Intravital Multiphoton Microscopy with Fluorescent Bile Salts in Rats as an In Vivo Biomarker for Hepatobiliary Transport Inhibition

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it mediates the elimination of monovalent bile salts into the bile. Inhibition of BSEP is considered a susceptibility factor for drug-induced liver injury that often goes undetected during nonclinical testing. Although in vitro assays exist for screening BSEP inhibition, a reliable and specific method for confirming Bsep inhibition in vivo would be a valuable follow up to a BSEP screening strategy, helping to put a translatable context around in vitro inhibition data, incorporating processes such as metabolism, protein binding, and other exposure properties that are lacking in most in vitro BSEP models. Here, we describe studies in which methods of quantitative intravital microscopy were used to identify dose-dependent effects of two known BSEP/Bsep inhibitors, 2-[4-[4-(butylcarbamoyl)-2-[(2,4-dichlorophenyl)sulfonylamino]phenoxy]-3-methoxyphenyl]acetic acid (AMG-009) and bosentan, on hepatocellular transport of the fluorescent bile salts cholylglycyl amidofluorescein and cholyl-lysyl-fluorescein in rats. Results of these studies demonstrate that the intravital microscopy approach is capable of detecting Bsep inhibition at drug doses well below those found to increase serum bile acid levels, and also indicate that basolateral efflux transporters play a significant role in preventing cytosolic accumulation of bile acids under conditions of Bsep inhibition in rats. Studies of this kind can both improve our understanding of exposures needed to inhibit Bsep in vivo and provide unique insights into drug effects in ways that can improve our ability interpret animal studies for the prediction of human drug hepatotoxicity

Ecological comparison of the risks of mother-to-child transmission and clinical manifestations of congenital toxoplasmosis according to prenatal treatment protocol

We compared the relative risks of mother-to-child transmission of Toxoplasma gondii and clinical manifestations due to congenital toxoplasmosis associated with intensive prenatal treatment in Lyon and Austria, short term treatment in 51% of Dutch women, and no treatment in Danish women. For each cohort, relative risks were standardized for gestation at seroconversion. In total, 856 mother–child pairs were studied: 549 in Lyon, 133 in Austria, 123 in Denmark and 51 in The Netherlands. The relative risk for mother-to-child transmission compared to Lyon was 1·24 (95% CI: 0·88, 1·59) in Austria; 0·59 (0·41, 0·81) in Denmark; and 0·65 (0·37, 1·01) in The Netherlands. Relative risks for clinical manifestations compared with Lyon (adjusted for follow-up to age 3 years) were: Austria 0·19 (0·04, 0·51); Denmark 0·60 (0·13, 1·08); and The Netherlands 1·46 (0·51, 2·72). There was no clear evidence that the risk of transmission or of clinical manifestations was lowest in centres with the most intensive prenatal treatment

Automated Data Management Information System (ADMIS)

ADMIS stores and controls data and documents associated with manned space flight effort. System contains all data oriented toward a specific document; it is primary source of reports generated by the system. Each group of records is composed of one document record, one distribution record for each recipient of the document, and one summary record

Measuring Distance and Properties of the Milky Way's Central Supermassive Black Hole with Stellar Orbits

We report new precision measurements of the properties of our Galaxy's supermassive black hole. Based on astrometric (1995-2007) and radial velocity (2000-2007) measurements from the W. M. Keck 10-meter telescopes, a fully unconstrained Keplerian orbit for the short period star S0-2 provides values for Ro of 8.0+-0.6 kpc, M_bh of 4.1+-0.6x10^6 Mo, and the black hole's radial velocity, which is consistent with zero with 30 km/s uncertainty. If the black hole is assumed to be at rest with respect to the Galaxy, we can further constrain the fit and obtain Ro = 8.4+-0.4 kpc and M_bh = 4.5+-0.4x10^6 Mo. More complex models constrain the extended dark mass distribution to be less than 3-4x10^5 Mo within 0.01 pc, ~100x higher than predictions from stellar and stellar remnant models. For all models, we identify transient astrometric shifts from source confusion and the assumptions regarding the black hole's radial motion as previously unrecognized limitations on orbital accuracy and the usefulness of fainter stars. Future astrometric and RV observations will remedy these effects. Our estimates of Ro and the Galaxy's local rotation speed, which it is derived from combining Ro with the apparent proper motion of Sgr A*, (theta0 = 229+-18 km/s), are compatible with measurements made using other methods. The increased black hole mass found in this study, compared to that determined using projected mass estimators, implies a longer period for the innermost stable orbit, longer resonant relaxation timescales for stars in the vicinity of the black hole and a better agreement with the M_bh-sigma relation.Comment: ApJ, accepted (26 pages, 16 figures, 7 tables

