In pursuit of negative Fukui functions: examples where the highest occupied molecular orbital fails to dominate the chemical reactivity

In our quest to explore molecules with chemically significant regions where the Fukui function is negative, we explored reactions where the frontier orbital that indicates the sites for electrophilic attack is not the highest occupied molecular orbital. The highest occupied molecular orbital (HOMO) controls the location of the regions where the Fukui function is negative, supporting the postulate that negative values of the Fukui function are associated with orbital relaxation effects and nodal surfaces of the frontier orbitals. Significant negative values for the condensed Fukui function, however, were not observed.

Assessment of TRPM7 functions by drug-like small molecules

Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a plasma membrane ion channel linked to a cytosolic protein kinase domain. Genetic inactivation of this bi-functional protein revealed its crucial role in Ca²⁺ signalling, Mg²⁺ metabolism, immune responses, cell motility, proliferation and differentiation. Malfunctions of TRPM7 are associated with anoxic neuronal death, cardiac fibrosis, tumour progression and macrothrombocytopenia. Recently, several groups have identified small organic compounds acting as inhibitors or activators of the TRPM7 channel. In follow-up studies, the identified TRPM7 modulators were successfully used to uncover new cellular functions of TRPM7 in situ including a crucial role of TRPM7 in Ca²⁺ signaling and Ca²⁺ dependent cellular processes. Hence, TRPM7 has been defined as a promising drug target. Here, we summarize the progress in this quickly developing field.     

In pursuit of ecotourism

Ecotourism is expected, by the tourism industry and academics, to grow rapidly over the next 20 years. Much has been written about ecotourism, often with missionary zeal, but there is little consensus about its definition. It is argued here that conservationists and protected area managers should adopt a definition of ecotourism which contributes to the maintenance of biodiversity and an appropriate definition is suggested.Ecotourism is not merely an alternative to mass tourism, nor is it the only alternative. The literature on nature tourism and the environmental impacts of the industry dates back to the late 1970s. Tourism is now the world's largest industry and it has an increasing impact on protected areas. Our understanding of these mechanisms, their ecological impacts and our capacity to manage tourism in protected areas lags behind the growth of tourism to protected areas.A rapid growth in nature tourism and tourism to protected areas has coincided with a shift in protected area management strategies towards integrated development. Tourism is one means available to protected area managers seeking to increase the economic value of a protected area and to offer sustainable opportunities for economic development to local people.This paper argues that potentially conflicting commercial, protected area and development interests all contribute to the emergence of ecotourism and have been doing so for many years. Ecotourism needs to be tightly defined if it is to benefit conservation. Protected area managers should consider how they can take control of nature tourism to the parks they manage and convert it into ecotourism for the benefit of conservation and the livelihoods of local people.     

In pursuit of the functions of the Wnt family of developmental regulators: Insights from Xenopus laevis

Wnts are a recently described family of secreted glycoproteins related to the Drosophila segment polarity gene, wingless, and to the proto-oncogene, int-1. Wnts are thought to function as developmental modulators, with signalling distances of only a few cell diameters. In Xenopus, at least six Wnts, including Xwnts-1, -3A, and -4, are expressed initially in the developing central nervous system, with some regions expressing multiple Xwnts. Xwnt-8 is expressed by mid-blastula stage, in ventral and lateral mesoderm. Xwnt-5A mRNAs are stored in the egg, and later are expressed throughout the embryo in both ectoderm and mesoderm, but with a pronounced enrichment in the head and tail. Recent studies in Xenopus have pursued the diverse roles of Xwnts in early development, the mechanisms by which Xwnts signal information between cells, and the cell physiological responses to Xwnt signals.     

In pursuit of effective toxicogenomics

Biological systems exhibit complex responses to xenobiotics varying from generic stress responses to very specific changes closely associated with the mechanism of toxicity. Until recently our view of this complexity was obscured by the simplicity of available analysis tools which allowed determination of only a few genes in any one study. Then genome sequencing and high throughput library screening projects delivered data on the genome sequence of many organisms, and clones were collected and made available to researchers in a previously unparalleled quantity. To exploit this new resource the microarray was developed from its predecessor the dot blot. Further development has expanded the number of clones contained on any one microarray to a point where the expression of many tens of thousands of genes in a biological system can be determined in a short period of time. What these data are revealing is the full complexity of the gene expression response to stimuli such as xenobiotic exposure. Toxicogenomics seeks to use the complexity of this response as a fingerprint or signature characteristic of that xenobiotic exposure. There are though two major experimental challenges that need to be dealt with for toxicogenomics to be successful. The first is technical and relates to the intrinsic difficulties associated with the accurate measurement of gene expression. For microarrays, this problem is multiplied by the number of genes on the microarray itself. To overcome this technical variability correct experimental design is critical. The second challenge concerns the biological system used. What genetic background, time point and dose of xenobiotic should be chosen? For in vitro systems should cell lines or primary cells be used? These factors, and more, could affect the gene expression profile obtained in response to the same xenobiotic exposure. Using both our data and data from public databases these issues are explored in this paper.     

Glycosyltransferases: managers of small molecules

Studies of the glycosyltransferases (GTs) of small molecules have greatly increased in recent years as new approaches have been used to identify their genes and characterize their catalytic activities. These enzymes recognize diverse acceptors, including plant metabolites, phytotoxins and xenobiotics. Glycosylation alters the hydrophilicity of the acceptors, their stability and chemical properties, their subcellular localisation and often their bioactivity. Considerable progress has been made in understanding the role of GTs in the plant and the utility of GTs as biocatalysts, the latter arising from their regio- and enantioselectivity and their ability to recognize substrates that are not limited to plant metabolites.     

Brain science: from the very small to the very large

We still lack a clear understanding of how brain imaging signals relate to neuronal activity. Recent work shows that the simultaneous activity of neuronal ensembles strongly correlates with local field potentials and imaging measurements.