EMERGING ROLE OF NEUROTROPHINS IN CARDIOVASCULAR REGULATION:IMPACT AND CHARACTERIZATION OF GENETIC VARIANT BDNF (VAL66MET) POLYMORPHISM ON THROMBOTIC EVENTS

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a key role in neuron plasticity (Donovan, et al., 2000), and vascular development (Kermani, et al., 2007). A single nucleotide polymorphism in the BDNF gene (BDNF Val66Met) has been associated with depression (Ventriglia, et al., 2002) (Momose, et al., 2002) (Sen, et al., 2003) (Neves-Pereira, et al., 2002), and recently, it has also been proposed as genetic risk factor for cardiovascular disease (CVD) (Bozzini, et al., 2009) (Jiang, et al., 2009). Intriguingly, reduced BDNF levels are detected in both depressed patients and in subjects with BDNF Val66Met polymorphism, and seem associated with increased coronary events and mortality in patients affected by acute coronary syndrome (Bozzini, et al., 2009). In this study we have assessed the impact of BDNF Val66Met polymorphism on the levels or activity of haemostatic system in relation to experimentally induced thrombosis. Humanized Val66Met BDNF homozygote knock-in mice (BDNF Met/Met) have an alterated arterial and venous thrombosis compared to BDNF Val/Val control mice. Thromboelastometry analyses showed that BDNF Met/Met mice present a significant modification both in clot firmness, clot elasticity, and in the clot formation time compared to BDNF Val/Val mice, suggesting alteration in platelet reactivity and fibrinogen, but normal levels of coagulation factors. Importantly, Tissue Factor (TF), the key activator of blood coagulation, was modified in BDNF Met/Met mice. In addition, data obtained by proteomic analysis of the aorta secretome isolated from Val/Val and Met/Met mice, confirmed with different techniques, revealed several differentially expressed proteins involved in the regulation of coagulation and thrombosis in plasma and/or aorta tissue of BDNF Met/Met compared to control mice. Our results further confirmed the emerging role of neurotrophins in cardiovascular regulation

Resource Control for Synchronous Cooperative Threads

We develop new methods to statically bound the resources needed for the execution of systems of concurrent, interactive threads. Our study is concerned with a \emph{synchronous} model of interaction based on cooperative threads whose execution proceeds in synchronous rounds called instants. Our contribution is a system of compositional static analyses to guarantee that each instant terminates and to bound the size of the values computed by the system as a function of the size of its parameters at the beginning of the instant. Our method generalises an approach designed for first-order functional languages that relies on a combination of standard termination techniques for term rewriting systems and an analysis of the size of the computed values based on the notion of quasi-interpretation. We show that these two methods can be combined to obtain an explicit polynomial bound on the resources needed for the execution of the system during an instant. As a second contribution, we introduce a virtual machine and a related bytecode thus producing a precise description of the resources needed for the execution of a system. In this context, we present a suitable control flow analysis that allows to formulte the static analyses for resource control at byte code level

An Elementary Affine λ-Calculus with Multithreading and Side Effects

International audienceLinear logic provides a framework to control the complexity of higher-order functional programs. We present an extension of this framework to programs with multithreading and side effects focusing on the case of elementary time. Our main contributions are as follows. First, we introduce a modal call-by-value λ-calculus with multithreading and side effects. Second, we provide a combinatorial proof of termination in elementary time for the language. Third, we introduce an elementary affine type system that guarantees the standard subject reduction and progress properties. Finally, we illustrate the programming of iterative functions with side effects in the presented formalism

Cost-benefit analysis of coastal flood defence measures in the North Adriatic Sea

The combined effect of global sea level rise and land subsidence phenomena poses a major threat to coastal settlements. Coastal flooding events are expected to grow in frequency and magnitude, increasing the potential economic losses and costs of adaptation. In Italy, a large share of the population and economic activities are located along the low-lying coastal plain of the North Adriatic coast, one of the most sensitive areas to relative sea level changes. Over the last half a century, this stretch of coast has experienced a significant rise in relative sea level, the main component of which was land subsidence; in the forthcoming decades, climate-induced sea level rise is expected to become the first driver of coastal inundation hazard. We propose an assessment of flood hazard and risk linked with extreme sea level scenarios, under both historical conditions and sea level rise projections in 2050 and 2100. We run a hydrodynamic inundation model on two pilot sites located along the North Adriatic coast of Emilia-Romagna: Rimini and Cesenatico. Here, we compare alternative extreme sea level scenarios accounting for the effect of planned and hypothetical seaside renovation projects against the historical baseline. We apply a flood damage model to estimate the potential economic damage linked to flood scenarios, and we calculate the change in expected annual damage according to changes in the relative sea level. Finally, damage reduction benefits are evaluated by means of cost-benefit analysis. Results suggest an overall profitability of the investigated projects over time, with increasing benefits due to increased probability of intense flooding in the near future

