Reaction rate theory for supramolecular kinetics: application to protein aggregation

Probing the reaction mechanisms of supramolecular processes in soft- and biological matter, such as protein aggregation, is inherently challenging. These processes emerge from the simultaneous action of multiple molecular mechanisms, each of which is associated with the rearrangement of a large number of weak bonds, resulting in a complex free energy landscape with many kinetic barriers. Reaction rate measurements of supramolecular processes at different temperatures can offer unprecedented insights into the underlying molecular mechanisms and their thermodynamic properties. However, to be able to interpret such measurements in terms of the underlying microscopic mechanisms, a key challenge is to establish which properties of the complex free energy landscapes are probed by the reaction rate. Here, we present a reaction rate theory for supramolecular kinetics based on Kramers rate theory for diffusive reactions over multiple kinetic barriers, and apply the results to protein aggregation. Using this framework and Monte Carlo simulations, we show that reaction rates for protein aggregation are of the Arrhenius-Eyring type and that the associated activation energies probe only one relevant barrier along the respective free energy landscapes. We apply this advancement to interpret, both in experiments and in coarse-grained computer simulations, reaction rate measurements of amyloid aggregation kinetics in terms of the underlying molecular mechanisms and associated thermodynamic signatures. Our results establish a general platform for probing the mechanisms and energetics of supramolecular phenomena in soft- and biological matter using the framework of chemical kinetics

The Effect of Acoustic Forcing on Instabilities and Breakdown in Swept-Wing Flow over a Backward-Facing Step

Instability interaction and breakdown were experimentally investigated in the flow over a swept backward-facing step. Acoustic forcing was used to excite the Tollmien-Schlichting (TS) instability and to acquire phase-locked results. The phase-averaged results illustrate the complex nature of the interaction between the TS and stationary cross flow instabilities. The weak stationary cross flow disturbance causes a distortion of the TS wavefront. The breakdown process is characterized by large positive and negative spikes in velocity. The positive spikes occur near the same time and location as the positive part of the TS wave. Higher-order spectral analysis was used to further investigate the nonlinear interactions between the TS instability and the traveling cross flow disturbances. The results reveal that a likely cause for the generation of the spikes corresponds to nonlinear interactions between the TS, traveling cross flow, and stationary cross flow disturbances. The spikes begin at low amplitudes of the unsteady and steady disturbances (2-4% U (sub e) (i.e. boundary layer edge velocity)) but can achieve very large amplitudes (20-30 percent U (sub e) (i.e. boundary layer edge velocity)) that initiate an early, though highly intermittent, breakdown to turbulence

1H NMR-based profiling reveals differential immune-metabolic networks during influenza virus infection in obese mice

Obese individuals are at greater risk for death from influenza virus infection. Paralleling human evidence, obese mice are also more susceptible to influenza infection mortality. However, the underlying mechanisms driving greater influenza severity in the obese remain unclear. Metabolic profiling has been utilized in infectious disease models to enhance prognostic or diagnostic methods, and to gain insight into disease pathogenesis by providing a more global picture of dynamic infection responses. Herein, metabolic profiling was used to develop a deeper understanding of the complex processes contributing to impaired influenza protection in obese mice and to facilitate generation of new explanatory hypotheses. Diet-induced obese and lean mice were infected with influenza A/Puerto Rico/8/34. 1H nuclear magnetic resonance-based metabolic profiling of urine, feces, lung, liver, mesenteric white adipose tissue, bronchoalveolar lavage fluid and serum revealed distinct metabolic signatures in infected obese mice, including perturbations in nucleotide, vitamin, ketone body, amino acid, carbohydrate, choline and lipid metabolic pathways. Further, metabolic data was integrated with immune analyses to obtain a more comprehensive understanding of potential immune-metabolic interactions. Of interest, uncovered metabolic signatures in urine and feces allowed for discrimination of infection status in both lean and obese mice at an early influenza time point, which holds prognostic and diagnostic implications for this methodology. These results confirm that obesity causes distinct metabolic perturbations during influenza infection and provide a basis for generation of new hypotheses and use of this methodology in detection of putative biomarkers and metabolic patterns to predict influenza infection outcome

