Association between carotid diameter and the advanced glycation endproduct Nε-Carboxymethyllysine (CML)

<p>Abstract</p> <p>Background</p> <p>N^ε-Carboxymethyllysine (CML) is the major non-cross linking advanced glycation end product (AGE). CML is elevated in diabetic patients and apparent in atherosclerotic lesions. AGEs are associated with hypertension and arterial stiffness potentially by qualitative changes of elastic fibers. We investigated whether CML affects carotid and aortic properties in normoglycemic subjects.</p> <p>Methods</p> <p>Hundred-two subjects (age 48.2 ± 11.3 years) of the FLEMENGHO study were stratified according to the median of the plasma CML level (200.8 ng/ml; 25^thpercentile: 181.6 ng/ml, 75^thpercentile: 226.1 ng/ml) into "high CML" versus "low CML" as determined by ELISA. Local carotid artery properties, carotid intima media thickness (IMT), aortic pulse wave velocity (PWV), blood pressure and fetuin-A were analyzed. In 26 patients after carotidectomy, CML was visualized using immunohistochemistry.</p> <p>Results</p> <p>According to the CML median, groups were similar for anthropometric and biochemical data. Carotid diameter was enlarged in the "high" CML group (485.7 ± 122.2 versus 421.2 ± 133.2 μm; P < 0.05), in particular in participants with elevated blood pressure and with "high" CML ("low" CML: 377.9 ± 122.2 μm and "high" CML: 514.5 ± 151.6 μm; P < 0.001). CML was associated fetuin-A as marker of vascular inflammation in the whole cohort (r = 0.28; P < 0.01) and with carotid diameter in hypertensive subjects (r = 0.42; P < 0.01). CML level had no effect on aortic stiffness. CML was detected in the subendothelial space of human carotid arteries.</p> <p>Conclusion</p> <p>In normoglycemic subjects CML was associated with carotid diameter without adaptive changes of elastic properties and with fetuin-A as vascular inflammation marker, in particular in subjects with elevated blood pressure. This may suggest qualitative changes of elastic fibers resulting in a defective mechanotransduction, in particular as CML is present in human carotid arteries.</p

Effect of AGM and Fetal Liver-Derived Stromal Cell Lines on Globin Expression in Adult Baboon (P. anubis) Bone Marrow-Derived Erythroid Progenitors

This study was performed to investigate the hypothesis that the erythroid micro-environment plays a role in regulation of globin gene expression during adult erythroid differentiation. Adult baboon bone marrow and human cord blood CD34+ progenitors were grown in methylcellulose, liquid media, and in co-culture with stromal cell lines derived from different developmental stages in identical media supporting erythroid differentiation to examine the effect of the micro-environment on globin gene expression. Adult progenitors express high levels of γ-globin in liquid and methylcellulose media but low, physiological levels in stromal cell co-cultures. In contrast, γ-globin expression remained high in cord blood progenitors in stromal cell line co-cultures. Differences in γ-globin gene expression between adult progenitors in stromal cell line co-cultures and liquid media required cell-cell contact and were associated with differences in rate of differentiation and γ-globin promoter DNA methylation. We conclude that γ-globin expression in adult-derived erythroid cells can be influenced by the micro-environment, suggesting new potential targets for HbF induction

Single-Molecule Observation of a Mechanically Activated <i>Cis</i>-to-<i>Trans</i> Cyclopropane Isomerization

The mechanochemical activation of <i>cis</i>-<i>gem</i>-difluorocyclopropane (<i>cis</i>-<i>g</i>DFC) mechanophore in toluene was characterized with single-molecule force spectroscopy. Unlike previously reported behavior in methyl benzoate (MB), two transitions are observed in the force vs extension curves of <i>cis</i>-<i>g</i>DFC polymers in toluene. The first transition occurs at the same force of ∼1300 pN observed previously in MB, but a second transition is observed at forces of ∼1800 pN that reveal the partial formation of the <i>trans-g</i>DFC isomer. The behavior is attributed to competing reactions of the <i>cis</i>-<i>g</i>DFC at the 1300 pN plateau: addition of oxygen to a ring-opened diradicaloid intermediate, and isomerization of <i>cis</i>-<i>g</i>DFC to its <i>trans</i> isomer

Force-Rate Characterization of Two Spiropyran-Based Molecular Force Probes

The mechanically accelerated ring-opening reaction of spiropyran to a colored merocyanine provides a useful method by which to image the molecular scale stress/strain distribution within a polymer, but the magnitude of the forces necessary for activation has yet to be quantified. Here, we report single molecule force spectroscopy studies of two spiropyran isomers. Ring opening on the time scale of tens of milliseconds is found to require forces of ∼240 pN, well below that of previously characterized covalent mechanophores. The lower threshold force is a combination of a low force-free activation energy and the fact that the change in rate with force (activation length) of each isomer is greater than that inferred in other systems. Finally, regiochemical effects on mechanochemical coupling are characterized, and increasing force reverses the relative ring opening rates of the two isomers

