The effects of peripheral and central high insulin on brain insulin signaling and amyloid-β in young and old APP/PS1 mice

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-β (Aβ), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APP(swe)/PS1(dE9) transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aβ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF Aβ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aβ, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on Aβ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aβ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aβ in young and old mice, independent of neuronal insulin signaling. SIGNIFICANCE STATEMENT The transportation of insulin from blood to brain is a saturable process relevant to understanding the link between hyperinsulinemia and AD. In vitro experiments have found direct connections between high insulin and extracellular Aβ, but these mechanisms presume that peripheral high insulin elevates brain insulin significantly. We found that physiological hyperinsulinemia in awake, behaving mice does not increase CNS insulin to an appreciable level yet modestly increases extracellular Aβ. We also found that the brain of aged APP/PS1 mice was not insulin resistant, contrary to the current state of the literature. These results further elucidate the relationship between insulin, the brain, and AD and its conflicting roles as both a risk factor and potential treatment

Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo

Epidemiological studies show that patients with type 2 diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia, specifically dementia due to Alzheimer’s disease (AD). These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading us to investigate the link between aberrant glucose metabolism, T2DM, and AD in murine models. Here, we combined two techniques — glucose clamps and in vivo microdialysis — as a means to dynamically modulate blood glucose levels in awake, freely moving mice while measuring real-time changes in amyloid-β (Aβ), glucose, and lactate within the hippocampal interstitial fluid (ISF). In a murine model of AD, induction of acute hyperglycemia in young animals increased ISF Aβ production and ISF lactate, which serves as a marker of neuronal activity. These effects were exacerbated in aged AD mice with marked Aβ plaque pathology. Inward rectifying, ATP-sensitive potassium (K(ATP)) channels mediated the response to elevated glucose levels, as pharmacological manipulation of K(ATP) channels in the hippocampus altered both ISF Aβ levels and neuronal activity. Taken together, these results suggest that K(ATP) channel activation mediates the response of hippocampal neurons to hyperglycemia by coupling metabolism with neuronal activity and ISF Aβ levels

Loss of intranetwork and internetwork resting state functional connections with Alzheimer\u27s disease progression

Alzheimer\u27s disease (AD) is the most common cause of dementia. Much is known concerning AD pathophysiology but our understanding of the disease at the systems level remains incomplete. Previous AD research has used resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) to assess the integrity of functional networks within the brain. Most studies have focused on the default-mode network (DMN), a primary locus of AD pathology. However, other brain regions are inevitably affected with disease progression. We studied rs-fcMRI in five functionally defined brain networks within a large cohort of human participants of either gender (n = 510) that ranged in AD severity from unaffected [clinical dementia rating (CDR) 0] to very mild (CDR 0.5) to mild (CDR 1). We observed loss of correlations within not only the DMN but other networks at CDR 0.5. Within the salience network (SAL), increases were seen between CDR 0 and CDR 0.5. However, at CDR 1, all networks, including SAL, exhibited reduced correlations. Specific networks were preferentially affected at certain CDR stages. In addition, cross-network relations were consistently lost with increasing AD severity. Our results demonstrate that AD is associated with widespread loss of both intranetwork and internetwork correlations. These results provide insight into AD pathophysiology and reinforce an integrative view of the brain\u27s functional organization

A heterotrimeric G protein, G alpha i-3, on Golgi membranes regulates the secretion of a heparan sulfate proteoglycan in LLC-PK1 epithelial cells

A heterotrimeric G-alpha-i subunit, alpha-i-3, is localized on Golgi membranes in LLC-PK1 and NRK epithelial cells where it colocalizes with mannosidase II by immunofluorescence. The alpha-i-3 was found to be localized on the cytoplasmic face of Golgi cisternae and it was distributed across the whole Golgi stack. The alpha-i-3 subunit is found on isolated rat liver Golgi membranes by Western blotting and G-alpha-i-3 on the Golgi apparatus is ADP ribosylated by pertussis toxin. LLC-PK1 cells were stably transfected with G-alpha-i-3 on an MT-1, inducible promoter in order to overexpress alpha-i-3 on Golgi membranes. The intracellular processing and constitutive secretion of the basement membrane heparan sulfate proteoglycan (HSPG) was measured in LLC-PK1 cells. Overexpression of alpha-i-3 on Golgi membranes in transfected cells retarded the secretion of HSPG and accumulated precursors in the medial-trans-Golgi. This effect was reversed by treatment of cells with pertussis toxin which results in ADP-ribosylation and functional uncoupling of G-alpha-i-3 on Golgi membranes. These results provide evidence for a novel role for the pertussis toxin sensitive G-alpha-i-3 protein in Golgi trafficking of a constitutively secreted protein in epithelial cells

