End-of-Life Caregivers and Profound Learning: A Grounded Theory Study

This study developed a deeper understanding of profound learning as experienced by volunteer end-of-life caregivers. This paper shares preliminary results of the study, including the following findings: Kinds of Knowledges; Tools; Engages the Human Condition; Relational

On fundamental domains and volumes of hyperbolic Coxeter-Weyl groups

We present a simple method for determining the shape of fundamental domains of generalized modular groups related to Weyl groups of hyperbolic Kac-Moody algebras. These domains are given as subsets of certain generalized upper half planes, on which the Weyl groups act via generalized modular transformations. Our construction only requires the Cartan matrix of the underlying finite-dimensional Lie algebra and the associated Coxeter labels as input information. We present a simple formula for determining the volume of these fundamental domains. This allows us to re-produce in a simple manner the known values for these volumes previously obtained by other methods.Comment: v2: to be published in Lett Math Phys (reference added, typo corrected

Fabrication and subband gap optical properties of silicon supersaturated with chalcogens by ion implantation and pulsed laser melting

Topographically flat, single crystal silicon supersaturated with the chalcogens S, Se, and Te was prepared by ion implantation followed by pulsed laser melting and rapid solidification. The influences of the number of laser shots on the atomic and carrier concentration-depth profiles were measured with secondary ion mass spectrometry and spreading resistance profiling, respectively. We found good agreement between the atomic concentration-depth profiles obtained from experiments and a one-dimensional model for plane-front melting, solidification, liquid-phase diffusion, with kinetic solute trapping, and surface evaporation. Broadband subband gap absorption is exhibited by all dopants over a wavelength range from 1 to 2.5 microns. The absorption did not change appreciably with increasing number of laser shots, despite a measurable loss of chalcogen and of electronic carriers after each shot.One of the authors M.T. acknowledges the financial support of the Fulbright Program. This research was supported in part by the U.S. Army ARDEC under Contract No. W15QKN-07- P-0092

Interaction between a MAPT variant causing frontotemporal dementia and mutant APP affects axonal transport.

In Alzheimer's disease, many indicators point to a central role for poor axonal transport, but the potential for stimulating axonal transport to alleviate the disease remains largely untested. Previously, we reported enhanced anterograde axonal transport of mitochondria in 8- to 11-month-old MAPTP301L knockin mice, a genetic model of frontotemporal dementia with parkinsonism-17T. In this study, we further characterized the axonal transport of mitochondria in younger MAPTP301L mice crossed with the familial Alzheimer's disease model, TgCRND8, aiming to test whether boosting axonal transport in young TgCRND8 mice can alleviate axonal swelling. We successfully replicated the enhancement of anterograde axonal transport in young MAPTP301L/P301L knockin animals. Surprisingly, we found that in the presence of the amyloid precursor protein mutations, MAPTP301L/P3101L impaired anterograde axonal transport. The numbers of plaque-associated axonal swellings or amyloid plaques in TgCRND8 brains were unaltered. These findings suggest that amyloid-β promotes an action of mutant tau that impairs axonal transport. As amyloid-β levels increase with age even without amyloid precursor protein mutation, we suggest that this rise could contribute to age-related decline in frontotemporal dementia.This work was supported by Alzheimer’s Research UK (ART/PG2009/2 to R.A.), MRC project grant (MR/L003813/1 to R.A., S.G.), Medical Research Council studentship (S.M.), Alzheimer’s Research UK studentship (ARUKPhD2013-13 to C.D.), Biotechnology and Biological Sciences Research Council Institute Strategic Programme Grant (M.P.C.), the Foundation for Alzheimer Research (FRA/SAO) (JPB) and the Belgian F.N.R.S. (K.A and JPB)

Mislocalization of neuronal tau in the absence of tangle pathology in phosphomutant tau knockin mice.

Hyperphosphorylation and fibrillar aggregation of the microtubule-associated protein tau are key features of Alzheimer's disease and other tauopathies. To investigate the involvement of tau phosphorylation in the pathological process, we generated a pair of complementary phosphomutant tau knockin mouse lines. One exclusively expresses phosphomimetic tau with 18 glutamate substitutions at serine and/or threonine residues in the proline-rich and first microtubule-binding domains to model hyperphosphorylation, whereas its phosphodefective counterpart has matched alanine substitutions. Consistent with expected effects of genuine phosphorylation, association of the phosphomimetic tau with microtubules and neuronal membranes is severely disrupted in vivo, whereas the phosphodefective mutations have more limited or no effect. Surprisingly, however, age-related mislocalization of tau is evident in both lines, although redistribution appears more widespread and more pronounced in the phosphomimetic tau knockin. Despite these changes, we found no biochemical or immunohistological evidence of pathological tau aggregation in mice of either line up to at least 2 years of age. These findings raise important questions about the role of tau phosphorylation in driving pathology in human tauopathies

