Physiological Notch Signaling Maintains Bone Homeostasis via RBPjk and Hey Upstream of NFATc1

Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1-mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo

Single Nucleotide Polymorphisms of Toll-Like Receptor 4 Decrease the Risk of Development of Hepatocellular Carcinoma

BACKGROUND: Toll-like receptor 4 (TLR4) is a key innate immunity receptor that initiates an inflammatory response. Growing evidence suggests that mutation of TLR4 gene may play a role in the development of cancers. This study aimed to investigate the temporal relationship of single nucleotide polymorphisms of TLR4 and the risk of hepatocellular carcinoma, a single center-based case-control study was conducted. METHODS: A systematic genetic analysis of sequence variants of TLR4 by evaluating ten single-nucleotide polymorphisms was performed from 216 hepatocellular carcinoma cases and 228 controls. RESULTS: Six single nucleotide polymorphisms of the TLR4 in the 5'-untranslated region and intron were associated with risk of hepatocellular carcinoma. Individuals carrying the heterozygous genotypes for the rs10759930, rs2737190, rs10116253, rs1927914, rs12377632 and rs1927911 had significantly decreased risk of hepatocellular carcinoma (adjusted odds ratio [OR], from 0.527 to 0.578, P<0.01) comparing with those carrying wild-type homozygous genotypes. In haplotype analysis, one haplotype (GCCCTTAG) of TLR4 was associated significantly with decrease of the occurrence of hepatocellular carcinoma (OR, 0.556, 95% confidence interval [CI], 0.407-0.758, P = 0.000). CONCLUSIONS: Collectively, these results suggested that the risk of hepatocellular carcinoma was associated with TLR4 sequence variation. TLR4 single nucleotide polymorphisms may play an important protective role in the development of hepatocellular carcinoma

Spatial inequity in access to healthcare facilities at a county level in a developing country: a case study of Deqing County, Zhejiang, China

Background The inequities in healthcare services between regions, urban and rural, age groups and diverse income groups have been growing rapidly in China. Equal access to basic medical and healthcare services has been recognized as “a basic right of the people” by Chinese government. Spatial accessibility to healthcare facilities has received huge attention in Chinese case studies but been less studied particularly at a county level due to limited availability of high-resolution spatial data. This study is focused on measuring spatial accessibility to healthcare facilities in Deqing County. The spatial inequity between the urban (town) and rural is assessed and three scenarios are designed and built to examine which scenario is instrumental for better reducing the spatial inequity. Methods This study utilizes highway network data, Digital Elevation Model (DEM), location of hospitals and clinics, 2010 census data at the finest level – village committee, residential building footprint and building height. Areal weighting method is used to disaggregate population data from village committee level to residential building cell level. Least cost path analysis is applied to calculate the travel time from each building cell to its closest healthcare facility. Then an integral accessibility will be calculated through weighting the travel time to the closest facility between three levels. The spatial inequity in healthcare accessibility between the town and rural areas is examined based on the coverages of areas and populations. The same method is used to compare three scenarios aimed at reducing such spatial inequity – relocation of hospitals, updates of weighting values, and the combination of both. Results 50.03 % of residents can reach a county hospital within 15 min by driving, 95.77 % and 100 % within 30 and 60 min respectively. 55.14 % of residents can reach a town hospital within 5 min, 98.04 % and 100 % within 15 and 30 min respectively. 57.86 % of residential building areas can reach a village clinic within 5 min, 92.65 % and 99.22 % within 10 and 15 min. After weighting the travel time between the three-level facilities, 30.87 % of residents can reach a facility within 5 min, 80.46 %% and 99.88 % within 15 and 30 min respectively. Conclusions The healthcare accessibility pattern of Deqing County has exhibited spatial inequity between the town and rural areas, with the best accessibility in the capital of the county and poorest in the West of the county. There is a high negative correlation between population ageing and healthcare accessibility. Allocation of more advanced medical and healthcare equipment and highly skillful doctors and nurses to village clinics will be an efficient means of reducing the spatial inequity and further consolidating the national medical security system. GIS (Geographical Information Systems) methods have proven successful method of providing quantitative evidence for policy analysis although the data sets and methods could be further improved

A temporally cyclic growth model of urban spatial morphology in China: evidence from Kunming Metropolis

