Regulation of glial activation and neuroinflammation are critical factors in the pathogenesis of Alzheimer's disease (AD). YKL-40, a primarily astrocytic protein encoded by the gene
, is a widely ...studied cerebrospinal fluid biomarker that increases with aging and early in AD. However, the function of
/YKL-40 in AD is unknown. In a cohort of patients with AD, we observed that a variant in the human
gene, which results in decreased CSF YKL-40 expression, was associated with slower AD progression. At baseline,
deletion in mice had no effect on astrocyte activation while modestly promoting microglial activation. In a mouse APP/PS1 model of AD,
deletion decreased amyloid plaque burden and increased periplaque expression of the microglial lysosomal marker CD68, suggesting that
may suppress glial phagocytic activation and promote amyloid accumulation. Accordingly,
knockdown increased phagocytosis of zymosan particles and of β-amyloid peptide in both astrocytes and microglia in vitro. We further observed that expression of
is regulated by the circadian clock, as deletion of the core clock proteins BMAL1 or CLOCK/NPAS2 strongly suppresses basal
expression, whereas deletion of the negative clock regulators PER1/PER2 increased
expression. Basal
mRNA was nonrhythmic because of a long mRNA half-life in astrocytes. However, inflammatory induction of
was gated by the clock. Our findings reveal
/YKL-40 as a modulator of glial phagocytic activation and AD pathogenesis in both mice and humans and suggest that the astrocyte circadian clock regulates inflammatory
induction.
We review the status of searches for sterile neutrinos in the ∼1eV range, with an emphasis on the latest results from short baseline oscillation experiments and how they fit within sterile neutrino ...oscillation models. We present global fit results to a three-active-flavor plus one-sterile-flavor model (3+1), where we find an improvement of Δχ2=35 for 3 additional parameters compared to a model with no sterile neutrino. This is a 5σ improvement, indicating that an effect that is like that of a sterile neutrino is highly preferred by the data. However we note that separate fits to the appearance and disappearance oscillation data sets within a 3+1 model do not show the expected overlapping allowed regions in parameter space. This “tension” leads us to explore two options: 3+2, where a second additional mass state is introduced, and a 3+1+decay model, where the ν4 state can decay to invisible particles. The 3+1+decay model, which is also motivated by improving compatibility with cosmological observations, yields the larger improvement, with a Δχ2=8 for 1 additional parameter beyond the 3+1 model, which is a 2.6σ improvement. Moreover the tension between appearance and disappearance experiments is reduced compared to 3+1, although disagreement remains. In these studies, we use a frequentist approach and also a Bayesian method of finding credible regions.
With respect to this tension, we review possible problems with the global fitting method. We note multiple issues, including problems with reproducing the experimental results, especially in the case of experiments that do not provide adequate data releases. We discuss an unexpected 5 MeV excess, observed in the reactor flux energy spectrum, that may be affecting the oscillation interpretation of the short baseline reactor data. We emphasize the care that must be taken in mapping to the true neutrino energy in the case of oscillation experiments that are subject to multiple interaction modes and nuclear effects. We point to problems with the “Parameter-Goodness-of-Fit test” that is used to quantify the tension. Lastly, we point out that analyses presenting limits often receive less scrutiny that signals.
While we provide a snapshot of the status of sterile neutrino searches today and global fits to their interpretation, we emphasize that this is a fast-moving field. We briefly review experiments that are expected to report new data in the immediate future. Lastly, we consider the 5-year horizon, where we propose that decay-at-rest neutrino sources are the best method of finally resolving the confusing situation.
The importance
of water moving between the atmosphere and aquifers has led to efforts to
develop and maintain coupled models of surface water and groundwater.
However, developing inputs to these ...models is usually time-consuming and
requires extensive knowledge of software engineering, often prohibiting their
use by many researchers and water managers, thus reducing these models'
potential to promote science-driven decision-making in an era of global
change and increasing water resource stress. In response to this need, we
have developed GSFLOW–GRASS, a bundled set of open-source tools that
develops inputs for, executes, and graphically displays the results of
GSFLOW, the U.S. Geological Survey's coupled groundwater and surface-water
flow model. In order to create a robust tool that can be widely implemented
over diverse hydro(geo)logic settings, we built a series of GRASS GIS
extensions that automatically discretizes a topological surface-water flow
network that is linked with an underlying gridded groundwater domain. As
inputs, GSFLOW–GRASS requires at a minimum a digital elevation model, a
precipitation and temperature record, and estimates of channel parameters and
hydraulic conductivity. We demonstrate the broad applicability of the toolbox
by successfully testing it in environments with varying degrees of drainage
integration, landscape relief, and grid resolution, as well as the presence
of irregular coastal boundaries. These examples also show how GSFLOW–GRASS
can be implemented to examine the role of groundwater–surface-water
interactions in a diverse range of water resource and land management
applications.
