Molecular mechanisms that regulate the coupled period of the mammalian circadian clock

In mammals, most cells in the brain and peripheral tissues generate circadian (~24hr) rhythms autonomously. These self-sustained rhythms are coordinated and entrained by a master circadian clock in the suprachiasmatic nucleus (SCN). Within the SCN, the individual rhythms of each neuron are synchronized through intercellular signaling. One important feature of SCN is that the synchronized period is close to the cell population mean of intrinsic periods. In this way, the synchronized period of the SCN stays close to the periods of cells in peripheral tissues. This is important for SCN to entrain cells throughout the body. However, the mechanism that drives the period of the coupled SCN cells to the population mean is not known. We use mathematical modeling and analysis to show that the mechanism of transcription repression plays a pivotal role in regulating the coupled period. Specifically, we use phase response curve analysis to show that the coupled period within the SCN stays near the population mean if transcriptional repression occurs via protein sequestration. In contrast, the coupled period is far from the mean if repression occurs through highly nonlinear Hill-type regulation (e.g. oligomer- or phosphorylation-based repression). Furthermore, we find that the timescale of intercellular coupling needs to be fast compared to that of intracellular feedback to maintain the mean period. These findings reveal the important relationship between the intracellular transcriptional feedback loop and intercellular coupling. This relationship explains why transcriptional repression appears to occur via protein sequestration in multicellular organisms, mammals and Drosophila, in contrast with the phosphorylation-based repression in unicellular organisms. That is, transition to protein sequestration is essential for synchronizing multiple cells with a period close to the population mean (~24hr).Comment: 21 pages, 16 figure

Long-term biocompatibility, imaging appearance and tissue effects associated with delivery of a novel radiopaque embolization bead for image-guided therapy

The objective of this study was to undertake a comprehensive long-term biocompatibility and imaging assessment of a new intrinsically radiopaque bead (LC Bead LUMI™) for use in transarterial embolization. The sterilized device and its extracts were subjected to the raft of ISO10993 biocompatibility tests that demonstrated safety with respect to cytotoxicity, mutagenicity, blood contact, irritation, sensitization, systemic toxicity and tissue reaction. Intra-arterial administration was performed in a swine model of hepatic arterial embolization in which 0.22–1 mL of sedimented bead volume was administered to the targeted lobe(s) of the liver. The beads could be visualized during the embolization procedure with fluoroscopy, DSA and single X-ray snapshot imaging modalities. CT imaging was performed before and 1 h after embolization and then again at 7, 14, 30 and 90 days. LC Bead LUMI™ could be clearly visualized in the hepatic arteries with or without administration of IV contrast and appeared more dense than soluble contrast agent. The CT density of the beads did not deteriorate during the 90 day evaluation period. The beads embolized predictably and effectively, resulting in areas devoid of contrast enhancement on CT imaging suggesting ischaemia-induced necrosis nearby the sites of occlusion. Instances of off target embolization were easily detected on imaging and confirmed pathologically. Histopathology revealed a classic foreign body response at 14 days, which resolved over time leading to fibrosis and eventual integration of the beads into the tissue, demonstrating excellent long-term tissue compatibility

Investigation of Nondestructive Testing Methods for Friction Stir Welding

Friction stir welding is a method of materials processing that enables the joining of similar and dissimilar materials. The process, as originally designed by The Welding Institute (TWI), provides a unique approach to manufacturing—where materials can be joined in many designs and still retain mechanical properties that are similar to, or greater than, other forms of welding. This process is not free of defects that can alter, limit, and occasionally render the resulting weld unusable. Most common amongst these defects are kissing bonds, wormholes and cracks that are often hidden from visual inspection. To identify these defects, various nondestructive testing methods are being used. This paper presents background to the process of friction stir welding and identifies major process parameters that affect the weld properties, the origin, and types of defects that can occur, and potential nondestructive methods for ex-situ detection and in-situ identification of these potential defects, which can then allow for corrective action to be taken

