SVM-based prediction of caspase substrate cleavage sites

BACKGROUND: Caspases belong to a class of cysteine proteases which function as critical effectors in apoptosis and inflammation by cleaving substrates immediately after unique sites. Prediction of such cleavage sites will complement structural and functional studies on substrates cleavage as well as discovery of new substrates. Recently, different computational methods have been developed to predict the cleavage sites of caspase substrates with varying degrees of success. As the support vector machines (SVM) algorithm has been shown to be useful in several biological classification problems, we have implemented an SVM-based method to investigate its applicability to this domain. RESULTS: A set of unique caspase substrates cleavage sites were obtained from literature and used for evaluating the SVM method. Datasets containing (i) the tetrapeptide cleavage sites, (ii) the tetrapeptide cleavage sites, augmented by two adjacent residues, P(1)' and P(2)' amino acids and (iii) the tetrapeptide cleavage sites with ten additional upstream and downstream flanking sequences (where available) were tested. The SVM method achieved an accuracy ranging from 81.25% to 97.92% on independent test sets. The SVM method successfully predicted the cleavage of a novel caspase substrate and its mutants. CONCLUSION: This study presents an SVM approach for predicting caspase substrate cleavage sites based on the cleavage sites and the downstream and upstream flanking sequences. The method shows an improvement over existing methods and may be useful for predicting hitherto undiscovered cleavage sites

A multi-factor model for caspase degradome prediction

<p>Abstract</p> <p>Background</p> <p>Caspases belong to a class of cysteine proteases which function as critical effectors in cellular processes such as apoptosis and inflammation by cleaving substrates immediately after unique tetrapeptide sites. With hundreds of reported substrates and many more expected to be discovered, the elucidation of the caspase degradome will be an important milestone in the study of these proteases in human health and disease. Several computational methods for predicting caspase cleavage sites have been developed recently for identifying potential substrates. However, as most of these methods are based primarily on the detection of the tetrapeptide cleavage sites - a factor necessary but not sufficient for predicting <it>in vivo </it>substrate cleavage - prediction outcomes will inevitably include many false positives.</p> <p>Results</p> <p>In this paper, we show that structural factors such as the presence of disorder and solvent exposure in the vicinity of the cleavage site are important and can be used to enhance results from cleavage site prediction. We constructed a two-step model incorporating cleavage site prediction and these factors to predict caspase substrates. Sequences are first predicted for cleavage sites using CASVM or GraBCas. Predicted cleavage sites are then scored, ranked and filtered against a cut-off based on their propensities for locating in disordered and solvent exposed regions. Using an independent dataset of caspase substrates, the model was shown to achieve greater positive predictive values compared to CASVM or GraBCas alone, and was able to reduce the false positives pool by up to 13% and 53% respectively while retaining all true positives. We applied our prediction model on the family of receptor tyrosine kinases (RTKs) and highlighted several members as potential caspase targets. The results suggest that RTKs may be generally regulated by caspase cleavage and in some cases, promote the induction of apoptotic cell death - a function distinct from their role as transducers of survival and growth signals.</p> <p>Conclusion</p> <p>As a step towards the prediction of <it>in vivo </it>caspase substrates, we have developed an accurate method incorporating cleavage site prediction and structural factors. The multi-factor model augments existing methods and complements experimental efforts to define the caspase degradome on the systems-wide basis.</p

A man with hypophosphataemia

Case report; A section on BMJ, 2011, v. 342, p. 715published_or_final_versio

Determinants of postnatal spleen tissue regeneration and organogenesis

Abstract The spleen is an organ that filters the blood and is responsible for generating blood-borne immune responses. It is also an organ with a remarkable capacity to regenerate. Techniques for splenic auto-transplantation have emerged to take advantage of this characteristic and rebuild spleen tissue in individuals undergoing splenectomy. While this procedure has been performed for decades, the underlying mechanisms controlling spleen regeneration have remained elusive. Insights into secondary lymphoid organogenesis and the roles of stromal organiser cells and lymphotoxin signalling in lymph node development have helped reveal similar requirements for spleen regeneration. These factors are now considered in the regulation of embryonic and postnatal spleen formation, and in the establishment of mature white pulp and marginal zone compartments which are essential for spleen-mediated immunity. A greater understanding of the cellular and molecular mechanisms which control spleen development will assist in the design of more precise and efficient tissue grafting methods for spleen regeneration on demand. Regeneration of organs which harbour functional white pulp tissue will also offer novel opportunities for effective immunotherapy against cancer as well as infectious diseases

