In patients who were treated with exogenous BMP-2 to repair bone fractures or defects, the levels of the inflammatory cytokines such as TNF-α and IL-1β in sera are significantly elevated, which may affect the outcome of bone regeneration. Mitogen-activated protein kinase (MAPK) cascades such as extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase 1/2 (JNK1/2) have a crucial role in osteogenic differentiation and are activated by both BMP-2 and TNF-α/IL-1β. However, previous studies suggested that the effects of BMP-2 and TNF-α/IL-1β in osteoblastic differentiation are opposite. Here, we investigated the exact role of MAPKs in a BMP-2 and TNF-α/IL-1β co-existed condition. Treatment with TNF-α/IL-1β inhibited BMP-2-induced alkaline phosphatase activity, calcium deposition, osteogenic transcriptional factor Runx2, and the expression of osteogenic markers in C2C12 and MC3T3-E1 cells. This inhibitory effect was independent of the canonical BMP/Smad pathway, suggesting the presence of an alternate regulatory pathway for BMP-2-induced Runx2 activity and subsequent osteoblastic differentiation. We then confirmed that BMP-2, TNF-α, and IL-1β alone can activate p38, ERK1/2, and JNK1/2, respectively. However, only inhibition of p38 and ERK1/2 signaling were required to modulate BMP-2-induced Runx2 expression. Finally, we determined that TNF-α/IL-1β decreased BMP-2-induced Runx2 expression through the activation of p38 and ERK1/2 signaling. Furthermore, strong activation of p38 and ERK1/2 signaling by transfection with CA-MKK3 or CA-MEK1 inhibited BMP-2-induced Runx2 expression and osteoblastic differentiation in C2C12 and MC3T3-E1 cells. Based on these results, we conclude that TNF-α/IL-1β- and BMP-2-activated p38 and ERK1/2 signaling have opposing roles that converge on Runx2 to regulate osteoblastic differentiation. The elucidation of these mechanisms may hasten the development of new strategies and improve the osteoinductive efficacy of BMP-2 in the clinic to enhance osteoblastic differentiation and bone formation.

This study aims to investigate the trends in prevalence, awareness, treatment and control of hypertension among rural residents aged 35-74 years in northern China during the country's rapid economic development from 1991 to 2011. Two surveys, conducted in 1991 and 2011, included 2196 and 1939 participants aged 35-74 years from same villages in Ji County, Tianjin of China, respectively. The prevalence of hypertension, adjusted by age and gender using the world standard population in 2000, increased 30% (39.9% vs 51.7%) between 1991 and 2011. The increase was greatest (68%) in women aged 35-44 years. Meanwhile, the prevalence of stage II hypertension increased by 75% overall, with a 4-fold increase in men aged 45-54 years. Although the awareness, treatment and control of hypertension increased significantly during the same period, they remained unacceptably poor. In conclusion, the community-based surveys showed that the prevalence of hypertension in rural residents of northern China aged 35-74 years increased rapidly over the past 20 years, and most dramatically in young women. Efforts in the primary prevention of hypertension, particularly for young women, and promoting education for hypertension awareness, treatment and control are of paramount importance in rural China.

A tunneling nanotube (TNT) is a newly discovered structure involved in cell–cell communication and is found in various types of cells. Here we identify S100A4 as an extracellular molecule and describe its role in attracting the growth direction of TNTs. Together with its putative receptor, receptor for advanced glycation end product, we demonstrate their involvement in TNT direction guidance. Our results further suggest a mechanism for direction guidance of TNTs. In TNT-initiating cells, p53 activates caspase-3, which leads to S100A4 cleavage and its subsequent decrease in cellular concentration. The decrease in cellular S100A4 induces the formation of a gradient of S100A4, from a low concentration in initiating cells toward a high concentration in target cells. This concentration gradient of S100A4 induces direction guidance for TNTs.

