Oxidant stress and platelet activation in hypercholesterolemia

Hypercholesterolemia is the dominant risk factor associated with atherothrombotic disorders in the western world. Consequently, much attention has been devoted to defining its role in the pathogenesis of atherosclerosis. It is currently recognized that hypercholesterolemia induces phenotypic changes in the microcirculation that are consistent with oxidative and nitrosative stresses. Superoxide is generated via several cellular systems and, once formed, participates in a number of reactions, yielding various free radicals, such as hydrogen peroxide, peroxynitrite, or oxidized low-density lipoproteins. Once oxidant stress is invoked, characteristic pathophysiologic features ensue, such as platelet activation and lipid peroxidation, which are both involved in the initiation and progression of the atherosclerotic lesions. Thus, therapeutic strategies that act to maintain the normal balance in the oxidant status of the vascular bed may prove effective in reducing the deleterious consequences of hypercholesterolemia

Ultra-sensitive voltage-controlled skyrmion-based spintronic diode

We have designed a passive spintronic diode based on a single skyrmion stabilized in a magnetic tunnel junction and studied its dynamics induced by voltage-controlled anisotropy (VCMA) and Dzyaloshinskii-Moriya interaction (VDMI). We have demonstrated that the sensitivity (rectified voltage over input microwave power) with realistic physical parameters and geometry can be larger than 10 kV/W which is one order of magnitude better than diodes employing a uniform ferromagnetic state. Our numerical and analytical results on the VCMA and VDMI-driven resonant excitation of skyrmions beyond the linear regime reveal a frequency dependence on the amplitude and no efficient parametric resonance. Skyrmions with a smaller radius produced higher sensitivities, demonstrating the efficient scalability of skyrmion-based spintronic diodes. These results pave the way for designing passive ultra-sensitive and energy efficient skyrmion-based microwave detectors.Comment: 11 pages, 3 figure

Insulin resistance as a determinant of platelet activation in obese women

OBJECTIVES We tested the hypothesis that insulin resistance, per se, contributes to increased platelet activation in obesity, independently of underlying inflammation. BACKGROUND Obesity, insulin resistance, and atherosclerosis are closely linked phenomena associated with low-grade inflammation. Obesity is associated with persistent platelet activation in otherwise healthy women. METHODS We performed a cross-sectional study in 40 obese and 20 non-obese healthy women using urinary thromboxane metabolite excretion as a non-invasive index of platelet activation. An index of insulin sensitivity, S, and plasma adiponectin, C-reactive protein (CRP), and CD40 ligand (CD40L) levels were measured. RESULTS Obese women had significantly (p < 0.0001) higher 11-dehydro-thromboxane B-2 (11-dehydro-TXB2) excretion (median 718 vs. 211 pg/mg creatinine), CRP (1.13 vs. 0.48 mg/1), and CD40L levels (4.45 vs. 0.90 ng/ml) than controls. Obese women had lower S, (median 2.51 vs. 5.0 10(4) min(-1)/[mu U/ml], p < 0.002) and adiponectin (6.3 vs. 10 mu g/ml, p < 0.01) than control subjects. On multiple regression analysis, waist-to-hip ratio (beta = 0.27, p < 0.05) and S, (beta = -0.72, p < 0.04) predicted 11-dehydro-TXB2 excretion rate, independently of adiponectin, CRP, CD40L, and lipid patterns. In order to investigate the cause-effect relationship of these associations, we examined the effects of a 12-week weight loss program or a 3-week pioglitazone treatment on urinary 11-dehydro-TXB2 in 10 women with impaired S-1 and visceral obesity. Successful weight loss (0.6 kg loss/week) achieved in 5 subjects was associated with increased S-1 (+92%) and decreased CD40L (-27%), CRP (-37%), and 11-dehydro-TXB2 (-53%) (p < 0.05). Consistently, improvement of insulin sensitivity achieved with pioglitazone significantly decreased urinary 11-dehydro-TXB2 excretion (-43%, p < 0.05) without changes in body weight. CONCLUSIONS Insulin resistance is a major determinant of platelet activation in female obesity

