In addition to its structural role, the skeleton serves as an endocrine organ that controls mineral metabolism and energy homeostasis. Three major cell types in bone - osteoblasts, osteoclasts, and ...osteocytes - dynamically form and maintain bone and secrete factors with systemic activity. Osteocalcin, an osteoblast-derived factor initially described as a matrix protein that regulates bone mineralization, has been suggested to be an osteoblast-derived endocrine hormone that regulates multiple target organs including pancreas, liver, muscle, adipose, testes, and the central and peripheral nervous system. Sclerostin is predominantly produced by osteocytes, and is best known as a paracrine-acting regulator of WNT signaling and activity of osteoblasts and osteoclasts on bone surfaces. In addition to this important paracrine role for sclerostin within bone, sclerostin protein has been noted to act at a distance to regulate adipocytes, energy homeostasis, and mineral metabolism in the kidney. In this article, we aim to bring together evidence supporting an endocrine function for sclerostin and osteocalcin, and discuss recent controversies regarding the proposed role of osteocalcin outside of bone. We summarize the current state of knowledge on animal models and human physiology related to the multiple functions of these bone-derived factors. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of osteocalcin and sclerostin.
Digital assets have come under various network security threats in the digital age. As a kind of security equipment to protect digital assets, intrusion detection system (IDS) is less efficient if ...the alert is not timely and IDS is useless if the accuracy cannot meet the requirements. Therefore, an intrusion detection model that combines machine learning with deep learning is proposed in this paper. The model uses the k-means and the random forest (RF) algorithms for the binary classification, and distributed computing of these algorithms is implemented on the Spark platform to quickly classify normal events and attack events. Then, by using the convolutional neural network (CNN), long short-term memory (LSTM), and other deep learning algorithms, the events judged as abnormal are further classified into different attack types finally. At this stage, adaptive synthetic sampling (ADASYN) is adopted to solve the unbalanced dataset. The NSL-KDD and CIS-IDS2017 datasets are used to evaluate the performance of the proposed model. The experimental results show that the proposed model has better TPR for most of attack events, faster data preprocessing speed, and potentially less training time. In particular, the accuracy of multi-target classification can reach as high as 85.24% in the NSL-KDD dataset and 99.91% in the CIC-IDS2017 dataset.
In this paper, we consider the Cauchy problem of a compressible Navier–Stokes system of Eills-type non-Newtonian fluids. We investigate the time decay properties of classical solutions for the ...compressible non-Newtonian fluid equations. More specifically, we construct a new linearized system in terms of a combination of the solutions, and then we investigate the long-time behavior of the Cauchy problem for the three-dimensional isentropic compressible Eills-type non-Newtonian fluids with an initial perturbation.
Osteocytes, cells ensconced within mineralized bone matrix, are the primary skeletal mechanosensors. Osteocytes sense mechanical cues by changes in fluid flow shear stress (FFSS) across their ...dendritic projections. Loading-induced reductions of osteocytic Sclerostin (encoded by Sost) expression stimulates new bone formation. However, the molecular steps linking mechanotransduction and Sost suppression remain unknown. Here, we report that class IIa histone deacetylases (HDAC4 and HDAC5) are required for loading-induced Sost suppression and bone formation. FFSS signaling drives class IIa HDAC nuclear translocation through a signaling pathway involving direct HDAC5 tyrosine 642 phosphorylation by focal adhesion kinase (FAK), a HDAC5 post-translational modification that controls its subcellular localization. Osteocyte cell adhesion supports FAK tyrosine phosphorylation, and FFSS triggers FAK dephosphorylation. Pharmacologic FAK catalytic inhibition reduces Sost mRNA expression in vitro and in vivo. These studies demonstrate a role for HDAC5 as a transducer of matrix-derived cues to regulate cell type-specific gene expression.
Purpose of Review
The purpose of this review is to discuss the molecular mechanisms involved in osteocyte dendrite formation, summarize the similarities between osteocytic and neuronal projections, ...and highlight the importance of osteocyte dendrite maintenance in human skeletal disease.
Recent Findings
It is suggested that there is a causal relationship between the loss of osteocyte dendrites and the increased osteocyte apoptosis during conditions including aging, microdamage, and skeletal disease. A few mechanisms are proposed to control dendrite formation and outgrowth, such as via the regulation of actin polymerization dynamics.
Summary
This review addresses the impact of osteocyte dendrites in bone health and disease. Recent advances in multi-omics, in vivo and in vitro models, and microscopy-based imaging have provided novel approaches to reveal the underlying mechanisms that regulate dendrite development. Future therapeutic approaches are needed to target the process of osteocyte dendrite formation.
