C231 MLN4924 is a first-in-class, small molecule inhibitor of the Nedd8 Activating Enzyme (NAE). ... more C231 MLN4924 is a first-in-class, small molecule inhibitor of the Nedd8 Activating Enzyme (NAE). Inhibition of NAE by MLN4924 leads to decreased neddylation and inhibition cullin-dependent ubiquitin ligase (CDL) activity. CDLs are enzyme complexes which control the ubiquitination and degradation of proteins with important roles in cell cycle progression and cell survival. CDL-mediated degradation of pIκBα regulates NF-κB signaling by freeing cytoplasmic NF-κB transcription factors to translocate to the nucleus promoting cell proliferation and survival. In tumors dependent on the NF-κB pathway for growth and survival, we hypothesized that MLN4924 inhibition of CDL activity will prevent pIκBα degradation and inhibit NF-κB signaling. Here, we demonstrate that MLN4924 is a potent inhibitor of NF-κB signaling in vitro and in vivo. We utilized models of ABC-like Diffuse Large B-cell Lymphoma (DLBCL, OCI-Ly10 cells) dependent on NF-κB signaling for survival and Germinal Center B-cell like DLBCL (OCI-Ly19 cells) that are not dependent on NF-κB signaling for survival. In vitro, we show that NAE inhibition by MLN4924 in OCI-Ly10 produces marked stabilization of pIκBα, inhibits NF-κB signaling resulting in G1 arrest and an acute induction of apoptosis. In contrast, in OCI-Ly19 cells we observed an elevation of multiple substrates of the CDLs, an accumulation of cells with increased DNA content (>4N) followed by a DNA damage response and induction of cell death. The mechanism of action in OCI-Ly19 cells is observed in other tumor cell lines that are not dependent on NF-κB signaling for survival. In vivo administration of MLN4924 to mice bearing xenograft tumors of OCI-Ly10 and OCI-Ly19 resulted in a pharmacodynamic response of NAE pathway inhibition. In both models, a single dose of MLN4924 resulted in time and dose-dependent inhibition of total neddylated cullin levels and stabilization of CDL substrates including the CDL3 Keap1 substrate, Nrf-2. Notably, in the OCI-Ly10 model, a single dose of MLN4924 resulted in a marked elevation of pIκBα levels, indicative of NF-κB pathway inhibition, and induction of apoptosis. In both OCI-Ly10 and OCI-Ly19 xenograft models, inhibition of the NAE pathway following repeated daily and intermittent dosing of MLN4924 translated into significant tumor growth inhibition. In the OCI-Ly10 model tumor regressions were observed showing this model to be particularly sensitive to MLN4924 treatment, reflecting the addiction of these tumors to NF-κB signaling. In summary, in tumors dependent on NF-κB signaling for growth and survival, MLN4924 inhibition of CDL activity provides a novel mechanism for targeted NF-κB pathway modulation and therapeutic intervention. In addition, these data demonstrate that MLN4924 is a novel agent that has broad activity in pre-clinical models of lymphoma.