Mapping The Interstellar Medium With Near-Infrared Diffuse Interstellar Bands

We map the distribution and properties of the Milky Way's interstellar medium as traced by diffuse interstellar bands (DIBs) detected in near-infrared stellar spectra from the SDSS-III/APOGEE survey. Focusing exclusively on the strongest DIB in the H band, at lambda similar to 1.527 mu m, we present a projected map of the DIB absorption field in the Galactic plane, using a set of about 60,000 sightlines that reach up to 15 kpc from the Sun and probe up to 30 mag of visual extinction. The strength of this DIB is linearly correlated with dust reddening over three orders of magnitude in both DIB equivalent width (Wpm) and extinction, with a power law index of 1.01 +/- 0.01, a mean relationship of W-DIB/A(v) = 0.1 angstrom mag(-1) and a dispersion of similar to 0.05 angstrom mag(-1) at extinctions characteristic of the Galactic midplane. These properties establish this DIB as a powerful, independent probe of dust extinction over a wide range of Av values. The subset of about 14,000 robustly detected DIB features have a W-DIB distribution that follows an exponential trend. We empirically determine the intrinsic rest wavelength of this transition to be lambda(0) = 15 272.42 angstrom and use it to calculate absolute radial velocities of the carrier, which display the kinematical signature of the rotating Galactic disk. We probe the DIB carrier distribution in three dimensions and show that it can be characterized by an exponential disk model with a scale height of about 100 pc and a scale length of about 5 kpc. Finally, we show that the DIB distribution also traces large-scale Galactic structures, including the Galactic long bar and the warp of the outer disk.NSF Astronomy & Astrophysics Postdoctoral Fellowship AST-1203017NSF AST-1109665Alfred P. Sloan FoundationNational Science FoundationU.S. Department of Energy Office of ScienceUniversity of ArizonaBrazilian Participation GroupBrookhaven National LaboratoryUniversity of CambridgeCarnegie Mellon UniversityUniversity of FloridaFrench Participation GroupGerman Participation GroupHarvard UniversityInstituto de Astrofisica de CanariasMichigan State/Notre Dame/JINA Participation GroupJohns Hopkins UniversityLawrence Berkeley National LaboratoryMax Planck Institute for AstrophysicsMax Planck Institute for Extraterrestrial PhysicsNew Mexico State UniversityNew York UniversityOhio State UniversityPennsylvania State UniversityUniversity of PortsmouthPrinceton UniversitySpanish Participation GroupUniversity of TokyoUniversity of UtahVanderbilt UniversityUniversity of VirginiaUniversity of WashingtonYale UniversitySpanish Ministry of Economy and Competitiveness AYA-2011-27754McDonald Observator

the SDSS-III APOGEE Spectral Line List for H-Band Spectroscopy

We present the H-band spectral line lists adopted by the Apache Point Observatory Galactic Evolution Experiment (APOGEE). The APOGEE line lists comprise astrophysical, theoretical, and laboratory sources from the literature, as well as newly evaluated astrophysical oscillator strengths and damping parameters. We discuss the construction of the APOGEE line list, which is one of the critical inputs for the APOGEE Stellar Parameters and Chemical Abundances Pipeline, and present three different versions that have been used at various stages of the project. The methodology for the newly calculated astrophysical line lists is reviewed. The largest of these three line lists contains 134,457 molecular and atomic transitions. In addition to the format adopted to store the data, the line lists are available in MOOG, Synspec, and Turbospectrum formats. The limitations of the line lists along with guidance for its use on different spectral types are discussed. We also present a list of H-band spectral features that are either poorly represented or completely missing in our line list. This list is based on the average of a large number of spectral fit residuals for APOGEE observations spanning a wide range of stellar parameters.Alfred P. Sloan FoundationNational Science FoundationU.S. Department of Energy Office of ScienceJanos Bolyai Research Scholarship of the Hungarian Academy of SciencesSpanish Ministry of Economy and Competitiveness AYA-2011-27754, AYA-2014-58082-PRSF 14-50-00043McDonald Observator

Immiscible fluid displacement in porous media with spatially correlated particle sizes

