\u3cem\u3eAPOE\u3c/em\u3e and Alzheimer’s Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction

Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for late onset Alzheimer’s Disease (AD), and is associated with impairments in cerebral metabolism and cerebrovascular function. A substantial body of literature now points to E4 as a driver of multiple impairments seen in AD, including blunted brain insulin signaling, mismanagement of brain cholesterol and fatty acids, reductions in blood brain barrier (BBB) integrity, and decreased cerebral glucose uptake. Various neuroimaging techniques, in particular positron emission topography (PET) and magnetic resonance imaging (MRI), have been instrumental in characterizing these metabolic and vascular deficits associated with this important AD risk factor. In the current mini-review article, we summarize the known effects of APOE on cerebral metabolism and cerebrovascular function, with a special emphasis on recent findings via neuroimaging approaches

Oral Gavage Delivery of Stable Isotope Tracer for in Vivo Metabolomics

Stable isotope-resolved metabolomics (SIRM) is a powerful tool for understanding disease. Advances in SIRM techniques have improved isotopic delivery and expanded the workflow from exclusively in vitro applications to in vivo methodologies to study systemic metabolism. Here, we report a simple, minimally-invasive and cost-effective method of tracer delivery to study SIRM in vivo in laboratory mice. Following a brief fasting period, we orally administered a solution of [U-13C] glucose through a blunt gavage needle without anesthesia, at a physiological dose commonly used for glucose tolerance tests (2 g/kg bodyweight). We defined isotopic enrichment in plasma and tissue at 15, 30, 120, and 240 min post-gavage. 13C-labeled glucose peaked in plasma around 15 min post-gavage, followed by period of metabolic decay and clearance until 4 h. We demonstrate robust enrichment of a variety of central carbon metabolites in the plasma, brain and liver of C57/BL6 mice, including amino acids, neurotransmitters, and glycolytic and tricarboxylic acid (TCA) cycle intermediates. We then applied this method to study in vivo metabolism in two distinct mouse models of diseases known to involve dysregulation of glucose metabolism: Alzheimer’s disease and type II diabetes. By delivering [U-13C] glucose via oral gavage to the 5XFAD Alzheimer’s disease model and the Lepob/ob type II diabetes model, we were able to resolve significant differences in multiple central carbon pathways in both model systems, thus providing evidence of the utility of this method to study diseases with metabolic components. Together, these data clearly demonstrate the efficacy and efficiency of an oral gavage delivery method, and present a clear time course for 13C enrichment in plasma, liver and brain of mice following oral gavage of [U-13C] glucose—data we hope will aid other researchers in their own 13C-glucose metabolomics study design

The evolution of foresight: What is mental time travel and is it unique to humans?

In a dynamic world, mechanisms allowing prediction of future situations can provide a selective advantage. We suggest that memory systems differ in the degree of flexibility they offer for anticipatory behavior and put forward a corresponding taxonomy of prospection. The adaptive advantage of any memory system can only lie in what it contributes for future survival. The most flexible is episodic memory, which we suggest is part of a more general faculty of mental time travel that allows us not only to go back in time, but also to foresee, plan, and shape virtually any specific future event. We review comparative studies and find that, in spite of increased research in the area, there is as yet no convincing evidence for mental time travel in nonhuman animals. We submit that mental time travel is not an encapsulated cognitive system, but instead comprises several subsidiary mechanisms. A theater metaphor serves as an analogy for the kind of mechanisms required for effective mental time travel. We propose that future research should consider these mechanisms in addition to direct evidence of future-directed action. We maintain that the emergence of mental time travel in evolution was a crucial step towards our current success

The near-infrared luminosity function of cluster galaxies beyond redshift one

We determined the K band luminosity function (LF) of cluster galaxies at redshift z~1.2, using near-infrared images of three X-ray luminous clusters at z=1.11,1.24,1.27. The composite LF was derived down to M*+4, by means of statistical background subtraction, and is well described by a Schechter function with K*=20.5 AB mag and alpha=-1. From the K band composite LF we derived the stellar mass function of cluster galaxies. Using available X-ray mass profiles we determined the M/L ratios of these three clusters, which tend to be lower than those measured in the local universe. With these data, no significant difference can be seen between the shapes of the cluster galaxies LF and the LF of field galaxies at similar redshift. We also found no significant evolution out to z ~1.2 in the bright (<M*+4) part of the cluster galaxies LF probed in this study, apart from a brightening of ~1.3 mag of the characteristic magnitude of the high redshift LF. We confirm, and extend to higher redshift, the result from previous work that the redshift evolution of the characteristic magnitude M* is consistent with passive evolution of a stellar population formed at z>2. The results obtained in this work support and extend previous findings that most of the stars in bright galaxies were formed at high redshift, and that K-bright (M>10^11 Msun) galaxies were already in place at z ~ 1.2, at least in the central regions of X-ray luminous clusters. Together with recent results on the field galaxies stellar mass function, this implies that most of the stellar mass is already assembled in massive galaxies by z ~ 1, both in low and high density environments.Comment: 16 pages, 10 figures, to appear in A&

