Small structural changes of the imidazopyridine diacylglycerol acyltransferase 2 (DGAT2) inhibitors produce an improved safety profile.

Small molecule DGAT2 inhibitors have shown promise for the treatment of metabolic diseases in preclinical models. Herein, we report the first toxicological evaluation of imidazopyridine-based DGAT2 inhibitors and show that the arteriopathy associated with imidazopyridine 1 can be mitigated with small structural modifications, and is thus not mechanism related.

Affine versus non-affine deformation in soft biological tissues, measured by the reorientation and stretching of collagen fibres through the thickness of compressed porcine skin.

Skin is a complex three-dimensional structure of cells, collagen fibres and other proteins. However most mechanical analyses treat skin as a two-dimensional membrane, neglecting the through thickness structure. In this paper we investigate through thickness reorientation of collagen fibres. The mode of deformation of skin is also considered. For modelling purposes deformation is usually assumed to be affine. This assumption was tested by constructing a simple geometrical, affine deformation model to predict the through thickness reorientation of collagen fibres, from their initial through thickness angle and the measured deformations of skin samples during compression. The measured reorientation of collagen fibres was found to be very variable, however the average reorientations were consistent with the predictions of the model, with the inclusion of a systematic error. The variation in the reorientation of individual fibres can be explained by the variations in the structure at a micrometre scale. The systematic deviation of reorientations from the model predictions can be explained by a non-affine relationship between the collagen fibres and ground substance at a micrometre scale. However, non-affine deformations at a micrometre scale caused by irregularities of structure are likely to average out at a millimetre scale, because at this level material is evenly distributed.

Further evaluation of probabilities in human scalp hair comparisons.

Placing value on associative hair evidence is an integral part of court presentation. A modified repeat of the hair probability study by Gaudette and Keeping has been undertaken, with steps taken to remedy shortcomings of the original work. The results of this study demonstrate that, with the application of rigid selection criteria, the frequency of coincidental matches in forensic science hair comparisons is low. It also demonstrates that routine hair classification is not feasible, because of inconsistency in examiner discrimination. The macroscopic selection of 5 to 13 mutually dissimilar hairs has been shown to be frequently unrepresentative of the microscopic range of features present in a known hair sample.

Ecological factors in rehabilitation of patients with severe spinal cord injuries.

The psychological perspective of disability views the extent of disability as substantially determined by the availability of essential resources in the physical and social environments of people with disabilities. This article reports the findings of a study of the post-hospital adjustment of individuals treated for injuries that produced paraplegia or quadriplegia. Comparisons of emotional and social adjustments were made between groups of respondents contrasted by size of community, independent living vs. physical dependence, employment status, and degree of social interaction. Resultant data documented the critical importance of these ecological variables. Practice implications of the findings are discussed.

Total synthesis of 16-desmethylepothilone B, epothilone B10, epothilone F, and related side chain modified epothilone B analogues.

The macrolactonization-based strategy for the total synthesis of epothilones has been streamlined and improved to a high level of efficiency and stereoselectivity. This strategy has been applied to the construction of vinyl iodide 19 which served as a common intermediate for the synthesis of a series of natural and designed epothilones including an epothilone B10 (3), epothilone F (5), 16-desmethylepothilone B (14), pyridine epothilones 57a-57g, dimeric epothilones 59 and 61, and benzenoid epothilones 63a-63g.

Total synthesis of epothilone E and related side-chain modified analogues via a Stille coupling based strategy.

A Stille coupling strategy has been utilized to complete a total synthesis of epothilone E from vinyl iodide 7 and thiazole-stannane 8h. The central core fragment 7 and its trans-isomer 11 were prepared from triene 15 using ring-closing metathesis (RCM), and were subsequently coupled to a variety of alternative stannanes to provide a library of epothilone analogues 18a-o and 19a-o. The Stille coupling approach was then used to prepare epothilone B analogues from the key macrolactone intermediate 24 which was itself synthesized by a macrolactonization based strategy.