Altered sleep and EEG power in the P301S Tau transgenic mouse model

OBJECTIVE: Sleep disturbances are prevalent in human tauopathies yet despite the importance of sleep, little is known about its relationship with tau pathology. Here, we investigate this interaction by analyzing sleep and tau pathology throughout tauopathy disease progression in P301S human tau transgenic mice. METHODS: P301S and wild‐type mice were analyzed by electroencephalography (EEG)/electromyography at 3, 6, 9, and 11 months of age for sleep/wake time, EEG power, and homeostatic response. Cortical volume and tau pathology was also assessed by anti‐phospho‐tau AT8 staining. RESULTS: P301S tau mice had significantly decreased rapid eye movement (REM) sleep at 9 months of age and decreased REM and non‐REM (NREM) sleep as well as increased wakefulness at 11 months. Sleep loss was characterized by fewer wake, REM, and NREM bouts, increased wake bout duration, and decreased sleep bout duration. Decreased REM and NREM sleep was associated with increased brainstem tau pathology in the sublaterodorsal area and parafacial zone, respectively. P301S mice also showed increased EEG power at 6 and 9 months of age and decreased power at 11 months. Decreased EEG power was associated with decreased cortical volume. Despite sleep disturbances, P301S mice maintained homeostatic response to sleep deprivation. INTERPRETATION: Our results indicate that tau pathology is associated with sleep disturbances that worsen with age and these changes may be related to tau pathology in brainstem sleep regulating regions as well as neurodegeneration. Tau‐induced sleep changes could affect disease progression and be a marker for therapeutic efficacy in this and other tauopathy models

Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer\u27s disease-Opportunities for Therapy

Two of the key functions of arteries in the brain are (1) the well-recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri-arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer\u27s disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer\u27s Association International Society to Advance Alzheimer\u27s Research and Treatment

Drying in a microfluidic chip: experiments and simulations

We present an experimental micro-model of drying porous media, based on microfluidic cells made of arrays of pillars on a regular grid, and complement these experiments with a matching two-dimensional pore-network model of drying. Disorder, or small-scale heterogeneity, was introduced into the cells by randomly varying the radii of the pillars. The microfluidic chips were filled with a volatile oil and then dried horizontally, such that gravitational effects were excluded. The experimental and simulated drying rates and patterns were then compared in detail, for various levels of disorder. The geometrical features were reproduced well, although the model under-predicted the formation of trapped clusters of drying fluid. Reproducing drying rates proved to be more challenging, but improved if the additional trapped clusters were added to the model. The methods reported can be adapted to a wide range of multi-phase flow problems, and allow for the rapid development of high-precision micro-models containing tens of thousands of individual elements

Gas Seepage and Pockmark Formation From Subsurface Reservoirs:Insights From Table-Top Experiments

Pockmarks are morphological depressions commonly observed in ocean and lake floors. Pockmarks form by fluid (typically gas) seepage thorough a sealing sedimentary layer, deforming and breaching the layer. The seepage-induced sediment deformation mechanisms, and their links to the resulting pockmarks morphology, are not well understood. To bridge this gap, we conduct laboratory experiments in which gas seeps through a granular (sand) reservoir, overlaid by a (clay) seal, both submerged under water. We find that gas rises through the reservoir and accumulates at the seal base. Once sufficient gas over-pressure is achieved, gas deforms the seal, and finally escapes via either: (a) doming of the seal followed by dome breaching via fracturing; (b) brittle faulting, delineating a plug, which is lifted by the gas seeping through the bounding faults; or (c) plastic deformation by bubbles ascending through the seal. The preferred mechanism is found to depend on the seal thickness and stiffness: in stiff seals, a transition from doming and fracturing to brittle faulting occurs as the thickness increases, whereas bubble rise is preferred in the most compliant, thickest seals. Seepage can also occur by mixed modes, such as bubbles rising in faults. Repeated seepage events suspend the sediment at the surface and create pockmarks. We present a quantitative analysis that explains the tendency for the various modes of deformation observed experimentally. Finally, we connect simple theoretical arguments with field observations, highlighting similarities and differences that bound the applicability of laboratory experiments to natural pockmarks.</p

