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This paper examines the impact of higher education on China’s manufacturing industry performance from the national and regional levels on fixed effects model. The research shows that the development of higher education has significantly promoted the improvement of China’s manufacturing industry performance. If the development of higher education increases by 1%, the performance of manufacturing industry will increase by 0.239%. Through the internal mechanism test, it is found that higher education can improve the performance of manufacturing industry by increasing the R&D projects, new product projects and enterprise invention patents. Further research shows that there is a double threshold nonlinear relationship between higher education and manufacturing industry performance with per capita GDP and government financial science and technology expenditure as threshold variables based on threshold model.

The objective of the present study was to investigate the effect of reused brine and fresh salt brine on nitrites and biogenic amines production in low-salt Paocai during fermentation, with insights into the impact of initial microbial loading and acidification. By monitoring the changes in microbial counts, physicochemical properties as well as the production of nitrites, biogenic amines and precursor amino acid nitrogen (AAN) in Paocai fermented with reused brine (RB), microorganism-reduced reused brine (MRRB), fresh salt brine (SB) and acidified fresh salt brine (ASB), the results showed that RB promoted the growth of lactic acid bacteria (LAB) and yeasts, causing a rapid consumption of reducing sugar. MRRB and RB inhibited the undesirable enterobacteria, while SB and ASB failed. Among the treatments, RB achieved highest AAN contents and lowest contents of nitrites (1.10 mg/kg), histamine (0.29 mg/kg), tyramine (0.79 mg/kg) and cadaverine (not detected) after fermentation. Comparing SB with ASB, it was found that initial acidification of salt brine eliminated cadaverine and reduced histamine contents by 33.93%. These results suggested that the initial microbial loading and acidification of brine could reduce nitrites and biogenic amines production in Paocai during fermentation, which might provide guidance for production of fermented vegetable with higher safety.

We, along with others, have shown previously that P21-activated kinase 1 (Pak1) plays a pivotal role in gastric cancer progression and metastasis. However, whether Pak1 controls gastric cancer metastasis by regulating microRNAs (miRNAs) has never been explored. Here, we report a novel mechanism of Pak1 in tumor metastasis. A detailed examination revealed that Pak1 interacts with and phosphorylates the serine 62 residue of ATF2 and then blocks its translocation into the nucleus. We also confirmed that ATF2 binds to the promoter of miR-132 and tightly regulates its transcription, thus explaining the regulatory mechanism of miR-132 by Pak1. miR-132 also significantly reduced cell adhesion, migration, and invasion of gastric cancer cells in vitro and significantly prevented tumor metastasis in vivo. miR-132 specifically inhibited hematogenous metastasis, but not lymph node or implantation metastases. In order to further delineate the effects of the Pak1/ATF2/miR-132 cascade on gastric cancer progression, we identified several targets of miR-132 using a bioinformatics TargetScan algorithm. Notably, miR-132 reduced the expression of CD44 and fibronectin1 (FN1), and such inhibition enabled lymphocytes to home in on gastric cancer cells and induce tumor apoptosis. Taken together, our studies establish a novel cell-signaling pathway and open new possibilities for therapeutic intervention of gastric cancer. Keywords: p21-activated kinase 1, activating transcription factor-2, miR-132, hematogenous metastasis

A growing number of reports have demonstrated that the widely-used herbicide Atrazine (ATR) can cause injury to dopamine (DA) neurons, but the exact mechanism remains unclear. In this study, we examined the effects of lactational ATR exposure in Sprague-Dawley rats on dopaminergic neuron health later in life. Compared with control rats, rats exposed to ATR during a critical period of neural development showed decreased striatal DA content and increased rates of DA turnover. The expression of Monoamine oxidase (MAO), which is associated with DA degradation, was up-regulated, and the expression of Vesicular Monoamine Transporter 2 (VMAT2), which is associated with DA transport, was down-regulated. The expression of transcription factor Nuclear Receptor Related Factor 1 (Nurr1), which is associated with DA neuron development, was down-regulated. Increased age (6-12 months old) increased the statistical significance of the differences of the above indicators in the ATR-treated rats compared to the control rats (P

// Zhenguo Cheng 1 , Funan Liu 2 , Hongyan Zhang 1 , Xiaodong Li 1 , Yanshu Li 1 , Jiabin Li 1 , Furong Liu 1 , Yu Cao 1 , Liu Cao 1 , Feng Li 1 1 Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China 2 Department of Surgical Oncology, The first Hospital of China Medical University, Shenyang 110001, China Correspondence to: Feng Li, email: fli@mail.cmu.edu.cn Keywords: gastric cancer, metastasis, miR-135a, FAK, p53 Received: September 27, 2016 Accepted: March 01, 2017 Published: March 10, 2017 ABSTRACT Tumor metastasis has been the major cause of recurrence and death in patients with gastric cancer. Here, we find miR-135a has a decreased expression in the metastatic cell lines compared with its parental cell lines by analyzing microRNA array. Further results show that miR-135a is downregulated in the majority of human gastric cancer tissues and cell lines. Decreased expression of miR-135a is associated with TNM stage and poor survival. Besides, regaining miR-135a in gastric cancer cells obviously inhibits tumor growth, migration, invasion and angiogenesis by targeting focal adhesion kinase (FAK) pathway. Bioinformatics analysis and molecular experiments further prove that miR-135a is a novel downstream gene of tumor suppressor p53. Blocking FAK with its inhibitor can also enhance miR-135a expression through inducing p53. In summary, this study reveals the expression and function of miR-135a in gastric cancer and uncovers a novel regulatory mechanism of miR-135a.

Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine; ATR) is widely used as an herbicide, and its accumulation in the environment is a health risk to humans; for instance, it has been shown to cause dopaminergic neurotoxicity. MicroRNAs (miRNAs) are endogenous small RNAs that regulate gene expression in diverse physiological contexts; however, the extent of their involvement in the development of Parkinson's disease (PD) is not known. In this study, we carried out miRNA profiling of peripheral blood and brain tissue in a rat model of PD in order to identify factors that mediate PD pathogenesis. The miRNAmiR-7 is known to cause the downregulation of α-synuclein (α-syn), which is linked to the neuropathology of PD. Here we found that miR-7 was upregulated in brain tissue but downregulated in peripheral blood of rats with ATR-induced PD. We also found that miR-7 regulates the expression of brain-derived neurotrophic factor (BDNF) through an auto regulatory mechanism. These findings indicate that miRNA-7 regulates the BDNF/α-syn axis in the early stages of PD and can serve as a biomarker or therapeutic target for disease treatment.

Reduction of biogenic amine and nitrites is of practical importance for promoting the safety of fermented vegetable. The aim of this study was to analyze the efficacy of package types in reducing biogenic amine and nitrite levels of Paocai during storage. And the related parameters including microbial growth, pH and generation of amino acid nitrogen (AAN) were also evaluated. The results showed that when compared with aerobic package (AP) and NaCl solution package (NP), vacuum package (VP) reduced the counts of lactic acid bacteria and yeasts to 6.98 and 1.21 LogCFU/g, respectively. The pH of Paocai was not significantly different among treatments. VP was more effective than AP and NP in suppressing the accumulation of histamine, tyramine and putrescine in Paocai, as evidenced by the contents that were 0.19, 0.15 and 0.43 mg/kg after storage, respectively. Additionally, VP and AP prevented cadaverine production throughout the storage while NP accelerated its production. For Paocai in VP and NP, the AAN content rose by 66.67% and 33.33%, respectively, while AAN in AP increased by 133.33% after storage. Meanwhile, nitrite accumulation in Paocai was mitigated by VP, as shown by nitrite content that were 56.04% and 36.31% lower than those in AP and NP groups, respectively, at the end of storage. Therefore, compared with conventional NP, VP was the most effective in suppressing the production of biogenic amines, nitrite and AAN, while AP accelerated the accumulation of these nitrogenous compounds, possibly implicated the application of VP to produce fermented vegetable with higher safety property.

Density functional theory calculations were performed to examine the interaction between large aromatic molecules such as benzene and phenol and stanene nanosheets. Before we consider the adsorption process, it is very necessary to optimize the atomic structure of the bare stanene and non-adsorbed benzene and phenol molecules. Our results showed that the benzene and phenol molecules are weakly physisorbed on the surface of stanene due to their lower binding energies at the surface. Phenol adsorption strength on the surface of stanene was found to be much stronger than the adsorption of benzene. Besides, the adsorption of benzene and phenol cannot make any considerable change in the electronic properties of stanene sheets. The electron density difference calculations also indicated that the electron density moves from the benzene molecule to the surface of stanene. The change densities were largely accumulated over the stanene sheet. Thus, stanene nanosheet can be suggested as a moderate host material for sensing benzene and phenol molecules.

This study analyses the implementation of the Forest Land Protection Act (FLPA) program in Georgia, USA and assesses the effectiveness of the program in forest conservation and sustainability. The program extended property tax relief to corporate and other large private forest landowners, improved uniformity in timberland taxation, and leveled the playing field for private forest landowners in the state. We examine the effectiveness of the program in conserving forests through participation rate, average size and site productivity of enrolled forestland, and trends in forest area. An econometric model is created to investigate the major factors affecting participation of the program. We found that the FLPA program is effective in attracting larger forest tracts, suggesting a positive contribution of the program to forest conservation and sustainability. It is also attractive to eligible forest lands that are under pressure from recreational uses. However, the effectiveness of the program is limited in attracting higher-productivity forest lands and lands having potential development uses.

ObjectivesA significant number of researches have evidenced that occupational lead (Pb) exposure increased risks of cardiovascular disease. However, evidences about the potential effects of Pb on the cardiac conduction system are sparse and inconclusive. Besides, ryanodine receptors (RyRs) induced dysfunction of cardiac excitation contraction coupling which is considered to be one of the mechanisms in cardiovascular diseases. Therefore, we examined the association between occupational Pb exposure and ECG conduction abnormalities, as well as RyRs in Pb-induced ECG abnormalities.MethodsWe investigated 529 Pb smelter workers, and measured blood lead (BPb), zinc protoporphyrin (ZPP), ECG outcomes and RyR expression levels. Based on BPb levels, the workers were divided into three groups: the BPb not elevated group, the BPb elevated group and the Pb poisoning group. Descriptive and multivariable analyses were performed.ResultsCompared with the BPb not elevated group, the Pb poisoning group had a higher incidence of high QRS voltage, and a lower level of RyR1 gene expression (pConclusionsOur study provided evidences that occupational exposure to Pb may be associated with worse ECG outcomes (high QRS voltage), which might be related to decreased levels of RyR1.

A large number of studies have evidenced that developmental neurotoxicity induced by lead (Pb) is related to oxidative injury. Furthermore, recent studies have found that developmental Pb exposure can induce neurodegeneration in old age. Because of the common presence of Pb in the environment, humans are exposed to this metal throughout their lifetime. However, few studies have explored the changes in lifespan profiles of neurotoxicity, as well as oxidative stress following lifetime Pb exposure. In the present study, rats were exposed to lead acetate from their embryonic stage to old age. Dynamic changes in neurodegeneration, oxidative stress, and endoplasmic reticulum (ER) stress in the brains at postnatal week 3 (PNW3, weaning), 41 weeks (PNW41, adulthood) and 70 weeks (PNW70, old age) were investigated. Pb exposure resulted in neurodegeneration with decreased neuronal densities and brain volumes in PNW3 and PNW70 rats; however, no significant changes occurred in PNW41 rats based on thionine stain analysis and magnetic resonance imaging (MRI) scans. Expression of the ER stress protein glucose-regulated protein 78 (GRP78) increased in Pb-exposed rats, which was associated with high levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in rat brains after Pb exposure in PNW3 and PNW70 rats. Our findings suggested that lifetime Pb exposure induced neurodegenerative injuries that began to occur in infancy, were relieved in adulthood, but intensified in old age. The critical periods for prevention or intervention in neurodegenerative diseases induced by Pb exposure occurred in early life.

