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We employ Reactive Dynamical Density Functional Theory (R-DDFT) and Reactive Brownian Dynamics (R-BD) simulations to investigate the dynamics of a suspension of active soft Gaussian colloids with binary interaction switching, i.e., a one-component colloidal system in which every particle stochastically switches at predefined rates between two interaction states with different mobility. Using R-DDFT we extend a theory previously developed to access the dynamics of inhomogeneous liquids [Archer et al., Phys. Rev. E: Stat., Nonlinear, Soft Matter Phys., 2007, 75, 040501] to study the influence of the switching activity on the self and distinct part of the Van Hove function in bulk solution, and determine the corresponding mean squared displacement of the switching particles. Our results demonstrate that, even though the average diffusion coefficient is not affected by the switching activity, it significantly modifies the non-equilibrium dynamics and diffusion coefficients of the individual particles, leading to a crossover from short to long times, with a regime for intermediate times showing anomalous diffusion. In addition, the self-part of the van Hove function has a Gaussian form at short and long times, but becomes non-Gaussian at intermediates ones, having a crossover between short and large displacements. The corresponding self-intermediate scattering function shows the two-step relaxation patters typically observed in soft materials with heterogeneous dynamics such as glasses and gels. We also introduce a phenomenological Continuous Time Random Walk (CTRW) theory to understand the heterogeneous diffusion of this system. R-DDFT results are in excellent agreement with R-BD simulations and the analytical predictions of CTRW theory, thus confirming that R-DDFT constitutes a powerful method to investigate not only the structure and phase behavior, but also the dynamical properties of non-equilibrium active switching colloidal suspensions.
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BACKGROUND: Cancer metastasis is a deathly process, and a better understanding of the different steps is needed. The shedding of circulating tumor cells (CTCs) and CTC-cluster from the primary tumor, its survival in circulation, and homing are key events of the metastasis cascade. In vitro models of CTCs and in vivo models of metastasis represent an excellent opportunity to delve into the behavior of metastatic cells, to gain understanding on how secondary tumors appear. METHODS: Using the zebrafish embryo, in combination with the mouse and in vitro assays, as an in vivo model of the spatiotemporal development of metastases, we study the metastatic competency of breast cancer CTCs and CTC-clusters and the molecular mechanisms. RESULTS: CTC-clusters disseminated at a lower frequency than single CTCs in the zebrafish and showed a reduced capacity to invade. A temporal follow-up of the behavior of disseminated CTCs showed a higher survival and proliferation capacity of CTC-clusters, supported by their increased resistance to fluid shear stress. These data were corroborated in mouse studies. In addition, a differential gene signature was observed, with CTC-clusters upregulating cell cycle and stemness related genes. CONCLUSIONS: The zebrafish embryo is a valuable model system to understand the biology of breast cancer CTCs and CTC-clusters.
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Neoplasias da Mama/patologia , Modelos Animais de Doenças , Células Neoplásicas Circulantes , Peixe-Zebra/embriologia , Animais , Linhagem Celular Tumoral , Embrião não Mamífero , Feminino , Humanos , Células MCF-7 , Camundongos , Metástase NeoplásicaRESUMO
Interacting particle systems with many degrees of freedom may undergo phase transitions to sustain atypical fluctuations of dynamical observables such as the current or the activity. In some cases, this leads to symmetry-broken space-time trajectories which enhance the probability of such events due to the emergence of ordered structures. Despite their conceptual and practical importance, these dynamical phase transitions (DPTs) at the trajectory level are difficult to characterize due to the low probability of their occurrence. However, during the last decade, advanced computational techniques have been developed to measure rare events in simulations of many-particle systems that allow the direct observation and characterization of these DPTs. Here we review the application of a particular rare-event simulation technique, based on cloning Monte Carlo methods, to characterize DPTs in paradigmatic stochastic lattice gases. In particular, we describe in detail some tricks and tips of the trade, paying special attention to the measurement of order parameters capturing the physics of the different DPTs, as well as to the finite-size effects (both in the system size and in the number of clones) that affect the measurements. Overall, we provide a consistent picture of the phenomenology associated with DPTs and their measurement.
