Effect of curcumin-nanoemulsion associated with photodynamic therapy in breast adenocarcinoma cell line

Curcumin, a natural compound has several antineoplastic activities and is a promising natural photosensitizer used in photodynamic therapy. However, its low solubility in physiological medium limit the clinical use of curcumin. This study aimed to analyze the action of curcumin-nanoemulsion, a new and well-designed Drug Delivery System (DDS+) molecule, used as a photosensitizing agent in photodynamic therapy in an in vitro breast cancer model, MCF-7 cells. The empty nanoemulsion fulfils all necessary requirements to be an excellent DDS. Furthermore, the use of curcumin-nanoemulsion in photodynamic therapy resulted in a high phototoxic effect after activation at 440?nm, decreasing to <10% viable tumor cells after two irradiations and increasing the reactive oxygen species (ROS) production. The use of curcumin-nanoemulsion associated with photodynamic therapy resulted in an increase in the levels of caspase 3/7 activity for the studied MCF-7 cell model, indicating that this therapy triggers a cascade of events that lead to cell death, such as cellular apoptosis. In conclusion, curcumin-nanoemulsion proved to be efficient as a photosensitizing agent, had phototoxic effects, significantly decreased the proliferation of MCF-7 cells and stimulating the ROS production in combination with photodynamic therapy, so, this formulation has a great potential for use in treatment of breast cancer.     

T lymphocytes migrate upstream after completing the leukocyte adhesion cascade

The leukocyte adhesion cascade is of critical importance for both the maintenance of immune homeostasis and the ability of immune cells to perform effector functions. Here, we present data showing CD4⁺ T cells migrate upstream (against the direction of flow) after completing the leukocyte adhesion cascade on surfaces displaying either ICAM-1 or ICAM-1 and VCAM-1, but migrate downstream on surfaces displaying only VCAM-1. Cells completing the cascade on HUVECs initially migrate upstream before reverting to more random migration, partly caused by transmigration of cells migrating against the flow. Furthermore, cells migrating upstream transmigrate faster than cells migrating downstream. On HUVECs, blocking interactions between LFA-1 and ICAM-1 resulted in downstream migration and slower transmigration. These results further suggest a possible physiological role for upstream migration in vivo.     

Interaction between single molecules of Mac-1 and ICAM-1 in living cells: an atomic force microscopy study

The interaction between integrin macrophage differentiation antigen associated with complement three receptor function (Mac-1) and intercellular adhesion molecule-1 (ICAM-1), which is controlled tightly by the ligand-binding activity of Mac-1, is central to the regulation of neutrophil adhesion in host defense. Several "inside-out" signals and extracellular metal ions or antibodies have been found to activate Mac-1, resulting in an increased adhesiveness of Mac-1 to its ligands. However, the molecular basis for Mac-1 activation is not well understood yet. In this work, we have carried out a single-molecule study of Mac-1/ICAM-1 interaction force in living cells by atomic force microscopy (AFM). Our results showed that the binding probability and adhesion force of Mac-1 with ICAM-1 increased upon Mac-1 activation. Moreover, by comparing the dynamic force spectra of different Mac-1 mutants, we expected that Mac-1 activation is governed by the downward movement of its alpha7 helix.     

Evolution of branched regulatory genetic pathways: directional selection on pleiotropic loci accelerates developmental system drift

Developmental systems are regulated by a web of interacting loci. One common and useful approach in studying the evolution of development is to focus on classes of interacting elements within these systems. Here, we use individual-based simulations to study the evolution of traits controlled by branched developmental pathways involving three loci, where one locus regulates two different traits. We examined the system under a variety of selective regimes. In the case where one branch was under stabilizing selection and the other under directional selection, we observed "developmental system drift": the trait under stabilizing selection showed little phenotypic change even though the loci underlying that trait showed considerable evolutionary divergence. This occurs because the pleiotropic locus responds to directional selection and compensatory mutants are then favored in the pathway under stabilizing selection. Though developmental system drift may be caused by other mechanisms, it seems likely that it is accelerated by the same underlying genetic mechanism as that producing the Dobzhansky-Muller incompatibilities that lead to speciation in both linear and branched pathways. We also discuss predictions of our model for developmental system drift and how different selective regimes affect probabilities of speciation in the branched pathway system.     

Dynamic domains and geometrical properties of HIV-1 gp120 during conformational changes induced by CD4 binding

The HIV-1 gp120 exterior envelope glycoprotein undergoes a series of conformational rearrangements while sequentially interacting with the receptor CD4 and coreceptor CCR5 or CXCR4 on the surface of host cells to initiate virus entry. Both the crystal structures of the HIV-1 gp120 core bound by the CD4 and antigen 17b, and the SIV gp120 core pre-bound by the CD4 are known. We have performed dynamic domain studies on the homology models of the CD4-bound and unliganded HIV-1 gp120 with modeled V3 and V4 loops to explore details of conformational changes, hinge axes, and hinge bending regions in the gp120 structures upon CD4 binding. Four dynamic domains were clustered and intricately motional modes for domain pairs were discovered. Together with the detailed comparative analyses of geometrical properties between the unliganded and liganded gp120 models, an induced fit model was proposed to explain events accompanying the CD4 engagement to the gp120, which provided new insight into the dynamics of the molecular induced binding mechanism that complements the molecular dynamics and crystallographic studies.     

