CompareMS2 2.0: An Improved Software for Comparing Tandem Mass Spectrometry Datasets

It has long been known that biological species can be identified from mass spectrometry data alone. Ten years ago, we described a method and software tool, compareMS2, for calculating a distance between sets of tandem mass spectra, as routinely collected in proteomics. This method has seen use in species identification and mixture characterization in food and feed products, as well as other applications. Here, we present the first major update of this software, including a new metric, a graphical user interface and additional functionality. The data have been deposited to ProteomeXchange with dataset identifier PXD034932.publishedVersio

Cognitive Decline in Older Patients With Non- ST Elevation Acute Coronary Syndrome.

Background Dementia is a growing health burden of an aging population. This study aims to evaluate the prevalence of cognitive impairment and the predictors of cognitive decline at 1 year in older patients with non-ST-elevation acute coronary syndrome undergoing invasive care. Methods and Results Older patients with non-ST-elevation acute coronary syndrome were recruited into the ICON1 study. Cognition was evaluated using Montreal Cognitive Assessment. The composite major adverse cardiovascular events comprised death, myocardial infarction, unplanned revascularization, stroke, and significant bleeding at 1 year. Of 298 patients, 271 had cognitive assessment at baseline, and 211 (78%) had follow-up Montreal Cognitive Assessment at 1 year. Mean age was 80.5±4.8 years. There was a high prevalence (n=130, 48.0%) of undiagnosed cognitive impairment (Montreal Cognitive Assessment score <26) at baseline. Cognitive impairment patients were more likely to reach major adverse cardiovascular events by Kaplan-Meier analysis ( P=0.047). Seventy-four patients (35.1%) experienced cognitive decline (Montreal Cognitive Assessment score drop by ≥2 points) at 1 year. Recurrent myocardial infarction was independently associated with cognitive decline at 1 year (odds ratio 3.19, 95% confidence interval 1.18-8.63, P=0.02) after adjustment for age and sex. Conclusions In older patients undergoing invasive management of non-ST-elevation acute coronary syndrome, there is a high prevalence of undiagnosed cognitive impairment at baseline. Recurrent myocardial infarction is independently associated with cognitive decline at 1 year. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01933581

Serum profiling by MALDI-TOF mass spectrometry as a diagnostic tool for domoic acid toxicosis in California sea lions

<p>Abstract</p> <p>Background</p> <p>There are currently no reliable markers of acute domoic acid toxicosis (DAT) for California sea lions. We investigated whether patterns of serum peptides could diagnose acute DAT. Serum peptides were analyzed by MALDI-TOF mass spectrometry from 107 sea lions (acute DAT n = 34; non-DAT n = 73). Artificial neural networks (ANN) were trained using MALDI-TOF data. Individual peaks and neural networks were qualified using an independent test set (n = 20).</p> <p>Results</p> <p>No single peak was a good classifier of acute DAT, and ANN models were the best predictors of acute DAT. Performance measures for a single median ANN were: sensitivity, 100%; specificity, 60%; positive predictive value, 71%; negative predictive value, 100%. When 101 ANNs were combined and allowed to vote for the outcome, the performance measures were: sensitivity, 30%; specificity, 100%; positive predictive value, 100%; negative predictive value, 59%.</p> <p>Conclusions</p> <p>These results suggest that MALDI-TOF peptide profiling and neural networks can perform either as a highly sensitive (100% negative predictive value) or a highly specific (100% positive predictive value) diagnostic tool for acute DAT. This also suggests that machine learning directed by populations of predictive models offer the ability to modulate the predictive effort into a specific type of error.</p

Comprehensive Overview of Bottom-up Proteomics using Mass Spectrometry

Proteomics is the large scale study of protein structure and function from biological systems through protein identification and quantification. "Shotgun proteomics" or "bottom-up proteomics" is the prevailing strategy, in which proteins are hydrolyzed into peptides that are analyzed by mass spectrometry. Proteomics studies can be applied to diverse studies ranging from simple protein identification to studies of proteoforms, protein-protein interactions, protein structural alterations, absolute and relative protein quantification, post-translational modifications, and protein stability. To enable this range of different experiments, there are diverse strategies for proteome analysis. The nuances of how proteomic workflows differ may be challenging to understand for new practitioners. Here, we provide a comprehensive overview of different proteomics methods to aid the novice and experienced researcher. We cover from biochemistry basics and protein extraction to biological interpretation and orthogonal validation. We expect this work to serve as a basic resource for new practitioners in the field of shotgun or bottom-up proteomics

Global redox proteome and phosphoproteome analysis reveals redox switch in Akt.

