Consumption of a high-energy Western diet triggers mild adaptive β cell proliferation to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. In ...the present study we show that the toll-like receptors TLR2 and TLR4 inhibited the diet-induced replication of β cells in mice and humans. The combined, but not the individual, loss of TLR2 and TLR4 increased the replication of β cells, but not that of α cells, leading to enlarged β cell area and hyperinsulinemia in diet-induced obesity. Loss of TLR2 and TLR4 increased the nuclear abundance of the cell cycle regulators cyclin D2 and Cdk4 in a manner dependent on the signaling mediator Erk. These data reveal a regulatory mechanism controlling the proliferation of β cells in diet-induced obesity and suggest that selective targeting of the TLR2/TLR4 pathways may reverse β cell failure in patients with diabetes.
Cellular therapies for liver diseases and in vitro models for drug testing both require functional human hepatocytes (Hum-H), which have unfortunately been limited due to the paucity of donor liver ...tissues. Human pluripotent stem cells (hPSCs) represent a promising and potentially unlimited cell source to derive Hum-H. However, the hepatic functions of these hPSC-derived cells to date are not fully comparable to adult Hum-H and are more similar to fetal ones. In addition, it has been challenging to obtain functional hepatic engraftment of these cells with prior studies having been done in immunocompromised animals. In this report, we demonstrated successful engraftment of human induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iPS-H) in immunocompetent mice by pre-engineering 3D cell co-aggregates with stromal cells (SCs) followed by encapsulation in recently developed biocompatible hydrogel capsules. Notably, upon transplantation, human albumin and α1-antitrypsin (A1AT) in mouse sera secreted by encapsulated iPS-H/SCs aggregates reached a level comparable to the primary Hum-H/SCs control. Further immunohistochemistry of human albumin in retrieved cell aggregates confirmed the survival and function of iPS-H. This proof-of-concept study provides a simple yet robust approach to improve the engraftment of iPS-H, and may be applicable to many stem cell-based therapies.
Synaptic crosstalk is ubiquitous in many brain regions, but its effect on firing activities of neural network has rarely been studied. In this study, a heterogeneous neural network constructed with ...one Hindmarsh–Rose neuron model and one Fitzhugh–Nagumo neuron model is developed, in which the synaptic crosstalk is emulated by two mutually coupled memristors. The effect of crosstalk intensities on the firing activities of the neural network are discussed by time series, phase diagrams, Lyapunov exponents, and dynamic mapping. For different crosstalk intensities, the coexisting periodic firing and chaotic firing, the coexisting periodic firing and periodic firing, the coexisting chaotic firing and periodic firing, and the coexisting chaotic firing and chaotic firing are observed in the neural network under different memristor’s initial values. Furthermore, the effect of crosstalk intensity on synchronous firing between two neurons is also revealed and it is found that the two heterogeneous neurons transit from initially oscillate independently to gradually achieve fully synchronous firing behavior as the crosstalk intensities decrease. Finally, the numerical simulations are verified by circuit simulation experiment based on Multisim.
Islet encapsulation and transplantation promises to improve upon current treatments for type 1 diabetes mellitus, though several limitations remain. Macroscale devices have been designed for in vivo ...transplantation and retrieval, but traditional geometries do not support clinically adequate mass transfer of nutrients to and insulin from the encapsulated tissue. Microcapsule technologies have improved mass transfer properties, but their clinical translation remains challenging as their complete retrieval is difficult, should the graft become a safety concern. Here, the design, characterization and testing of a novel encapsulation structure, comprised of elastomer‐reinforced interconnected toroidal hydrogels is reported. These donut‐shaped hydrogels feature a high surface area, higher than conventional spherical capsules of the same volume, bestowing suitable mass transport conditions, while allowing interconnection and reversible deformation for intraperitoneal implantation and retrieval. Diabetes correction up to 12 weeks and complete retrieval is achieved in a diabetic mouse model, providing a proof‐of‐concept for the potential application as a type 1 diabetes cell replacement therapy.
A novel islet encapsulation device comprising interconnected toroidal (i.e., donut‐shaped) hydrogels, is reported. Hydrogel reinforcement with a 3D‐printed double helix elastomer scaffold allows for robust and facile intraperitoneal implantation and retrieval. The interconnected torus design also confers scalability without sacrificing oxygen delivery to the encapsulated cells. Finally, diabetes correction is achieved for 12 weeks in a rat‐to‐mouse xenograft.
