nearest event to date (z=0.106). This event
with a duration of 40 s and peak energy of >190 keV appears to be a typical
long duration GRB. However, the isotropic gamma-ray energy <~10^50 erg, about
three orders of magnitude smaller than the cosmological population. This event
as well as the other nearby but somewhat controversial event GRB 980425 are
clear outliers for the much discussed isotropic-energy peak-energy relation and
luminosity spectral-lag relations. Radio calorimetry shows that both these
events are under-energetic explosions. We conclude that there does indeed exist
a large population of under-energetic events.Comment: 11 pages, 3 figure
SN 2005hj: Evidence for Two Classes of Normal-Bright SNe Ia and Implications for Cosmology
HET Optical spectra covering the evolution from about 6 days before to about
5 weeks after maximum light and the ROTSE-IIIb unfiltered light curve of the
"Branch-normal" Type Ia Supernova SN 2005hj are presented. The host galaxy
shows HII region lines at redshift of z=0.0574, which puts the peak unfiltered
absolute magnitude at a somewhat over-luminous -19.6. The spectra show weak and
narrow SiII lines, and for a period of at least 10 days beginning around
maximum light these profiles do not change in width or depth and they indicate
a constant expansion velocity of ~10,600 km/s. We analyzed the observations
based on detailed radiation dynamical models in the literature. Whereas delayed
detonation and deflagration models have been used to explain the majority of
SNe Ia, they do not predict a long velocity plateau in the SiII minimum with an
unvarying line profile. Pulsating delayed detonations and merger scenarios form
shell-like density structures with properties mostly related to the mass of the
shell, M_shell, and we discuss how these models may explain the observed SiII
line evolution; however, these models are based on spherical calculations and
other possibilities may exist. SN 2005hj is consistent with respect to the
onset, duration, and velocity of the plateau, the peak luminosity and, within
the uncertainties, with the intrinsic colors for models with M_shell=0.2 M_sun.
Our analysis suggests a distinct class of events hidden within the
Branch-normal SNe Ia. If the predicted relations between observables are
confirmed, they may provide a way to separate these two groups. We discuss the
implications of two distinct progenitor classes on cosmological studies
employing SNe Ia, including possible differences in the peak luminosity to
light curve width relation.Comment: ApJ accepted, 31 page
Experimental Reconstruction of Lomonosov's Discovery of Venus's Atmosphere with Antique Refractors During the 2012 Transit of Venus
In 1761, the Russian polymath Mikhail Vasilievich Lomonosov (1711-1765)
discovered the atmosphere of Venus during its transit over the Sun's disc. In
this paper we report on experimental reenactments of Lomonosov's discovery with
antique refractors during the transit of Venus June 5-6, 2012. We conclude that
Lomonosov's telescope was fully adequate to the task of detecting the arc of
light around Venus off the Sun's disc during ingress or egress if proper
experimental techniques as described by Lomonosov in his 1761 report are
employed.Comment: 14 pages, 9 figure
An eclipsing binary distance to the Large Magellanic Cloud accurate to 2 per cent
In the era of precision cosmology it is essential to determine the Hubble
Constant with an accuracy of 3% or better. Currently, its uncertainty is
dominated by the uncertainty in the distance to the Large Magellanic Cloud
(LMC) which as the second nearest galaxy serves as the best anchor point of the
cosmic distance scale. Observations of eclipsing binaries offer a unique
opportunity to precisely and accurately measure stellar parameters and
distances. The eclipsing binary method was previously applied to the LMC but
the accuracy of the distance results was hampered by the need to model the
bright, early-type systems used in these studies. Here, we present distance
determinations to eight long-period, late- type eclipsing systems in the LMC
composed of cool giant stars. For such systems we can accurately measure both
the linear and angular sizes of their components and avoid the most important
problems related to the hot early-type systems. Our LMC distance derived from
these systems is demonstrably accurate to 2.2 % (49.97 +/- 0.19 (statistical)
+/- 1.11 (systematic) kpc) providing a firm base for a 3 % determination of the
Hubble Constant, with prospects for improvement to 2 % in the future.Comment: 34 pages, 5 figures, 13 tables, published in the Nature, a part of
our data comes from new unpublished OGLE-IV photometric dat
Feasibility of a lifestyle intervention in early pregnancy to prevent deterioration of glucose tolerance
<p>Abstract</p> <p>Background</p> <p>In conjunction with the growing prevalence of obesity and the older age of pregnant women gestational diabetes (GDM) is a major health problem.</p> <p>The aim of the study was to evaluate if a lifestyle intervention since early pregnancy is feasible in improving the glucose tolerance of women at a high-risk for GDM in Finland.</p> <p>Methods</p> <p>A 75-g oral glucose tolerance test (OGTT) was performed in early pregnancy (n = 102). Women at high risk for GDM (n = 54) were randomized at weeks 8-12 from Apr 2005 to May 2006 to a lifestyle intervention group (n = 27) or to a close follow-up group (n = 27). An OGTT was performed again at weeks 26-28 for the lifestyle intervention and close follow-up groups.</p> <p>Results</p> <p>The values of the OGTT during the second trimester did not differ between the lifestyle intervention and close follow-up groups. In the lifestyle intervention group three women had GDM in the second trimester and respectively one woman in the close follow up group. Insulin therapy was not required in both groups. The intervention resulted in somewhat lower weight gain 11.4 ± 6.0 kg vs. 13.9 ± 5.1 kg, p = 0.062, adjusted by the prepregnancy weight.</p> <p>Conclusions</p> <p>Early intervention with an OGTT and simple lifestyle advice is feasible. A more intensive lifestyle intervention did not offer additional benefits with respect to glucose tolerance, although it tended to ameliorate the weight gain.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01130012">NCT01130012</a></p