Reconstruction of a scalar-tensor theory of gravity in an accelerating universe

The present acceleration of the Universe strongly indicated by recent observational data can be modeled in the scope of a scalar-tensor theory of gravity. We show that it is possible to determine the structure of this theory (the scalar field potential and the functional form of the scalar-gravity coupling) along with the present density of dustlike matter from the following two observable cosmological functions: the luminosity distance and the linear density perturbation in the dustlike matter component as functions of redshift. Explicit results are presented in the first order in the small inverse Brans-Dicke parameter 1/omega.Comment: 4 pages, LaTeX 2.09, REVTeX 3.0, two-column forma

CANDELS Observations of the Structural Properties and Evolution of Galaxies in a Cluster at z=1.62

We discuss the structural and morphological properties of galaxies in a z=1.62 proto-cluster using near-IR imaging data from Hubble Space Telescope Wide Field Camera 3 data of the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey (CANDELS). The cluster galaxies exhibit a clear color-morphology relation: galaxies with colors of quiescent stellar populations generally have morphologies consistent with spheroids, and galaxies with colors consistent with ongoing star formation have disk-like and irregular morphologies. The size distribution of the quiescent cluster galaxies shows a deficit of compact (< 1kpc), massive galaxies compared to CANDELS field galaxies at z=1.6. As a result the cluster quiescent galaxies have larger average effective sizes compared to field galaxies at fixed mass at greater than 90% significance. Combined with data from the literature, the size evolution of quiescent cluster galaxies is relatively slow from z~1.6 to the present, growing as (1+z)^(-0.6+/-0.1). If this result is generalizable, then it implies that physical processes associated with the denser cluster region seems to have caused accelerated size growth in quiescent galaxies prior to z=1.6 and slower subsequent growth at z<1.6 compared to galaxies in the lower density field. The quiescent cluster galaxies at z=1.6 have higher ellipticities compared to lower redshift samples at fixed mass, and their surface-brightness profiles suggest that they contain extended stellar disks. We argue the cluster galaxies require dissipationless (i.e., gas-poor or "dry") mergers to reorganize the disk material and to match the relations for ellipticity, stellar mass, size, and color of early-type galaxies in z<1 clusters.Comment: Accepted for publication in ApJ. 14 pages in emulateapj format. Replacement includes improvements from referee report, and updates and additions to reference

Recommendations for exercise adherence measures in musculoskeletal settings : a systematic review and consensus meeting (protocol)

Background: Exercise programmes are frequently advocated for the management of musculoskeletal disorders; however, adherence is an important pre-requisite for their success. The assessment of exercise adherence requires the use of relevant and appropriate measures, but guidance for appropriate assessment does not exist. This research will identify and evaluate the quality and acceptability of all measures used to assess exercise adherence within a musculoskeletal setting, seeking to reach consensus for the most relevant and appropriate measures for application in research and/or clinical practice settings. Methods/design: There are two key stages to the proposed research. First, a systematic review of the quality and acceptability of measures used to assess exercise adherence in musculoskeletal disorders; second, a consensus meeting. The systematic review will be conducted in two phases and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure a robust methodology. Phase one will identify all measures that have been used to assess exercise adherence in a musculoskeletal setting. Phase two will seek to identify published and unpublished evidence of the measurement and practical properties of identified measures. Study quality will be assessed against the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) guidelines. A shortlist of best quality measures will be produced for consideration during stage two: a meeting of relevant stakeholders in the United Kingdom during which consensus on the most relevant and appropriate measures of exercise adherence for application in research and/or clinical practice settings will be sought. Discussion: This study will benefit clinicians who seek to evaluate patients’ levels of exercise adherence and those intending to undertake research, service evaluation, or audit relating to exercise adherence in the musculoskeletal field. The findings will impact upon new research studies which aim to understand the factors that predict adherence with exercise and which test different adherence-enhancing interventions. PROSPERO reference: CRD4201300621

Developing the Agile Implementation Playbook for Integrating Evidence-Based Health Care Services into Clinical Practice