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Understanding the physics of non-equilibrium systems remains one of the major open questions in statistical physics. This problem can be partially handled by investigating macroscopic fluctuations of key magnitudes that characterise the non-equilibrium behaviour of the system of interest; their statistics, associated structures and microscopic origin. During the last years, some new general and powerful methods have appeared to delve into fluctuating behaviour that have drastically changed the way to address this problem in the realm of diffusive systems: macroscopic fluctuation theory (MFT) and a set of advanced computational techniques that make it possible to measure the probability of rare events. Notwithstanding, a satisfactory theory is still lacking in a particular case of intrinsically non-equilibrium systems, namely those in which energy is not conserved but dissipated continuously in the bulk of the system (e.g. granular media). In this work, we put forward the dissipated energy as a relevant quantity in this case and analyse in a pedagogical way its fluctuations, by making use of a suitable generalisation of macroscopic fluctuation theory to driven dissipative media.
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We use computer simulations to study the relaxation dynamics of a model for oil-in-water microemulsion droplets linked with telechelic polymers. This system exhibits both gel and glass phases and we show that the competition between these two arrest mechanisms can result in a complex, three-step decay of the time correlation functions, controlled by two different localization lengthscales. For certain combinations of the parameters, this competition gives rise to an anomalous logarithmic decay of the correlation functions and a subdiffusive particle motion, which can be understood as a simple crossover effect between the two relaxation processes. We establish a simple criterion for this logarithmic decay to be observed. We also find a further logarithmically slow relaxation related to the relaxation of floppy clusters of particles in a crowded environment, in agreement with recent findings in other models for dense chemical gels. Finally, we characterize how the competition of gel and glass arrest mechanisms affects the dynamical heterogeneities and show that for certain combination of parameters these heterogeneities can be unusually large. By measuring the four-point dynamical susceptibility, we probe the cooperativity of the motion and find that with increasing coupling this cooperativity shows a maximum before it decreases again, indicating the change in the nature of the relaxation dynamics. Our results suggest that compressing gels to large densities produces novel arrested phases that have a new and complex dynamics.
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Fluctuations arise universally in nature as a reflection of the discrete microscopic world at the macroscopic level. Despite their apparent noisy origin, fluctuations encode fundamental aspects of the physics of the system at hand, crucial to understand irreversibility and nonequilibrium behavior. To sustain a given fluctuation, a system traverses a precise optimal path in phase space. Here we show that by demanding invariance of optimal paths under symmetry transformations, new and general fluctuation relations valid arbitrarily far from equilibrium are unveiled. This opens an unexplored route toward a deeper understanding of nonequilibrium physics by bringing symmetry principles to the realm of fluctuations. We illustrate this concept studying symmetries of the current distribution out of equilibrium. In particular we derive an isometric fluctuation relation that links in a strikingly simple manner the probabilities of any pair of isometric current fluctuations. This relation, which results from the time-reversibility of the dynamics, includes as a particular instance the Gallavotti-Cohen fluctuation theorem in this context but adds a completely new perspective on the high level of symmetry imposed by time-reversibility on the statistics of nonequilibrium fluctuations. The new symmetry implies remarkable hierarchies of equations for the current cumulants and the nonlinear response coefficients, going far beyond Onsager's reciprocity relations and Green-Kubo formulas. We confirm the validity of the new symmetry relation in extensive numerical simulations, and suggest that the idea of symmetry in fluctuations as invariance of optimal paths has far-reaching consequences in diverse fields.
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The possibility of efficiently converting heat into work at the microscale has triggered an intense research effort to understand quantum heat engines, driven by the hope of quantum superiority over classical counterparts. In this work, we introduce a model featuring an atom-doped optical quantum cavity propelling a classical piston through radiation pressure. The model, based on the Jaynes-Cummings Hamiltonian of quantum electrodynamics, demonstrates the generation of mechanical work through thermal energy injection. We establish the equivalence of the piston expansion work with Alicki's work definition, analytically for quasistatic transformations and numerically for finite-time protocols. We further employ the model to construct quantum Otto and Carnot engines, comparing their performance in terms of energetics, work output, efficiency, and power under various conditions. This model thus provides a platform to extract useful work from an open quantum system to generate net motion, and it sheds light on the quantum concepts of work and heat.
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The study of metastasis-competent cells at the single-cell level represents an opportunity to decipher the molecular mechanisms associated with the metastatic cascade as well as to understand the functional and molecular heterogeneity of these cells. In this context, preclinical in vivo models of cancer metastasis are valuable tools to understand the behavior of cancer cells throughout the process. Here we describe a detailed protocol for the isolation and recovery of individual viable human metastatic cells from zebrafish embryos xenotransplanted with cancer cells for downstream molecular analysis. We cover the critical steps for the dissociation of the xenografted zebrafish embryos to generate a single-cell suspension, and the micromanipulation for their recovery as single cells.