Neutrino oscillation models involving extra mass eigenstates beyond the standard three (3+N) are fit to global short baseline experimental data. We find that 3+1 has a best fit of Δm412=1.75 eV2 with ...a Δχnull-min2 (dof) of 52.34 (3). The 3+2 fit has a Δχnull-min2 (dof) of 56.99 (7). For the first time, we show Bayesian credible intervals for a 3+1 model. These are found to be in agreement with frequentist intervals. The results of these new fits favor a higher Δm2 value than previous studies, which may have an impact on future sterile neutrino searches such as the Fermilab SBN program.
The environmental impact of human activities has been a concern for engineers and architects for centuries, from limitation of energy and raw materials to predicting future energy and resource ...demands. This review demonstrates how life cycle assessment (LCA) and life cycle costing (LCC) tools can be used to support design decisions in the building industry throughout the design process. The study is primarily based on DGNB certification projects in Denmark conducted by the engineering consultancy company Ramboll and focuses on how LCA and LCC tools can be used in the early design stages to quantify decision making and how tools are used in the final stages of a certification process to verify the building geometry with regard to life cycle costs and environmental impacts.
We report on the first measurement of the astrophysical neutrino flux using particle showers (cascades) in IceCube data from 2010–2015. Assuming standard oscillations, the astrophysical neutrinos in ...this dedicated cascade sample are dominated (∼90 %) by electron and tau flavors. The flux, observed in the sensitive energy range from 16 TeV to 2.6 PeV, is consistent with a single power-law model as expected from Fermi-type acceleration of high energy particles at astrophysical sources. We find the flux spectral index to be γ = 2.53 ± 0.07 and a flux normalization for each neutrino flavor of ϕastro = 1.66+0.25 −0.27 at E0 = 100 TeV , in agreement with IceCube's complementary muon neutrino results and with all-neutrino flavor fit results. In the measured energy range we reject spectral indices γ ≤ 2.28 at ≥ 3 σ significance level. Because of high neutrino energy resolution and low atmospheric neutrino backgrounds, this analysis provides the most detailed characterization of the neutrino flux at energies below ∼100 TeV compared to previous IceCube results. Results from fits assuming more complex neutrino flux models suggest a flux softening at high energies and a flux hardening at low energies (p value ≥ 0.06). The sizable and smooth flux measured below ∼100 TeV remains a puzzle. In order to not violate the isotropic diffuse gamma-ray background as measured by the Fermi Large Area Telescope, it suggests the existence of astrophysical neutrino sources characterized by dense environments which are opaque to gamma rays.
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CMK, CTK, FMFMET, NUK, UL
We measure a large set of observables in inclusive charged current muon neutrino scattering on argon with the MicroBooNE liquid argon time projection chamber operating at Fermilab. We evaluate three ...neutrino interaction models based on the widely used GENIE event generator using these observables. The measurement uses a data set consisting of neutrino interactions with a final state muon candidate fully contained within the MicroBooNE detector. These data were collected in 2016 with the Fermilab Booster Neutrino Beam, which has an average neutrino energy of Formula omitted, using an exposure corresponding to Formula omitted protons-on-target. The analysis employs fully automatic event selection and charged particle track reconstruction and uses a data-driven technique to separate neutrino interactions from cosmic ray background events. We find that GENIE models consistently describe the shapes of a large number of kinematic distributions for fixed observed multiplicity.
Abstract Background There is considerable variation in progressive brain volume changes in schizophrenia. Whether this is related to the clinical heterogeneity that characterizes the illness remains ...to be determined. This study examines the relationship between change in brain volume over time and individual variation in psychopathology, as measured by five continuous symptom dimensions (i.e. negative, positive, disorganization, mania and depression). Methods Global brain volume measurements from 105 schizophrenia patients and 100 healthy comparison subjects, obtained at inclusion and 5-year follow-up, were used in this study. Symptom dimension scores were calculated by factor analysis of clinical symptoms. Using linear regression analyses and independent-samples t-tests, the relationship between symptom dimensions and progressive brain volume changes, corrected for age, gender and intracranial volume, was examined. Antipsychotic medication, outcome and IQ were investigated as potential confounders. Results In patients, the disorganization dimension was associated with change in total brain (β = − 0.295, p = 0.003) and cerebellar (β = − 0.349, p < 0.001) volume. Furthermore, higher levels of disorganization were associated with lower IQ, irrespective of psychiatric status (i.e. patient or control). In healthy comparison subjects, disorganization score was not associated with progressive brain volume changes. Conclusion Heterogeneity in progressive brain volume changes in schizophrenia is particularly associated with variation in disorganization. Schizophrenia patients with high levels of disorganization exhibit more progressive decrease of global brain volumes and have lower total IQ. We propose that these patients form a phenotypically and biologically homogenous subgroup that may be useful for etiological (e.g., genetic) studies.
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