Problem: Despite the more than $32 billion the National Institutes of Health has invested annually, evidence-based health care services are not reliably implemented, sustained, or distributed in health care delivery organizations, resulting in suboptimal care and patient harm. New organizational approaches and frameworks that reflect the complex nature of health care systems are needed to achieve this goal. Approach: To guide the implementation of evidence-based health care services at their institution, the authors used a number of behavioral theories and frameworks to develop the Agile Implementation (AI) Playbook, which was finalized in 2015. The AI Playbook leverages these theories in an integrated approach to selecting an evidence-based health care service to meet a specific opportunity, rapidly implementing the service, evaluating its fidelity and impact, and sustaining and scaling up the service across health care delivery organizations. The AI Playbook includes an interconnected eight-step cycle: (1) identify opportunities; (2) identify evidence-based health care services; (3) develop evaluation and termination plans; (4) assemble a team to develop a minimally viable service; (5) perform implementation sprints; (6) monitor implementation performance; (7) monitor whole system performance; and (8) develop a minimally standardized operating procedure. Outcomes: The AI Playbook has helped to improve care and clinical outcomes for intensive care unit survivors and is being used to train clinicians and scientists in AI to be quality improvement advisors. Next Steps: The authors plan to continue disseminating the details of the AI Playbook and illustrating how health care delivery organizations can successfully leverage it

Cluster galaxies in XMMU J2235-2557: galaxy population properties in most massive environments at z~1.4

We present a multi-wavelength study of galaxy populations in the core of the massive, X-ray luminous cluster XMMU J2235 at z=1.39, based on VLT and HST optical and near-infrared photometry. Luminosity functions in the z, H, and Ks bands show a faint-end slope consistent with being flat, and a characteristic magnitude M* close to passive evolution predictions of M* of local massive clusters, with a formation redshift z>2. The color-magnitude and color-mass diagrams show evidence of a tight red sequence of massive galaxies, with overall old stellar populations, generally early-type morphology, typically showing early-type spectral features and rest-frame far-UV emission consistent with very low star formation rates (SFR<0.2Msun/yr). Star forming spectroscopic members, with SFRs of up to ~100Msun/yr, are all located at clustercentric distances >~250kpc, with the central cluster region already appearing effectively quenched. Massive galaxies in the core of this cluster appear to be in an advanced evolutionary stage in terms of both star formation and mass assembly. The high-mass end of the galaxy stellar mass function is essentially already in place, and the stellar mass fraction estimated within r500 (~1%, Kroupa IMF) is already similar to that of local massive clusters. On the other hand, morphological analysis of the massive red sequence galaxies suggests that they are smaller than similarly massive local early-types. While possibly affected by systematics and biases, this result might imply that, in spite of the overall early assembly of these sources, their evolution is not complete, and processes like minor (and likely dry) merging might still shape their structural properties to resemble those of their local counterparts, without substantially affecting their stellar mass or host stellar populations.[abridged]Comment: 14 pages, 9 figures, accepted for publication in Astronomy & Astrophysic

Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis

Thyroid hormones (THs) are essential for embryonic brain development but the genetic mechanisms involved in the action of maternal THs (MTHs) are still largely unknown. As the basis for understanding the underlying genetic mechanisms of MTHs regulation we used an established zebrafish monocarboxylic acid transporter 8 (MCT8) knock-down model and characterised the transcriptome in 25hpf zebrafish embryos. Subsequent mapping of differentially expressed genes using Reactome pathway analysis together with in situ expression analysis and immunohistochemistry revealed the genetic networks and cells under MTHs regulation during zebrafish embryogenesis. We found 4,343 differentially expressed genes and the Reactome pathway analysis revealed that TH is involved in 1681 of these pathways. MTHs regulated the expression of core developmental pathways, such as NOTCH and WNT in a cell specific context. The cellular distribution of neural MTH-target genes demonstrated their cell specific action on neural stem cells and differentiated neuron classes. Taken together our data show that MTHs have a role in zebrafish neurogenesis and suggest they may be involved in cross talk between key pathways in neural development. Given that the observed MCT8 zebrafish knockdown phenotype resembles the symptoms in human patients with Allan-Herndon-Dudley syndrome our data open a window into understanding the genetics of this human congenital condition.Portuguese Fundacao para Ciencia e Tecnologia (FCT) [PTDC/EXPL/MARBIO/0430/2013]; CCMAR FCT Plurianual financing [UID/Multi/04326/2013]; FCT [SFRH/BD/111226/2015, SFRH/BD/108842/2015, SFRH/BPD/89889/2012]; FCT-IF Starting Grant [IF/01274/2014]info:eu-repo/semantics/publishedVersio