Minimum design requirements for a poroelastic mimic of articular cartilage

The exceptional functional performance of articular cartilage (load-bearing and lubrication) is attributed to its poroelastic structure and resulting interstitial fluid pressure. Despite this, there remains no engineered cartilage repair material capable of achieving physiologically relevant poroelasticity. In this work we develop in silico models to guide the design approach for poroelastic mimics of articular cartilage. We implement the constitutive models in FEBio, a PDE solver for multiphasic mechanics problems in biological and soft materials. We investigate the influence of strain rate, boundary conditions at the contact interface, and fiber modulus on the reaction force and load sharing between the solid and fluid phases. The results agree with the existing literature that when fibers are incorporated the fraction of load supported by fluid pressure is greatly amplified and increases with the fiber modulus. This result demonstrates that a stiff fibrous phase is a primary design requirement for poroelastic mimics of articular cartilage. The poroelastic model is fit to experimental stress-relaxation data from bovine and porcine cartilage to determine if sufficient design constraints have been identified. In addition, we fit experimental data from FiHy™, an engineered material which is claimed to be poroelastic. The fiber-reinforced poroelastic model was able to capture the primary physics of these materials and demonstrates that FiHy™ is beginning to approach a cartilage-like poroelastic response. We also develop a fiber-reinforced poroelastic model with a bonded interface (rigid contact) to fit stress relaxation data from an osteochondral explant and FiHy™ + bone substitute. The model fit quality is similar for both the chondral and osteochondral configurations and clearly captures the first order physics. Based on this, we propose that physiological poroelastic mimics of articular cartilage should be developed under a fiber-reinforced poroelastic framework

Experimental investigation and modelling of T-stubs undergoing large displacements

This paper investigates the development of second (2nd) order effects, arising from geometric and material non-linearities of T-stubs bolted to a rigid support, through a combination of experimental, numerical and analytical approaches. Experimental data is presented for a broad range of T-stub geometries, designed to ensure that significant 2nd order effects always develop, that will complement the existing library of limited test results. Finite element models, incorporating combined tensile (ductile) and shear damage initiation, evolution and failure in both the flange and bolt, are also developed to elucidate how key geometric/material parameters influence the resistance and ductility of T-stubs undergoing large displacement. It will be shown that the restraining effect from the bolt is integral to the activation of catenary action in the flange and the development of a second hardening branch in the tensile response, leading to identification of two new modes of failure that are not currently considered in classical theory or by EC3 (Part 1.8). A mechanical model is formulated to identify the key geometric and material parameters controlling the initiation, and development, of the second hardening branch. Finally, a criterion is proposed to estimate the critical displacement from when 2nd order effects become active

Finite element analysis of bolted T-stubs undergoing large displacement: a preliminary study

To properly assess the robustness of steel Moment Resisting Frames (MRFs), the non-linear response of structural members and connections would need to be quantified. Under the influence of extreme load cases, structural joints are subjected to both material and geometric nonlinearities, known commonly as second-order effects. These effects cannot be disregarded if catenary actions develop in the connecting beam member. The rotational capacity of bolted joints is directly dependent on the deformation capacity of its components in bending which are typically represented by the equivalent T-stub. A T-stub is composed of a single T-section bolted to a support whose stiffness may be equivalent or greater than that of the T-element. To accurately characterise the response of a T-stub undergoing large displacement, the non-linear behaviour of its flange will need to be thoroughly investigated. In the flange, second order effects are caused by the development of axial (or membrane) forces which can be significant for those T-stubs connected to a rigid support. Hitherto, little information exists on the influence of second-order effects on the response of bolted T-stubs and, consequently, there are no existing guidelines on how to include these effects in design. In this paper, we present the results of a parametric investigation, using finite element (FE) analysis, to assess the influence of second-order effects in T-stubs bolted to a rigid support. Both material and geometrical non-linearities were considered since they are known to have a critical impact upon the performance of T-stubs. A benchmark FE model is first generated and validated against experimental data; it is then used to carry out a parametric investigation, by alternately considering and neglecting geometric non-linearity, to identify the geometric configurations that experience significant second order effects. A method to assess the contributions of membrane forces to the overall deformation response of a T-stub is also propose

Deep Brain Stimulation in Anorexia Nervosa: Hope for the Hopeless or Exploitation of the Vulnerable? The Oxford Neuroethics Gold Standard Framework

