The Melanocortin-4 Receptor Integrates Circadian Light Cues and Metabolism

The melanocortin system directs diverse physiological functions from coat color to body weight homoeostasis. A commonality among melanocortin-mediated processes is that many animals modulate similar processes on a circannual basis in response to longer, summer days, suggesting an underlying link between circadian biology and the melanocortin system. Despite key neuroanatomical substrates shared by both circadian and melanocortin-signaling pathways, little is known about the relationship between the two. Here we identify a link between circadian disruption and the control of glucose homeostasis mediated through the melanocortin-4 receptor (Mc4r). Mc4r-deficient mice exhibit exaggerated circadian fluctuations in baseline blood glucose and glucose tolerance. Interestingly, exposure to lighting conditions that disrupt circadian rhythms improve their glucose tolerance. This improvement occurs through an increase in glucose clearance by skeletal muscle and is food intake and body weight independent. Restoring Mc4r expression to the paraventricular nucleus prevents the improvement in glucose tolerance, supporting a role for the paraventricular nucleus in the integration of circadian light cues and metabolism. Altogether these data suggest that Mc4r signaling plays a protective role in minimizing glucose fluctuations due to circadian rhythms and environmental light cues and demonstrate a previously undiscovered connection between circadian biology and glucose metabolism mediated through the melanocortin system

A Study of Archiving Strategies in Multi-Objective PSO for Molecular Docking

Molecular docking is a complex optimization problem aimed at predicting the position of a ligand molecule in the active site of a receptor with the lowest binding energy. This problem can be formulated as a bi-objective optimization problem by minimizing the binding energy and the Root Mean Square Deviation (RMSD) difference in the coordinates of ligands. In this context, the SMPSO multi-objective swarm-intelligence algorithm has shown a remarkable performance. SMPSO is characterized by having an external archive used to store the non-dominated solutions and also as the basis of the leader selection strategy. In this paper, we analyze several SMPSO variants based on different archiving strategies in the scope of a benchmark of molecular docking instances. Our study reveals that the SMPSOhv, which uses an hypervolume contribution based archive, shows the overall best performance.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

2021 Tajogaite eruption records infiltration of crustal fluids within the upper mantle beneath La Palma, Canary Islands

The 2021 Tajogaite eruption at La Palma has represented a unique opportunity to investigate the characteristics of the mantle source feeding modern volcanism in the Canary Islands. With the aim of track the fingerprint of carbon in the local oceanic lithosphere-asthenosphere system, we report the isotopic composition of CO2 (δ13C values versus Vienna Pee Dee Belemnite) in olivine- and clinopyroxene-hosted fluid inclusions (FI) from the 2021 Tajogaite lavas and from lavas/ultramafic xenoliths (olivine-clinopyroxenites, clinopyroxenites, dunites and harzburgites) from the nearby 1677 San Antonio eruption cone/lavas, in an attempt to characterize the origin and evolution of carbon within the local mantle source. Our results indicate that the 2021 and 1677 lavas exhibit δ13C values ranging from −4.94‰ to −2.71‰ and CO2/3He ratios from 3.37 to 6.14 × 109. Ultramafic xenoliths fall in a comparable range of values despite showing higher CO2 concentrations. Our δ13C values fall within the range of carbon isotope results previously reported for the Dos Aguas cold spring located in the Taburiente Caldera (northern La Palma), suggesting an apparent carbon isotope homogeneity at the scale of the entire island. The (relatively narrow) δ13C vs. CO2/3He ratio range of La Palma samples is interpreted to reflect either i) variable extents of open-system degassing of a common mantle endmember having δ13C of ∼1.7‰, or ii) mixing between depleted mantle-like carbon (−6‰ < δ13C < −4‰) and crustal carbon (δ13C = 0‰) endmembers. Both models testify a crustal carbon component recycled in the local mantle. This component, also detected in mantle xenoliths from the neighboring island of El Hierro and the easternmost Lanzarote, indicates a regional characteristic of the mantle beneath the Canary Islands, interpreted as a result of infiltration of carbon-rich melts during past metasomatic events in the local mantle

The noble gas signature of the 2021 Tajogaite eruption (La Palma, Canary Islands)

