THE ROLE OF RECEPTOR TYROSINE KINASE AXL IN PANCREATIC DUCTAL ADENOCARCINOMA AND ITS REGULATION BY HEMATOPOIETIC PROGENITOR KINASE 1

Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies with less than 5% of five year survival rate. New molecular markers and new therapeutic targets are urgently needed for patients with PDA. Oncogenic receptor tyrosine kinase Axl has been reported to be overexpressed in many types of human malignancies, including diffuse glioma, melanoma, osteosarcoma, and carcinomas of lung, colon, prostate, breast, ovary, esophagus, stomach, and kidney. However, the expression and functions of Axl in PDA are unclear. We hypothesized that Axl contributes to the development and progression of PDA. We examined Axl expression in 54 human PDA samples and their paired benign pancreatic tissue by immunohistochemistry, we found that Axl was overexpressed in 70% of stage II PDAs, but only 22% of benign ducts (P=0.0001). Axl overexpression was associated with higher frequencies of distant metastasis and was an independent prognostic factor for both poor overall and recurrence-free survivals in patients with stage II PDA (p = 0.03 and 0.04). Axl silencing by shRNA in pancreatic cancer cell lines, panc-28 and Panc-1, decreased tumor cell migration and invasion and sensitized PDA cells to apoptosis stimuli such as γ-irradiation and serum starvation. In addition, we found that Axl-mediated Akt and NF-κB activation and up regulation of MMP2 were involved in the invasion, migration and survival of PDA cells. Thus, we demonstrate that Axl plays an important role in the development and progression of PDA. Targeting Axl signaling pathway may represent a new approach for the treatment of PDA. To understand the molecular mechanisms of Axl overexpression in PDA, we found that Axl expression was down-regulated by hematopoietic progenitor kinase 1 (HPK1), a newly identified tumor suppressor in PDA. HPK1 is lost in over 95% of PDAs. Restoration of HPK1 in PDA cells down-regulated Axl expression. HPK1-mediated Axl degradation was inhibited by leupeptin, baflomycin A1, and monensin, suggesting that HPK1-mediated Axl degradation was through endocytosis-lysosome pathway. HPK1 interacted with and phosphorylated dynamin, a critical component of endocytosis pathway. Overexpression of dominant negative form of dynamin blocked the HPK1-mediated Axl degradation. Therefore we concluded that HPK1-mediated Axl degradation was through endocytosis-lysosome pathway and loss of HPK1 expression may contribute to Axl overexpression in PDAs

Identifying the Relative Contributions of Climate and Grazing to Both Direction and Magnitude of Alpine Grassland Productivity Dynamics from 1993 to 2011 on the Northern Tibetan Plateau

Alpine grasslands on the Tibetan Plateau are claimed to be sensitive and vulnerable to climate change and human disturbance. The mechanism, direction and magnitude of climatic and anthropogenic influences on net primary productivity (NPP) of various alpine pastures remain under debate. Here, we simulated the potential productivity (with only climate variables being considered as drivers; NPPP) and actual productivity (based on remote sensing dataset including both climate and anthropogenic drivers; NPPA) from 1993 to 2011. We denoted the difference between NPPP and NPPA as NPPpc to quantify how much forage can be potentially consumed by livestock. The actually consumed productivity (NPPac) by livestock were estimated based on meat production and daily forage consumption per standardized sheep unit. We hypothesized that the gap between NPPpc and NPPac (NPPgap) indicates the direction of vegetation dynamics, restoration or degradation. Our results show that growing season precipitation rather than temperature significantly relates with NPPgap, although warming was significant for the entire study region while precipitation only significantly increased in the northeastern places. On the Northern Tibetan Plateau, 69.05% of available alpine pastures showed a restoration trend with positive NPPgap, and for 58.74% of alpine pastures, stocking rate is suggested to increase in the future because of the positive mean NPPgap and its increasing trend. This study provides a potential framework for regionally regulating grazing management with aims to restore the degraded pastures and sustainable management of the healthy pastures on the Tibetan Plateau. View Full-Tex

Grazing Exclusion to Recover Degraded Alpine Pastures Needs Scientific Assessments across the Northern Tibetan Plateau

The northern Tibetan Plateau is the most traditional and important semi- nomadic region in Tibet. The alpine vegetation is sensitive and vulnerable to climate change and human activities, and is also important as an ecological security in protecting the headwaters of major rivers in Asia. Therefore, the Tibetan alpine grasslands have fundamental significance to both Mainland China and South Asia. The pasture degradation, however, likely threatens the livelihood of residents and the habitats of wildlife on this plateau. Since 2004, the government has launched a series of ecological restoration projects and economic compensatory payment polices. Many fences were additionally built on degraded pastures to prevent new degradation, to promote functionality recovery, and to balance the stocking rate with forage productivity. The grazed vs. fenced paired pastures across different zonal grassland communities along evident environmental gradients provide us with a natural comparative experiment platform to test the relative contributions of natural and anthropogenic factors. This study critically reviews the background, significance of and debates on short-term grazing exclusion with fences in this region. We also aim to figure out scientific and standardized workflows for assessing the effectiveness of grazing exclusion and compensatory payments in the future. View Full-Tex

Effects of Nutritional Level of Concentrate‐Based Diets on Meat Quality and Expression Levels of Genes Related to Meat Quality in Hainan Black Goats