Neurosurgical interventions for psychiatric disorders have a long and troubled history (1, 2) but have become much more refined in the last few decades due to the rapid development of neuroimaging and robotic technologies (2). These advances have enabled the design of less invasive techniques, which are more focused, such as deep brain stimulation (DBS) (3). DBS involves electrode insertion into specific neural targets implicated in pathological behavior, which are then repeatedly stimulated at adjustable frequencies. DBS has been used for Parkinson's disease and movement disorders since the 1960s (4-6) and over the last decade has been applied to treatment-refractory psychiatric disorders, with some evidence of benefit in obsessive-compulsive disorder (OCD), major depressive disorder, and addictions (7). Recent consensus guidelines on best practice in psychiatric neurosurgery (8) stress, however, that DBS for psychiatric disorders remains at an experimental and exploratory stage. The ethics of DBS-in particular for psychiatric conditions-is debated (1, 8-10). Much of this discourse surrounds the philosophical implications of competence, authenticity, personality, or identity change following neurosurgical interventions, but there is a paucity of applied guidance on neuroethical best practice in psychiatric DBS, and health-care professionals have expressed that they require more (11). This paper aims to redress this balance by providing a practical, applied neuroethical gold standard framework to guide research ethics committees, researchers, and institutional sponsors. We will describe this as applied to our protocol for a particular research trial of DBS in severe and enduring anorexia nervosa (SE-AN) (https://clinicaltrials.gov/ct2/show/NCT01924598, unique identifier NCT01924598), but believe it may have wider application to DBS in other psychiatric disorders

Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphants

Mutations and inadequate methylation profiles of CITED2 are associated with human congenital heart disease (CHD). In mouse, Cited2 is necessary for embryogenesis, particularly for heart development, and its depletion in embryonic stem cells (ESC) impairs cardiac differentiation. We have now determined that Cited2 depletion in ESC affects the expression of transcription factors and cardiopoietic genes involved in early mesoderm and cardiac specification. Interestingly, the supplementation of the secretome prepared from ESC overexpressing CITED2, during the onset of differentiation, rescued the cardiogenic defects of Cited2-depleted ESC. In addition, we demonstrate that the proteins WNT5A and WNT11 held the potential for rescue. We also validated the zebrafish as a model to investigate cited2 function during development. Indeed, the microinjection of morpholinos targeting cited2 transcripts caused developmental defects recapitulating those of mice knockout models, including the increased propensity for cardiac defects and severe death rate. Importantly, the co-injection of anti-cited2 morpholinos with either CITED2 or WNT5A and WNT11 recombinant proteins corrected the developmental defects of Cited2-morphants. This study argues that defects caused by the dysfunction of Cited2 at early stages of development, including heart anomalies, may be remediable by supplementation of exogenous molecules, offering the opportunity to develop novel therapeutic strategies aiming to prevent CHD.Agência financiadora: Fundação para a Ciência e a Tecnologia (FCT) Comissão de Coordenação e Desenvolvimento Regional do Algarve (CCDR Algarve) ALG-01-0145-FEDER-28044; DFG 568/17-2 Algarve Biomedical Center (ABC) Municipio de Louléinfo:eu-repo/semantics/publishedVersio

Interface Coupling in Twisted Multilayer Graphene by Resonant Raman Spectroscopy of Layer Breathing Modes.

Raman spectroscopy is the prime nondestructive characterization tool for graphene and related layered materials. The shear (C) and layer breathing modes (LBMs) are due to relative motions of the planes, either perpendicular or parallel to their normal. This allows one to directly probe the interlayer interactions in multilayer samples. Graphene and other two-dimensional (2d) crystals can be combined to form various hybrids and heterostructures, creating materials on demand with properties determined by the interlayer interaction. This is the case even for a single material, where multilayer stacks with different relative orientations have different optical and electronic properties. In twisted multilayer graphene there is a significant enhancement of the C modes due to resonance with new optically allowed electronic transitions, determined by the relative orientation of the layers. Here we show that this applies also to the LBMs, which can be now directly measured at room temperature. We find that twisting has a small effect on LBMs, quite different from the case of the C modes. This implies that the periodicity mismatch between two twisted layers mostly affects shear interactions. Our work shows that ultralow-frequency Raman spectroscopy is an ideal tool to uncover the interface coupling of 2d hybrids and heterostructures

Intrinsic and Extrinsic Performance Limits of Graphene Devices on SiO2

The linear dispersion relation in graphene[1,2] gives rise to a surprising prediction: the resistivity due to isotropic scatterers (e.g. white-noise disorder[3] or phonons[4-8]) is independent of carrier density n. Here we show that acoustic phonon scattering[4-6] is indeed independent of n, and places an intrinsic limit on the resistivity in graphene of only 30 Ohm at room temperature (RT). At a technologically-relevant carrier density of 10^12 cm^-2, the mean free path for electron-acoustic phonon scattering is >2 microns, and the intrinsic mobility limit is 2x10^5 cm^2/Vs, exceeding the highest known inorganic semiconductor (InSb, ~7.7x10^4 cm^2/Vs[9]) and semiconducting carbon nanotubes (~1x10^5 cm^2/Vs[10]). We also show that extrinsic scattering by surface phonons of the SiO2 substrate[11,12] adds a strong temperature dependent resistivity above ~200 K[8], limiting the RT mobility to ~4x10^4 cm^2/Vs, pointing out the importance of substrate choice for graphene devices[13].Comment: 16 pages, 3 figure

