Janus particles for biological imaging and sensing.

Janus particles, named after the two-faced Roman god Janus, have different surface makeups, structures or compartments on two sides. This review highlights recent advances in employing Janus particles as novel analytical tools for live cell imaging and biosensing. Unlike conventional particles used in analytical science, two-faced Janus particles provide asymmetry and directionality, and can combine different or even incompatible properties within a single particle. The broken symmetry enables imaging and quantification of rotational dynamics, revealing information beyond what traditional measurements offer. The spatial segregation of molecules on the surface of a single particle also allows analytical functions that would otherwise interfere with each other to be decoupled, opening up opportunities for novel multimodal analytical methods. We summarize here the development of Janus particles, a few general methods for their fabrication and, more importantly, the emerging and novel applications of Janus particles as multi-functional imaging probes and sensors.

Tracking single-particle rotation during macrophage uptake.

We investigated the rotational dynamics of single microparticles during their internalization by macrophage cells. The microparticles used were triblock patchy particles that display two fluorescent patches on their two poles. The optical anisotropy made it possible to directly visualize and quantify the orientation and rotation of the particles. We show that particles exhibit a mixture of fast and slow rotation as they are uptaken by macrophages and transiently undergo directional rotation during their entry into the cell. The size of the particles and the surface presentation of ligands exerted a negligible influence on this heterogeneity of particle rotation.

[MANAGEMENT RECOMMENDATIONS FOR DIRECT ORAL ANTICOAGULANTS (DOACs) ANTI Xa AND ANTI IIa]. / RECOMENDACIONES DE MANEJO DE LOS ANTICOAGULANTES ORALES DIRECTOS (DOACS) ANTI Xa Y ANTI IIa.

Direct oral anticoagulants have emerged as the drugs that have changed the management of the antithrombotic treatment in the last 15 years. Their advantages, like a more friendly way of anticoagulation and their lower risk of bleeding, especially in the brain, have positioned these new anticoagulants as the first drug of choice in the two most frequent indications of anticoagulation, atrial fibrillation, and the venous thromboembolic disease. However, not all the patients can receive these agents, not all the direct oral anticoagulants have the same characteristics, and most importantly, not all the diseases with an indication of an anticoagulant drug can be treated with them. Therefore, it is mandatory that all the faculties involved in the management of these drugs must know them in depth, to decide the best treatment for the patient. This position paper, from a group of experts in anticoagulation in Argentina, can help the general practitioner in the daily use of direct oral anticoagulants based on the new evidence and the experience of a wide group of professionals. The way we relate to the anticoagulant treatment has changed in the last years. The doctors who work with them must also do so.

Los anticoagulantes orales directos han surgido como una de las herramientas que ha cambiado el manejo de la enfermedad trombótica en los últimos 15 años. Sus ventajas, desde el punto de vista de la facilidad de uso y menor riesgo de sangrado, especialmente de sangrado cerebral, han posicionado a estos nuevos anticoagulantes como la primera alternativa de tratamiento en las dos indicaciones más frecuentes en que necesitamos estas drogas, la fibrilación auricular y la enfermedad tromboembólica venosa. Sin embargo, no todos los pacientes pueden recibir estos agentes, no todos los anticoagulantes directos tienen las mismas propiedades y fundamentalmente, no todas las enfermedades con indicación de un anticoagulante pueden tratarse con ellos;con lo cual es necesario que todos los profesionales que están involucrados en el manejo de estos medicamentos estén obligados a conocerlos en profundidad, para poder decidir el mejor tratamiento en cada caso particular. Este documento de posición de expertos de diferentes especialidades de Argentina, presenta lineamientos para el uso correcto de los anticoagulantes directos en base a nueva evidencia y a la experiencia de uso de un amplio grupo de profesionales. La forma de relacionarnos con el tratamiento anticoagulante ha cambiado. Los médicos que trabajamos con ellos también debemos hacerlo.

Differences between metabolically healthy and unhealthy obesity in PAI-1 level: Fibrinolysis, body size phenotypes and metabolism.

