Synthesis of novel substituted pyrimidine derivatives bearing a sulfamide group and their in vitro cancer growth inhibition activity

The synthesis of two series of novel substituted pyrimidine derivatives bearing a sulfamide group have been described and their in vitro cancer growth inhibition activities have been evaluated against three human tumour cell lines (HT-29, M21, and MCF7). In general, growth inhibition activity has been enhanced by the introduction of a bulky substituent on the aromatic ring with the best compound having GI₅₀ < 6 μM for all the human tumour cell lines. The MCF7 selective compounds were evaluated on four additional human invasive breast ductal carcinoma cell lines (MDA-MB-231, MDA-MB-468, SKBR3, and T47D) and were selective against T47D cell line in all cases except one, suggesting a potential antiestrogen activity.     

Biogenesis of nanotubular network in Toxoplasma parasitophorous vacuole induced by parasite proteins

The intracellular parasite Toxoplasma gondii develops within a nonfusogenic vacuole containing a network of elongated nanotubules that form connections with the vacuolar membrane. Parasite secretory proteins discharged from dense granules (known as GRA proteins) decorate this intravacuolar network after invasion. Herein, we show using specific gene knockout mutants, that the unique nanotubule conformation of the network is induced by the parasite secretory protein GRA2 and further stabilized by GRA6. The vacuolar compartment generated by GRA2 knockout parasites was dramatically disorganized, and the normally tubular network was replaced by small aggregated material. The defect observed in Deltagra2 parasites was evident from the initial stages of network formation when a prominent cluster of multilamellar vesicles forms at a posterior invagination of the parasite. The secretory protein GRA6 failed to localize properly to this posterior organizing center in Deltagra2 cells, indicating that this early conformation is essential to proper assembly of the network. Construction of a Deltagra6 mutant also led to an altered mature network characterized by small vesicles instead of elongated nanotubules; however, the initial formation of the posterior organizing center was normal. Complementation of the Deltagra2 knockout with mutated forms of GRA2 showed that the integrity of both amphipathic alpha-helices of the protein is required for correct formation of the network. The induction of nanotubues by the parasite protein GRA2 may be a conserved feature of amphipathic alpha-helical regions, which have also been implicated in the organization of Golgi nanotubules and endocytic vesicles in mammalian cells.     

The significance of the sub-Antarctic Kerguelen Islands for the assessment of the vulnerability of native communities to climate change,alien insect invasions and plant viruses

The suite of environments and anthropogenic modifications of sub-Antarctic islands provide key opportunities to improve our understanding of the potential consequences of climate change and biological species invasions on terrestrial ecosystems. The profound impact of human introduced invasive species on indigenous biota, and the facilitation of establishment as a result of changing thermal conditions, has been well documented on the French sub-Antarctic Kerguelen Islands (South Indian Ocean). The present study provides an overview of the vulnerability of sub-Antarctic terrestrial communities with respect to two interacting factors, namely climate change and alien insects. We present datasets assimilated by our teams on the Kerguelen Islands since 1974, coupled with a review of the literature, to evaluate the mechanism and impact of biological invasions in this region. First, we consider recent climatic trends of the Antarctic region, and its potential influence on the establishment, distribution and abundance of alien insects, using as examples one fly and one beetle species. Second, we consider to what extent limited gene pools may restrict alien species’ colonisations. Finally, we consider the vulnerability of native communities to aliens using the examples of one beetle, one fly, and five aphid species taking into consideration their additional impact as plant virus vectors. We conclude that the evidence assimilated from the sub-Antarctic islands can be applied to more complex temperate continental systems as well as further developing international guidelines to minimise the impact of alien species.     

Spire and Cordon-bleu: multifunctional regulators of actin dynamics

WASP-homology 2 (WH2) domains, which were first identified in the WASP/Scar (suppressor of cAMP receptor)/WAVE (WASP-family verprolin homologous protein) family of proteins, are multifunctional regulators of actin assembly. Two recently discovered actin-binding proteins, Spire and Cordon-bleu (Cobl), which have roles in axis patterning in developmental processes, use repeats of WH2 domains to generate a large repertoire of novel regulatory activities, including G-actin sequestration, actin-filament nucleation, filament severing and barbed-end dynamics regulation. We describe how these multiple functions selectively operate in a cellular context to control the dynamics of the actin cytoskeleton. In vivo, Spire and Cobl can synergize with other actin regulators. As an example, we outline potential methods to gain insight into the functional basis for reported genetic interactions among Spire, profilin and formin.     

Neutral effect of recombination on base composition in Drosophila

Recombination is thought to have various evolutionary effects on genome evolution. In this study, we investigated the relationship between the base composition and recombination rate in the Drosophila melanogaster genome. Because of a current debate about the accuracy of the estimates of recombination rate in Drosophila, we used eight different measures of recombination rate from recent work. We confirmed that the G + C content of large introns and flanking regions is positively correlated with recombination rate, suggesting that recombination has a neutral effect on base composition in Drosophila. We also confirmed that this neutral effect of recombination is the main determinant of the correlation between synonymous codon usage bias and recombination rate in Drosophila.     

