Description: Background Exposure of vascular smooth muscle cells (VSMCs) to excessive cyclic stretch such as in hypertension causes a shift in their phenotype. The focal adhesion protein zyxin can transduce such biomechanical stimuli to the nucleus of both endothelial cells and VSMCs, albeit with different thresholds and kinetics. However, there is no distinct vascular phenotype in young zyxin-deficient mice, possibly due to functional redundancy among other gene products belonging to the zyxin family. Analyzing zyxin function in VSMCs at the cellular level might thus offer a better mechanistic insight. We aimed to characterize zyxin-dependent changes in gene expression in VSMCs exposed to biomechanical stretch and define the functional role of zyxin in controlling the resultant VSMC phenotype. Methods and Results DNA microarray analysis was used to identify genes and pathways that were zyxin regulated in static and stretched human umbilical artery–derived and mouse aortic VSMCs. Zyxin-null VSMCs showed a remarkable shift to a growth-promoting, less apoptotic, promigratory and poorly contractile phenotype with 90% of the stretch-responsive genes being zyxin dependent. Interestingly, zyxin-null cells already seemed primed for such a synthetic phenotype, with mechanical stretch further accentuating it. This could be accounted for by higher RhoA activity and myocardin-related transcription factor-A mainly localized to the nucleus of zyxin-null VSMCs, and a condensed and localized accumulation of F-actin upon stretch. Conclusions At the cellular level, zyxin is a key regulator of stretch-induced gene expression. Loss of zyxin drives VSMCs toward a synthetic phenotype, a process further consolidated by exaggerated stretch.

Description: De novo gene mutations in normal human memory B cells De novo gene mutations in normal human memory B cells, Published online: 23 October 2018; doi:10.1038/s41375-018-0289-4 De novo gene mutations in normal human memory B cells

Description: Background Despite the high prevalence of chronic venous insufficiency and varicose veins in the Western world, suitable pharmaceutical therapies for these venous diseases have not been explored to date. In this context, we recently reported that a chronic increase in venous wall stress or biomechanical stretch is sufficient to cause development of varicose veins through the activation of the transcription factor activator protein 1. Methods and Results We investigated whether deleterious venous remodeling is suppressed by the pleiotropic effects of statins. In vitro, activator protein 1 activity was inhibited by two 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, rosuvastatin and atorvastatin, in stretch-stimulated human venous smooth muscle cells. Correspondingly, both statins inhibited venous smooth muscle cell proliferation as well as mRNA expression of the activator protein 1 target gene monocyte chemotactic protein 1 ( MCP1 ). In isolated mouse veins exposed to an increased level of intraluminal pressure, statin treatment diminished proliferation of venous smooth muscle cells and protein abundance of MCP1 while suppressing the development of varicose veins in a corresponding animal model by almost 80%. Further analyses of human varicose vein samples from patients chronically treated with statins indicated a decrease in venous smooth muscle cell proliferation and MCP1 abundance compared with samples from untreated patients. Conclusions Our findings imply that both atorvastatin and rosuvastatin effectively inhibit the development of varicose veins, at least partially, by interfering with wall stress–mediated activator protein 1 activity in venous smooth muscle cells. For the first time, this study reveals a potential pharmacological treatment option that may be suitable to prevent growth of varicose veins and to limit formation of recurrence after varicose vein surgery.

Description: Nature Nanotechnology 11, 432 (2016). doi:10.1038/nnano.2015.339 Authors: K. Wagner, A. Kákay, K. Schultheiss, A. Henschke, T. Sebastian & H. Schultheiss In the research field of magnonics, it is envisaged that spin waves will be used as information carriers, promoting operation based on their wave properties. However, the field still faces major challenges. To become fully competitive, novel schemes for energy-efficient control of spin-wave propagation in two dimensions have to be realized on much smaller length scales than used before. In this Letter, we address these challenges with the experimental realization of a novel approach to guide spin waves in reconfigurable, nano-sized magnonic waveguides. For this purpose, we make use of two inherent characteristics of magnetism: the non-volatility of magnetic remanence states and the nanometre dimensions of domain walls formed within these magnetic configurations. We present the experimental observation and micromagnetic simulations of spin-wave propagation inside nano-sized domain walls and realize a first step towards a reconfigurable domain-wall-based magnonic nanocircuitry.

