Matching small β\beta functions using centroid jitter and two beam position monitors

Matching to small beta functions is required to preserve emittance in plasma accelerators. The plasma wake provides strong focusing fields, which typically require beta functions on the mm-scale, comparable to those found in the final focusing of a linear collider. Such beams can be time consuming to experimentally produce and diagnose. We present a simple, fast, and noninvasive method to measure Twiss parameters in a linac using two beam position monitors only, relying on the similarity of the beam phase space and the jitter phase space. By benchmarking against conventional quadrupole scans, the viability of this technique was experimentally demonstrated at the FLASHForward plasma-accelerator facility.Comment: 8 pages, 7 figure

Automating the application of smart materials for protein crystallization

The fabrication and validation of the first semi-liquid nonprotein nucleating agent to be administered automatically to crystallization trials is reported. This research builds upon prior demonstration of the suitability of molecularly imprinted polymers (MIPs; known as 'smart materials') for inducing protein crystal growth. Modified MIPs of altered texture suitable for high-throughput trials are demonstrated to improve crystal quality and to increase the probability of success when screening for suitable crystallization conditions. The application of these materials is simple, time-efficient and will provide a potent tool for structural biologists embarking on crystallization trials. © 2015, IUCR. All rights reserved

<i>In vitro</i> conditions for performance evaluation of products for intravascular administration:Developing appropriate test media using Amphotericin B as a model drug

Currently, there are no compendial in vitro release tests specifically indicated for parenteral formulations. Consideration of biorelevant and clinically relevant test media represents a valuable approach for the development of in vitro tests that ideally can provide information on the formulation performance in vivo. The aim of this study was to investigate the effect of different media components on the solubility of Amphotericin B (a poorly soluble highly protein-bound drug) in order to develop biorelevant and clinically relevant media for future in vitro release testing from its liposomal formulation. Three categories of media were considered in the development approach: Category 1 media: effect of albumin concentration; category 2 media: effect of biorelevant concentrations of plasma components (bile salts, phospholipids, cholesterol, albumin); category 3 media: attaining clinically relevant solubility with biorelevant and synthetic surfactants with and without albumin and setting the basis for the development of a simulated hypoalbuminaemic plasma medium. All the surfactants tested increased Amphotericin B solubility while the simultaneous presence of albumin had a negative effect on solubility. Clinically relevant media with the use of biorelevant or synthetic surfactants and albumin were developed. One medium in which the solubility of Amphotericin B was reduced was identified as potential candidate medium to simulate hypoalbuminaemic plasma. The development of biorelevant and clinically relevant media and understanding the effect of media components and their interactions, supports future development of meaningful in vivo predictive release tests for parenteral formulations.</p

Possible protective effect of green tea intake on risk of adult leukaemia

In a case–control study of 107 adults with leukaemia and 110 orthopaedic controls in China, a reduced risk was found with longer duration, higher quantity, and frequency of green tea intake

<i>In vitro</i> conditions for performance evaluation of products for intravascular administration:Developing appropriate test media using Amphotericin B as a model drug

Currently, there are no compendial in vitro release tests specifically indicated for parenteral formulations. Consideration of biorelevant and clinically relevant test media represents a valuable approach for the development of in vitro tests that ideally can provide information on the formulation performance in vivo. The aim of this study was to investigate the effect of different media components on the solubility of Amphotericin B (a poorly soluble highly protein-bound drug) in order to develop biorelevant and clinically relevant media for future in vitro release testing from its liposomal formulation. Three categories of media were considered in the development approach: Category 1 media: effect of albumin concentration; category 2 media: effect of biorelevant concentrations of plasma components (bile salts, phospholipids, cholesterol, albumin); category 3 media: attaining clinically relevant solubility with biorelevant and synthetic surfactants with and without albumin and setting the basis for the development of a simulated hypoalbuminaemic plasma medium. All the surfactants tested increased Amphotericin B solubility while the simultaneous presence of albumin had a negative effect on solubility. Clinically relevant media with the use of biorelevant or synthetic surfactants and albumin were developed. One medium in which the solubility of Amphotericin B was reduced was identified as potential candidate medium to simulate hypoalbuminaemic plasma. The development of biorelevant and clinically relevant media and understanding the effect of media components and their interactions, supports future development of meaningful in vivo predictive release tests for parenteral formulations.</p

Defining the molecular basis of BubR1 kinetochore interactions and APC/C-CDC20 inhibition.

BubR1 is essential for the mitotic checkpoint that prevents aneuploidy in cellular progeny by triggering anaphase delay in response to kinetochores incorrectly/not attached to the mitotic spindle. Here, we define the molecular architecture of the functionally significant N-terminal region of human BubR1 and present the 1.8 A crystal structure of its tetratricopeptide repeat (TPR) domain. The structure reveals divergence from the classical TPR fold and is highly similar to the TPR domain of budding yeast Bub1. Shared distinctive features include a disordered loop insertion, a 3(10)-helix, a tight turn involving glycine positive Phi angles, and noncanonical packing of and between the TPR motifs. We also define the molecular determinants of the interaction between BubR1 and kinetochore protein Blinkin. We identify a shallow groove on the concave surface of the BubR1 TPR domain that forms multiple discrete and potentially cooperative interactions with Blinkin. Finally, we present evidence for a direct interaction between BubR1 and Bub1 mediated by regions C-terminal to their TPR domains. This interaction provides a mechanism for Bub1-dependent kinetochore recruitment of BubR1. We thus present novel molecular insights into the structure of BubR1 and its interactions at the kinetochore-microtubule interface. Our studies pave the way for future structure-directed engineering aimed at dissecting the roles of kinetochore-bound and other pools of BubR1 in vivo

<i>In vitro - in vivo </i>relations for the parenteral liposomal formulation of Amphotericin B:A clinically relevant approach with PBPK modeling

In vitro release testing is a useful tool for the quality control of controlled release parenteral formulations, but in vitro release test conditions that reflect or are able to predict the in vivo performance are advantageous. Therefore, it is important to investigate the factors that could affect drug release from formulations and relate them to in vivo performance. In this study the effect of media composition including albumin presence, type of buffer and hydrodynamics on drug release were evaluated on a liposomal Amphotericin B formulation (Ambisome®). A physiologically based pharmacokinetic (PBPK) model was developed using plasma concentration profiles from healthy subjects, in order to investigate the impact of each variable from the in vitro release tests on the prediction of the in vivo performance. It was found that albumin presence was the most important factor for the release of Amphotericin B from Ambisome®; both hydrodynamics setups, coupled with the PBPK model, had comparable predictive ability for simulating in vivo plasma concentration profiles. The PBPK model was extrapolated to a hypothetical hypoalbuminaemic population and the Amphotericin B plasma concentration and its activity against fungal cells were simulated. Selected in vitro release tests for these controlled release parenteral formulations were able to predict the in vivo AmB exposure, and this PBPK driven approach to release test development could benefit development of such formulations.</p