Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline

Acknowledgments We would like to gratefully acknowledge all donors and their families for the tissue provided for this study. Human tissue samples were supplied by the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK, the Alzheimer’s Society and the Medical Research Council, and sourced from the MRC London Neurodegenerative Diseases Brain Bank, the Manchester Brain Bank, the South West Dementia Brain Bank (SWDBB), the Newcastle Brain Tissue Resource and the Oxford Brain Bank. The Newcastle Brain Tissue Resource and Oxford Brain Bank are also supported by the National Institute for Health Research (NIHR) Units. The South West Dementia Brain Bank (SWDBB) receives additional support from BRACE (Bristol Research into Alzheimer’s and Care of the Elderly). Alz-50, CP13, MC-1 and PHF-1 antibodies were gifted from Dr. Peter Davies and brain lystates from BACE1−/−mice were obtained from Prof Mike Ashford. The work presented here was funded by Alzheimer’s Research UK (Grant refs: ARUKPPG2014A-21 and ARUK-NSG2015-1 to BP and DK and NIH/NIA grants NIH/NINDS R01 NS082730 and R01 AG044372 to NK)Peer reviewedPublisher PD

Scintillation in the Circinus Galaxy water megamasers

We present observations of the 22 GHz water vapor megamasers in the Circinus galaxy made with the Tidbinbilla 70m telescope. These observations confirm the rapid variability seen earlier by Greenhill et al (1997). We show that this rapid variability can be explained by interstellar scintillation, based on what is now known of the interstellar scintillation seen in a significant number of flat spectrum AGN. The observed variability cannot be fully described by a simple model of either weak or diffractive scintillation.Comment: 10 pages, 5 figures. AJ accepte

Mineral status in canine medial coronoid process disease: a cohort study using analysis of hair by mass spectrometry

In several species, developmental skeletal diseases involving abnormal endochondral ossification have been associated with imbalanced mineral intake. Hair analysis reflects long-term mineral status. To determine the mineral content of hair from dogs with or without medial coronoid process disease (MCPD). Dogs with MCPD have a different profile of minerals known to influence metalloenzymes involved in endochondral ossification. After cleansing, chelation and acid digestion of hair samples (n=79 in total: control dogs, n=70 v MCPD, n=9), mineral profile (7 major and 25 trace elements) was determined by inductively coupled plasma-mass spectrometry. Dogs were of similar age (control, 4.05 [1.85-7.70] v MCPD, 4.30 [3.25-6.53] median (IQR) years; P=0.78) and gender (control, n=43/27 v MCPD, n=4/5 males/females). 28/70 (40 per cent) of control and 8/9 (88 per cent) of MCPD dogs were neutered, respectively. Hair from dogs with MCPD contained significantly lower amounts (µg/g/DM) of copper, sulphur and zinc (all at P<0.001). Age, sex and neutered status had no effect on hair mineral status. Based on hair analysis, a role for mineral imbalance including copper, sulphur and zinc in the aetiopathogenesis of canine MCPD is suggested. Hair mineral analysis may prove useful as a biomarker for susceptible puppies

Temperature Dependence Of Wood Surface Energy

A thorough understanding of the wood surface is required to engineer adhesive bonding in composite applications. A surface analysis technique, dynamic contact angle (DCA) analysis, was used to examine the effects of temperature on the wood surface as measured by the contact angle and surface energy. A hydrophobic surface transition was found on the wood surface at 60 C, which coincides with the glass transition of lignin as measured by differential scanning calorimetry. The change in the surface at the glass transition can be attributed to the diffusion of nonpolar molecular groups to the surface. This could be the result of the migration and deposition of extractives, reorientation of macromolecules, or a combination of the two. Similar behavior has been observed in synthetic amorphous polymers. Although the surface of wood is complex, the results indicate that it can be investigated and understood like synthetic polymer materials

Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight

Despite clear associations between vitamin D deficiency and obesity and/or type 2 diabetes, a causal relationship is not established. Vitamin D receptors (VDRs) are found within multiple tissues, including the brain. Given the importance of the brain in controlling both glucose levels and body weight, we hypothesized that activation of central VDR links vitamin D to the regulation of glucose and energy homeostasis. Indeed, we found that small doses of active vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D3) (calcitriol), into the third ventricle of the brain improved glucose tolerance and markedly increased hepatic insulin sensitivity, an effect that is dependent upon VDR within the paraventricular nucleus of the hypothalamus. In addition, chronic central administration of 1,25D3 dramatically decreased body weight by lowering food intake in obese rodents. Our data indicate that 1,25D3-mediated changes in food intake occur through action within the arcuate nucleus. We found that VDR colocalized with and activated key appetite-regulating neurons in the arcuate, namely proopiomelanocortin neurons. Together, these findings define a novel pathway for vitamin D regulation of metabolism with unique and divergent roles for central nervous system VDR signaling. Specifically, our data suggest that vitamin D regulates glucose homeostasis via the paraventricular nuclei and energy homeostasis via the arcuate nuclei