Lipid membrane-mediated attraction between curvature inducing objects

Biological and Soft Matter Physic

Using Unsupervised Patterns to Extract Gene Regulation Relationships for Network Construction

BACKGROUND: The gene expression is usually described in the literature as a transcription factor X that regulates the target gene Y. Previously, some studies discovered gene regulations by using information from the biomedical literature and most of them require effort of human annotators to build the training dataset. Moreover, the large amount of textual knowledge recorded in the biomedical literature grows very rapidly, and the creation of manual patterns from literatures becomes more difficult. There is an increasing need to automate the process of establishing patterns. METHODOLOGY/PRINCIPAL FINDINGS: In this article, we describe an unsupervised pattern generation method called AutoPat. It is a gene expression mining system that can generate unsupervised patterns automatically from a given set of seed patterns. The high scalability and low maintenance cost of the unsupervised patterns could help our system to extract gene expression from PubMed abstracts more precisely and effectively. CONCLUSIONS/SIGNIFICANCE: Experiments on several regulators show reasonable precision and recall rates which validate AutoPat's practical applicability. The conducted regulation networks could also be built precisely and effectively. The system in this study is available at http://ikmbio.csie.ncku.edu.tw/AutoPat/

The Internal Sequence of the Peptide-Substrate Determines Its N-Terminus Trimming by ERAP1

Background: Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims N-terminally extended antigenic peptide precursors down to mature antigenic peptides for presentation by major histocompatibility complex (MHC) class I molecules. ERAP1 has unique properties for an aminopeptidase being able to trim peptides in vitro based on their length and the nature of their C-termini. Methodology/Principal Findings: In an effort to better understand the molecular mechanism that ERAP1 uses to trim peptides, we systematically analyzed the enzyme's substrate preferences using collections of peptide substrates. We discovered strong internal sequence preferences of peptide N-terminus trimming by ERAP1. Preferences were only found for positively charged or hydrophobic residues resulting to trimming rate changes by up to 100 fold for single residue substitutions and more than 40,000 fold for multiple residue substitutions for peptides with identical N-termini. Molecular modelling of ERAP1 revealed a large internal cavity that carries a strong negative electrostatic potential and is large enough to accommodate peptides adjacent to the enzyme's active site. This model can readily account for the strong preference for positively charged side chains. Conclusions/Significance: To our knowledge no other aminopeptidase has been described to have such strong preferences for internal residues so distal to the N-terminus. Overall, our findings indicate that the internal sequence of the peptide can affect its trimming by ERAP1 as much as the peptide's length and C-terminus. We therefore propose that ERAP1 recognizes the full length of its peptide-substrate and not just the N- and C- termini. It is possible that ERAP1 trimming preferences influence the rate of generation and the composition of antigenic peptides in vivo

A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours

Contains fulltext : 89517timmer-bonte.pdf (publisher's version ) (Closed access)BACKGROUND: This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel. METHODS: A total of 22 patients received paclitaxel (135-175 mg m(-2)) intravenously, administered once every three weeks for up to six cycles, with oral tosedostat (90-240 mg) daily. RESULTS: One DLT (grade 3 dyspnoea) was observed in one patient with tosedostat 180 mg combined with paclitaxel 175 mg m(-2). A high number of paclitaxel infusion reactions was noted during the second administration (59%) and this prompted interruption of tosedostat dosing for 5 days around every second and subsequent paclitaxel infusion. No formal MTD was determined because of the high frequency of paclitaxel infusion reactions that may have been influenced by tosedostat. Most frequently observed drug-related adverse events were alopecia, fatigue (95% each), peripheral sensory neuropathy (59%), paclitaxel hypersensitivity (59%) and rash (55%). One patient died because of eosinophilic myocarditis, possibly related to study medication. There was no PK interaction between tosedostat and paclitaxel. In all, 3 patients had a partial response and 12 patients had stable disease lasting >3 months. CONCLUSION: The combination of tosedostat with paclitaxel was well tolerated except for the high incidence of paclitaxel-related infusion reactions