Explore the vast range of titles available.

Gamma aminobutyric acid (GABA)-mediated synapses and the oscillations they orchestrate are altered in autism. GABA-acting benzodiazepines exert in some patients with autism paradoxical effects, raising the possibility that like in epilepsies, GABA excites neurons because of elevated intracellular concentrations of chloride. Following a successful pilot study, 1 we have now performed a double-blind clinical trial using the diuretic, chloride-importer antagonist bumetanide that reduces intracellular chloride reinforcing GABAergic inhibition. Sixty children with autism or Asperger syndrome (3–11 years old) received for 3 months placebo or bumetanide (1 mg daily), followed by 1-month wash out. Determination of the severity of autism was made with video films at day 0 (D0) and D90 by blind, independent evaluators. Bumetanide reduced significantly the Childhood Autism Rating Scale (CARS) (D90−D0; P <0.004 treated vs placebo), Clinical Global Impressions ( P <0.017 treated vs placebo) and Autism Diagnostic Observation Schedule values when the most severe cases (CARS values above the mean±s.d.; n =9) were removed (Wilcoxon test: P -value=0.031; Student’s t -test: P -value=0.017). Side effects were restricted to an occasional mild hypokalaemia (3.0–3.5 mM l −1 K + ) that was treated with supplemental potassium. In a companion study, chronic bumetanide treatment significantly improved accuracy in facial emotional labelling, and increased brain activation in areas involved in social and emotional perception (Hadjikhani et al. , submitted). Therefore, bumetanide is a promising novel therapeutic agent to treat autism. Larger trials are warranted to better determine the population best suited for this treatment.

Networks of flexible filaments often involve regions of tight contact. Predictively understanding the equilibrium configurations of these systems is challenging due to intricate couplings between topology, geometry, large nonlinear deformations, and friction. Here, we perform an in-depth study of a simple, yet canonical, problem that captures the essence of contact between filaments. In the orthogonal clasp, two filaments are brought into contact, with each centerline lying in one of a pair of orthogonal planes. Our data from X-ray tomography (μCT) and mechanical testing experiments are in excellent agreement with finite element method (FEM) simulations. Despite the apparent simplicity of the physical system, the data exhibit strikingly unintuitive behavior, even when the contact is frictionless. Specifically, we observe a curvilinear diamond-shaped ridge in the contact-pressure field between the two filaments, sometimes with an inner gap. When a relative displacement is imposed between the filaments, friction is activated, and a highly asymmetric pressure field develops. These findings contrast to the classic capstan analysis of a single filament wrapped around a rigid body. Both the μCT and FEM data indicate that the cross-sections of the filaments can deform significantly. Nonetheless, an idealized geometrical theory assuming undeformable tube cross-sections and neglecting elasticity rationalizes our observations qualitatively and highlights the central role of the small, but nonzero, tube radius of the filaments. We believe that our orthogonal clasp analysis provides a building block for future modeling efforts in frictional contact mechanics of more complex filamentary structures.

Biological membranes exhibit the ability to self-repair and dynamically change their shape while remaining impermeable. Yet, these defining features are difficult to reconcile with mechanical robustness. Here, we report on the spontaneous formation of a carbon nanoskin at the oil–water interface that uniquely combines self-healing attributes with high stiffness. Upon the diffusion-controlled self-assembly of a reactive molecular surfactant at the interface, a solid elastic membrane forms within seconds and evolves into a continuous carbon monolayer with a thickness of a few nanometers. This nanoskin has a stiffness typical for a 2D carbon material with an elastic modulus in bending of more than 40–100 GPa; while brittle, it shows the ability to self-heal upon rupture, can be reversibly reshaped, and sustains complex shapes. We anticipate such an unusual 2D carbon nanomaterial to inspire novel approaches towards the formation of synthetic cells with rigid shells, additive manufacturing of composites, and compartmentalization in industrial catalysis. Biological membranes exhibit the ability to self-repair and dynamically change their shape while remaining impermeable but these defining features are difficult to reconcile with mechanical robustness. Here, the authors report on the spontaneous formation of a carbon nanoskin at the oil-water interface that uniquely combines self-healing attributes with high stiffness.

There are growing numbers of infants and children living with single-ventricle congenital heart disease (SV). However, cardiac dysfunction and, ultimately, heart failure (HF) are common in the SV population and the ability to predict the progression to HF in SV patients has been limited, primarily due to an incomplete understanding of the disease pathogenesis. Here, we tested the hypothesis that non-invasive circulating metabolomic profiles can serve as novel biomarkers in the SV population. We performed systematic metabolomic and pathway analyses on a subset of pediatric SV non-failing (SVNF) and failing (SVHF) serum samples, compared with samples from biventricular non-failing (BVNF) controls. We determined that serum metabolite panels were sufficient to discriminate SVHF subjects from BVNF subjects, as well as SVHF subjects from SVNF subjects. Many of the identified significantly dysregulated metabolites were amino acids, energetic intermediates and nucleotides. Specifically, we identified pyruvate, palmitoylcarnitine, 2-oxoglutarate and GTP as promising circulating biomarkers that could be used for SV risk stratification, monitoring response to therapy and even as novel targets of therapeutic intervention in a population with few other options.

Significant surgical and medical advances over the past several decades have resulted in a growing number of infants and children surviving with hypoplastic left heart syndrome (HLHS) and other congenital heart defects associated with a single systemic right ventricle (RV). However, cardiac dysfunction and ultimately heart failure (HF) remain the most common cause of death and indication for transplantation in this population. Moreover, while early recognition and treatment of single ventricle-related complications are essential to improving outcomes, there are no proven therapeutic strategies for single systemic RV HF in the pediatric population. Importantly, prototypical adult HF therapies have been relatively ineffective in mitigating the need for cardiac transplantation in HLHS, likely due to several unique attributes of the failing HLHS myocardium. Here, we discuss the most commonly used medical therapies for the treatment of HF symptoms in HLHS and other single systemic RV patients. Additionally, we provide an overview of potential novel therapies for systemic ventricular failure in the HLHS and related populations based on fundamental science, pre-clinical, clinical, and observational studies in the current literature.

While operative and perioperative care continues to improve for single ventricle congenital heart disease (SV), long-term morbidities and mortality remain high. Importantly, phosphodiesterase-5 inhibitor therapies (PDE5i) are increasingly used, however, little is known regarding the direct myocardial effects of PDE5i therapy in the SV population. Our group has previously demonstrated that the failing SV myocardium is characterized by increased PDE5 activity and impaired mitochondrial bioenergetics. Here we sought to determine whether serum circulating factors contribute to pathological metabolic remodeling in SV, and whether PDE5i therapy abrogates these changes. Using an established model whereby primary cardiomyocytes are treated with patient sera +/- PDE5i, we assessed the impact of circulating factors on cardiomyocyte metabolism. Mass spectrometry-based lipidomics and metabolomics were performed to identify phospholipid and metabolite changes. Mitochondrial bioenergetics were assessed using the Seahorse Bioanalyzer and a stable isotope based mitochondrial enzyme activity assay. Relative mitochondrial copy number was quantified using RT-qPCR. Our data suggest that serum circulating factors contribute to fundamental changes in cardiomyocyte bioenergetics, including impaired mitochondrial function associated with decreased cardiolipin and other phospholipid species, increased reactive oxygen species (ROS) generation, and altered metabolite milieu. Treatment with PDE5i therapy was sufficient to abrogate a number of these metabolic changes, including a rescue of phosphatidylglycerol levels, a reduction in ROS, improved energy production, and normalization of several key metabolic intermediates. Together, these data suggest PDE5i therapy has direct cardiomyocyte effects and contributes to beneficial cardiomyocyte metabolic remodeling in SV failure.

Cet ouvrage se situe dans le prolongement du volume Interactions et Intercompréhension : une approche comparative qui interrogeait les notions d'acceptabilité et d'intercompréhension entre l'homme, l'animal et la machine. Nous poursuivons ici ces interrogations et enrichissons la réflexion autour de la question d'incertitude en termes d'implications théoriques et méthodologiques pour optimiser à la fois l'intercompréhension et la connaissance scientifique interdisciplinaire.

We perform a compare-and-contrast investigation between the equilibrium shapes of physical and ideal trefoil knots, both in closed and open configurations. Ideal knots are purely geometric abstractions for the tightest configuration tied in a perfectly flexible, self-avoiding tube with an inextensible centerline and undeformable cross-sections. Here, we construct physical realizations of tight trefoil knots tied in an elastomeric rod, and use X-ray tomography and 3D finite element simulation for detailed characterization. Specifically, we evaluate the role of elasticity in dictating the physical knot's overall shape, self-contact regions, curvature profile, and cross-section deformation. We compare the shape of our elastic knots to prior computations of the corresponding ideal configurations. Our results on tight physical knots exhibit many similarities to their purely geometric counterparts, but also some striking dissimilarities that we examine in detail. These observations raise the hypothesis that regions of localized elastic deformation, not captured by the geometric models, could act as precursors for the weak spots that compromise the strength of knotted filaments.

We present a methodology to simulate the mechanics of knots in elastic rods using geometrically nonlinear, full three-dimensional (3D) finite element analysis. We focus on the mechanical behavior of knots in tight configurations, for which the full 3D deformation must be taken into account. To set up the topology of our knotted structures, we apply a sequence of prescribed displacement steps to the centerline of an initially straight rod that is meshed with 3D solid elements. Self-contact is enforced with a normal penalty force combined with Coulomb friction. As test cases, we investigate both overhand and figure-of-eight knots. Our simulations are validated with precision model experiments, combining rod fabrication and X-ray tomography. Even if the focus is given to the methods, our results reveal that 3D deformation of tight elastic knots is central to their mechanical response. These findings contrast to a previous analysis of loose knots, for which 1D centerline-based rod theories sufficed for a predictive understanding. Our method serves as a robust framework to access complex mechanical behavior of tightly knotted structures that are not readily available through experiments nor existing reduced-order theories.

Networks of flexible filaments often involve regions of tight contact. Predictively understanding the equilibrium configurations of these systems is challenging due to intricate couplings between topology, geometry, large nonlinear deformations, and friction. Here, we perform an in-depth study of a simple yet canonical problem that captures the essence of contact between filaments. In the orthogonal clasp, two filaments are brought into contact, with each centerline lying in one of a pair of orthogonal planes. Our data from X-ray tomography (micro-CT) and mechanical testing experiments are in excellent agreement with the finite element method (FEM) simulations. Despite the apparent simplicity of the physical system, the data exhibits strikingly unintuitive behavior, even when the contact is frictionless. Specifically, we observe a curvilinear diamond-shaped ridge in the contact pressure field between the two filaments, sometimes with an inner gap. When a relative displacement is imposed between the filaments, friction is activated, and a highly asymmetric pressure field develops. These findings contrast to the classic capstan analysis of a single filament wrapped around a rigid body. Both the micro-CT and the FEM data indicate that the cross-sections of the filaments can deform significantly. Nonetheless, an idealized geometrical theory assuming undeformable tube cross-sections and neglecting elasticity rationalizes our observations qualitatively and highlights the central role of the small but finite tube radius of the filaments. We believe that our orthogonal clasp analysis provides a building block for future modeling efforts in frictional contact mechanics of more complex filamentary structures.