Dynamic ordering of driven vortex matter in the peak effect regime of amorphous MoGe films and 2H-NbSe2 crystals

Dynamic ordering of driven vortex matter has been investigated in the peak effect regime of both amorphous MoGe films and 2H-NbSe2 crystals by mode locking (ML) and dc transport measurements. ML features allow us to trace how the shear rigidity of driven vortices evolves with the average velocity. Determining the onset of ML resonance in different magnetic fields and/or temperatures, we find that the dynamic ordering frequency (velocity) exhibits a striking divergence in the higher part of the peak effect regime. Interestingly, this phenomenon is accompanied by a pronounced peak of dynamic critical current. Mapping out field-temperature phase diagrams, we find that divergent points follow well the thermodynamic melting curve of the ideal vortex lattice over wide field and/or temperature ranges. These findings provide a link between the dynamic and static melting phenomena which can be distinguished from the disorder induced peak effect.Comment: 9 pages, 6 figure

Left ventricular remodeling in swine after myocardial infarction: a transcriptional genomics approach

Despite the apparent appropriateness of left ventricular (LV) remodeling following myocardial infarction (MI), it poses an independent risk factor for development of heart failure. There is a paucity of studies into the molecular mechanisms of LV remodeling in large animal species. We took an unbiased molecular approach to identify candidate transcription factors (TFs) mediating the genetic reprogramming involved in post-MI LV remodeling in swine. Left ventricular tissue was collected from remote, non-infarcted myocardium, 3 weeks after MI-induction or sham-surgery. Microarray analysis identified 285 upregulated and 278 downregulated genes (FDR < 0.05). Of these differentially expressed genes, the promoter regions of the human homologs were searched for common TF binding sites (TFBS). Eighteen TFBS were overrepresented >two-fold (p < 0.01) in upregulated and 13 in downregulated genes. Left ventricular nuclear protein extracts were assayed for DNA-binding activity by protein/DNA array. Out of 345 DNA probes, 30 showed signal intensity changes >two-fold. Five TFs were identified in both TFBS and protein/DNA array analyses, which showed matching changes for COUP-TFII and glucocorticoid receptor (GR) only. Treatment of swine with the GR antagonist mifepristone after MI reduced the post-MI increase in LV mass, but LV dilation remained unaffected. Thus, using an unbiased approach to study post-MI LV remodeling in a physiologically relevant large animal model, we identified COUP-TFII and GR as potential key mediators of post-MI remodeling

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Development of a New Biomechanical ex vivo Perfusion System - Studies on effects of biomechanical and inflammatory stress on hemostatic genes in human vascular endothelium

The vascular endothelium is a multifunctional interface constantly exposed to biomechanical forces such as shear and tensile stress. Biomechanical stress is involved in the pathophysiological process of the vessel wall and thus affects vascular remodeling, atherosclerosis and thrombogenesis. Many different systems have been designed to subject endothelial cells to mechanical stress. However, previous systems have had large limitations in creating physiologically relevant biomechanical stress protocols. Therefore, there is a need for more refined biological perfusion systems that as accurately as possible mimics the in vivo conditions. In the present work, a new biomechanical ex vivo perfusion system for integrative physiological and molecular biology studies of intact vessels of different sizes as well as artificial vessels was developed. This model was constructed for advanced perfusion protocols under strictly controlled biomechanical (shear stress, tensile stress) as well as metabolic (temperature, pH, oxygen tension) conditions. The system enables monitoring and regulation of vessel lumen diameter, shear stress, mean pressure, variable pulsatile pressure and flow profiles, and diastolic reversed flow. The vessel lumen measuring technique is based on detection of the amount of flourescein over a vessel segment. A combination of flow resistances, on/off switches and capacitances creates a wide range of possible combinations of pulsatile pressures and flow profiles. The perfusion platform was extensively evaluated technically as well as biologically by perfusion of high precision made glass capillaries, human umbilical arteries as well as endothelialized artificial vessels. Artificial vessels with a confluent human umbilical vein endothelial cell layer were exposed to different levels of shear stress or different levels of static or pulsatile pressure. Shear stress was a more powerful stimulus than static or pulsatile tensile stress. While shear stress affected mRNA expression of all six studied genes (t-PA, PAI-1, u-PA, thrombomodulin, eNOS and VCAM-1), neither gene was found to be regulated by tensile stress. Shear stress suppressed t-PA and VCAM-1 in a dose response dependent way. The expression of thrombomodulin was also reduced by shear stress. u-PA, eNOS and PAI-1 were induced by shear stress, but showed no obvious dose response effect for these genes. Further, the unexpected suppression of t-PA by shear stress was studied by using mechanistic experiments with pharmacologic inhibitors. Our data indicate that the suppressive effect of shear stress on t-PA was mediated by suppression of JNK and not by p38 MAPK and ERK1/2. The interplay between inflammatory stress and different combination of tensile as well as shear stress was studied on six key anti- and pro-thrombotic genes in HUVEC. The endothelial cell response to TNF-α was not modulated by tensile stress. Again, shear stress was a more potent stimulus. Shear stress counteracted the cytokine-induced expression of VCAM-1, and the cytokine-suppressed expression of thrombomodulin and eNOS. Shear stress and TNF-α additively induced PAI-1, whereas shear stress blocked the cytokine effect on t-PA and u-PA. In conclusion, these findings illustrate that biomechanical forces, particularly shear stress, have important regulatory effects on endothelial gene function. A possible pathophysiological scenario is that an unfavourable hemodynamic milieu leads to a lower threshold for the induction of genes related to endothelial dysfunction in lesion-prone areas upon negative stress, such as inflammation

Magnetization reversal of ferromagnetic nanowires studied by magnetic force microscopy

The magnetization reversal of two-dimensional arrays of parallel ferromagnetic Fe nanowires embedded in nanoporous alumina templates has been studied. By combining bulk magnetization measurements (superconducting quantum interference device magnetometry) with field-dependent magnetic force microscopy (MFM), we have been able to decompose the macroscopic hysteresis loop in terms of the irreversible magnetic responses of individual nanowires. The latter are found to behave as monodomain ferromagnetic needles, with hysteresis loops displaced (asymmetric) as a consequence of the strong dipolar interactions between them. The application of field-dependent MFM provides a microscopic method to obtain the hysteresis curve of the array, by simply registering the fraction of up and down magnetized wires as a function of applied field. The observed deviations from the rectangular shape of the macroscopic hysteresis loop of the array can be ascribed to the spatial variation of the dipolar field through the inhomogeneously filled membrane. The system studied proves to be an excellent example of the two-dimensional classical Preisach model, well known from the field of hysteresis modeling and micromagnetism.This work was part of the research program of the Stichting voor Fundamenteel Onderzoek der Materie (FOM), which is supported by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NOW). C.U. and F.L. acknowledge grants funded by the European Union in the framework of its TMR Marie Curie Program. M.K. acknowledges a grant funded by Deutsche Forschungsgemeinschaft (DFG)