Accumulating evidence suggests that high-fat diet (HFD) induced metabolic disorders are associated with dysbiosis of gut microbiota. However, no study has explored the effect of HFD on the gastric microbiota. This study established the HFD animal model to determine the impact of HFD on the gastric microbiota and its relationship with the alterations of gut microbiota. A total of 40 male C57BL/6 mice were randomly allocated to receive a standard chow diet (CD) or HFD for 12 weeks (12CD group and 12HFD group) and 24 weeks (24CD group and 24HFD group) (n = 10 mice per group). Body weight and length were measured and Lee’s index was calculated at different time points. The insulin sensitivity and serum levels of metabolic parameters including blood glucose, insulin and lipid were also evaluated. The gastric mucosa and fecal microbiota of mice were characterized by 16S rRNA gene sequencing. The body weight was much heavier and the Lee’s index was higher in 24HFD group than 12HFD. The insulin resistance and serum level of lipid were increased in 24HFD group compared to 12HFD, indicating the aggravation of metabolic disorders as HFD went on. 16S rRNA gene sequencing showed dysbiosis of gastric microbiota with decreased community diversity while no significant alteration in gut microbiota after 12 weeks of HFD. The phyla Firmicutes and Proteobacteria tended to increase whereas Bacteroidetes and Verrucomicrobia decrease in the gastric microbiota of 12HFD mice compared to 12CD. Moreover, a remarkable reduction of bacteria especially Akkermansia muciniphila, which has beneficial effects on host metabolism, was observed firstly in the stomach of 12HFD group and then in the gut of 24HFD group, indicating the earlier alterations of microbiota in stomach than gut after HFD. We also found structural segregation of microbiota in the stomach as well as gut between 12HFD and 24HFD group, which is accompanied by the aggregation of metabolic disorders. These data suggest that HFD affects not only gut microbiota but also gastric microbiota and the disruption of microbial ecosystem in the digestive tract may play a part in the development and progression of metabolic diseases although molecular mechanism requires further investigation.

Introduction A large number of studies have shown that the developmental neurotoxicity induced by lead is related to oxidative injury, meanwhile, oxidative stress is among the most common mechanisms of neurodegeneration. However, few studies have explored the role of oxidative stress in age-related cognitive impairment caused by prolonged lead exposure and oxidative stress. Methods In the present study, rats were exposed to low-level lead from the embryonic stage to old age. Dynamic changes in neurodegeneration, endoplasmic reticulum (ER) stress, and oxidative stress in brains during postnatal weeks 3, 41 and 70 (PNW3, PNW41 and PNW70, respectively) were investigated. Results Lead exposure resulted in neurodegeneration in PNW70 rats based on magnetic resonance imaging (MRI) scans and thionine stain analysis. Amyloid precursor protein (APP) and tau mRNA expression in PNW41 and PNW70 brains increased in a time- and dose-dependent manner. APP and Tau protein levels significantly increased with lead exposure at PNW3 and PNW70. Mechanistically, the expression of the ER stress protein glucose-regulated protein 78 (GRP78) was higher in the presence of lead than in normal controls, which was associated with high levels of 8-hydroxy-2’-deoxyguanosine (8-OHdG) in brain tissues after lead exposure in PNW3 and PNW70, their changes were like as APP and tau protein that were a u- or j-shaped curve with time of lead exposure. Conclusion Our findings suggest that the neurodegenerative injuries induced by lead exposure may be mediated by ER and oxidative stresses, and there is a critical period for prevention or intervention AD in early life and later life, however middle-aged people at the latent stage of neurodegenerative process should not be ignored.

Atrazine (ATR, 2-chloro-4-ethylamino-6-isopropylamino-s-triazine) is used worldwide as a herbicide, and its presence in the environment has resulted in documented human exposure. A lack of strong evidence for genetic heritability of idiopathic Parkinson's disease has focused attention on environmental toxicants in the disease etiology, particularly agrichemicals. Parkinson's disease is associated with advanced age and is characterized by the degeneration of dopaminergic neurons, but it is unclear whether specific neuronal damage could result from insults during development. The juvenile period is particularly vulnerable to environmental agent, therefore, we evaluated the effects of a 28-day exposure to ATR on the dopaminergic system in pubertal rats. Sprague-Dawley rats were treated orally with ATR at 50, 100, and 200 mg/kg bw, daily from postnatal days 27 to 54. In this study, we examined the hypothesis that pubertal exposure to ATR would disrupt the development of the nigrostriatal dopamine (DA) system. The content of DA and levodopa (L-DA) were examined in striatum samples by HPLC-FL, and the mRNA and protein expression of tyrosine hydroxylase, orphan nuclear hormone receptor (Nurr1), Nurr1 interacting protein (NuIP), and cyclin-dependent kinase inhibitors of the CipKip family (p57kip2) were examined in samples of the nigrostriatum by use of fluorescence Real-Time quantitative polymerase chain reaction (PCR). Exposure of juvenile rats to the high dose of ATR led to reduced levels of DA and L-DA, genes expression of NuIP, Nurr1, and p57kip2 in animals.

Estrogen receptor α (ERα) is a key transcriptional factor in the proliferation and differentiation in mammary epithelia and has been determined to be an important predictor of breast cancer prognosis and therapeutic target. Meanwhile, diverse transcriptional co-regulators of ERα play crucial and complicated roles in breast cancer progression. Mediator of DNA damage checkpoint 1 (MDC1) has been identified as a critical upstream mediator in the cellular response to DNA damage, however, some non-DNA damage responsive functions of MDC1 haven't been fully defined. In this study, we have identified MDC1 as a co-activator of ERα in breast cancer cells and demonstrated that MDC1 associates with ERα. MDC1 was also recruited to estrogen response element (ERE) of ERα target gene. Knockdown of MDC1 reduced the transcription of the endogenous ERα target genes, including p21. MDC1 depletion led to the promotion of breast cancer progression, and the expression of MDC1 is lower in breast cancer. Taken together, these results suggested that MDC1 was involved in the enhancement of ERα-mediated transactivation in breast cancer cells. This positive regulation by MDC1 might contribute to the suppression of breast cancer progression by acting as a barrier of positive to negative ERα function transformation.