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Neoplasias , Perciformes , Humanos , Animais , Peixe-Zebra , Xenoenxertos , MicromanipulaçãoRESUMO
Elongated nanostructures to be remotely and magnetically propelled in biologically relevant media, have gained attention as offering themselves as effective tools or carriers in theragnostics applications. However, the magnetic actuation associated remains challenging due to the lack of mechanical information in the media of interest, taking into account biophysical or biomedical purposes. In this study, we detail the magnetic actuation of magnetically propelled chained nanocomposites considering their dynamics, in which their velocity can be modulated in terms of the viscosity of the medium considered, given a magnetic field gradient. Simpler cases of distilled water, a water/glycerol mixture and a fluid made of cell extracts (imitating the cytosol of cells) of known viscosity are the basis experiments for the study of more complex media inside HeLa cells, murine NIH-3T3 fibroblasts and zebrafish larvae, offering the mechanical information required. The experimental results indicate that the magnetically propelled performance of the chained nanostructures can be precisely controlled in potentially changing scenarios, where drug and heat delivery, magnetic separation, or microfluidic technologies are demanded, using a magnetic field gradient and providing good estimations of the dynamical parameters involved.
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Glicerol , Nanocompostos , Humanos , Camundongos , Animais , Células HeLa , Extratos Celulares , Peixe-Zebra , ÁguaRESUMO
The dynamic intercommunication between tumour cells and cells from the microenvironment, such as cancer-associated fibroblast (CAFs), is a key factor driving breast cancer (BC) metastasis. Clusters of circulating tumour cells (CTCs), known to bare a higher efficiency at establishing metastases, are found in the blood of BC patients, often accompanied by CAFs in heterotypic CTC-clusters. Previously we have shown the utility of CTC-clusters models and the zebrafish embryo as a model of metastasis to understand the biology of breast cancer CTC-clusters. In this work, we use the zebrafish embryo to study the interactions between CTCs in homotypic clusters and CTC-CAFs in heterotypic CTC-clusters to identify potential pro-metastatic traits derived from CTC-CAF communication. We found that upon dissemination CAFs seem to exert a pro-survival and pro-proliferative effect on the CTCs, but only when CTCs and CAFs remain joined as cell clusters. Our data indicate that the clustering of CTC and CAF allows the establishment of physical interactions that when maintained over time favour the selection of CTCs with a higher capacity to survive and proliferate upon dissemination. Importantly, this effect seems to be dependent on the survival of disseminated CAFs and was not observed in the presence of normal fibroblasts. Moreover, we show that CAFs can exert regulatory effects on the CTCs without being involved in promoting tumour cell invasion. Lastly, we show that the physical communication between BC cells and CAFs leads to the production of soluble factors involved in BC cell survival and proliferation. These findings suggest the existence of a CAF-regulatory effect on CTC survival and proliferation sustained by cell-to-cell contacts and highlight the need to understand the molecular mechanisms that mediate the interaction between the CTCs and CAFs in clusters enhancing the metastatic capacity of CTCs.
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Gene therapy has long been proposed for cancer treatment. However, the use of therapeutic nucleic acids presents several limitations such as enzymatic degradation, rapid clearance, and poor cellular uptake and efficiency. In this work we propose the use of putrescine, a precursor for higher polyamine biosynthesis for the preparation of cationic nanosystems for cancer gene therapy. We have formulated and characterized putrescine-sphingomyelin nanosystems (PSN) and studied their endocytic pathway and intracellular trafficking in cancer cells. After loading a plasmid DNA (pDNA) encoding the apoptotic Fas Ligand (FasL), we proved their therapeutic activity by measuring the cell death rate after treatment of MDA-MB-231 cells. We have also used xenografted zebrafish embryos as a first in vivo approach to demonstrate the efficacy of the proposed PSN-pDNA formulation in a more complex model. Finally, intratumoral and intraperitoneal administration to mice-bearing MDA-MB-231 xenografts resulted in a significant decrease in tumour cell growth, highlighting the potential of the developed gene therapy nanoformulation for the treatment of triple negative breast cancer.
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Neoplasias da Mama , Neoplasias , Humanos , Camundongos , Animais , Feminino , Putrescina , Peixe-Zebra , Ciclo Celular , Morte Celular , Linhagem Celular TumoralRESUMO
Heart failure (HF) syndrome is a global public health issue. On the other hand, type 2 diabetes is a risk factor associated with overweight/obesity and a sedentary lifestyle. This consensus aims to compile information available on the relationship between HF and type 2 diabetes and present, in a summarized and practical way, the management recommendations based on scientific evidence. The document includes the description of the epidemiology of HF and type 2 diabetes; pathophysiology of HF and type 2 diabetes; cardiovascular complications of type 2 diabetes; stages of HF; management of type 2 diabetes in patients with HF; and management of HF in patients with type 2 diabetes. Lastly, in the conclusions section, the growing trend of both events and the need to start preventive activities is presented, as well as the favorable role of antidiabetic drugs in the treatment of patients with HF.