As part of a wider study of floodplain vegetation along the River Murray, we carried out a field ... more As part of a wider study of floodplain vegetation along the River Murray, we carried out a field survey in 1987-1988 involving collection of floristic and vegetation condition data from 335 sample plots (each 400 m 2 in area), between Hume Dam and Lake Alexandrina (including the Edward-Wakool anabranch system). The floodplain vegetation is dominated by just two tree species, River Red Gum (Eucalyptus camaldulensis) and Black Box (Eucalyptus largiflorens), but the composition of the understorey shows much greater variation, both along the river and across the floodplain. A total of 499 plant species, subspecies and varieties were recorded from the survey plots, of which 316 (63%) were native and 183 (37%) were exotic. From analysis of the floristic data we identified 37 vegetation communities, not including the vegetation of permanent wetlands and cleared areas; 21 communities were distinguished in the River Red Gum zone, 12 communities in the Black Box zone, and 4 communities on rises within the floodplain. The main floristic division among the River Red Gum communities was between Riverine Plain/ Headwaters Zone communities of the upper Murray, and Mallee Zone communities of the lower Murray. Among the Black Box communities, the main floristic division was between inner floodplain communities and outer floodplain communities, with a further division between South Australian communities and New South Wales/Victorian communities. Major factors influencing the floristic patterns included flooding frequency/duration and soil salinity. Eucalypt health declined steadily downstream and was poorest in the lower reaches of the river below the Darling Junction, where 60% of the trees were healthy, 18% unhealthy (at least 40% of the canopy dead) and 22% dead. By comparison, at the upper end of the river, above Tocumwal, 84% of the trees were healthy, 14% unhealthy and only 2% dead. Overall, the condition of Black Box trees (44% unhealthy or dead) was worse than the condition of River Red Gum trees (29% unhealthy or dead). Eucaypt regeneration was also poorest below the Darling Junction, with regenerants present in 77% of plots upstream of the Darling but only 35% of plots downstream. The findings of poor tree health and sparse regeneration below the Darling coincide with the most heavily regulated part of the Murray, where the reduction in flooding due to upstream storages and water extraction, mainly for irrigation, has been greatest. Black Box regeneration was much sparser overall than River Red Gum regeneration (regenerants present in 69% of River Red Gum plots but only 29% of Black Box plots). The poor condition of the Black Box trees, coupled with their poor regeneration, suggests that the long-term future of this species along the Murray, particularly below the Darling Junction, is tenuous, even though it is a dominant component of the vegetation.
We show that certain types of organic molecules that might exist on Mars are resistant to UV phot... more We show that certain types of organic molecules that might exist on Mars are resistant to UV photolysis. Data obtained by thermal decomposition of irradiated organic molecules could help constrain the chemical composition of Martian organics.
The Phoenix lander is the first mission since Viking that could detect organics. Mellitic acid is... more The Phoenix lander is the first mission since Viking that could detect organics. Mellitic acid is a possible decay product of meteoritic organics. We irradiate mellitic acid with UV, producing a residue to analyze and compare to Phoenix results.
The permafrost organic carbon (OC) stock is of global significance because of its large pool size... more The permafrost organic carbon (OC) stock is of global significance because of its large pool size, and the potential positive feedback to climate warming. However, due to the lack of systematic field observations and appropriate upscaling methodologies, substantial uncertainties exist in the permafrost OC budget, which limits our understanding of the fate of frozen carbon in a warming world. In particular, the lack of comprehensive estimates of OC stocks across alpine permafrost means that current knowledge on this issue remains incomplete. Here we evaluated the pool size and spatial variations of permafrost OC stock to 3 metres depth on the Tibetan Plateau by combining systematic measurements from a substantial number of pedons (i.e., 342 three-metre-deep cores and 177 50-cm-deep pits) with a machine learning technique (i.e., support vector machine, SVM). We also quantified uncertainties in permafrost carbon budget by conducting a Monte Carlo simulation. Our results revealed that t...
Soil respiration, resulting in decomposition of soil organic carbon (SOC), emits CO 2 to the atmo... more Soil respiration, resulting in decomposition of soil organic carbon (SOC), emits CO 2 to the atmosphere and increases under climate warming. However, the impact of heavy metal pollution on soil respiration in croplands is not well understood. Here we show significantly increased soil respiration and efflux of both CO 2 and CH 4 with a concomitant reduction in SOC storage from a metal polluted rice soil in China. This change is linked to a decline in soil aggregation, in microbial abundance and in fungal dominance. The carbon release is presumably driven by changes in carbon cycling occurring in the stressed soil microbial community with heavy metal pollution in the soil. The pollution-induced increase in soil respiration and loss of SOC storage will likely counteract efforts to increase SOC sequestration in rice paddies for climate change mitigation.
Understanding the relationships between plateau pika population and plants biomass is essential f... more Understanding the relationships between plateau pika population and plants biomass is essential for improving small herbivores management in alpine meadow ecosystems. Four degrees of active burrow densities were classified to evaluate pika populations and biomass allocation interactions. Our results showed that plant composition, overall vegetation height and cover, dominant species were significantly different among four sites. Additionally, plant functional groups, above ground, below ground and total biomass, root:shoot ratios and the living roots proportion were the greatest at the zero-density site, and those at the medium-density site were the lowest. We postulate that pika activities may not be the cause of the differences, but a symptom of grassland degradation. Further, pika population fluctuations should be monitored, and when the population exceeds the economic threshold of low-density (110 pikas or/and 512 active burrows ha À1) or reaches high-density (200 pikas or/and 1360 active burrows ha À1), integrated management strategies should be implemented to protect damage.