Mediator of DNA damage checkpoint protein 1 (MDC1) is essential for DNA damage response. However, the role of MDC1 in modulating gene transcription independently of DNA damage and the underlying mechanisms have not been fully defined. Androgen receptor (AR) is the central signaling pathway in prostate cancer (PCa) and its target genes are involved in both promotion and suppression of PCa. Here, we functionally identified MDC1 as a co-activator of AR. We demonstrate that MDC1 facilitates the association between AR and histone acetyltransferase GCN5, thereby increasing histone H3 acetylation level on cis-regulatory elements of AR target genes. MDC1 knockdown promotes PCa cells growth and migration. Moreover, depletion of MDC1 results in decreased expression of a subset of the endogenous androgen-induced target genes, including cell cycle negative regulator p21 and PCa metastasis inhibitor Vinculin, in AR positive PCa cell lines. Finally, the expression of MDC1 and p21 correlates negatively with aggressive phenotype of clinical PCa. These studies suggest that MDC1 as an epigenetic modifier regulates AR transcriptional activity and MDC1 may function as a tumor suppressor of PCa, and provide new insight into co-factor-AR-signaling pathway mechanism and a better understanding of the function of MDC1 on PCa.

// Yang Li 1, * , Qiang Ke 1, * , Yangguang Shao 1 , Ge Zhu 1 , Yanshu Li 1 , Nanxi Geng 1 , Feng Jin 2 , Feng Li 1 1 Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China 2 Department of Breast Surgery, Department of Surgical Oncology, Research Unit of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China * These authors have contributed equally to this work Correspondence to: Feng Li, e-mail: fli@mail.cmu.edu.cn Keywords: EMT, Breast cancer, GATA1, PAK5, Phosphorylation Received: October 01, 2014 Accepted: December 21, 2014 Published: January 21, 2015 ABSTRACT Epithelial-mesenchymal transition (EMT) is a key process in tumor metastatic cascade that is characterized by the loss of cell-cell junctions, resulting in the acquisition of migratory and invasive properties. E-cadherin is a major component of intercellular junctions and the reduction or loss of its expression is a hallmark of EMT. Transcription factor GATA1 has a critical anti-apoptotic role in breast cancer, but its function for metastasis has not been investigated. Here, we found that GATA1, as a novel E-cadherin repressor, promotes EMT in breast cancer cells. GATA1 binds to E-cadherin promoter, down-regulates E-cadherin expression, disrupts intercellular junction and promotes metastasis of breast cancer cell in vivo . Moreover, GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin , leading to the EMT of breast cancer cells. Our findings provide insights into the novel function of GATA1, contributing to a better understanding of the EMT, indicating that GATA1 and its phosphorylation may play an important role in the metastasis of breast cancer.

This study presents an empirical analysis of the relationship between industrial timberland ownership and financial performance of forest products companies in the United States. Based on the structure-conduct-performance model of the industrial organization theory, we develop and estimate a three-stage least squares model system that links timberland ownership with performance. Our results show that holding timberland improves a forest products company’s profitability and lowers its systematic risk. Still, these benefits cannot overcome the costs induced by institutional arrangements, leading most forest products companies to divest their timberlands.

The herbicide, atrazine (ATR), is used worldwide and its contamination in the environment has resulted in documented human exposure. It has also been shown that ATR results in dopaminergic neurotoxicity, however, few studies have investigated the long-term effects of ATR following in utero exposure. Therefore, we evaluated the effects of ATR exposure in Sprague Dawley rats during gestational on the offspring dopaminergic system development. Pregnant dams were treated with oral ATR at 0, 25, 50 mg/kg/day from gestational day 0 to postnatal day 1. In this study, we examined the hypothesis that ATR could cross the placental barrier and have long-term adverse effects on the synthesis, degradation and reuptake of DA in the brain. For this purpose,we examine the concentration of levodopa (L-DA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in stratum. The mRNA and protein expression of orphan nuclear hormone (Nurr1), tyrosine hydroxylase(TH), vesicular monoaminetransporter 2 (VMAT2), dopamine transporter (DAT), monoamine (MAO), and catechol-O-methyl transferase (COMT) in the midbrain were examined by fluorescence PCR and Western blot when the offspring reached six-month old or one year old .When measured 6 months post-treatment, the level of DA and expression of Nurr1, VMAT2, DAT and TH were reduced in the striatum and Substantia nigra, respectively.

Atrazine (2-chloro-4-ethylamino-6-isopropylamino- s -triazine) is used worldwide as a herbicide, and its presence in the environment has resulted in documented human exposure. Atrazine has been shown to cause dopaminergic neurotoxicity. The juvenile period is particularly vulnerable to environmental agents, but only few studies have investigated the long-term effects of atrazine following exposure during the pubertal development. Therefore, we evaluated the effects of a 41-day exposure to atrazine on the dopaminergic system in rats. Sprague-Dawley rats were treated orally with atrazine at 25 or 50 mg/kg bw, daily from postnatal day 22 to 62. The content of dopamine (DA) was examined in striatum samples by HPLC-FL, and the mRNA and protein expression of tyrosine hydroxylase (TH), orphan nuclear hormone (Nurr1), dopamine transporter (DAT) and vesicular monoaminetransporter 2 (VMAT2) were examined in samples of the ventral mid-brain by use of fluorescence PCR and Western-blot analysis when the rats reached the age of one year. Exposure of juvenile rats to the high dose of atrazine led to reduced levels of DA and mRNA of Nurr1 in one-year-old animals. This study shows that the long-term adverse effects of atrazine on the dopaminergic system have a special relevance after juvenile exposure.