Inside-out planet formation. VII. Astrochemical models of protoplanetary disks and implications for planetary compositions

Inside-Out Planet Formation (IOPF) proposes that the abundant systems of close-in Super-Earths and Mini-Neptunes form in situ at the pressure maximum associated with the Dead Zone Inner Boundary (DZIB). We present a model of physical and chemical evolution of protoplanetary disk midplanes that follows gas advection, radial drift of pebbles and gas-grain chemistry to predict abundances from ∼300 au down to the DZIB near 0.2 au. We consider typical disk properties relevant for IOPF, i.e. accretion rates 10−9<m˙/(M⊙yr−1)<10−8 and viscosity parameter α = 10−4, and evolve for fiducial duration of 105 yrs. For outer, cool disk regions, we find that C and up to 90% of O nuclei start locked in CO and O2 ice, which keeps abundances of CO2 and H2O one order of magnitude lower. Radial drift of icy pebbles is influential, with gas-phase abundances of volatiles enhanced up to two orders of magnitude at ice-lines, while the outer disk becomes depleted of dust. Disks with decreasing accretion rates gradually cool, which draws in icelines closer to the star. At ≲ 1 au, advective models yield water-rich gas with C/O ratios ≲ 0.1, which may be inherited by atmospheres of planets forming here via IOPF. For planetary interiors built by pebble accretion, IOPF predicts volatile-poor compositions. However, advectively-enhanced volatile mass fractions of ∼10% can occur at the water ice line

The shear mode of multilayer graphene

The quest for materials capable of realizing the next generation of electronic and photonic devices continues to fuel research on the electronic, optical and vibrational properties of graphene. Few-layer graphene (FLG) flakes with less than ten layers each show a distinctive band structure. Thus, there is an increasing interest in the physics and applications of FLGs. Raman spectroscopy is one of the most useful and versatile tools to probe graphene samples. Here, we uncover the interlayer shear mode of FLGs, ranging from bilayer graphene (BLG) to bulk graphite, and suggest that the corresponding Raman peak measures the interlayer coupling. This peak scales from ~43 cm−1 in bulk graphite to ~31 cm−1 in BLG. Its low energy makes it sensitive to near-Dirac point quasiparticles. Similar shear modes are expected in all layered materials, providing a direct probe of interlayer interactions

The metabolic interplay between dietary carbohydrate and exercise and its role in acute appetite-regulation in males: a randomised controlled study

Understanding the metabolic determinants of post-exercise appetite-regulation would facilitate the development of adjunctive-therapeutics to supress compensatory eating behaviours and improve the efficacy of exercise as a weight loss treatment. Metabolic responses to acute exercise are however dependent on pre-exercise nutritional practices, including carbohydrate intake. We therefore aimed to determine the interactive effects of dietary carbohydrate and exercise on plasma hormonal and metabolite responses and explore mediators of exercise-induced changes in appetite-regulation across nutritional states. In this randomised crossover study, participants completed four 120 min visits: (i) control (water) followed by rest; (ii) control followed by exercise (30 min at ∼75% V̇O2 max); (iii) carbohydrate (75 g maltodextrin) followed by rest; and (iv) carbohydrate followed by exercise. An ad libitum meal was provided at the end of each 120 min visit, with blood sample collection and appetite assessment performed at pre-defined intervals. We found that dietary carbohydrate and exercise exerted independent effects on the hormones GLP-1 (Carbohydrate: 16.8 pmol/L, Exercise: 7.4 pmol/L), ghrelin (Carbohydrate: -48.8 pmol/L, Exercise: -22.7 pmol/L) and glucagon (Carbohydrate: 9.8 ng/L, Exercise: 8.2 ng/L) that were linked to the generation of distinct plasma 1H-NMR metabolic phenotypes. These metabolic responses were associated with changes in appetite and energy intake, and plasma acetate and succinate were subsequently identified as potential novel mediators of exercise-induced appetite and energy intake responses. In summary, dietary carbohydrate and exercise independently influence gastrointestinal hormones associated with appetite regulation. Future work is warranted to probe the mechanistic importance of plasma acetate and succinate in post-exercise appetite-regulation