Multi-casting approach for vascular networks in cellularized hydrogels

Vascularization is essential for living tissue and remains a major challenge in the field of tissue engineering. A lack of a perfusable channel network within a large and densely populated tissue engineered construct leads to necrotic core formation, preventing fabrication of functional tissues and organs. We report a new method for producing a hierarchical, three-dimensional (3D) and perfusable vasculature in a large, cellularized fibrin hydrogel. Bifurcating channels, varying in size from 1 mm to 200-250 µm, are formed using a novel process in which we convert a 3D printed thermoplastic material into a gelatin network template, by way of an intermediate alginate hydrogel. This enables a CAD-based model design, which is highly customizable, reproducible, and which can yield highly complex architectures, to be made into a removable material, which can be used in cellular environments. Our approach yields constructs with a uniform and high density of cells in the bulk, made from bioactive collagen and fibrin hydrogels. Using standard cell staining and immuno-histochemistry techniques, we showed good cell seeding and the presence of tight junctions between channel endothelial cells, and high cell viability and cell spreading in the bulk hydrogel.This research was supported by the European Research Council (ERC, grant no. 240446), and an Engineering for Clinical Practice Grant from the Department of Engineering, University of Cambridge. A.W.J. acknowledges the support of the Engineering and Physical Sciences Research Council (EPSRC) through a PhD studentship (EP/L504920/1). R.A.B. gratefully acknowledges financial support from the National Institute for Health Research

Collagen scaffolds as a tool for understanding the biological effect of silicates

Dietary silicon is essential in the maintenance of bone and cartilage. However, the mechanism by which silicon, in the form of silicates, triggers a biological response has never been uncovered. Here we demonstrate the incorporation of orthosilicic acid (Si(OH)4), the form of silicon in the body, within collagen scaffolds for use as an in vitro platform to identify key genes affected by silicates. Ice-templated collagen–silicate scaffolds, containing 0.21 wt% silicon, were validated by examining the mRNA levels for an array of genes in human osteoblasts and mesenchymal stromal cells (MSC) after 48 h in culture. Several novel genes, such as tumor necrosis factor alpha (TNF), were identified as having potential links to orthosilicic acid, verifying that collagen–silicate scaffolds are a versatile platform for identifying novel mechanisms in which silicates regulate musculoskeletal tissue.The authors gratefully acknowledge the financial support of the Gates Cambridge Trust , ERC Advanced Grant 320598 3D-E and from the National Institute for Health Research. RJ is supported by the Medical Research Council (Grant number MC_US_A090_0008/Unit Programme number U1059).This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S0167577X15300203#

The Turbulent Structure of the Arctic Summer Boundary Layer During The Arctic Summer Cloud‐Ocean Study

The mostly ice covered Arctic Ocean is dominated by low‐level liquid‐ or mixed‐phase clouds. Turbulence within stratocumulus is primarily driven by cloud top cooling that induces convective instability. Using a suite of in situ and remote sensing instruments we characterize turbulent mixing in Arctic stratocumulus, and for the first time we estimate profiles of the gradient Richardson number at relatively high resolution in both time (10 min) and altitude (10 m). It is found that the mixing occurs both within the cloud, as expected, and by wind shear instability near the surface. About 75% of the time these two layers are separated by a stably stratified inversion at 100–200 m altitude. Exceptions are associated with low cloud bases that allow the cloud‐driven turbulence to reach the surface. The results imply that turbulent coupling between the surface and the cloud is sporadic or intermittent

A Theory of Cheap Control in Embodied Systems

We present a framework for designing cheap control architectures for embodied agents. Our derivation is guided by the classical problem of universal approximation, whereby we explore the possibility of exploiting the agent's embodiment for a new and more efficient universal approximation of behaviors generated by sensorimotor control. This embodied universal approximation is compared with the classical non-embodied universal approximation. To exemplify our approach, we present a detailed quantitative case study for policy models defined in terms of conditional restricted Boltzmann machines. In contrast to non-embodied universal approximation, which requires an exponential number of parameters, in the embodied setting we are able to generate all possible behaviors with a drastically smaller model, thus obtaining cheap universal approximation. We test and corroborate the theory experimentally with a six-legged walking machine. The experiments show that the sufficient controller complexity predicted by our theory is tight, which means that the theory has direct practical implications. Keywords: cheap design, embodiment, sensorimotor loop, universal approximation, conditional restricted Boltzmann machineComment: 27 pages, 10 figure