Constraints on the Progenitor System of the Type Ia Supernova SN 2011fe/PTF11kly
Type Ia supernovae (SNe) serve as a fundamental pillar of modern cosmology,
owing to their large luminosity and a well-defined relationship between
light-curve shape and peak brightness. The precision distance measurements
enabled by SNe Ia first revealed the accelerating expansion of the universe,
now widely believed (though hardly understood) to require the presence of a
mysterious "dark" energy. General consensus holds that Type Ia SNe result from
thermonuclear explosions of a white dwarf (WD) in a binary system; however,
little is known of the precise nature of the companion star and the physical
properties of the progenitor system. Here we make use of extensive historical
imaging obtained at the location of SN 2011fe/PTF11kly, the closest SN Ia
discovered in the digital imaging era, to constrain the visible-light
luminosity of the progenitor to be 10-100 times fainter than previous limits on
other SN Ia progenitors. This directly rules out luminous red giants and the
vast majority of helium stars as the mass-donating companion to the exploding
white dwarf. Any evolved red companion must have been born with mass less than
3.5 times the mass of the Sun. These observations favour a scenario where the
exploding WD of SN 2011fe/PTF11kly, accreted matter either from another WD, or
by Roche-lobe overflow from a subgiant or main-sequence companion star.Comment: 22 pages, 6 figures, submitte
Dilation of the ascending aorta in Turner syndrome - a prospective cardiovascular magnetic resonance study
<p>Abstract</p> <p>Background</p> <p>The risk of aortic dissection is 100-fold increased in Turner syndrome (TS). Unfortunately, risk stratification is inadequate due to a lack of insight into the natural course of the syndrome-associated aortopathy. Therefore, this study aimed to prospectively assess aortic dimensions in TS.</p> <p>Methods</p> <p>Eighty adult TS patients were examined twice with a mean follow-up of 2.4 ± 0.4 years, and 67 healthy age and gender-matched controls were examined once. Aortic dimensions were measured at nine predefined positions using 3D, non-contrast and free-breathing cardiovascular magnetic resonance. Transthoracic echocardiography and 24-hour ambulatory blood pressure were also performed.</p> <p>Results</p> <p>At baseline, aortic diameters (body surface area indexed) were larger at all positions in TS. Aortic dilation was more prevalent at all positions excluding the distal transverse aortic arch. Aortic diameter increased in the aortic sinus, at the sinotubular junction and in the mid-ascending aorta with growth rates of 0.1 - 0.4 mm/year. Aortic diameters at all other positions were unchanged. The bicuspid aortic valve conferred higher aortic sinus growth rates (p < 0.05). No other predictors of aortic growth were identified.</p> <p>Conclusion</p> <p>A general aortopathy is present in TS with enlargement of the ascending aorta, which is accelerated in the presence of a bicuspid aortic valve.</p
The increasing importance of atmospheric demand for ecosystem water and carbon fluxes
Soil moisture supply and atmospheric demand for water independently limitâand profoundly affectâvegetation productivity and water use during periods of hydrologic stress1, 2, 3, 4. Disentangling the impact of these two drivers on ecosystem carbon and water cycling is difficult because they are often correlated, and experimental tools for manipulating atmospheric demand in the field are lacking. Consequently, the role of atmospheric demand is often not adequately factored into experiments or represented in models5, 6, 7. Here we show that atmospheric demand limits surface conductance and evapotranspiration to a greater extent than soil moisture in many biomes, including mesic forests that are of particular importance to the terrestrial carbon sink8, 9. Further, using projections from ten general circulation models, we show that climate change will increase the importance of atmospheric constraints to carbon and water fluxes in all ecosystems. Consequently, atmospheric demand will become increasingly important for vegetation function, accounting for >70% of growing season limitation to surface conductance in mesic temperate forests. Our results suggest that failure to consider the limiting role of atmospheric demand in experimental designs, simulation models and land management strategies will lead to incorrect projections of ecosystem responses to future climate conditions
Echoes from Ancient Supernovae in the Large Magellanic Cloud
In principle, the light from historical supernovae could still be visible as
scattered-light echoes even centuries later. However, while echoes have been
discovered around some nearby extragalactic supernovae well after the
explosion, targeted searches have not recovered any echoes in the regions of
historical Galactic supernovae. The discovery of echoes can allow us to
pinpoint the supernova event both in position and age and, most importantly,
allow us to acquire spectra of the echo light to type the supernova centuries
after the direct light from the explosion first reached the Earth. Here we
report on the discovery of three faint new variable surface brightness
complexes with high apparent proper motion pointing back to well-defined
positions in the Large Magellanic Cloud (LMC). These positions correspond to
three of the six smallest (and likely youngest) previously catalogued supernova
remnants, and are believed to be due to thermonuclear (Type Ia) supernovae.
Using the distance and proper motions of these echo arcs, we estimate ages of
610 and 410 yr for the echoes #2 and #3.Comment: 13 pages, 3 figures, 1 table. PDF format. Note: This paper has been
accepted by Nature for publication as a letter. It is embargoed for
discussion in the popular press until publication in Natur
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