The genetic content of wild-type human cytomegalovirus was investigated by sequencing the 235 645 bp genome of a low passage strain (Merlin). Substantial regions of the genome (genes RL1-UL11, ...UL105-UL112 and UL120-UL150) were also sequenced in several other strains, including two that had not been passaged in cell culture. Comparative analyses, which employed the published genome sequence of a high passage strain (AD169), indicated that Merlin accurately reflects the wild-type complement of 165 genes, containing no obvious mutations other than a single nucleotide substitution that truncates gene UL128. A sizeable subset of genes exhibits unusually high variation between strains, and comprises many, but not all, of those that encode proteins known or predicted to be secreted or membrane-associated. In contrast to unpassaged strains, all of the passaged strains analysed have visibly disabling mutations in one or both of two groups of genes that may influence cell tropism. One comprises UL128, UL130 and UL131A, which putatively encode secreted proteins, and the other contains RL5A, RL13 and UL9, which are members of the RL11 glycoprotein gene family. The case in support of a lack of protein-coding potential in the region between UL105 and UL111A was also strengthened.
Obesity, diabetes and metabolic disease represent an ongoing and rapidly worsening public health issue in both the developed, and much of the developing world. Although there are many factors that ...influence fat storage, it has been clearly demonstrated that the homeostatic cornerstone of metabolism lies within the hypothalamus. Moreover, neuronal damage to vital areas of the hypothalamus can drive reregulation or dysregulation of endocrine function, energy expenditure and appetite, thereby promoting a shift in overall metabolic function towards a state of obesity. Therefore, identification of treatments that influence the hypothalamus to improve obesity and associated metabolic diseases has long been a medical goal. Interestingly, evidence from animal studies suggests that activating the vestibular system, specifically the macular gravity receptor, influences the hypothalamus in a way that decreases body fat storage and causes a metabolic shift towards a leaner state. Given that the macular element of the vestibular system has been shown to activate with transdermal electrical stimulation applied to the mastoids, this may be a potential therapeutic approach for obesity, diabetes or related metabolic diseases, whereby repetitive stimulation of the vestibular system influences hypothalamic control of metabolic homeostasis, thereby encouraging decreased fat storage. Here, we present an up-to-date review of the current literature surrounding the vestibular influence of the hypothalamus and associated homeostatic sites in the context of current and novel therapeutic approaches for improved clinical management of obesity and diabetes.
Herpesviruses comprise an abundant, widely distributed group of large DNA viruses of humans and other vertebrates, and overall are among the most extensively studied large DNA viruses. Many ...herpesvirus genome sequences have been determined, and interpreted in terms of gene contents to give detailed views of both ubiquitous and lineage-specific functions. Availability of gene sequences has also enabled evaluations of evolutionary relationships. For herpesviruses of mammals, a robust phylogenetic tree has been constructed, which shows many features characteristic of synchronous development of virus and host lineages over large evolutionary timespans. It has also emerged that three distinct groupings of herpesviruses exist: the first containing viruses with mammals, birds and reptiles as natural hosts; the second containing viruses of amphibians and fish; and the third consisting of a single invertebrate herpesvirus. Within each of the first two groups, the genomes show clear evidence of descent from a common ancestor, but relationships between the three groups are extremely remote. Detailed analyses of capsid structures provide the best evidence for a common origin of the three groups. At a finer level, the structure of the capsid shell protein further suggests an element of common origin between herpesviruses and tailed DNA bacteriophages.
The gene complement of wild-type human cytomegalovirus (HCMV) is incompletely understood, on account of the size and complexity of the viral genome and because laboratory strains have undergone ...deletions and rearrangements during adaptation to growth in culture. We have determined the sequence (241 087 bp) of chimpanzee cytomegalovirus (CCMV) and have compared it with published HCMV sequences from the laboratory strains AD169 and Toledo, with the aim of clarifying the gene content of wild-type HCMV. The HCMV and CCMV genomes are moderately diverged and essentially collinear. On the basis of conservation of potential protein-coding regions and other sequence features, we have discounted 51 previously proposed HCMV ORFs, modified the interpretations for 24 (including assignments of multiple exons) and proposed ten novel genes. Several errors were detected in the published HCMV sequences. We presently recognize 165 genes in CCMV and 145 in AD169; this compares with an estimate of 189 unique genes for AD169 made in 1990. Our best estimate for the complement of wild-type HCMV is 164 to 167 genes.
