Biomimicking Extracellular Vesicles with Fully Artificial Ones: A Rational Design of EV-BIOMIMETICS toward Effective Theranostic Tools in Nanomedicine

Extracellular Vesicles (EVs) are the protagonists in cell communication and membrane trafficking, being responsible for the delivery of innumerable biomolecules and signaling moieties. At the moment, they are of paramount interest to researchers, as they naturally show incredibly high efficiency and specificity in delivering their cargo. For these reasons, EVs are employed or inspire the development of nanosized therapeutic delivery systems. In this Perspective, we propose an innovative strategy for the rational design of EV-mimicking vesicles (EV-biomimetics) for theranostic scopes. We first report on the current state-of-the-art use of EVs and their byproducts, such as surface-engineered EVs and EV-hybrids, having an artificial cargo (drug molecule, genetic content, nanoparticles, or dye incorporated in their lumen). Thereafter, we report on the new emerging field of EV-mimicking vesicles for theranostic scopes. We introduce an approach to prepare new, fully artificial EV-biomimetics, with particular attention to maintaining the natural reference lipidic composition. We overview those studies investigating natural EV membranes and the possible strategies to identify key proteins involved in site-selective natural homing, typical of EVs, and their cargo transfer to recipient cells. We propose the use also of molecular simulations, in particular of machine learning models, to approach the problem of lipid organization and self-assembly in natural EVs. We also discuss the beneficial feedback that could emerge combining the experimental tests with atomistic and molecular simulations when designing an EV-biomimetics lipid bilayer. The expectations from both research and industrial fields on fully artificial EV-biomimetics, having the same key functions of natural ones plus new diagnostic or therapeutic functions, could be enormous, as they can greatly expand the nanomedicine applications and guarantee on-demand and scalable production, off-the-shelf storage, high reproducibility of morphological and functional properties, and compliance with regulatory standards

Exponential number of equilibria and depinning threshold for a directed polymer in a random potential

By extending the Kac-Rice approach to manifolds of finite internal dimension, we show that the mean number $\left\langle\mathcal{N}_\mathrm{tot}\right\rangle$ of all possible equilibria (i.e. force-free configurations, a.k.a. equilibrium points) of an elastic line (directed polymer), confined in a harmonic well and submitted to a quenched random Gaussian potential in dimension $d=1+1$, grows exponentially $\left\langle\mathcal{N}_\mathrm{tot}\right\rangle\sim\exp{(r\,L)}$ with its length $L$. The growth rate $r$ is found to be directly related to the generalised Lyapunov exponent (GLE) which is a moment-generating function characterising the large-deviation type fluctuations of the solution to the initial value problem associated with the random Schr\"odinger operator of the 1D Anderson localization problem. For strong confinement, the rate $r$ is small and given by a non-perturbative (instanton, Lifshitz tail-like) contribution to GLE. For weak confinement, the rate $r$ is found to be proportional to the inverse Larkin length of the pinning theory. As an application, identifying the depinning with a landscape "topology trivialization" phenomenon, we obtain an upper bound for the depinning threshold $f_c$, in the presence of an applied force, for elastic lines and $d$-dimensional manifolds, expressed through the mean modulus of the spectral determinant of the Laplace operators with a random potential. We also discuss the question of counting of stable equilibria. Finally, we extend the method to calculate the asymptotic number of equilibria at fixed energy (elastic, potential and total), and obtain the (annealed) distribution of the energy density over these equilibria (i.e. force-free configurations). Some connections with the Larkin model are also established.Comment: v1: 6 pages main text + 14 pages supplemental material, 10 figures. v2: LaTeX, 79 pages, 18 eps figures, new material (Sections 6, 10, 11 & Appendices C, E, F, G

Gait measurements in the transverse plane using a wearable system: An experimental study of test-retest reliability

3D gait analysis comprises the study of kinematics in the sagittal, coronal, and transverse planes. The transverse plane measurements are usually less used and generally show the lowest reliability. Nevertheless, the knee and ankle joint center trajectories, in the transverse plane, provide new parameters that may be important in clinical gait analysis. The aim of this study is to analyze the test-retest variability of these parameters. Gait measurements were performed using H-Gait, a wearable system based on magnetic and inertial sensors. A normal weight and an overweight subject were recruited and were asked to walk at their preferred speed for 6 trials. For both of them, the angle between the right and left knee and ankle joint center trajectories were analyzed. Overall, results showed a standard deviation across trials always lower than 2°. This small standard deviation was found also in the overweight subject, for whom it is usually challenging to obtain reliable gait measurements. In addition, a greater knee angle between the right and left joint center trajectories was found in the overweight subject compared to the normal weight. The promising results of this study suggest that the new parameters introduced might be suitable to assess gait of subjects with different anthropometric characteristics

On quantization of r-matrices for Belavin-Drinfeld Triples

We suggest a formula for quantum universal $R$-matrices corresponding to quasitriangular classical $r$-matrices classified by Belavin and Drinfeld for all simple Lie algebras. The $R$-matrices are obtained by twisting the standard universal $R$-matrix.Comment: 12 pages, LaTe

