Rapid effects of 1alpha,25-dihydroxyvitamin D3 on osteoblasts: Studies of membrane transducers that affect calcium signals

1,25-dihydroxyvitamin D3 [1,25(OH)2D 3] exerts pleiotropic effects on osteoblasts via both long-term nuclear receptor-mediated and rapid membrane-initiated pathways during bone remodeling and mineral homeostasis. This study explored the membrane transducers that mediate rapid effects of 1,25(OH)2D3 on osteoblasts, including sphingomyelinase (SMase) and L-type voltage sensitive calcium channels (VSCCs). ^ It was previously demonstrated that 1,25(OH)2D3 stimulates transmembrane influx of Ca2+ through VSCCs in ROS 17/2.8 osteoblasts, however the molecular identity of 1,25(OH)2D 3-regulated VSCC has not been known. In this study, on the basis of in vitro tests of three unique ribozymes specifically cleaving a1C mRNA, I transfected ROS 17/2.8 cells with vectors coding recombinant ribozyme modified with U1 snRNA structure, and successfully selected stable clonal cells in which the expression of a1C was strikingly reduced. Ca2+ influx studies in these cells compared to control transfectants showed selective attenuation of depolarization- and 1,25(OH)2D3-regulated Ca2+ responses. These results allow us to conclude that the cardiac ( a1C ) subtype of the L-type VSCC is the major membrane transducer of Ca 2+ influx in osteoblasts. ^ I also demonstrated that 1,25(OH)2D3 induces a rapid hydrolysis of membrane sphingomyelin (SM) in ROS 17/2.8 cells, with the concomitant generation of ceramide, detectable at 15 minute, and maximal at 1 hour after addition. Sphingosine, sphingosine-1-phosphate (SPP) and sphingosylphosphorylcholine (SPC), downstream products of SM hydrolysis, but not ceramide, elicit Ca 2+ release from intracellular stores. Considering ceramide, sphingosine, and SPP as second messengers modulating intracellular kinases or phosphatases, these findings implicate sphingolipid-signaling pathways in transducing rapid effects of 1,25(OH)2D3 on osteoblasts. In structure/function analyses of sphingolipid signaling, it was observed that psychosine elicits Ca2+ release from intracellular stores. This challenges the dogma that sphingosine phosphorylation permits mobilization of Ca2+ , because psychosine is a sphingosine analog galactosylated at 1-carbon, preventing phosphorylation at that site. Psychosine is the pathological metabolite found in patients with Krabbe's disease, suggesting that psychosine disrupts the physiological sphingolipid signaling by chronic release of Ca2+ from intracellular stores. ^ Slower SM turnover than Ca2+ influx through VSCCs in response to 1,25(OH)2D3 demonstrates ceramide does not mediate the 1,25(OH)2D3-induced Ca2+ signaling, a conclusion endorsed further by the failure of ceramide to induce Ca 2+ signaling. ^

Effect of nonnormal random components on level and power in group-randomized trials

The use of group-randomized trials is particularly widespread in the evaluation of health care, educational, and screening strategies. Group-randomized trials represent a subset of a larger class of designs often labeled nested, hierarchical, or multilevel and are characterized by the randomization of intact social units or groups, rather than individuals. The application of random effects models to group-randomized trials requires the specification of fixed and random components of the model. The underlying assumption is usually that these random components are normally distributed. This research is intended to determine if the Type I error rate and power are affected when the assumption of normality for the random component representing the group effect is violated. ^ In this study, simulated data are used to examine the Type I error rate, power, bias and mean squared error of the estimates of the fixed effect and the observed intraclass correlation coefficient (ICC) when the random component representing the group effect possess distributions with non-normal characteristics, such as heavy tails or severe skewness. The simulated data are generated with various characteristics (e.g. number of schools per condition, number of students per school, and several within school ICCs) observed in most small, school-based, group-randomized trials. The analysis is carried out using SAS PROC MIXED, Version 6.12, with random effects specified in a random statement and restricted maximum likelihood (REML) estimation specified. The results from the non-normally distributed data are compared to the results obtained from the analysis of data with similar design characteristics but normally distributed random effects. ^ The results suggest that the violation of the normality assumption for the group component by a skewed or heavy-tailed distribution does not appear to influence the estimation of the fixed effect, Type I error, and power. Negative biases were detected when estimating the sample ICC and dramatically increased in magnitude as the true ICC increased. These biases were not as pronounced when the true ICC was within the range observed in most group-randomized trials (i.e. 0.00 to 0.05). The normally distributed group effect also resulted in bias ICC estimates when the true ICC was greater than 0.05. However, this may be a result of higher correlation within the data. ^

In What Sense Are Emotions Evaluations?