China's paddy soils are crucial both for food security through high cereal productivity, and for ... more China's paddy soils are crucial both for food security through high cereal productivity, and for climate mitigation through high soil carbon storage. These functions are increasingly threatened by widespread heavy metal pollution, resulting from rapid industrial development. Heavy metal-polluted soils generally have a reduced microbial biomass and reduced soil respiration, as well as reduced functional diversity through changes in microbial community structure. Here we show that heavy metal pollution enhances soil respiration and CO2 efflux from a Chinese rice paddy soil, and leads to a soil organic carbon (SOC) loss, which is correlated with a decline in the fungal-tobacterial ratio of the reduced soil microbial community. The pollution-induced SOC loss could offset 70% of the yearly SOC increase from China's paddy soils. Thus, heavy metal pollution impacts long term productivity and the potential for C sequestration in China's paddy soils.
This abstract describes plans for cartographic processing of data from the Imager for Mars PathÞn... more This abstract describes plans for cartographic processing of data from the Imager for Mars PathÞnder (IMP) [1, 2] by the U. S. Geological Survey, cartographic products to be distributed, and progress to date in creating those products. Cartographic Datasets The IMP camera returned more than 16,000 images. Premission plans to obtain two panoramic datasets from which to map the whole landing site were expanded because of the supranominal data return rate to allow the return of Þve such panoramic sets (Table 1) containing over 3,500 images [2]. Table 1-Panoramic IMP Datasets for Cartography Camera Position Lossy Data Compression Lossless Data Compression Undeployed First Look (F)
On 25 May 2008 the Phoenix spacecraft landed on the Northern Plains of Mars (68.22oN, 234.25oW), ... more On 25 May 2008 the Phoenix spacecraft landed on the Northern Plains of Mars (68.22oN, 234.25oW), and operated for five months through mid-summer (solar longitude LS=76o to 149o). The lidar instrument on the Phoenix spacecraft measured the backscatter of pulsed light emitted upward into the atmosphere, and provided height resolved measurements of dust that were continuous in time. The essential
Maps of energy demand from buildings in Great Britain have been created at 1 km square resolution... more Maps of energy demand from buildings in Great Britain have been created at 1 km square resolution. They reveal the spatial variation of demand for heat and electricity, of importance for energy distribution studies and particularly for bioenergy research given the significant distance-based restrictions on the viability of bioenergy crops. Maps representing the spatial variation of energy demand for the year 2009 were created using publicly available sub-national gas and electricity consumption data. A new statistical model based on census data was used to increase the spatial resolution. The energy demand was split into thermal energy (the heat energy required for space heating and hot water) and electricity used for purposes other than heating (non-heating electricity or NHE), and was determined separately for the domestic and non-domestic sectors. "Scenario factors", representing the fractional change at national level in the demand for heat and NHE, were derived from scenarios constructed by UKERC. These scenarios represent a range of pathways from the present day to 2050. The present work focused on the two cases of greatest relevance, the "Low Carbon" (LC) and "Additional Policies" (ADD) scenarios, and factors for both were derived, for the demand types described, for every five years between 2000 and 2050. Approximate future spatial energy demands can be obtained by applying the scenario factors to the base mapping data for 2009.
The objective of the Phoenix Mars mission is to determine if Mars' polar region can support l... more The objective of the Phoenix Mars mission is to determine if Mars' polar region can support life. Since liquid water is a basic ingredient for life, as we know, an important goal of the mission is to determine if liquid water exists at the landing site. It is believed that a layer of martian soil preserves ice by forming a
This abstract focuses on the 2007 Phoenix Lander site selection work, including entry, descent, a... more This abstract focuses on the 2007 Phoenix Lander site selection work, including entry, descent, and landing (EDL)-based requirements, analyses of candidate sites, and a summary of what has been accomplished to date.
