Recent national trends in Salvia divinorum use and substance-use disorders among recent and former Salvia divinorum users compared with nonusers.

CONTEXT: Media and scientific reports have indicated an increase in recreational use of Salvia divinorum. Epidemiological data are lacking on the trends, prevalence, and correlates of S. divinorum use in large representative samples, as well as the extent of substance use and mental health problems among S. divinorum users. OBJECTIVE: To examine the national trend in prevalence of S. divinorum use and to identify sociodemographic, behavioral, mental health, and substance-use profiles of recent (past-year) and former users of S. divinorum. DESIGN: Analyses of public-use data files from the 2006-2008 United States National Surveys on Drug Use and Health (N = 166,453). SETTING: Noninstitutionalized individuals aged 12 years or older were interviewed in their places of residence. MAIN MEASURES: Substance use, S. divinorum, self-reported substance use disorders, criminality, depression, and mental health treatment were assessed by standardized survey questions administered by the audio computer-assisted self-interviewing method. RESULTS: Among survey respondents, lifetime prevalence of S. divinorum use had increased from 0.7% in 2006 to 1.3% in 2008 (an 83% increase). S. divinorum use was associated with ages 18-25 years, male gender, white or multiple race, residence of large metropolitan areas, arrests for criminal activities, and depression. S. divinorum use was particularly common among recent drug users, including users of lysergic acid diethylamide (53.7%), ecstasy (30.1%), heroin (24.2%), phencyclidine (22.4%), and cocaine (17.5%). Adjusted multinomial logistic analyses indicated polydrug use as the strongest determinant for recent and former S. divinorum use. An estimated 43.0% of past-year S. divinorum users and 28.9% of former S. divinorum users had an illicit or nonmedical drug-use disorder compared with 2.5% of nonusers. Adjusted logistic regression analyses showed that recent and former S. divinorum users had greater odds of having past-year depression and a substance-use disorder (alcohol or drugs) than past-year alcohol or drug users who did not use S. divinorum. CONCLUSION: S. divinorum use is prevalent among recent or active drug users who have used other hallucinogens or stimulants. The high prevalence of substance use disorders among recent S. divinorum users emphasizes the need to study health risks of drug interactions.

Defining seasonal marine microbial community dynamics

Here we describe, the longest microbial time-series analyzed to date using high-resolution 16S rRNA tag pyrosequencing of samples taken monthly over 6 years at a temperate marine coastal site off Plymouth, UK. Data treatment effected the estimation of community richness over a 6-year period, whereby 8794 operational taxonomic units (OTUs) were identified using single-linkage preclustering and 21 130 OTUs were identified by denoising the data. The Alphaproteobacteria were the most abundant Class, and the most frequently recorded OTUs were members of the Rickettsiales (SAR 11) and Rhodobacteriales. This near-surface ocean bacterial community showed strong repeatable seasonal patterns, which were defined by winter peaks in diversity across all years. Environmental variables explained far more variation in seasonally predictable bacteria than did data on protists or metazoan biomass. Change in day length alone explains >65% of the variance in community diversity. The results suggested that seasonal changes in environmental variables are more important than trophic interactions. Interestingly, microbial association network analysis showed that correlations in abundance were stronger within bacterial taxa rather than between bacteria and eukaryotes, or between bacteria and environmental variables.

Beyond long-term averages: making biological sense of a rapidly changing world

Biological responses to climate change are typically communicated in generalized terms such as poleward and altitudinal range shifts, but adaptation efforts relevant to management decisions often require forecasts that incorporate the interaction of multiple climatic and nonclimatic stressors at far smaller spatiotemporal scales. We argue that the desire for generalizations has, ironically, contributed to the frequent conflation of weather with climate, even within the scientific community. As a result, current predictions of ecological responses to climate change, and the design of experiments to understand underlying mechanisms, are too often based on broad-scale trends and averages that at a proximate level may have very little to do with the vulnerability of organisms and ecosystems. The creation of biologically relevant metrics of environmental change that incorporate the physical mechanisms by which climate trains patterns of weather, coupled with knowledge of how organisms and ecosystems respond to these changes, can offer insight into which aspects of climate change may be most important to monitor and predict. This approach also has the potential to enhance our ability to communicate impacts of climate change to nonscientists and especially to stakeholders attempting to enact climate change adaptation policies.