Laboratory and on ice tests to evaluate kinematics of Para ice hockey players

Sprint and technique abilities of Para ice hockey players are of great importance to increase skating performance. To assess skating abilities, kinematics is widely used. This study had two purposes: (1) to assess two-dimensional kinematics of Para ice hockey players’ performance in the laboratory and on ice (sprint and agility) tests and (2) to quantify the relationship between the laboratory and on ice performance. Seven athletes were recruited. In the laboratory, three alternated reach tests were performed in which athletes touched the ground as many times as possible with hands, elbows, or shoulders. The sprint test consisted of 30-m skating at the highest speed starting from standstill, whereas the agility test consisted of sprinting for four left curves and four right curves. Athletes’ movements in the laboratory and on ice tests were acquired using a portable technology. In the laboratory, the best performance was realized when participants touched the ground with hand or elbow. In the sprint test, lower speed and trunk inclination were observed in the first 10 m. In the agility test, greater blade angle was observed in the left curves, compared with the right curves. Significant correlations were found between the laboratory and on ice test performance. Overall, these findings are a useful indicator of athletes’ skating abilities and could be used to increase athletes’ ability to accelerate rapidly and improve sledge manoeuvrability. For detailed player information, kinematics should still be evaluated using sport specific tests and video analysis

Risk assessment in different Judo techniques for children and adolescent athletes

Judo is a combat sport that involves throwing the opponent onto the back. When being thrown, head biomechanics may be related to head injury risk. This study aimed to assess head injury risks associated with four Judo techniques in children and adolescents with different experience levels. Twenty children (<12 years) and 20 adolescents (≥ 12 years) judoka were recruited. Each group was divided into non-expert and expert. Two inertial sensors were fixed on fallers’ head and torso. Two backward (o-soto-gari and o-uchi-gari) and two forward (ippon-seoi-nage and tai-otoshi) techniques were performed. Peak of linear and angular head acceleration magnitude, impact time duration, neck angle, and the Gadd Severity Index were assessed. Children did not show differences between techniques or experience levels. In contrast, adolescents showed greater linear acceleration peak in o-soto-gari than tai-otoshi (p = 0.03), greater angular acceleration peak in o-soto-gari and o-uchi-gari than ippon-seoi-nage (p < 0.05), and greater neck flexion in o-uchi-gari than ippon-seoi-nage (p = 0.004). Compared to expert adolescents, non-expert adolescents showed greater angular acceleration peak, impact duration, and the Gadd Severity Index in o-soto-gari (p < 0.05) and greater neck extension in o-uchi-gari (p = 0.02). Current results pointed out higher risks for adolescents judoka while being thrown with backward techniques, especially for non-expert participants. This study highlights the need of training athletes in controlling head and neck during back falls from a young age to become expert judoka in adulthood

Vapor pressure measurements over supercooled water in the temperature range from −10 1 °C to +10 −2 °C

An accurate measurement of saturation vapor pressure of supercooled water is a strong challenge in metrology, mainly due to difficulties concerning keeping water at a liquid state at temperatures well below the melting point; thus few experimental data covering limited temperature ranges (down to about 253 K) are reported in literature. For this reason, an investigation of the water vapor – supercooled water equilibrium along the saturation line is carried out at Istituto Nazionale di Ricerca Metrologica (INRIM). Measurements cover the temperature range from 261.26 K to 273.25 K, corresponding to a saturation vapor pressure from about 244 Pa to 611 Pa. The experimental apparatus includes a borosilicate glass sample cell, kept in a liquid bath at a constant temperature with millikelvin stability and connected to a manifold where the pressure is measured using a capacitive diaphragm pressure gauge. In this work, the water sample preparation, the measuring method and measurement corrections are reported; moreover, a comparison between experimental and literature data is conducted along with the most used vapor pressure formulations. Measurement results are discussed and uncertainty sources estimated. The resulting expanded relative uncertainty (k = 2) varies from 0.085% at 261.26 K to 0.039% at 273.25 K

Lipidic Formulations Inspired by COVID Vaccines as Smart Coatings to Enhance Nanoparticle-Based Cancer Therapy

Recent advances in nanomedicine have led to the introduction and subsequent establishment of nanoparticles in cancer treatment and diagnosis. Nonetheless, their application is still hindered by a series of challenges related to their biocompatibility and biodistribution. In this paper, we take inspiration from the recently produced and widely spread COVID vaccines, based on the combinational use of ionizable solid lipid nanoparticles, cholesterol, PEGylated lipids, and neutral lipids able to incorporate mRNA fragments. Here, we focus on the implementation of a lipidic formulation meant to be used as a smart coating of solid-state nanoparticles. The composition of this formulation is finely tuned to ensure efficient and stable shielding of the cargo. The resulting shell is a highly customized tool that enables the possibility of further functionalizations with targeting agents, peptides, antibodies, and fluorescent moieties for future in vitro and in vivo tests and validations. Finally, as a proof of concept, zinc oxide nanoparticles doped with iron and successively coated with this lipidic formulation are tested in a pancreatic cancer cell line, BxPC-3. The results show an astonishing increase in cell viability with respect to the same uncoated nanoparticles. The preliminary results presented here pave the way towards many different therapeutic approaches based on the massive presence of highly biostable and well-tolerated nanoparticles in tumor tissues, such as sonodynamic therapy, photodynamic therapy, hyperthermia, and diagnosis by means of magnetic resonance imaging