El síndrome de insuficiencia cardíaca (IC) es un problema de salud pública global. Por su parte, la diabetes tipo 2 es un factor de riesgo asociado a sobrepeso/obesidad y sedentarismo. El presente consenso busca recopilar la información disponible sobre la relación entre la IC y la diabetes tipo 2, y presentar, de manera práctica y resumida, las recomendaciones de manejo basadas en la evidencia científica. El documento se estructura en la descripción de la epidemiología de la IC y la diabetes tipo 2; la fisiopatología de la IC y la diabetes tipo 2; las complicaciones cardiovasculares de la diabetes tipo 2; los estadios de la IC; el manejo de la diabetes tipo 2 en pacientes con IC; y el manejo de la IC en pacientes con diabetes tipo 2. Por último, en el apartado de conclusiones se presenta una clara tendencia creciente de ambos eventos y se señala la necesidad del inicio de actividades preventivas, así como también el papel favorable de los fármacos antidiabéticos en el tratamiento de los pacientes con IC.
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Cardiologia , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Hipertensão , Humanos , Diabetes Mellitus Tipo 2/complicações , Consenso , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão/epidemiologiaRESUMO
Correction for 'Effectiveness of a novel gene nanotherapy based on putrescine for cancer treatment' by Saínza Lores et al., Biomater. Sci., 2023, https://doi.org/10.1039/d2bm01456d.
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Gene therapy is a promising therapeutic approach that has experienced significant groth in recent decades, with gene nanomedicines reaching the clinics. However, it is still necessary to continue developing novel vectors able to carry, protect, and release the nucleic acids into the target cells, to respond to the widespread demand for new gene therapies to address current unmet clinical needs. We propose here the use of zebrafish embryos as an in vivo platform to evaluate the potential of newly developed nanosystems for gene therapy applications in cancer treatment. Zebrafish embryos have several advantages such as low maintenance costs, transparency, robustness, and a high homology with the human genome. In this work, a new type of putrescine-sphingomyelin nanosystems (PSN), specifically designed for cancer gene therapy applications, was successfully characterized and demonstrated its potential for delivery of plasmid DNA (pDNA) and miRNA (miR). On one hand, we were able to validate a regulatory effect of the PSN/miR on gene expression after injection in embryos of 0 hpf. Additionally, experiments proved the potential of the model to study the transport of the associated nucleic acids (pDNA and miR) upon incubation in zebrafish water. The biodistribution of PSN/pDNA and PSN/miR in vivo was also assessed after microinjection into the zebrafish vasculature, demonstrating that the nucleic acids remained associated with the PSN in an in vivo environment, and could successfully reach disseminated cancer cells in zebrafish xenografts. Altogether, these results demonstrate the potential of zebrafish as an in vivo model to evaluate nanotechnology-based gene therapies for cancer treatment, as well as the capacity of the developed versatile PSN formulation for gene therapy applications.
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Analyzing different tumor regions by next generation sequencing allows the assessment of intratumor genetic heterogeneity (ITGH), a phenomenon that has been studied widely in some tumor types but has been less well explored in endometrial carcinoma (EC). In this study, we sought to characterize the spatial and temporal heterogeneity of 9 different ECs using whole-exome sequencing, and by performing targeted sequencing validation of the 42 primary tumor regions and 30 metastatic samples analyzed. In addition, copy number alterations of serous carcinomas were assessed by comparative genomic hybridization arrays. From the somatic mutations, identified by whole-exome sequencing, 532 were validated by targeted sequencing. Based on these data, the phylogenetic tree reconstructed for each case allowed us to establish the tumors' evolution and correlate this to tumor progression, prognosis, and the presence of recurrent disease. Moreover, we studied the genetic landscape of an ambiguous EC and the molecular profile obtained was used to guide the selection of a potential personalized therapy for this patient, which was subsequently validated by preclinical testing in patient-derived xenograft models. Overall, our study reveals the impact of analyzing different tumor regions to decipher the ITGH in ECs, which could help make the best treatment decision.
