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1.
Prediction of high anti-angiogenic activity peptides in silico using a generalized linear model and feature selection.
Blanco, JL, Porto-Pazos, AB, Pazos, A, Fernandez-Lozano, C
Scientific reports. 2018;(1):15688
Abstract
Screening and in silico modeling are critical activities for the reduction of experimental costs. They also speed up research notably and strengthen the theoretical framework, thus allowing researchers to numerically quantify the importance of a particular subset of information. For example, in fields such as cancer and other highly prevalent diseases, having a reliable prediction method is crucial. The objective of this paper is to classify peptide sequences according to their anti-angiogenic activity to understand the underlying principles via machine learning. First, the peptide sequences were converted into three types of numerical molecular descriptors based on the amino acid composition. We performed different experiments with the descriptors and merged them to obtain baseline results for the performance of the models, particularly of each molecular descriptor subset. A feature selection process was applied to reduce the dimensionality of the problem and remove noisy features - which are highly present in biological problems. After a robust machine learning experimental design under equal conditions (nested resampling, cross-validation, hyperparameter tuning and different runs), we statistically and significantly outperformed the best previously published anti-angiogenic model with a generalized linear model via coordinate descent (glmnet), achieving a mean AUC value greater than 0.96 and with an accuracy of 0.86 with 200 molecular descriptors, mixed from the three groups. A final analysis with the top-40 discriminative anti-angiogenic activity peptides is presented along with a discussion of the feature selection process and the individual importance of each molecular descriptors According to our findings, anti-angiogenic activity peptides are strongly associated with amino acid sequences SP, LSL, PF, DIT, PC, GH, RQ, QD, TC, SC, AS, CLD, ST, MF, GRE, IQ, CQ and HG.
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2.
Accurate PDZ/Peptide Binding Specificity with Additive and Polarizable Free Energy Simulations.
Panel, N, Villa, F, Fuentes, EJ, Simonson, T
Biophysical journal. 2018;(5):1091-1102
Abstract
PDZ domains contain 80-100 amino acids and bind short C-terminal sequences of target proteins. Their specificity is essential for cellular signaling pathways. We studied the binding of the Tiam1 PDZ domain to peptides derived from the C-termini of its Syndecan-1 and Caspr4 targets. We used free energy perturbation (FEP) to characterize the binding energetics of one wild-type and 17 mutant complexes by simulating 21 alchemical transformations between pairs of complexes. Thirteen complexes had known experimental affinities. FEP is a powerful tool to understand protein/ligand binding. It depends, however, on the accuracy of molecular dynamics force fields and conformational sampling. Both aspects require continued testing, especially for ionic mutations. For six mutations that did not modify the net charge, we obtained excellent agreement with experiment using the additive, AMBER ff99SB force field, with a root mean square deviation (RMSD) of 0.37 kcal/mol. For six ionic mutations that modified the net charge, agreement was also good, with one large error (3 kcal/mol) and an RMSD of 0.9 kcal/mol for the other five. The large error arose from the overstabilization of a protein/peptide salt bridge by the additive force field. Four of the ionic mutations were also simulated with the polarizable Drude force field, which represents the first test of this force field for protein/ligand binding free energy changes. The large error was eliminated and the RMS error for the four mutations was reduced from 1.8 to 1.2 kcal/mol. The overall accuracy of FEP indicates it can be used to understand PDZ/peptide binding. Importantly, our results show that for ionic mutations in buried regions, electronic polarization plays a significant role.
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3.
Methionine oxidation by hydrogen peroxide in peptides and proteins: A theoretical and Raman spectroscopy study.