Drying and percolation in spatially correlated porous media

We study how the dynamics of a drying front propagating through a porous medium are affected by small-scale correlations in material properties. For this, we first present drying experiments in micro-fluidic micro-models of porous media. Here, the fluid pressures develop more intermittent dynamics as local correlations are added to the structure of the pore spaces. We also consider this problem numerically, using a model of invasion percolation with trapping, and find that there is a crossover in invasion behaviour associated with the length-scale of the disorder in the system. The critical exponents that describe large enough events are similar to the classic invasion percolation problem, while the addition of a finite correlation length significantly affects the exponent values of avalanches and bursts, up to some characteristic size. We thus find that even a weak local structure can interfere with the universality of invasion percolation phenomena. This has implications for a variety of multi-phase flow problems, such as drying, drainage, and fluid invasion

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

Analysis of colour-magnitude diagrams of rich LMC clusters: NGC 1831

We present the analysis of a deep colour-magnitude diagram (CMD) of NGC 1831, a rich star cluster in the LMC. The data were obtained with HST/WFPC2 in the F555W (~V) and F814W (~I) filters, reaching m_555 ~ 25. We discuss and apply a method of correcting the CMD for sampling incompleteness and field star contamination. Efficient use of the CMD data was made by means of direct comparisons of the observed to model CMDs. The model CMDs are built by an algorithm that generates artificial stars from a single stellar population, characterized by an age, a metallicity, a distance, a reddening value, a present day mass function and a fraction of unresolved binaries. Photometric uncertainties are empirically determined from the data and incorporated into the models as well. Statistical techniques are presented and applied as an objective method to assess the compatibility between the model and data CMDs. By modelling the CMD of the central region in NGC 1831 we infer a metallicity Z = 0.012, 8.75 < log(tau) < 8.80, 18.54 < (m-M)_0 < 18.68 and 0.00 < E(B-V) < 0.03. For the position dependent PDMF slope (alpha = -dlog(Phi(M))/dlog(M)), we clearly observe the effect of mass segregation in the system: for projected distances R < 30 arcsec, alpha ~ 1.7, whereas 2.2 < alpha < 2.5 in the outer regions of NGC 1831.Comment: 12 pages, 14 figure

A case of pregnancy with Rhesus antibody and bicornuate uterus - a favourable outcome: a case report

Introduction: In 1% of Rhesus negative women sensitisation occurs without any overt sensitising event during pregnancy. This accounts for late immunisation during a first pregnancy and is responsible for 18-27% of cases of alloimmunisation. The incidence of congenital uterine anomalies in a fertile population is 3.2% of which 5% are bicornuate uterus. Bicornuate uterus can lead to early miscarriages, preterm labor, fetal growth retardation and congenital malformations. Case presentation: A 23-year-old lady in her first pregnancy developed Anti-D antibodies at 28 weeks of gestation without any known sensitising event. In view of increasing anti-D titres, at 36 weeks she was delivered. Incidentally during caesarean section she was found to have bicornuate uterus. The neonate was treated with phototherapy and blood transfusion following delivery. Conclusion: Rhesus antibodies when managed by close monitoring and timely delivery can lead to favourable outcome. Bicornuate uterus does not always lead to complications like miscarriage, growth retardation or preterm labour and does not need any special intervention

The stellar mass to light ratio in the isolated spiral NGC 4414

We present high resolution CO(1-0) interferometric observations and deep HST B-V-I images of the flocculent isolated Sc type spiral NGC 4414. The goal is to determine the stellar mass-to-light (M/L) ratio in a galactic disk. The stars are seen without a dust screen, the central gas mass is very low (undetected), and we show that the dark matter is negligible in the central regions. We have developed an axisymmetric analytical gravitational potential model to account for the central light (mass) profile, the dynamics of the molecular gas in the highly obscured molecular ring, and the stellar light profile outside the highly obscured region. The contribution of dark matter is constrained by the extremely extended HI rotation curve and is small, possibly negligible, at distances less than 5 -- 7 kpc from the center. Furthermore, the M/L ratios we derive are low, about 1.5 in I band and 0.5 in K' band. The B and V band M/L ratios vary greatly due to absorption by dust, reaching 4 in the molecular ring and decreasing to about 1.6 -- 1.8 at larger radii. This unequivocally shows that models, like most maximum disk models, assuming constant M/L ratios in an optical waveband, simply are not appropriate. We illustrate this by making mock maximum disk models with a constant V band M/L ratio. The key is having the central light distribution unobscured such that it can be used to trace the mass. A primitive attempt to determine the intrinsic M/L ratio yields values close to unity in the B,V, and I bands and slightly below 0.5 in K'.Comment: 12 pages, 10 figures, accepted in A&

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