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Neoplasias do Endométrio , Heterogeneidade Genética , Evolução Clonal/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA/genética , Neoplasias do Endométrio/genética , Feminino , Humanos , Mutação , FilogeniaRESUMO
We analyze the fluctuations of the dissipated energy in a simple and general model where dissipation, diffusion, and driving are the key ingredients. The full dissipation distribution, which follows from hydrodynamic fluctuation theory, shows non-Gaussian tails and no negative branch, thus violating the fluctuation theorem as expected from the irreversibility of the dynamics. It exhibits simple scaling forms in the weak- and strong-dissipation limits, with large fluctuations favored in the former case but strongly suppressed in the latter. The typical path associated with a given dissipation fluctuation is also analyzed in detail. Our results, confirmed in extensive simulations, strongly support the validity of hydrodynamic fluctuation theory to describe fluctuating behavior in driven dissipative media.
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Phase transitions not allowed in equilibrium steady states may happen, however, at the fluctuating level. We observe for the first time this striking and general phenomenon measuring current fluctuations in an isolated diffusive system. While small fluctuations result from the sum of weakly correlated local events, for currents above a critical threshold the system self-organizes into a coherent traveling wave which facilitates the current deviation by gathering energy in a localized packet, thus breaking translation invariance. This results in Gaussian statistics for small fluctuations but non-Gaussian tails above the critical current. Our observations, which agree with predictions derived from hydrodynamic fluctuation theory, strongly suggest that rare events are generically associated with coherent, self-organized patterns which enhance their probability.
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Previous data support that mental health is affected during pandemic and lockdown situations. Yet, little is known about the positive factors that protect mental health during a lockdown. This study analyzed mental health status-particularly emotional problems-and the role of several sociodemographic and clinical variables; it also explored whether there is a positive relationship between self-compassion and better mental health status. A cross-sectional study was carried out in Spain with the participation of 917 fluent Spanish-speaking residents in a survey conducted approximately midway through the COVID-19 lockdown. The survey tested for anxiety, depression, and stress using the Depression Anxiety Stress Scale-21 (DASS-21), the Self-Compassion Scale (SCS) to measure self-compassion values, and the Perceived Vulnerability to Disease Questionnaire (PVDQ) to assess the degree of risk perceived by participants. Around 30% of the individuals surveyed (recruited by snowball sampling) showed clinically significant levels of anxiety, depression, and stress. The variables most frequently associated with anxiety, depression, and stress were low levels of self-compassion, age, gender, previous physical symptoms, a previous mental disorder, being a student, and perceived vulnerability to disease. We discuss the hypothetical protective role against anxiety, depression, and stress of certain skills such as self-compassion and the possibility that increasing self-compassion may be used to promote better mental health in similar situations.
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COVID-19/psicologia , Empatia , Saúde Mental , Estresse Psicológico/epidemiologia , Adulto , Ansiedade/epidemiologia , Controle de Doenças Transmissíveis , Estudos Transversais , Depressão/epidemiologia , Feminino , Humanos , Masculino , Espanha/epidemiologia , Inquéritos e QuestionáriosRESUMO
The crosstalk between cancer cells and the tumor microenvironment (TME) is a key determinant of cancer metastasis. Cancer-associated fibroblasts (CAFs), one of the main cellular components of TME, promote cancer cell invasion and dissemination through mechanisms including cell-cell interactions and the paracrine secretion of growth factors, cytokines and chemokines. During metastasis, circulating tumor cells (CTCs) are shed from the primary tumor to the bloodstream, where they can be detected as single cells or clusters. The current knowledge about the biology of CTC clusters positions them as key actors in metastasis formation. It also indicates that CTCs do not act alone and that they may be aided by stromal and immune cells, which seem to shape their metastatic potential. Among these cells, CAFs are found associated with CTCs in heterotypic CTC clusters, and their presence seems to increase their metastatic efficiency. In this review, we summarize the current knowledge on the role that CAFs play on metastasis and we discuss their implication on the biogenesis, metastasis-initiating capacity of CTC clusters, and clinical implications. Moreover, we speculate about possible therapeutic strategies aimed to limit the metastatic potential of CTC clusters involving the targeting of CAFs as well as their difficulties and limitations.
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We study the dynamics of three elastic particles in a finite interval where two light particles are separated by a heavy "piston." The piston undergoes surprisingly complex motion that is oscillatory at short time scales but seemingly chaotic at longer scales. The piston also makes long-duration excursions close to the ends of the interval that stem from the breakdown of energy equipartition. Many of these dynamical features can be understood by mapping the motion of three particles on the line onto the trajectory of an elastic billiard in a highly skewed tetrahedral region. We exploit this picture to construct a qualitative random walk argument that predicts a power-law tail, with exponent -3/2, for the distribution of time intervals between successive piston crossings of the interval midpoint. These predictions are verified by numerical simulations.