Towards Biomechanics-Aware Design of a Steerable Drilling Robot for Spinal Fixation Procedures with Flexible Pedicle Screws

Towards reducing the failure rate of spinal fixation surgical procedures in osteoporotic patients, we propose a unique biomechanically-aware framework for the design of a novel concentric tube steerable drilling robot (CT-SDR). The proposed framework leverages a patient-specific finite element (FE) biomechanics model developed based on Quantitative Computed Tomography (QCT) scans of the patient's vertebra to calculate a biomechanically-optimal and feasible drilling and implantation trajectory. The FE output is then used as a design requirement for the design and evaluation of the CT-SDR. Providing a balance between the necessary flexibility to create curved optimal trajectories obtained by the FE module with the required strength to not buckle during drilling through a hard simulated bone material, we showed that the CT-SDR can reliably recreate this drilling trajectory with errors between 1.7-2.2%Comment: 6 pages, 7 figures, Accepted for Publication at the 2023 International Symposium on Medical Robotic

BIOMECHANICAL APPROACH TO BALLET MOVEMENTS: A PRELIMINARY STUDY

Movements in ballet dance often involve extreme joint positions and muscular efforts that may exceed normal ranges of motion and generate high stresses on bone and soft tissues. The primary aim of this study was to apply the principles and techniques of biomechanics to study ballet movements. Ground reaction forces and plantar pressure distribution were registered with a Kistler Platform and a Tekscan Systems respectively. Knee joint action in the sagittal plane was simultaneously collected with an electrogoniometer. Peak vertical forces, peak pressures and knee flexion-extension were analyzed and discussed. A better understanding of these biomechanical aspects may lead to a decrease of the injury risks and also to more graceful and efficient dance movements

Physical Exercise Affects Adipose Tissue Profile and Prevents Arterial Thrombosis in BDNF Val66Met Mice

Adipose tissue accumulation is an independent and modifiable risk factor for cardiovascular disease (CVD). The recent CVD European Guidelines strongly recommend regular physical exercise (PE) as a management strategy for prevention and treatment of CVD associated with metabolic disorders and obesity. Although mutations as well as common genetic variants, including the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, are associated with increased body weight, eating and neuropsychiatric disorders, and myocardial infarction, the effect of this polymorphism on adipose tissue accumulation and regulation as well as its relation to obesity/thrombosis remains to be elucidated. Here, we showed that white adipose tissue (WAT) of humanized knock-in BDNFVal66Met (BDNFMet/Met) mice is characterized by an altered morphology and an enhanced inflammatory profile compared to wild-type BDNFVal/Val. Four weeks of voluntary PE restored the adipocyte size distribution, counteracted the inflammatory profile of adipose tissue, and prevented the prothrombotic phenotype displayed, per se, by BDNFMet/Met mice. C3H10T1/2 cells treated with the Pro-BDNFMet peptide well recapitulated the gene alterations observed in BDNFMet/Met WAT mice. In conclusion, these data indicate the strong impact of lifestyle, in particular of the beneficial effect of PE, on the management of arterial thrombosis and inflammation associated with obesity in relation to the specific BDNF Val66Met mutation

Biology and Role of Extracellular Vesicles (EVs) in the Pathogenesis of Thrombosis

Extracellular vesicles (EVs) are well-established mediators of cell-to-cell communication. EVs can be released by every cell type and they can be classified into three major groups according to their biogenesis, dimension, density, and predominant protein markers: exosomes, microvesicles, and apoptotic bodies. During their formation, EVs associate with specific cargo from their parental cell that can include RNAs, free fatty acids, surface receptors, and proteins. The biological function of EVs is to maintain cellular and tissue homeostasis by transferring critical biological cargos to distal or neighboring recipient cells. On the other hand, their role in intercellular communication may also contribute to the pathogenesis of several diseases, including thrombosis. More recently, their physiological and biochemical properties have suggested their use as a therapeutic tool in tissue regeneration as well as a novel option for drug delivery. In this review, we will summarize the impact of EVs released from blood and vascular cells in arterial and venous thrombosis, describing the mechanisms by which EVs affect thrombosis and their potential clinical applications