The present study investigated the effects of the nutritional levels of diets on meat quality and related gene expression in Hainan black goat. Twenty-four goats were divided into six dietary treatments and were fed a concentrate-based diet with two levels of crude protein (CP) (15% or 17%) and three levels of digestive energy (DE) (11.72, 12.55 or 13.39 MJ/kg DM) for 90 days. Goats fed the concentrate-based diet with 17% CP had significantly (P \u3c 0.05) higher average daily gains (ADG) and better feed conversion rates (FCR). The pH 24h value tended to decrease (P \u3c 0.05) with increasing DE levels. The tenderness of Longissimus dorsi muscle (LD) and Semimembranosus muscle (SM) reduced with increasing CP levels (P \u3c 0.05). With increasing DE levels, tenderness was increased (P \u3c 0.05). The heart fatty acid-binding protein (H-FABP) mRNA expression levels in LD and SM increased with increasing DE levels (P \u3c 0.05), but decreased with increasing CP levels (P \u3c 0.05). The calpastatin (CAST) and μ-calpain mRNA expressions levels in LD and SM were affected significantly (P \u3c 0.05) by CP and DE levels in the diet. Therefore, the nutritional levels of diets affect meat quality and expression levels of genes associated with meat quality in Hainan black goats

The New Core Promoter Element XCPE1 (X Core Promoter Element 1) Directs Activator-, Mediator-, and TATA-Binding Protein-Dependent but TFIID-Independent RNA Polymerase II Transcription from TATA-Less Promoters

The core promoter is a critical DNA element required for accurate transcription and regulation of transcription. Several core promoter elements have been previously identified in eukaryotes, but those cannot account for transcription from most RNA polymerase II-transcribed genes. Additional, as-yet-unidentified core promoter elements must be present in eukaryotic genomes. From extensive analyses of the hepatitis B virus X gene promoter, here we identify a new core promoter element, XCPE1 (the X gene core promoter element 1), that drives RNA polymerase II transcription. XCPE1 is located between nucleotides −8 and +2 relative to the transcriptional start site (+1) and has a consensus sequence of G/A/T-G/C-G-T/C-G-G-G/A-A-G/C(+1)-A/C. XCPE1 shows fairly weak transcriptional activity alone but exerts significant, specific promoter activity when accompanied by activator-binding sites. XCPE1 is also found in the core promoter regions of about 1% of human genes, particularly in poorly characterized TATA-less genes. Our in vitro transcription studies suggest that the XCPE1-driven transcription can be highly active in the absence of TFIID because it can utilize either free TBP or the complete TFIID complex. Our findings suggest the possibility of the existence of a TAF1 (TFIID)-independent transcriptional initiation mechanism that may be used by a category of TATA-less promoters in higher eukaryotes

Nutrient Enrichment Mediates the Relationships of Soil Microbial Respiration with Climatic Factors in an Alpine Meadow

Quantifying the effects of nutrient additions on soil microbial respiration (Rm) and its contribution to soil respiration (Rs) are of great importance for accurate assessment ecosystem carbon (C) flux. Nitrogen (N) addition either alone (coded as LN and HN) or in combination with phosphorus (P) (coded as LN + P and HN + P) were manipulated in a semiarid alpine meadow on the Tibetan Plateau since 2008. Either LN or HN did not affect Rm, while LN + P enhanced Rm during peak growing periods, but HN + P did not affect Rm. Nutrient addition also significantly affected Rm/Rs, and the correlations of Rm/Rs with climatic factors varied with years. Soil water content (Sw) was the main factor controlling the variations of Rm/Rs. During the years with large rainfall variations, Rm/Rs was negatively correlated with Sw, while, in years with even rainfall, Rm/Rs was positively correlated with Sw. Meanwhile, in N + P treatments the controlling effects of climatic factors on Rm/Rs were more significant than those in CK. Our results indicate that the sensitivity of soil microbes to climatic factors is regulated by nutrient enrichment. The divergent effects of Sw on Rm/Rs suggest that precipitation distribution patterns are key factors controlling soil microbial activities and ecosystem C fluxes in semiarid alpine meadow ecosystems

Land Use and Land Cover Change in the Kailash Sacred Landscape of China

Land use and land cover change (LUCC) is an important driver of ecosystem function and services. Thus, LUCC analysis may lay foundation for landscape planning, conservation and management. It is especially true for alpine landscapes, which are more susceptible to climate changes and human activities. However, the information on LUCC in sacred landscape is limited, which will hinder the landscape conservation and development. We chose Kailash Sacred Landscape in China (KSL-China) to investigate the patterns and dynamics of LUCC and the driving forces using remote sensing data and meteorological data from 1990 to 2008. A supervised classification of land use and land cover was established based on field survey. Rangelands presented marked fluctuations due to climatic warming and its induced drought, for example, dramatic decreases were found in high- and medium-cover rangelands over the period 2000–2008. And recession of most glaciers was also observed in the study period. Instead, an increase of anthropogenic activities accelerated intensive alteration of land use, such as conversion of cropland to built-up land. We found that the change of vegetation cover was positively correlated with growing season precipitation (GSP). In addition, vegetation cover was substantially reduced along the pilgrimage routes particularly within 5 km of the routes. The findings of the study suggest that climatic warming and human disturbance are interacted to cause remarkable LUCC. Tourism development was responsible land use change in urban and pilgrimage routes. This study has important implications for landscape conservation and ecosystem management. The reduction of rangeland cover may decrease the rangeland quality and pose pressure for the carrying capacity of rangelands in the KSL-China. With the increasing risk of climate warming, rangeland conservation is imperative. The future development should shift from livestock-focus animal husbandry to service-based ecotourism in the sacred landscape