The Tension Activated Carbon–Carbon Bond

Over the last century, chemists have mastered the ability to precisely connect pairs of carbon atoms for the synthesis of complex structures ranging from pharmaceuticals to polymeric materials. Less attention has been given to precision C–C bond disconnection. In the past two decades, mechanical force has emerged as a unique vectoral stimulus to drive selective and productive C–C bond activations, leading to distinct reaction trajectories, as well as unprecedented mechanoresponsive materials. However, the molecular details of force to chemical transduction are poorly captured by conventional chemical intuition, making it challenging to understand and predict structure-reactivity relationships under tension. Here, we utilize a physical organic model inspired by the classical Morse potential and its differential forms to identify the effective force constant (keff) and the force-free reaction energy (ΔE) as key molecular features that govern mechanochemical kinetics. Through a comprehensive experimental and computational investigation with four norborn-2-en-7-one (NEO) mechanophores, we establish the relationship between these features and the force-dependent energetic changes along the reaction pathways. We found a linear model accurately predicts the transition force (f*) required for C–C bond activation in over 30 mechanophores. These results demonstrate a general mechanistic framework for mechanochemical reactions under tensile force, and provide a highly accessible tool for the large-scale computational screening in the design of mechanophores

Mechanism Dictates Mechanics: A Molecular Substituent Effect in the Macroscopic Fracture of a Covalent Polymer Network

Here, we report covalent polymer gels in which the macroscopic fracture “reaction” is controlled by mechanophores embedded within mechanically active network strands. We synthesized poly(ethylene glycol) (PEG) gels through the end-linking of azide-terminated tetra-arm PEG (Mn = 5 kDa) with bis-alkyne linkers. Networks were formed under identical conditions, except that the bis-alkyne was varied to include either a cis-diaryl (1) or cis-dialkyl (2) linked cyclobutane mechanophore that acts as a mechanochemical “weak link” through a force-coupled cycloreversion. A control network featuring a bis-alkyne without cyclobutane (3) was also synthesized. The networks show the same linear elasticity (G\u27 = 23~24 kPa, 0.1 – 100 Hz) and equilibrium mass swelling ratios (Q = 10~11 in tetrahydrofuran), but they exhibit tearing energies that span a factor of 8 (3.4 J∙m-2, 10.5 J∙m-2, and 27.1 J∙m-2 for networks with 1, 2, and 3, respectively). The difference in fracture energy is well aligned with the force-coupled scission kinetics of the mechanophores observed in single-molecule force spectroscopy experiments, implicating local resonance stabilization of a diradical transition state in the cycloreversion of 1 as a key determinant of the relative ease with which its network is torn. The connection between macroscopic fracture and small molecule reaction mechanism suggests opportunities for molecular understanding and optimization of polymer network behavior. </div

Solvent Polarity Effects on the Mechanochemistry of Spiropyran Ring Opening

The spiropyran mechanophore (SP) is employed as a reporter of molecular tension in a wide range of polymer matrices, but the influence of surrounding environment on the force-coupled kinetics of its ring opening has not been quantified. Here, we report single-molecule force spectroscopy studies of SP ring opening in five solvents that span normalized Reichardt solvent polarity factors (ETN) of 0.1–0.59. Individual multimechanophore polymers were activated under increasing tension at constant 300 nm s–1 displacement in an atomic force microscope. The extension results in a plateau in the force–extension curve, whose midpoint occurs at a transition force f* that corresponds to the force required to increase the rate constant of SP activation to approximately 30 s–1. More polar solvents lead to mechanochemical reactions that are easier to trigger; f* decreases across the series of solvents, from a high of 415 ± 13 pN in toluene to a low of 234 ± 9 pN in n-butanol. The trend in mechanochemical reactivity is consistent with the developing zwitterionic character on going from SP to the ring-opened merocyanine product. The force dependence of the rate constant (Δx‡) was calculated for all solvent cases and found to increase with ETN, which is interpreted to reflect a shift in the transition state to a later and more productlike position. The inferred shift in the transition state position is consistent with a double-well (two-step) reaction potential energy surface, in which the second step is rate determining, and the intermediate is more polar than the product

Principal Component Analysis for the Classification of Cardiac Motion Abnormalities Based on Echocardiographic Strain and Strain Rate Imaging

© Springer International Publishing Switzerland 2015. Clinical value of the quantitative assessment of regional myocardial function through segmental strain and strain rate has already been demonstrated. Traditional methods for diagnosing heart diseases are based on values extracted at specific time points during the cardiac cycle, known as ‘techno-markers’, and as a consequence they may fail to provide an appropriate description of the strain (rate) characteristics. This study concerns the statistical analysis of the whole cardiac cycle by the Principal Component Analysis (PCA) method and modeling the major patterns of the strain (rate) curves. Experimental outcomes show that the PCA features can outperform their traditional counterparts in categorizing healthy and infarcted myocardial segments and are able to drive considerable benefit to a classification system by properly modeling the complex structure of the strain rate traces.status: publishe