Trajectory Synthesis for Fisher Information Maximization

Estimation of model parameters in a dynamic system can be significantly improved with the choice of experimental trajectory. For general, nonlinear dynamic systems, finding globally "best" trajectories is typically not feasible; however, given an initial estimate of the model parameters and an initial trajectory, we present a continuous-time optimization method that produces a locally optimal trajectory for parameter estimation in the presence of measurement noise. The optimization algorithm is formulated to find system trajectories that improve a norm on the Fisher information matrix. A double-pendulum cart apparatus is used to numerically and experimentally validate this technique. In simulation, the optimized trajectory increases the minimum eigenvalue of the Fisher information matrix by three orders of magnitude compared to the initial trajectory. Experimental results show that this optimized trajectory translates to an order of magnitude improvement in the parameter estimate error in practice.Comment: 12 page

Analysis of the pancreatic low molecular weight proteome in an animal model of acute pancreatitis

We used a peptidomic approach for the analysis of the low molecular weight proteome in rat pancreatic tissue extracts. The goal was to develop a method that allows identifying endogenous peptides produced in the pancreas in the course of acute pancreatitis. The workflow combines peptides enrichment by centrifugal ultrafiltration, fractionation by isoelectric focusing, and LC-MS/MS analysis without prior enzymatic digestion. The method was assessed on pancreatic extracts from 3 rats with caerulein-induced pancreatitis and 3 healthy controls. A qualitative analysis of the peptide patterns obtained from the different samples was performed to determine the main biological processes associated to the identified peptides. Comparison of peptidomic and immunoblot data for alpha-tubulin, beta-tubulin and coatomer gamma showed that the correlation between the number of identified peptides and the protein abundance was variable. Nevertheless, peptidomic analysis highlighted inflammatory and stress proteins, which peptide pattern was related to acute pancreatitis pathobiology. For these proteins, the higher number of peptides in pancreatitis samples reflected an increase in protein abundance. Moreover, for murinoglobulin-1 or carboxypeptidase B, peptide pattern could be related to protein function. These data suggest that peptidomic analysis is a complementary approach to proteomics for investigating pathobiological processes involved in acute pancreatitis

P5343 - The presence of anti-apolipoprotein A1 autoantibodies is associated with a pro-atherogenic profile in HIV-infected patients

Background: With the access to antiretroviral therapy (ART), the mortality related to the human immunodeficiency virus (HIV) has dropped, shifting the clinical challenges towards chronic disease management, including cardiovascular disease (CVD) risk assessment. Factors that potentially contribute to the physiopathology of HIV-related CVD include the HI-virus itself, adverse effects of ART, and processes such as dyslipidemia, inflammation, immune/autoimmune activation and endothelial injury. Among autoantibodies of possible cardiovascular relevance, those directed against apolipoprotein A-1 (anti-apoA-1 IgG) were shown to predict major adverse cardiovascular events and promote atherogenesis. Purpose: The aim of the study was to evaluate the prevalence of anti-apoA1 IgG in HIV-free and ART experienced and naïve HIV-infected patients as well as the association between anti-apoA1 IgG levels and, indices of viral suppression, clinical parameters (10 year Framingham Risk Score (FRS)) and inflammatory biomarkers, known to underlie atherosclerosis burden in these patients. Methods: Anti-apoA1 IgG serum levels were assessed by a homemade ELISA assay in 144 participants from a South African cohort divided in three groups: HIV-free (n=50), HIV-infected/ART experienced (n=50) and HIV-infected/ART naïve (n=44). Inflammatory biomarkers were measured. Results: HIV-infected patients displayed an increased pro-atherogenic biomarker profile compared to HIV-free subjects, but not difference in the FRS was observed between these two groups. Regarding anti-apoA1 IgG, 24% of HIV-free patients tested positive compared to 40% and 70% in HIV-infected/ART experienced and naïve groups, respectively. HIV-infected, anti-apoA1 IgG positive patients showed a significant decrease in CD4+ counts (p=0.003) and a significant increase in viremia (p=0.0130), mean heart rate (p=0.0243), albuminuria (p=0.0155), pro-inflammatory biomarkers (IFNγ, IL-10, TNFα, MIPα; all p&lt;0.05), circulating levels of intercellular adhesion molecule (ICAM-1) (p=0.0217) and vascular cell adhesion molecule (VCAM-1) (p=0.003) compared to anti-apoA1 IgG negative ones. Of note, while this profile was maintained in HIV-infected/ART experienced, these significant differences were lost in HIV-infected/ART naïve patients. No significant difference in FRS was observed between anti-apoA1 IgG positive vs negative individuals in all groups. Conclusions: HIV-infected patients presented with an increased prevalence of anti-apoA1 IgG compared to HIV-free subjects. In HIV-infected/ART experienced patients, anti-apoA1 IgG levels were associated with low CD4+ counts, levels of adhesion molecules and pro-inflammatory responses, features associated with increased cardiovascular events. ART highlighted pro-atherogenic differences between HIV-infected anti-apoA1 IgG negative and positive patients.</p

