Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of ...the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2
CD9
subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1
and PLVAP
endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα
collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.
After decades of slow progress, the pace of research on membrane protein structures is beginning to quicken thanks to various improvements in technology, including protein engineering and microfocus ...X-ray diffraction. Here we review these developments and, where possible, highlight generic new approaches to solving membrane protein structures based on recent technological advances. Rational approaches to overcoming the bottlenecks in the field are urgently required as membrane proteins, which typically comprise ~30% of the proteomes of organisms, are dramatically under-represented in the structural database of the Protein Data Bank.
Since their discovery more than 50 years ago, Earth's Van Allen radiation belts have been considered to consist of two distinct zones of trapped, highly energetic charged particles. The outer zone is ...composed predominantly of megaelectron volt (MeV) electrons that wax and wane in intensity on time scales ranging from hours to days, depending primarily on external forcing by the solar wind. The spatially separated inner zone is composed of commingled high-energy electrons and very energetic positive ions (mostly protons), the latter being stable in intensity levels over years to decades. In situ energy-specific and temporally resolved spacecraft observations reveal an isolated third ring, or torus, of high-energy (>2 MeV) electrons that formed on 2 September 2012 and persisted largely unchanged in the geocentric radial range of 3.0 to ~3.5 Earth radii for more than 4 weeks before being disrupted (and virtually annihilated) by a powerful interplanetary shock wave passage.
The most obvious impairments associated with spinal cord injury (SCI) are loss of sensation and motor control. However, many subjects with SCI also develop persistent neuropathic pain below the ...injury which is often severe, debilitating and refractory to treatment. The underlying mechanisms of persistent neuropathic SCI pain remain poorly understood. Reports in amputees describing phantom limb pain demonstrate a positive correlation between pain intensity and the amount of primary somatosensory cortex (S1) reorganization. Of note, this S1 reorganization has also been shown to reverse with pain reduction. It is unknown whether a similar association between S1 reorganization and pain intensity exists in subjects with SCI. The aim of this investigation was to determine whether the degree of S1 reorganization following SCI correlated with on-going neuropathic pain intensity. In 20 complete SCI subjects (10 with neuropathic pain, 10 without neuropathic pain) and 21 control subjects without SCI, the somatosensory cortex was mapped using functional magnetic resonance imaging during light brushing of the right little finger, thumb and lip. S1 reorganization was demonstrated in SCI subjects with the little finger activation point moving medially towards the S1 region that would normally innervate the legs. The amount of S1 reorganization in subjects with SCI significantly correlated with on-going pain intensity levels. This study provides evidence of a link between the degree of cortical reorganization and the intensity of persistent neuropathic pain following SCI. Strategies aimed at reversing somatosensory cortical reorganization may have therapeutic potential in central neuropathic pain.
Inward radial diffusion driven by ULF waves has long been known to be capable of accelerating radiation belt electrons to very high energies within the heart of the belts, but more recent work has ...shown that radial diffusion values can be highly event‐specific, and mean values or empirical models may not capture the full significance of radial diffusion to acceleration events. Here we present an event of fast inward radial diffusion, occurring during a period following the geomagnetic storm of 17 March 2015. Ultrarelativistic electrons up to ∼8 MeV are accelerated in the absence of intense higher‐frequency plasma waves, indicating an acceleration event in the core of the outer belt driven primarily or entirely by ULF wave‐driven diffusion. We examine this fast diffusion rate along with derived radial diffusion coefficients using particle and fields instruments on the Van Allen Probes spacecraft mission.
Plain Language Summary
Large increases in the amount of electrons within the Earth's radiation belts can happen quite suddenly and are related to the effects of the Sun's solar wind. These changes are important since these particles can be damaging to communications and technology satellites that orbit close to Earth, at times disrupting GPS and cell phone signals or causing greater disturbances down at ground level. There are two primary mechanisms that cause the increase in high‐energy electrons that we observe with scientific satellites. This study highlights a space weather event, following the intense geomagnetic storm of March 2015, in which we have evidence of one specific type of acceleration mechanism called inward radial diffusion, and no evidence of a competing mechanism. This shows that enhancements can be caused by the one mechanism alone, which is still an open question in radiation belt physics. If we know definitively that intense enhancements can result from inward radial diffusion alone, this helps inform and improve our physics‐based forecast and prediction models of space weather.
Key Points
Fast radial diffusion of ultrarelativistic electrons is observed days after storm main phase
Event‐specific radial diffusion can be orders of magnitude higher than statistical values
ULF‐wave driven acceleration can account for intense particle enhancement observed in inner magnetosphere
Abstract
Between 5 and 4 thousand years ago, crippling megadroughts led to the disruption of ancient civilizations across parts of Africa and Asia, yet the extent of these climate extremes in ...mainland Southeast Asia (MSEA) has never been defined. This is despite archeological evidence showing a shift in human settlement patterns across the region during this period. We report evidence from stalagmite climate records indicating a major decrease of monsoon rainfall in MSEA during the mid- to late Holocene, coincident with African monsoon failure during the end of the Green Sahara. Through a set of modeling experiments, we show that reduced vegetation and increased dust loads during the Green Sahara termination shifted the Walker circulation eastward and cooled the Indian Ocean, causing a reduction in monsoon rainfall in MSEA. Our results indicate that vegetation-dust climate feedbacks from Sahara drying may have been the catalyst for societal shifts in MSEA via ocean-atmospheric teleconnections.
We describe the design and performance of the near-infrared (1.51-1.70 m), fiber-fed, multi-object (300 fibers), high resolution (R = λ/Δλ ∼ 22,500) spectrograph built for the Apache Point ...Observatory Galactic Evolution Experiment (APOGEE). APOGEE is a survey of ∼105 red giant stars that systematically sampled all Milky Way populations (bulge, disk, and halo) to study the Galaxy's chemical and kinematical history. It was part of the Sloan Digital Sky Survey III (SDSS-III) from 2011 to 2014 using the 2.5 m Sloan Foundation Telescope at Apache Point Observatory, New Mexico. The APOGEE-2 survey is now using the spectrograph as part of SDSS-IV, as well as a second spectrograph, a close copy of the first, operating at the 2.5 m du Pont Telescope at Las Campanas Observatory in Chile. Although several fiber-fed, multi-object, high resolution spectrographs have been built for visual wavelength spectroscopy, the APOGEE spectrograph is one of the first such instruments built for observations in the near-infrared. The instrument's successful development was enabled by several key innovations, including a "gang connector" to allow simultaneous connections of 300 fibers; hermetically sealed feedthroughs to allow fibers to pass through the cryostat wall continuously; the first cryogenically deployed mosaic volume phase holographic grating; and a large refractive camera that includes mono-crystalline silicon and fused silica elements with diameters as large as ∼400 mm. This paper contains a comprehensive description of all aspects of the instrument including the fiber system, optics and opto-mechanics, detector arrays, mechanics and cryogenics, instrument control, calibration system, optical performance and stability, lessons learned, and design changes for the second instrument.
Two of the largest geomagnetic storms of the last decade were witnessed in 2015. On 17 March 2015, a coronal mass ejection-driven event occurred with a Dst (Disturbance Storm Time Ring Current Index) ...value reaching 223 nanoteslas. On 22 June 2015 another strong storm (Dst reaching 204 nanoteslas) was recorded. These two storms each produced almost total loss of radiation belt high-energy (E (Energy) greater than or approximately equal to 1 millielectronvolt) electron fluxes. Following the dropouts of radiation belt fluxes there were complex and rather remarkable recoveries of the electrons extending up to nearly 10 millielectronvolts in kinetic energy. The energized outer zone electrons showed a rich variety of pitch angle features including strong butterfly distributions with deep minima in flux at alpha equals 90 degrees. However, despite strong driving of outer zone earthward radial diffusion in these storms, the previously reported impenetrable barrier at L (L-shell magnetic field line value) approximately equal to 2.8 was pushed inward, but not significantly breached, and no E (Energy) greater than or approximately equal to 2.0 millielectronvolts electrons were seen to pass through the radiation belt slot region to reach the inner Van Allen zone. Overall, these intense storms show a wealth of novel features of acceleration, transport, and loss that are demonstrated in the present detailed analysis.
Subfossil pollen and plant macrofossil data derived from
14
C-dated sediment profiles can provide quantitative information on glacial and interglacial climates. The data allow climate variables ...related to growing-season warmth, winter cold, and plant-available moisture to be reconstructed. Continental-scale reconstructions have been made for the mid-Holocene (MH, around 6 ka) and Last Glacial Maximum (LGM, around 21 ka), allowing comparison with palaeoclimate simulations currently being carried out as part of the fifth Assessment Report (AR5) of the Intergovernmental Panel on Climate Change. The synthesis of the available MH and LGM climate reconstructions and their uncertainties, obtained using modern-analogue, regression and model-inversion techniques, is presented for four temperature variables and two moisture variables. Reconstructions of the same variables based on surface-pollen assemblages are shown to be accurate and unbiased. Reconstructed LGM and MH climate anomaly patterns are coherent, consistent between variables, and robust with respect to the choice of technique. They support a conceptual model of the controls of Late Quaternary climate change whereby the first-order effects of orbital variations and greenhouse forcing on the seasonal cycle of temperature are predictably modified by responses of the atmospheric circulation and surface energy balance.
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