1,127 research outputs found
The pleckstrin homology domain of oxysterol-binding protein recognises a determinant specific to Golgi membranes
AbstractBackground: Peripheral membrane proteins are targeted to the cytoplasmic face of specific intracellular membranes. The organelle-specific ligands recognised by peripheral proteins include both other proteins and lipids. Oxysterol-binding protein (OSBP) translocates from the cytoplasm to the Golgi apparatus on binding oxygenated derivatives of cholesterol. The mechanism by which OSBP recognises the Golgi is unknown. It does, however, contain a pleckstrin homology (PH) domain, which in other proteins has been found to mediate regulated membrane binding, although in all previously studied examples the binding is to the plasma membrane.Results: The PH domains of OSBP and of a yeast homologue, Osh1p, were sufficient to target fusion proteins specifically to mammalian Golgi membranes. In addition, high level expression disrupted Golgi architecture and prevented forward traffic of cargo protein. In vitro, the OSBP PH domain bound to Golgi membranes in a manner apparently dependent on phosphatidylinositol-4,5-bisphosphate (Pl(4,5)P2) or a related phosphatidylinositide. The OSBP PH domain bound to Pl(4,5)P2 in liposomes with a submicromolar dissociation constant.Conclusions: The PH domains of OSBP and its yeast homologue recognise a determinant which is specific to Golgi membranes and important for Golgi function. The determinant appears to be a combination of a phosphatidylinositol polyphosphate and a second, Golgi-specific feature
Comparison of Inter and Intra-Operator Differences for Cephalometric Landmark Identification on Three-Dimensional CBCT Images using Pro Plan CMF
Objective: To establish reliability of cephalometric landmark identification in threedimensions using ProPlan CMF software.
Methods: Two orthodontist identified a series of 33 cephalometric landmarks on 20 CBCT scans of Class I, pre-orthodontic patients and repeated the landmark identification about two months later. Intraclass correlations (ICC) were calculated by landmark in the X, Y, and Z dimensions and F-test were used to assess difference in landmark location in the X, Y, and Z dimensions.
Results: The majority of landmarks had good to excellent ICC for both inter- and intraobserver reliability. F-test also showed the majority of landmarks had no significant difference between the observers.
Conclusion: Most landmarks showed good to very good reliability and reproducibility using ProPlan CMF, with some landmarks proving more reliable than others and further research is needed to establish the utility and practicality of three-dimensional cephalometrics as a common diagnostic tool in orthodontics
A Double-Blind, Placebo-Controlled Withdrawal Trial of Dexmethylphenidate Hydrochloride in Children with Attention Deficit Hyperactivity Disorder
Objectives:
d,l-threo-methylphenidate HCl (d,l-MPH) is the most common treatment of attention deficit
hyperactivity disorder (ADHD). A previous report showed placebo-controlled efficacy for the purified disomer
(dexmethylphenidate hydrochloride, d-MPH, Focalinâą) with a 2:1 potency compared to dl, and
suggested a 6-hour duration of action. This study complements that report by studying the effect of
placebo-controlled discontinuation and retesting the duration of action.
Methods:
A 6-week, open-label titration of d-MPH (2.5â10 mg twice-a-day) was followed by a doubleblind,
placebo-controlled, 2-week withdrawal study of responders.
Results:
In the open titration, 82% of the 89 enrolled patients achieved a Clinical Global Impressionâ
Improvement (CGI-I) rating of much or very much improved. Only 5 patients discontinued for adverse
events. Seventy-five patients continued into the placebo-controlled discontinuation. For the randomly
assigned d-MPH (n = 35) and placebo (n = 40) groups, mean ages, respectively, were 10.1 ± 2.9 and 9.9 ±
2.7 years, 86% and 78% were male, and 70.6% and 80.0% took the ceiling dose of 10 mg twice-daily,
respectively. Each group had 80% combined-type ADHD and 20% inattentive type. By the end of the 2-
week, placebo-masked withdrawal, significantly more placebo patients (24 of 39) than d-MPH continuers
(6 of 35) relapsed (61.5% versus 17.1%, p = 0.001). Compared to d-MPH continuers, placebo patients
deteriorated significantly more in the 2-week period on teacher ratings of the 18 ADHD symptoms rated 0â
3 (p = 0.028), the 3 p.m. and 6 p.m. parent ADHD symptom ratings (p = 0.0026 and p = 0.0381,
respectively), and clinic (2â3 p.m.) and home (6 p.m.) Math Tests (p = 0.024 and p < 0.0001, respectively).