Discerning the modular nature of human diseases through computational approaches calls for diverse data. The finding sites of diseases, like other disease phenotypes, possess rich information in understanding disease genetics. Yet, analysis of the rich knowledge of disease finding sites has not been comprehensively investigated. In this study, we built a large-scale disease organ network (DON) based on 76,561 disease-organ associations (for 37,615 diseases and 3492 organs) extracted from the United Medical Language System (UMLS) Metathesaurus. We investigated how phenotypic organ similarity among diseases in DON reflects disease gene sharing. We constructed a disease genetic network (DGN) using curated disease-gene associations and demonstrated that disease pairs with higher organ similarities not only are more likely to share genes, but also tend to share more genes. Based on community detection algorithm, we showed that phenotypic disease clusters on DON significantly correlated with genetic disease clusters on DGN. We compared DON with a state-of-art disease phenotype network, disease manifestation network (DMN), that we have recently constructed, and demonstrated that DON contains complementary knowledge for disease genetics understanding.

The p21-activated kinases have been implicated in the control of cell cycle progression. However, the biological mechanism underlying the role of p21-activated kinase 4 (PAK4) in cell cycle control remains unknown. Here, by using quantitative RT–PCR and immunoblot analyses, we discovered that over-expression of PAK4 could suppress cyclin-dependent kinase inhibitor 1C (p57Kip2) expression in the MCF-7 human breast cancer cell line, whereas lentiviral vector-mediated small interfering RNA (siRNA) knockdown of PAK4 markedly promoted p57Kip2 expression in MCF-7 cells. Furthermore, PAK4-mediated down-regulation of p57Kip2 was reversed by MG132, a specific proteasome inhibitor. The ubiquitination assay confirmed that the activity of PAK4 attenuated p57Kip2 protein stability through the ubiquitin-proteasome pathway in MCF-7 cells. Moreover, a significant inverse correlation between PAK4 and p57Kip2 protein levels was observed in breast cancer tissues by immunohistochemical analysis. Taken together, our data demonstrate a novel function for PAK4 in regulating the stability of p57Kip2, possibly through the ubiquitin-proteasome pathway, leading to increased proliferation of breast cancer cells. Thus, PAK4 may be used as a potential diagnostic and therapeutic target for human breast cancer. Anat Rec, 296:1561–1567, 2013. © 2013 Wiley Periodicals, Inc.

Lead, a ubiquitous neurotoxicant, can result in learning and memory dysfunction. Long term potentiation in the hippocampus, a potential neural substrate for learning and memory, is thought to be linked to calcium-triggered intracellular events. In this study, laser scanning confocal microscopy was used to examine the effects of Pb(2+) on intracellular and endoplasmic reticulum free calcium concentration ([Ca(2+)](i) and [Ca(2+)](ER)) in cultured neonatal rat hippocampal neurons and their possible antagonism by methionine choline; understanding these effects would help explain the lead-induced cognitive and learning dysfunction and explore efficient safety and relief strategies. The results showed that Pb(2+) increased [Ca(2+)](i) and decreased [Ca(2+)](ER) linearly in a time- and concentration-dependant manner, and Pb(2+) addition after the applying of a ryanodine receptor (RyR) antagonist and an inositol-1,4,5-triphosphate receptor (IP(3)R) antagonist did not increase [Ca(2+)](i). The addition of 10, 20, or 40 mmol/L methionine choline simultaneously with addition of 10 μmol/L Pb(2+) decreased [Ca(2+)](i) in Ca(2+)-free culture medium by 39.0%, 66.0%, and 61.6%, respectively, in a concentration-dependant manner in a certain dose range. Our results suggest that Pb(2+) induces ER calcium release to increase the resting [Ca(2+)](i); and methionine choline inhibit this increase in [Ca(2+)](i).

The relation between lead (Pb) and iron (Fe) becomes increasingly concerned because they are both divalent metals that are absorbed by the same intestinal mechanism, and Pb exposure and Fe deficiency in the developmental brain, as well as Fe overload in the aged brain, can cause cognitive deficits. However, the interaction between Pb exposure and Fe status in the brain has not been established. Therefore, in the current study, we examined the effects of maternal ingestion of Pb in drinking water during gestation and lactation on the Fe status and the expression of divalent metal transporter 1 (DMT1) and ferroportin 1 (FP1) in the brain of offspring. The offspring were followed through old age, with measurements taken at postnatal week 3 (PNW3), 41 (PNW41) and 70 (PNW70). Pb exposure increases the Fe content in the old-aged rats' brain, which might be not subjected to DMT1 mediating, but may be associated with the decrease expression of FP1. Furthermore, the effect of Pb on FP1 expression is regulated at transcriptional and posttranscriptional levels. The perturbation in Fe homeostasis may contribute to the neurotoxicology consequences induced by Pb exposure, and FP1 may play a role in Pb-induced Fe cumulation in the brain.

Sulfate-reducing bacteria (SRB) have been studied extensively in the petroleum industry due to their role in corrosion, but very little is known about sulfur-oxidizing bacteria (SOB), which drive the oxidization of sulfur-compounds produced by the activity of SRB in petroleum reservoirs. Here, we surveyed the community structure, diversity and abundance of SRB and SOB simultaneously based on 16S rRNA, dsrB and soxB gene sequencing, and quantitative PCR analyses, respectively in petroleum reservoirs with different physicochemical properties. Similar to SRB, SOB were found widely inhabiting the analyzed reservoirs with high diversity and different structures. The dominant SRB belonged to the classes Deltaproteobacteria and Clostridia, and included the Desulfotignum, Desulfotomaculum, Desulfovibrio, Desulfobulbus, and Desulfomicrobium genera. The most frequently detected potential SOB were Sulfurimonas, Thiobacillus, Thioclava, Thiohalomonas and Dechloromonas, and belonged to Betaproteobacteria, Alphaproteobacteria, and Epsilonproteobacteria. Among them, Desulfovibrio, Desulfomicrobium, Thioclava, and Sulfurimonas were highly abundant in the low-temperature reservoirs, while Desulfotomaculum, Desulfotignum, Thiobacillus, and Dechloromonas were more often present in high-temperature reservoirs. The relative abundances of SRB and SOB varied and were present at higher proportions in the relatively high-temperature reservoirs. Canonical correspondence analysis also revealed that the SRB and SOB communities in reservoirs displayed high niche specificity and were closely related to reservoir temperature, pH of the formation brine, and sulfate concentration. In conclusion, this study extends our knowledge about the distribution of SRB and SOB communities in petroleum reservoirs.

