Neuroanatomical spread of amyloid β and tau in Alzheimer's disease: implications for primary prevention.

With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer's disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid β and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid β uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer's disease dementia patients) with available amyloid β and tau PET data. Amyloid β PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid β PET composite showed a 120% increase in the accumulation rate of amyloid β compared to the global composite (P < 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid β and tau pathology. To detect early changes in amyloid β pathology, focusing on the earliest sites of amyloid β accumulation results in more powerful and efficient study designs in early Alzheimer's disease. Targeted composites could be used to re-examine the thresholds for amyloid β-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid β treatments may benefit from the use of focal composites when estimating drug effects on amyloid β and tau changes in populations with minimal amyloid β and tau pathology and limited expected short-term accumulation

Computational psychiatry: a Rosetta Stone linking the brain to mental illness.

PCF is supported by the Bernard Wolfe Health Neuroscience Fund and the Wellcome Trust. This work was carried out within the Wellcome- and MRC-funded Behavioural and Clinical Neuroscience Institute and the Cambridge and Peterborough NHS Foundation Trust.This is the accepted manuscript. The final version is available from the Lancet Psychiatry at: http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366%2814%2970298-6/fulltex

Ocular Irrigating Solutions: A Comparison Between Balanced Salt Solution and L-410 (PO-EIS)

The ability of two ocular irrigating solutions to reduce postoperative corneal edema after intracapsular cataract extraction was compared using ultrasonic pachymetry. All patients had anterior chamber intraocular lenses implanted. The solutions were balanced salt solution and solution L-410 (PO-EIS), an eye irrigation solution containing dextran 40 and bicarbonate. Corneas irrigated with either solution showed no significant difference in postoperative edema. The use of L-410 (as an alternative to balanced salt solution) may not be necessary in intracapsular cataract extraction

A Generalized Theory of Semiflexible Polymers

NA bending on length scales shorter than a persistence length plays an integral role in the translation of genetic information from DNA to cellular function. Quantitative experimental studies of these biological systems have led to a renewed interest in the polymer mechanics relevant for describing the conformational free energy of DNA bending induced by protein-DNA complexes. Recent experimental results from DNA cyclization studies have cast doubt on the applicability of the canonical semiflexible polymer theory, the wormlike chain (WLC) model, to DNA bending on biologically relevant length scales. This paper develops a theory of the chain statistics of a class of generalized semiflexible polymer models. Our focus is on the theoretical development of these models and the calculation of experimental observables. To illustrate our methods, we focus on a specific, illustrative model of DNA bending. We show that the WLC model generically describes the long-length-scale chain statistics of semiflexible polymers, as predicted by renormalization group arguments. In particular, we show that either the WLC or our present model adequately describes force-extension, solution scattering, and long-contour-length cyclization experiments, regardless of the details of DNA bend elasticity. In contrast, experiments sensitive to short-length-scale chain behavior can in principle reveal dramatic departures from the linear elastic behavior assumed in the WLC model. We demonstrate this explicitly by showing that our toy model can reproduce the anomalously large short-contour-length cyclization factors recently measured by Cloutier and Widom. Finally, we discuss the applicability of these models to DNA chain statistics in the context of future experiments

Biological Consequences of Tightly Bent DNA: The Other Life of a Macromolecular Celebrity

The mechanical properties of DNA play a critical role in many biological functions. For example, DNA packing in viruses involves confining the viral genome in a volume (the viral capsid) with dimensions that are comparable to the DNA persistence length. Similarly, eukaryotic DNA is packed in DNA-protein complexes (nucleosomes) in which DNA is tightly bent around protein spools. DNA is also tightly bent by many proteins that regulate transcription, resulting in a variation in gene expression that is amenable to quantitative analysis. In these cases, DNA loops are formed with lengths that are comparable to or smaller than the DNA persistence length. The aim of this review is to describe the physical forces associated with tightly bent DNA in all of these settings and to explore the biological consequences of such bending, as increasingly accessible by single-molecule techniques.Comment: 24 pages, 9 figure

Saturation Spectroscopy of Iodine in Hollow-core Optical Fibre

We present high-resolution spectroscopy of Iodine vapour that is loaded and trapped within the core of a hollow-core photonic crystal fibre (HC-PCF). We compare the observed spectroscopic features to those seen in a conventional iodine cell and show that the saturation characteristics differ significantly. Despite the confined geometry it was still possible to obtain sub-Doppler features with a spectral width of ~6 MHz with very high contrast. We provide a simple theory which closely reproduces all the key observations of the experiment.Comment: 12 pages, 7 figure

