Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.

Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia

SAMHD1 Phosphorylation Coordinates the Anti-HIV-1 Response by Diverse Interferons and Tyrosine Kinase Inhibition.

Macrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1. Here we show that stimulation by type I, type II, and to a lesser degree, type III interferons share activation of SAMHD1 via dephosphorylation at threonine-592 as a consequence of signaling. Cyclin-dependent kinase 1 (CDK1), a known effector kinase for SAMHD1, was downregulated at the protein level by all IFN types tested. Pharmacologic inhibition or small interfering RNA (siRNA)-mediated knockdown of CDK1 phenocopied the effects of IFN on SAMHD1. A panel of FDA-approved tyrosine kinase inhibitors potently induced activation of SAMHD1 and subsequent HIV-1 inhibition. The viral restriction imposed via IFNs or dasatinib could be overcome through depletion of SAMHD1, indicating that their effects are exerted primarily through this pathway. Our results demonstrate that SAMHD1 activation, but not transcriptional upregulation or protein induction, is the predominant mechanism of HIV-1 restriction induced by type I, type II, and type III IFN signaling in macrophages. Furthermore, SAMHD1 activation presents a pharmacologically actionable target through which HIV-1 infection can be subverted

Gibbons-Hawking Boundary Terms and Junction Conditions for Higher-Order Brane Gravity Models

We derive the most general junction conditions for the fourth-order brane gravity constructed of arbitrary functions of curvature invariants. We reduce these fourth-order theories to second order theories at the expense of introducing new scalar and tensor fields - the scalaron and the tensoron. In order to obtain junction conditions we apply the method of generalized Gibbons-Hawking boundary terms which are appended to the appropriate actions. After assuming the continuity of the scalaron and the tensoron on the brane, we recover junction conditions for such general brane universe models previously obtained by different methods. The derived junction conditions can serve studying the cosmological implications of the higher-order brane gravity models.Comment: REVTEX4, 6 pages, no figures, version to match a JCAP accepted pape

The Shared Health Appointments and Reciprocal Enhanced Support (SHARES) study: study protocol for a randomized trial

Abstract Background Diabetes shared medical appointments (SMAs) and reciprocal peer support programs have been found in efficacy trials to help adults with diabetes improve their self-management and achieve short-term gains in clinical and patient-centered outcomes. In order to translate this evidence to system-level interventions, there is a need for large-scale, pragmatic trials that examine the effectiveness, implementation, and costs of SMAs and reciprocal peer support across diverse settings. Methods The Shared Health Appointments and Reciprocal Enhanced Support (SHARES) study is a multisite, cluster randomized trial that is evaluating the effectiveness and implementation of SMAs with and without an additional reciprocal Peer-to-Peer (P2P) support program, when compared to usual care. The P2P program comprises periodic peer support group sessions and telephone contact between SMA participant pairs to promote more effective diabetes self-management. We will examine outcomes across three different treatment groups: (1) SMAs, (2) SMAs plus P2P, and (3) usual care. We will collect and analyze data over a 2.5-year implementation period at five geographically diverse Veterans Affairs (VA) health systems. The primary outcome is the relative change in hemoglobin A1c over time. Secondary outcomes are changes in systolic blood pressure, antihypertensive medication use, statin use, and insulin initiation over the study period. The unit of analysis is the individual, adjusted by the individual’s SMA group (the cluster). We will use mixed methods to rigorously evaluate processes and costs of implementing these programs in each of the clinic settings. Discussion We hypothesize that patients will experience improved outcomes immediately following participation in SMAs and that augmenting SMAs with reciprocal peer support will help to maintain these gains over time. The results of this study will be among the first to examine the effects of diabetes SMAs alone and in conjunction with P2P in a range of real-life clinical settings. In addition, the study will provide important information on contextual factors associated with successful program implementation. Trial registration ClinicalTrials.gov, ID: NCT02132676 . Registered on 21 August 2013.https://deepblue.lib.umich.edu/bitstream/2027.42/136794/1/13063_2017_Article_1959.pd

What Is the Profile of Overweight Individuals Who Are Unsuccessful Responders to a Low-Energy Diet? A PREVIEW Sub-study

This study was performed to evaluate the profile of overweight individuals with pre-diabetes enrolled in PREVIEW who were unable to achieve a body weight loss of >= 8% of the baseline value in response to a 2-month low-energy diet (LED). Their baseline profile reflected potential stress-related vulnerability that predicted a reduced response of body weight to a LED programme. The mean daily energy deficit maintained by unsuccessful weight responders of both sexes was less than the estimated level in successful female (656 vs. 1,299 kcal, p < 0.01) and male (815 vs. 1,659 kcal, p < 0.01) responders. Despite this smaller energy deficit, unsuccessful responders displayed less favorable changes in susceptibility to hunger and appetite sensations. They also did not benefit from the intervention regarding the ability to improve sleep quality. In summary, these results show that some individuals display a behavioral vulnerability which may reduce the ability to lose weight in response to a diet-based weight loss program. They also suggest that this vulnerability may be accentuated by a prolonged diet restriction.Peer reviewe