To investigate the spatial distribution of microbial communities and their drivers in petroleum reservoir environments, we performed pyrosequencing of microbial partial 16S rRNA, derived from 20 geographically separated water-flooding reservoirs and two reservoirs that had not been flooded, in China. The results indicated that distinct underground microbial communities inhabited the different reservoirs. Compared with the bacteria, archaeal alpha-diversity was not strongly correlated with the environmental variables. The variation of the bacterial and archaeal community compositions was affected synthetically, by the mining patterns, spatial isolation, reservoir temperature, salinity and pH of the formation brine. The environmental factors explained 64.22% and 78.26% of the total variance for the bacterial and archaeal communities, respectively. Despite the diverse community compositions, shared populations (48 bacterial and 18 archaeal genera) were found and were dominant in most of the oilfields. Potential indigenous microorganisms, including Carboxydibrachium, Thermosinus and Neptunomonas, were only detected in a reservoir that had not been flooded with water. This study indicates that: 1) the environmental variation drives distinct microbial communities in different reservoirs; 2) compared with the archaea, the bacterial communities were highly heterogeneous within and among the reservoirs; and 3) despite the community variation, some microorganisms are dominant in multiple petroleum reservoirs.

Managers are typically interested in using equations that provide accurate volumes for large, merchantable trees while modelers are often more interested in equations that meet statistical assumptions. Therefore, modelers often use weighted (WLS) rather than ordinary least squares (OLS) to fit individual tree volume equations since the random error variance is not constant. Since OLS and WLS produce different parameter estimates, perhaps the method chosen will impact the predicted optimum economic rotation age. To address this concern, individual tree volumes were obtained from plots established in an unthinned loblolly pine plantation in southeastern Arkansas. Parameters of the combined- variable function were then estimated using OLS and WLS for the same dataset. Stand-level projections and predicted diameter distributions for two planting densities (748 and 2,692 seedlings per hectare) were then obtained from a growth and yield model (PTAEDA 3.1) and individual tree volumes were predicted using the two parameter estimation approaches. When conducting economic analyses, we found the optimum rotation age between OLS and WLS can differ by as much as 11 yrs (i.e. 10 yr clearcut vs 21 yr clearcut).

Summary The expression of TfR/CD71 in T-cell surface plays a pivotal role in T-cell activation and proliferation. Anti-human-TfR monoclonal antibody could be used as an immunosuppressant in transplant therapy because of their potential to suppress T-cell responses to alloantigens. We therefore examined the feasibility of an anti-human-TfR chimeric antibody (D2C) in suppression of T-cell activation in vitro and graft-versus-host reaction (GVHR) in animals. D2C is a chimeric antibody produced by introducing the human Fc fragment. This antibody showed low antigenicity but high suppressive effect manifested by high potency to block the activation and proliferation of lymphocytes in response to alloantigens. D2C also showed capability to mediate complement-dependent cytotoxicity, which could be correlated with TfR expression in peripheral blood mononuclear cells (PBMCs). Importantly, administration of D2C significantly prolonged survival time of nude mice transplanted with human PBMCs when compared with that of control IgG-treated animals (61.2 ± 4.46 vs. 22.1 ± 5.5 days), which is associated with inhibited GVHR characterized by decreased interleukin-1 and tumor necrosis factor α production derived from transplanted PBMCs. Human-TfR chimeric antibody such as D2C could be a valuable option for the treatment of acute form of graft-versus-host disease.

Overexpression, genetic amplification and mutations of p21-activated kinase 4 (PAK4) were found in a variety of human cancers. PAK4 regulated actin cytoskeleton reorganization by phosphorylating LIMK1 and promoted cancer cells migration. Using yeast two-hybrid screen, we identified a novel PAK4 binding protein, DGCR6L, which was associated with cancer cell metastasis. We confirmed PAK4 binding to the DGCR6L specifically by GST pull-down assay, and found an association between endogenous PAK4 and DGCR6L by immunoprecipitation in mammalian cells. Furthermore, L115 of DGCR6L was the critical amino acid to bind 466-572aa in the very C-terminus of PAK4. Importantly, DGCR6L was required for the formation of PAK4-DGCR6L-beta-actin complex. Overexpressed DGCR6L promoted migration of AGS cells mediated by PAK4, whereas knock-down of DGCR6L markedly inhibited the migration of those cells. Moreover, DGCR6L (L115V), which did not bind to PAK4, lost the ability to promote AGS cells migration. DGCR6L colocalized with PAK4 or F-actin and enhanced the phosphorylation level of LIMK1 and cofilin in a dose dependent manner. Taken together, our results demonstrated that DGCR6L, a novel PAK4 interacting protein, regulated PAK4-mediated migration of human gastric cancer cells via LIMK1.

This paper uses the gravity model to investigate determinants of China's wood products trade from 1995 to 2004. The results suggest that trade partners' forest resource endowment and China's own logging restrictions policy affect its wood products imports and exports. China's exported wood products are shown to be inferior goods while China's imported wood products are labor intensive for the exporting countries. Due to rises in Chinese currency against other major currency, transportation costs, and foreign trade actions, China's wood products exports and imports may slow down. The results may have implications on trade and global forest resource conservation.

This study used panel data models with spatial error correlation to analyze private tree planting in the US South from 1955 to 2003. Controlling for statewide, fixed effects allows us to disentangle the effect of spatial interaction from that of state heterogeneity and omitted variables. The results show that there is significant spatial interdependence among the southern states in private tree planting. Harvest rates, softwood sawtimber price, income levels, cost of capital, and federal and state cost-share programs are important factors affecting nonindustrial private (nonindustrial private forestland [NIPF]) tree planting. Harvest rates, softwood sawtimber and pulpwood prices, and planting cost are important factors affecting forest industry (FI) tree planting. Finally, the Soil Bank Program has had substitution effects on southern FI tree planting and nonsubsidized NIPF tree planting.