C231 MLN4924 is a first-in-class, small molecule inhibitor of the Nedd8 Activating Enzyme (NAE). ... more C231 MLN4924 is a first-in-class, small molecule inhibitor of the Nedd8 Activating Enzyme (NAE). Inhibition of NAE by MLN4924 leads to decreased neddylation and inhibition cullin-dependent ubiquitin ligase (CDL) activity. CDLs are enzyme complexes which control the ubiquitination and degradation of proteins with important roles in cell cycle progression and cell survival. CDL-mediated degradation of pIκBα regulates NF-κB signaling by freeing cytoplasmic NF-κB transcription factors to translocate to the nucleus promoting cell proliferation and survival. In tumors dependent on the NF-κB pathway for growth and survival, we hypothesized that MLN4924 inhibition of CDL activity will prevent pIκBα degradation and inhibit NF-κB signaling. Here, we demonstrate that MLN4924 is a potent inhibitor of NF-κB signaling in vitro and in vivo. We utilized models of ABC-like Diffuse Large B-cell Lymphoma (DLBCL, OCI-Ly10 cells) dependent on NF-κB signaling for survival and Germinal Center B-cell like DLBCL (OCI-Ly19 cells) that are not dependent on NF-κB signaling for survival. In vitro, we show that NAE inhibition by MLN4924 in OCI-Ly10 produces marked stabilization of pIκBα, inhibits NF-κB signaling resulting in G1 arrest and an acute induction of apoptosis. In contrast, in OCI-Ly19 cells we observed an elevation of multiple substrates of the CDLs, an accumulation of cells with increased DNA content (>4N) followed by a DNA damage response and induction of cell death. The mechanism of action in OCI-Ly19 cells is observed in other tumor cell lines that are not dependent on NF-κB signaling for survival. In vivo administration of MLN4924 to mice bearing xenograft tumors of OCI-Ly10 and OCI-Ly19 resulted in a pharmacodynamic response of NAE pathway inhibition. In both models, a single dose of MLN4924 resulted in time and dose-dependent inhibition of total neddylated cullin levels and stabilization of CDL substrates including the CDL3 Keap1 substrate, Nrf-2. Notably, in the OCI-Ly10 model, a single dose of MLN4924 resulted in a marked elevation of pIκBα levels, indicative of NF-κB pathway inhibition, and induction of apoptosis. In both OCI-Ly10 and OCI-Ly19 xenograft models, inhibition of the NAE pathway following repeated daily and intermittent dosing of MLN4924 translated into significant tumor growth inhibition. In the OCI-Ly10 model tumor regressions were observed showing this model to be particularly sensitive to MLN4924 treatment, reflecting the addiction of these tumors to NF-κB signaling. In summary, in tumors dependent on NF-κB signaling for growth and survival, MLN4924 inhibition of CDL activity provides a novel mechanism for targeted NF-κB pathway modulation and therapeutic intervention. In addition, these data demonstrate that MLN4924 is a novel agent that has broad activity in pre-clinical models of lymphoma.