Acetylsalicylic acid interferes with embryonic kidney growth and development by a prostaglandin-independent mechanism

AIM: To evaluate the effects of the non-selective, non-steroidal anti-inflammatory drug (NSAID) acetylsalicylic acid (ASA), on ex vivo embryonic kidney growth and development. METHODS: Pairs of fetal mouse kidneys at embryonic day 12.5 were cultured ex vivo in increasing concentrations of ASA (0.04-0.4 mg/mL) for up to 7 d. One organ from each pair was grown in control media and was used as the internal control for the experimental contralateral organ. In some experiments, organs were treated with ASA for 48 h and then transferred either to control media alone or control media containing 10 μmol/L prostaglandin E2 (PGE2) for a further 5 d. Fetal kidneys were additionally obtained from prostaglandin synthase 2 homozygous null or heterozygous (PTGS2-/- and PTGS2-/+) embryos and grown in culture. Kidney cross-sectional area was used to determine treatment effects on kidney growth. Whole-mount labelling to fluorescently detect laminin enabled crude determination of epithelial branching using confocal microscopy. RESULTS: Increasing ASA concentration (0.1, 0.2 and 0.4 mg/mL) significantly inhibited metanephric growth (P < 0.05). After 7 d of culture, exposure to 0.2 mg/mL and 0.4 mg/mL reduced organ size to 53% and 23% of control organ size respectively (P < 0.01). Addition of 10 μmol/L PGE2 to culture media after exposure to 0.2 mg/mL ASA for 48 h resulted in a return of growth area to control levels. Application of control media alone after cessation of ASA exposure showed no benefit on kidney growth. Despite the apparent recovery of growth area with 10 μmol/L PGE2, no obvious renal tubular structures were formed. The number of epithelial tips generated after 48 h exposure to ASA was reduced by 40% (0.2 mg/mL; P < 0.05) and 47% (0.4 mg/mL; P < 0.01). Finally, growth of PTGS2-/- and PTGS2+/- kidneys in organ culture showed no differences, indicating that PTGS2 derived PGE2 may at best have a minor role. CONCLUSION: ASA reduces early renal growth and development but the role of prostaglandins in this may be minor

Enabling GPU Accelerated Computing in the SUNDIALS Time Integration Library

As part of the Exascale Computing Project (ECP), a recent focus of development efforts for the SUite of Nonlinear and DIfferential/ALgebraic equation Solvers (SUNDIALS) has been to enable GPU-accelerated time integration in scientific applications at extreme scales. This effort has resulted in several new GPU-enabled implementations of core SUNDIALS data structures, support for programming paradigms which are aware of the heterogeneous architectures, and the introduction of utilities to provide new points of flexibility. In this paper, we discuss our considerations, both internal and external, when designing these new features and present the features themselves. We also present performance results for several of the features on the Summit supercomputer and early access hardware for the Frontier supercomputer, which demonstrate negligible performance overhead resulting from the additional infrastructure and significant speedups when using both NVIDIA and AMD GPUs

The Population of Damped Lyman-alpha and Lyman Limit Systems in the Cold Dark Matter Model

Lyman limit and damped Lyman-alpha absorption systems probe the distribution of collapsed, cold gas at high redshift. Numerical simulations that incorporate gravity and gas dynamics can predict the abundance of such absorbers in cosmological models. We develop a semi-analytical method to correct the numerical predictions for the contribution of unresolved low mass halos, and we apply this method to the Katz et al. (1996) simulation of the standard cold dark matter model ($\Omega=1$, $h=0.5$, $\Omega_b=0.05$, $\sigma_8=0.7$). Using this simulation and higher resolution simulations of individual low mass systems, we determine the relation between a halo's circular velocity $v_c$ and its cross section for producing Lyman limit or damped absorption. We combine this relation with the Press-Schechter formula for the abundance of halos to compute the number of absorbers per unit redshift. The resolution correction increases the predicted abundances by about a factor of two at z=2, 3, and 4, bringing the predicted number of damped absorbers into quite good agreement with observations. Roughly half of the systems reside in halos with circular velocities v_c>100\kms and half in halos with 35\kms. Halos with v_c>150\kms typically harbor two or more systems capable of producing damped absorption. Even with the resolution correction, the predicted abundance of Lyman limit systems is a factor of three below observational estimates, signifying either a failure of standard CDM or a failure of these simulations to resolve the systems responsible for most Lyman limit absorption. By comparing simulations with and without star formation, we find that depletion of the gas supply by star formation affects absorption line statistics at $z>=2$ only for column densities exceeding $N_{HI}=10^{22} cm^{-2}$.Comment: AASlatex, 17 pages w/ 3 embedded ps figures. Submitted to Ap