It has recently been reported that transmembrane protease, serine 3 (TMPRSS3) is overexpressed in cancer. However, TMPRSS3 expression and its biological roles in breast cancer (BC) have not been reported. This study aims to investigate the TMPRSS3 expression in BC and its relation with the outcome of the BC. This study involves a total of 149 BC tissues and adjacent non-cancerous tissues that were diagnosed between 2004 and 2007. Immunohistochemistry is used to compare the pattern of TMPRSS3 expression in BC and in adjacent non-cancerous tissues. Kaplan-Meier and Cox regression analyses were used to assess the prognostic significance of TMPRSS3 expression among BC patients. The results are as follow: TMPRSS3 expression is significantly in BC compared to adjacent non-cancerous tissues. High TMPRSS3 expression was related to TNM stage, lymph node metastasis, and Ki-67 expression. Furthermore, the overall survival (OS) and disease-free survival (DFS) in BC patients with high TMPRSS3 expression were lower than those in patients with low TMPRSS3 expression. Based on multivariate analysis, lymph node metastasis, TNM stage and TMPRSS3 expression are independent prognostic factors for OS in BC, while lymph node metastasis and TMPRSS3 expression are independent prognostic factors for DFS in BC. This study proves that TMPRSS3 expression is an independent prognostic factor for BC patients. Bioinformatic analysis of potential TMPRSS3 binding proteins revealed that TMPRSS3 could be a key regulator of cancer pathways. This study helps us better understand the function of TMPRSS3 in cancer.

Cell division cycle 42 (CDC42), an important member of the Ras homolog (Rho) family, plays a key role in regulating multiple cellular processes such as cell cycle progression, migration, cell cytoskeleton organization, cell fate determination and differentiation. Among the downstream effectors of CDC42, P21-activated kinases (PAKs) obtain the most attention. Although a large body of evidence indicates that CDC42/PAKs pathway plays important role in tumor growth, invasion and metastasis, the mechanism of their negative regulation remains unclear. Here, we identified CDC42, a PAKs activating factor, was a target of miR-133. Ectopic overexpression of miRNAs not only downregulated CDC42 expression and PAKs activation, but also inhibited cancer cell proliferation and migration. We also found that miR-133 was down-regulated in 180 pairs gastric cancer tissues. miR-133 expression was negatively associated with tumor size, invasion depth and peripheral organ metastasis. Besides, dysfunction of miR-133 was an independent prognosis factor for overall survival. Our findings could provide new insights into the molecular mechanisms of gastric carcinogenesis, and may help facilitating development of CDC42/PAK-based therapies for human cancer.

High atrazine (2-chloro-4-ethytlamino-6-isopropylamine-1,3,5-triazine; ATR) contents in the environment threaten the health conditions of organisms. We examined the effects of ATR exposure on Sprague-Dawley rats during gestation and on the dopaminergic neurons of offspring during lactation. Pregnant dams were orally treated with 0 mg/kg/day to 50 mg/kg/day of ATR from gestational day 5 to postnatal day 22. Afterward, neither offspring nor dams received ATR. Dopamine (DA) content was examined in striatum samples by HPLC-FL; the mRNA expressions of tyrosine hydroxylase (TH), orphan nuclear hormone (Nurr1), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) in the ventral midbrain samples were examined by fluorescence PCR when the offspring reached one year of age. After the pregnant rats were exposed to ATR, the DA concentrations and mRNA levels of Nurr1 were decreased in their offspring. Decreased Nurr1 levels were also accompanied by changes in the mRNA levels of VMAT2, which controls the transport and reuptake of DA.

Cetuximab (Erbitux, C225) is a chimeric monoclonal antibody that binds to the extracellular domain of epidermal growth factor receptor (EGFR), inhibiting tumor growth, invasion, angiogenesis and metastasis. However, the mechanisms underlying the effect of Cetuximab in human oral squamous cell carcinoma (OSCC) remain unclear. Here, we report that Cetuximab modulates EGFR protein stability through the ubiquitin/proteasome pathway, resulting in the inhibition of human OSCC growth. Cetuximab significantly inhibited the migration and invasion of human OSCC cells by blocking epithelial/mesenchymal transition (EMT) and the AKT and ERK pathways. Furthermore, Cetuximab-inhibited cell growth by modulating the expression of integrin β5. Taken together, these results provide novel insights into the mechanism of Cetuximab action and suggest potential therapeutic strategies for OSCC.

The p21-activated kinases have been implicated in the control of cell cycle progression. However, the biological mechanism underlying the role of p21-activated kinase 4 (PAK4) in cell cycle control remains unknown. Here, by using quantitative RT-PCR and immunoblot analyses, we discovered that over-expression of PAK4 could suppress cyclin-dependent kinase inhibitor 1C (p57(Kip2) ) expression in the MCF-7 human breast cancer cell line, whereas lentiviral vector-mediated small interfering RNA (siRNA) knockdown of PAK4 markedly promoted p57(Kip2) expression in MCF-7 cells. Furthermore, PAK4-mediated down-regulation of p57(Kip2) was reversed by MG132, a specific proteasome inhibitor. The ubiquitination assay confirmed that the activity of PAK4 attenuated p57(Kip2) protein stability through the ubiquitin-proteasome pathway in MCF-7 cells. Moreover, a significant inverse correlation between PAK4 and p57(Kip2) protein levels was observed in breast cancer tissues by immunohistochemical analysis. Taken together, our data demonstrate a novel function for PAK4 in regulating the stability of p57(Kip2) , possibly through the ubiquitin-proteasome pathway, leading to increased proliferation of breast cancer cells. Thus, PAK4 may be used as a potential diagnostic and therapeutic target for human breast cancer.

To explore the effect of long-term lead exposure on brain iron in aged rats.SPF female and male Sprague-Dawley rats were respectively randomly divided into three groups: control, low lead-exposed, high lead-exposed. Lead-exposed female rats drank 0.8g/L or 1.5g/L lead acetate solutions through pregnancy until weaning and then the pups received 0.3g/L or 0.9g/L lead acetate solution depending on their group. Control group rats drank deionized water throughout the experiment. At the postnatal 18 months, one pup for per group was given an ultra structural detection of hippocampus, and the other male pups were measured the lead and iron concentration of blood and brain by GE MR 3.0T MR scanner and ICP-AES.In comparing with control group, the lead concentrations of blood and brain in lead-exposed groups were significantly higher, and the iron contents of brain and cortex, hippocampus, thalamus were significantly higher in 0.9g/L lead-exposed group. Also, it was highly positively correlated between blood lead and iron of blood, cortex, hippocampus, thalamus, respectively. With the dose of lead-exposed increased, cytoplasm, nucleus, mitochondrial structure and synaptic structure had suffered vary degrees of damage from ultra structural detection of hippocampus, it could be observed early neuronal apoptosis.Lead induced neurodegenerative diseases might be related to iron overload which caused by lead exposure.

Considering unstable oscillation in the process of rotating machinery caused by changing in load lubrication and gear meshing stiffness in shaft system, the coupled nonlinear dynamic equation of rotating mechanical drive system is established with time-varying stiffness and nonlinear friction force based on Lagrange theory. The average equation of system is solved with the aid of method of multiple scales. Besides, according to Hopf bifurcation theory the stability of system is analyzed, the necessary and sufficient condition of Hopf bifurcation and periodic motion's stability are given, and the influence of supercritical and subcritical bifurcation on torsional vibration of rotating mechanical drive system is analyzed under the condition of parametric resonance and internal resonance. Last, the numerical simulation verifies the results. A significant contribution of this study is to ensure smooth running of rotating machinery system, and provide a theoretical basis for the future design of mechanical component.

Background Connective tissue growth factor (CTGF) has been shown to be implicated in tumor development and progression. However, the role of CTGF in gastric cancer remains largely unknown. Results In this study, we showed that CTGF was highly expressed in gastric cancer tissues compared with matched normal gastric tissues. The CTGF expression in tumor tissue was associated with histologic grade, lymph node metastasis and peritoneal dissemination (P < 0.05). Patients with positive CTGF expression had significantly lower cumulative postoperative 5 year survival rate than those with negative CTGF expression (22.9% versus 48.1%, P < 0.001). We demonstrated that knockdown of CTGF expression significantly inhibited cell growth of gastric cancer cells and decreased cyclin D1 expression. Moreover, knockdown of CTGF expression also markedly reduced the migration and invasion of gastric cancer cells and decreased the expression of matrix metalloproteinase (MMP)-2 and MMP-9. Animal studies revealed that nude mice injected with the CTGF knockdown stable cell lines featured a smaller number of peritoneal seeding nodules than the control cell lines. Conclusions These data suggest that CTGF plays an important role in cell growth and invasion in human gastric cancer and it appears to be a potential prognostic marker for patients with gastric cancer.

Cimetidine has been shown to have anti-metastatic activity and improves the survival of patients with colorectal cancer. One hypothesis is its modulation of the expression of the cell adhesion molecule by target organ endothelial cells. Because of the inconclusive results in clinical trials of gastric cancer, we investigated the effects of cimetidine on the adhesion of gastric cancer cells to activated endothelial cells and on the expression of some cell adhesion molecules. Human endothelial cells were pre-incubated with cimetidine for 6 h, incubated with the cytokine tumor necrosis factor for 4 h, and the endothelial surface expression of E-selectin was evaluated by flow cytometry, immunostaining and ELISA. Further, we investigated E-selectin mRNA expression by RT-PCR. Three gastric cancer cell lines (SGC-7901, MGC-803, BGC-823) and a normal gastric epithelial cell line, GES-1, were studied for the surface expression of sialyl Lewis x by flow cytometry and immunostaining. Adherence of CFSE-labeled gastric cancer cells and GES-1 cells to endothelial cell monolayers was determined. Cimetidine significantly reduced E-selectin expression of activated endothelial cells, but did not influence E-selectin expression at the mRNA level. Three gastric cancer cell lines expressed high levels of sialyl Lewis x, whereas GES-1 did not. Cimetidine also significantly decreased gastric cancer cell adherence to stimulated endothelial cells. The inhibition of E-selectin expression corresponded to the reduction of tumor cell adherence. The effects of cimetidine on tumor adhesion were almost nullified by pre-incubation with E-selectin and sialyl Lewis x antibody. Furthermore, there was no significant change of GES-1 adherence to endothelial cells by TNF-α, cimetidine, E-selectin and sialyl Lewis x antibody. The inhibiton of gastric cancer cell adherence to cytokine-stimulated endothelial cells treated with cimetidine appears to result from blocking endothelial E-selectin expression. These data support the hypothesis that cimetidine may exert its anti-metastatic effects in gastric cancer, in part, by inhibiting E-selectin/sialyl Lewis x-mediated adherence of gastric cancer cells to endothelial cells in the metastasis target organs.

Effects of concentrated solar radiation on photovoltaic performance are investigated in well-developed GaAs quantum dot (QD) solar cells with 1-Sun efficiencies of 18%–19%. In these devices, the conversion processes are enhanced by nanoscale potential barriers and/or AlGaAs atomically thin barriers around QDs, which prevent photoelectron capture to QDs. Under concentrated radiation, the short circuit current increases proportionally to the concentration and the open circuit voltage shows the logarithmic increase. In the range up to hundred Suns, the contributions of QDs to the photocurrent are proportional to the light concentration. The ideality factors of 1.1–1.3 found from the VOC-Sun characteristics demonstrate effective suppression of recombination processes in barrier-separated QDs. The conversion efficiency shows the wide maximum in the range of 40–90 Suns and reaches 21.6%. Detailed analysis of I-V-Sun characteristics shows that at low intensities, the series resistance decreases inversely proport...