Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy

GRB 130831a: Rise and demise of a magnetar at z = 0.5

Open Access.--14th Marcel Grossman Meeting On Recent Developments in Theoretical and Experimental General Relativity, Astrophysics and Relativistic Field Theories; University of Rome "La Sapienza"Rome; Italy; 12 July 2015 through 18 July 2015; Code 142474.-- http://www.icra.it/mg/mg14/Gamma-ray bursts (GRBs) are the brightest explosions in the universe, yet the properties of their energy sources are far from understood. Very important clues, however, can be deduced by studying the afterglows of these events. We present observations of GRB 130831A and its afterglow obtained with Swift, Chandra, and multiple ground-based observatories. This burst shows an uncommon drop in the X-ray light curve at about 100 ks after the trigger, with a decay slope of α 7. The standard Forward Shock (FS) model offers no explanation for such a behaviour. Instead, a model in which a newly born magnetar outflow powers the early X-ray emission is found to be viable. After the drop, the X-ray afterglow resumes its decay with a slope typical of FS emission. The optical emission, on the other hand, displays no clear break across the X-ray drop and its decay is consistent with that of the late X-rays. Using both the X-ray and optical data, we show that the FS model can explain the emission after 100 ks. We model our data to infer the kinetic energy of the ejecta and thus estimate the efficiency of a magnetar “central engine” of a GRB. Furthermore, we break down the energy budget of this GRB into prompt emission, late internal dissipation, kinetic energy of the relativistic ejecta, and compare it with the energy of the accompanying supernova, SN 2013fu. Copyright © 2018 by the Editors.All rights reserved.Peer reviewe

The sustainable materials roadmap

Over the past 150 years, our ability to produce and transform engineered materials has been responsible for our current high standards of living, especially in developed economies. However, we must carefully think of the effects our addiction to creating and using materials at this fast rate will have on the future generations. The way we currently make and use materials detrimentally affects the planet Earth, creating many severe environmental problems. It affects the next generations by putting in danger the future of the economy, energy, and climate. We are at the point where something must drastically change, and it must change now. We must create more sustainable materials alternatives using natural raw materials and inspiration from nature while making sure not to deplete important resources, i.e. in competition with the food chain supply. We must use less materials, eliminate the use of toxic materials and create a circular materials economy where reuse and recycle are priorities. We must develop sustainable methods for materials recycling and encourage design for disassembly. We must look across the whole materials life cycle from raw resources till end of life and apply thorough life cycle assessments (LCAs) based on reliable and relevant data to quantify sustainability. We need to seriously start thinking of where our future materials will come from and how could we track them, given that we are confronted with resource scarcity and geographical constrains. This is particularly important for the development of new and sustainable energy technologies, key to our transition to net zero. Currently 'critical materials' are central components of sustainable energy systems because they are the best performing. A few examples include the permanent magnets based on rare earth metals (Dy, Nd, Pr) used in wind turbines, Li and Co in Li-ion batteries, Pt and Ir in fuel cells and electrolysers, Si in solar cells just to mention a few. These materials are classified as 'critical' by the European Union and Department of Energy. Except in sustainable energy, materials are also key components in packaging, construction, and textile industry along with many other industrial sectors. This roadmap authored by prominent researchers working across disciplines in the very important field of sustainable materials is intended to highlight the outstanding issues that must be addressed and provide an insight into the pathways towards solving them adopted by the sustainable materials community. In compiling this roadmap, we hope to aid the development of the wider sustainable materials research community, providing a guide for academia, industry, government, and funding agencies in this critically important and rapidly developing research space which is key to future sustainability.journal articl

2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines: Developed in collaboration with the International Society for Heart and Lung Transplantation

Heart failure (HF) is a major and growing public health problem in the United States. Approximately 5 million patients in this country have HF, and over 550,000 patients are diagnosed with HF for the first time each year. The disorder is the primary reason for 12 to 15 million office visits and 6.5 million hospital days each year. From 1990 to 1999, the annual number of hospitalizations has increased from approximately 810,000 to over 1 million for HF as a primary diagnosis and from 2.4 to 3.6 million for HF as a primary or secondary diagnosis. In 2001, nearly 53 000 patients died of HF as a primary cause. The number of HF deaths has increased steadily despite advances in treatment, in part because of increasing numbers of patients with HF due to better treatment and “salvage” of patients with acute myocardial infarctions (MIs) earlier in life. Heart failure is primarily a condition of the elderly, and thus the widely recognized “aging of the population” also contributes to the increasing incidence of HF. The incidence of HF approaches 10 per 1000 population after age 65, and approximately 80% of patients hospitalized with HF are more than 65 years old. Heart failure is the most common Medicare diagnosis-related group (i.e., hospital discharge diagnosis), and more Medicare dollars are spent for the diagnosis and treatment of HF than for any other diagnosis. The total estimated direct and indirect costs for HF in 2005 were approximately $27.9 billion. In the United States, approximately$2.9 billion annually is spent on drugs for the treatment of HF

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Heavy element production in a compact object merger observed by JWST

The mergers of binary compact objects such as neutron stars and black holes are of central interest to several areas of astrophysics, including as the progenitors of gamma-ray bursts (GRBs) 1, sources of high-frequency gravitational waves (GWs) 2 and likely production sites for heavy-element nucleosynthesis by means of rapid neutron capture (the r-process) 3. Here we present observations of the exceptionally bright GRB 230307A. We show that GRB 230307A belongs to the class of long-duration GRBs associated with compact object mergers 4–6 and contains a kilonova similar to AT2017gfo, associated with the GW merger GW170817 (refs. 7–12). We obtained James Webb Space Telescope (JWST) mid-infrared imaging and spectroscopy 29 and 61 days after the burst. The spectroscopy shows an emission line at 2.15 microns, which we interpret as tellurium (atomic mass A = 130) and a very red source, emitting most of its light in the mid-infrared owing to the production of lanthanides. These observations demonstrate that nucleosynthesis in GRBs can create r-process elements across a broad atomic mass range and play a central role in heavy-element nucleosynthesis across the Universe

The impact of PICALM genetic variations on reserve capacity of posterior cingulate in AD continuum

Phosphatidylinositolbinding clathrin assembly protein (PICALM) gene is one novel genetic player associated with late-onset Alzheimer’s disease (LOAD), based on recent genome wide association studies (GWAS). However, how it affects AD occurrence is still unknown. Brain reserve hypothesis highlights the tolerant capacities of brain as a passive means to fight against neurodegenerations. Here, we took the baseline volume and/or thickness of LOAD-associated brain regions as proxies of brain reserve capacities and investigated whether PICALM genetic variations can influence the baseline reserve capacities and the longitudinal atrophy rate of these specific regions using data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. In mixed population, we found that brain region significantly affected by PICALM genetic variations was majorly restricted to posterior cingulate. In sub-population analysis, we found that one PICALM variation (C allele of rs642949) was associated with larger baseline thickness of posterior cingulate in health. We found seven variations in health and two variations (rs543293 and rs592297) in individuals with mild cognitive impairment were associated with slower atrophy rate of posterior cingulate. Our study provided preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non-demented elderly

Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions