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Extracellular vesicles (EVs) are small vesicles ensuring transport of molecules between cells and throughout the body. EVs contain cell type-specific signatures and have been proposed as biomarkers in a variety of diseases. Their small size (<1 μm) and biological and physical functions make them obvious candidates for therapeutic agents in immune therapy, vaccination, regenerative medicine and drug delivery. However, due to the complexity and heterogeneity of their origin and composition, the actual mechanism through which these vesicles exert their functions is still unknown and represents a great biomedical challenge. Moreover, because of their small dimensions, the quantification, size distribution and biophysical characterization of these particles are challenging and still subject to controversy. Here, we address the advantage of atomic force microscopy (AFM), for the characterization of isolated EVs. We review AFM imaging of EVs immobilized on different substrates (mica, glass) to identify the influence of isolation and deposition methods on the size distribution, morphology and mechanical properties of EVs.

The unconventional N-methyl-D-aspartate (NMDA) receptor subunits GluN3A and GluN3B can, when associated with the other glycine-binding subunit GluN1, generate excitatory conductances purely activated by glycine. However, functional GluN1/GluN3 receptors have not been identified in native adult tissues. We discovered that GluN1/GluN3A receptors are operational in neurons of the mouse adult medial habenula (MHb), an epithalamic area controlling aversive physiological states. In the absence of glycinergic neuronal specializations in the MHb, glial cells tuned neuronal activity via GluN1/GluN3A receptors. Reducing GluN1/GluN3A receptor levels in the MHb prevented place-aversion conditioning. Our study extends the physiological and behavioral implications of glycine by demonstrating its control of negatively valued emotional associations via excitatory glycinergic NMDA receptors.

The locomotion of many soft-bodied animals is driven by the propagation of rhythmic waves of contraction and extension along the body. These waves are classically attributed to globally synchronized periodic patterns in the nervous system embodied in a central pattern generator (CPG). However, in many primitive organisms such as earthworms and insect larvae, the evidence for a CPG is weak, or even non-existent. We propose a neuromechanical model for rhythmically coordinated crawling that obviates the need for a CPG, by locally coupling the local neuro-muscular dynamics in the body to the mechanics of the body as it interacts frictionally with the substrate. We analyse our model using a combination of analytical and numerical methods to determine the parameter regimes where coordinated crawling is possible and compare our results with experimental data. Our theory naturally suggests mechanisms for how these movements might arise in developing organisms and how they are maintained in adults, and also suggests a robust design principle for engineered motility in soft systems.

Birds, fish and other animals routinely use unsteady effects to save energy by alternating between phases of active propulsion and passive coasting. Here, we construct a minimal model for such behaviour that can be couched as an optimal control problem via an analogy to travelling with a rechargeable battery. An analytical solution of the optimal control problem proves that intermittent locomotion has lower energy requirements relative to steady-state strategies. Additional realistic hypotheses, such as the assumption that metabolic cost at a given power should be minimal (the fixed gear hypothesis), a nonlinear dependence of the energy storage rate on propulsion and/or a preferred average speed, allow us to generalize the model and demonstrate the flexibility of intermittent locomotion with implications for biological and artificial systems.

Controlled gliding during descent has been thought of as a crucial intermediate step toward the evolution of powered flight in a variety of animals. Here we develop and analyse a model for the controlled descent of thin bodies in quiescent fluids. Focusing on motion in two dimensions for simplicity, we formulate the question of steering an elliptical body to a desired landing location with a specific orientation using the framework of optimal control theory with a single control variable. We derive both time- and energy-optimal trajectories using a combination of numerical and analytical approximations. In particular, we find that energy-optimal strategies converge to constant control, while time-optimal strategies converge to bang–coast–bang control that leads to bounding flight, alternating between tumbling and gliding phases. Our study of these optimal strategies thus places natural limits on how they may be implemented in biological and biomimetic systems.

The trait of extraversion is one of the longest-standing domains that captures the social dimension of personality and can potentially explain the covariation of a wide variety of behaviors. To date, there is a growing recognition that human behavior should be specified not only through the psychological mechanisms underlying each trait but also through their underlying neurobehavioral systems. While imaging studies have revealed important initial insights into the structural and functional neural correlates of extraversion, current knowledge about the relationships between extraversion and brain structures is still rather limited, especially with regard to the relationship between extraversion and white matter (WM). In this study, we aimed to investigate WM microstructure in extraversion in greater depth. Thirty-five healthy volunteers (21 women; mean age 35) underwent magnetic resonance imaging, as a part of a larger project aimed at investigating the longitudinal effect of motor training. WM integrity was assessed using the diffusion tensor imaging technique combining multiple diffusion tensor measures. Extraversion was assessed by the Eysenck Personality Questionnaire-Revised. Voxelwise correlation analyses between fractional anisotropy, axial diffusivities, and radial diffusivities maps and extraversion score showed decreased connectivity in the right inferior fronto-occipital fasciculus and forceps major among individuals who had high extraversion ratings. In conclusion, individual differences in extraversion may reflect differential organization of the WM tracts connecting frontal cortex, temporal, and occipital areas, which are related to socioemotional and control functions.

Feedback linearisation is a well-known technique in the controls community but has not been widely taken up in the vibrations community. It has the advantage of linearising nonlinear system models, thereby enabling the avoidance of the complicated mathematics associated with nonlinear problems. A particular and common class of problems is considered, where the nonlinearity is present in a system parameter and a formulation in terms of the usual second-order matrix differential equation is presented. The classical texts all cast the feedback linearisation problem in first-order form, requiring repeated differentiation of the output, usually presented in the Lie algebra notation. This becomes unnecessary when using second-order matrix equations of the problem class considered herein. Analysis is presented for the general multidegree of freedom system for those cases when a full set of sensors and actuators is available at every degree of freedom and when the number of sensors and actuators is fewer than the number of degrees of freedom. Adaptive feedback linearisation is used to address the problem of nonlinearity that is not known precisely. The theory is illustrated by means of a three-degree-of-freedom nonlinear aeroelastic model, with results demonstrating the effectiveness of the method in suppressing flutter.

The locomotion of many soft-bodied animals is driven by the propagation of rhythmic waves of contraction and extension along the body. These waves are classically attributed to globally synchronized periodic patterns in the nervous system embodied in a central pattern generator (CPG). However, in many primitive organisms such as earthworms and insect larvae, the evidence for a CPG is weak, or even non-existent. We propose a neuromechanical model for rhythmically coordinated crawling that obviates the need for a CPG, by locally coupling the local neuro-muscular dynamics in the body to the mechanics of the body as it interacts frictionally with the substrate. We analyse our model using a combination of analytical and numerical methods to determine the parameter regimes where coordinated crawling is possible and compare our results with experimental data. Our theory naturally suggests mechanisms for how these movements might arise in developing organisms and how they are maintained in adults, and also suggests a robust design principle for engineered motility in soft systems.

Purpose Lapatinib is a small molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor type 2 (HER2). Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab. Updated efficacy and initial biomarker results from this trial are reported. Methods Women with HER2-positive, locally advanced or metastatic breast cancer previously treated with anthracycline-, taxane-, and trastuzumab-containing regimens were randomized to lapatinib 1,250 mg/day continuously plus capecitabine 2,000 mg/m 2 days 1–14 of a 21-day cycle or capecitabine 2,500 mg/m 2 on the same schedule. The primary endpoint was time to progression (TTP) as determined by an independent review panel. Relationship between progression-free survival (PFS) and tumor HER2 expression and serum levels of HER2 extracellular domain (ECD) were assessed. Results 399 women were randomized. The addition of lapatinib prolonged TTP with a hazard ratio (HR) of 0.57 (95% CI, 0.43–0.77; P  < 0.001) and provided a trend toward improved overall survival (HR: 0.78, 95% CI: 0.55–1.12, P  = 0.177), and fewer cases with CNS involvement at first progression (4 vs. 13, P  = 0.045). Baseline serum HER2 ECD did not predict for benefit from lapatinib. Conclusion The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive, advanced breast cancer progressing after treatment with anthracycline-, taxane-, and trastuzumab-based therapy. Biomarker studies could not identify a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine.

Birds, fish and other animals routinely use unsteady effects to save energy by alternating between phases of active propulsion and passive coasting. Here, we construct a minimal model for such behaviour that can be couched as an optimal control problem via an analogy to travelling with a rechargeable battery. An analytical solution of the optimal control problem proves that intermittent locomotion has lower energy requirements relative to steady-state strategies. Additional realistic hypotheses, such as the assumption that metabolic cost at a given power should be minimal (the fixed gear hypothesis), a nonlinear dependence of the energy storage rate on propulsion and/or a preferred average speed, allow us to generalize the model and demonstrate the flexibility of intermittent locomotion with implications for biological and artificial systems.