A Systems Biology Approach to Characterize the Regulatory Networks Leading to Trabectedin Resistance in an In Vitro Model of Myxoid Liposarcoma

Trabectedin, a new antitumor compound originally derived from a marine tunicate, is clinically effective in soft tissue sarcoma. The drug has shown a high selectivity for myxoid liposarcoma, characterized by the translocation t(12;16)(q13; p11) leading to the expression of FUS-CHOP fusion gene. Trabectedin appears to act interfering with mechanisms of transcription regulation. In particular, the transactivating activity of FUS-CHOP was found to be impaired by trabectedin treatment. Even after prolonged response resistance occurs and thus it is important to elucidate the mechanisms of resistance to trabectedin. To this end we developed and characterized a myxoid liposarcoma cell line resistant to trabectedin (402-91/ET), obtained by exposing the parental 402-91 cell line to stepwise increases in drug concentration. The aim of this study was to compare mRNAs, miRNAs and proteins profiles of 402-91 and 402-91/ET cells through a systems biology approach. We identified 3,083 genes, 47 miRNAs and 336 proteins differentially expressed between 402-91 and 402-91/ET cell lines. Interestingly three miRNAs among those differentially expressed, miR-130a, miR-21 and miR-7, harbored CHOP binding sites in their promoter region. We used computational approaches to integrate the three regulatory layers and to generate a molecular map describing the altered circuits in sensitive and resistant cell lines. By combining transcriptomic and proteomic data, we reconstructed two different networks, i.e. apoptosis and cell cycle regulation, that could play a key role in modulating trabectedin resistance. This approach highlights the central role of genes such as CCDN1, RB1, E2F4, TNF, CDKN1C and ABL1 in both pre- and post-transcriptional regulatory network. The validation of these results in in vivo models might be clinically relevant to stratify myxoid liposarcoma patients with different sensitivity to trabectedin treatment

Multilocation Corn Stover Harvest Effects on Crop Yields and Nutrient Removal

Corn (Zea mays L.) stover was identified as an important feedstock for cellulosic bioenergy production because of the extensive area upon which the crop is already grown. This report summarizes 239 site-years of field research examining effects of zero, moderate, and high stover removal rates at 36 sites in seven different states. Grain and stover yields from all sites as well as N, P, and K removal from 28 sites are summarized for nine longitude and six latitude bands, two tillage practices (conventional vs no tillage), two stover-harvest methods (machine vs calculated), and two crop rotations {continuous corn (maize) vs corn/soybean [Glycine max (L.) Merr.]}. Mean grain yields ranged from 5.0 to 12.0 Mg ha−1 (80 to 192 bu ac−1). Harvesting an average of 3.9 or 7.2 Mg ha−1(1.7 or 3.2 tons ac−1) of the corn stover resulted in a slight increase in grain yield at 57 and 51 % of the sites, respectively. Average no-till grain yields were significantly lower than with conventional tillage when stover was not harvested, but not when it was collected. Plant samples collected between physiological maturity and combine harvest showed that compared to not harvesting stover, N, P, and K removal was increased by 24, 2.7, and 31 kg ha−1, respectively, with moderate (3.9 Mg ha−1) harvest and by 47, 5.5, and 62 kg ha−1, respectively, with high (7.2 Mg ha−1) removal. This data will be useful for verifying simulation models and available corn stover feedstock projections, but is too variable for planning site-specific stover harvest

Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated

Nutrients cause grassland biomass to outpace herbivory

Human activities are transforming grassland biomass via changing climate, elemental nutrients, and herbivory. Theory predicts that food-limited herbivores will consume any additional biomass stimulated by nutrient inputs ('consumer-controlled'). Alternatively, nutrient supply is predicted to increase biomass where herbivores alter community composition or are limited by factors other than food ('resource-controlled'). Using an experiment replicated in 58 grasslands spanning six continents, we show that nutrient addition and vertebrate herbivore exclusion each caused sustained increases in aboveground live biomass over a decade, but consumer control was weak. However, at sites with high vertebrate grazing intensity or domestic livestock, herbivores consumed the additional fertilization-induced biomass, supporting the consumer-controlled prediction. Herbivores most effectively reduced the additional live biomass at sites with low precipitation or high ambient soil nitrogen. Overall, these experimental results suggest that grassland biomass will outstrip wild herbivore control as human activities increase elemental nutrient supply, with widespread consequences for grazing and fire risk

Interactive Effects of Time, CO\u3csub\u3e2\u3c/sub\u3e, N, and Diversity on Total Belowground Carbon Allocation and Ecosystem Carbon Storage in a Grassland Community