Sjöberg, B, Foley, S, Cardey, B, Fromm, M, Enescu, M
Journal of photochemistry and photobiology. B, Biology. 2018;:95-99
Abstract
The oxidation of proteins results in their deterioration via the oxidation of reactive amino acids. Oxidation of the amino acid, methionine plays an important role during biological conditions of oxidative stress, and equally a role in protein stability. In this study the oxidation of the methionine residue using the tripeptide GlyMetGly with respect to hydrogen peroxide has been studied using both Raman spectroscopy and DFT calculations. Spectral modifications following the formation of methionine sulfoxide are shown with the appearance of the SO vibration whilst there is also the modification of the CS vibrations at approximately 700 cm-1. The changes in the intensity of the CS stretching band were used to calculate the kinetic rate constant as 7.9 ± 0.6 × 10-3 dm3 mol-1 s-1. The energy barrier for the reaction. is determined both experimentally and using DFT calculations. The reaction of the dairy protein beta-lactoglobulin with hydrogen peroxide is equally studied using the same technique. The solvent accessible surface area of the methionine residues within the protein were also determined and a comparison of the reaction rate constant and the energy barriers of reaction for the oxidation of the tripeptide and for the protein respectively thus, provides information about the role of the protein environment in the oxidation process.
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4.
On the feasibility of mining CD8+ T cell receptor patterns underlying immunogenic peptide recognition.
De Neuter, N, Bittremieux, W, Beirnaert, C, Cuypers, B, Mrzic, A, Moris, P, Suls, A, Van Tendeloo, V, Ogunjimi, B, Laukens, K, et al
Immunogenetics. 2018;(3):159-168
Abstract
Current T cell epitope prediction tools are a valuable resource in designing targeted immunogenicity experiments. They typically focus on, and are able to, accurately predict peptide binding and presentation by major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells. However, recognition of the peptide-MHC complex by a T cell receptor (TCR) is often not included in these tools. We developed a classification approach based on random forest classifiers to predict recognition of a peptide by a T cell receptor and discover patterns that contribute to recognition. We considered two approaches to solve this problem: (1) distinguishing between two sets of TCRs that each bind to a known peptide and (2) retrieving TCRs that bind to a given peptide from a large pool of TCRs. Evaluation of the models on two HIV-1, B*08-restricted epitopes reveals good performance and hints towards structural CDR3 features that can determine peptide immunogenicity. These results are of particular importance as they show that prediction of T cell epitope and T cell epitope recognition based on sequence data is a feasible approach. In addition, the validity of our models not only serves as a proof of concept for the prediction of immunogenic T cell epitopes but also paves the way for more general and high-performing models.
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5.
Investigation of robustness for supercritical fluid chromatography separation of peptides: Isocratic vs gradient mode.
Enmark, M, Glenne, E, Leśko, M, Langborg Weinmann, A, Leek, T, Kaczmarski, K, Klarqvist, M, Samuelsson, J, Fornstedt, T
Journal of chromatography. A. 2018;:177-187
Abstract
We investigated and compared the robustness of supercritical fluid chromatography (SFC) separations of the peptide gramicidin, using either isocratic or gradient elution. This was done using design of experiments in a design space of co-solvent fraction, water mass fraction in co-solvent, pressure, and temperature. The density of the eluent (CO2-MeOH-H2O) was experimentally determined using a Coriolis mass flow meter to calculate the volumetric flow rate required by the design. For both retention models, the most important factor was the total co-solvent fraction and water mass fraction in co-solvent. Comparing the elution modes, we found that gradient elution was more than three times more robust than isocratic elution. We also observed a relationship between the sensitivity to changes and the gradient steepness and used this to draw general conclusions beyond the studied experimental system. To test the robustness in a practical context, both the isocratic and gradient separations were transferred to another laboratory. The gradient elution was highly reproducible between laboratories, whereas the isocratic system was not. Using measurements of the actual operational conditions (not the set system conditions), the isocratic deviation was quantitatively explained using the retention model. The findings indicate the benefits of using gradient elution in SFC as well as the importance of measuring the actual operational conditions to be able to explain observed differences between laboratories when conducting method transfer.
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6.
Lixisenatide Versus Insulin Glulisine on Fasting and Postbreakfast Systemic Hemodynamics in Type 2 Diabetes Mellitus Patients.
