ELM: the status of the 2010 eukaryotic linear motif resource

Linear motifs are short segments of multidomain proteins that provide regulatory functions independently of protein tertiary structure. Much of intracellular signalling passes through protein modifications at linear motifs. Many thousands of linear motif instances, most notably phosphorylation sites, have now been reported. Although clearly very abundant, linear motifs are difficult to predict de novo in protein sequences due to the difficulty of obtaining robust statistical assessments. The ELM resource at http://elm.eu.org/ provides an expanding knowledge base, currently covering 146 known motifs, with annotation that includes >1300 experimentally reported instances. ELM is also an exploratory tool for suggesting new candidates of known linear motifs in proteins of interest. Information about protein domains, protein structure and native disorder, cellular and taxonomic contexts is used to reduce or deprecate false positive matches. Results are graphically displayed in a ‘Bar Code’ format, which also displays known instances from homologous proteins through a novel ‘Instance Mapper’ protocol based on PHI-BLAST. ELM server output provides links to the ELM annotation as well as to a number of remote resources. Using the links, researchers can explore the motifs, proteins, complex structures and associated literature to evaluate whether candidate motifs might be worth experimental investigation

Linkage of a national clinical liver transplant database with administrative hospital data: methods and validation.

INTRODUCTION: The UK Liver Transplant Audit (UKLTA) database contains clinical information on all liver transplants carried out in the UK. To expand its potential for research and service evaluation, we linked it to the Hospital Episode Statistics (HES), an administrative database of all admissions to English National Health Service (NHS) hospitals. MATERIALS AND METHODS: In the UKLTA database, we identified the linkable records of first liver transplantation between April 1997 and March 2010. We linked UKLTA records to HES records on the basis of NHS number, gender, date of birth, and postcode, as well as procedure codes for liver transplantation and dates of transplant. In linked records, agreement of primary liver disease diagnoses according to both databases was expressed as a proportion of the linked records and using kappa statistic. RESULTS: There were 5,815 linkable records in the UKLTA database, of which 4,959 records were successfully linked with HES (85.3%). Among these, 4,922 records (99.3%) had at least one diagnosis coded in HES relevant to an indication for liver transplantation. The overall agreement of primary liver disease diagnoses between UKLTA data and HES was 77.8% (95% CI 76.6%-79.0%) with a kappa of 0.75 (0.74-0.76). Diagnostic agreement can be further improved by using broader groupings of clinically related diagnoses. CONCLUSION: Linkage of clinical data and administrative hospital data provides a rich resource for the study of liver transplantation

miR-29a maintains mouse hematopoietic stem cell self-renewal by regulating Dnmt3a

Hematopoietic stem cells (HSCs) possess the ability to generate all hematopoietic cell types and to self-renew over long periods, but the mechanisms that regulate their unique properties are incompletely understood. Herein, we show that homozygous deletion of the miR-29a/b-1 bicistron results in decreased numbers of hematopoietic stem and progenitor cells (HSPCs), decreased HSC self-renewal, and increased HSC cell cycling and apoptosis. The HSPC phenotype is specifically due to loss of miR-29a, because miR-29b expression is unaltered in miR-29a/b-1-null HSCs, and only ectopic expression of miR-29a restores HSPC function both in vitro and in vivo. HSCs lacking miR-29a/b-1 exhibit widespread transcriptional dysregulation and adopt gene expression patterns similar to normal committed progenitors. A number of predicted miR-29 target genes, including Dnmt3a, are significantly upregulated in miR-29a/b-1-null HSCs. The loss of negative regulation of Dnmt3a by miR-29a is a major contributor to the miR-29a/b-1-null HSPC phenotype, as both in vitro Dnmt3a short hairpin RNA knockdown assays and a genetic haploinsufficiency model of Dnmt3a restored the frequency and long-term reconstitution capacity of HSCs from miR-29a/b-1-deficient mice. Overall, these data demonstrate that miR-29a is critical for maintaining HSC function through its negative regulation of Dnmt3a