Globcurrent: Sentinel-3 synergy in action

The ESA Data User Element (DUE) funded GlobCurrent project (http://www.globcurrent.org) aims to: (i) advance the quantitative estimation of ocean surface currents from satellite sensor synergy; and (ii) demonstrate impact in user-led scientific, operational and commercial applications that, in turn, will improve and strengthen the uptake of satellite measurements. Today, a synergetic approach for quantitative analysis can build on high-resolution imaging radar and spectrometer data, infrared radiometer data and radar altimeter measurements. It will further integrate Sentinel-3 in combination with Sentinel-1 SAR data. From existing and past missions, it is often demonstrated that sharp gradients in the sea surface temperature (SST) field and the ocean surface chlorophyll-a distribution are spatially correlated with the sea surface roughness anomaly fields at small spatial scales, in the sub-mesocale (1-10 km) to the mesoscale (30-80 km). At the larger mesoscale range (>50 km), information derived from radar altimeters often depict the presence of coherent structures and eddies. The variability often appears largest in regions where the intense surface current regimes (>100 - 200 km) are found. These 2-dimensional structures manifested in the satellite observations represent evidence of the upper ocean (~100-200 m) dynamics. Whereas the quasi geostrophic assumption is valid for the upper ocean dynamics at the larger scale (>100 km), possible triggering mechanisms for the expressions at the mesoscale-to-submesoscale may include spiraling tracers of inertial motion and the interaction of the wind-driven Ekman layer with the quasi-geostrophic current field. This latter, in turn, produces bands of downwelling (convergence) and upwelling (divergence) near fronts. A regular utilization of the sensor synergy approach with the combination of Sentinel-3 and Sentinel-1 will provide a highly valuable data set for further research and development to better relate the 2-dimensional surface expressions and the upper ocean dynamics.

Ocean Virtual Laboratory: A new way to explore multi-sensor synergy demonstrated over the Agulhas region

Ocean Virtual Laboratory is an ESA-funded project to prototype the concept of a single point of access for all satellite remote-sensing data with ancillary model output and in situ measurements for a given region. The idea is to provide easy access for the non-specialist to both data and state-of-the-art processing techniques and enable their easy analysis and display. The project, led by OceanDataLab, is being trialled in the region of the Agulhas Current, as it contains signals of strong contrast (due to very energetic upper ocean dynamics) and special SAR data acquisitions have been recorded there. The project also encourages the take up of Earth Observation data by developing training material to help those not in large scientific or governmental organizations make the best use of what data are available. The website for access is: http://ovl-project.oceandatalab.com/

Surface properties of Rosetta's targets (21) Lutetia and (2867) Steins from ESO observations

Aims. The aim of this work is to constrain the size, composition and surface properties of asteroids (2867) Steins and (21) Lutetia, targets of the Rosetta mission. Rosetta is en route to rendezvous with comet 67P/Churyumov-Gerasimenko.

Methods. Thermal-Infrared N-band observations for Lutetia and Steins were obtained using, respectively, TIMMI2 on the ESO 3.6-m telescope at La Silla and VISIR at the UT3 VLT telescope on Cerro Paranal; visible light curves for Steins were obtained using NTT+SUSI2, while R-band photometry for Lutetia was obtained with the 2.0-m Faulkes Telescope North on Haleakala. For Steins, the NEATM model was used to constrain its visible geometric albedo and beaming parameter. A detailed thermophysical model was implemented and used to analyze our set of observations of Lutetia as well as previous reported measurements.