Protein oxidation sits at the intersection of multiple signalling pathways, yet the magnitude and extent of crosstalk between oxidation and other post-translational modifications remains unclear. Here, we delineate global changes in adipocyte signalling networks following acute oxidative stress and reveal considerable crosstalk between cysteine oxidation and phosphorylation-based signalling. Oxidation of key regulatory kinases, including Akt, mTOR and AMPK influences the fidelity rather than their absolute activation state, highlighting an unappreciated interplay between these modifications. Mechanistic analysis of the redox regulation of Akt identified two cysteine residues in the pleckstrin homology domain (C60 and C77) to be reversibly oxidized. Oxidation at these sites affected Akt recruitment to the plasma membrane by stabilizing the PIP3 binding pocket. Our data provide insights into the interplay between oxidative stress-derived redox signalling and protein phosphorylation networks and serve as a resource for understanding the contribution of cellular oxidation to a range of diseases

Relationship of Platelet Reactivity With Bleeding Outcomes During Long-Term Treatment With Dual Antiplatelet Therapy for Medically Managed Patients With Non-ST-Segment Elevation Acute Coronary Syndromes

Background--The relationship between "on-treatment" low platelet reactivity and longitudinal risks of major bleeding dual antiplatelet therapy following acute coronary syndromes remains uncertain, especially for patients who do not undergo percutaneous coronary intervention. Methods and Results--We analyzed 2428medicallymanaged acute coronary syndromes patients fromthe Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial who had serial platelet reactivity measurements (P2Y12 reaction units; PRUs) and were randomized to aspirin+prasugrel versus aspirin+clopidogrel for up to 30 months. Contal's method was used to determine whether a cut point for steady-state PRU values could distinguish high versus low bleeding risk using 2-level composites: Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe/life-threatening or moderate bleeding unrelated to coronary artery bypass grafting (CABG) and non-CABG Thrombolysis In Myocardial Infarction (TIMI) major orminor bleeding. Exploratory analyses used 3-level composites that incorporatedmild andminimalGUSTOand TIMI events.Continuousmeasures of PRUs (per 10-unit decrease)were not independently associatedwith the 2-levelGUSTO (adjusted hazard ratio [HR], 1.01; 95% CI, 0.96-1.06) or TIMI composites (1.02; 0.98-1.07). Furthermore, no PRU cut point could significantly distinguish bleeding risk using the 2-level composites.However, the PRUcut point of 75 differentiated bleeding riskwith the 3-level composites ofGUSTO(26.5% vs 12.6%; adjusted HR, 2.28; 95% CI, 1.77-2.94; P<0.001) and TIMI bleeding events (25.9% vs 12.2%; adjusted HR, 2.30; 95% CI, 1.78-2.97; P<0.001). Conclusions--Among medically managed non-ST-segment elevation acute coronary syndromes patients receiving prolonged dual antiplatelet therapy, PRU values were not significantly associated with the long-term risk of major bleeding events, suggesting that low on-treatment platelet reactivity does not independently predict serious bleeding risk

Volcanic Contribution to Decadal Changes in Tropospheric Temperature

Despite continued growth in atmospheric levels of greenhouse gases, global mean surface and tropospheric temperatures have shown slower warming since 1998 than previously. Possible explanations for the slow-down include internal climate variability, external cooling influences and observational errors. Several recent modelling studies have examined the contribution of early twenty-first-century volcanic eruptions to the muted surface warming. Here we present a detailed analysis of the impact of recent volcanic forcing on tropospheric temperature, based on observations as well as climate model simulations. We identify statistically significant correlations between observations of stratospheric aerosol optical depth and satellite-based estimates of both tropospheric temperature and short-wave fluxes at the top of the atmosphere. We show that climate model simulations without the effects of early twenty-first-century volcanic eruptions overestimate the tropospheric warming observed since 1998. In two simulations with more realistic volcanic influences following the 1991 Pinatubo eruption, differences between simulated and observed tropospheric temperature trends over the period 1998 to 2012 are up to 15% smaller, with large uncertainties in the magnitude of the effect. To reduce these uncertainties, better observations of eruption-specific properties of volcanic aerosols are needed, as well as improved representation of these eruption-specific properties in climate model simulations

Grand Challenges of Advanced Computing for Energy Innovation Report from the Workshop Held July 31-August 2, 2012

On July 31-August 2 of 2012, the U.S. Department of Energy (DOE) held a workshop entitled Grand Challenges of Advanced Computing for Energy Innovation. This workshop built on three earlier workshops that clearly identified the potential for the Department and its national laboratories to enable energy innovation. The specific goal of the workshop was to identify the key challenges that the nation must overcome to apply the full benefit of taxpayer-funded advanced computing technologies to U.S. energy innovation in the ways that the country produces, moves, stores, and uses energy. Perhaps more importantly, the workshop also developed a set of recommendations to help the Department overcome those challenges. These recommendations provide an action plan for what the Department can do in the coming years to improve the nation’s energy future