62 research outputs found
Neonatal SSRI Exposure Programs a Hypermetabolic State in Adult Mice
Background. Selective serotonin reuptake inhibitor (SSRI) therapy complicates up to 10% of pregnancies. During therapy, SSRIs exert pleiotropic antidepressant, anorexigenic, and neurotrophic effects. Intrauterine SSRI exposure has been modeled by neonatal administration to developmentally immature rodents, and it has paradoxically elicited features of adult depression. We hypothesized neonatal SSRI exposure likewise programs a rebound hypermetabolic state in adult mice. Methods. C57BL/6 pups were randomized to saline or sertraline (5 mg/kg/d) from P1–P14. Because estrogen increases tryptophan hydroxylase 2 (TPH2) expression, a subset of female mice underwent sham surgery or bilateral ovariectomy (OVX). Metabolic rate was determined by indirect calorimetry. Results. In both male and female mice, neonatal SSRI exposure increased adult caloric intake and metabolic rate. SSRI-exposed female mice had significantly decreased adult weight with a relative increase in brain weight and melatonin excretion, independent of ovarian status. Cerebral cortex TPH2 expression was increased in SSRI-exposed male mice but decreased in OVX SSRI-exposed female mice. Conclusions. SSRI exposure during a critical neurodevelopmental window increases adult caloric intake and metabolic rate. Ovarian status modulated central TPH2 expression, but not adult energy balance, suggesting programmed neural connectivity or enhanced melatonin production may play a more important role in the post-SSRI hypermetabolic syndrome
Sharpening the predictions of big-bang nucleosynthesis
Motivated by the recent measurement of the primeval abundance of deuterium,
we re-examine the nuclear inputs to big-bang nucleosynthesis (BBN). Using
Monte-Carlo realization of the nuclear cross-section data to directly estimate
the theoretical uncertainties for the yields of D, 3-He and 7-Li, we show that
previous estimates were a factor of 2 too large. We sharpen the BBN
determination of the baryon density based upon deuterium, rho_B = (3.6 +/- 0.4)
* 10^{-31} g/cm^3 (Omega_B h^2 = 0.019 +/- 0.0024), which leads to a predicted
4-He abundance, Y_P = 0.246 +/- 0.0014 and a stringent limit to the equivalent
number of light neutrino species: N_nu < 3.20 (all at 95% cl). The predicted
7-Li abundance, 7-Li/H = (3.5 + 1.1 - 0.9) * 10^{-10}, is higher than that
observed in pop II stars, (1.7 +/- 0.3) * 10^{-10} (both, 95% cl). We identify
key reactions and the energies where further work is needed.Comment: 5 pages, 4 figures (epsfig), REVTeX; submitted to Phys. Rev. Let
U.S. Billion-ton Update: Biomass Supply for a Bioenergy and Bioproducts Industry
The Report, Biomass as Feedstock for a Bioenergy and Bioproducts Industry: The Technical Feasibility of a Billion-Ton Annual Supply (generally referred to as the Billion-Ton Study or 2005 BTS), was an estimate of “potential” biomass within the contiguous United States based on numerous assumptions about current and future inventory and production capacity, availability, and technology. In the 2005 BTS, a strategic analysis was undertaken to determine if U.S. agriculture and forest resources have the capability to potentially produce at least one billion dry tons of biomass annually, in a sustainable manner—enough to displace approximately 30% of the country’s present petroleum consumption. To ensure reasonable confidence in the study results, an effort was made to use relatively conservative assumptions. However, for both agriculture and forestry, the resource potential was not restricted by price. That is, all identified biomass was potentially available, even though some potential feedstock would more than likely be too expensive to actually be economically available.
In addition to updating the 2005 study, this report attempts to address a number of its shortcoming
Vandetanib (Zactima, ZD6474) Antagonizes ABCC1- and ABCG2-Mediated Multidrug Resistance by Inhibition of Their Transport Function
ABCC1 and ABCG2 are ubiquitous ATP-binding cassette transmembrane proteins that play an important role in multidrug resistance (MDR). In this study, we evaluated the possible interaction of vandetanib, an orally administered drug inhibiting multiple receptor tyrosine kinases, with ABCC1 and ABCG2 in vitro.MDR cancer cells overexpressing ABCC1 or ABCG2 and their sensitive parental cell lines were used. MTT assay showed that vandetanib had moderate and almost equal-potent anti-proliferative activity in both sensitive parental and MDR cancer cells. Concomitant treatment of MDR cells with vandetanib and specific inhibitors of ABCC1 or ABCG2 did not alter their sensitivity to the former drug. On the other hand, clinically attainable but non-toxic doses of vandetanib were found to significantly enhance the sensitivity of MDR cancer cells to ABCC1 or ABCG2 substrate antitumor drugs. Flow cytometric analysis showed that vandetanib treatment significantly increase the intracellular accumulation of doxorubicin and rhodamine 123, substrates of ABCC1 and ABCG2 respectively, in a dose-dependent manner (P<0.05). However, no significant effect was shown in sensitive parental cell lines. Reverse transcription-PCR and Western blot analysis showed that vandetanib did not change the expression of ABCC1 and ABCG2 at both mRNA and protein levels. Furthermore, total and phosphorylated forms of AKT and ERK1/2 remained unchanged after vandetanib treatment in both sensitive and MDR cancer cells.Vandetanib is unlikely to be a substrate of ABCC1 or ABCG2. It overcomes ABCC1- and ABCG2-mediated drug resistance by inhibiting the transporter activity, independent of the blockade of AKT and ERK1/2 signal transduction pathways
Further Defining Spectral Type "Y" and Exploring the Low-mass End of the Field Brown Dwarf Mass Function
