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Structural characterization of the D290V mutation site in hnRNPA2 low-complexity-domain polymers.
Human genetic studies have given evidence of familial, disease-causing mutations in the analogous amino acid residue shared by three related RNA binding proteins causative of three neurological diseases. Alteration of aspartic acid residue 290 of hnRNPA2 to valine is believed to predispose patients to multisystem proteinopathy. Mutation of aspartic acid 262 of hnRNPA1 to either valine or asparagine has been linked to either amyotrophic lateral sclerosis or multisystem proteinopathy. Mutation of aspartic acid 378 of hnRNPDL to either asparagine or histidine has been associated with limb girdle muscular dystrophy. All three of these aspartic acid residues map to evolutionarily conserved regions of low-complexity (LC) sequence that may function in states of either intrinsic disorder or labile self-association. Here, we present a combination of solid-state NMR spectroscopy with segmental isotope labeling and electron microscopy on the LC domain of the hnRNPA2 protein. We show that, for both the wild-type protein and the aspartic acid 290-to-valine mutant, labile polymers are formed in which the LC domain associates into an in-register cross-β conformation. Aspartic acid 290 is shown to be charged at physiological pH and immobilized within the polymer core. Polymers of the aspartic acid 290-to-valine mutant are thermodynamically more stable than wild-type polymers. These observations give evidence that removal of destabilizing electrostatic interactions may be responsible for the increased propensity of the mutated LC domains to self-associate in disease-causing conformations
Forecasting the response of Earth's surface to future climatic and land use changes: a review of methods and research needs
In the future, Earth will be warmer, precipitation events will be more extreme, global mean sea level will rise, and many arid and semiarid regions will be drier. Human modifications of landscapes will also occur at an accelerated rate as developed areas increase in size and population density. We now have gridded global forecasts, being continually improved, of the climatic and land use changes (C&LUC) that are likely to occur in the coming decades. However, besides a few exceptions, consensus forecasts do not exist for how these C&LUC will likely impact Earth-surface processes and hazards. In some cases, we have the tools to forecast the geomorphic responses to likely future C&LUC. Fully exploiting these models and utilizing these tools will require close collaboration among Earth-surface scientists and Earth-system modelers. This paper assesses the state-of-the-art tools and data that are being used or could be used to forecast changes in the state of Earth's surface as a result of likely future C&LUC. We also propose strategies for filling key knowledge gaps, emphasizing where additional basic research and/or collaboration across disciplines are necessary. The main body of the paper addresses cross-cutting issues, including the importance of nonlinear/threshold-dominated interactions among topography, vegetation, and sediment transport, as well as the importance of alternate stable states and extreme, rare events for understanding and forecasting Earth-surface response to C&LUC. Five supplements delve into different scales or process zones (global-scale assessments and fluvial, aeolian, glacial/periglacial, and coastal process zones) in detail
Neuroanatomical and cellular degeneration associated with a social disorder characterized by new ritualistic belief systems in a TDP-C patient vs. a Pick patient
Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with predominant degeneration of anterior temporal cortices often develop a language disorder of semantic knowledge loss and/or a social disorder often characterized by compulsive rituals and belief systems corresponding to predominant left or right hemisphere involvement, respectively. The neural substrates of these complex social disorders remain unclear. Here, we present a comparative imaging and postmortem study of two patients, one with FTLD-TDP (subtype C) and one with FTLD-tau (subtype Pick disease), who both developed new rigid belief systems. The FTLD-TDP patient developed a complex set of values centered on positivity and associated with specific physical and behavioral features of pigs, while the FTLD-tau patient developed compulsive, goal-directed behaviors related to general themes of positivity and spirituality. Neuroimaging showed left-predominant temporal atrophy in the FTLD-TDP patient and right-predominant frontotemporal atrophy in the FTLD-tau patient. Consistent with antemortem cortical atrophy, histopathologic examinations revealed severe loss of neurons and myelin predominantly in the anterior temporal lobes of both patients, but the FTLD-tau patient showed more bilateral, dorsolateral involvement featuring greater pathology and loss of projection neurons and deep white matter. These findings highlight that the regions within and connected to anterior temporal lobes may have differential vulnerability to distinct FTLD proteinopathies and serve important roles in human belief systems
The Brightness of Colour
Background: The perception of brightness depends on spatial context: the same stimulus can appear light or dark depending on what surrounds it. A less well-known but equally important contextual phenomenon is that the colour of a stimulus can also alter its brightness. Specifically, stimuli that are more saturated (i.e. purer in colour) appear brighter than stimuli that are less saturated at the same luminance. Similarly, stimuli that are red or blue appear brighter than equiluminant yellow and green stimuli. This non-linear relationship between stimulus intensity and brightness, called the Helmholtz-Kohlrausch (HK) effect, was first described in the nineteenth century but has never been explained. Here, we take advantage of the relative simplicity of this 'illusion' to explain it and contextual effects more generally, by using a simple Bayesian ideal observer model of the human visual ecology. We also use fMRI brain scans to identify the neural correlates of brightness without changing the spatial context of the stimulus, which has complicated the interpretation of related fMRI studies.Results: Rather than modelling human vision directly, we use a Bayesian ideal observer to model human visual ecology. We show that the HK effect is a result of encoding the non-linear statistical relationship between retinal images and natural scenes that would have been experienced by the human visual system in the past. We further show that the complexity of this relationship is due to the response functions of the cone photoreceptors, which themselves are thought to represent an efficient solution to encoding the statistics