Bioprinted Scaffold Remodels the Neuromodulatory Microenvironment for Enhancing Bone Regeneration

Herein, a 3D bioprinted scaffold is proposed, containing a calcitonin gene-related peptide (CGRP) and the β-adrenergic receptor blocker propranolol (PRN) as a new method to achieve effective repair of bone defects. By leveraging the neuromodulation mechanism of bone regeneration, CGRP and PRN loaded mesoporous silica nanoparticles are added into a hybrid bio-ink, which initially contains gelatin methacrylate, Poly (ethylene glycol) diacrylate and bone marrow mesenchymal stem cells (BMSCs). Subsequently, the optimized bio-ink is used for 3D bioprinting to create a composite scaffold with a pre-designed micro-nano hierarchical structure. The migration and tube formation of human umbilical vein endothelial cells (HUVECs) can be promoted by the scaffold, which is beneficial to the formation of a new capillary network during the bone repair process. With the release of CGRP from the scaffold, the secretion of neuropeptides by sensory nerves is simulated. Meanwhile, the release of PRN can inhibit the binding process of catecholamine to β-adrenergic receptor, co-promoting the osteogenic differentiation of BMSCs with CGRP and silicon ions, which will effectively enhance bone repair of a critical-sized cranial defect in a rat model. In conclusion, this study provides a promising strategy for bone defect repair by understanding the neuromodulatory mechanisms during bone regeneration.     

Thiamine pyrophosphatase activity in the Golgi apparatus of calcitonin-treated osteoclasts.

The thiamine pyrophosphatase (TPPase) activity described by Novikoff and Goldfisher was examined in osteoclasts affected by calcitonin in order to elucidate whether the morphological and functional changes of the osteoclasts have an influence over the secretion function of their Golgi apparatus. The Golgi apparatus of osteoclasts of which the ruffled border had disappeared and bone resorption discontinued as the result of treatment with calcitonin showed a slight TPPase activity. The reaction products of the enzyme in these inactive osteoclasts were distinctly fewer than that of control osteoclasts, which were not affected by calcitonin. From these results, it is suggested that there may be a connection between the morphological and functional changes of osteoclasts and the secretion function of the Golgi apparatus.     

Receptors for calcitonin gene-related peptide,adrenomedullin, and amylin: the contributions of novel receptor-activity-modifying proteins

The discovery of receptor-activity-modifying proteins (RAMP) revealed a new principle for the function of G protein-coupled receptors. The initially orphan calcitonin receptor-like receptor (CRLR) was identified as a CGRP receptor when coexpressed with RAMP1. The same receptor is specific for adrenomedullin (ADM) in the presence of RAMP2. Calcitonin receptors (CTR) with 60% homology to the CRLR predominantly recognize calcitonin in the absence of RAMP. An amylin/CGRP receptor was recognized when a calcitonin receptor (CTR) was coexpressed with RAMP1. In the presence of RAMP3, the CTR only interacts with amylin. Noncovalent association of the RAMP with the CRLR or the CTR reveals heterodimeric RAMP/receptor complexes at the cell surface. Thus, two Class II G protein-coupled receptors, the CRLR and CTR, associate with three RAMP to form high affinity receptors for CGRP, ADM, or amylin. Here, the molecular composition and the functional properties of these receptors is reviewed.     

Pharmacology and biology of corticotropin-releasing factor (CRF) receptors

The biology of corticotropin-releasing factor (CRF) finds increasing interest in the scientific community because of the neuromodulatory actions of CRF on brain functions such as learning, anxiety, feeding, and locomotion. Additional actions on immunumodulation and apoptosis have recently been discovered. All actions of CRF are mediated by G protein-coupled receptors, which trigger different, sometimes opposite actions in different regions of the central nervous system. The CRF system exhibits considerable plasticity by the involvement of numerous different ligands, splice variants, and transductional couplings. The generation of multiple splice variants is facilitated by the intron exon structure of the CRF receptor genes.     