Perceptual Context in Cognitive Hierarchies

Cognition does not only depend on bottom-up sensor feature abstraction, but also relies on contextual information being passed top-down. Context is higher level information that helps to predict belief states at lower levels. The main contribution of this paper is to provide a formalisation of perceptual context and its integration into a new process model for cognitive hierarchies. Several simple instantiations of a cognitive hierarchy are used to illustrate the role of context. Notably, we demonstrate the use context in a novel approach to visually track the pose of rigid objects with just a 2D camera

MIRO: A robot “Mammal” with a biomimetic brain-based control system

We describe the design of a novel commercial biomimetic brain-based robot, MIRO, developed as a prototype robot companion. The MIRO robot is animal-like in several aspects of its appearance, however, it is also biomimetic in a more significant way, in that its control architecture mimics some of the key principles underlying the design of the mammalian brain as revealed by neuroscience. Specifically, MIRO builds on decades of previous work in developing robots with brain-based control systems using a layered control architecture alongside centralized mechanisms for integration and action selection. MIRO’s control system operates across three core processors, P1-P3, that mimic aspects of spinal cord, brainstem, and forebrain functionality respectively. Whilst designed as a versatile prototype for next generation companion robots, MIRO also provides developers and researchers with a new platform for investigating the potential advantages of brain-based control

Fifty years of spellchecking

A short history of spellchecking from the late 1950s to the present day, describing its development through dictionary lookup, affix stripping, correction, confusion sets, and edit distance to the use of gigantic databases

G-CSF Prevents the Progression of Structural Disintegration of White Matter Tracts in Amyotrophic Lateral Sclerosis: A Pilot Trial

Background: The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.Methods: Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 mu g/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS), a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days). The total number of adverse events (AE) and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI), brain volumetry, and voxel-based morphometry.Results: Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA) encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.Conclusions: Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect, DTI measurements suggest that the widespread and progressive microstructural neural damage in ALS can be modulated by G-CSF treatment. These findings may carry significant implications for further clinical trials on ALS using growth factors

Solid state NMR of isotope labelled murine fur: a powerful tool to study atomic level keratin structure and treatment effects

We have prepared mouse fur extensively $^{13}$C,$^{15}$N-labelled in all amino acid types enabling application of 2D solid state NMR techniques which establish covalent and spatial proximities within, and in favorable cases between, residues. $^{13}$C double quantum-single quantum correlation and proton driven spin diffusion techniques are particularly useful for resolving certain amino acid types. Unlike 1D experiments on isotopically normal material, the 2D methods allow the chemical shifts of entire spin systems of numerous residue types to be determined, particularly those with one or more distinctively shifted atoms such as Gly, Ser, Thr, Tyr, Phe, Val, Leu, Ile and Pro. Also the partial resolution of the amide signals into two signal envelopes comprising of $\alpha$-helical, and $\beta$-sheet/random coil components, enables resolution of otherwise overlapped $\alpha$-carbon signals into two distinct cross peak families corresponding to these respective secondary structural regions. The increase in resolution conferred by extensive labelling offers new opportunities to study the chemical fate and structural environments of specific atom and amino acid types under the influence of commercial processes, and therapeutic or cosmetic treatments.Medical Research Council (Grant ID: RG75828), Engineering and Physical Sciences Research Council (Ph.D. studentships), National Institute of Health Researc

Beyond persons: extending the personal / subpersonal distinction to non-rational animals and artificial agents

The distinction between personal level explanations and subpersonal ones has been subject to much debate in philosophy. We understand it as one between explanations that focus on an agent’s interaction with its environment, and explanations that focus on the physical or computational enabling conditions of such an interaction. The distinction, understood this way, is necessary for a complete account of any agent, rational or not, biological or artificial. In particular, we review some recent research in Artificial Life that pretends to do completely without the distinction, while using agent-centered concepts all the way. It is argued that the rejection of agent level explanations in favour of mechanistic ones is due to an unmotivated need to choose among representationalism and eliminativism. The dilemma is a false one if the possibility of a radical form of externalism is considered