Manipulation of magnetic solitons under the influence of DMI gradients

Magnetic solitons are promising for applications due to their intrinsic properties such as small size, topological stability, ultralow power manipulation and potentially ultrafast operations. To date, research has focused on the manipulation of skyrmions, domain walls, and vortices by applied currents. The discovery of new methods to control magnetic parameters, such as the interfacial Dzyaloshinskii-Moriya interaction (DMI) by strain, geometry design, temperature gradients, and applied voltages promises new avenues for energetically efficient manipulation of magnetic structures. The latter has shown significant progress in 2d material-based technology. In this work, we present a comprehensive study using numerical and analytical methods of the stability and motion of different magnetic textures under the influence of DMI gradients. Our results show that under the influence of linear DMI gradients, N\'eel and Bloch-type skyrmions and radial vortex exhibit motion with finite skyrmion Hall angle, while the circular vortex undergoes expulsion dynamics. This work provides a deeper and crucial understanding of the stability and gradient-driven dynamics of magnetic solitons, and paves the way for the design of alternative low-power sources of magnetization manipulation in the emerging field of 2d materials.Comment: 19 pages, 5 figure

A spintronic Huxley-Hodgkin-analogue neuron implemented with a single magnetic tunnel junction

Spiking neural networks aim to emulate the brain's properties to achieve similar parallelism and high-processing power. A caveat of these neural networks is the high computational cost to emulate, while current proposals for analogue implementations are energy inefficient and not scalable. We propose a device based on a single magnetic tunnel junction to perform neuron firing for spiking neural networks without the need of any resetting procedure. We leverage two physics, magnetism and thermal effects, to obtain a bio-realistic spiking behavior analogous to the Huxley-Hodgkin model of the neuron. The device is also able to emulate the simpler Leaky-Integrate and Fire model. Numerical simulations using experimental-based parameters demonstrate firing frequency in the MHz to GHz range under constant input at room temperature. The compactness, scalability, low cost, CMOS-compatibility, and power efficiency of magnetic tunnel junctions advocate for their broad use in hardware implementations of spiking neural networks.Comment: 23 pages, 6 figures, 2 table

A magneto-mechanical accelerometer based on magnetic tunnel junctions

Accelerometers have widespread applications and are an essential component in many areas such as automotive, consumer electronics and industrial applications. Most commercial accelerometers are based on micro-electromechanical system (MEMS) that are limited in downscaling and power consumption. Spintronics-based accelerometers have been proposed as alternatives, however, current proposals suffer from design limitations that result in reliability issues and high cost. Here we propose spintronic accelerometers with magnetic tunnel junctions (MTJs) as building block, which map accelerations into a measurable voltage across the MTJ terminals. The device exploits elastic and dipolar coupling as a sensing mechanism and the spintronic diode effect for the direct read out of the acceleration. The proposed technology represents a potentially competitive and scalable solution to current capacitive MEMS-based approaches that could lead to a step forward in many of the commercial applications.Comment: main document with 4 figures + supplemental informatio

Evaluating spintronics-compatible implementations of Ising machines

The commercial and industrial demand for the solution of hard combinatorial optimization problems push forward the development of efficient solvers. One of them is the Ising machine which can solve combinatorial problems mapped to Ising Hamiltonians. In particular, spintronic hardware implementations of Ising machines can be very efficient in terms of area and performance, and are relatively low-cost considering the potential to create hybrid CMOS-spintronic technology. Here, we perform a comparison of coherent and probabilistic paradigms of Ising machines on several hard Max-Cut instances, analyzing their scalability and performance at software level. We show that probabilistic Ising machines outperform coherent Ising machines in terms of the number of iterations required to achieve the problem s solution. Nevertheless, high frequency spintronic oscillators with sub-nanosecond synchronization times could be very promising as ultrafast Ising machines. In addition, considering that a coherent Ising machine acts better for Max-Cut problems because of the absence of the linear term in the Ising Hamiltonian, we introduce a procedure to encode Max-3SAT to Max-Cut. We foresee potential synergic interplays between the two paradigms.Comment: 26 pages, 6 Figures, submitted for publication in Phys. Rev. Applied (it will be presented at intermag 2023 in Japan

LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro

Published version. Source at http://dx.doi.org/10.1007/s00125-016-4036-y Aims/hypothesis: Activation of inflammatory pathways is involved in the pathogenesis of type 2 diabetes mellitus. On the basis of its role in vascular inflammation and in metabolic disorders, we hypothesised that the TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) could be involved in the pathogenesis of type 2 diabetes mellitus. Methods: Plasma levels of LIGHT were measured in two cohorts of type 2 diabetes mellitus patients (191 Italian and 40 Norwegian). Human pancreatic islet cells and arterial endothelial cells were used to explore regulation and relevant effects of LIGHT in vitro. Results: Our major findings were: (1) in both diabetic cohorts, plasma levels of LIGHT were significantly raised compared with sex- and age-matched healthy controls (n = 32); (2) enhanced release from activated platelets seems to be an important contributor to the raised LIGHT levels in type 2 diabetes mellitus; (3) in human pancreatic islet cells, inflammatory cytokines increased the release of LIGHT and upregulated mRNA and protein levels of the LIGHT receptors lymphotoxin β receptor (LTβR) and TNF receptor superfamily member 14 (HVEM/TNFRSF14); (4) in these cells, LIGHT attenuated the insulin release in response to high glucose at least partly via pro-apoptotic effects; and (5) in human arterial endothelial cells, glucose boosted inflammatory response to LIGHT, accompanied by an upregulation of mRNA levels of HVEM (also known as TNFRSF14) and LTβR (also known as LTBR). Conclusions/interpretation: Our findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation

Quality control and quantification in IG/TR next-generation sequencing marker identification: protocols and bioinformatic functionalities by EuroClonality-NGS

Assessment of clonality, marker identification and measurement of minimal residual disease (MRD) of immunoglobulin (IG) and T cell receptor (TR) gene rearrangements in lymphoid neoplasms using next-generation sequencing (NGS) is currently under intensive development for use in clinical diagnostics. So far, however, there is a lack of suitable quality control (QC) options with regard to standardisation and quality metrics to ensure robust clinical application of such approaches. The EuroClonality-NGS Working Group has therefore established two types of QCs to accompany the NGS-based IG/TR assays. First, a central polytarget QC (cPT-QC) is used to monitor the primer performance of each of the EuroClonality multiplex NGS assays; second, a standardised human cell line-based DNA control is spiked into each patient DNA sample to work as a central in-tube QC and calibrator for MRD quantification (cIT-QC). Having integrated those two reference standards in the ARResT/Interrogate bioinformatic platform, EuroClonality-NGS provides a complete protocol for standardised IG/TR gene rearrangement analysis by NGS with high reproducibility, accuracy and precision for valid marker identification and quantification in diagnostics of lymphoid malignancies.This work was supported by Ministry of Health of the Czech Republic, grant no. 16-34272A; computational resources were provided by the CESNET LM2015042 and the CERIT Scientific Cloud LM2015085, provided under the programme “Projects of Large Research, Development, and Innovations Infrastructures”. Analyses in Prague (JT, EF and MS) were supported by Ministry of Health, Czech Republic, grant no. 00064203, and by PRIMUS/17/MED/11. Analyses in the Monza (Centro Ricerca Tettamanti, SS, AG and GC) laboratory were supported by the Italian Association for Cancer Research (AIRC) and Comitato Maria Letizia Verga