The 6 p.m. scores replicated the significant effect at 6 hours reported in the previous study.
Conclusions:
d-MPH is safe, tolerable, and effective, with a 6-hour duration of effect suggested by the
significant difference from placebo at 6 hours on a double-blind discontinuation
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Mooring observations from the Oregon continental shelf : April-September 1999 : a component of the prediction of wind-driven coastal circulation project
This report documents oceanographic and meteorological measurements made from instruments deployed on four moorings over the continental shelf west of Oregon, from spring through
summer, 1999. These moorings were a component of an observational and numerical modeling program to study the response of the coastal ocean to wind forcing.
The Dynamics and Prediction of Wind-Driven Coastal Circulation was funded by the National Oceanographic Partnership Program (NOPP) with the principal goal to develop nowcast and
forecast systems for wind-driven coastal flow fields. The observational program was designed to provide measurements that would allow testing and improvement of the modeling capability.
See http://www.oce.orst.edu/po/research/nopp/, http://diana.OCE.ORST.EDU/cmoweb/nopp/,
and Austin et al. (2000) for description of the modeling program and a description of other
aspects of the observational program.
This report is divided into two sections. The first section contains descriptions of the
instrumentation deployed on the NOPP moorings including locations, sampling rates, and
calibrations. The second section contains plots of the observations. Several views of the time
series recorded by the moorings are presented. Time series of vertically separated velocity,
temperature, and salinity are shown for each mooring. Velocity and temperature observations from the same depth on horizontally separated moorings are also shown. These data are
presented as both 40-hour low-pass filtered and 1-hour low-pass filtered time series. Time is
given as day of year 1999 in all of the time series plots; conversion to calendar date is provided in Table 5
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Observations from moorings on the Oregon continental shelf, January - March 2003 : a component of the Coastal Ocean Advances in Shelf Transport (COAST) experiment
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A modified law-of-the-wall applied to oceanic bottom boundary layers
Near the bottom, the velocity profile in the bottom boundary layer over the continental
shelf exhibits a characteristic law-of-the-wall that is consistent with local estimates of
friction velocity from near-bottom turbulence measurements. Farther from the bottom, the
velocity profile exhibits a deviation from the law-of-the-wall. Here the velocity gradient
continues to decrease with height but at a rate greater than that predicted by the law-of-the-wall
with the local friction velocity. We argue that the shape of the velocity profile is
made consistent with the local friction velocity by the introduction of a new length scale
that, near the boundary, asymptotes to a value that varies linearly from the bottom. Farther
from the boundary, this length scale is consistent with the suppression of velocity
fluctuations either by stratification in the upper part of the boundary layer or by proximity
to the free surface. The resultant modified law-of-the-wall provides a good representation
of velocity profiles observed over the continental shelf when a local estimate of the
friction velocity from coincident turbulence observations is used. The modified law-of-the-
wall is then tested on two very different sets of observations, from a shallow tidal
channel and from the bottom of the Mediterranean outflow plume. In both cases it is
argued that the observed velocity profile is consistent with the modified law-of-the-wall.
Implicit in the modified law-of-the-wall is a new scaling for turbulent kinetic energy
dissipation rate. This new scaling diverges from the law-of-the-wall prediction above 0.2D
(where D is the thickness of the bottom boundary layer) and agrees with observed profiles
to 0.6D
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Convectively Driven Mixing in the Bottom Boundary Layer
Closely spaced vertical profiles through the bottom boundary layer over a sloping continental shelf during relaxation from coastal upwelling reveal structure that is consistent with convectively driven mixing. Parcels of fluid were observed adjacent to the bottom that were warm (by several millikelvin) relative to fluid immediately above. On average, the vertical gradient of potential temperature in the superadiabatic (statically unstable) bottom layer was found to be â1.7 Ă 10â»âŽ K mâ»Âč, or 6.0 Ă 10â»â” kg mâ»âŽ in potential density. Turbulent dissipation rates (Δ) increased toward the bottom but were relatively constant over the dimensionless depth range 0.4â1.0z/D (where D is the mixed layer height). The Rayleigh number Ra associated with buoyancy anomalies in the bottom mixed layer is estimated to be approximately 10ÂčÂč, much larger than the value of approximately 10Âł required to initiate convection in simple laboratory or numerical experiments. An evaluation of the data in which the bottom