Tonneijck, L, Muskiet, MHA, Twisk, JW, Kramer, MHH, Danser, AHJ, Joles, JA, Smits, MM, van Raalte, DH
Hypertension (Dallas, Tex. : 1979). 2018;(2):314-322
Abstract
The prolonged treatment effects of a short-acting GLP-1RA (glucagon-like peptide-1 receptor agonist), such as lixisenatide, on fasting and postprandial systemic hemodynamics in type 2 diabetes mellitus patients are unknown. In this secondary analysis, we included 34 overweight insulin glargine-treated type 2 diabetes mellitus patients (mean±SD age, 62±7 years; HbA1c, 8.0±0.9%; systolic blood pressure [BP], 133.9±16.1 mm Hg; diastolic BP, 75.4±8.39 mm Hg) that were randomized to once-daily lixisenatide 20 μg or once-daily titrated insulin glulisine for 8 weeks. Systemic hemodynamics (oscillometric device and finger photoplethysmography), arterial stiffness (applanation tonometry), and cardiac sympathovagal balance (heart rate variability) were measured in the fasting state and repetitively (up to minute 175) after a standardized mixed breakfast. Acetaminophen was given orally to estimate gastric emptying rate. Lixisenatide did not affect fasting systemic hemodynamics compared with insulin glulisine from baseline to week 8. Postbreakfast overall, lixisenatide compared with insulin glulisine tended to increase systolic BP by 5.2±2.9 mm Hg (P=0.087) and increased diastolic BP by 5.4±1.4 mm Hg (P<0.001), with respective maximal differences of +10.2±3.7 mm Hg (P=0.007) and +7.2±1.5 mm Hg (P<0.001). Lixisenatide increased systemic vascular resistance (P<0.001) and arterial stiffness (P=0.007). No between-group differences in overall postbreakfast heart rate, cardiac output, or cardiac sympathovagal balance, and circulating catecholamines, angiotensin II, or aldosterone were observed. Both treatments lowered HbA1c similarly, whereas lixisenatide achieved greater reductions in postbreakfast plasma glucose excursions. Lixisenatide slowed gastric emptying rate, which statistically explained changes in postbreakfast BP. Lixisenatide compared with once-daily titrated insulin glulisine for 8 weeks does not affect fasting but increases postbreakfast BP in insulin glargine-treated type 2 diabetes mellitus patients. This effect could, at least in part, be explained by reduced passage rate of nutrients and water and activation of the gastrovascular reflex.
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7.
Gluten Immunogenic Peptides as Standard for the Evaluation of Potential Harmful Prolamin Content in Food and Human Specimen.
Cebolla, Á, Moreno, ML, Coto, L, Sousa, C
Nutrients. 2018;(12)
Abstract
Gluten is a complex mixture of storage proteins in cereals like wheat, barley, and rye. Prolamins are the main components of gluten. Their high content in proline and glutamine makes them water-insoluble and difficult to digest in the gastrointestinal tract. Partial digestion generates peptide sequences which trigger immune responses in celiac and gluten-sensitive patients. Gluten detection in food is challenging because of the diversity, in various food matrices, of protein proportions or modifications and the huge number of immunogenic sequences with differential potential immunoactivity. Attempts to develop standard reference materials have been unsuccessful. Recent studies have reported the detection of a limited number of dominant Gluten Immunogenic Peptides (GIP) that share similarities to epitopes presented in the α-gliadin 33-mer, which showed to be highly proteolytic resistant and is considered to be the most immunodominant peptide within gluten in celiac disease (CD). GIP were detectable and quantifiable in very different kind of difficult to analyze food, revealing the potential immunogenicity by detecting T-cell activity of celiac patients. But GIP were also found in stool and urine of celiac patients on a supposedly gluten-free diet (GFD), showing the capacity to resist and be absorbed and excreted from the body, providing the first simple and objective means to assess adherence to the GFD. Methods to specifically and sensitively detect the most active GIP in food and biological fluids are rational candidates may use similar analytical standard references for determination of the immunopathological risk of gluten exposure in gluten-related diseases.
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8.
Lactobacillus helveticus-fermented milk containing lactononadecapeptide (NIPPLTQTPVVVPPFLQPE) improves cognitive function in healthy middle-aged adults: a randomised, double-blind, placebo-controlled trial.