Here, we characterize the temporal evolution of volatiles during the Tajogaite eruption by analyzing the elemental (He-Ar-CO2-N2) and isotopic (He-Ar-Ne) composition of fluid inclusions (FI) in phenocrysts (olivine+pyroxene) identified in erupted lavas. Our 2021 lava samples identify substantial temporal variations in volatile composition. We show that, during the 2021 Tajogaite eruption, the He-CO2-N2 concentrations in FI increased since October 15th; this increase was accompanied by increasing 40Ar/36Ar ratios (from ~300 to >500), and paralleled a major shift in bulk lava chemistry, with increasing Mg contents (Mg#, from 47 to 52 to 55–59), CaO/Al2O3 (from 0.65 to 0.74 to 0.75–0.90), Ni and Cr, and decreasing TiO2, P2O5 and incompatible elements. The olivine core composition also became more forsteritic (from Mg# = 80–81 to Mg# = 84–86). Mineral thermobarometry and FI barometry results indicate that the eruption was sustained by magmas previously stored in at least two magma accumulation zones, at respectively ~6–12 km and 15–30 km, corroborating previous seismic and FI evidence. We therefore propose that the compositional changes seen throughout the eruption can be explained by an increased contribution - since early/mid-October - of more primitive, lessdegassed magma from the deeper (mantle) reservoir. Conversely, Rc/Ra values (3He/4He ratios corrected for atmospheric contamination) remained constant throughout the whole eruption at MORB-like values (7.38 ± 0.22 Ra, 1σ), suggesting an isotopically homogeneous magma feeding source. The Tajogaite He isotope signature is within the range of values observed for the 1677 San Antonio lavas (7.37 ± 0.17Ra, 1σ), but is more radiogenic than the 3He/4He values (>9 Rc/Ra) observed in the Caldera de Taburiente to the north. The 3He/4He ratios (6.75 ± 0.20 Ra, 1σ) measured in mantle xenoliths from the San Antonio volcano indicate a relatively radiogenic nature of the mantle beneath the Cumbre Vieja ridge. Based on these results and mixing modeling calculations, we propose that the homogeneous He isotopic signatures observed in volatiles from the Tajogaite/San Antonio lavas reflect three component mixing between a MORB-like source, a radiogenic component and small additions (6–15%) of a high 3He/4He reservoir-derived (>9Ra) fluid components. The simultaneous occurrence of high 3 He/4 He (>9Ra)- and MORB-like He signatures in northern and southern La Palma is interpreted to reflect smallscale heterogeneities in the local mantle, arising from spatially variable proportions of MORB, radiogenic, and high 3He/4He component

Identification of two novel mutations in CDHR1 in consanguineous Spanish families with autosomal recessive retinal dystrophy.

Inherited retinal dystrophies present extensive phenotypic and genetic heterogeneity, posing a challenge for patients' molecular and clinical diagnoses. In this study, we wanted to clinically characterize and investigate the molecular etiology of an atypical form of autosomal recessive retinal dystrophy in two consanguineous Spanish families. Affected members of the respective families exhibited an array of clinical features including reduced visual acuity, photophobia, defective color vision, reduced or absent ERG responses, macular atrophy and pigmentary deposits in the peripheral retina. Genetic investigation included autozygosity mapping coupled with exome sequencing in the first family, whereas autozygome-guided candidate gene screening was performed by means of Sanger DNA sequencing in the second family. Our approach revealed nucleotide changes in CDHR1; a homozygous missense variant (c.1720C > G, p.P574A) and a homozygous single base transition (c.1485 + 2T > C) affecting the canonical 5' splice site of intron 13, respectively. Both changes co-segregated with the disease and were absent among cohorts of unrelated control individuals. To date, only five mutations in CDHR1 have been identified, all resulting in premature stop codons leading to mRNA nonsense mediated decay. Our work reports two previously unidentified homozygous mutations in CDHR1 further expanding the mutational spectrum of this gene

Hepatic Glucagon-Receptor Signaling Enhances Insulin-Stimulated Glucose Disposal in Rodents

Glucagon receptor (GCGR) agonists cause hyperglycemia but also weight loss. However, GLP1R/GCGR mixed agonists do not exhibit the diabetogenic effects often attributed to GCGR activity. Thus, we sought to investigate the effect of glucagon agonism on insulin action and glucose homeostasis. Acute GCGR agonism induced immediate hyperglycemia, followed by improved glucose tolerance and enhanced glucose-stimulated insulin secretion. Moreover, acute GCGR agonism improved insulin tolerance in a dose-dependent manner in both lean and obese mice. Improved insulin tolerance was independent of GLP1R, FGF21, and hepatic glycogenolysis. Moreover, we observed increased glucose infusion rate, disposal, uptake, and suppressed endogenous glucose production during euglycemic clamps. Mice treated with insulin and GCGR agonist had enhanced phosphorylation of hepatic AKT at Ser473; this effect was reproduced in isolated mouse primary hepatocytes and resulted in increased AKT kinase activity. These data reveal that GCGR agonism enhances glucose tolerance in part, by augmenting insulin action, with implications for the use of GCGR agonism in therapeutic strategies for diabetes

Ratones knock-out del receptor lpa1 de ácido lisofosfatídico presentan un acusado déficit de la isoenzima glutaminasa KGA (GLS) y una morfología alterada en las espinas dendríticas de hipocampo y corteza

