The (in)dependence of alternative splicing and gene duplication

Alternative splicing (AS) and gene duplication (GD) both are processes that diversify the protein repertoire. Recent examples have shown that sequence changes introduced by AS may be comparable to those introduced by GD. In addition, the two processes are inversely correlated at the genomic scale: large gene families are depleted in splice variants and vice versa. All together, these data strongly suggest that both phenomena result in interchangeability between their effects. Here, we tested the extent to which this applies with respect to various protein characteristics. The amounts of AS and GD per gene are anticorrelated even when accounting for different gene functions or degrees of sequence divergence. In contrast, the two processes appear to be independent in their influence on variation in mRNA expression. Further, we conducted a detailed comparison of the effect of sequence changes in both alternative splice variants and gene duplicates on protein structure, in particular the size, location, and types of sequence substitutions and insertions/deletions. We find that, in general, alternative splicing affects protein sequence and structure in a more drastic way than gene duplication and subsequent divergence. Our results reveal an interesting paradox between the anticorrelation of AS and GD at the genomic level, and their impact at the protein level, which shows little or no equivalence in terms of effects on protein sequence, structure, and function. We discuss possible explanations that relate to the order of appearance of AS and GD in a gene family, and to the selection pressure imposed by the environment.     

Spatial scale,topography and thermoregulatory behaviour interact when modelling species’ thermal niches

The spatial scale at which climate and species’ occupancy data are gathered, and the resolution at which ecological models are run, can strongly influence predictions of species performance and distributions. Running model simulations at coarse rather than fine spatial resolutions, for example, can determine if a model accurately predicts the distribution of a species. The impacts of spatial scale on a model's accuracy are particularly pronounced across mountainous terrain. Understanding how these discrepancies arise requires a modelling approach in which the underlying processes that determine a species’ distribution are explicitly described. Here we use a process‐based model to explore how spatial resolution, topography and behaviour alter predictions of a species thermal niche, which in turn constrains its survival and geographic distribution. The model incorporates biophysical equations to predict the operative temperature (T_e), thermal‐dependent performance and survival of a typical insect, with a complex life‐cycle, in its microclimate. We run this model with geographic data from a mountainous terrain in South Africa using climate data at three spatial resolutions. We also explore how behavioural thermoregulation affects predictions of a species performance and survival by allowing the animal to select the optimum thermal location within each coarse‐grid cell. At the regional level, coarse‐resolution models predicted lower T_e at low elevations and higher T_e at high elevations than models run at fine‐resolutions. These differences were more prominent on steep, north‐facing slopes. The discrepancies in T_e in turn affected estimates of the species thermal niche. The modelling framework revealed how spatial resolution and topography influence predictions of species distribution models, including the potential impacts of climate change. These systematic biases must be accounted for when interpreting the outputs of future modelling studies, particularly when species distributions are predicted to shift from uniform to topographically heterogeneous landscapes.     

Optimization of α-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site

We have optimized a novel series of potent p38 MAP kinase inhibitors based on an α-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions.     

Theoretical calculations, synthesis and base pairing properties of oligonucleotides containing 8-amino-2'-deoxyadenosine

Theoretical calculations on double and triple helices containing 8-amino-2'-deoxyadenosine were made to analyze the possible differences in base pairing properties between 8-aminoadenine and adenine. These calculations indicate a strong preferential stabilization of the triplex over the duplex when adenine is replaced by 8-aminoadenine. In addition, a protected phosphoramidite derivative of 8-amino-2'-deoxyadenosine was prepared for the introduction of 8-aminoadenine into synthetic oligonucleotides using the phosphite-triester approach. DNA triple helical structures are normally observed at acidic pH. However, when oligonucleotides carrying 8-aminoadenine are used, very stable triple helical structures can be observed even at neutral pH. Biological applications of triple helices could benefit from the use of 8-aminoadenine derivatives.     

Phylogenetic relationships in Bupleurum (apiaceae) based on nuclear ribosomal DNA its sequence data

BACKGROUND AND AIMS: The genus Bupleurum has long been recognized as a natural group, but its infrageneric classification is controversial and has not yet been studied in the light of sequence data. METHODS: Phylogenetic relationships among 32 species (35 taxa) of the genus Bupleurum were investigated by comparative sequencing of the ITS region of the 18-26S nuclear ribosomal DNA repeat. Exemplar taxa from all currently accepted sections and subsections of the genus were included, along with outgroups from four other early branching Apioideae genera (Anginon, Heteromorpha, Physospermum and Pleurospermum). RESULTS: Phylogenies generated by maximum parsimony, maximum likelihood, and neighbour-joining methods show similar topologies, demonstrating monophyly of Bupleurum and the division of the genus into two major clades. This division is also supported by analysis of the 5.8S coding sequence alone. The first branching clade is formed by all the species of the genus with pinnate-reticulate veined leaves and B. rigidum with a unique type of leaf venation. The other major clade includes the remaining species studied, all of which have more or less parallel-veined leaves. CONCLUSIONS: These phylogenetic results do not agree with any previous classifications of the genus. Molecular data also suggest that the endemic Macaronesian species B. salicifolium is a neoendemic, as the sequence divergence between the populations in Madeira and Canary Islands, and closer mainland relatives in north-west Africa is small. All endemic north-west African taxa are included in a single unresolved but well-supported clade, and the low nucleotide variation of ITS suggests a recent radiation within this group. The only southern hemisphere species, B. mundii (southern Africa), is shown to be a neoendemic, apparently closely related to B. falcatum, a Eurasian species.