Effects of ursodeoxycholic acid on synthesis of cholesterol and bile acids in healthy subjects

Background/Aims: Ursodeoxycholic acid ( UDCA) decreases biliary secretion of cholesterol and is therefore used for the dissolution of cholesterol gallstones. It remains unclear whether these changes in biliary cholesterol excretion are associated with changes in cholesterol synthesis and bile acid synthesis. We therefore studied the activities of rate-limiting enzymes of cholesterol synthesis and bile acid synthesis, 3-hydroxy-3-methyl-glutarylcoenzyme A reductase and cholesterol 7alpha-hydroxylase, respectively, in normal subjects during UDCA feeding. Methods: UDCA was given to 8 healthy volunteers ( 5 men, 3 women; age 24-44 years) in a single dose of 10-15 mg/kg body weight for 40 days. Before and during ( days 3, 5, 10, 20, 30 and 40) UDCA treatment, urinary excretion of mevalonic acid and serum concentrations of 7alpha-hydroxy-4-cholesten-3-one (7alpha-HCO) were determined as markers of cholesterol and bile acid synthesis, respectively. The Wilcoxon signed rank test and Spearman's rank correlation coefficient were used for statistical analysis. Results: Cholesterol synthesis and serum lipid concentrations remained unchanged during UDCA treatment for 40 days. However, synthesis of bile acids increased during long-term treatment with UDCA as reflected by an increase in 7alpha-HCO serum concentrations from 39.7 +/- 21.3 ng/ml (median 32.8 ng/ml) before treatment to 64.0 +/- 30.4 ng/ml (median 77.5 ng/ml) at days 30-40 of UDCA treatment ( p < 0.05). Conclusions: UDCA treatment does not affect cholesterol synthesis in the liver, but does increase bile acid synthesis after prolonged treatment. This may represent a compensatory change following decreased absorption of endogenous bile acids as observed with UDCA therapy

SAD phasing of XFEL data depends critically on the error model.

A nonlinear least-squares method for refining a parametric expression describing the estimated errors of reflection intensities in serial crystallographic (SX) data is presented. This approach, which is similar to that used in the rotation method of crystallographic data collection at synchrotrons, propagates error estimates from photon-counting statistics to the merged data. Here, it is demonstrated that the application of this approach to SX data provides better SAD phasing ability, enabling the autobuilding of a protein structure that had previously failed to be built. Estimating the error in the merged reflection intensities requires the understanding and propagation of all of the sources of error arising from the measurements. One type of error, which is well understood, is the counting error introduced when the detector counts X-ray photons. Thus, if other types of random errors (such as readout noise) as well as uncertainties in systematic corrections (such as from X-ray attenuation) are completely understood, they can be propagated along with the counting error, as appropriate. In practice, most software packages propagate as much error as they know how to model and then include error-adjustment terms that scale the error estimates until they explain the variance among the measurements. If this is performed carefully, then during SAD phasing likelihood-based approaches can make optimal use of these error estimates, increasing the chance of a successful structure solution. In serial crystallography, SAD phasing has remained challenging, with the few examples of de novo protein structure solution each requiring many thousands of diffraction patterns. Here, the effects of different methods of treating the error estimates are estimated and it is shown that using a parametric approach that includes terms proportional to the known experimental uncertainty, the reflection intensity and the squared reflection intensity to improve the error estimates can allow SAD phasing even from weak zinc anomalous signal

Disease spread through animal movements: a static and temporal network analysis of pig trade in Germany

Background: Animal trade plays an important role for the spread of infectious diseases in livestock populations. As a case study, we consider pig trade in Germany, where trade actors (agricultural premises) form a complex network. The central question is how infectious diseases can potentially spread within the system of trade contacts. We address this question by analyzing the underlying network of animal movements. Methodology/Findings: The considered pig trade dataset spans several years and is analyzed with respect to its potential to spread infectious diseases. Focusing on measurements of network-topological properties, we avoid the usage of external parameters, since these properties are independent of specific pathogens. They are on the contrary of great importance for understanding any general spreading process on this particular network. We analyze the system using different network models, which include varying amounts of information: (i) static network, (ii) network as a time series of uncorrelated snapshots, (iii) temporal network, where causality is explicitly taken into account. Findings: Our approach provides a general framework for a topological-temporal characterization of livestock trade networks. We find that a static network view captures many relevant aspects of the trade system, and premises can be classified into two clearly defined risk classes. Moreover, our results allow for an efficient allocation strategy for intervention measures using centrality measures. Data on trade volume does barely alter the results and is therefore of secondary importance. Although a static network description yields useful results, the temporal resolution of data plays an outstanding role for an in-depth understanding of spreading processes. This applies in particular for an accurate calculation of the maximum outbreak size.Comment: main text 33 pages, 17 figures, supporting information 7 pages, 7 figure

Autoindexing the diffraction patterns from crystals with a pseudotranslation

Lattice patterns containing alternating strong and weak reflections can be identified by a targeted search for the weak signals, permitting a wider range of diffraction patterns to be indexed automatically

New LISA dynamics feedback control scheme: Common-mode isolation of test mass control and probes of test-mass acceleration

The Drag-Free and Attitude Control System is a central element of LISA technology, ensuring the very high dynamic stability of spacecraft and test masses required in order to reach the sensitivity that gravitational wave astronomy in space requires. Applying electrostatic forces on test-masses is unavoidable but should be restricted to the minimum necessary to keep the spacecraft-test masses system in place, while granting the optimal quality of test-mass free-fall. To realise this, we propose a new test-mass suspension scheme that applies forces and torques only in proportion to any differential test mass motion observed, and we demonstrate that the new scheme significantly mitigates the amount of suspension forces and torques needed to control the whole system. The mathematical method involved allows us to derive a new observable measuring the differential acceleration of test masses projected on the relevant sensitive axes, which will have important consequences for LISA data calibration, processing and analysis