Results. The visible photometry of Steins was used along with data from the literature to yield a slope parameter of G=0.32(-0.11)(+0.14). Problems during the observations led to the loss of measurements on two of the three N-band filters requested for Steins. Using the remaining data and the polarimetric albedo recently published, we were able to constrain the thermal beaming parameter as eta > 1.2, which is more similar to near-Earth asteroids and suggests either high thermal inertia or a very rough surface. For Lutetia, the best fit visible geometric albedo obtained with our model and the reported observation is p(nu)=0.129, significantly lower than that obtained if one applies the same model to previously reported measurements. The discrepancy cannot be explained solely by assuming inhomogeneities in the surface properties and we suggest that the most plausible explanation is the presence of one or more large craters on the northern hemisphere. For both sets of measurements, the implied single scattering albedo of Lutetia is compatible with laboratory measurements of carbonaceous chondrite meteorites.

Degradation, cyclic adenosine monophosphate production, insulin secretion, and glycemic effects of two novel N-terminal Ala(2)-substituted analogs of glucose-dependent insulinotropic polypeptide with preserved biological activity in vivo

Glucose-dependent insulinotropic polypeptide (GIP) has significant potential in diabetes therapy due to its ability to serve as a glucose-dependent activator of insulin secretion. However, its biological activity is severely compromised by the ubiquitous enzyme dipeptidylpeptidase IV (DPP IV), which removes the N-terminal Tyr(1)-Ala(2) dipeptide from GIP. Therefore, 2 novel N-terminal Ala(2)-substituted analogs of GIP, with Ala substituted by 2-aminobutyric acid (Abu) or sarcosine (Sar), were synthesized and tested for metabolic stability and biological activity both in vitro and in vivo. Incubation with DPP IV gave half-lives for degradation of native GIP, (Abu(2))GIP, and (Sar(2))GIP to be 2.3, 1.9, and 1.6 hours, respectively, while in human plasma, the half-lives were 6.2, 7.6, and 5.4 hours, respectively. In Chinese hamster lung (CHL) cells expressing the cloned human GIP receptor, native GIP, (Abu(2))GIP, and (Sar(2))GIP dose-dependently stimulated cyclic adenosine monophosphate (camp) production with EC50 values of 18.2, 38.5, and 54.6 nmol/L, respectively. In BRIN-BD11 cells, both (Abu(2))GIP and (Sar(2))GIP (10(-13) to 10(-8) mol/L) dose-dependently stimulated insulin secretion with significantly enhanced effects at 16.7 mmol/L compared with 5.6 mmol/L glucose. In obese diabetic (ob/ob) mice, GIP and (Sar(2))GIP significantly increased (1.4-fold to 1.5-fold; P <.05) plasma insulin concentrations, whereas (Abu(2))GIP exerted only minor effects. Changes in plasma glucose were small reflecting the severe insulin resistance of this mutant. The present data show that substitution of the penultimate N-terminal Ala(2) in GIP by Abu or Sar results in analogs with moderately reduced metabolic stability and biological activity in vitro, but with preserved biological activity in vivo. (C) 2003 Elsevier Inc. All rights reserved.

Stokes imaging, Doppler mapping and Roche tomography of the AM Herculis system V834 Cen

We report on new simultaneous phase-resolved spectroscopic and polarimetric observations of the polar (AM Herculis star) V834 Cen during a high state of accretion. Strong emission lines and high levels of variable circular and linear polarization are observed over the orbital period. The polarization data are modelled using the Stokes imaging technique of Potter et al. The spectroscopic emission lines are investigated using the Doppler tomography technique of Marsh and Horne and the Roche tomography technique of Dhillon and Watson. Up to now, all three techniques have been used separately to investigate the geometry and accretion dynamics in cataclysmic variables. For the first time, we apply all three techniques to simultaneous data for a single system. This allows us to compare and test each of the techniques against each other and hence to derive a better understanding of the geometry, dynamics and system parameters of V834 Cen.

Studies on acyl pyrrolidine inhibitors of HCV RNA-dependent RNA polymerase to identify a molecule with replicon antiviral activity

The SAR development is described for a series of N-acyl pyrrolidine inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase, NS5B, from tractable Delta 21 enzyme inhibitors to an example with antiviral activity in a cellular assay (HCV replicon). (c) 2007 Elsevier Ltd. All rights reserved.