BACKGROUND: Different studies have recognized the existence of subtypes of obesity and normal weight, in which it is reported that not all patients show the same cardiometabolic risk, called "metabolically healthy" and "metabolically unhealthy". In several reviews, differences in the inflammatory profile have been studied, but there is not information on the relationship of body size phenotypes with thrombosis risk. OBJECTIVE: Determine the association between body size phenotypes and fibrinolytic activity by measuring the concentration of plasminogen activator inhibitor-1 (PAI-1). METHODS: A cross-sectional study was conducted in women aged 40 to 65 years. Anthropometric measurements and biochemical determinations were performed on all participants. The fibrinolytic activity was determined by measuring PAI-1 by ELISA. Karelis criteria were used to define metabolic status. Four groups were formed: Metabolically healthy normal weight (MHNW), Metabolically unhealthy normal weight (MUNW), Metabolically healthy obese (MHO) and Metabolically unhealthy obese (MUO). RESULTS: 230 women were included in our study with a mean age 52.3 ±â€¯5.9 years. The concentration of PAI-1 showed a significant difference between the groups MHNW, MUNW, MHO, MUO [2.3 (0.08, 13.6), 12.7, (0.08, 33.1), 23.4 (2.6, 28.8) and 22.8 (2.0, 46.7) ng/mL, respectively, p = 0.006]. Multiple regression analysis identified that BMI and HOMA-IR were independent factors influencing PAI-1 levels. CONCLUSION: This study is the first one that recognizes differences in the fibrinolytic activity between body size phenotypes. The groups with the lowest fibrinolytic activity were MUO and MHO, however, MUNW also present alterations of fibrinolysis, thus suggesting a prothrombotic state.

Effect of partial PEGylation on particle uptake by macrophages.

Controlling the internalization of synthetic particles by immune cells remains a grand challenge for developing successful drug carrier systems. Polyethylene glycol (PEG) is frequently used as a protective coating on particles to evade immune clearance, but it also hinders the interactions of particles with their intended target cells. In this study, we investigate a spatial decoupling strategy, in which PEGs are coated on only one hemisphere of particles, so that the other hemisphere is available for functionalization of cell-targeting ligands without the hindrance effect from the PEGs. The partial coating of PEGs is realized by creating two-faced Janus particles with different surface chemistries on opposite sides. We show that a half-coating of PEGs reduces the macrophage uptake of particles as effectively as a complete coating. Owing to the surface asymmetry, Janus particles that are internalized enter macrophage cells via a combination of ligand-guided phagocytosis and macropinocytosis. By spatially segregating PEGs and ligands for targeting T cells on Janus particles, we demonstrate that the Janus particles bind T cells uni-directionally from the ligand-coated side, bypassing the hindrance from the PEGs on the other hemisphere. The results reveal a new mechanistic understanding on how a spatial coating of PEGs on particles changes the phagocytosis of particles. This study also suggests a new design principle for therapeutic particles - the spatial decoupling of PEGs and cell-targeting moieties reduces the interference between the two functions while attaining the protective effect of PEGs for macrophage evasion.

Seeing the unseen: Imaging rotation in cells with designer anisotropic particles.

Cellular functions are enabled by cascades of transient biological events. Imaging and tracking the dynamics of these events have proven to be a powerful means of understanding the principles of cellular processes. These studies have typically focused on translational dynamics. By contrast, investigations of rotational dynamics have been scarce, despite emerging evidence that rotational dynamics are an inherent feature of many cellular processes and may also provide valuable clues to understanding those cell functions. Such studies have been impeded by the limited availability of suitable rotational imaging probes. This has recently changed thanks to the advances in the development of anisotropic particles for rotational imaging. In this review, we will summarize current techniques for imaging rotation using particle probes that are anisotropic in shape or optical properties. We will highlight two studies that demonstrate how these techniques can be applied to explore important facets of cellular functions.

Interrogating Cellular Functions with Designer Janus Particles.

Janus particles have two distinct surfaces or compartments. This enables novel applications that are impossible with homogeneous particles, ranging from the engineering of active colloidal metastructures to creating multimodal therapeutic materials. Recent years have witnessed a rapid development of novel Janus structures and exploration of their applications, particularly in the biomedical arena. It, therefore, becomes crucial to understand how Janus particles with surface or structural anisotropy might interact with biological systems and how such interactions may be exploited to manipulate biological responses. This perspective highlights recent studies that have employed Janus particles as novel toolsets to manipulate, measure, and understand cellular functions. Janus particles have been shown to have biological interactions different from uniform particles. Their surface anisotropy has been used to control the cell entry of synthetic particles, to spatially organize stimuli for the activation of immune cells, and to enable direct visualization and measurement of rotational dynamics of particles in living systems. The work included in this perspective showcases the significance of understanding the biological interactions of Janus particles and the tremendous potential of harnessing such interactions to advance the development of Janus structure-based biomaterials.