Abstract: In this chapter, we first introduce the idea that emotions are evaluations. Next, we explore two approaches attempting to account for this idea in terms of attitudes that are alleged to become emotional when taking evaluative contents. According to the first approach, emotions are evaluative judgments. According to the second, emotions are perceptual experiences of evaluative properties. We explain why this theory remains unsatisfactory insofar as it shares with the evaluative judgement theory the idea that emotions are evaluations in virtue of their contents. We then outline an alternative – the attitudinal theory of emotions. It parts with current theorizing about the emotions in elucidating the fact that emotions are evaluations not in terms of what they represent, but in terms of the attitude subjects take towards what they represent. We explore what sorts of attitudes emotions are and claim that they are felt bodily attitudes.

Luxurious Merovingian Textiles Excavated from Burials in the Saint Denis Basilica, France, 6th-7th century

A new examination of the textile fragments found in the Merovingian burials in the basilica of Saint Denis, near Paris, has recently underscored the diversity of fabrics used to make garments in which members of the royal court were buried. Among them, some woolens of fine quality had been dyed with indigotin. The most astonishing fibre found belongs to a mixed textile (not skin) with beaver fibers and wool. Silks contained shellfish purple and in one case kermes? Two dyestuffs associated with royalty and privilege. Along with this was large number of gold threads, probably produced locally and that were used in tablet-woven borders or for embroideries. In addition, several figured silks, of oriental origin, testify to the importance of this "foreign" material and the taste for textiles woven with complex techniques and probably what had originally had beautiful designs. Although none of these designs have been preserved and many colors have been greatly damaged, the technical characteristics of the remnants indicate proveniences as far as Byzantium, Sassanid Persia and the Chinese court. Such precious textiles show the high social status and political power of the Merovingian court, a testament to their ability to access such luxurious and costly textiles through diplomacy and/or trade with other powerful empires. The examination of these rare textiles along with other fine silks and luxury objects from the same period found in France expand our view of the fundamental role of textiles in the political sphere of this early period of European history.

Temperature reconstruction from 10 to 120 kyr b2k from the NGRIP ice core

In order to reconstruct the temperature of the North Greenland Ice Core Project (NGRIP) site, new measurements of δ15N have been performed covering the time period from the beginning of the Holocene to Dansgaard–Oeschger (DO) event 8. Together with previously measured and mostly published δ15N data, we present for the first time a NGRIP temperature reconstruction for the whole last glacial period from 10 to 120 kyr b2k (thousand years before 2000 AD) including every DO event based on δ15N isotope measurements combined with a firn densification and heat diffusion model. The detected temperature rises at the onset of DO events range from 5 °C (DO 25) up to 16.5 °C (DO 11) with an uncertainty of ±3 °C. To bring measured and modelled data into agreement, we had to reduce the accumulation rate given by the NGRIP ss09sea06bm timescale in some periods by 30 to 35%, especially during the last glacial maximum. A comparison between reconstructed temperature and δ18Oice data confirms that the isotopic composition of the stadial was strongly influenced by seasonality. We evidence an anticorrelation between the variations of the δ18Oice sensitivity to temperature (referred to as α) and obliquity in agreement with a simple Rayleigh distillation model. Finally, we suggest that α might be influenced by the Northern Hemisphere ice sheet volume.

Response of liquid xenon to Compton electrons down to 1.5 keV

The response of liquid xenon to low-energy electronic recoils is relevant in the search for dark-matter candidates which interact predominantly with atomic electrons in the medium, such as axions or axionlike particles, as opposed to weakly interacting massive particles which are predicted to scatter with atomic nuclei. Recently, liquid-xenon scintillation light has been observed from electronic recoils down to 2.1 keV, but without applied electric fields that are used in most xenon dark-matter searches. Applied electric fields can reduce the scintillation yield by hindering the electron-ion recombination process that produces most of the scintillation photons. We present new results of liquid xenon's scintillation emission in response to electronic recoils as low as 1.5 keV, with and without an applied electric field. At zero field, a reduced scintillation output per unit deposited energy is observed below 10 keV, dropping to nearly 40% of its value at higher energies. With an applied electric field of 450 V/cm, we observe a reduction of the scintillation output to about 75% relative to the value at zero field. We see no significant energy dependence of this value between 1.5 and 7.8 keV. With these results, we estimate the electronic-recoil energy thresholds of ZEPLIN-III, XENON10, XENON100, and XMASS to be 2.8, 2.5, 2.3, and 1.1 keV, respectively, validating their excellent sensitivity to low-energy electronic recoils.