Ultrastructural study of the effects of cytochalasin D administration on the structure and acid trimetaphosphatase activity of osteoclast.

To determine the role of the cytoskeleton consisting of the microfilaments in osteoclasts, cytochalasin D (CD) conjugated with PBS was administered intravenously to rats at a dose of 1 mg/100 g b.w. Control rats were given only PBS. Then the osteoclasts in the metaphyses of the humeri were examined ultrastructurally, as well as acid trimetaphosphatase (TMPase) cytochemistry. The plasma calcium (Ca) concentrations before and after CD and calcitonin administration were also measured. CD administration first caused a prominent reduction of ruffled borders and spreading of clear zones associated with the occurrence of large pale vacuoles in adjacent cytoplasm. At 1 hr after CD administration, the osteoclasts mostly lacked both ruffled borders and clear zones, but still maintained a normal intracellular organization of cytoplasmic organelles. Morphometric analysis confirmed that CD administration resulted in about 70% reduction of both ruffled border and clear zone areas. TMPase secretion from osteoclasts towards the resorbing bone surfaces was strongly inhibited by CD administration. At 1 hr after administration, although CD caused a decrease of plasma Ca concentrations in 4 of 7 examined rats similar to that caused by calcitonin treatment, there was a slight increase of plasma Ca concentrations in the other 3 rats. These results suggest that the structure and bone-resorbing function of the ruffled border-clear zone complex of the osteoclast is highly regulated by cytoskeleton consisting of microfilaments containing F-actin.     

Apatite‐Binding Nanoparticulate Agonist of Hedgehog Signaling for Bone Repair

The hedgehog signaling pathway plays a critical role in bone development and regeneration. Applications of hedgehog morphogens or small molecular agonists are of interest in bone repair but constrained by low stability, high dose requirement, and nonspecific targeting in vivo. Herein, a nanoparticulate agonist as a new type of hedgehog signaling activator is developed for efficacious bone healing. The shell of nanoparticulate agonist consists of palmitic acid and oxysterol, which could modify hedgehog function and bind with the smoothened receptor to positively modulate hedgehog signaling. Meanwhile, the core is assembled with the sonic hedgehog gene/polyethyleneimine complex, which could synergistically enhance hedgehog signaling with oxysterol constituents. Moreover, alendronate is introduced into the nanoparticulate agonist to bind with hydroxyapatite for potential bone tissue targeting. Lastly, the nanoparticulate agonist surface is decorated with the guanidine group to overcome cell membrane barriers. The created multifunctional nanoparticulate agonist is successfully integrated onto apatite‐coated 3D scaffolds and demonstrates greatly improved osteogenesis in vitro and calvarial bone healing. This work suggests a novel biomaterial design to specifically promote hedgehog signaling for the treatment of bone defects.     

何时采取局部措施或系统措施

通过分析过程输出可获得许多与过程实际性能有关的信息，如果能对得到的信息进行正确的分析，就可确定过程中是否在正常方式正确的分析，就可确定过程是否在正常方式下运行，过程不正常运行可能是普通原因或特殊原因，因此，为了使过程正常运行，需要针对性地采取系统措施或局部措施。     

An optimal maintenance model using a number of different actions

In this paper, we study an optimal maintenance model. The state of a system is determined by the distribution of its operating time. Whenever the system fails, a number of actions can be chosen, including the repair actions, the replacement actions and the action of discarding the system. The objective of this paper is to determine an optimal policy which maximizes the expected total discounted reward. By using the semi-Markov decision process approach, the method of successive approximations is suggested for determining the optimal reward function and the corresponding optimal policy.     