Recomendaciones de manejo de los anticoagulantes orales directos (DOACs) anti Xa y anti IIa / Recommendations for the practical management of the direct oral anticoagulants anti Xa and anti IIa

Resumen Los anticoagulantes orales directos han surgido como una de las herramientas que ha cambiado el manejo de la enfermedad trombótica en los últimos 15 años. Sus ventajas, desde el punto de vista de la facilidad de uso y menor riesgo de sangrado, especialmente de sangrado cerebral, han posicionado a estos nuevos anticoagulantes como la primera alternativa de tratamiento en las dos indicaciones más frecuentes en que necesitamos estas drogas, la fibrilación auricular y la enfermedad tromboembólica venosa. Sin embargo, no todos los pacientes pueden recibir estos agentes, no todos los anticoagulantes directos tienen las mismas pro piedades y fundamentalmente, no todas las enfermedades con indicación de un anticoagulante pueden tratarse con ellos;con lo cual es necesario que todos los profesionales que están involucrados en el manejo de estos medicamentos estén obligados a conocerlos en profundidad, para poder decidir el mejor tratamiento en cada caso particular. Este documento de posición de expertos de diferentes especialidades de Argentina, presenta lineamientos para el uso correcto de los anticoagulantes directos en base a nueva evidencia y a la experiencia de uso de un amplio grupo de profesionales. La forma de relacionarnos con el tratamiento anticoagulante ha cambiado. Los médicos que trabajamos con ellos también debemos hacerlo.

Abstract Direct oral anticoagulants have emerged as the drugs that have changed the man agement of the antithrombotic treatment in the last 15 years. Their advantages, like a more friendly way of anticoagulation and their lower risk of bleeding, especially in the brain, have positioned these new anticoagu lants as the first drug of choice in the two most frequent indications of anticoagulation, atrial fibrillation, and the venous thromboembolic disease. However, not all the patients can receive these agents, not all the direct oral anticoagulants have the same characteristics, and most importantly, not all the diseases with an indication of an anticoagulant drug can be treated with them. Therefore, it is mandatory that all the faculties involved in the management of these drugs must know them in depth, to decide the best treatment for the patient. This position paper, from a group of experts in anticoagulation in Argentina, can help the general practitioner in the daily use of direct oral anticoagulants based on the new evidence and the experience of a wide group of professionals. The way we relate to the anticoagulant treatment has changed in the last years. The doctors who work with them must also do so.

Janus particles as artificial antigen-presenting cells for T cell activation.

Here we show that the multifunctionality of Janus particles can be exploited for in vitro T cell activation. We engineer bifunctional Janus particles on which the spatial distribution of two ligands, anti-CD3 and fibronectin, mimics the "bull's eye" protein pattern formed in the membrane junction between a T cell and an antigen-presenting cell. Different levels of T cell activation can be achieved by simply switching the spatial distribution of the two ligands on the surfaces of the "bull's eye" particles. We find that the ligand pattern also affects clustering of intracellular proteins. This study demonstrates that anisotropic particles, such as Janus particles, can be developed as artificial antigen-presenting cells for modulating T cell activation.

Complicaciones hemorrágicas en relación con la intensidad del tratamiento anticoagulante oral / Hemorrhagic complications of anticoagulant therapy related to dose intensity

Los reemplazos valvulares mecánicos requieren tratamiento anticoagulante a largo plazo. La asociación con aspirina ha demostrado reducir aún más la probabilidad de eventos tromboembólicos. Sin embargo, con el tratamiento combinado y en las dosis testeadas en varios ensayos clínicos, se ha notado un aumento de la frecuencia de hemorragia, principalmente gastrointestinal. En Julio de 1988 iniciamos un estudio prospectivo randomizado con el fin de comparar la combinación de bajas dosis de anticoagulación oral (RIN 2,5-3,5) con aspirina (100 mg) (rama A) versus dosis más intensa de anticoagulación (RIN 3,5-4,5) (rama B). La media de seguimiento fue de 2,2 años. Ambos tratamientos ofrecieron similar protección antitrombótica. La incidencia de episodios embólicos fue de 1,3/100 ptes-año en la rama A y 1,6/100 ptes-año en la rama B. Episodios de hemorragia mayor se presentaron en 1,1/100 ptes-año y 2,4/100 ptes-año respectivamente. No hubo un aumento de las hemorragias gastrointestinales en la rama de tratamiento combinado, resultando además en una significativa reducción de la muerte de origen vascular de 3,3/100 ptes-año a 1,3/100 ptes-año (p=0,038) y en un riesgo acumulativo de embolia, hemorragia mayor y muerte de causa vascular de 3,3/100 ptes-año a 1,3/100 ptes-año (p=0,034).