A comparative study of WASP-67b and HAT-P-38b from WFC3 data

Atmospheric temperature and planetary gravity are thought to be the main parameters affecting cloud formation in giant exoplanet atmospheres. Recent attempts to understand cloud formation have explored wide regions of the equilibrium temperature-gravity parameter space. In this study, we instead compare the case of two giant planets with nearly identical equilibrium temperature ($T_\mathrm{eq}$ $\sim 1050 \, \mathrm{K}$) and gravity ($g \sim 10 \, \mathrm{m \, s}^{-1})$. During $HST$ Cycle 23, we collected WFC3/G141 observations of the two planets, WASP-67 b and HAT-P-38 b. HAT-P-38 b, with mass 0.42 M$_\mathrm{J}$ and radius 1.4 $R_\mathrm{J}$, exhibits a relatively clear atmosphere with a clear detection of water. We refine the orbital period of this planet with new observations, obtaining $P = 4.6403294 \pm 0.0000055 \, \mathrm{d}$. WASP-67 b, with mass 0.27 M$_\mathrm{J}$ and radius 0.83 $R_\mathrm{J}$, shows a more muted water absorption feature than that of HAT-P-38 b, indicating either a higher cloud deck in the atmosphere or a more metal-rich composition. The difference in the spectra supports the hypothesis that giant exoplanet atmospheres carry traces of their formation history. Future observations in the visible and mid-infrared are needed to probe the aerosol properties and constrain the evolutionary scenario of these planets.Comment: 16 pages, 17 figures, 8 tables, accepted for publication in The Astronomical Journa

A Neutron Star Binary Merger Model for GW170817/GRB170817a/SSS17a

The merging neutron star gravitational wave event GW170817 has been observed throughout the entire electromagnetic spectrum from radio waves to $\gamma$-rays. The resulting energetics, variability, and light curves are shown to be consistent with GW170817 originating from the merger of two neutron stars, in all likelihood followed by the prompt gravitational collapse of the massive remnant. The available $\gamma$-ray, X-ray and radio data provide a clear probe for the nature of the relativistic ejecta and the non-thermal processes occurring within, while the ultraviolet, optical and infrared emission are shown to probe material torn during the merger and subsequently heated by the decay of freshly synthesized $r$-process material. The simplest hypothesis that the non-thermal emission is due to a low-luminosity short $\gamma$-ray burst (sGRB) seems to agree with the present data. While low luminosity sGRBs might be common, we show here that the collective prompt and multi-wavelength observations are also consistent with a typical, powerful sGRB seen off-axis. Detailed follow-up observations are thus essential before we can place stringent constraints on the nature of the relativistic ejecta in GW170817.Comment: 9 pages, 5 figures, accepted to ApJ Letter

A Resident-Based Reimbursement System for Intermediate Care Facilities for the Mentally Retarded

In this article, the authors present a resident-based reimbursement system for intermediate care facilities for the mentally retarded (ICFs-MR), which represent a large and growing proportion of the Medicaid budget. The statistical relationship between resident disability level and the expected cost of caring for the individual is estimated, allowing for the prediction of expected resource use across the population of ICF-MR residents. The system incorporates an indirect cost rate, a base direct care rate (constant across all providers), and an individual-specific direct care rate, based on the expected cost of care

Electromagnetic Evidence that SSS17a is the Result of a Binary Neutron Star Merger

11 hours after the detection of gravitational wave source GW170817 by the Laser Interferometer Gravitational-Wave Observatory and Virgo Interferometers, an associated optical transient SSS17a was discovered in the galaxy NGC 4993. While the gravitational wave data indicate GW170817 is consistent with the merger of two compact objects, the electromagnetic observations provide independent constraints of the nature of that system. Here we synthesize all optical and near-infrared photometry and spectroscopy of SSS17a collected by the One-Meter Two-Hemisphere collaboration. We find that SSS17a is unlike other known transients. The source is best described by theoretical models of a kilonova consisting of radioactive elements produced by rapid neutron capture (the r-process). We find that SSS17a was the result of a binary neutron star merger, reinforcing the gravitational wave result.Comment: 21 pages, 4 figures, accepted to Scienc

Endoplasmic reticulum and lysosomal Ca2+ stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts.

Mutations in β-glucocerebrosidase (encoded by GBA1) cause Gaucher disease (GD), a lysosomal storage disorder, and increase the risk of developing Parkinson disease (PD). The pathogenetic relationship between the two disorders is unclear. Here, we characterised Ca2+ release in fibroblasts from type I GD and PD patients together with age-matched, asymptomatic carriers, all with the common N370S mutation in β-glucocerebrosidase. We show that endoplasmic reticulum (ER) Ca2+ release was potentiated in GD and PD patient fibroblasts but not in cells from asymptomatic carriers. ER Ca2+ signalling was also potentiated in fibroblasts from aged healthy subjects relative to younger individuals but not further increased in aged PD patient cells. Chemical or molecular inhibition of β-glucocerebrosidase in fibroblasts and a neuronal cell line did not affect ER Ca2+ signalling suggesting defects are independent of enzymatic activity loss. Conversely, lysosomal Ca2+ store content was reduced in PD fibroblasts and associated with age-dependent alterations in lysosomal morphology. Accelerated remodelling of Ca2+ stores by pathogenic GBA1 mutations may therefore feature in PD