Ohsawa, K, Nakamura, F, Uchida, N, Mizuno, S, Yokogoshi, H
International journal of food sciences and nutrition. 2018;(3):369-376
Abstract
This study aimed to determine the effects of a Lactobacillus helveticus-fermented milk drink containing lactononadecapeptide (NIPPLTQTPVVVPPFLQPE) on the cognitive function of healthy middle-aged adults. A randomised, double-blind controlled study was conducted in healthy participants who were randomly assigned to receive a L. helveticus-fermented milk drink (190 g/day) or the equivalent amount of a placebo drink once a day for eight weeks. Cognitive function was evaluated using the Japanese version of the repeatable battery for the assessment of neuropsychological status (RBANS) test. There was a statistically significant improvement in the total score, attention score, and delayed memory score of participants who received the L. helveticus-fermented milk drink. There was also a significant difference in the attention score between the placebo and test groups after eight weeks (p = .028). Therefore, supplementation of healthy middle-aged adults with a L. helveticus-fermented milk drink for eight weeks improved both attention and delayed memory.
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9.
Perspectives of ruthenium(ii) polyazaaromatic photo-oxidizing complexes photoreactive towards tryptophan-containing peptides and derivatives.
Estalayo-Adrián, S, Garnir, K, Moucheron, C
Chemical communications (Cambridge, England). 2018;(4):322-337
Abstract
RuII polyazaaromatic complexes have been studied with the aim of developing molecular tools for DNA and oligonucleotides. In this context, RuII-TAP (TAP = 1,4,5,8-tetraazaphenanthrene) complexes have been developed as specific photoreagents targeting the genetic material. The advantage of such compounds is due to the formation of photo-addition products between the Ru-TAP complex and the biomolecule, originating from a photo-induced electron transfer process that takes place between the excited Ru-TAP complex and guanine (G) bases of DNA. This photo-addition has been more recently extended to amino acids in view of applications involving peptides, such as inhibition or photocontrol of proteins. More particularly, tryptophan (Trp) and Trp-containing peptides are also able to be photo-oxidized by RuII-TAP complexes, leading to the formation of photo-addition products. This mini review focuses on recent advances in the search for RuII polyazaaromatic photo-oxidizing complexes of interest as molecular tools and photoreagents for Trp-containing peptides and proteins. Different possible future directions in this field are also discussed.
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10.
Reduction of Parenteral Nutrition and Hydration Support and Safety With Long-Term Teduglutide Treatment in Patients With Short Bowel Syndrome-Associated Intestinal Failure: STEPS-3 Study.
Seidner, DL, Fujioka, K, Boullata, JI, Iyer, K, Lee, HM, Ziegler, TR
Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2018;(4):520-527
Abstract
BACKGROUND Patients with intestinal failure associated with short bowel syndrome (SBS-IF) require parenteral support (PS) to maintain fluid balance or nutrition. Teduglutide (TED) reduced PS requirements in patients with SBS-IF in the randomized, placebo (PBO)-controlled STEPS study (NCT00798967) and its 2-year, open-label extension, STEPS-2 (NCT00930644). METHODS STEPS-3 (NCT01560403), a 1-year, open-label extension study in patients with SBS-IF who completed STEPS-2, further monitored the safety and efficacy of TED (0.05 mg/kg/day). Baseline was the start of TED treatment, in either STEPS or STEPS-2. At the end of STEPS-3, patients treated with TED in both STEPS and STEPS-2 (TED-TED) received TED for ≤42 months, and patients treated with TED only in STEPS-2 (no TED treatment [NT]/PBO-TED) received TED for ≤36 months. RESULTS Fourteen patients enrolled (TED-TED, n = 5; NT/PBO-TED, n = 9) and 13 completed STEPS-3. At the last dosing visit, mean (SD) PS was reduced from baseline by 9.8 (14.4 [50%]) and 3.9 (2.8 [48%]) L/week in TED-TED and NT/PBO-TED, respectively. Mean (SD) PS infusions decreased by 3.0 (4.6) and 2.1 (2.2) days per week from baseline in TED-TED and NT/PBO-TED, respectively. Two patients achieved PS independence; 2 additional patients who achieved independence in STEPS-2 maintained enteral autonomy throughout STEPS-3. All patients reported ≥1 treatment-emergent adverse event (TEAE); 3 patients had TEAEs that were reported as treatment related. No patient had a treatment-related treatment-emergent serious AE. CONCLUSIONS Long-term TED treatment yielded a safety profile consistent with previous studies, sustained efficacy, and a further decline in PS requirements.