Proteomic analysis of heat shock-induced protection in acute pancreatitis

Acute pancreatitis is an inflammatory disease of the pancreas, which can result in serious morbidity or death. Acute pancreatitis severity can be reduced in experimental models by preconditioning animals with a short hyperthermia prior to disease induction. Heat shock proteins 27 and 70 are key effectors of this protective effect. In this study, we performed a comparative proteomic analysis using a combination of liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis and isobaric tagging to investigate changes in pancreatic proteins expression that were associated with thermal stress, both in healthy rats and in a model of caerulein-induced pancreatitis. In agreement with previous studies, we observed modulation of heat shock and inflammatory proteins expression in response to heat stress or pancreatitis induction. We also identified numerous other proteins, whose pancreatic level changed following pancreatitis induction, when acute pancreatitis severity was reduced by prior thermal stress, or in healthy rats in response to hyperthermia. Interestingly, we showed that the expression of various proteins associated with the secretory pathway was modified in the different experimental models, suggesting that modulation of this process is involved in the protective effect against pancreatic tissue damage

Proteomic discovery and verification of serum amyloid A as a predictor marker of patients at risk of post-stroke infection : a pilot study

Post-stroke infections occur in 20-36% of stroke patients and are associated with high morbidity and mortality rates. Early identification of patients at risk of developing an infection could improve care via an earlier treatment leading to a better outcome. We used proteomic tools in order to discover biomarkers able to stratify patients at risk of post-stroke infection. The post hoc analysis of a prospective cohort study including 40 ischemic stroke patients included 21 infected and 19 non-infected participants. A quantitative, isobaric labeling, proteomic strategy was applied to the plasma samples of 5 infected and 5 non-infected patients in order to highlight any significantly modulated proteins. A parallel reaction monitoring (PRM) assay was applied to 20 additional patients (10 infected and 10 non-infected) to verify discovery results. The most promising protein was pre-validated using an ELISA immunoassay on 40 patients and at different time points after stroke onset. Tandem mass analysis identified 266 proteins, of which only serum amyloid A (SAA1/2) was significantly (p = 0.007) regulated between the two groups of patients. This acute-phase protein appeared to be 2.2 times more abundant in infected patients than in non-infected ones. These results were verified and validated using PRM and ELISA immunoassays, which showed that infected patients had significantly higher concentrations of SAA1/2 than non-infected patients at hospital admission, but also at 1, 3, and 5 days after admission. The present study demonstrated that SAA1/2 is a promising predictor, at hospital admission, of stroke patients at risk of developing an infection. Further large, multicenter validation studies are needed to confirm these results. If confirmed, SAA1/2 concentrations could be used to identify the patients most at risk of post-stroke infections and therefore implement treatments more rapidly, thus reducing mortality. The online version of this article (doi:10.1186/s12014-017-9162-0) contains supplementary material, which is available to authorized users

Proteomic profiling in an animal model of acute pancreatitis

Acute pancreatitis (AP) is an inflammatory disease of the pancreas, which evolves in approximately 20% of the patients to a severe illness associated with a high mortality rate. In this study, we performed a comparative proteomic analysis of pancreatic tissue extracts from rats with AP and healthy rodent controls in order to identify changes in protein expression related to the pathobiological processes of this disease. Pancreatic extracts from diseased and controls rats were analyzed by 2-DE and MS/MS. A total of 125 proteins were identified from both samples. Comparative analysis allowed the detection of 42 proteins or protein fragments differentially expressed between diseased and control pancreas, some of them being newly described in AP. Interestingly, these changes were representative of the main pathobiological pathways involved in this disease. We observed activation of digestive proteases and increased expression of various inflammatory markers, including several members of the alpha-macroglobulin family. We also detected changes related to oxidative and cell stress responses. Finally, we highlighted modifications of 14-3-3 proteins that could be related to apoptosis regulation. These results showed the interest of proteomic analysis to identify changes characterizing pancreatic tissue damage and, therefore, to highlight new potential biomarkers of AP

MOESM1 of Proteomic discovery and verification of serum amyloid A as a predictor marker of patients at risk of post-stroke infection: a pilot study

Additional file 1. List of proteins identified when comparing the proteomes of five infected and five non-infected patients

People living with HIV display increased anti-apolipoprotein A1 auto-antibodies, inflammation, and kynurenine metabolites : a case–control study

Objective This study aimed to study the relationship between auto-antibodies against apolipoprotein A1 (anti-apoA1 IgG), human immunodeficiency virus (HIV) infection, anti-retroviral therapy (ART), and the tryptophan pathways in HIV-related cardiovascular disease. Design This case–control study conducted in South Africa consisted of control volunteers ( n  = 50), people living with HIV (PLWH) on ART ( n  = 50), and untreated PLWH ( n  = 44). Cardiovascular risk scores were determined, vascular measures were performed, and an extensive biochemical characterisation (routine, metabolomic, and inflammatory systemic profiles) was performed. Methods Anti-apoA1 IgG levels were assessed by an in-house ELISA. Inflammatory biomarkers were measured with the Meso Scale Discovery® platform, and kynurenine pathway metabolites were assessed using targeted metabolomic profiling conducted by liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS). Results Cardiovascular risk scores and vascular measures exhibited similarities across the three groups, while important differences were observed in systemic inflammatory and tryptophan pathways. Anti-apoA1 IgG seropositivity rates were 15%, 40%, and 70% in control volunteers, PLWH ART-treated, and PLWH ART-naïve, respectively. Circulating anti-apoA1 IgG levels were significantly negatively associated with CD4+ cell counts and positively associated with viremia and pro-inflammatory biomarkers (IFNγ, TNFα, MIPα, ICAM-1, VCAM-1). While circulating anti-apoA1 IgG levels were associated with increased levels of kynurenine in both control volunteers and PLWH, the kynurenine/tryptophan ratio was significantly increased in PLWH ART-treated. Conclusion HIV infection increases the humoral response against apoA1, which is associated with established HIV severity criteria and kynurenine pathway activation.</p