Description: Background and Purpose— The aim was to investigate prospectively the all-cause mortality risk up to and after coronary heart disease (CHD) and stroke events in European middle-aged men. Methods— The study population comprised 10 424 men 50 to 59 years of age recruited between 1991 and 1994 in France (N=7855) and Northern Ireland (N=2747) within the Prospective Epidemiological Study of Myocardial Infarction. Incident CHD and stroke events and deaths from all causes were prospectively registered during the 10-year follow-up. In Cox’s proportional hazards regression analysis, CHD and stroke events during follow-up were used as time-dependent covariates. Results— A total of 769 CHD and 132 stroke events were adjudicated, and 569 deaths up to and 66 after CHD or stroke occurred during follow-up. After adjustment for study country and cardiovascular risk factors, the hazard ratios of all-cause mortality were 1.58 (95% confidence interval 1.18–2.12) after CHD and 3.13 (95% confidence interval 1.98–4.92) after stroke. Conclusions— These findings support continuous efforts to promote both primary and secondary prevention of cardiovascular disease.

Description: At low emittance synchrotron sources it has become possible to perform structure determinations from the measurement of multiple microcrystals which were previously considered too small for diffraction experiments. Conventional mounting techniques do not fulfill the requirements of these new experiments. They significantly contribute to background scattering and it is difficult to locate the crystals, making them incompatible with automated serial crystallography. We have developed a micro-fabricated sample holder from single crystalline silicon with micropores, which carries up to thousands of crystals and significantly reduces the background scattering level. For loading, the suspended microcrystals are pipetted onto the chip and excess mother liquor is subsequently soaked off through the micropores. Crystals larger than the pore size are retained and arrange themselves according to the micropore pattern. Using our chip we were able to collect 1.5 Å high resolution diffraction data from protein microcrystals with sizes of 4 micrometers and smaller. Scientific Reports 5 doi: 10.1038/srep10451

Description: Objective— We previously reported that hemopexin (Hx), a heme scavenger, is significantly increased and associated with proinflammatory high-density lipoprotein under atherogenic conditions. Although it is established that Hx together with macrophages plays a role in mitigating oxidative damage, the role of Hx in the development of atherosclerosis is unknown. Approach and Results— We used Hx and apoE double-knockout mice (HxE –/– ) to determine the role of Hx in the development of atherosclerosis. HxE –/– mice had significantly more free heme, reactive oxygen species, and proinflammatory high-density lipoprotein in their circulation, when compared with control apoE –/– mice. Atherosclerotic plaque area (apoE –/– =9.72±2.5 x 10 4 μm 2 and HxE –/– =27.23±3.6 x 10 4 μm 2 ) and macrophage infiltration (apoE –/– =38.8±5.8 x 10 3 μm 2 and HxE –/– =103.4±17.8 x 10 3 μm 2 ) in the aortic sinus were significantly higher in the HxE –/– mice. Atherosclerotic lesions in the aortas were significantly higher in the HxE –/– mice compared with apoE –/– mice. Analysis of polarization revealed that macrophages from HxE –/– mice were more M1-like. Ex vivo studies demonstrated that HxE –/– macrophage cholesterol efflux capacity was significantly reduced when compared with apoE –/– mice. Injection of human Hx into HxE –/– mice reduced circulating heme levels and human Hx pretreatment of naive bone marrow cells ex vivo resulted in a shift from M1- to M2-like macrophages. Conclusions— We conclude that Hx plays a novel protective role in alleviating heme-induced oxidative stress, improving inflammatory properties of high-density lipoprotein, macrophage phenotype and function, and inhibiting the development of atherosclerosis in apoE –/– mice.

Description: A ribosome-related signature in peripheral blood CLL B cells is linked to reduced survival following treatment Cell Death and Disease 7, e2249 (June 2016). doi:10.1038/cddis.2016.148 Authors: T Sbarrato, E Horvilleur, T Pöyry, K Hill, L C Chaplin, R V Spriggs, M Stoneley, L Wilson, S Jayne, T Vulliamy, D Beck, I Dokal, M J S Dyer, A M Yeomans, G Packham, M Bushell, S D Wagner & A E Willis