Three New Eclipsing White-dwarf - M-dwarf Binaries Discovered in a Search for Transiting Planets Around M-dwarfs

We present three new eclipsing white-dwarf / M-dwarf binary systems discovered during a search for transiting planets around M-dwarfs. Unlike most known eclipsing systems of this type, the optical and infrared emission is dominated by the M-dwarf components, and the systems have optical colors and discovery light curves consistent with being Jupiter-radius transiting planets around early M-dwarfs. We detail the PTF/M-dwarf transiting planet survey, part of the Palomar Transient Factory (PTF). We present a Graphics Processing Unit (GPU)-based box-least-squares search for transits that runs approximately 8X faster than similar algorithms implemented on general purpose systems. For the discovered systems, we decompose low-resolution spectra of the systems into white-dwarf and M-dwarf components, and use radial velocity measurements and cooling models to estimate masses and radii for the white dwarfs. The systems are compact, with periods between 0.35 and 0.45 days and semimajor axes of approximately 2 solar radii (0.01 AU). We use the Robo-AO laser guide star adaptive optics system to tentatively identify one of the objects as a triple system. We also use high-cadence photometry to put an upper limit on the white dwarf radius of 0.025 solar radii (95% confidence) in one of the systems. We estimate that 0.08% (90% confidence) of M-dwarfs are in these short-period, post-common-envelope white-dwarf / M-dwarf binaries where the optical light is dominated by the M-dwarf. Similar eclipsing binary systems can have arbitrarily small eclipse depths in red bands and generate plausible small-planet-transit light curves. As such, these systems are a source of false positives for M-dwarf transiting planet searches. We present several ways to rapidly distinguish these binaries from transiting planet systems.Comment: 14 pages, 14 figures, submitted to Ap

Ecological inference using data from accelerometers needs careful protocols

1. Accelerometers in animal-attached tags are powerful tools in behavioural ecology, they can be used to determine behaviour and provide proxies for movement-based energy expenditure. Researchers are collecting and archiving data across systems, seasons and device types. However, using data repositories to draw ecological inference requires a good understanding of the error introduced according to sensor type and position on the study animal and protocols for error assessment and minimisation. 2. Using laboratory trials, we examine the absolute accuracy of tri-axial accelerometers and determine how inaccuracies impact measurements of dynamic body acceleration (DBA), a proxy for energy expenditure, in human participants. We then examine how tag type and placement affect the acceleration signal in birds, using pigeons Columba livia flying in a wind tunnel, with tags mounted simultaneously in two positions, and back- and tail-mounted tags deployed on wild kittiwakes Rissa tridactyla. Finally, we present a case study where two generations of tag were deployed using different attachment procedures on red-tailed tropicbirds Phaethon rubricauda foraging in different seasons. 3. Bench tests showed that individual acceleration axes required a two-level correction to eliminate measurement error. This resulted in DBA differences of up to 5% between calibrated and uncalibrated tags for humans walking at a range of speeds. Device position was associated with greater variation in DBA, with upper and lower back-mounted tags varying by 9% in pigeons, and tail- and back-mounted tags varying by 13% in kittiwakes. The tropicbird study highlighted the difficulties of attributing changes in signal amplitude to a single factor when confounding influences tend to covary, as DBA varied by 25% between seasons. 4. Accelerometer accuracy, tag placement and attachment critically affect the signal amplitude and thereby the ability of the system to detect biologically meaningful phenomena. We propose a simple method to calibrate accelerometers that can be executed under field conditions. This should be used prior to deployments and archived with resulting data. We also suggest a way that researchers can assess accuracy in previously collected data, and caution that variable tag placement and attachment can increase sensor noise and even generate trends that have no biological meaning

A collaborative approach to adopting/adapting guidelines - the Australian 24-hour Movement Guidelines for the early years (birth to 5 years): an integration of physical activity, sedentary behavior, and sleep

