This section looks back on a ground-breaking contribution to public health, reproduces an extract of the original text and adds a commentary on its significance from a modern perspective. To ...complement the theme of this month’s issue, John R Williams looks at the Declaration of Helsinki and how it has evolved over time. The original declaration is reproduced here in full with permission of the World Medical Association.
U.S. estimates of the natural rate of interest – the real short-term interest rate that would prevail absent transitory disturbances – have declined dramatically since the start of the global ...financial crisis. For example, estimates using the Laubach–Williams (2003) model indicate the natural rate in the United States fell to close to zero during the crisis and has remained there into 2016. Explanations for this decline include shifts in demographics, a slowdown in trend productivity growth, and global factors affecting real interest rates. This paper applies the Laubach–Williams methodology to the United States and three other advanced economies – Canada, the Euro Area, and the United Kingdom. We find that large declines in trend GDP growth and natural rates of interest have occurred over the past 25years in all four economies. These country-by-country estimates are found to display a substantial amount of comovement over time, suggesting an important role for global factors in shaping trend growth and natural rates of interest.
According to standard macroeconomic models, the zero lower bound greatly reduces the effectiveness of monetary policy and increases the efficacy of fiscal policy. However, private-sector decisions ...depend on the entire path of expected future short-term interest rates, not just the current short-term rate. Put differently, longer-term yields matter. We show how to measure the zero bound's effects on yields of any maturity. Indeed, 1- and 2-year Treasury yields were surprisingly unconstrained throughout 2008 to 2010, suggesting that monetary and fiscal policy were about as effective as usual during this period. Only beginning in late 2011 did these yields become more constrained.
GABA release from interneurons in VTA, projections from the nucleus accumbens (NAc), and rostromedial tegmental nucleus (RMTg) was selectively activated in rat brain slices. The inhibition induced by ...μ-opioid agonists was pathway dependent. Morphine induced a 46% inhibition of IPSCs evoked from the RMTg, 18% from NAc, and IPSCs evoked from VTA interneurons were almost insensitive (11% inhibition). In vivo morphine treatment resulted in tolerance to the inhibition of RMTg, but not local interneurons or NAc, inputs. One common sign of opioid withdrawal is an increase in adenosine-dependent inhibition. IPSCs evoked from the NAc were potently inhibited by activation of presynaptic adenosine receptors, whereas IPSCs evoked from RMTg were not changed. Blockade of adenosine receptors selectively increased IPSCs evoked from the NAc during morphine withdrawal. Thus, the acute action of opioids, the development of tolerance, and the expression of withdrawal are mediated by separate GABA afferents to dopamine neurons.
•GABA pathways to dopamine neurons are selectively sensitive to μ-opioid agonists•GABA pathways to dopamine neurons are selectively sensitive to adenosine agonists•Pathways that are most sensitive to opioids and adenosine are different•Morphine withdrawal is expressed selectively at terminals from nucleus accumbens
Matsui et al. studied three opioid-sensitive GABA inputs to VTA dopamine neurons. The balance between initial sensitivity, development of tolerance, and expression of withdrawal were different for each pathway. Thus, different neuronal pathways regulate the three stages of opioid action.
Vascular development in the mammalian retina is a paradigm for CNS vascular development in general, and its study is revealing fundamental mechanisms that explain the efficacy of antiangiogenic ...therapies in retinal vascular disease. During development of the mammalian retina, hypoxic astrocytes are hypothesized to secrete VEGF, which attracts growing endothelial cells as they migrate radially from the optic disc. However, published tests of this model using astrocyte-specific deletion of Vegf in the developing mouse retina appear to contradict this theory. Here, we report that selectively eliminating Vegf in neonatal retinal astrocytes with a Gfap-Cre line that recombines with approximately 100% efficiency had no effect on proliferation or radial migration of astrocytes, but completely blocked radial migration of endothelial cells, strongly supporting the hypoxic astrocyte model. Using additional Cre driver lines, we found evidence for essential and partially redundant actions of retina-derived (paracrine) and astrocyte-derived (autocrine) VEGF in controlling astrocyte proliferation and migration. We also extended previous studies by showing that HIF-1α in retinal neurons and HIF-2α in Müller glia play distinct roles in retinal vascular development and disease, adding to a growing body of data that point to the specialization of these 2 hypoxia-sensing transcription factors.