Supply driven mortgage choice

Variable mortgage contracts dominate the UK mortgage market (Miles, 2004). The dominance of the variable rate mortgage contracts has important consequences for the transmission mechanism of monetary policy decisions and systemic risks (Khandani et al., 2012; Fuster and Vickery, 2013). This raises an obvious concern that a mortgage market such as that in the UK, where the major proportion of mortgage debt is either at a variable or fixed for less than two years rate (Badarinza, et al., 2013; CML, 2012), is vulnerable to alterations in the interest rate regime. Theoretically, mortgage choice is determined by demand and supply factors. So far, most of the existing literature has focused on the demand side perspective, and what is limited is consideration of supply side factors in empirical investigation on mortgage choice decisions. This paper uniquely explores whether supply side factors may partially explain observed/ex-post mortgage type decisions. Empirical results detect that lenders’ profit motives and mortgage funding/pricing issues may have assisted in preferences toward variable rate contracts. Securitisation is found to positively impact upon gross mortgage lending volumes while negatively impacting upon the share of variable lending flows. This shows that an increase in securitisation not only improves liquidity in the supply of mortgage funds, but also has the potential to shift mortgage choices toward fixed mortgage debt. The policy implications may involve a number of measures, including reconsideration of the capital requirements for the fixed, as opposed to the variable rate mortgage debt, growing securitisation and optimisation of the mortgage pricing policies

A three-year prospective study of the presentation and clinical outcomes of major bleeding episodes associated with oral anticoagulant use in the UK (ORANGE study).

The outcomes of patients developing major bleeding while on oral anticoagulants remain largely unquantified. The objectives of this study were to: (i) describe the burden of major hemorrhage associated with all available oral anticoagulants in terms of proportion of bleeds which are intracranial hemorrhages, in-hospital mortality and duration of hospitalization following major bleeding; (ii) identify risk factors for mortality; and (iii) compare the characteristics of major hemorrhage between cases treated with warfarin and direct oral anticoagulants for the subgroups of patients with atrial fibrillation or venous thromboembolism. This was a multicenter, 3-year prospective cohort study of patients aged ≥18 years on oral anticoagulants who developed major hemorrhage leading to hospitalization. The patients were followed up for 30 days or until discharge or death, whichever occurred first. In total 2,192 patients (47% female, 81% on warfarin, median age 80 years) were reported between October 2013 and August 2016 from 32 hospitals in the UK. Bleeding sites were intracranial (44%), gastrointestinal (33%), and other (24%). The in-hospital mortality was 21% (95% CI: 19%-23%) overall, and 33% (95% CI: 30%-36%) for patients with intracranial hemorrhage. Intracranial hemorrhage, advanced age, spontaneous bleeding, liver failure and cancer were risk factors for death. Compared to warfarin-treated patients, patients treated with direct oral anticoagulants were older and had lower odds of subdural/epidural, subarachnoid and intracerebral bleeding. The mortality rate due to major bleeding was not different between patients being treated with warfarin or direct oral anticoagulants. Major bleeding while on oral anticoagulant therapy leads to considerable hospital stays and short-term mortality

Urokinase plasminogen activator secreted by cancer-associated fibroblasts induces tumor progression via PI3K/AKT and ERK signaling in esophageal squamous cell carcinoma

published_or_final_versio

Site-specific incorporation of phosphotyrosine using an expanded genetic code.

Access to phosphoproteins with stoichiometric and site-specific phosphorylation status is key to understanding the role of protein phosphorylation. Here we report an efficient method to generate pure, active phosphotyrosine-containing proteins by genetically encoding a stable phosphotyrosine analog that is convertible to native phosphotyrosine. We demonstrate its general compatibility with proteins of various sizes, phosphotyrosine sites and functions, and reveal a possible role of tyrosine phosphorylation in negative regulation of ubiquitination

Comprehensive annotation of the Parastagonospora nodorum reference genome using next-generation genomics, transcriptomics and proteogenomics

Parastagonospora nodorum, the causal agent of Septoria nodorum blotch (SNB), is an economically important pathogen of wheat (Triticum spp.), and a model for the study of necrotrophic pathology and genome evolution. The reference P. nodorum strain SN15 was the first Dothideomycete with a published genome sequence, and has been used as the basis for comparison within and between species. Here we present an updated reference genome assembly with corrections of SNP and indel errors in the underlying genome assembly from deep resequencing data as well as extensive manual annotation of gene models using transcriptomic and proteomic sources of evidence (https://github.com/robsyme/Parastagonospora_nodorum_SN15). The updated assembly and annotation includes 8,366 genes with modified protein sequence and 866 new genes. This study shows the benefits of using a wide variety of experimental methods allied to expert curation to generate a reliable set of gene models