of images. Finally, we show that the locus of the response to the relationship between images and scenes lies in the primary visual cortex (V1), if not earlier in the visual system, since the brightness of colours (as opposed to their luminance) accords with activity in V1 as measured with fMRI.Conclusions: The data suggest that perceptions of brightness represent a robust visual response to the likely sources of stimuli, as determined, in this instance, by the known statistical relationship between scenes and their retinal responses. While the responses of the early visual system (receptors in this case) may represent specifically the statistics of images, post receptor responses are more likely represent the statistical relationship between images and scenes. A corollary of this suggestion is that the visual cortex is adapted to relate the retinal image to behaviour given the statistics of its past interactions with the sources of retinal images: the visual cortex is adapted to the signals it receives from the eyes, and not directly to the world beyond
Cortical similarities in psychiatric and mood disorders identified in federated VBM analysis via COINSTAC
The tectonics of the western Ordos Plateau, Ningxia, China: Slip rates on the Luoshan and East Helanshan Faults
Analysis of the locus, style, and rate of faulting is fundamental to understanding the kinematics of continental deformation. The Ordos Plateau lies to the northeast of Tibet, within the India-Eurasia collision zone. Previous studies have suggested that it behaves rigidly and rotates anticlockwise within a large-scale zone of ENE-WSW left-lateral shearing. For this rotation to be accommodated, the eastern and western margins of the Ordos Plateau should be undergoing right-lateral shearing and yet the dominant faulting style appears to be extensional. We focus specifically on the kinematics of the faults bounding the western margin of the Ordos Plateau and make new slip rate estimates for two of the major faults in the region: the right-lateral strike-slip Luoshan Fault and the normal-slip East Helanshan Fault. We use a combination of infrared stimulated luminescence dating of offset landforms with high-resolution imagery and topography from the Pleiades satellites to determine an average right-lateral slip rate of 4.3 ± 0.4 mm/a (1σ uncertainty) on the Luoshan Fault. Similarly, we use 10Be exposure dating to determine a vertical throw rate on the East Helanshan Fault of <0.6 ± 0.1 mm/a, corresponding to an extension rate of <0.7 ± 0.1 mm/a (1σ uncertainty). Both of these results agree well with slip rates determined from the latest campaign GPS data. We therefore conclude that right-lateral shearing is the dominant motion occurring in the western Ordos region, supporting a kinematic model of large-scale anticlockwise rotation of the whole Ordos Plateau
Forecasting the Response of Earth\u27s Surface to Future Climatic and Land Use Changes: A Review of Methods and Research Needs
In the future, Earth will be warmer, precipitation events will be more extreme, global mean sea level will rise, and many arid and semiarid regions will be drier. Human modifications of landscapes will also occur at an accelerated rate as developed areas increase in size and population density. We now have gridded global forecasts, being continually improved, of the climatic and land use changes (C&LUC) that are likely to occur in the coming decades. However, besides a few exceptions, consensus forecasts do not exist for how these C&LUC will likely impact Earth-surface processes and hazards. In some cases, we have the tools to forecast the geomorphic responses to likely future C&LUC. Fully exploiting these models and utilizing these tools will require close collaboration among Earth-surface scientists and Earth-system modelers. This paper assesses the state-of-the-art tools and data that are being used or could be used to forecast changes in the state of Earth\u27s surface as a result of likely future C&LUC. We also propose strategies for filling key knowledge gaps, emphasizing where additional basic research and/or collaboration across disciplines are necessary. The main body of the paper addresses cross-cutting issues, including the importance of nonlinear/threshold-dominated interactions among topography, vegetation, and sediment transport, as well as the importance of alternate stable states and extreme, rare events for understanding and forecasting Earth-surface response to C&LUC. Five supplements delve into different scales or process zones (global-scale assessments and fluvial, aeolian, glacial/periglacial, and coastal process zones) in detail
Measurement of associated Z plus charm production in proton-proton collisions at root s=8TeV
A study of the associated production of a Z boson and a charm quark jet (Z + c), and a comparison to production with a b quark jet (Z + b), in pp collisions at a centre-of-mass energy of 8 TeV are presented. The analysis uses a data sample corresponding to an integrated luminosity of 19.7 fb(-1), collected with the CMS detector at the CERN LHC. The Z boson candidates are identified through their decays into pairs of electrons or muons. Jets originating from heavy flavour quarks are identified using semileptonic decays of c or b flavoured hadrons and hadronic decays of charm hadrons. The measurements are performed in the kinematic region with two leptons with pT(l) > 20 GeV, vertical bar eta(l)vertical bar 25 GeV and vertical bar eta(jet)vertical bar Z + c + X) B(Z -> l(+)l(-)) = 8.8 +/- 0.5 (stat)+/- 0.6 (syst) pb. The ratio of the Z+c and Z+b production cross sections is measured to be sigma(pp -> Z+c+X)/sigma (pp -> Z+b+X) = 2.0 +/- 0.2 (stat)+/- 0.2 (syst). The Z+c production cross section and the cross section ratio are also measured as a function of the transverse momentum of theZ boson and of the heavy flavour jet. The measurements are compared with theoretical predictions.Peer reviewe
Measurement of the underlying event activity in inclusive Z boson production in proton-proton collisions at root s=13 TeV
This paper presents a measurement of the underlying event activity in proton-proton collisions at a center-of-mass energy of 13TeV, performed using inclusive Z boson production events collected with the CMS experiment at the LHC. The analyzed data correspond to an integrated luminosity of 2.1 fb(-1). The underlying event activity is quantified in terms of the charged particle multiplicity, as well as of the scalar sum of the charged particles' transverse momenta in different topological regions defined with respect to the Z boson direction. The distributions are unfolded to the stable particle level and compared with predictions from various Monte Carlo event generators, as well as with similar CDF and CMS measurements at center-of-mass energies of 1.96 and 7TeV respectively.Peer reviewe
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