Peter Jost is known to the international tribology community as the father of the subject—‘the man who made the world spin a little easier’. He was the author of the eponymous ‘Jost Report’, the ...report of the Working Group set up in 1964 to investigate the state of lubrication education and research in the UK. Over the following five decades, up to his death in 2016, he was tireless in extolling the importance of tribology to manufacturing efficiency, energy conversion and environmental sustainability. He was instrumental in establishing the International Tribology Council and its prestigious gold, silver and bronze medals. Jost was himself the recipient of numerous national and international awards. In 1976, he was the President of the Institution of Production Engineers, and in 2013, he received the Sustained Achievement Award from the Royal Academy of Engineering. What is less well known is the story behind the Jost report—what was it that led the recently elected Labour government and its newly established Ministry of Technology to investigate lubrication and to choose Jost to lead the investigating panel? The story illustrates the combination of serendipity and determination on which success can so often depend.
Optogenetics provides an alternative to electrical stimulation to manipulate membrane voltage, and trigger or modify action potentials (APs) in excitable cells. We compare biophysically and ...energetically the cellular responses to direct electrical current injection versus optical stimulation mediated by genetically expressed light-sensitive ion channels, e.g., Channelrhodopsin-2 (ChR2). Using a computational model of ChR2(H134R mutant), we show that both stimulation modalities produce similar-in-morphology APs in human cardiomyocytes, and that electrical and optical excitability vary with cell type in a similar fashion. However, whereas the strength-duration curves for electrical excitation in ventricular and atrial cardiomyocytes closely follow the theoretical exponential relationship for an equivalent RC circuit, the respective optical strength-duration curves significantly deviate, exhibiting higher nonlinearity. We trace the origin of this deviation to the waveform of the excitatory current—a nonrectangular self-terminating inward current produced in optical stimulation due to ChR2 kinetics and voltage-dependent rectification. Using a unifying charge measure to compare energy needed for electrical and optical stimulation, we reveal that direct electrical current injection (rectangular pulse) is more efficient at short pulses, whereas voltage-mediated negative feedback leads to self-termination of ChR2 current and renders optical stimulation more efficient for long low-intensity pulses. This applies to cardiomyocytes but not to neuronal cells (with much shorter APs). Furthermore, we demonstrate the cell-specific use of ChR2 current as a unique modulator of intrinsic activity, allowing for optical control of AP duration in atrial and, to a lesser degree, in ventricular myocytes. For self-oscillatory cells, such as Purkinje, constant light at extremely low irradiance can be used for fine control of oscillatory frequency, whereas constant electrical stimulation is not feasible due to electrochemical limitations. Our analysis offers insights for designing future new energy-efficient stimulation strategies in heart or brain.
Situating Ecology as a Big-Data Science FARLEY, SCOTT S.; DAWSON, ANDRIA; GORING, SIMON J. ...
BioScience/Bioscience,
08/2018, Volume:
68, Issue:
8
Journal Article
Peer reviewed
Open access
Ecology has joined a world of big data. Two complementary frameworks define big data: data that exceed the analytical capacities of individuals or disciplines or the “Four Vs” axes of volume, ...variety, veracity, and velocity. Variety predominates in ecoinformatics and limits the scalability of ecological science. Volume varies widely. Ecological velocity is low but growing as data throughput and societal needs increase. Ecological big-data systems include in situ and remote sensors, community data resources, biodiversity databases, citizen science, and permanent stations. Technological solutions include the development of open code- and data-sharing platforms, flexible statistical models that can handle heterogeneous data and sources of uncertainty, and cloud-computing delivery of high-velocity computing to large-volume analytics. Cultural solutions include training targeted to early and current scientific workforce and strengthening collaborations among ecologists and data scientists. The broader goal is to maximize the power, scalability, and timeliness of ecological insights and forecasting.
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