Synthesis, biological evaluation and molecular modelling of sulfonohydrazides as selective PI3K p110alpha inhibitors

A series of 2-methyl-5-nitrobenzenesulfonohydrazides were prepared and evaluated as inhibitors of PI3K. An isoquinoline derivative shows good selectivity for the p110α isoform over p110β and p110δ, and also demonstrates good in vitro activity in a cell proliferation assay. Molecular modelling provides a rationalisation for the observed SAR.     

Influences on circulating oestrogens in postmenopausal women: relationship with breast cancer

Sex hormones are intrinsically linked to the development and treatment of the majority of breast cancers. High oestradiol levels are associated with elevated breast cancer risk in the postmenopausal setting and are given increasing importance in determining chemoprevention target groups. This review aims to evaluate the impact of various lifestyle factors including body mass index, diet, smoking, and alcohol on normal physiological sex hormone profiles. The role of genetic polymorphisms is also discussed, and all are placed within the context of designing future epidemiological studies and breast cancer risk algorithms.     

Functional foods from biotech--an unappetizing prospect?

In the early 1990s, functional foods promised to solve global malnutrition and put palatable options for treating ailments on grocery shelves. Since then, a meager number of products have ripened while the rest have turned sour.     

Influence of type of muscle contraction, gender, and lifting experience on postactivation potentiation performance

Postactivation potentiation (PAP) or enhanced contractile capabilities may be influenced by a number of factors. This study examined the influence of type of muscle contraction (isometric vs. dynamic), gender, and previous weightlifting experience on PAP as demonstrated by changes in jump height and power output. Thirty young men (n = 15) and women (n = 15), classified as either having previous weightlifting experience (n = 20) or not (n = 10), performed 3 different sets of countermovement jumps, with the first set used to determine baseline measures of jump height and power. The second set was performed after a maximal isometric squat protocol (maximal voluntary contraction [MVC]-PAP) to induce PAP, and the third set of jumps was performed after a maximal dynamic squat (DS) protocol (DS-PAP). A 3-way repeated measures analysis of variance determined that jump height after the MVC-PAP protocol was significantly higher than both the pretest and DS-PAP values, that men performed significantly better than women, and that the experienced lifters responded more favorably than the inexperienced lifters. Jump power was also significantly greater for the MVC-PAP condition compared with the other 2 conditions, and DS-PAP power also improved when compared with the pretest values, with men performing significantly better than women. All results remained consistent after accounting for height and weight differences (body mass index) between the groups. In conclusion, the isometric condition (MVC-PAP) evoked a greater muscle postactivation potentiation than the dynamic condition (DS-PAP), and postactivation was enhanced by previous weightlifting experience. The practical manipulation of MVC by pushing, squatting, or both against fixed objects, such as walls and low ceilings, could be a very simple and cost-effective way to arouse a state of PAP before sports performance that requires high force and power outputs.     

Quantification of global transcription patterns in prokaryotes using spotted microarrays

We describe an analysis, applicable to any spotted microarray dataset produced using genomic DNA as a reference, that quantifies prokaryotic levels of mRNA on a genome-wide scale. Applying this to Mycobacterium tuberculosis, we validate the technique, show a correlation between level of expression and biological importance, define the complement of invariant genes and analyze absolute levels of expression by functional class to develop ways of understanding an organism's biology without comparison to another growth condition.     

Application of biomaterials to advance induced pluripotent stem cell research and therapy

Derived from any somatic cell type and possessing unlimited self-renewal and differentiation potential, induced pluripotent stem cells (iPSCs) are poised to revolutionize stem cell biology and regenerative medicine research, bringing unprecedented opportunities for treating debilitating human diseases. To overcome the limitations associated with safety, efficiency, and scalability of traditional iPSC derivation, expansion, and differentiation protocols, biomaterials have recently been considered. Beyond addressing these limitations, the integration of biomaterials with existing iPSC culture platforms could offer additional opportunities to better probe the biology and control the behavior of iPSCs or their progeny in vitro and in vivo. Herein, we discuss the impact of biomaterials on the iPSC field, from derivation to tissue regeneration and modeling. Although still exploratory, we envision the emerging combination of biomaterials and iPSCs will be critical in the successful application of iPSCs and their progeny for research and clinical translation.     

van der Waals forces influencing adhesion of cells

Adhesion molecules, often thought to be acting by a ‘lock and key’ mechanism, have been thought to control the adhesion of cells. While there is no doubt that a coating of adhesion molecules such as fibronectin on a surface affects cell adhesion, this paper aims to show that such surface contamination is only one factor in the equation. Starting from the baseline idea that van der Waals force is a ubiquitous attraction between all molecules, and thereby must contribute to cell adhesion, it is clear that effects from geometry, elasticity and surface molecules must all add on to the basic cell attractive force. These effects of geometry, elasticity and surface molecules are analysed. The adhesion force measured between macroscopic polymer spheres was found to be strongest when the surfaces were absolutely smooth and clean, with no projecting protruberances. Values of the measured surface energy were then about 35 mJ m⁻², as expected for van der Waals attractions between the non-polar molecules. Surface projections such as abrasion roughness or dust reduced the molecular adhesion substantially. Water cut the measured surface energy to 3.4 mJ m⁻². Surface active molecules lowered the adhesion still further to less than 0.3 mJ m⁻². These observations do not support the lock and key concept.     

Structural Studies of Truncated Forms of the Prion Protein PrP

Prions are proteins that adopt self-propagating aberrant folds. The self-propagating properties of prions are a direct consequence of their distinct structures, making the understanding of these structures and their biophysical interactions fundamental to understanding prions and their related diseases. The insolubility and inherent disorder of prions have made their structures difficult to study, particularly in the case of the infectious form of the mammalian prion protein PrP. Many investigators have therefore preferred to work with peptide fragments of PrP, suggesting that these peptides might serve as structural and functional models for biologically active prions. We have used x-ray fiber diffraction to compare a series of different-sized fragments of PrP, to determine the structural commonalities among the fragments and the biologically active, self-propagating prions. Although all of the peptides studied adopted amyloid conformations, only the larger fragments demonstrated a degree of structural complexity approaching that of PrP. Even these larger fragments did not adopt the prion structure itself with detailed fidelity, and in some cases their structures were radically different from that of pathogenic PrP^Sc.     

Why replication is important in landscape genetics: American black bear in the Rocky Mountains

We investigated how landscape features influence gene flow of black bears by testing the relative support for 36 alternative landscape resistance hypotheses, including isolation by distance (IBD) in each of 12 study areas in the north central U.S. Rocky Mountains. The study areas all contained the same basic elements, but differed in extent of forest fragmentation, altitude, variation in elevation and road coverage. In all but one of the study areas, isolation by landscape resistance was more supported than IBD suggesting gene flow is likely influenced by elevation, forest cover, and roads. However, the landscape features influencing gene flow varied among study areas. Using subsets of loci usually gave models with the very similar landscape features influencing gene flow as with all loci, suggesting the landscape features influencing gene flow were correctly identified. To test if the cause of the variability of supported landscape features in study areas resulted from landscape differences among study areas, we conducted a limiting factor analysis. We found that features were supported in landscape models only when the features were highly variable. This is perhaps not surprising but suggests an important cautionary note - that if landscape features are not found to influence gene flow, researchers should not automatically conclude that the features are unimportant to the species' movement and gene flow. Failure to investigate multiple study areas that have a range of variability in landscape features could cause misleading inferences about which landscape features generally limit gene flow. This could lead to potentially erroneous identification of corridors and barriers if models are transferred between areas with different landscape characteristics.