Objectives: The objective of the present study was to utilize mice with knocked-down lysophosphatidic acid 1 (LPA1) receptor to ascertain changes in glutamatergic transmission that may help to explain part of the cognitive and memory deficits shown by these KO-LPA1 mice. Material & methods: A well characterized KO-LPA1 mouse strain was used as animal model and compared with wild-type (WT) and heterozygous animals. Expression studies were implemented by immunohistochemistry and Western analysis of mouse brain regions, real-time quantitative RT-PCR of GA isoforms, enzymatic analysis of regional GA activity and Golgi staining to assess dendritic spine morphology and density. Results: A strong reduction of KGA immunoreactivity was mostly revealed in cerebral cortex and hippocampus of KO-LPA1 mice versus WT and heterozygous animals. In contrast, neither mRNA levels nor enzyme activity were significantly altered in KO mice suggesting compensatory mechanisms for neurotransmitter Glu synthesis. Interestingly, Golgi staining of hippocampal and cortical neurons revealed a clear morphology change toward a less-mature undifferentiated spine phenotype, without changes in the total number of spines. Conclusions: The molecular mechanisms underlying KGA downregulation in null LPA1 mutant mice are unknown. However, LPA increases neuronal differentiation, arborization and neurite outgrowth of developing neurons, while Gln-derived Glu, through GA reaction, has been also involved in neuronal growth and differentiation. It is tempting to speculate that downregulation of KGA protein in KO-LPA1 mice induce morphological changes in dendritic spines of cortical and hippocampal neurons which, in turn, may account for memory and cognitive deficits shown by KO-LPA1 mice.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Acknowledgements: Red de Trastornos Adictivos, RTA, (RD12/0028/0013/) RETICS, ISCIII, y Consejería Innovación, Ciencia y Empresa, Junta de Andalucía (Proyecto de Excelencia CVI-6656)

The 2HWC HAWC Observatory Gamma Ray Catalog

We present the first catalog of TeV gamma-ray sources realized with the recently completed High Altitude Water Cherenkov Observatory (HAWC). It is the most sensitive wide field-of-view TeV telescope currently in operation, with a 1-year survey sensitivity of ~5-10% of the flux of the Crab Nebula. With an instantaneous field of view >1.5 sr and >90% duty cycle, it continuously surveys and monitors the sky for gamma ray energies between hundreds GeV and tens of TeV. HAWC is located in Mexico at a latitude of 19 degree North and was completed in March 2015. Here, we present the 2HWC catalog, which is the result of the first source search realized with the complete HAWC detector. Realized with 507 days of data and represents the most sensitive TeV survey to date for such a large fraction of the sky. A total of 39 sources were detected, with an expected contamination of 0.5 due to background fluctuation. Out of these sources, 16 are more than one degree away from any previously reported TeV source. The source list, including the position measurement, spectrum measurement, and uncertainties, is reported. Seven of the detected sources may be associated with pulsar wind nebulae, two with supernova remnants, two with blazars, and the remaining 23 have no firm identification yet.Comment: Submitted 2017/02/09 to the Astrophysical Journa

The Sensitivity of HAWC to High-Mass Dark Matter Annihilations

The High Altitude Water Cherenkov (HAWC) observatory is a wide field-of-view detector sensitive to gamma rays of 100 GeV to a few hundred TeV. Located in central Mexico at 19 degrees North latitude and 4100 m above sea level, HAWC will observe gamma rays and cosmic rays with an array of water Cherenkov detectors. The full HAWC array is scheduled to be operational in Spring 2015. In this paper, we study the HAWC sensitivity to the gamma-ray signatures of high-mass (multi- TeV) dark matter annihilation. The HAWC observatory will be sensitive to diverse searches for dark matter annihilation, including annihilation from extended dark matter sources, the diffuse gamma-ray emission from dark matter annihilation, and gamma-ray emission from non-luminous dark matter subhalos. Here we consider the HAWC sensitivity to a subset of these sources, including dwarf galaxies, the M31 galaxy, the Virgo cluster, and the Galactic center. We simulate the HAWC response to gamma rays from these sources in several well-motivated dark matter annihilation channels. If no gamma-ray excess is observed, we show the limits HAWC can place on the dark matter cross-section from these sources. In particular, in the case of dark matter annihilation into gauge bosons, HAWC will be able to detect a narrow range of dark matter masses to cross-sections below thermal. HAWC should also be sensitive to non-thermal cross-sections for masses up to nearly 1000 TeV. The constraints placed by HAWC on the dark matter cross-section from known sources should be competitive with current limits in the mass range where HAWC has similar sensitivity. HAWC can additionally explore higher dark matter masses than are currently constrained.Comment: 15 pages, 4 figures, version to be published in PR