Posttranscriptional Upregulation of IDH1 by HuR Establishes a Powerful Survival Phenotype in Pancreatic Cancer Cells.

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C \u3e 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDAC cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDAC cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDAC cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR–IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer

Underperforming policy networks : the biopesticides network in the United Kingdom

Loosely integrated and incomplete policy networks have been neglected in the literature. They are important to consider in terms of understanding network underperformance. The effective delivery and formulation of policy requires networks that are not incomplete or underperforming. The biopesticides policy network in the United Kingdom is considered and its components identified with an emphasis on the lack of integration of retailers and environmental groups. The nature of the network constrains the actions of its agents and frustrates the achievement of policy goals. A study of this relatively immature policy network also allows for a focus on network formation. The state, via an external central government department, has been a key factor in the development of the network. Therefore, it is important to incorporate such factors more systematically into understandings of network formation. Feedback efforts from policy have increased interactions between productionist actors but the sphere of consumption remains insufficiently articulated

A comprehensive categorical and bibliometric analysis of published research articles on pediatric pain from 1975-2010

The field of pediatric pain research began in the mid-1970's and has undergone significant growth and development in recent years as evidenced by the variety of books, conferences, and journals on the topic as well as the number of disciplines engaged in work in this area. Using categorical and bibliometric meta-trend analysis, the current study offers a synthesis of research on pediatric pain published between 1975 and 2010 in peer-reviewed journals. Abstracts from 4256 articles, retrieved from Web of Science, were coded across four categories: article type, article topic, type and age of participants, and pain stimulus. The affiliation of the first author and number of citations were also gathered. The results suggest a significant increase in the number of publications over the time period investigated, with 96% of the included articles published since 1990 and most research being multi-authored publications in pain- focused journals. First authors were most often from the United States, and affiliated with a medical department. The majority of studies were original research articles; the most frequent topics were pain characterization (39.86%), pain intervention (37.49%), and pain assessment (25.00%). Clinical samples were most frequent, with participants most often characterized as children (6-12 years) or adolescents (13-18 years) experiencing chronic or acute pain. The findings provide a comprehensive overview of contributions in the field of pediatric pain research over 35 years and offers recommendations for future research in the area. (C) 2015 International Association for the Study of Pai

Bunch microclimate influence amino acids and phenolic profiles of Pinot noir grape berries

IntroductionThe increase of temperature due to climate change at different phenological stages of grapevine has already been demonstrated to affect accumulation of primary and secondary metabolites in grape berries. This has a significant implication for Pinot noir especially in New Zealand context as these compounds can have direct and indirect effects on wine quality. MethodsThis study investigates how varying bunch microclimate through changes in temperature applied at veraison stage can affect: fresh weight, total soluble solids, the accumulation of anthocyanins, total phenolics and amino acids of the grape berries. This was studied over two growing seasons (2018/19 and 2019/20) with Pinot noir vines being grown at two different temperatures in controlled environment (CE) chambers. The vines were exposed to 800 µmol/m2/s irradiance with diurnal changes in day (22°C or 30°C) and night (15°C) temperatures. This experimental set up enabled us to determine the accumulation of these metabolite at harvest (both seasons) and throughout berry development (second season). Results and discussionThe results showed that berry weight was not influenced by temperature increase. The total soluble solids (TSS) were significantly increased at 30°C, however, this was not at the expense of berry weight (i.e., water loss). Anthocyanin content was reduced at higher temperature in the first season but there was no change in phenolic content in response to temperature treatments in either season. The concentrations of total amino acids at harvest increased in response to the higher temperature in the second season only. In addition, in the time course analysis of the second season, the accumulation of amino acids was increased at mid-ripening and ripening stage with the increased temperature. Significant qualitative changes in amino acid composition specifically the α-ketoglutarate family (i.e., glutamine, arginine, and proline) were found between the two temperatures. SignificanceThis study is the first to provide detailed analysis and quantification of individual amino acids and phenolics in Pinot noir in response to changes in temperature applied at veraison which could aid to develop adaptation strategies for viticulture in the future

Noise induced transitions in semiclassical cosmology

A semiclassical cosmological model is considered which consists of a closed Friedmann-Robertson-Walker in the presence of a cosmological constant, which mimics the effect of an inflaton field, and a massless, non-conformally coupled quantum scalar field. We show that the back-reaction of the quantum field, which consists basically of a non local term due to gravitational particle creation and a noise term induced by the quantum fluctuations of the field, are able to drive the cosmological scale factor over the barrier of the classical potential so that if the universe starts near zero scale factor (initial singularity) it can make the transition to an exponentially expanding de Sitter phase. We compute the probability of this transition and it turns out to be comparable with the probability that the universe tunnels from "nothing" into an inflationary stage in quantum cosmology. This suggests that in the presence of matter fields the back-reaction on the spacetime should not be neglected in quantum cosmology.Comment: LaTex, 33.tex pages, no figure

Economic sustainability modeling provides decision support for assessing hybrid poplar-based biofuel development in California

Biofuels are expected to play a major role in meeting California's long-term energy needs, but many factors influence the commercial viability of the various feedstock and production technology options. We developed a spatially explicit analytic framework that integrates models of plant growth, crop adoption, feedstock location, transportation logistics, economic impact, biorefinery costs and biorefinery energy use and emissions. We used this framework to assess the economic potential of hybrid poplar as a feedstock for jet fuel production in Northern California. Results suggest that the region has sufficient suitable croplands (2.3 million acres) and nonarable lands (1.5 million acres) for poplar cultivation to produce as much as 2.26 billion gallons of jet fuel annually. However, there are major obstacles to such large-scale production, including, on nonarable lands, low poplar yields and broad spatial distribution and, on croplands, competition with existing crops. We estimated the production cost of jet fuel to be $4.40 to$5.40 per gallon for poplar biomass grown on nonarable lands and $3.60 to$4.50 per gallon for biomass grown on irrigated cropland; the current market price is $2.12 per gallon. Improved poplar yields, use of supplementary feedstocks at the biorefinery and economic supports such as carbon credits could help to overcome these barriers

Semiclassical Equations for Weakly Inhomogeneous Cosmologies

The in-in effective action formalism is used to derive the semiclassical correction to Einstein's equations due to a massless scalar quantum field conformally coupled to small gravitational perturbations in spatially flat cosmological models. The vacuum expectation value of the stress tensor of the quantum field is directly derived from the renormalized in-in effective action. The usual in-out effective action is also discussed and it is used to compute the probability of particle creation. As one application, the stress tensor of a scalar field around a static cosmic string is derived and the backreaction effect on the gravitational field of the string is discussed.Comment: 35 pages, UAB-FT 316, Latex (uses a4wide.sty, a4.sty included in the file)(replaced due to tex problems

Exact Gravitational Shock Wave Solution of Higher Order Theories

We find an {\it exact} pp--gravitational wave solution of the fourth order gravity field equations. Outside the (delta--like) source this {\it not} a vacuum solution of General Relativity. It represents the contribution of the massive, $m=(-\beta)^{-1/2}$, spin--two field associated to the Ricci squared term in the gravitational Lagrangian. The fourth order terms tend to make milder the singularity of the curvature at the point where the particle is located. We generalize this analysis to $D$--dimensions, extended sources, and higher than fourth order theories. We also briefly discuss the scattering of fields by this kind of plane gravitational waves.Comment: 12 pages, REVTEX, Fully revised version. Amplitude of the wave computed. Discussion section added. Figure added. To appear in Phys. Rev.