Predicting if ecosystems will mitigate or exacerbate rising CO2 requires understanding how elevated CO2 will interact with coincident changes in diversity and nitrogen (N) availability to affect ecosystem carbon (C) storage. Yet achieving such understanding has been hampered by the difficulty of quantifying belowground C pools and fluxes. Thus, we used mass balance calculations to quantify the effects of diversity, CO2, and N on both the total amount of C allocated belowground by plants (total belowground C allocation, TBCA) and ecosystem C storage in a periodically burned, 8-year Minnesota grassland biodiversity, CO2, and N experiment (BioCON). Annual TBCA increased in response to elevated CO2, enriched N, and increasing diversity. TBCA was positively related to standing root biomass. After removing the influence of root biomass, the effect of elevated CO2 remained positive, suggesting additional drivers of TBCA apart from those that maintain high root biomass. Removing root biomass effects resulted in the effects of N and diversity becoming neutral or negative (depending on year), suggesting that the positive effects of diversity and N on TBCA were related to treatmentdriven differences in root biomass. Greater litter production in high diversity, elevated CO2, and enhanced N treatments increased annual ecosystem C loss in fire years and C gain in non-fire years, resulting in overall neutral C storage rates. Our results suggest that frequently burned grasslands are unlikely to exhibit enhanced C sequestration with increasing atmospheric CO2 levels or N deposition

Measurement of D-s(+) and D-s(*+) production in B meson decays and from continuum e(+)e(-) annihilation at √s=10.6 GeV

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APSNew measurements of Ds+ and Ds*+ meson production rates from B decays and from qq̅ continuum events near the Υ(4S) resonance are presented. Using 20.8 fb-1 of data on the Υ(4S) resonance and 2.6 fb-1 off-resonance, we find the inclusive branching fractions B(B⃗Ds+X)=(10.93±0.19±0.58±2.73)% and B(B⃗Ds*+X)=(7.9±0.8±0.7±2.0)%, where the first error is statistical, the second is systematic, and the third is due to the Ds+→φπ+ branching fraction uncertainty. The production cross sections σ(e+e-→Ds+X)×B(Ds+→φπ+)=7.55±0.20±0.34pb and σ(e+e-→Ds*±X)×B(Ds+→φπ+)=5.8±0.7±0.5pb are measured at center-of-mass energies about 40 MeV below the Υ(4S) mass. The branching fractions ΣB(B⃗Ds(*)+D(*))=(5.07±0.14±0.30±1.27)% and ΣB(B⃗Ds*+D(*))=(4.1±0.2±0.4±1.0)% are determined from the Ds(*)+ momentum spectra. The mass difference m(Ds+)-m(D+)=98.4±0.1±0.3MeV/c2 is also measured.This work was supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the Swiss NSF, A. P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Normative productivity of the global vegetation

<p>Abstract</p> <p>Background</p> <p>The biosphere models of terrestrial productivity are essential for projecting climate change and assessing mitigation and adaptation options. Many of them have been developed in connection to the International Geosphere-Biosphere Program (IGBP) that backs the work of the Intergovernmental Panel on Climate Change (IPCC). In the end of 1990s, IGBP sponsored release of a data set summarizing the model outputs and setting certain norms for estimates of terrestrial productivity. Since a number of new models and new versions of old models were developed during the past decade, these normative data require updating.</p> <p>Results</p> <p>Here, we provide the series of updates that reflects evolution of biosphere models and demonstrates evolutional stability of the global and regional estimates of terrestrial productivity. Most of them fit well the long-living Miami model. At the same time we call attention to the emerging alternative: the global potential for net primary production of biomass may be as high as 70 PgC y^-1, the productivity of larch forest zone may be comparable to the productivity of taiga zone, and the productivity of rain-green forest zone may be comparable to the productivity of tropical rainforest zone.</p> <p>Conclusion</p> <p>The departure from Miami model's worldview mentioned above cannot be simply ignored. It requires thorough examination using modern observational tools and techniques for model-data fusion. Stability of normative knowledge is not its ultimate goal – the norms for estimates of terrestrial productivity must be evidence-based.</p

Strategies to Target Tumor Immunosuppression

The tumor microenvironment is currently in the spotlight of cancer immunology research as a key factor impacting tumor development and progression. While antigen-specific immune responses play a crucial role in tumor rejection, the tumor hampers these immune responses by creating an immunosuppressive microenvironment. Recently, major progress has been achieved in the field of cancer immunotherapy, and several groundbreaking clinical trials demonstrated the potency of such therapeutic interventions in patients. Yet, the responses greatly vary among individuals. This calls for the rational design of more efficacious cancer immunotherapeutic interventions that take into consideration the “immune signature” of the tumor. Multimodality treatment regimens that aim to enhance intratumoral homing and activation of antigen-specific immune effector cells, while simultaneously targeting tumor immunosuppression, are pivotal for potent antitumor immunity