Dealing with Selfishness and Moral Hazard in Noncooperative Wireless Networks

For noncooperative networks in which each node is a selfish agent, certain incentives must be given to intermediate nodes to let them forward the data for others. What makes the scenario worse is that, in a multihop noncooperative network, the end points can only observe whether or not the end-to-end transaction was successful or not, but not the individual actions of intermediate nodes. Thus, in the absence of properly designed incentive schemes, rational and selfish intermediate nodes may choose to forward data packets at a very low priority or simply drop the packets, and they could put the blame on the unreliable channel. In this paper, assuming the receiver is a trusted authority, we propose several methods that discourage the hidden actions under hidden information in multihop noncooperative networks with high probability. We design several algorithmic mechanisms for a number of routing scenarios such that each selfish agent will maximize its expected utility (i.e., profit) when it truthfully declares its type (i.e., cost and its actions) and it truthfully follows its declared actions. Our simulations show that the payments by our mechanisms are only slightly larger than the actual cost incurred by all intermediate nodes.     

Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon,GIP, GLP-1, and GLP-2 receptors

The glucagon-like peptides include glucagon, GLP-1, and GLP-2, and exert diverse actions on nutrient intake, gastrointestinal motility, islet hormone secretion, cell proliferation and apoptosis, nutrient absorption, and nutrient assimilation. GIP, a related member of the glucagon peptide superfamily, also regulates nutrient disposal via stimulation of insulin secretion. The actions of these peptides are mediated by distinct members of the glucagon receptor superfamily of G protein-coupled receptors. These receptors exhibit unique patterns of tissue-specific expression, exhibit considerable amino acid sequence identity, and share similar structural and functional properties with respect to ligand binding and signal transduction. This article provides an overview of the biology of these receptors with an emphasis on understanding the unique actions of glucagon-related peptides through studies of the biology of their cognate receptors.     

Synthetic Bone-Like Structures Through Omnidirectional Ceramic Bioprinting in Cell Suspensions

The integration of hierarchical structure, chemistry, and functional activity within tissue-engineered scaffolds is of great importance in mimicking native bone tissue. Bone is a highly mineralized tissue which forms at ambient conditions by continuous crystallization of the mineral phase within an organic matrix in the presence of bone residing cells. Despite recent advances in the biofabrication of complex engineered tissues, replication of the heterogeneity of bone microenvironments has been a major challenge in constructing biomimetic bone scaffolds. Herein, inspired by the bone biomineralization process, the first example of bone mimicking constructs by 3D writing of a novel apatite-transforming ink in a supportive microgel matrix with living cells is demonstrated. Using this technique, complex bone-mimicked constructs are made at room temperature without requiring invasive chemicals, radiation, or postprocessing steps. This study demonstrates that mineralized constructs can be deposited within a high density of stem cells, directing the cellular organization, and promoting osteogenesis in vitro. These findings offer a new strategy for fabrication of bone mimicking constructs for bone tissue regeneration with scope to generate custom bone microenvironments for disease modeling, multicellular delivery, and in vivo bone repair.     

Discovery and Evaluation of a Functional Ternary Polymer Blend for Bone Repair: Translation from a Microarray to a Clinical Model

Skeletal tissue regeneration is often required following trauma, where substantial bone or cartilage loss may be encountered and is a significant driver for the development of biomaterials with a defined 3D structural network. Solvent blending is a process that avoids complications associated with conventional thermal or mechanical polymer blending or synthesis, opening up large areas of chemical and physical space, while potentially simplifying regulatory pathways towards in vivo application. Here ternary mixtures of natural and synthetic polymers were solvent blended and evaluated as potential bone tissue engineering matrices for osteoregeneration by the assessment of growth and differentiation of STRO‐1+ skeletal stem cells. Several of the blend materials were found to be excellent supports for human bone marrow‐derived STRO‐1+ skeletal cells and fetal skeletal cells, with the optimized blend exhibiting in vivo osteogenic potential, suggesting that these polymer blends could act as suitable matrices for bioengineering of hard tissues.     