Immiscible fluid displacement in porous media is fundamental for many environmental processes, including infiltration of water in soils, groundwater remediation, enhanced recovery of hydrocarbons and CO2 geosequestration. Microstructural heterogeneity, in particular of particle sizes, can significantly impact immiscible displacement. For instance, it may lead to unstable flow and preferential displacement patterns. We present a systematic, quantitative pore-scale study of the impact of spatial correlations in particle sizes on the drainage of a partially-wetting fluid. We perform pore-network simulations with varying flow rates and different degrees of spatial correlation, complemented with microfluidic experiments. Simulated and experimental displacement patterns show that spatial correlation leads to more preferential invasion, with reduced trapping of the defending fluid, especially at low flow rates. Numerically, we find that increasing the correlation length reduces the fluid-fluid interfacial area and the trapping of the defending fluid, and increases the invasion pattern asymmetry and selectivity. Our experiments, conducted for low capillary numbers, support these findings. Our results delineate the significant effect of spatial correlations on fluid displacement in porous media, of relevance to a wide range of natural and engineered processes

Primary, secondary and tertiary prevention of Relative Energy Deficiency in Sport (REDs): a narrative review by a subgroup of the IOC consensus on REDs

Author's accepted manuscriptRelative Energy Deficiency in Sport (REDs) is common among female and male athletes representing various sports at different performance levels, and the underlying cause is problematic low energy availability (LEA). It is essential to prevent problematic LEA to decrease the risk of serious health and performance consequences. This narrative review addresses REDs primary, secondary and tertiary prevention strategies and recommends best practice prevention guidelines targeting the athlete health and performance team, athlete entourage (eg, coaches, parents, managers) and sport organisations. Primary prevention of REDs seeks to minimise exposure to and reduce behaviours associated with problematic LEA. Some of the important strategies are educational initiatives and de-emphasising body weight and leanness, particularly in young and subelite athletes. Secondary prevention encourages the early identification and management of REDs signs or symptoms to facilitate early treatment to prevent development of more serious REDs outcomes. Recommended strategies for identifying athletes at risk are self-reported screening instruments, individual health interviews and/or objective assessment of REDs markers. Tertiary prevention (clinical treatment) seeks to limit short-term and long-term severe health consequences of REDs. The cornerstone of tertiary prevention is identifying the source of and treating problematic LEA. Best practice guidelines to prevent REDs and related consequences include a multipronged approach targeting the athlete health and performance team, the athlete entourage and sport organisations, who all need to ensure a supportive and safe sporting environment, have sufficient REDs knowledge and remain observant for the early signs and symptoms of REDs.acceptedVersio

The young age of the extremely metal-deficient blue compact dwarf galaxy SBS 1415+437

We use Multiple Mirror Telescope (MMT) spectrophotometry and Hubble Space Telescope (HST) Faint Object Spectrograph (FOS) spectra and Wide Field and Planetary Camera 2 (WFPC2) V and I images to study the properties and evolutionary status of the nearby (D = 11.4 Mpc) extremely metal-deficient blue compact dwarf (BCD) galaxy SBS 1415+437=CG 389. The oxygen abundance in the galaxy is 12+log(O/H)=7.60+/-0.01 or Zsun/21. The helium mass fraction in SBS 1415+437 is Y=0.246+/-0.004 which agrees with the primordial helium abundance determined by Izotov & Thuan using a much larger sample of BCDs. The alpha-elements-to-oxygen abundance ratios (Ne/O, S/O, Ar/O) are in very good agreement with the mean values for other metal-deficient BCDs and are consistent with the scenario that these elements are made in massive stars. The Fe/O abundance ratio is ~2 times smaller than the solar ratio. The Si/O ratio is close to the solar value, implying that silicon is not significantly depleted into dust grains. The values of the N/O and C/O ratios imply that intermediate-mass stars have not had time to evolve in SBS 1415+437 and release their nucleosynthesis products and that both N and C in the BCD have been made by massive stars only. This sets an upper limit of ~100 Myr on the age of SBS 1415+437. The (V-I) color of the low-surface-brightness component of the galaxy is blue (<0.4 mag) indicative of a very young underlying stellar population. The (V-I) - I color-magnitude diagrams of the resolved stellar populations in different regions of SBS 1415+437 suggest propagating star formation from the NE side of the galaxy to the SW. All regions in SBS 1415+437 possess very blue spectral energy distributions (SED). We find that the ages of the stellar populations in SBS 1415+437 to range from a few Myr to 100 Myr.Comment: 25 pages, 12 PS and 5 JPG figures, to appear in Ap