Licenced doses of approved COVID-19 vaccines may not be optimal: A review of the early-phase, dose-finding trials

Although over 13 billion COVID-19 vaccine doses have been administered globally, the issue of whether the optimal doses are being used has received little attention. To address this question we reviewed the reports of early-phase dose-finding trials of the nine COVID-19 vaccines approved by World Health Organization, extracting information on study design and findings on reactogenicity and early humoral immune response. The number of different doses evaluated for each vaccine varied widely (range 1-7), as did the number of subjects studied per dose (range 15-190). As expected, the frequency and severity of adverse reactions generally increased at higher doses, although most were clinically tolerable. Higher doses also tended to elicit better immune responses, but differences between the highest dose and the second-highest dose evaluated were small, typically less than 1.6-fold for both binding antibody concentration and neutralising antibody titre. All of the trials had at least one important design limitation - few doses evaluated, large gaps between adjacent doses, or an inadequate sample size - although this is not a criticism of the study investigators, who were working under intense time pressures at the start of the epidemic. It is therefore open to question whether the single dose taken into clinical efficacy trials, and subsequently authorised by regulatory agencies, was optimal. In particular, our analysis indicates that the recommended doses for some vaccines appear to be unnecessarily high. Although reduced dosing for booster injections is an active area of research, the priming dose also merits study. We conclude by suggesting improvements in the design of future vaccine trials, for both next-generation COVID-19 vaccines and for vaccines against other pathogens

Direct measurement of diurnal polar motion by ring laser gyroscopes

We report the first direct measurements of the very small effect of forced diurnal polar motion, successfully observed on three of our large ring lasers, which now measure the instantaneous direction of Earth's rotation axis to a precision of 1 part in 10^8 when averaged over a time interval of several hours. Ring laser gyroscopes provide a new viable technique for directly and continuously measuring the position of the instantaneous rotation axis of the Earth and the amplitudes of the Oppolzer modes. In contrast, the space geodetic techniques (VLBI, SLR, GPS, etc.) contain no information about the position of the instantaneous axis of rotation of the Earth, but are sensitive to the complete transformation matrix between the Earth-fixed and inertial reference frame. Further improvements of gyroscopes will provide a powerful new tool for studying the Earth's interior.Comment: 5 pages, 4 figures, agu2001.cl

Studying the X-ray hysteresis in GX 339-4: the disc and iron line over one decade

We report on a comprehensive and consistent investigation into the X-ray emission from GX 339-4. All public observations in the 11 year RXTE archive were analysed. Three different types of model - single powerlaw, broken powerlaw and a disc + powerlaw - were fitted to investigate the evolution of the disc, along with a fixed gaussian component at 6.4 keV to investigate any iron line in the spectrum. We show that the relative variation in flux and X-ray colour between the two best sampled outbursts are very similar. The decay of the disc temperature during the outburst is clearly seen in the soft state. The expected decay is S_Disc \propto T^4; we measure T^4.75\pm0.23. This implies that the inner disc radius is approximately constant in the soft state. We also show a significant anti-correlation between the iron line significant width and the X-ray flux in the soft state while in the hard state the EW is independent of the flux. This results in hysteresis in the relation between X-ray flux and both line flux and EW. To compare the X-ray binary outburst to the behaviour seen in AGN, we construct a Disc Fraction Luminosity Diagram for GX 339-4, the first for an X-ray binary. The shape qualitatively matches that produced for AGN. Linking this with the radio emission from GX 339-4 the change in radio spectrum between the disc and power-law dominated states is clearly visible.Comment: Accepted for publication in MNRAS, 20 pages, 17 figures. For high-res version see http://www.astro.soton.ac.uk/~r.j.dunn/publications.htm

Empathic forecasting: How do we predict other people's feelings?

When making affective forecasts, people commit the impact bias. They overestimate the impact an emotional event has on their affective experience. In three studies we show that people also commit the impact bias when making empathic forecasts, affective forecasts for someone else. They overestimate the impact an emotional event has on someone else's affective experience (Study 1), they do so for friends and strangers (Study 2), and they do so when other sources of information are available (Study 3). Empathic forecasting accuracy, the correlation between one person's empathic forecast and another person's actual affective experience, was lower than between-person forecasting correspondence, the correlation between one person's empathic forecast and another person's affective forecast. Empathic forecasts do not capture other people's actual experience very well but are similar to what other people forecast for themselves. This may enhance understanding between people