Actin-based motility: from molecules to movement

Extensive progress has been made recently in understanding the mechanism by which cells move and extend protrusions using site-directed polymerization of actin in response to signalling. Insights into the molecular mechanism of production of force and movement by actin polymerization have been provided by a crosstalk between several disciplines, including biochemistry, biomimetic approaches and computational studies. This review focuses on the biochemical properties of the proteins involved in actin-based motility and shows how these properties are used to generate models of force production, how the predictions of different theoretical models are tested using a biochemically controlled reconstituted motility assay and how the changes in motility resulting from changes to the concentrations of components of the assay can help understand diverse aspects of the motile behavior of living cells.     

The mutational burden of acral melanoma revealed by whole‐genome sequencing and comparative analysis

Acral melanoma is a subtype of melanoma with distinct epidemiological, clinical and mutational profiles. To define the genomic alterations in acral melanoma, we conducted whole‐genome sequencing and SNP array analysis of five metastatic tumours and their matched normal genomes. We identified the somatic mutations, copy number alterations and structural variants in these tumours and combined our data with published studies to identify recurrently mutated genes likely to be the drivers of acral melanomagenesis. We compared and contrasted the genomic landscapes of acral, mucosal, uveal and common cutaneous melanoma to reveal the distinctive mutational characteristics of each subtype.     

Single-filament kinetic studies provide novel insights into regulation of actin-based motility

Polarized assembly of actin filaments forms the basis of actin-based motility and is regulated both spatially and temporally. Cells use a variety of mechanisms by which intrinsically slower processes are accelerated, and faster ones decelerated, to match rates observed in vivo. Here we discuss how kinetic studies of individual reactions and cycles that drive actin remodeling have provided a mechanistic and quantitative understanding of such processes. We specifically consider key barbed-end regulators such as capping protein and formins as illustrative examples. We compare and contrast different kinetic approaches, such as the traditional pyrene-polymerization bulk assays, as well as more recently developed single-filament and single-molecule imaging approaches. Recent development of novel biophysical methods for sensing and applying forces will in future allow us to address the very important relationship between mechanical stimulus and kinetics of actin-based motility.     

Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa

Pseudoxanthoma elasticum (PXE) is a heritable elastic tissue disorder recently shown to be attributable to mutations in the ABCC6 ( MRP6) gene. Whereas PXE has been identified in all ethnic groups studied to date, the prevalence of this disease in various populations is uncertain, although often assumed to be similar. A notable exception however is the prevalence of PXE among South African Afrikaners. A previous report has suggested that a founder effect may explain the higher prevalence of PXE in Afrikaners, a European-derived population that first settled in South Africa in the 17th century. To investigate this hypothesis, we performed haplotype and mutational analysis of DNA from 24 South African families of Afrikaner, British and Indian descent. Among the 17 Afrikaner families studied, three common haplotypes and six different disease-causing variants were identified. Three of these mutant alleles were missense variants, two were nonsense mutations and one was a single base-pair insertion. The most common variant accounted for 53% of the PXE alleles, whereas other mutant alleles appeared at lower frequencies ranging from 3% to 12%. Haplotype analysis of the Afrikaner families showed that the three most frequent mutations were identical-by-descent, indicating a founder origin of PXE in this population.     

Oxidative pentose phosphate pathway-dependent sugar sensing as a mechanism for regulation of root ion transporters by photosynthesis

Root ion transport systems are regulated by light and/or sugars, but the signaling mechanisms are unknown. We showed previously that induction of the NRT2.1 NO(3)(-) transporter gene by sugars was dependent on carbon metabolism downstream hexokinase (HXK) in glycolysis. To gain further insights on this signaling pathway and to explore more systematically the mechanisms coordinating root nutrient uptake with photosynthesis, we studied the regulation of 19 light-/sugar-induced ion transporter genes. A combination of sugar, sugar analogs, light, and CO(2) treatments provided evidence that these genes are not regulated by a common mechanism and unraveled at least four different signaling pathways involved: regulation by light per se, by HXK-dependent sugar sensing, and by sugar sensing upstream or downstream HXK, respectively. More specific investigation of sugar-sensing downstream HXK, using NRT2.1 and NRT1.1 NO(3)(-) transporter genes as models, highlighted a correlation between expression of these genes and the concentration of glucose-6-P in the roots. Furthermore, the phosphogluconate dehydrogenase inhibitor 6-aminonicotinamide almost completely prevented induction of NRT2.1 and NRT1.1 by sucrose, indicating that glucose-6-P metabolization within the oxidative pentose phosphate pathway is required for generating the sugar signal. Out of the 19 genes investigated, most of those belonging to the NO(3)(-), NH(4)(+), and SO(4)(2-) transporter families were regulated like NRT2.1 and NRT1.1. These data suggest that a yet-unidentified oxidative pentose phosphate pathway-dependent sugar-sensing pathway governs the regulation of root nitrogen and sulfur acquisition by the carbon status of the plant to coordinate the availability of these three elements for amino acid synthesis.