Trypsin is the most commonly used enzyme in mass spectrometry for protein digestion with high substrate specificity. Many peptide identification algorithms incorporate these specificity rules as filtering criteria. A generally accepted "Keil rule" is that trypsin cleaves next to arginine or lysine, but not before proline. Since this rule was derived two decades ago based on a small number of experimentally confirmed cleavages, we decided to re-examine it using 14.5 million tandem spectra (2 orders of magnitude increase in the number of observed tryptic cleavages). Our analysis revealed a surprisingly large number of cleavages before proline. We examine several hypotheses to explain these cleavages and argue that trypsin specificity rules used in peptide identification algorithms should be modified to "legitimatize" cleavages before proline. Our approach can be applied to analyze any protease, and we further argue that specificity rules for other enzymes should also be re-evaluated based on statistical evidence derived from large MS/MS data sets.
Recent proliferation of low-cost DNA sequencing techniques will soon lead to an explosive growth in the number of sequenced genomes and will turn manual annotations into a luxury. Mass spectrometry recently emerged as a valuable technique for proteogenomic annotations that improves on the state-of-the-art in predicting genes and other features. However, previous proteogenomic approaches were limited to a single genome and did not take advantage of analyzing mass spectrometry data from multiple genomes at once. We show that such a comparative proteogenomics approach (like comparative genomics) allows one to address the problems that remained beyond the reach of the traditional "single proteome" approach in mass spectrometry. In particular, we show how comparative proteogenomics addresses the notoriously difficult problem of "one-hit-wonders" in proteomics, improves on the existing gene prediction tools in genomics, and allows identification of rare post-translational modifications. We therefore argue that complementing DNA sequencing projects by comparative proteogenomics projects can be a viable approach to improve both genomic and proteomic annotations.
Left ventricular thrombus (LVT) is a serious complication of acute myocardial infarction (MI) and also non-ischemic cardiomyopathies. We performed a narrative literature review, manual-search of reference lists of included articles and relevant reviews. Our literature review indicates that the incidence of LVT following acute MI has decreased, probably due to improvement in patient care as a result of better and earlier reperfusion techniques. Predictors of LVT include anterior MI, involvement of left ventricular (LV) apex (regardless of the coronary territory affected), LV akinesis or dyskinesis, reduced LV ejection fraction (LVEF), severe diastolic dysfunction and large infarct size. LVT is associated with increased risk of systemic embolism, stroke, cardiovascular events and death, and there is evidence that anticoagulant therapy for at least 3 months can reduce the risk of these events. Cardiac magnetic resonance (CMR) has the highest diagnostic accuracy for LVT, followed by echocardiography with the use of echocardiographic contrast agents (ECAs). Although current guidelines suggest use of vitamin K antagonist (VKA) for a minimum of 3 to 6 months, there is growing evidence of the benefits of direct acting oral anticoagulants in treatment of LVT. Embolic events appear to occur even after resolution of LVT suggesting that anticoagulant therapy needs to be considered for a longer period in some cases. Recommendations for the use of triple therapy in the presence of the LVT are mostly based on extrapolation from outcome data in patients with atrial fibrillation (AF) and MI. We conclude that the presence of LVT is more likely in patients with anterior STsegment elevation MI (STEMI) (involving the apex) and reduced ejection fraction (EF). LVT should be considered a marker of increased long-term thrombotic risk that may persist even after thrombus resolution.Ongoing clinical trials are expected to elucidate the best management strategies for patients with LVT.
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