Chronic central neuropeptide Y infusion in normal rats: status of the hypothalamo-pituitary-adrenal axis, and vagal mediation of hyperinsulinaemia

Summary: Neuropeptide Y in the hypothalamus is a potent physiological stimulator of feeding, and may contribute to the characteristic metabolic defects of obesity when hypothalamic levels remain chronically elevated. Since corticosterone and insulin are important regulators of fuel metabolism, the longitudinal effects of chronic (6 days) intracerebroventricular infusion of neuropeptide Y in normal rats on the hypothalamo-pituitary-adrenal axis and on insulin secretion were studied. Neuropeptide Y-infused rats were either allowed to eat ad libitum, or were pair-fed with normophagic control rats. Neuropeptide Y increased the basal plasma concentrations of adrenocorticotropic hormone and corticosterone during the first 2 days of its intracerebroventricular infusion and increased cold stress-induced plasma adrenocorticotropic hormone concentrations. After 4-6 days of central neuropeptide Y infusion, however, basal plasma adrenocorticotropic hormone and corticosterone concentrations were no different from control values (except in ad libitum-fed rats in which corticosteronaemia remained elevated), they were unaffected by the stress of cold exposure, and the hypothalamic content of corticotropin-releasing factor immunoreactivity was significantly decreased. A state of hyperinsulinaemia was present throughout the 6 days of intracerebroventricular neuropeptide Y infusion, being more marked in the ad libitum-fed than in the pair-fed group. The proportions of insulin, proinsulin, and conversion intermediates in plasma and pancreas were unchanged. Hyperinsulinaemia of the pair-fed neuropeptide Y-infused rats was accompanied by muscle insulin resistance and white adipose tissue insulin hyperresponsiveness, as assessed by the in vivo uptake of 2-deoxyglucose. Finally, bilateral subdiaphragmatic vagotomy prevented both the basal and the marked glucose-induced hyperinsulinaemia of animals chronically infused with neuropeptide Y, demonstrating that central neuropeptide Y-induced hyperinsulinaemia is mediated by the parasympathetic nervous syste

Maximum likelihood map making with the Laser Interferometer Space Antenna

International audienceGiven the recent advances in gravitational-wave detection technologies, the detection and characterization of gravitational-wave backgrounds (GWBs) with the Laser Interferometer Space Antenna (LISA) is a real possibility. To assess the abilities of the LISA satellite network to reconstruct anisotropies of different angular scales and in different directions on the sky, we develop a map-maker based on an optimal quadratic estimator. The resulting maps are maximum likelihood representations of the GWB intensity on the sky integrated over a broad range of frequencies. We test the algorithm by reconstructing known input maps with different input distributions and over different frequency ranges. We find that, in an optimal scenario of well understood noise and high frequency, high SNR signals, the maximum scales LISA may probe are ℓmax≲15. The map-maker also allows to test the directional dependence of LISA noise, providing insight on the directional sky sensitivity we may expect

Planck 2015 results. XIV. Dark energy and modified gravity

We study the implications of Planck data for models of dark energy (DE) and modified gravity (MG), beyond the cosmological constant scenario. We start with cases where the DE only directly affects the background evolution, considering Taylor expansions of the equation of state, principal component analysis and parameterizations related to the potential of a minimally coupled DE scalar field. When estimating the density of DE at early times, we significantly improve present constraints. We then move to general parameterizations of the DE or MG perturbations that encompass both effective field theories and the phenomenology of gravitational potentials in MG models. Lastly, we test a range of specific models, such as k-essence, f(R) theories and coupled DE. In addition to the latest Planck data, for our main analyses we use baryonic acoustic oscillations, type-Ia supernovae and local measurements of the Hubble constant. We further show the impact of measurements of the cosmological perturbations, such as redshift-space distortions and weak gravitational lensing. These additional probes are important tools for testing MG models and for breaking degeneracies that are still present in the combination of Planck and background data sets. All results that include only background parameterizations are in agreement with LCDM. When testing models that also change perturbations (even when the background is fixed to LCDM), some tensions appear in a few scenarios: the maximum one found is \sim 2 sigma for Planck TT+lowP when parameterizing observables related to the gravitational potentials with a chosen time dependence; the tension increases to at most 3 sigma when external data sets are included. It however disappears when including CMB lensing

neXtProt: a knowledge platform for human proteins

neXtProt (http://www.nextprot.org/) is a new human protein-centric knowledge platform. Developed at the Swiss Institute of Bioinformatics (SIB), it aims to help researchers answer questions relevant to human proteins. To achieve this goal, neXtProt is built on a corpus containing both curated knowledge originating from the UniProtKB/Swiss-Prot knowledgebase and carefully selected and filtered high-throughput data pertinent to human proteins. This article presents an overview of the database and the data integration process. We also lay out the key future directions of neXtProt that we consider the necessary steps to make neXtProt the one-stop-shop for all research projects focusing on human proteins

Correction: Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Intravenous Ketamine As Adjunctive Therapy in Treatment-Resistant Depression (TRD)

Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18–70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = −0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555

The UniProt-GO Annotation database in 2011

The GO annotation dataset provided by the UniProt Consortium (GOA: http://www.ebi.ac.uk/GOA) is a comprehensive set of evidenced-based associations between terms from the Gene Ontology resource and UniProtKB proteins. Currently supplying over 100 million annotations to 11 million proteins in more than 360 000 taxa, this resource has increased 2-fold over the last 2 years and has benefited from a wealth of checks to improve annotation correctness and consistency as well as now supplying a greater information content enabled by GO Consortium annotation format developments. Detailed, manual GO annotations obtained from the curation of peer-reviewed papers are directly contributed by all UniProt curators and supplemented with manual and electronic annotations from 36 model organism and domain-focused scientific resources. The inclusion of high-quality, automatic annotation predictions ensures the UniProt GO annotation dataset supplies functional information to a wide range of proteins, including those from poorly characterized, non-model organism species. UniProt GO annotations are freely available in a range of formats accessible by both file downloads and web-based views. In addition, the introduction of a new, normalized file format in 2010 has made for easier handling of the complete UniProt-GOA data set

Carrier Screening for Spinal Muscular Atrophy (SMA) in 107,611 Pregnant Women during the Period 2005–2009: A Prospective Population-Based Cohort Study

BACKGROUND: Spinal muscular atrophy (SMA) is the most common neuromuscular autosomal recessive disorder. The American College of Medical Genetics has recently recommended routine carrier screening for SMA because of the high carrier frequency (1 in 25-50) as well as the severity of that genetic disease. Large studies are needed to determine the feasibility, benefits, and costs of such a program. METHODS AND FINDINGS: This is a prospective population-based cohort study of 107,611 pregnant women from 25 counties in Taiwan conducted during the period January 2005 to June 2009. A three-stage screening program was used: (1) pregnant women were tested for SMA heterozygosity; (2) if the mother was determined to be heterozygous for SMA (carrier status), the paternal partner was then tested; (3) if both partners were SMA carriers, prenatal diagnostic testing was performed. During the study period, a total of 2,262 SMA carriers with one copy of the SMN1 gene were identified among the 107,611 pregnant women that were screened. The carrier rate was approximately 1 in 48 (2.10%). The negative predictive value of DHPLC coupled with MLPA was 99.87%. The combined method could detect approximately 94% of carriers because most of the cases resulted from a common single deletion event. In addition, 2,038 spouses were determined to be SMA carriers. Among those individuals, 47 couples were determined to be at high risk for having offspring with SMA. Prenatal diagnostic testing was performed in 43 pregnant women (91.49%) and SMA was diagnosed in 12 (27.91%) fetuses. The prevalence of SMA in our population was 1 in 8,968. CONCLUSION: The main benefit of SMA carrier screening is to reduce the burden associated with giving birth to an affected child. In this study, we determined the carrier frequency and genetic risk and provided carrier couples with genetic services, knowledge, and genetic counseling

The Next Generation Global Gravitational Wave Observatory: The Science Book

The next generation of ground-based gravitational-wave detectors will observe coalescences of black holes and neutron stars throughout the cosmos, thousands of them with exceptional fidelity. The Science Book is the result of a 3-year effort to study the science capabilities of networks of next generation detectors. Such networks would make it possible to address unsolved problems in numerous areas of physics and astronomy, from Cosmology to Beyond the Standard Model of particle physics, and how they could provide insights into workings of strongly gravitating systems, astrophysics of compact objects and the nature of dense matter. It is inevitable that observatories of such depth and finesse will make new discoveries inaccessible to other windows of observation. In addition to laying out the rich science potential of the next generation of detectors, this report provides specific science targets in five different areas in physics and astronomy and the sensitivity requirements to accomplish those science goals. This report is the second in a six part series of reports by the GWIC 3G Subcommittee: i) Expanding the Reach of Gravitational Wave Observatories to the Edge of the Universe, ii) The Next Generation Global Gravitational Wave Observatory: The Science Book (this report), iii) 3G R&D: R&D for the Next Generation of Ground-based Gravitational Wave Detectors, iv) Gravitational Wave Data Analysis: Computing Challenges in the 3G Era, v) Future Ground-based Gravitational-wave Observatories: Synergies with Other Scientific Communities, and vi) An Exploration of Possible Governance Models for the Future Global Gravitational-Wave Observatory Network

Cosmology with the laser interferometer space antenna

The Laser Interferometer Space Antenna (LISA) has two scientific objectives of cosmological focus: to probe the expansion rate of the universe, and to understand stochastic gravitational-wave backgrounds and their implications for early universe and particle physics, from the MeV to the Planck scale. However, the range of potential cosmological applications of gravitational-wave observations extends well beyond these two objectives. This publication presents a summary of the state of the art in LISA cosmology, theory and methods, and identifies new opportunities to use gravitational-wave observations by LISA to probe the universe