Indirect adjustment for multiple missing variables applicable to environmental epidemiology

AbstractObjectivesDevelop statistical methods for survival models to indirectly adjust hazard ratios of environmental exposures for missing risk factors.MethodsA partitioned regression approach for linear models is applied to time to event survival analyses of cohort study data. Information on the correlation between observed and missing risk factors is obtained from ancillary data sources such as national health surveys. The relationship between the missing risk factors and survival is obtained from previously published studies. We first evaluated the methodology using simulations, by considering the Weibull survival distribution for a proportional hazards regression model with varied baseline functions, correlations between an adjusted variable and an adjustment variable as well as selected censoring rates. Then we illustrate the method in a large, representative Canadian cohort of the association between concentrations of ambient fine particulate matter and mortality from ischemic heart disease.ResultsIndirect adjustment for cigarette smoking habits and obesity increased the fine particulate matter-ischemic heart disease association by 3%–123%, depending on the number of variables considered in the adjustment model due to the negative correlation between these two risk factors and ambient air pollution concentrations in Canada. The simulations suggested that the method yielded small relative bias (<40%) for most cohort designs encountered in environmental epidemiology.ConclusionsThis method can accommodate adjustment for multiple missing risk factors simultaneously while accounting for the associations between observed and missing risk factors and between missing risk factors and health endpoints

Lattice dynamics and spin excitations in the metal-organic framework [CH3_3NH3_3][Co(HCOO)3_3]

In metal-organic-framework (MOF) perovskites, both magnetic and ferroelectric orderings can be readily realized by compounding spin and charge degrees of freedom. The hydrogen bonds that bridge the magnetic framework and organic molecules have long been thought of as a key in generating multiferroic properties. However, the underlying physical mechanisms remain unclear. Here, we combine neutron diffraction, quasielastic and inelastic neutron scattering, and THz spectroscopy techniques to thoroughly investigate the dynamical properties of the multiferroic MOF candidate [CH$_3$NH$_3$][Co(HCOO)$_3$] through its multiple phase transitions. The wide range of energy resolutions reachable by these techniques enables us to scrutinize the coupling between the molecules and the framework throughout the phase transitions and interrogate a possible magnetoelectric coupling. Our results also reveal a structural change around 220 K which may be associated with the activation of a nodding donkey mode of the methylammonium molecule due to the ordering of the CH$_3$ groups. Upon the occurrence of the modulated phase transition around 130 K, the methylammonium molecules undergo a freezing of its reorientational motions which is concomitant with a change of the lattice parameters and anomalies of collective lattice vibrations. No significant change has been however observed in the lattice dynamics around the magnetic ordering, which therefore indicates the absence of a substantial magneto-electric coupling in zero-field

Infusion of Reconstituted High-Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial

Background CSL112 is a new formulation of human apolipoprotein A‐I (apoA‐I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double‐blind, multicenter, dose‐ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease. Methods and Results Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2‐hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations \u3e3× upper limits of normal and study drug–related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA‐I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7‐, 3.4‐, and 6.8‐g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (\u3e3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7‐, 3.4‐, and 6.8‐g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion‐site bruising. CSL112 resulted in rapid (Tmax≈2 hours) and dose‐dependent increases in apoA‐I (145% increase in the 6.8‐g group) and total cholesterol efflux (up to 3.1‐fold higher than placebo) (P\u3c0.001). Conclusions CSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA‐I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420

Compactifications of reductive groups as moduli stacks of bundles

Grothendieck and Harder proved that every principal bundle over the projective line with split reductive structure group (and trivial over the generic point) can be reduced to a maximal torus. Furthermore, this reduction is unique modulo automorphisms and the Weyl group. In a series of six variations on this theme, we prove corresponding results for principal bundles over the following schemes and stacks: (1) a line modulo the group of nth roots of unity; (2) a football, that is, an orbifold of genus zero with two marked points; (3) a gerbe over a football whose structure group is the nth roots of unity; (4) a chain of lines meeting in nodes; (5) a line modulo an action of a split torus; and (6) a chain modulo an action of a split torus. We also prove that the automorphism groups of such bundles are smooth, affine, and connected.Comment: 28 pages; minor improvements, in particular to the proof of Theorem 5.