A vortex ring is a torus-shaped fluidic vortex. During its formation, the fluid experiences a rich variety of intriguing geometrical intermediates from spherical to toroidal. Here we show that these ...constantly changing intermediates can be 'frozen' at controlled time points into particles with various unusual and unprecedented shapes. These novel vortex ring-derived particles, are mass-produced by employing a simple and inexpensive electrospraying technique, with their sizes well controlled from hundreds of microns to millimetres. Guided further by theoretical analyses and a laminar multiphase fluid flow simulation, we show that this freezing approach is applicable to a broad range of materials from organic polysaccharides to inorganic nanoparticles. We demonstrate the unique advantages of these vortex ring-derived particles in several applications including cell encapsulation, three-dimensional cell culture, and cell-free protein production. Moreover, compartmentalization and ordered-structures composed of these novel particles are all achieved, creating opportunities to engineer more sophisticated hierarchical materials.
In this paper, we report a special memristor-based Jerk system in which self-excited and hidden attractors can be generated by adjusting one decisive system parameter. With increasing the parameter ...from negative to positive, the system has a transition from unstable equilibriums to no equilibrium point, and thus leading to the occurrence of coexisting self-excited and hidden attractors in the modified Jerk system simultaneously. More interestingly, the memristor parameters play an important role in the coexistence of attractors and the formation of the Feigenbaum remerging trees, and these two dynamic behaviors can be found in both hidden and self-excited attractor regions. In addition, the study of state-switching proves that the memristor’s internal initial state is very sensitive to the system. In order to verify the complex dynamic behavior of the system, an analog circuit simulation based on Multisim is developed and two types of attractors and their coexisting attractors are successfully captured.
Abstract
The delivery of encapsulated islets or stem cell-derived insulin-producing cells (i.e., bioartificial pancreas devices) may achieve a functional cure for type 1 diabetes, but their efficacy ...is limited by mass transport constraints. Modeling such constraints is thus desirable, but previous efforts invoke simplifications which limit the utility of their insights. Herein, we present a computational platform for investigating the therapeutic capacity of generic and user-programmable bioartificial pancreas devices, which accounts for highly influential stochastic properties including the size distribution and random localization of the cells. We first apply the platform in a study which finds that endogenous islet size distribution variance significantly influences device potency. Then we pursue optimizations, determining ideal device structures and estimates of the curative cell dose. Finally, we propose a new, device-specific islet equivalence conversion table, and develop a surrogate machine learning model, hosted on a web application, to rapidly produce these coefficients for user-defined devices.
We describe here designs of compartmentalized hydrogel microparticles with a tunable extracellular matrix (ECM) support for cell encapsulation and scalable 3D cell culture. The microparticles, ...rapidly formed by a one-step, multi-fluidic electrostatic spraying technique (>10 000 min
), have a uniform spherical shape, a nearly monodisperse size distribution and controlled compartmentalization. They not only have a high surface area for mass transfer but also offer defined space and essential ECM support for various scalable and efficient 3D cell culture, co-culture and microtissue production applications.
Synaptic crosstalk is a prevalent phenomenon among neuronal synapses, playing a crucial role in the transmission of neural signals. Therefore, considering synaptic crosstalk behavior and ...investigating the dynamical behavior of discrete neural networks are highly necessary. In this paper, we propose a heterogeneous discrete neural network (HDNN) consisting of a three-dimensional KTz discrete neuron and a Chialvo discrete neuron. These two neurons are coupled mutually by two discrete memristors and the synaptic crosstalk is considered. The impact of crosstalk strength on the firing behavior of the HDNN is explored through bifurcation diagrams and Lyapunov exponents. It is observed that the HDNN exhibits different coexisting attractors under varying crosstalk strengths. Furthermore, the influence of different crosstalk strengths on the synchronized firing of the HDNN is investigated, revealing a gradual attainment of phase synchronization between the two discrete neurons as the crosstalk strength decreases.
Synthetic scaffolds are crucial to applications in regenerative medicine; however, the foreign body response can impede regeneration and may lead to failure of the implant. Herein we report the ...development of a tissue engineering scaffold that allows attachment and proliferation of regenerating cells while reducing the foreign body response by localized delivery of an anti-inflammatory agent. Electrospun fibers composed of poly(l-lactic) acid (PLLA) and poly(ε-caprolactone) (PCL) were prepared with and without the steroid anti-inflammatory drug, dexamethasone. Analysis of subcutaneous implants demonstrated that the PLLA fibers encapsulating dexamethasone evoked a less severe inflammatory response than the other fibers examined. They also displayed a controlled release of dexamethasone over a period of time conducive to tissue regeneration and allowed human mesenchymal stem cells to adhere to and proliferate on them in vitro. These observations demonstrate their potential as a building block for tissue engineering scaffolds.
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