The Intrinsic Substrate Specificity of the Human Tyrosine Kinome

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy.

Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Professional Doctorate at Anglia Ruskin University: A model of successful practice

Description to be added.Cannot be left empt

Nitrogen and oxygen isotopomeric constraints on the sources of nitrous oxide and the role of submarine groundwater discharge in a temperate eutrophic salt-wedge estuary

Estuaries have been identified as sources of nitrous oxide (N2O) emissions to the atmosphere but questions remain as to which production pathway(s) govern the oversaturation of N2O observed in most estuaries worldwide. Here, we use a suite of nitrate and N2O isotopes, as well as the N-15 site preference signatures of N2O to assess (1) the relative importance of different N2O production pathways in a eutrophic groundwater-impacted salt-wedge estuary and the aquifers underlying the estuary and (2) the influence of groundwater input on the overall N2O saturation in the estuary. This is one of the few studies to examine the effect of groundwater-surface water interaction on N2O cycling using N2O isotopes. The site preference values of N2O in the deep aquifer below the estuary were distinctive (83 parts per thousand +/- 25 parts per thousand) and were much higher than in either surface water (21 parts per thousand +/- 6 parts per thousand) or shallow groundwater (44 parts per thousand +/- 8 parts per thousand), suggesting the influence of multiple biotic and/or abiotic processes which proceed through multiple cycles, and/or the occurrence of a yet unidentified N2O production pathway. Isotope endmember considerations revealed that nitrifier-denitrification was the major N2O production pathway within the shallow aquifer whereas within the estuarine water column, N2O saturation was governed by chemodenitrification and discharge of N2O-laden submarine groundwater. Our study not only emphasizes the substantial, yet often underappreciated role of submarine groundwater discharge in estuarine N2O budgets, but also highlights the need to reevaluate the importance of the noncanonical denitrification pathways (i.e., chemodenitrification and nitrifier-denitrification) in controlling the overall N2O production from estuarine and groundwater environments