BACKGROUND: In 2017, the Australian Government funded the update of the National Physical Activity Recommendations for Children 0-5&nbsp;years, with the intention that they be an integration of movement behaviours across the 24-h period. The benefit for Australia was that it could leverage research in Canada in the development of their 24-h guidelines for the early years. Concurrently, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group published a model to produce guidelines based on adoption, adaption and/or de novo development using the GRADE evidence-to-decision framework. Referred to as the GRADE-ADOLOPMENT approach, it allows guideline developers to follow a structured and transparent process in a more efficient manner, potentially avoiding the need to unnecessarily repeat costly tasks such as conducting systematic reviews. The purpose of this paper is to outline the process and outcomes for adapting the Canadian 24-Hour Movement Guidelines for the Early Years to develop the Australian 24-Hour Movement Guidelines for the Early Years guided by the GRADE-ADOLOPMENT framework. METHODS: The development process was guided by the GRADE-ADOLOPMENT approach. A Leadership Group and Consensus Panel were formed and existing credible guidelines identified. The draft Canadian 24-h integrated movement guidelines for the early years best met the criteria established by the Panel. These were evaluated based on the evidence in the GRADE tables, summaries of findings tables and draft recommendations from the Canadian Draft Guidelines. Updates to each of the Canadian systematic reviews were conducted and the Consensus Panel reviewed the evidence for each behaviour separately and made a decision to adopt or adapt the Canadian recommendations for each behaviour or create de novo recommendations. An online survey was then conducted (n&nbsp;=&nbsp;302) along with five focus groups (n&nbsp;=&nbsp;30) and five key informant interviews (n&nbsp;=&nbsp;5) to obtain feedback from stakeholders on the draft guidelines. RESULTS: Based on the evidence from the Canadian systematic reviews and the updated systematic reviews in Australia, the Consensus Panel agreed to adopt the Canadian recommendations and, apart from some minor changes to the wording of good practice statements, keep the wording of the guidelines, preamble and title of the Canadian Guidelines. The Australian Guidelines provide evidence-informed recommendations for a healthy day (24-h), integrating physical activity, sedentary behaviour (including limits to screen time), and sleep for infants (&lt;1&nbsp;year), toddlers (1-2&nbsp;years) and preschoolers (3-5&nbsp;years). CONCLUSIONS: To our knowledge, this is only the second time the GRADE-ADOLOPMENT approach has been used. Following this approach, the judgments of the Australian Consensus Panel did not differ sufficiently to change the directions and strength of the recommendations and as such, the Canadian recommendations were adopted with very minor alterations. This allowed the Guidelines to be developed much faster and at lower cost. As such, we would recommend the GRADE-ADOLOPMENT approach, especially if a credible set of guidelines, with all supporting materials and developed using a transparent process, is available. Other countries may consider using this approach when developing and/or revising national movement guidelines

Testing an Emerging Paradigm in Migration Ecology Shows Surprising Differences in Efficiency between Flight Modes

To maximize fitness, flying animals should maximize flight speed while minimizing energetic expenditure. Soaring speeds of large-bodied birds are determined by flight routes and tradeoffs between minimizing time and energetic costs. Large raptors migrating in eastern North America predominantly glide between thermals that provide lift or soar along slopes or ridgelines using orographic lift (slope soaring). It is usually assumed that slope soaring is faster than thermal gliding because forward progress is constant compared to interrupted progress when birds pause to regain altitude in thermals. We tested this slope-soaring hypothesis using high-frequency GPS-GSM telemetry devices to track golden eagles during northbound migration. In contrast to expectations, flight speed was slower when slope soaring and eagles also were diverted from their migratory path, incurring possible energetic costs and reducing speed of progress towards a migratory endpoint. When gliding between thermals, eagles stayed on track and fast gliding speeds compensated for lack of progress during thermal soaring. When thermals were not available, eagles minimized migration time, not energy, by choosing energetically expensive slope soaring instead of waiting for thermals to develop. Sites suited to slope soaring include ridges preferred for wind-energy generation, thus avian risk of collision with wind turbines is associated with evolutionary trade-offs required to maximize fitness of time-minimizing migratory raptors

Isolation of Proteinase K-Sensitive Prions Using Pronase E and Phosphotungstic Acid

Disease-related prion protein, PrPSc, is classically distinguished from its normal cellular precursor, PrPC, by its detergent insolubility and partial resistance to proteolysis. Molecular diagnosis of prion disease typically relies upon detection of protease-resistant fragments of PrPSc using proteinase K, however it is now apparent that the majority of disease-related PrP and indeed prion infectivity may be destroyed by this treatment. Here we report that digestion of RML prion-infected mouse brain with pronase E, followed by precipitation with sodium phosphotungstic acid, eliminates the large majority of brain proteins, including PrPC, while preserving >70% of infectious prion titre. This procedure now allows characterization of proteinase K-sensitive prions and investigation of their clinical relevance in human and animal prion disease without being confounded by contaminating PrPC