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The cellular mechanisms underlying intrinsic epileptogenesis in human hypothalamic hamartoma (HH) are unknown. We previously reported that HH tissue is composed predominantly of GABAergic neurons, but how GABAergic-neuron-rich HH tissue is intrinsically epileptogenic is unclear. Here, we tested the hypotheses that some HH neurons exhibit immature features and that GABA excites these neurons via activation of GABA A receptors (GABA A Rs). Gramicidinperforated and cell-attached patch-clamp recordings were performed using freshly-dissociated HH neurons to evaluate GABA A R-mediated currents, Cl -equilibrium potentials, and intracellular Clconcentrations. Single-cell RT-PCR and immunocytochemical techniques were used to examine cation-Cl -co-transporter (NKCC1 and KCC2) gene and KCC2 protein expression and molecular markers of maturation. From a total of 93 acutely-dissociated HH neurons from 34 patients, 76% were small (soma: 6-9 μm) and 24% were large (soma: >20 μm) in size. Under gramicidin-perforated patch recording conditions, GABA A R activation depolarized/excited large but hyperpolarized/ inhibited small HH neurons in most cases. Compared to small HH neurons, large HH neurons exhibited more positive Cl -equilibrium potentials, higher intracellular Cl -concentrations, lower KCC2 expression, and an immature phenotype, consistent with GABA A R-mediated excitation. Taken collectively, we provide novel evidence for and mechanistic insights into HH epileptogenicity: GABA A R-mediated excitation.

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BackgroundExperimental autoimmune encephalomyelitis (EAE) models are important vehicles for studying the effect of infectious elements such as Pertussis toxin (PTx) on disease processes related to acute demyelinating encephalomyelitis (ADEM) or multiple sclerosis (MS). PTx has pleotropic effects on the immune system. This study was designed to investigate the effects of PTx administered intracerebroventricularly (icv) in preventing downstream immune cell infiltration and demyelination of the spinal cord.Methods and FindingsEAE was induced in C57BL/6 mice with MOG35–55. PTx icv at seven days post MOG immunization resulted in mitigation of clinical motor symptoms, minimal T cell infiltration, and the marked absence of axonal loss and demyelination of the spinal cord. Integrity of the blood brain barrier was compromised in the brain whereas spinal cord BBB integrity remained intact. PTx icv markedly increased microglia numbers in the brain preventing their migration to the spinal cord. An in vitro transwell study demonstrated that PTx inhibited migration of microglia.ConclusionCentrally administered PTx abrogated migration of microglia in EAE mice, limiting the inflammatory cytokine milieu to the brain and prevented dissemination of demyelination. The effects of PTx icv warrants further investigation and provides an attractive template for further study regarding the pleotropic effects of infectious elements such as PTx in the pathogenesis of autoimmune disorders.

License plate recognition systems are widely used in modern smart cities, such as toll payment systems, parking fee payment systems and residential access control. Such electronic systems are not only convenient for people's daily life, but also provide safe and efficient services for managers. License plate recognition algorithm is a mature but imperfect technology. The traditional location recognition algorithm is easily affected by light, shadow, background complexity or other factors, resulting in the failure to meet the application of real scenes. With the development of deep learning, the license plate recognition algorithm can extract deeper features, thus greatly improving the detection and recognition accuracy. Therefore, this paper discusses the application of deep learning in license plate recognition, and the main work is as follows: 1) Introduce the most advanced algorithms from the three main technical difficulties: license plate skew, image noise and license plate blur; 2) According to the process, the deep learning algorithms are classified into direct detection algorithms and indirect detection algorithms, and the advantages and disadvantages of the current license plate detection algorithms and character recognition algorithms are analyzed; 3) The differences in data sets, workstation, accuracy and time of different license plate recognition systems are compared; 4) Compare and illustrate the existing public license plate datasets according to the number of pictures, resolution and environmental complexity, and make a prospect for the future research direction of license plate recognition. INDEX TERMS Image processing, image analysis, image classification, license plate recognition, deep learning.