As part of a wider study of floodplain vegetation along the River Murray, we carried out a field ... more As part of a wider study of floodplain vegetation along the River Murray, we carried out a field survey in 1987-1988 involving collection of floristic and vegetation condition data from 335 sample plots (each 400 m 2 in area), between Hume Dam and Lake Alexandrina (including the Edward-Wakool anabranch system). The floodplain vegetation is dominated by just two tree species, River Red Gum (Eucalyptus camaldulensis) and Black Box (Eucalyptus largiflorens), but the composition of the understorey shows much greater variation, both along the river and across the floodplain. A total of 499 plant species, subspecies and varieties were recorded from the survey plots, of which 316 (63%) were native and 183 (37%) were exotic. From analysis of the floristic data we identified 37 vegetation communities, not including the vegetation of permanent wetlands and cleared areas; 21 communities were distinguished in the River Red Gum zone, 12 communities in the Black Box zone, and 4 communities on rises within the floodplain. The main floristic division among the River Red Gum communities was between Riverine Plain/ Headwaters Zone communities of the upper Murray, and Mallee Zone communities of the lower Murray. Among the Black Box communities, the main floristic division was between inner floodplain communities and outer floodplain communities, with a further division between South Australian communities and New South Wales/Victorian communities. Major factors influencing the floristic patterns included flooding frequency/duration and soil salinity. Eucalypt health declined steadily downstream and was poorest in the lower reaches of the river below the Darling Junction, where 60% of the trees were healthy, 18% unhealthy (at least 40% of the canopy dead) and 22% dead. By comparison, at the upper end of the river, above Tocumwal, 84% of the trees were healthy, 14% unhealthy and only 2% dead. Overall, the condition of Black Box trees (44% unhealthy or dead) was worse than the condition of River Red Gum trees (29% unhealthy or dead). Eucaypt regeneration was also poorest below the Darling Junction, with regenerants present in 77% of plots upstream of the Darling but only 35% of plots downstream. The findings of poor tree health and sparse regeneration below the Darling coincide with the most heavily regulated part of the Murray, where the reduction in flooding due to upstream storages and water extraction, mainly for irrigation, has been greatest. Black Box regeneration was much sparser overall than River Red Gum regeneration (regenerants present in 69% of River Red Gum plots but only 29% of Black Box plots). The poor condition of the Black Box trees, coupled with their poor regeneration, suggests that the long-term future of this species along the Murray, particularly below the Darling Junction, is tenuous, even though it is a dominant component of the vegetation.
We show that certain types of organic molecules that might exist on Mars are resistant to UV phot... more We show that certain types of organic molecules that might exist on Mars are resistant to UV photolysis. Data obtained by thermal decomposition of irradiated organic molecules could help constrain the chemical composition of Martian organics.
The Phoenix lander is the first mission since Viking that could detect organics. Mellitic acid is... more The Phoenix lander is the first mission since Viking that could detect organics. Mellitic acid is a possible decay product of meteoritic organics. We irradiate mellitic acid with UV, producing a residue to analyze and compare to Phoenix results.
The permafrost organic carbon (OC) stock is of global significance because of its large pool size... more The permafrost organic carbon (OC) stock is of global significance because of its large pool size, and the potential positive feedback to climate warming. However, due to the lack of systematic field observations and appropriate upscaling methodologies, substantial uncertainties exist in the permafrost OC budget, which limits our understanding of the fate of frozen carbon in a warming world. In particular, the lack of comprehensive estimates of OC stocks across alpine permafrost means that current knowledge on this issue remains incomplete. Here we evaluated the pool size and spatial variations of permafrost OC stock to 3 metres depth on the Tibetan Plateau by combining systematic measurements from a substantial number of pedons (i.e., 342 three-metre-deep cores and 177 50-cm-deep pits) with a machine learning technique (i.e., support vector machine, SVM). We also quantified uncertainties in permafrost carbon budget by conducting a Monte Carlo simulation. Our results revealed that t...
Soil respiration, resulting in decomposition of soil organic carbon (SOC), emits CO 2 to the atmo... more Soil respiration, resulting in decomposition of soil organic carbon (SOC), emits CO 2 to the atmosphere and increases under climate warming. However, the impact of heavy metal pollution on soil respiration in croplands is not well understood. Here we show significantly increased soil respiration and efflux of both CO 2 and CH 4 with a concomitant reduction in SOC storage from a metal polluted rice soil in China. This change is linked to a decline in soil aggregation, in microbial abundance and in fungal dominance. The carbon release is presumably driven by changes in carbon cycling occurring in the stressed soil microbial community with heavy metal pollution in the soil. The pollution-induced increase in soil respiration and loss of SOC storage will likely counteract efforts to increase SOC sequestration in rice paddies for climate change mitigation.
Understanding the relationships between plateau pika population and plants biomass is essential f... more Understanding the relationships between plateau pika population and plants biomass is essential for improving small herbivores management in alpine meadow ecosystems. Four degrees of active burrow densities were classified to evaluate pika populations and biomass allocation interactions. Our results showed that plant composition, overall vegetation height and cover, dominant species were significantly different among four sites. Additionally, plant functional groups, above ground, below ground and total biomass, root:shoot ratios and the living roots proportion were the greatest at the zero-density site, and those at the medium-density site were the lowest. We postulate that pika activities may not be the cause of the differences, but a symptom of grassland degradation. Further, pika population fluctuations should be monitored, and when the population exceeds the economic threshold of low-density (110 pikas or/and 512 active burrows ha À1) or reaches high-density (200 pikas or/and 1360 active burrows ha À1), integrated management strategies should be implemented to protect damage.
