The origin of the anomalous superconducting properties of MgB(2)

Magnesium diboride differs from ordinary metallic superconductors in several important ways, including the failure of conventional models to predict accurately its unusually high transition temperature, the effects of isotope substitution on the critical transition temperature, and its anomalous specific heat. A detailed examination of the energy associated with the formation of charge-carrying pairs, referred to as the 'superconducting energy gap', should clarify why MgB(2) is different. Some early experimental studies have indicated that MgB(2) has multiple gaps, but past theoretical studies have not explained from first principles the origin of these gaps and their effects. Here we report an ab initio calculation of the superconducting gaps in MgB(2) and their effects on measurable quantities. An important feature is that the electronic states dominated by orbitals in the boron plane couple strongly to specific phonon modes, making pair formation favourable. This explains the high transition temperature, the anomalous structure in the specific heat, and the existence of multiple gaps in this material. Our analysis suggests comparable or higher transition temperatures may result in layered materials based on B, C and N with partially filled planar orbitals.     

An unexpected specialization for horizontal disparity in primate primary visual cortex

The horizontal separation of the eyes means that objects nearer or farther than the fixation point project to different locations on the two retinae, differing principally in their horizontal coordinates (horizontal binocular disparity). Disparity-selective neurons have generally been studied with disparities applied in only one direction (often horizontal), which cannot determine whether the encoding is specialized for processing disparities along the horizontal axis. It is therefore unclear if disparity selectivity represents a specialization for naturally occurring disparities. I used random dot stereograms to study disparity-selective neurons from the primary visual cortex (V1) of awake fixating monkeys. Many combinations of vertical and horizontal disparity were used, characterizing the surface of responses as a function of two-dimensional disparity. Here I report that the response surface usually showed elongation along the horizontal disparity axis, despite the isotropic stimulus. Thus these neurons modulated their firing rate over a wider range of horizontal disparity than vertical disparity. This demonstrates that disparity-selective cells are specialized for processing horizontal disparity, and that existing models of disparity selectivity require substantial revision.     

A naturally occurring MTA1 variant sequesters oestrogen receptor-alpha in the cytoplasm

Oestrogen receptor (ER) is a good prognostic marker for the treatment of breast cancers. Upregulation of metastatic tumour antigen 1 (MTA1) is associated with the invasiveness and metastatic potential of several human cancers and acts as a co-repressor of nuclear ER-alpha. Here we identify a naturally occurring short form of MTA1 (MTA1s) that contains a previously unknown sequence of 33 amino acids with an ER-binding motif, Leu-Arg-Ile-Leu-Leu (LRILL). MTA1s localizes in the cytoplasm, sequesters ER in the cytoplasm, and enhances non-genomic responses of ER. Deleting the LRILL motif in MTA1s abolishes its co-repressor function and its interaction with ER, and restores nuclear localization of ER. Dysregulation of human epidermal growth factor receptor-2 in breast cancer cells enhances the expression of MTA1s and the cytoplasmic sequestration of ER. Expression of MTA1s in breast cancer cells prevents ligand-induced nuclear translocation of ER and stimulates malignant phenotypes. MTA1s expression is increased in human breast tumours with no or low nuclear ER. The regulation of the cellular localization of ER by MTA1s represents a mechanism for redirecting nuclear receptor signalling by nuclear exclusion.     

Agricultural sustainability and intensive production practices

A doubling in global food demand projected for the next 50 years poses huge challenges for the sustainability both of food production and of terrestrial and aquatic ecosystems and the services they provide to society. Agriculturalists are the principal managers of global usable lands and will shape, perhaps irreversibly, the surface of the Earth in the coming decades. New incentives and policies for ensuring the sustainability of agriculture and ecosystem services will be crucial if we are to meet the demands of improving yields without compromising environmental integrity or public health.     

Thyroid hormone controls carnitine status through modifications of γ-butyrobetaine hydroxylase activity and gene expression

The carnitine system plays a key role in β-oxidation of long-chain fatty acids by permitting their transport into the mitochondrial matrix. The effects of hypothyroidism and hyperthyroidism were studied on γ-butyrobetaine hydroxylase (BBH), the enzyme responsible for carnitine biosynthesis in the rat. In rat liver, BBH activity was decreased in the hypothyroid state and increased in hyperthyroid animals. The modifications in BBH activity correlated with changes in the enzyme Vmax values. These changes were shown to be related to hepatic BBH mRNA abundance. Thyroid hormones are known to interact with lipid metabolism, in particular by increasing long-chain fatty acid oxidation through activation of carnitine-dependent fatty acid import into mitochondria. Our study showed that thyroid hormones also increased carnitine bioavailability. Received 23 October 2001; received after revision 11 January 2002; accepted 15 January 2002     