We present the discovery of another seven Y dwarfs from the Wide-field
Infrared Survey Explorer (WISE). Using these objects, as well as the first six
WISE Y dwarf discoveries from Cushing et al., we further explore the transition
between spectral types T and Y. We find that the T/Y boundary roughly coincides
with the spot where the J-H colors of brown dwarfs, as predicted by models,
turn back to the red. Moreover, we use preliminary trigonometric parallax
measurements to show that the T/Y boundary may also correspond to the point at
which the absolute H (1.6 um) and W2 (4.6 um) magnitudes plummet. We use these
discoveries and their preliminary distances to place them in the larger context
of the Solar Neighborhood. We present a table that updates the entire stellar
and substellar constituency within 8 parsecs of the Sun, and we show that the
current census has hydrogen-burning stars outnumbering brown dwarfs by roughly
a factor of six. This factor will decrease with time as more brown dwarfs are
identified within this volume, but unless there is a vast reservoir of cold
brown dwarfs invisible to WISE, the final space density of brown dwarfs is
still expected to fall well below that of stars. We also use these new Y dwarf
discoveries, along with newly discovered T dwarfs from WISE, to investigate the
field substellar mass function. We find that the overall space density of
late-T and early-Y dwarfs matches that from simulations describing the mass
function as a power law with slope -0.5 < alpha < 0.0; however, a power-law may
provide a poor fit to the observed object counts as a function of spectral type
because there are tantalizing hints that the number of brown dwarfs continues
to rise from late-T to early-Y. More detailed monitoring and characterization
of these Y dwarfs, along with dedicated searches aimed at identifying more
examples, are certainly required.Comment: 91 pages, 15 figures, accepted for publication in The Astrophysical
Journa
The James Webb Space Telescope Mission
Twenty-six years ago a small committee report, building on earlier studies,
expounded a compelling and poetic vision for the future of astronomy, calling
for an infrared-optimized space telescope with an aperture of at least .
With the support of their governments in the US, Europe, and Canada, 20,000
people realized that vision as the James Webb Space Telescope. A
generation of astronomers will celebrate their accomplishments for the life of
the mission, potentially as long as 20 years, and beyond. This report and the
scientific discoveries that follow are extended thank-you notes to the 20,000
team members. The telescope is working perfectly, with much better image
quality than expected. In this and accompanying papers, we give a brief
history, describe the observatory, outline its objectives and current observing
program, and discuss the inventions and people who made it possible. We cite
detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space
Telescope Overview, 29 pages, 4 figure
The Science Performance of JWST as Characterized in Commissioning
This paper characterizes the actual science performance of the James Webb
Space Telescope (JWST), as determined from the six month commissioning period.
We summarize the performance of the spacecraft, telescope, science instruments,
and ground system, with an emphasis on differences from pre-launch
expectations. Commissioning has made clear that JWST is fully capable of
achieving the discoveries for which it was built. Moreover, almost across the
board, the science performance of JWST is better than expected; in most cases,
JWST will go deeper faster than expected. The telescope and instrument suite
have demonstrated the sensitivity, stability, image quality, and spectral range
that are necessary to transform our understanding of the cosmos through
observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures;
https://iopscience.iop.org/article/10.1088/1538-3873/acb29
Reduced blood pressure of CFTR-F508del carriers correlates with diminished arterial reactivity rather than circulating blood volume in mice.
The F508del mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common cause of cystic fibrosis (CF). Both CF patients and F508del carriers have decreased blood pressure. While this has been attributed to salt depletion, recent studies have shown F508del expression interferes with smooth muscle cell calcium mobilization. We tested the hypothesis that carriers of the F508del mutation have lower adult blood pressures and reduced aortic contractility without a reduction in circulating blood volume. By radiotelemetry, F508del heterozygous mice had significantly lower arterial pressures than wild-type C57BL/6 controls, with the greatest effect seen at the time of dark-to-light cycle transition (mean difference of 10 mmHg). To replicate the vascular effects of sympathetic arousal, isoproterenol and epinephrine were co-infused, and F508del mice again had significantly reduced arterial pressures. Aortas isolated from F508del heterozygous mice had significantly decreased constriction to noradrenaline (0.9 ± 0.2 versus 2.9 ± 0.7 mN). Inhibition of wild-type CFTR or the inositol triphosphate receptor replicated the phenotype of F508del aortas. CFTR carrier status did not alter circulating blood volume. We conclude the CFTR-F508del mutation decreases aortic contractility and lowers arterial pressures. As a cAMP-activated chloride channel that facilitates calcium mobilization, we speculate wild-type CFTR co-activation during adrenergic receptor stimulation buffers the vasodilatory response to catecholamines, and loss of this compensatory vasoconstrictor tone may contribute to the lower arterial pressures seen in heterozygote carriers of a CFTR-F508del mutation
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