Hypothalamic actions of neuromedin U.

The central nervous system and gut peptide neuromedin U (NMU) inhibits feeding after intracerebroventricular injection. This study explored the hypothalamic actions of NMU on feeding and the hypothalamo-pituitary-adrenal axis. Intraparaventricular nucleus (intra-PVN) NMU dose-dependently inhibited food intake, with a minimum effective dose of 0.1 nmol and a robust effect at 0.3 nmol. Feeding inhibition was mapped by NMU injection into eight hypothalamic areas. NMU (0.3 nmol) inhibited food intake in the PVN (0-1 h, 59 ± 6.9% of the control value; P < 0.001) and arcuate nucleus (0-1 h, 76 ± 10.4% of the control value; P < 0.05). Intra-PVN NMU markedly increased grooming and locomotor behavior and dose-dependently increased plasma ACTH (0.3 nmol NMU, 24.8 ± 1.9 pg/ml; saline, 11.4 ± 1.0; P < 0.001) and corticosterone (0.3 nmol NMU, 275.4 ± 40.5 ng/ml; saline, 129.4 ± 25.0; P < 0.01). Using hypothalamic explants in vitro, NMU stimulated CRH (100 nM NMU, 5.9 ± 0.95 pmol/explant; basal, 3.8 ± 0.39; P < 0.01) and arginine vasopressin release (100 nM NMU, 124.5 ± 21.8 fmol/explant; basal, 74.5 ± 7.6; P < 0.01). Leptin stimulated NMU release (141.9 ± 20.4 fmol/explant; basal, 92.9 ± 9.4; P < 0.01). Thus, we describe a novel role for NMU in the PVN to stimulate the hypothalamo-pituitary-adrenal axis and locomotor and grooming behavior and to inhibit feeding

Neuromedin U partially mediates leptin-induced hypothalamo-pituitary adrenal (HPA) stimulation and has a physiological role in the regulation of the HPA axis in the rat.

Intracerebroventricular (ICV) administration of the hypothalamic neuropeptide neuromedin U (NMU) or the adipostat hormone leptin increases plasma ACTH and corticosterone. The relationship between leptin and NMU in the regulation of the hypothalamo-pituitary adrenal (HPA) axis is currently unknown. In this study, leptin (1 nM) significantly increased the release of CRH from ex vivo hypothalamic explants by 207 ± 8.4% (P < 0.05 vs. basal), an effect blocked by the administration of anti-NMU IgG. The ICV administration of leptin (10 μg, 0.625 nmol) increased plasma ACTH and corticosterone 20 min after injection [plasma ACTH (picograms per milliliter): vehicle, 63 ± 20, leptin, 135 ± 36, P < 0.05; plasma corticosterone (nanograms per milliliter): vehicle, 285 ± 39, leptin, 452 ± 44, P < 0.01]. These effects were partially attenuated by the prior administration of anti-NMU IgG. Peripheral leptin also stimulated ACTH release, an effect attenuated by prior ICV administration of anti-NMU IgG. We examined the diurnal pattern of hypothalamic NMU mRNA expression and peptide content, plasma leptin, and plasma corticosterone. The diurnal changes in hypothalamic NMU mRNA expression were positively correlated with hypothalamic NMU peptide content, plasma corticosterone, and plasma leptin. The ICV administration of anti-NMU IgG significantly attenuated the dark phase rise in corticosterone [corticosterone (nanograms per milliliter): vehicle, 493 ± 38; NMU IgG, 342 ± 47 (P < 0.05)]. These studies suggest that NMU may play a role in the regulation of the HPA axis and partially mediate leptin-induced HPA stimulation. Copyright © 2006 by The Endocrine Society

Evolution favors protein mutational robustness in sufficiently large populations

BACKGROUND: An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual, but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties. RESULTS: Here we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by existing mathematical theories, and can be quantitatively related to the way that the proteins occupy their neutral network. CONCLUSIONS: Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon may contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations

Ghrelin causes hyperphagia and obesity in rats.

Ghrelin, a circulating growth hormone–releasing pep-tide derived from the stomach, stimulates food intake. The lowest systemically effective orexigenic dose of ghrelin was investigated and the resulting plasma ghre-lin concentration was compared with that during fast-ing. The lowest dose of ghrelin that produced a significant stimulation of feeding after intraperitoneal injection was 1 nmol. The plasma ghrelin concentration after intraperitoneal injection of 1 nmol of ghrelin (2.83 0.13 pmol/ml at 60 min postinjection) was not significantly different from that occurring after a 24-h fast (2.79 0.32 pmol/ml). After microinjection into defined hypothalamic sites, ghrelin (30 pmol) stimu-lated food intake most markedly in the arcuate nucleus (Arc) (0–1 h food intake, 427 43 % of control; P &lt

The host galaxies and explosion sites of long-duration gamma-ray bursts: Hubble Space Telescope near-infrared imaging

We present the results of a Hubble Space Telescope WFC3/F160WSnapshot survey of the host galaxies of 39 long-duration gamma-ray bursts (LGRBs) at z < 3. We have non-detections of hosts at the locations of four bursts. Sufficient accuracy to astrometrically align optical afterglowimages and determine the location of the LGRB within its hostwas possible for 31/35 detected hosts. In agreement with other work, we find the luminosity distribution of LGRB hosts is significantly fainter than that of a star formation rate-weighted field galaxy sample over the same redshift range, indicating LGRBs are not unbiasedly tracing the star formation rate. Morphologically, the sample of LGRB hosts is dominated by spiral-like or irregular galaxies. We find evidence for evolution of the population of LGRB hosts towards lower luminosity, higher concentrated hosts at lower redshifts. Their half-light radii are consistent with other LGRB host samples where measurements were made on rest-frame UV observations. In agreement with recent work, we find their 80 per cent enclosed flux radii distribution to be more extended than previously thought, making them intermediate between core-collapse supernova (CCSN) and superluminous supernova (SLSN) hosts. The galactocentric projectedoffset distribution confirms LGRBs as centrally concentrated, much more so than CCSNe and similar to SLSNe. LGRBs are strongly biased towards the brighter regions in their host light distributions, regardless of their offset. We find a correlation between the luminosity of the LGRB explosion site and the intrinsic column density, NH, towards the burst. © 2017 The Authors