Purpose of Review
The purpose of this review is to summarize the different roles of the transcription factor SP7 in regulating bone formation and remodeling, discuss current studies in investigating ...the causal relationship between SP7 mutations and human skeletal disease, and highlight potential therapeutic treatments that targeting SP7 and the gene networks that it controls.
Recent Findings
Cell-type and stage-specific functions of SP7 have been identified during bone formation and remodeling. Normal bone development regulated by SP7 is strongly associated with human bone health. Dysfunction of SP7 results in common or rare skeletal diseases, including osteoporosis and osteogenesis imperfecta with different inheritance patterns. SP7-associated signaling pathways, SP7-dependent target genes, and epigenetic regulations of SP7 serve as new therapeutic targets in the treatment of skeletal disorders.
Summary
This review addresses the importance of SP7-regulated bone development in studying bone health and skeletal disease. Recent advances in whole genome and exome sequencing, GWAS, multi-omics, and CRISPR-mediated activation and inhibition have provided the approaches to investigate the gene-regulatory networks controlled by SP7 in bone and the therapeutic targets to treat skeletal disease.
It is well-known that the Cauchy problem of the compressible liquid crystals flow admits a unique global-in-time solution, belonging to C0(R0+,Hl(R3)) with l⩾3; moreover the lower-order or ...higher-order derivative of solution enjoys the same decay-in-time rate as well as the linear solution (i.e., the solution of the corresponding linear problem). In this paper we further prove that highest-order derivative of the unique solution also enjoys the same decay-in-time rate as well as the linear solution by developing new analytical skills. In other words, the optimal decay rate for the highest-order derivative of solution can be also obtained.
Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during "osteocytogenesis" is poorly understood. Here we ...show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites. Profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates defects in osteocyte maturation in the absence of Sp7. Sp7-dependent osteocyte gene networks are associated with human skeletal diseases. Moreover, humans with a SP7
mutation show defective osteocyte morphology. Sp7-dependent genes that mark osteocytes are enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. These findings reveal a role for Sp7 and its target gene Osteocrin in osteocytogenesis, revealing that pathways that control osteocyte development influence human bone diseases.
Bone cells must constantly respond to hormonal and mechanical cues to change gene expression programs. Of the myriad of epigenomic mechanisms used by cells to dynamically alter cell type-specific ...gene expression, histone acetylation and deacetylation has received intense focus over the past two decades. Histone deacetylases (HDACs) represent a large family of proteins with a conserved deacetylase domain first described to deacetylate lysine residues on histone tails. It is now appreciated that multiple classes of HDACs exist, some of which are clearly misnamed in that acetylated lysine residues on histone tails is not the major function of their deacetylase domain. Here, we will review the roles of proteins bearing deacetylase domains in bone cells, focusing on current genetic evidence for each individual HDAC gene. While class I HDACs are nuclear proteins whose primary role is to deacetylate histones, class IIa and class III HDACs serve other important cellular functions. Detailed knowledge of the roles of individual HDACs in bone development and remodeling will set the stage for future efforts to specifically target individual HDAC family members in the treatment of skeletal diseases such as osteoporosis.
•Our cells bear three main classes of histone deacetylases (HDACs).•Class I HDACs deacetylate histones and regulate chromatin structure.•Class IIa HDACs shuttle between the cytoplasm and the nucleus.•Class III HDACs are NAD+-dependent Sirtuin deacetylases.•Multiple roles of HDACs in skeletal biology are reviewed here.
The amniote phallus and limbs differ dramatically in their morphologies but share patterns of signaling and gene expression in early development. Thus far, the extent to which genital and limb ...transcriptional networks also share cis-regulatory elements has remained unexplored. We show that many limb enhancers are retained in snake genomes, suggesting that these elements may function in non-limb tissues. Consistent with this, our analysis of cis-regulatory activity in mice and Anolis lizards reveals that patterns of enhancer activity in embryonic limbs and genitalia overlap heavily. In mice, deletion of HLEB, an enhancer of Tbx4, produces defects in hindlimbs and genitalia, establishing the importance of this limb-genital enhancer for development of these different appendages. Further analyses demonstrate that the HLEB of snakes has lost hindlimb enhancer function while retaining genital activity. Our findings identify roles for Tbx4 in genital development and highlight deep similarities in cis-regulatory activity between limbs and genitalia.
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•Many amniote limb enhancers are retained in snake genomes•An overlapping set of enhancers is active during mouse limb and phallus development•The Tbx4 HLEB enhancer functions during hindlimb and phallus formation in mice•Snake HLEB has lost hindlimb enhancer activity but retains genitalia function
Amniote limbs and phallus have very different morphologies, but Infante et al. show, in mouse and Anolis lizards, that these structures share many enhancers during development. One example, shared enhancer element, controls mouse hindlimb and genitalia development and is conserved in snakes because of its function in genitalia.
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