Nonbenzamidine acylsulfonamide tissue factor–factor VIIa inhibitors

Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P′ binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype.     

SAR and factor IXa crystal structure of a dual inhibitor of factors IXa and Xa

Modifications to the P4 moiety and pyrazole C3 substituent of factor Xa inhibitor SN-429 provided several new compounds, which are 5-10nM inhibitors of factor IXa. An X-ray crystal structure of one example complexed to factor IXa shows that these compounds adopt a similar binding mode to that previously observed with pyrazole inhibitors in the factor Xa active site both with regard to how the inhibitor binds and the position of Tyr99.     

Rational design, synthesis and structure-activity relationships of a cyclic succinate series of TNF-alpha converting enzyme inhibitors. Part 2: lead optimization

Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-[[4-(4-quinolinyloxymethyl)anilinyl]carbonyl]-1-cyclohexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-alpha release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]-5-piperidinecarboxamide] exhibited an IC(50) value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs.     

The Israel National Skin Bank: Quality Assurance and Graft Performance of Stored Tissues

The Israel National Skin Bank (INSB) was founded jointly by the Israel Defense Forces (IDF) Medical Corps and the Ministry of Health in 1986. The prime purpose of the Skin Bank is to treat burn victims incurred at war or during mass casualty incidences. The INSB Protocol is comprised of international skin bank protocols and our previous and present research results. They provide the framework for selecting optimal guidelines for procurement, processing, preservation, storage and evaluation of transplantation performance of viable skin grafts. For evaluation and direct comparison of graft performance of glycerolized or cryopreserved skin stored for long periods, we have applied a mouse recipient model developed by us. This model assesses graft performance before the rejection process takes place. The in vivo design has inherent clinical relevance, which is especially appealing. Cryopreserved skin performed better than glycerolized skin (p > 0.027), but fresh skin performed significantly better than cryopreserved skin (p > 0.003), as analyzed by the Mann–Whitney non-parametric test. Then graft performance of skin specimens were cryopreserved by programmed or stepwise freezing and stored at -80°C or in liquid nitrogen for 1 and 6–10 months was evaluated. The average score of skin preserved by programmed freezing and stored in liquid nitrogen is the highest for both storage periods. This method has a highly significant advantage (p < 0.007) over the others for 6–10 months storage, evaluated by graft adherence. Several interaction factors determine the quality of cryopreserved skin. Highly significant is the interaction factor/'combined effect' of sample variability with the method of cryopreservation or with the storage period. Finally, the results of paired comparison of selected histology criteria of cryopreserved to fresh skin indicated that storage of skin for up to 5 years did not impair significantly its performance compared to fresh skin, whereas, after six years of storage, there was a highly significant (p < 0.001) impairment in skin quality. We offer a simplified in vivo model and analysis for cryopreserved skin graft performance, suggesting that the evaluation procedures, which are issues of great interest in skin banking, may help future skin banks to make informed choices and decisions regarding quality issues.     

Adherence of Bilophila wadsworthia to cultured human embryonic intestinal cells

Adherence of Bilophila wadsworthia to the cultured human embryonic intestinal cell line, Intestine 407 (Int 407), varied among the strains tested from strongly adherent (76-100% cells positive for one or more adherent bacteria) to non- or weakly adherent (0-25% positive cells). Although negative staining revealed that infrequent cells of an adherent strain, WAL 9077, the adherent type-strain, WAL 7959, and a non-adherent strain, WAL 8448, expressed loosely associated fimbrial structures, a role for these structures in adhesion could not be confirmed with either scanning or thin-section electron micrography. Ruthenium red staining of thin-section preparations and subsequent electron microscopy failed to reveal an extensive extracellular polysaccharide layer. SDS-PAGE analysis of crude outer membrane fractions of WAL 9077 and WAL 8448 demonstrated clear differences in their major and minor outer membrane protein components. Thus, we postulate that the adherence of B. wadsworthia to Int 407 cells is mediated by an outer membrane or cell wall component.     

Two-step, predictive, isometric force model tested on data from human and rat muscles

Functionalelectrical stimulation can assist paralyzed individuals to performfunctional movements, but muscle fatigue is a major limitation to itspractical use. An accurate and predictive mathematical model canfacilitate the design of stimulation patterns that optimize aspects ofthe force transient while minimizing fatigue. Solution nonuniqueness, amajor shortcoming in previous work, was overcome with a simpler model.The model was tested on data collected during isometric contractions ofrat gastrocnemius muscles and human quadriceps femoris muscles undervarious physiological conditions. For each condition tested, parametervalues were identified using the force response to one or twostimulation trains. The parameterized model was then used to predictforces in response to other stimulation patterns. The predicted forcesclosely matched the measured forces. The model was not sensitive toinitial parameter estimates, demonstrating solution uniqueness. Bypredicting the force that develops in response to an arbitrary patternof stimulation, we envision the present model helping identify optimalstimulation patterns for activation of skeletal muscle duringfunctional electrical stimulation.

     

Photoperiod-induced differences in uterine growth in Phodopus sungorus are evident at an early age when serum estradiol and uterine estrogen receptor levels are not different

Sexual development is inhibited in Siberian hamsters (Phodopus sungorus) in short days (SD), and a small uterus is an obvious indicator of photo-inhibition. The small uterus in SD is presumably due to the delayed onset of estrous cycles. However, in an earlier study, the investigators reported that serum estradiol (E2) concentration was significantly higher in young females raised in SD than in long days (LD), with the highest concentrations measured in SD at 4 weeks of age. These seemingly contradictory findings were investigated in the present study. First, uterine mass and body mass were measured in SD- and LD-reared hamsters from 1 to 12 weeks of age. Uterine mass was significantly greater in LD than in SD by 3 weeks of age and onward. Thereafter, our investigation focused on 4-week-old hamsters. Serum E2 concentrations in LD and in SD were not significantly different and there were no significant LD–SD differences in uterine estrogen receptors (ER), as measured by immunohistochemistry and quantitative real-time RT-PCR. Therefore, alternative explanations for the photoperiodic difference in uterine size in young Siberian hamsters are considered.     

A unified probabilistic model of the perception of three-dimensional structure from optic flow

Human observers can perceive the three- dimensional (3-D) structure of their environment using various cues, an important one of which is optic flow. The motion of any point’s projection on the retina depends both on the point’s movement in space and on its distance from the eye. Therefore, retinal motion can be used to extract the 3-D structure of the environment and the shape of objects, in a process known as structure-from-motion (SFM). However, because many combinations of 3-D structure and motion can lead to the same optic flow, SFM is an ill-posed inverse problem. The rigidity hypothesis is a constraint supposed to formally solve the SFM problem and to account for human performance. Recently, however, a number of psychophysical results, with both moving and stationary human observers, have shown that the rigidity hypothesis alone cannot account for human performance in SFM tasks, but no model is known to account for the new results. Here, we construct a Bayesian model of SFM based mainly on one new hypothesis, that of stationarity, coupled with the rigidity hypothesis. The predictions of the model, calculated using a new and powerful methodology called Bayesian programming, account for a wide variety of experimental findings.