Directed evolution of a magnetic resonance imaging contrast agent for noninvasive imaging of dopamine

The development of molecular probes that allow in vivo imaging of neural signaling processes with high temporal and spatial resolution remains challenging. Here we applied directed evolution techniques to create magnetic resonance imaging (MRI) contrast agents sensitive to the neurotransmitter dopamine. The sensors were derived from the heme domain of the bacterial cytochrome P450-BM3 (BM3h). Ligand binding to a site near BM3h's paramagnetic heme iron led to a drop in MRI signal enhancement and a shift in optical absorbance. Using an absorbance-based screen, we evolved the specificity of BM3h away from its natural ligand and toward dopamine, producing sensors with dissociation constants for dopamine of 3.3–8.9 μM. These molecules were used to image depolarization-triggered neurotransmitter release from PC12 cells and in the brains of live animals. Our results demonstrate the feasibility of molecular-level functional MRI using neural activity–dependent sensors, and our protein engineering approach can be generalized to create probes for other targets.Charles A. Dana Foundation. Brain and Immuno-ImagingRaymond and Beverley Sackler FoundationNational Institutes of Health (U.S.) (grant R01-DA28299)National Institutes of Health (U.S.) (grant DP2-OD2441)National Institutes of Health (U.S.) (grant R01-GM068664)Jacobs Institute for Molecular Engineering for Medicine. Jacobs Institute for Molecular Engineering for MedicineNational Institutes of Health (U.S.) (grant R01-DE013023

An ultraviolet-optical flare from the tidal disruption of a helium-rich stellar core

The flare of radiation from the tidal disruption and accretion of a star can be used as a marker for supermassive black holes that otherwise lie dormant and undetected in the centres of distant galaxies. Previous candidate flares have had declining light curves in good agreement with expectations, but with poor constraints on the time of disruption and the type of star disrupted, because the rising emission was not observed. Recently, two `relativistic' candidate tidal disruption events were discovered, each of whose extreme X-ray luminosity and synchrotron radio emission were interpreted as the onset of emission from a relativistic jet. Here we report the discovery of a luminous ultraviolet-optical flare from the nuclear region of an inactive galaxy at a redshift of 0.1696. The observed continuum is cooler than expected for a simple accreting debris disk, but the well-sampled rise and decline of its light curve follows the predicted mass accretion rate, and can be modelled to determine the time of disruption to an accuracy of two days. The black hole has a mass of about 2 million solar masses, modulo a factor dependent on the mass and radius of the star disrupted. On the basis of the spectroscopic signature of ionized helium from the unbound debris, we determine that the disrupted star was a helium-rich stellar core.Comment: To appear in Nature on May 10, 201

Search for the Decays B^0 -> D^{(*)+} D^{(*)-}

Using the CLEO-II data set we have searched for the Cabibbo-suppressed decays B^0 -> D^{(*)+} D^{(*)-}. For the decay B^0 -> D^{*+} D^{*-}, we observe one candidate signal event, with an expected background of 0.022 +/- 0.011 events. This yield corresponds to a branching fraction of Br(B^0 -> D^{*+} D^{*-}) = (5.3^{+7.1}_{-3.7}(stat) +/- 1.0(syst)) x 10^{-4} and an upper limit of Br(B^0 -> D^{*+} D^{*-}) D^{*\pm} D^\mp and B^0 -> D^+ D^-, no significant excess of signal above the expected background level is seen, and we calculate the 90% CL upper limits on the branching fractions to be Br(B^0 -> D^{*\pm} D^\mp) D^+ D^-) < 1.2 x 10^{-3}.Comment: 12 page postscript file also available through http://w4.lns.cornell.edu/public/CLNS, submitted to Physical Review Letter

Synthesis and Oligonucleotide Incorporation of Fluorescent Cytosine Analogue tC: a Promising Nucleic Acid Probe

The tricyclic cytosine, tC, is a fluorescent base analogue with excellent properties for investigating intrinsic characteristics of nucleic acid as well as interactions between nucleic acids and other molecules. Its unique fluorescence properties and insignificant influence on overall structure and dynamics of nucleic acid after incorporation makes tC particularly interesting in fluorescence resonance energy transfer and anisotropy measurements. We here describe a straightforward synthesis of the standard monomer form of tC for DNA solid-phase synthesis, the tC phosphoramidite, and its subsequent incorporation into oligonucleotides. The total synthesis of the tC phosphoramidite takes approximately 8 days and its incorporation and the subsequent oligonucleotide purification an additional day

Improved Measurement of the Pseudoscalar Decay Constant fDsf_{D_{s}}

We present a new determination of the Ds decay constant, f_{Ds} using 5 million continuum charm events obtained with the CLEO II detector. Our value is derived from our new measured ratio of widths for Ds -> mu nu/Ds -> phi pi of 0.173+/- 0.021 +/- 0.031. Taking the branching ratio for Ds -> phi pi as (3.6 +/- 0.9)% from the PDG, we extract f_{Ds} = (280 +/- 17 +/- 25 +/- 34){MeV}. We compare this result with various model calculations.Comment: 23 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN