Mechanically Induced Amorphization of Diaqua-bis(Omeprazolate)-Magnesium Dihydrate

The influence of milling diaqua-bis(omeprazolate)-magnesium dihydrate (DABOMD), an active pharmaceutical ingredient (API), was investigated. DABOMD was processed in a planetary ball mill at different milling times, from 1 to 300 min. The milling process resulted in a prominent comminution (size reduction) and amorphization of the API. DABOMD amorphization was identified with various characterization techniques including thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and attenuated total reflection-Fourier transform infrared spectroscopy. The solid–solid crystalline to amorphous phase transformation is driven by compression, shear stresses, and heat generated in the planetary ball mill. This leads to distortion and breakage of hydrogen bonds, release of water molecules from the crystalline lattice of DABOMD and the accumulation of defects, and eventually a collapse of the crystalline order. Model fitting of the kinetics of comminution and the amorphization of DABOMD revealed a series of events: a rapid comminution at the start of milling driven by crystal cleavage of DABOMD, followed by partial amorphization, which is driven by rapid water diffusion, and subsequently, a slow steady comminution and amorphization

Linac Coherent Light Source Undulator RF BPM System

The Linac Coherent Light Source (LCLS) will be the world's first x-ray free-electron laser (FEL) when it becomes operational in 2009. The LCLS is currently in the construction phase. The beam position monitor (BPM) system planned for the LCLS undulator will incorporate a high-resolution X-band cavity BPM system described in this paper. The BPM system will provide high-resolution measurements of the electron beam trajectory on a pulse-to-pulse basis and over many shots. The X-band cavity BPM size, simple fabrication, and high resolution make it an ideal choice for LCLS beam position detection. We will discuss the system specifications, design, and prototype test results

Influences of Excluded Volume of Molecules on Signaling Processes on Biomembrane

We investigate the influences of the excluded volume of molecules on biochemical reaction processes on 2-dimensional surfaces using a model of signal transduction processes on biomembranes. We perform simulations of the 2-dimensional cell-based model, which describes the reactions and diffusion of the receptors, signaling proteins, target proteins, and crowders on the cell membrane. The signaling proteins are activated by receptors, and these activated signaling proteins activate target proteins that bind autonomously from the cytoplasm to the membrane, and unbind from the membrane if activated. If the target proteins bind frequently, the volume fraction of molecules on the membrane becomes so large that the excluded volume of the molecules for the reaction and diffusion dynamics cannot be negligible. We find that such excluded volume effects of the molecules induce non-trivial variations of the signal flow, defined as the activation frequency of target proteins, as follows. With an increase in the binding rate of target proteins, the signal flow varies by i) monotonically increasing; ii) increasing then decreasing in a bell-shaped curve; or iii) increasing, decreasing, then increasing in an S-shaped curve. We further demonstrate that the excluded volume of molecules influences the hierarchical molecular distributions throughout the reaction processes. In particular, when the system exhibits a large signal flow, the signaling proteins tend to surround the receptors to form receptor-signaling protein clusters, and the target proteins tend to become distributed around such clusters. To explain these phenomena, we analyze the stochastic model of the local motions of molecules around the receptor.Comment: 31 pages, 10 figure

Pinealectomy affects bone mineral density and structure - an experimental study in sheep

<p>Abstract</p> <p>Background</p> <p>Osteoporosis and associated fractures are a major public health burden and there is great need for a large animal model. Melatonin, the hormone of the pineal gland, has been shown to influence bone metabolism. This study aims to evaluate whether absence of melatonin due to pinealectomy affects the bone mass, structure and remodeling in an ovine animal model.</p> <p>Methods</p> <p>Female sheep were arranged into four groups: Control, surgically ovariectomized (Ovx), surgically pinealectomized (Px) and Ovx+Px. Before and 6 months after surgery, iliac crest biopsies were harvested and structural parameters were measured using μCT. Markers of bone formation and resorption were determined. To evaluate long term changes after pinealectomy, bone mineral density (BMD) was analyzed at the distal radius at 0, 3, 9, 18 and 30 months.</p> <p>Results</p> <p>Cancellous bone volume (BV/TV) declined after 6 months by -13.3% Px and -21.5% OvxPx. The bone loss was due to increased trabecular separation as well as decreased thickness. The histomorphometric quantification and determination of collagen degradation products showed increased bone resorption following pinealectomy. Ovariectomy alone results in a transient bone loss at the distal radius followed by continuous increase to baseline levels. The bone resorption activity after pinealectomy causes a bone loss which was not transient, since a continuous decrease in BMD was observed until 30 months.</p> <p>Conclusions</p> <p>The changes after pinealectomy in sheep are indicative of bone loss. Overall, these findings suggest that the pineal gland may influence bone metabolism and that pinealectomy can be used to induce bone loss in sheep.</p

Bone turnover markers in sheep and goat: a review of the scientific literature

Bone turnover markers (BTMs) are product of bone cell activity and are generally divided in bone formation and bone resorption markers. The purpose of this review was to structure the available information on the use of BTMs in studies on small ruminants, especially for monitoring their variations related to diet, exercise, gestation and metabolic lactation state, circadian and seasonal variations, and also during skeletal growth. Pre-clinical and translational studies using BTMs with sheep and goats as animal models in orthopaedic research studies to help in the evaluation of the fracture healing process and osteoporosis research are also described in this review. The available information from the reviewed studies was systematically organized in order to highlight the most promising BTMs in small ruminant research, as well as provide a wide view of the use of sheep and goat as animal models in orthopaedic research, type of markers and commercial assay kits with cross-reactivity in sheep and goat, method of sample and storage of serum and urine for bone turnover markers determination and the usefulness and limitations of bone turnover markers in the different studies, therefore an effective tool for researchers that seek answers to different questions while using BTMs in small ruminants.José Arthur de A. Camassa acknowledges to the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil, for his PhD scholarship 202248/2015-1.info:eu-repo/semantics/publishedVersio

Probing the Interaction of the Diarylquinoline TMC207 with Its Target Mycobacterial ATP Synthase

Infections with Mycobacterium tuberculosis are substantially increasing on a worldwide scale and new antibiotics are urgently needed to combat concomitantly emerging drug-resistant mycobacterial strains. The diarylquinoline TMC207 is a highly promising drug candidate for treatment of tuberculosis. This compound kills M. tuberculosis by binding to a new target, mycobacterial ATP synthase. In this study we used biochemical assays and binding studies to characterize the interaction between TMC207 and ATP synthase. We show that TMC207 acts independent of the proton motive force and does not compete with protons for a common binding site. The drug is active on mycobacterial ATP synthesis at neutral and acidic pH with no significant change in affinity between pH 5.25 and pH 7.5, indicating that the protonated form of TMC207 is the active drug entity. The interaction of TMC207 with ATP synthase can be explained by a one-site binding mechanism, the drug molecule thus binds to a defined binding site on ATP synthase. TMC207 affinity for its target decreases with increasing ionic strength, suggesting that electrostatic forces play a significant role in drug binding. Our results are consistent with previous docking studies and provide experimental support for a predicted function of TMC207 in mimicking key residues in the proton transfer chain and blocking rotary movement of subunit c during catalysis. Furthermore, the high affinity of TMC207 at low proton motive force and low pH values may in part explain the exceptional ability of this compound to efficiently kill mycobacteria in different microenvironments