Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer's disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an ...early noninvasive phenotype, but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir ((18)F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (apolipoprotein E) (rs429358, P=5.5 × 10(-14)) and on chromosome 3 upstream of BCHE (butyrylcholinesterase) (rs509208, P=2.7 × 10(-8)) in a region previously associated with serum BCHE activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. BCHE has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of BCHE-modulating agents in the AD spectrum.
Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele ...associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.
We report on a strategy for using SABRE (signal amplification by reversible exchange) for polarizing 1H and 13C nuclei of weakly interacting ligands which possess biologically relevant and ...nonaromatic motifs. We first demonstrate this via the polarization of acetonitrile, using Ir(IMes)(COD)Cl as the catalyst precursor, and confirm that the route to hyperpolarization transfer is via the J-coupling network. We extend this work to the polarization of propionitrile, benzylnitrile, benzonitrile, and trans-3-hexenedinitrile in order to assess its generality. In the 1H NMR spectrum, the signal for acetonitrile is enhanced 8-fold over its thermal counterpart when Ir(H)2(IMes)(MeCN)3+ is the catalyst. Upon addition of pyridine or pyridine-d 5, the active catalyst changes to Ir(H)2(IMes)(py)2(MeCN)+ and the resulting acetonitrile 1H signal enhancement increases to 20- and 60-fold, respectively. In 13C NMR studies, polarization transfers optimally to the quaternary 13C nucleus of MeCN while the methyl 13C is hardly polarized. Transfer to 13C is shown to occur first via the 1H–1H coupling between the hydrides and the methyl protons and then via either the 2 J or 1 J couplings to the respective 13Cs, of which the 2 J route is more efficient. These experimental results are rationalized through a theoretical treatment which shows excellent agreement with experiment. In the case of MeCN, longitudinal two-spin orders between pairs of 1H nuclei in the three-spin methyl group are created. Two-spin order states, between the 1H and 13C nuclei, are also created, and their existence is confirmed for Me13CN in both the 1H and 13C NMR spectra using the Only Parahydrogen Spectroscopy protocol.
ABSTRACT
A new set of thermodynamic models is presented for calculating phase relations in bulk compositions extending from peridotite to granite, from 0·001 to 70 kbar and from 650°C to peridotite ...liquidus temperatures, in the system K2O–Na2O–CaO–FeO–MgO–Al2O3–SiO2–H2O–TiO2–Fe2O3–Cr2O3 (KNCFMASHTOCr). The models may be used to calculate phase equilibria in partial melting of a large range of mantle and crustal compositions. They provide a good fit to experimental phase relation topologies and melt compositions across the compositional range of the model. Compared with the preliminary model of Jennings, E. S. & Holland, T. J. B. (2015) (A simple thermodynamic model for melting of peridotite in the system NCFMASOCr. Journal of Petrology56, 869–892) for peridotite–basalt melting relations, the inclusion of K2O and TiO2 allows for better modelling of small melt fractions in peridotite melting, and in reproducing rutile-bearing eclogite melting at high pressures. An improved order–disorder model for spinel is now incorporated. Above 10 kbar pressure, wet partial melting relations may be significantly affected by the dissolution of silicates in aqueous fluid, so the set of models includes an aqueous low-density silicate-bearing fluid in addition to a high-density H2O-bearing silicate melt. Oxygen fugacity may be readily calculated for the whole range of bulk compositions investigated, and the effect of water content on melt fO2 is assessed.
While the characterization of materials by NMR is hugely important in the physical and biological sciences, it also plays a vital role in medical imaging. This success is all the more impressive ...because of the inherently low sensitivity of the method. We establish here that Ir(H)2(IMes)(py)3Cl undergoes both pyridine (py) loss as well as the reductive elimination of H2. These reversible processes bring para-H2 and py into contact in a magnetically coupled environment, delivering an 8100-fold increase in 1H NMR signal strength relative to non-hyperpolarized py at 3 T. An apparatus that facilitates signal averaging has been built to demonstrate that the efficiency of this process is controlled by the strength of the magnetic field experienced by the complex during the magnetization transfer step. Thermodynamic and kinetic data combined with DFT calculations reveal the involvement of Ir(H)2(η2-H2)(IMes)(py)2+, an unlikely yet key intermediate in the reaction. Deuterium labeling yields an additional 60% improvement in signal, an observation that offers insight into strategies for optimizing this approach.
We present new limits on exotic keV-scale physics based on 478 kg d of Majorana Demonstrator commissioning data. Constraints at the 90% confidence level are derived on bosonic dark matter (DM) and ...solar axion couplings, Pauli exclusion principle violating (PEPV) decay, and electron decay using monoenergetic peak signal limits above our background. Our most stringent DM constraints are set for 11.8 keV mass particles, limiting g_{Ae}<4.5×10^{-13} for pseudoscalars and (α^{'}/α)<9.7×10^{-28} for vectors. We also report a 14.4 keV solar axion coupling limit of g_{AN}^{eff}×g_{Ae}<3.8×10^{-17}, a 1/2β^{2}<8.5×10^{-48} limit on the strength of PEPV electron transitions, and a lower limit on the electron lifetime of τ_{e}>1.2×10^{24} yr for e^{-}→ invisible.
Aims/hypothesis
The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989–1998) and second ...(1999–2008) halves of the period.
Methods
All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture–recapture methodology. Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied.
Results
Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half.
Conclusions/interpretation
The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3–4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.
We present first results of the H2O Southern Galactic Plane Survey (HOPS), using the Mopra Radio Telescope with a broad-band backend and a beam size of about 2 arcmin. We have observed 100 deg2 of ...the southern Galactic plane at 12 mm (19.5-27.5 GHz), including spectral line emission from H2O masers, multiple metastable transitions of ammonia, cyanoacetylene, methanol and radio recombination lines. In this paper, we report on the characteristics of the survey and H2O maser emission. We find 540 H2O masers, of which 334 are new detections. The strongest maser is 3933 Jy and the weakest is 0.7 Jy, with 62 masers over 100 Jy. In 14 maser sites, the spread in the velocity of the H2O maser emission exceeds 100 km s−1. In one region, the H2O maser velocities are separated by 351.3 km s−1. The rms noise levels are typically between 1 and 2 Jy, with 95 per cent of the survey under 2 Jy. We estimate completeness limits of 98 per cent at around 8.4 Jy and 50 per cent at around 5.5 Jy. We estimate that there are between 800 and 1500 H2O masers in the Galaxy that are detectable in a survey with similar completeness limits to HOPS. We report possible masers in NH3 (11,9) and (8,6) emission towards G19.61−0.23 and in the NH3 (3,3) line towards G23.33−0.30.
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