Initiation of cancer and other diseases by catechol ortho-quinones: a unifying mechanism

Exposure to estrogens is a risk factor for breast and other human cancers. Initiation of breast, prostate and other cancers has been hypothesized to result from reaction of specific estrogen metabolites, catechol estrogen-3,4-quinones, with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine by 1,4-Michael addition. The catechol of the carcinogenic synthetic estrogen hexestrol, a hydrogenated derivative of diethylstilbestrol, is metabolized to its quinone, which reacts with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine. The catecholamine dopamine and the metabolite catechol (1,2-dihydroxybenzene) of the leukemogen benzene can also be oxidized to their quinones, which react with DNA to form predominantly analogous depurinating adducts. Apurinic sites formed by depurinating adducts are converted into tumor-initiating mutations by error-prone repair. These mutations could initiate cancer by estrogens and benzene, and Parkinson's disease by the neurotransmitter dopamine. These data suggest a unifying molecular mechanism of initiation for many cancers and neurodegenerative diseases and lay the groundwork for designing strategies to assess risk and prevent these diseases. Received 4 September 2001; received after revision 28 November 2001; accepted 2 December 2001     

Mutant deoxynucleotide carrier is associated with congenital microcephaly

The disorder Amish microcephaly (MCPHA) is characterized by severe congenital microcephaly, elevated levels of alpha-ketoglutarate in the urine and premature death. The disorder is inherited in an autosomal recessive pattern and has been observed only in Old Order Amish families whose ancestors lived in Lancaster County, Pennsylvania. Here we show, by using a genealogy database and automated pedigree software, that 23 nuclear families affected with MCPHA are connected to a single ancestral couple. Through a whole-genome scan, fine mapping and haplotype analysis, we localized the gene affected in MCPHA to a region of 3 cM, or 2 Mb, on chromosome 17q25. We constructed a map of contiguous genomic clones spanning this region. One of the genes in this region, SLC25A19, which encodes a nuclear mitochondrial deoxynucleotide carrier (DNC), contains a substitution that segregates with the disease in affected individuals and alters an amino acid that is highly conserved in similar proteins. Functional analysis shows that the mutant DNC protein lacks the normal transport activity, implying that failed deoxynucleotide transport across the inner mitochondrial membrane causes MCPHA. Our data indicate that mitochondrial deoxynucleotide transport may be essential for prenatal brain growth.     

Systematic screen for human disease genes in yeast

High similarity between yeast and human mitochondria allows functional genomic study of Saccharomyces cerevisiae to be used to identify human genes involved in disease. So far, 102 heritable disorders have been attributed to defects in a quarter of the known nuclear-encoded mitochondrial proteins in humans. Many mitochondrial diseases remain unexplained, however, in part because only 40-60% of the presumed 700-1,000 proteins involved in mitochondrial function and biogenesis have been identified. Here we apply a systematic functional screen using the pre-existing whole-genome pool of yeast deletion mutants to identify mitochondrial proteins. Three million measurements of strain fitness identified 466 genes whose deletions impaired mitochondrial respiration, of which 265 were new. Our approach gave higher selection than other systematic approaches, including fivefold greater selection than gene expression analysis. To apply these advantages to human disorders involving mitochondria, human orthologs were identified and linked to heritable diseases using genomic map positions.     

Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development

To rapidly identify genes required for early vertebrate development, we are carrying out a large-scale, insertional mutagenesis screen in zebrafish, using mouse retroviral vectors as the mutagen. We will obtain mutations in 450 to 500 different genes--roughly 20% of the genes that can be mutated to produce a visible embryonic phenotype in this species--and will clone the majority of the mutated alleles. So far, we have isolated more than 500 insertional mutants. Here we describe the first 75 insertional mutants for which the disrupted genes have been identified. In agreement with chemical mutagenesis screens, approximately one-third of the mutants have developmental defects that affect primarily one or a small number of organs, body shape or swimming behavior; the rest of the mutants show more widespread or pleiotropic abnormalities. Many of the genes we identified have not been previously assigned a biological role in vivo. Roughly 20% of the mutants result from lesions in genes for which the biochemical and cellular function of the proteins they encode cannot be deduced with confidence, if at all, from their predicted amino-acid sequences. All of the genes have either orthologs or clearly related genes in human. These results provide an unbiased view of the genetic construction kit for a vertebrate embryo, reveal the diversity of genes required for vertebrate development and suggest that hundreds of genes of unknown biochemical function essential for vertebrate development have yet to be identified.