Anthropogenic environmental change is driving the rapid loss of biodiversity. Large declines in the abundance of historically common species are now emerging as a major concern. Identifying declining ...populations through long-term biodiversity monitoring is vital for implementing timely conservation measures. It is, therefore, critical to evaluate the likelihood that persistent long-term population trends of a given size could be detected using existing monitoring data and methods. Here, we test the power to detect declines in Australia’s common landbirds using long-term citizen science monitoring. We use spatially explicit simulations of occupancy dynamics and virtual sampling, designed to mimic bird monitoring in better-sampled regions of Australia, to assess likely power in these data to detect trends relevant for conservation. We predict the statistical power for 326 common species that meet minimum requirements for monitoring data across 10 regions of Australia, estimating the number of species for which we would have a high (≥80%) chance of detecting declines of different sizes. The power to detect declines of ≥30% per decade was predicted to be high for at least one-third of the common species in 7 of 10 regions, with a total of 103 (32% of 326) unique species sufficiently monitored in at least one region. These species spanned 12 taxonomic orders, four orders of magnitude in body mass, and a broad diversity of dietary guilds, suggesting the current species pool will likely serve as robust indicators for a broad range of environmental states and pressures. Power was strongly affected by species’ detectability, and power to detect even large declines was negligible when species are detected on ≤50% of visits to an occupied site. Predicted power for many species fell just short of the 80% threshold in one or more regions, which suggests an increase in effort targeting these species could greatly enhance the species and regional representation of these data. Against the backdrop of unprecedented biodiversity losses, this study shows how critical evaluation of existing monitoring schemes is valuable both for assessing the contribution of citizen science schemes to biodiversity monitoring and for designing strategic monitoring to significantly improve the knowledge these schemes provide.
Phylogenetic relationships within the subfamily Gammaherpesvirinae of the family Herpesviridae were investigated for three species in the genus Lymphocryptovirus (or gamma1 group) and nine in the ...genus Rhadinovirus (or gamma2 group). Alignments of amino acid sequences from up to 28 genes were used to derive trees by maximum-likelihood and Bayesian Monte Carlo Markov chain methods. Two problem areas were identified involving an unresolvable multifurcation for a clade within the gamma2 group, and a high divergence for Murid herpesvirus 4 (MHV4). A robust final tree was obtained, which was valid for genes from across the virus genomes and was rooted by reference to previous analyses of the whole family Herpesviridae. This tree comprised four major lineages: the gamma1 group of primate viruses; a clade of artiodactyl gamma2 viruses; a clade of perissodactyl gamma2 viruses; and a clade of gamma2 viruses with a multifurcation at its base and containing Old World and New World primate viruses, Bovine herpesvirus 4 and MHV4. Developing previous work it was proposed, on the basis of similarities between the gammaherpesvirus tree and the tree of corresponding mammalian hosts, that the first three of these major viral lineages arose in a coevolutionary manner with host lineages, while the fourth had its origin in an ancient interspecies transfer. Transfer of dates from mammalian palaeontology then allowed estimation of dates for nodes in the gammaherpesvirus tree.
The extracellular matrix (ECM) can induce chemotherapy resistance via AKT-mediated inhibition of apoptosis. Here, we show that loss of the ECM protein TGFBI (transforming growth factor beta induced) ...is sufficient to induce specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer cells. Paclitaxel-resistant cells treated with recombinant TGFBI protein show integrin-dependent restoration of paclitaxel sensitivity via FAK- and Rho-dependent stabilization of microtubules. Immunohistochemical staining for TGFBI in paclitaxel-treated ovarian cancers from a prospective clinical trial showed that morphological changes of paclitaxel-induced cytotoxicity were restricted to areas of strong expression of TGFBI. These data show that ECM can mediate taxane sensitivity by modulating microtubule stability.
Molecular evolution of the γ–Herpesvirinae McGeoch, Duncan J.; McGeoch, Duncan J.
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
04/2001, Letnik:
356, Številka:
1408
Journal Article
Recenzirano
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Genomic sequences available for members of the γ-Herpesvirinae allow analysis of many aspects of the group's evolution. This paper examines four topics: (i) the phylogeny of the group; (ii) the ...histories of γ-herpesvirus-specific genes; (iii) genomic variation of human herpesvirus 8 (HHV-8); and (iv) the relationship between Epstein-Barr virus types 1 and 2 (EBV-1 and EBV-2). A phylogenetic tree based on eight conserved genes has been constructed for eight γ-herpesviruses and extended to 14 species with smaller gene sets. This gave a generally robust assignment of evolutionary relationships, with the exception of murine herpesvirus 4 (MHV-4), which could not be placed unambiguously on the tree and which has evidently experienced an unusually high rate of genomic change. The γ-herpesviruses possess a variable complement of genes with cellular homologues. In the clearest cases these virus genes were shown to have originated from host genome lineages in the distant past. HHV-8 possesses at its left genomic terminus a highly diverse gene (K1) and at its right terminus a gene (K15) having two diverged alleles. It was proposed that the high diversity of K1 results from a positive selection on K1 and a hitchhiking effect that reduces diversity elsewhere in the genome. EBV-1 and EBV-2 differ in their alleles of the EBNA-2, EBNA-3A, EBNA-3B and EBNA-3C genes. It was suggested that EBV-1 and EBV-2 may recombine in mixed infections so that their sequences outside these genes remain homogeneous. Models for genesis of the types, by recombination between diverged parents or by local divergence from a single lineage, both present difficulties.
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