Rapid urbanization and complexity of political-economic transition in China has brought about continuous and remarkable changes of urban morphology over the past decades, which were driven by a mixture of spatial, social-economic and institutional forces. Understanding such urban morphological evolution requires new mixed evidences and holistic perspectives. In this paper, it is argued that two dominant types of urban growth in China: low-density expansion and high-density infill might be driven by different forces at different stages. To interpret the processes of urban development, two easy-to-understand morphological indicators: expansion-induced investment density index” (EID) and “infill-induced investment density index” (IID) are defined to measure the investment density per unit of developed land and used to compare the morphological changes between different phases in a long period by integrating spatial and socio-economic data. The temporal variation of these indicators suggests a cyclic growth model (CGM), which means the periodic switch between low density expansion and high-density infill. Using Kunming metropolis as a case study, this paper has confirmed that its urban morphological evolution from 1950-2014 was periodically and reciprocally driven by a set of vis-à-vis dualistic dynamics, in which low-density expansion is led by pro-growth infrastructure oriented public investment, while the high-density infill is activated by collective and rational actions of individual enterprises and their economic behaviors. It is concluded that the confirmed CGM model, together with two morphological indicators, offers a new holistic perspective and method to easily and integrally interpret urban morphological evolution and accordingly has potential theoretical implications for reasonably understanding the urbanisation in China

A Review on Flux Decline Control Strategies in Pressure-Driven Membrane Processes

Concentration polarization(CP) and membrane fouling are two major drawbacks for pressure-driven membrane filtration processes (PDMPs) because they cause severe flux decline, which requires effective control strategies. Many articles have proposed the diverse potential applications of various Control strategies in reducing CP and membrane fouling. This paper reviews various mechanisms and influencing factors on flux decline, as well as their control strategies in PDMPs. Nine effective control strategies are summarized, generalized, and compared in this paper. On the basis of their functions and influences, they can be also classified as the following: (1) modification: pretreatment of feed, modification of feed characteristics, selection and modification of membrane; (2) design: shear-enhanced filtration modules, applied field enhancement and CP drawer; (3) operation: optimization of operating parameters, hydraulic flushing and two-phase flow. Then, the general and practical guidelines are given. On the basis of this review, future research perspectives related to flux decline control strategies are proposed.</p

Threshold flux for shear-enhanced nanofiltration: Experimental observation in dairy wastewater treatment

High and stable permeate flux can be obtained with shear-enhanced nanofiltration (NF) in model dairy wastewater treatment. In order to sustain such flux in long-term operation, critical fouling conditions should be studied and an optimum flux needs to be selected. Based on resistance-in-series and particle deposition models, a threshold flux was proposed to make a distinction between low and high fouling rates. At and below threshold flux, adsorption and reversible fouling are almost stable, and the fouling rate is low and nearly constant, irrespective of permeate flux; while above it, flux declines markedly with increasing flux mainly due to incremental reversible fouling. Flux remained quite stable with slight fouling (20% for undiluted milk). This threshold flux is determined by pressure stepping experiments as the point above which flux ceases to increase linearly with transmembrane pressure (TMP). Each flux step only needs to last a few minutes to ensure reversible fouling stabilization at high shear rate. In shear-enhanced filtration, these threshold fluxes are, of course, larger than critical ones, and more compatible with industrial expectations. It is concluded that the separation performance of membranes should be evaluated at or below threshold flux to eliminate the effect of fouling, and the effect of feed characteristic on membrane fouling should be investigated above threshold flux, while operating at threshold flux is recommended for industrial long-term operation. (C) 2012 Elsevier B.V. All rights reserved

Membrane fouling in photocatalytic membrane reactors (PMRs) for water and wastewater treatment: A critical review

Photocatalytic membrane reactors (PMRs), as an efficient, low cost and environmentally friendly treatment technology, have shown a great potential to become a &quot;zero&quot; waste process in water/wastewater industry. At present, the main technical barrier to its commercialization is membrane fouling, which usually increases operating costs and decreases treatment efficiency.</p

Fouling behavior of dairy wastewater treatment by nanofiltration under shear-enhanced extreme hydraulic conditions

High pressures can be employed in shear-enhanced nanofiltration (NF) process in order to obtain large permeate flux, and under this extreme hydraulic condition, membrane fouling behavior may be different and need to be investigated. In this study, a rotating disk laboratory module capable of very high shear rates and pressure was used to treat model dairy wastewater with a NF270 membrane. The presence of lipids had a negligible effect on flux profile and permeate quality, although it slightly increased adsorption fouling. Higher shear rates decreased concentration polarization and produced higher permeate fluxes with lower permeability loss. After the flux remained stable for several hours, adsorption fouling and subsequent cake layer formation occurred. The surface adsorption of small foulants such as lactose and calcium ions caused a slow flux decline, and in the absence of chemical cleaning, it induced cake fouling and severe flux decline. Inorganic ions such as calcium and phosphate engaged with milk proteins in micelles or aggregates, and thus inorganic scaling was negligible and alkaline cleaning could remove most surface fouling. We concluded that, with suitable chemical cleaning, a high and stable flux could be obtained for a long time in dairy wastewater treatment by NF under shear-enhanced extreme hydraulic conditions. (C) 2011 Elsevier B.V. All rights reserved