Age-related fatigability in knee extensors and knee flexors during dynamic fatiguing contractions

This study investigated the effects of dynamic knee extension and flexion fatiguing task on torque and neuromuscular responses in young and older individuals. Eighteen young (8 males; 25.1 ± 3.2 years) and 17 older (8 males; 69.7 ± 3.7 years) volunteered. Following a maximal voluntary isometric contraction test, participants performed a fatiguing task involving 22 maximal isokinetic (concentric) knee extension and flexion contractions at 60°/s, while surface EMG was recorded simultaneously from the knee extensors (KE) and flexors (KF). Fatigue-induced relative torque reductions were similar between age groups for KE (peak torque decrease: 25.15% vs 26.81%); however, KF torque was less affected in older individuals (young vs older peak torque decrease: 27.6% vs 11.5%; p < 0.001) and this was associated with greater increase in hamstring EMG amplitude (p < 0.001) and hamstrings/quadriceps peak torque ratio (p < 0.01). Furthermore, KE was more fatigable than KF only among older individuals (peak torque decrease: 26.8% vs 11.5%; p < 0.001). These findings showed that the age-related fatigue induced by a dynamic task was greater for the KE, with greater age-related decline in KE compared to KF.     

Predicted threshold against forward and backward loss of balance for perturbed walking

The biomechanical mechanisms of loss of balance have been studied before for slip condition but have not been investigated for arbitrary perturbation profiles under non-slip conditions in sagittal plane. This study aimed to determine the thresholds of center of mass (COM) velocity and position relative to the base of support (BOS) that predict forward and backward loss of balance during walking with a range of BOS perturbations. Perturbations were modeled as sinusoidal BOS motions in the vertical or anterior-posterior direction or as sagittal rotation. The human body was modeled using a seven-link model. Forward dynamics alongside with dynamic optimization were used to find the thresholds of initial COM velocity for each initial COM position that would predict forward or backward loss of balance. The effects of perturbation frequency and amplitude on these thresholds were modeled based on the simulation data. Experimental data were collected from 15 able-bodied individuals and three individuals with disability during perturbed walking. The simulation results showed similarity with the stability region reported for slip and non-slip conditions. The feasible stability region shrank when the perturbation frequency and amplitude increased, especially for larger initial COM velocities. 89.5% (70.9%) and 82.4% (68.2%) of the measured COM position and velocity combinations during low (high) perturbations were located inside the simulated limits of the stability region, for able-bodied and disabled individuals, respectively. The simulation results demonstrated the effects of different perturbation levels on the stability region. The obtained stability region can be used for developing rehabilitative programs in interactive environments.     

Two-year changes in corneal stiffness parameters after accelerated corneal cross-linking

The objective of this non-randomized trial was comparison of two-year changes in dynamic corneal response (DCR) between 18 mW/cm² (5- min) and 9 mW/cm² (10-min) cross-linking (CXL) protocols, using novel stiffness parameters and correlating them to clinical indices. The two groups were evaluated before and 2 years after the procedure using Corvis ST (Oculus Optikgeräte GmbH, Germany) and DCR parameters such as deformation amplitude ratio at 1 mm and 2 mm (DA ratio-1 mm and DA ratio-2 mm) and integrated radius and stiffness parameters at A1 (SP-A1). Two-year follow-up was completed for 16 of the 30 eyes in the 5-min group and 21 of the 25 eyes in the 10-min group; data from those who were lost to follow-up was not included in the analyses. Mean age at baseline was 21.7 ± 4.9 and 21.5 ± 5.2 years in the 5- and 10-min groups, respectively (P = 0.895). At 2 years after CXL, in the 5-min group, the reduction in integrated radius (−1.12 ± 1.27 mm, P = 0.003) was significant, and the increase in SP-A1 (7.11 ± 14.86 mmHg/mm, P = 0.075) was borderline, while in the 10-min group, the decrease in DA ratio-2 mm (−0.43 ± 0.58, P = 0.003) and integrated radius (−1.89 ± 1.72 mm, P < 0.001), and increase in SP-A1 (7.67 ± 10.92 mmHg/mm, P = 0.004) were significant. In both groups, the strongest and significant correlation was observed between DCR parameters and changes in radius of curvature. In conclusion, results indicated corneal strengthening with both protocols especially with the 9 mW/cm². Corvis ST indices can provide “in vivo” biomechanical evidence on the efficacy of CXL that may occur prior to clinical indices.     

Investigation of left heart flow using a numerical correlation to model heart wall motion

A three-dimensional computational fluid dynamics (CFD) method has been developed to model the flow in the left heart including atrium and ventricle. Since time resolution of the medical scans does not fit the requirements of the CFD calculations, the main challenge in a numerical simulation of heart chambers is wall motion modeling. This study employs a novel three-dimensional approximation scheme to correlate the wall boundary and grid movement in systole and diastole. It uses a geometry extracted from medical images in the literature and deformed based on the reported flow rates. The opening and closing of the mitral (MV) and the aortic valve (AV) considered as simultaneous events. Unstructured tetragonal grids were used for the meshing of the domain. The calculation was performed by a Navier–Stokes solver using the arbitrary Lagrange–Euler (ALE) formulation. Results show that the proposed correlation for the wall motion could predict the main features of heart flows.