Analysis of the genome and transcriptome of Cryptococcus neoformans var. grubii reveals complex RNA expression and microevolution leading to virulence attenuation.

Cryptococcus neoformans is a pathogenic basidiomycetous yeast responsible for more than 600,000 deaths each year. It occurs as two serotypes (A and D) representing two varieties (i.e. grubii and neoformans, respectively). Here, we sequenced the genome and performed an RNA-Seq-based analysis of the C. neoformans var. grubii transcriptome structure. We determined the chromosomal locations, analyzed the sequence/structural features of the centromeres, and identified origins of replication. The genome was annotated based on automated and manual curation. More than 40,000 introns populating more than 99% of the expressed genes were identified. Although most of these introns are located in the coding DNA sequences (CDS), over 2,000 introns in the untranslated regions (UTRs) were also identified. Poly(A)-containing reads were employed to locate the polyadenylation sites of more than 80% of the genes. Examination of the sequences around these sites revealed a new poly(A)-site-associated motif (AUGHAH). In addition, 1,197 miscRNAs were identified. These miscRNAs can be spliced and/or polyadenylated, but do not appear to have obvious coding capacities. Finally, this genome sequence enabled a comparative analysis of strain H99 variants obtained after laboratory passage. The spectrum of mutations identified provides insights into the genetics underlying the micro-evolution of a laboratory strain, and identifies mutations involved in stress responses, mating efficiency, and virulence.

New perspectives on neoplasia and the RNA world

Key tenets of modern biology are the central place of protein in cell regulation and the flow of genetic information from DNA to RNA to protein. However, it is becoming increasingly apparent that genomes are much more complex than hitherto thought with remarkably complex regulatory systems. The notion that the fraction of the genome involved in coding protein is all that matters is increasingly being questioned as the roles of non-coding RNA (ncRNA) in cellular systems becomes recognised. The RNA world, including microRNA (miRNA), small inhibitory RNA (siRNA) and other RNA species, are now recognised as being crucial for the regulation of chromatin structure, gene expression, mRNA processing and splicing, mRNA stability and translational control. Furthermore such ncRNA systems may be perturbed in disease states and most notably in neoplasia, including in haematological malignancies. Here the burgeoning evidence for a role of miRNA in neoplasia is reviewed and the importance of understanding the RNA world emphasised. Copyright (c) 2005 John Wiley & Sons, Ltd.

The pathogenesis of venous thromboembolism in cancer: emerging links with tumour biology.

Venous thromboembolism (VTE) is a frequent complication in individuals with cancer and is considered to be a cause of substantial mortality. Epidemiological studies identify malignancy as an independent VTE risk factor and show that cancer patients are at increased risk of both initial and recurrent VTE events. The risk due to cancer is compounded by the effects of chemotherapy and other treatments. The pathogenesis of cancer-associated VTE is complex involving multiple interactions between tumours and various components of haemostasis. The development of a systemic hypercoagulable state is considered a key pathogenetic feature and is attributed to tumour expression of tissue factor and other procoagulants, activation of vascular cells by tumour-derived cytokines and adhesive interactions between tumour cells and host cells. An increasing body of evidence indicates that the activation of haemostasis in malignant disease contributes to tumour growth and progression by stimulation of intracellular signalling pathways. The interaction of tissue factor, thrombin and other coagulation factors with protease activated receptor (PAR) proteins expressed by tumour cells and host vascular cells leads to the induction of genes related to the processes of angiogenesis, cell survival and cell adhesion and migration.

Virtual Engineering Centre - Examples of Virtual Prototyping and Multidisciplinary Design Optimization

The requirement for the use of Virtual Engineering, encompassing the construction of Virtual Prototypes using Multidisciplinary Design Optimisation, for the development of future aerospace platforms and systems is discussed. Some of the activities at the Virtual Engineering Centre, a University of Liverpool initiative, are described and a number of case studies involving a range of applications of Virtual Engineering illustrated.

Clinical and therapeutic relevance of PIM1 kinase in gastric cancer

Gastric cancer is a leading cause of cancer-related mortality, and chemotherapeutic options are currently limited. PIM1 kinase, an oncogene that promotes tumorigenesis in several cancer types, might represent a novel therapeutic target in gastric cancer.

Mutational spectrum of the ZEB1 gene in corneal dystrophies supports a genotype-phenotype correlation

Mutations in ZEB1 have been reported in posterior polymorphous corneal dystrophy (PPCD3; MIM #609141) and Fuchs' endothelial corneal dystrophy (FECD6; MIM #613270). Although PPCD and keratoconus are clinically and pathologically distinct, PPCD has been associated with keratoconus, suggesting a common genetic basis. The purpose of our study was to perform mutational screening of the ZEB1 gene in patients affected with keratoconus or PPCD.

Minor allele frequency of myeloproliferative neoplasm mutations in the Irish blood donor population

Myeloproliferative neoplasms (MPNs) are rare diseases that include classic entities; polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. In this short report, minor allele frequencies of common MPN mutations are compared between the Irish blood donor population and other populations of European descent using data from the Haplotype Map project. The Affymetrix array 6.0 platform was utilised identifying nine single nucleotide polymorphisms (SNPs) and six proxy SNPs. The variability of allele frequencies for MPN mutations could account for the different incidence rates seen between populations of European ancestry, giving a better understanding of the genetic predisposition to MPNs. 

