Predictability and evolutionary determinism - the search for quantitative explanationquantitative explanation.

Physics describes reality through the understanding and elucidation of physical laws. From these laws, the universe is predictable. It has indeed been suggested that explanation of observable phenomena comes from our ability to predict these events, through our understanding of physical laws and causal processes.

Selective Hydroxylation of C(sp )-H Bonds in Steroids.

Steroids are highly prevalent structures in small-molecule therapeutics, with the level of oxidation being key to their biological activity and physicochemical properties. These C(sp )-rich tetracycles contain many stereocentres, which are important for creating specific vectors and protein binding orientations. Therefore, the ability to hydroxylate steroids with a high degree of regio-, chemo- and stereoselectivity is essential for researchers working in this field.

Population Genetics: How Many Variable Genes Affect Variable Traits?

How many genes control a given trait? And are genes with defined knockout phenotypes affecting a given trait the same genes that also underlie population-wide variation in that trait? A new study in Drosophila melanogaster has some surprising answers.

Alternative evolutionary outcomes following endosymbiont-mediated selection on male mating preference alleles.

In many arthropods, intracellular bacteria, such as those of the genus Wolbachia, may spread through host populations as a result of cytoplasmic incompatibility (CI). Here, there is sterility or reduced fertility in crosses between infected males and uninfected females. As the bacterium is maternally inherited, the reduced fertility of uninfected females increases the frequency of the infection.

Genetic Variation: Harmful Recessive Mutations Have Unexpected Effects on Variation.

New data are causing the standard model for the effect of selection on linked neutral variation in low recombination regions, combining the effects of background selection and selective sweeps, to be refined to include harmful recessive mutations creating associative overdominance.

Group antenatal care for Aboriginal and Torres Strait Islander women: An acceptability study.

Background: Good quality antenatal care is essential to improve the perinatal outcomes of Aboriginal and Torres Strait Islander women in Australia. Group antenatal care (GAC) is an innovative model which places clinical assessment, education and social support into a group setting. Previous studies have found GAC to be associated with improved perinatal outcomes, particularly for vulnerable populations, and high satisfaction levels among group members.

Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models.

Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.

Mutation Rates: Simpler Than We Thought?

Mutation rate variation is often explained by varying optimal rates, or through effective population sizes determining the effectiveness of selection. But a rate difference between humans and owl monkeys is now explained mechanistically as a consequence of differing reproductive longevities.

Biased image cropping and non-independent samples.

Any figure in a research article will typically represent only a small portion of the total data gained by a researcher for that experiment, and it is therefore key that the figure accurately reflects what was found overall. Furthermore, if individual observations form clusters with differing mean properties, those individual observations would not represent independent samples from the populations being compared. In this example, the question of how to fairly represent and treat image data is addressed.

Why are estimates of the strength and direction of natural selection from wild populations not congruent with observed rates of phenotypic change?

Observing adaptive evolution is difficult. In the fossil record, phenotypic evolution happens much more slowly than in artificial selection experiments or in experimental evolution. Yet measures of selection on phenotypic traits, with high heritabilities, suggest that phenotypic evolution should also be rapid in the wild, and this discrepancy often remains even after accounting for correlations between different traits (i.

LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation.

The actin and microtubule cytoskeletons are critically important for cancer cell proliferation, and drugs that target microtubules are widely-used cancer therapies. However, their utility is compromised by toxicities due to dose and exposure. To overcome these issues, we characterized how inhibition of the actin and microtubule cytoskeleton regulatory LIM kinases could be used in drug combinations to increase efficacy.

Discovery, Development, and SAR of Aminothiazoles as LIMK Inhibitors with Cellular Anti-Invasive Properties.

As part of a program to develop a small molecule inhibitor of LIMK, a series of aminothiazole inhibitors were discovered by high throughput screening. Scaffold hopping and subsequent SAR directed development led to a series of low nanomolar inhibitors of LIMK1 and LIMK2 that also inhibited the direct biomarker p-cofilin in cells and inhibited the invasion of MDA MB-231-luc cells in a matrigel inverse invasion assay.

Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3.

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing.

Transposable element invasions.

Transposable elements have an ongoing, largely parasitic interaction with their hosts. We are interested in the timescale of this interaction. In a recent publication, we have examined the sequence divergence between class II DNA transposons from mammalian genomes.

Alu elements in primates are preferentially lost from areas of high GC content.

The currently-accepted dogma when analysing human Alu transposable elements is that 'young' Alu elements are found in low GC regions and 'old' Alus in high GC regions. The correlation between high GC regions and high gene frequency regions make this observation particularly difficult to explain. Although a number of studies have tackled the problem, no analysis has definitively explained the reason for this trend.

Quantitative genetics: heritability is not always missing.

Quantitative trait loci (QTLs) underlying multifactorial disorders explain little of the heritability - most is 'missing'. A new yeast study has identified QTLs which explain most heritability in traits. Why is heritability missing in human diseases but not here?

Aedes aegypti mosquitoes exhibit decreased repellency by DEET following previous exposure.

DEET (N,N-Diethyl-m-toluamide) is one of the most widely used mosquito repellents. Although DEET has been shown to be extremely effective, recent studies have revealed that certain individual insects are unaffected by its presence. A genetic basis for this has been shown in Aedes aegypti mosquitoes and the fruit fly Drosophila melanogaster, but, for the triatomine bug, Rhodnius prolixus, a decrease in response to DEET occurred shortly after previous exposure, indicating that non-genetic factors may also be involved in DEET "insensitivity".

The diversity of class II transposable elements in mammalian genomes has arisen from ancestral phylogenetic splits during ancient waves of proliferation through the genome.

DNA transposons make up 3% of the human genome, approximately the same percentage as genes. However, because of their inactivity, they are often ignored in favor of the more abundant, active, retroelements. Despite this relative ignominy, there are a number of interesting questions to be asked of these transposon families.

Investigation of the origin and spread of a Mammalian transposable element based on current sequence diversity.

Almost half the human genome consists of mobile DNA elements, and their analysis is a vital part of understanding the human genome as a whole. Many of these elements are ancient and have persisted in the genome for tens or hundreds of millions of years, providing a window into the evolution of modern mammals. The Golem family have been used as model transposons to highlight computational analyses which can be used to investigate these elements, particularly the use of molecular dating with large transposon families.

Host-parasite relationships in the genome.

Transposable elements are best interpreted as genomic parasites, proliferating in genomes through their over-replication relative to the rest of the genome. A new study examining correlations across Drosophila species between transposable element numbers and rates of host evolution has brought into focus one of the most complex questions in transposable element biology-what it is that determines the proportion of the genome that is transposable elements.

Behavioral insensitivity to DEET in Aedes aegypti is a genetically determined trait residing in changes in sensillum function.

N,N-Diethyl-m-toluamide (DEET) is one of the most effective and commonly used mosquito repellents. However, during laboratory trials a small proportion of mosquitoes are still attracted by human odors despite the presence of DEET. In this study behavioral assays identified Aedes aegypti females that were insensitive to DEET, and the selection of either sensitive or insensitive groups of females with males of unknown sensitivity over several generations resulted in two populations with different proportions of insensitive females.