China's paddy soils are crucial both for food security through high cereal productivity, and for ... more China's paddy soils are crucial both for food security through high cereal productivity, and for climate mitigation through high soil carbon storage. These functions are increasingly threatened by widespread heavy metal pollution, resulting from rapid industrial development. Heavy metal-polluted soils generally have a reduced microbial biomass and reduced soil respiration, as well as reduced functional diversity through changes in microbial community structure. Here we show that heavy metal pollution enhances soil respiration and CO2 efflux from a Chinese rice paddy soil, and leads to a soil organic carbon (SOC) loss, which is correlated with a decline in the fungal-tobacterial ratio of the reduced soil microbial community. The pollution-induced SOC loss could offset 70% of the yearly SOC increase from China's paddy soils. Thus, heavy metal pollution impacts long term productivity and the potential for C sequestration in China's paddy soils.
This abstract describes plans for cartographic processing of data from the Imager for Mars PathÞn... more This abstract describes plans for cartographic processing of data from the Imager for Mars PathÞnder (IMP) [1, 2] by the U. S. Geological Survey, cartographic products to be distributed, and progress to date in creating those products. Cartographic Datasets The IMP camera returned more than 16,000 images. Premission plans to obtain two panoramic datasets from which to map the whole landing site were expanded because of the supranominal data return rate to allow the return of Þve such panoramic sets (Table 1) containing over 3,500 images [2]. Table 1-Panoramic IMP Datasets for Cartography Camera Position Lossy Data Compression Lossless Data Compression Undeployed First Look (F)
On 25 May 2008 the Phoenix spacecraft landed on the Northern Plains of Mars (68.22oN, 234.25oW), ... more On 25 May 2008 the Phoenix spacecraft landed on the Northern Plains of Mars (68.22oN, 234.25oW), and operated for five months through mid-summer (solar longitude LS=76o to 149o). The lidar instrument on the Phoenix spacecraft measured the backscatter of pulsed light emitted upward into the atmosphere, and provided height resolved measurements of dust that were continuous in time. The essential
Maps of energy demand from buildings in Great Britain have been created at 1 km square resolution... more Maps of energy demand from buildings in Great Britain have been created at 1 km square resolution. They reveal the spatial variation of demand for heat and electricity, of importance for energy distribution studies and particularly for bioenergy research given the significant distance-based restrictions on the viability of bioenergy crops. Maps representing the spatial variation of energy demand for the year 2009 were created using publicly available sub-national gas and electricity consumption data. A new statistical model based on census data was used to increase the spatial resolution. The energy demand was split into thermal energy (the heat energy required for space heating and hot water) and electricity used for purposes other than heating (non-heating electricity or NHE), and was determined separately for the domestic and non-domestic sectors. "Scenario factors", representing the fractional change at national level in the demand for heat and NHE, were derived from scenarios constructed by UKERC. These scenarios represent a range of pathways from the present day to 2050. The present work focused on the two cases of greatest relevance, the "Low Carbon" (LC) and "Additional Policies" (ADD) scenarios, and factors for both were derived, for the demand types described, for every five years between 2000 and 2050. Approximate future spatial energy demands can be obtained by applying the scenario factors to the base mapping data for 2009.
The objective of the Phoenix Mars mission is to determine if Mars' polar region can support l... more The objective of the Phoenix Mars mission is to determine if Mars' polar region can support life. Since liquid water is a basic ingredient for life, as we know, an important goal of the mission is to determine if liquid water exists at the landing site. It is believed that a layer of martian soil preserves ice by forming a
This abstract focuses on the 2007 Phoenix Lander site selection work, including entry, descent, a... more This abstract focuses on the 2007 Phoenix Lander site selection work, including entry, descent, and landing (EDL)-based requirements, analyses of candidate sites, and a summary of what has been accomplished to date.
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