Debating Darwin at the Cape

This paper focuses attention on the fortunes of Darwin's theory among the English-speaking community in Cape Colony during the latter part of the nineteenth century. The paper begins with a review of early encounters with Darwin dwelling particularly on the response of figures like Roderick Noble - professor and editor of the Cape Monthly Magazine, the geologist John Shaw, and Sir Henry Barkly, governor of the colony. Besides these more theoretical responses, Darwin's ideas were also mobilised in a range of scientific inquiries on such subjects as birds and butterflies. But most conspicuous was the use of evolutionary thought-forms in the work of the eminent philologist Wilhelm Bleek, cousin of Darwin's leading German apologist, Ernst Haeckel. The prevailing sense is of a liberal intelligentsia calmly interacting with a novel theory with all due deference. During the 1870s, an address by Langham Dale at the South African Public Library injected new energy into the Darwin discussion. Dale expressed disquiet over some of the anthropological implications of evolution as well as its apparent reductionism, and this stimulated a range of reactions. Several anonymous commentators responded but the most sustained evaluation of Dale's position emanated from the Queenstown physician and later politician, Sir William Bisset Berry. Then, in 1874, copious extracts from John Tyndall's infamous 'Belfast Address' were printed in the Cape Monthly and this added yet further impetus to the debate. Tyndall's seeming materialism bothered a number of readers, not least Hon William Porter, former attorney-general of Cape Colony. To figures like these the materialist extrapolations of radical Darwinians such as Haeckel were deeply disturbing, not just for religious reasons, but because they seemed to destabilise the moral and pedagogic progressivism that lay at the heart of their civilising credo. While reservations about Darwin's proposals were certainly audible, taken in the round Darwinian conversations among the English-speaking literati at the Cape were conducted with liberal sentiments, not least when evolutionary science approached questions of race. For Darwin's writings were seen to confirm a monogenetic account of the origin and unity of the human race, and could readily be called upon to justify the paternalistic ideology that governed colonial affairs.

Betydelsen av livsloppsperspektivet och den sociala utbytesteorin för förståelsen av närståendevård som en möjliggörare för ett gott åldrande : en kvalitativ studie

Bakgrunden till avhandlingen är att andelen äldre ökar i Finland, vilket medför ett behov av nya ekonomiska lösningar samtidigt som vårdkvaliteten tryggas. Närståendevård är en för samhället förmånlig vårdform som möjliggör att äldre får bo hemma längre samtidigt som institutionsvården minskar. Det är i enlighet med den finländska regeringens målsättningar och närståendevården ska därför utökas. I forskning om närståendevård har man främst fokuserat på vårdarens upplevelser och det finns ett behov av att öka kunskapen om vårdtagarnas upplevelser. Avhandlingens syfte är således att undersöka äldre vårdtagares upplevelser av närståendevård och åldrande genom att tillämpa livsloppsperspektivet och den sociala utbytesteorin. Avhandlingens fyra frågeställningar är ifall närståendevård upplevs som en god vårdform sett ur vårdtagarens synvinkel, vad som upplevs som positivt och negativt med vårdformen, vilken betydelse reciprocitet har för vårdtagaren och vilka möjligheter hon eller han har till reciprocitet i relationen till närståendevårdaren samt vilken betydelse vårdtagarens tidigare livsskeden har för hans eller hennes upplevelser av närståendevård. I avhandlingen behandlas även utvecklingen inom socialgerontologiska teorier. Två av de mest använda socialgerontologiska teorierna på 2000-talet är livsloppsperspektivet och den sociala utbytesteorin. Livsloppsperspektivet innebär att man tar i beaktande många olika faktorer såsom t.ex. samhälleliga förändringar och en individs tidigare livsskeden när man studerar åldrande. Den sociala utbytesteorin utgår från att det en människa ger åt en annan, förväntar hon sig tillbaka. I en obalanserad utbytesrelation uppstår missnöje och en känsla av maktlöshet hos den som enbart är mottagare. Det är en situation som äldre riskerar att hamna i, då deras resurser inte alltid värdesätts av den yngre, arbetsföra generationen. I denna kvalitativa studie har semistrukturerade temaintervjuer genomförts. Sju svenskspråkiga närståendevårdtagare i åldern 71-80 har intervjuats i Österbotten. Materialet har analyserats med hjälp av kvalitativ innehållsanalys. Resultaten visar att vårdtagarna överlag upplever närståendevård som en god vårdform med många fördelar. Vårdtagarna uppskattar framför allt att få bo hemma och tryggheten i att vårdas av någon anhörig som känner dem väl och hela tiden är tillgänglig. Flera vårdtagare upplever oro inför framtiden, eftersom de inte vet vad som händer om eller när närståendevårdarens hälsa försämras. Flera vårdtagare upplever frustration över sitt hälsotillstånd och hade inte förväntat sig att åldrandet skulle se ut på det sätt som det gör. Missnöjet tycks inte vara en följd av avsaknad av reciprocitet i relationen till närståendevårdaren, utan de negativa känslorna handlar om att acceptera det försämrade hälsotillståndet efter att tidigare ha levt ett aktivare liv.