boundary layer was unstably stratified indicates that the greater the buoyancy anomaly is, the greater the turbulent dissipation rate in the neutral layer away from the bottom will be. The vertical structures of averaged profiles of potential density, potential temperature, and turbulent dissipation rate versus nondimensional depth are similar to their distinctive structure in the upper ocean during convection. Nearby moored observations indicate that periods of static instability near the bottom follow events of northward flow and local fluid warming by lateral advection. The rate of local fluid warming is consistent with several estimates of offshore buoyancy transport near the bottom. It is suggested that the concentration of offshore Ekman transport near the bottom of the Ekman layer when the flow atop the layer is northward can provide the differential transport of buoyant bottom fluid when the density in the bottom boundary layer decreases up the slope
CTGF drives autophagy, glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growth
Previous studies have demonstrated that loss of caveolin-1 (Cav-1) in stromal cells drives the activation of the TGF-ÎČ signaling, with increased transcription of TGF-ÎČ target genes, such as connective tissue growth factor (CTGF). In addition, loss of stromal Cav-1 results in the metabolic reprogramming of cancer-associated fibroblasts, with the induction of autophagy and glycolysis. However, it remains unknown if activation of the TGF-ÎČ / CTGF pathway regulates the metabolism of cancer-associated fibroblasts. Therefore, we investigated whether CTGF modulates metabolism in the tumor microenvironment. For this purpose, CTGF was overexpressed in normal human fibroblasts or MDA-MB-231 breast cancer cells. Overexpression of CTGF induces HIF-1α-dependent metabolic alterations, with the induction of autophagy/mitophagy, senescence, and glycolysis. Here, we show that CTGF exerts compartment-specific effects on tumorigenesis, depending on the cell-type. In a xenograft model, CTGF overexpressing fibroblasts promote the growth of co-injected MDA-MB-231 cells, without any increases in angiogenesis. Conversely, CTGF overexpression in MDA-MB-231 cells dramatically inhibits tumor growth in mice. Intriguingly, increased extracellular matrix deposition was seen in tumors with either fibroblast or MDA-MB-231 overexpression of CTGF. Thus, the effects of CTGF expression on tumor formation are independent of its extracellular matrix function, but rather depend on its ability to activate catabolic metabolism. As such, CTGF-mediated induction of autophagy in fibroblasts supports tumor growth via the generation of recycled nutrients, whereas CTGF-mediated autophagy in breast cancer cells suppresses tumor growth, via tumor cell self-digestion. Our studies shed new light on the compartment-specific role of CTGF in mammary tumorigenesis, and provide novel insights into the mechanism(s) generating a lethal tumor microenvironment in patients lacking stromal Cav-1. As loss of Cav-1 is a stromal marker of poor clinical outcome in women with primary breast cancer, dissecting the downstream signaling effects of Cav-1 are important for understanding disease pathogenesis, and identifying novel therapeutic targets
Progression of mitral regurgitation in rheumatic valve disease : role of left atrial remodeling
Introduction: Mitral regurgitation (MR) is the most common valve abnormality in rheumatic heart disease (RHD) often associated with stenosis. Although the mechanism by which MR develops in RHD is primary, longstanding volume overload with left atrial (LA) remodeling may trigger the development of secondary MR, which can impact on the overall progression of MR. This study is aimed to assess the incidence and predictors of MR progression in patients with RHD. Methods: Consecutive RHD patients with non-severe MR associated with any degree of mitral stenosis were selected. The primary endpoint was a progression of MR, which was defined as an increase of one grade in MR severity from baseline to the last follow-up echocardiogram. The risk of MR progression was estimated accounting for competing risks. Results: The study included 539 patients, age of 46.2 ± 12 years and 83% were women. At a mean follow-up time of 4.2 years (interquartile range [IQR]: 1.2â6.9 years), 54 patients (10%) displayed MR progression with an overall incidence of 2.4 per 100 patient-years. Predictors of MR progression by the Cox model were age (adjusted hazard ratio [HR] 1.541, 95% CI 1.222â1.944), and LA volume (HR 1.137, 95% CI 1.054â1.226). By considering competing risk analysis, the direction of the association was similar for the rate (Cox model) and incidence (Fine-Gray model) of MR progression. In the model with LA volume, atrial fibrillation (AF) was no longer a predictor of MR progression. In the subgroup of patients in sinus rhythm, 59 had an onset of AF during follow-up, which was associated with progression of MR (HR 2.682; 95% CI 1.133â6.350). Conclusions: In RHD patients with a full spectrum of MR severity, progression of MR occurs over time is predicted by age and LA volume. LA enlargement may play a role in the link between primary MR and secondary MR in patients with RHD
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