[[omega-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents.

A series of [(ureidoethoxy)benzyl]-2,4-thiazolidinediones and [[(heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones was synthesized from the corresponding aldehydes. Compds. from the urea series, exemplified by I, showed antihyperglycemic potency comparable with known agents of the type such as pioglitazone and troglitazone (CS-045). The benzoxazole II, a cyclic analog of I, was a very potent enhancer of insulin sensitivity, and by modification of the arom. heterocycle, an aminopyridine, III, was identified as a lead compd. from SAR studies. Evaluation of antihyperglycemic activity together with effects on blood Hb content, to det. the therapeutic index, was performed in 8-day repeat administration studies in genetically obese C57 B1/6 ob/ob mice. From these studies, III (BRL 49653) has been selected, on the basis of antihyperglycemic potency combined with enhanced selectivity against redns. in blood Hb content, for further evaluation.

Search for Rapid Changes in the Visible-Light Corona during the 21 June 2001 Total Solar Eclipse

Some 8000 images obtained with the Solar Eclipse Coronal Imaging System (SECIS) fast-frame CCD camera instrument located at Lusaka, Zambia, during the total eclipse of 21 June 2001 have been analysed to search for short-period oscillations in intensity that could be a signature of solar coronal heating mechanisms by MHD wave dissipation. Images were taken in white-light and Fe xiv green-line (5303 ) channels over 205 seconds (frame rate 39 s(-1)), approximately the length of eclipse totality at this location, with a pixel size of four arcseconds square. The data are of considerably better quality than those that we obtained during the 11 August 1999 total eclipse (Rudawy et al.: Astron. Astrophys. 416, 1179, 2004), in that the images are much better exposed and enhancements in the drive system of the heliostat used gave a much improved image stability. Classical Fourier and wavelet techniques have been used to analyse the emission at 29 518 locations, of which 10 714 had emission at reasonably high levels, searching for periodic fluctuations with periods in the range 0.1 -aEuro parts per thousand 17 seconds (frequencies 0.06 -aEuro parts per thousand 10 Hz). While a number of possible periodicities were apparent in the wavelet analysis, none of the spatially and time-limited periodicities in the local brightness curves was found to be physically important. This implies that the pervasive Alfv,n wave-like phenomena (Tomczyk et al.: Science 317, 1192, 2007) using polarimetric observations with the Coronal Multi-Channel Polarimeter (CoMP) instrument do not give rise to significant oscillatory intensity fluctuations.

Re-exploration of the PHCCC Scaffold: Discovery of Improved Positive Allosteric Modulators of mGluR4

This paper describes a detailed structure activity relationship (SAR) analysis of the metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulator, (-)-N-phenyl-7-(hydroxyimino)cyclopropa[b]-chromen-la-carboxamide (PHCCC). We have now developed compounds with improved potency and efficacy; in addition, compounds are presented that show selectivity for mGluR4 versus the other mGluR subtypes.

Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead

This Letter describes the synthesis and SAR of two mGluR4 positive allosteric modulator leads, 6 and 7. VU001171 (6) represents the most potent (EC50 = 650 nM), efficacious (141% Glu Max) and largest fold shift (36-fold) of any mGluR4 PAM reported to date. However, this work highlights the challenges in hit-to-lead for mGluR4 PAMs, with multiple confirmed HTS hits displaying little or no tractable SAR. (C) 2008 Elsevier Ltd. All rights reserved.

New anti-HIV aptamers based on tetra-end-linked DNA G-quadruplexes: effect of the base sequence on anti-HIV activity.

This communication reports on the synthesis and biophysical, biological and SAR studies of a small library of new anti-HIV aptamers based on the tetra-end-linked G-quadruplex structure. The new aptamers showed EC(50) values against HIV-1 in the range of 0.04-0.15 µM as well as affinities for the HIV-1 gp120 envelope in the same order of magnitude