Designing procedural illustrations

Ideally, illustrations for procedural documents should show actions from the point of view of performers, especially if performers' bodies need to be positioned a particular way to perform actions. At the same time, illustrations also should ameliorate the limits of two-dimensional displays (such as the printed page or electronic screen) by showing bodies, objects, and movements across the display plane. These two requirements may conflict, possibly necessitating use of compromise views.     

Noncompressible Hemostasis and Bone Regeneration Induced by an Absorbable Bioadhesive Self-Healing Hydrogel

Bone bleeding and bone defects arising from trauma or bone tumor resection pose a great threat to patients and they are challenging problems to orthopedic surgeons. Traditional hemostatic materials are not suitable for bone fractures where compression cannot be applied, neither are they effective during surgeries where large amounts of body fluids prevent them from adhering to the large and irregular bone wound sites. This research introduces a catechol-conjugated chitosan (CHI-C) multi-functional hydrogel with adhesion, self-healing, cytocompatibility, hemocompatibility, and blood cell coagulation capacity. The hydrogel can be injected into internal and irregular bleeding sites and bone defective areas, and then rapidly self-heals (within 2 min) to an integrated hydrogel that fully fills the defective sites and strongly sticks to bleeding areas in the presence of body fluids during surgery. In vivo experiments using a rabbit ilium bone defect model demonstrate quick hemostasis after the hydrogel is applied and the blood loss is only ¼ compared to the untreated injuries. In addition, the bone regeneration is not interfered by the hydrogel and the bone defect is no longer visible with disappearance of the hydrogel after 4 weeks. This multi-functional hydrogel is potentially valuable for clinical applications towards tissue adhesion, hemostasis, and bone regeneration.     

Energieeffizienz durch Substitution von fossiler Energie durch nachhaltige Elektrizität

The directive for energy efficiency of the European Union should be brought into effect in the EU member states until June 2014. The main sectors concerned are the public purse, energy service providers, industry and small and medium-sized businesses. The sector of households is only indirectly included by actions of energy service providers or by the eco design directive for appliances and products. Energy efficiency should be economic by energy savings and thus avoided energy costs.     

Parathyroid hormone 1 receptor: insights into structure and function

The parathyroid hormone (PTH) and parathyroid hormone type 1 receptor (PTH1-Rc) are major players in regulating blood calcium homeostasis. PTH1-Rc is a G protein-coupled receptor (GPCR) and it is also activated by PTH-related protein (PTHrP), which has potent effects in several target tissues including bone, via endocrine, paracrine, and autocrine mechanisms in prenatal and adult stages of life, and in several diseases. Another layer of complexity is added by the recently discovered PTH2-Rc subtype displaying unique tissue distribution and ligand specificity, and the potential presence in mammals of a third receptor subtype. Understanding of the mechanisms regulating PTH1-Rc gene expression, receptor desensitization, endocytosis, recycling, and intracellular signaling is advancing and provides insights to understand PTH1-Rc's role in both normal and pathophysiology. In addition, development of an experimentally based model of the PTH-PTH1-Rc complex by combining photoaffinity crosslinking, mutagenesis, conformational analysis, and molecular modeling sheds light, at the atomic resolution, on the molecular mechanisms involved in ligand binding, receptor activation, and coupling to intracellular effectors. Taken together, these lines of investigation offer not only a better understanding of GPCR mechanisms of action in general, but also contribute to the treatment of PTH/PTHrP-PTH1-Rc-related disease states and to the rational development of novel mechanism-based drugs to treat them.     

Characteristics of disorders of water-electrolyte homeostasis in rats with transplantable hepatomas

The growth of ascitic Zajdela and solid 27 hepatomas in vivo is accompanied by significant changes in parathyroid hormones, calcitonin and aldosterone blood levels. In periods close to terminal ones, their level decreases presumably as a result of energy deficiency in the endocrine glands. The arising hormonal shifts are a result of a "metabolic stress" caused by the growing tumour.     