The Role of Legal Services in the Antipoverty Program

Large-scale adaptive radiations might explain the runaway success of a minority of extant vertebrate clades. This hypothesis predicts, among other things, rapid rates of morphological evolution during the early history of major groups, as lineages invade disparate ecological niches. However, few studies of adaptive radiation have included deep time data, so the links between extant diversity and major extinct radiations are unclear. The intensively studied Mesozoic dinosaur record provides a model system for such investigation, representing an ecologically diverse group that dominated terrestrial ecosystems for 170 million years. Furthermore, with 10,000 species, extant dinosaurs (birds) are the most speciose living tetrapod clade. We assembled composite trees of 614-622 Mesozoic dinosaurs/birds, and a comprehensive body mass dataset using the scaling relationship of limb bone robustness. Maximum-likelihood modelling and the node height test reveal rapid evolutionary rates and a predominance of rapid shifts among size classes in early (Triassic) dinosaurs. This indicates an early burst niche-filling pattern and contrasts with previous studies that favoured gradualistic rates. Subsequently, rates declined in most lineages, which rarely exploited new ecological niches. However, feathered maniraptoran dinosaurs (including Mesozoic birds) sustained rapid evolution from at least the Middle Jurassic, suggesting that these taxa evaded the effects of niche saturation. This indicates that a long evolutionary history of continuing ecological innovation paved the way for a second great radiation of dinosaurs, in birds. We therefore demonstrate links between the predominantly extinct deep time adaptive radiation of non-avian dinosaurs and the phenomenal diversification of birds, via continuing rapid rates of evolution along the phylogenetic stem lineage. This raises the possibility that the uneven distribution of biodiversity results not just from large-scale extrapolation of the process of adaptive radiation in a few extant clades, but also from the maintenance of evolvability on vast time scales across the history of life, in key lineages

The gold standard: accurate stellar and planetary parameters for eight Kepler M dwarf systems enabled by parallaxes

We report parallaxes and proper motions from the Hawaii Infrared Parallax Program for eight nearby M dwarf stars with transiting exoplanets discovered by Kepler. We combine our directly measured distances with mass-luminosity and radius–luminosity relationships to significantly improve constraints on the host stars’ properties. Our astrometry enables the identification of wide stellar companions to the planet hosts. Within our limited sample, all the multi-transiting planet hosts (three of three) appear to be single stars, while nearly all (four of five) of the systems with a single detected planet have wide stellar companions. By applying strict priors on average stellar density from our updated radius and mass in our transit fitting analysis, we measure the eccentricity probability distributions for each transiting planet. Planets in single-star systems tend to have smaller eccentricities than those in binaries, although this difference is not significant in our small sample. In the case of Kepler-42bcd, where the eccentricities are known to be ≃0, we demonstrate that such systems can serve as powerful tests of M dwarf evolutionary models by working in L⋆ − ρ⋆ space. The transit-fit density for Kepler- 42bcd is inconsistent with model predictions at 2.1σ (22%), but matches more empirical estimates at 0.2σ (2%), consistent with earlier results showing model radii of M dwarfs are underinflated. Gaia will provide high-precision parallaxes for the entire Kepler M dwarf sample, and TESS will identify more planets transiting nearby, late-type stars, enabling significant improvements in our understanding of the eccentricity distribution of small planets and the parameters of late-type dwarfs.Support for Program number HST-HF2-51364.001-A was provided by NASA through a grant from the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Incorporated, under NASA contract NAS5-26555.Some of the data presented in this paper were obtained from the Mikulski Archive for Space Telescopes (MAST). STScI is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS5-26555. Support for MAST for non-HST data is provided by the NASA Office of Space Science via grant NNX09AF08G and by other grants and contracts. This paper includes data collected by the Kepler mission. Funding for the Kepler mission is provided by the NASA Science Mission directorate. The authors acknowledge the Texas Advanced Computing Center (TACC) at The University of Texas at Austin for providing HPC resources that have contributed to the research results reported within this paper. URL: http://www.tacc.utexas.edu. (HST-HF2-51364.001-A - NASA through Space Telescope Science Institute; NAS5-26555 - NASA; NNX09AF08G - NASA Office of Space Science; NASA Science Mission directorate

Pharmacist-led management of chronic pain in primary care:results from a randomised controlled exploratory trial

To compare the effectiveness of pharmacist medication review, with or without pharmacist prescribing, with standard care, for patients with chronic pain