Simulation of surface EMG signals for a multilayer volume conductor with a superficial bone or blood vessel

This study analytically describes surface electromyogram (EMG) signals generated by a planar multilayer volume conductor constituted by different subdomains modeling muscle, bone (or blood vessel), fat, and skin tissues. The bone is cylindrical in shape, with a semicircular section. The flat portion of the boundary of the bone subdomain is interfaced with the fat layer tissue, the remaining part of the boundary is in contact with the muscle layer. The volume conductor is a model of physiological tissues in which the bone is superficial, as in the case of the tibia bone, backbone, and bones of the forearm. The muscle fibers are considered parallel to the axes of the bone, so that the model is space invariant in the direction of propagation of the action potential. The proposed model, being analytical, allows faster simulations of surface EMG with respect to previously developed models including bone or blood vessels based on the finite-element method. Surface EMG signals are studied by simulating a library of single-fiber action potentials (SFAP) of fibers in different locations within the muscle domain, simulating the generation, propagation, and extinction of the action potential. The decay of the amplitude of the SFAPs in the direction transversal to the fibers is assessed. The decay in the direction of the bone has a lower rate with respect to the opposite direction. Similar results are obtained by simulating motor unit action potentials (MUAPs) constituted by 100 fibers with territory 5 mm2. M waves and interference EMG signals are also simulated based on the library of SFAPs. Again, the decay of the amplitude of the simulated interference EMG signals is lower approaching the bone with respect to going farther from it. The findings of this study indicate the effect of a superficial bone in enhancing the EMG signals in the transversal direction with respect to the fibers of the considered muscle. This increases the effect of crosstalk. The same mathematical method used to simulate a superficial bone can be applied to simulate other physiological tissues. For example, superficial blood vessels (e.g., basilic vein, brachial artery) can influence the recorded EMG signals. As the electrical conductivity of blood is high (it is of the same order as the longitudinal conductivity in the muscle), the effect on EMG signals is opposite compared to the effect of a superficial bone.     

Fuzzy predictive filters in model predictive control

The application of model predictive control (MPG) to complex, nonlinear processes results in a nonconvex optimization problem for computing the optimal control actions. This optimization problem can be addressed by discrete search techniques, such as the branch-and-bound method, which has been successfully applied to MPG. The discretization, however, introduces a tradeoff between the number of discrete actions (computation time) and the performance. This paper proposes a solution to these problems by using a fuzzy predictive filter to construct the discrete control alternatives. The filter is represented as an adaptive set of control actions multiplied by a gain factor. This keeps the number of necessary alternatives low and increases the performance. Herewith, the problems introduced by the discretization of the control actions are diminished. The proposed MPC method using fuzzy predictive filters is applied by the temperature control of an air-conditioned test room. Simulations and real-time results show the advantages of the proposed method     

Tough Lessons From Bone: Extreme Mechanical Anisotropy at the Mesoscale

Bone is mechanically and structurally anisotropic with oriented collagen fibrils and nanometer‐sized mineral particles aggregating into lamellar or woven bone.[1] Direct measurements of anisotropic mechanical properties of sublamellar tissue constituents are complicated by the existence of an intrinsic hierarchical architecture. Methods such as nanoindentation provide insight into effective modulus values; however, bulk material properties cannot sufficiently be characterized since such measurements represent properties of near‐surface volumes and are partially averaged over fibril orientations.[2–5] In this study, we focus on the material properties of bone at one single level of hierarchy. By measuring properties of individual parallel‐fibered units of fibrollamellar bone under tension under controlled humidity conditions, an unusually high anisotropy is found. Here, we clearly demonstrate ratios as large as 1:20 in elastic modulus and 1:15 in tensile strength between orientations perpendicular and parallel to the main collagen fiber orientation in native wet bone; these ratios reduce to 1:8 and 1:7, respectively, under dry conditions. This extreme anisotropy appears to be caused by the existence of periodic, weak interfaces at the mesoscopic length scale. These interfaces are thought to be relevant to the proper mechanical and physiological performance of bone.