WITHAFERIN A: A NOVEL THERAPEUTIC APPROACH FOR MALIGANT BRAIN TUMORS

High-grade gliomas, including the astrocytoma glioblastoma multiforme (GBM), are the most common adult primary malignant brain tumor. The mean post-diagnosis survival time of patients with GBM is approximately 14 months and has improved only minimally over the last several decades given a lack of novel and effective therapeutic strategies or interventions. Similar issues persist for other forms of brain cancer, notably medulloblastomas (MB) in the pediatric patient population. Given our inability to extend survival and enhance quality of life adequately in these brain tumor patients, there is a critical need for novel chemotherapeutic agents in the treatment of GBM and MB that may work as monotherapy agents or in synergistic combinations with current interventions. In this work, the role of the natural product withaferin A (WA), a steroidal lactone with intriguing cytotoxic properties, was studied alone or in combination with currently approved anti-cancer agents (temozolomide, radiation therapy, and proteosome inhibitors) against GBM and MB brain tumors. It was shown that WA could produce G2/M cell cycle arrest and apoptosis with inhibitory modulation of the Akt/mammalian target of rapamycin (mTOR) pathway in GBM. Similarly, WA inhibited Wnt/β-catenin signaling through degradation of transcription factor (TCF)/lymphoid enhancer-binding factor (LEF) family members in MB. Overall, exposure to WA was associated with generalized N-acetyl-L-cysteine-repressible cellular oxidation, thiol reactivity, and alterations in the heat shock protein (HSP) 90 chaperone axis. WA failed to alter intrinsic HSP90 activity but reduced the association between HSP90 and co-chaperone Cdc37. These findings were expanded to demonstrate WA-mediated potentiation of cytotoxicity with concurrent proteasomal inhibition through an accumulation of aberrant proteins. WA also increased tumor cell radiosensitivity through disruption of normal DNA damage recognition and repair. While WA failed to significantly enhance the cytotoxicity of temozolomide (TMZ), it demonstrated the ability to re-sensitize TMZ-resistant GBM through reduction in O6-methylguanine-DNA methyltransferase (MGMT). This study identifies novel utility for the cytotoxic steroid lactone WA in the treatment of the malignant brain tumors GBM and MB through its alterations of oncogenic cellular signaling pathways, protein homeostasis, and the DNA-damage response mechanism. As such, WA represents a promising experimental therapeutic that warrants further translational exploration

Streamlined life cycle assessment of transparent silica aerogel made by supercritical drying

This is the post-print version of the Article. The official published version can be accessed from the link below - Copyright @ 2011 ElsevierWhen developing sustainable building fabric technologies, it is essential that the energy use and CO2 burden arising from manufacture does not outweigh the respective in-use savings. This study investigates this paradigm by carrying out a streamlined life cycle assessment (LCA) of silica aerogel. This unique, nanoporous translucent insulation material has the lowest thermal conductivity of any solid, retaining up to four times as much heat as conventional insulation, whilst being highly transparent to light and solar radiation. Monolithic silica aerogel has been cited as the ‘holy grail’ of future glazing technology. Alternatively, translucent granular aerogel is now being produced on a commercial scale. In each case, many solvents are used in production, often accompanied by intensive drying processes, which may consume large amounts of energy and CO2. To date, there has been no peer-reviewed LCA of this material conducted to the ISO 14000 standard. Primary data for this ‘cradle-to-factory gate’ LCA is collected for silica aerogel made by low and high temperature supercritical drying. In both cases, the mass of raw materials and electricity usage for each process is monitored to determine the total energy use and CO2 burden. Findings are compared against the predicted operational savings arising from retrofitting translucent silica aerogel to a single glazed window to upgrade its thermal performance. Results should be treated as a conservative estimate as the aerogel is produced in a laboratory, which has not been developed for mass manufacture or refined to reduce its environmental impact. Furthermore, the samples are small and assumptions to upscale the manufacturing volume occur without major changes to production steps or equipment used. Despite this, parity between the CO2 burden and CO2 savings is achieved in less than 2 years, indicating that silica aerogel can provide a measurable environmental benefit.This work is funded by the EPSRC, Brunel University and Buro Happold Ltd, the University of Bath is funded by the EPSRC grant EP/F018622/1

A note on the comparison of three near infrared reflectance spectroscopy calibration strategies for assessing herbage quality of ryegrass

peer-reviewedPerennial ryegrass (n = 1,836), Italian ryegrass (n = 137) and hybrid ryegrass (n = 103) herbage was taken from harvested plots from the Irish national variety evaluation scheme and analysed for in vitro dry matter digestibility, water soluble carbohydrate concentration, crude protein concentration and buffering capacity. Spectral data were obtained using near infrared reflectance spectroscopy and three calibration strategies (global, species-specific or local) were utilised to relate the reference values to the spectral data. The local strategy generally provided the poorest estimation of herbage composition, with global and species-specific calibration strategies producing similarly accurate estimates of each quality trait. The higher accuracy and easier maintenance of the global strategy make it the recommended calibration method for analysing quality of ryegrass.Department of Agriculture, Food and the Marine Research Stimulus Fund (07 526

Comparison of herbage yield, nutritive value and ensilability traits of three ryegrass species evaluated for the Irish Recommended List

peer-reviewedThis study examined 169 of the newest varieties of three ryegrass species, perennial (Lolium perenne L.), Italian (Lolium multiflorum Lam.) and hybrid (Lolium boucheanum Kunth), from Recommended List trials in Ireland. The traits examined were yield, dry matter concentration, three nutritive value traits (in vitro dry matter digestibility, water-soluble carbohydrate on a dry matter basis and crude protein concentration) and two ensilability traits (buffering capacity and water soluble carbohydrate concentration on an aqueous phase basis). Varietal monocultures of each species underwent a six cut combined simulated grazing and silage management in each of two years following sowing. Perennial ryegrass yielded less than both other species in one-year-old swards, but less than only Italian ryegrass in two-year-old swards, but generally had the higher in vitro dry matter digestibility and crude protein values. Italian ryegrass displayed the most favourable ensilability characteristics of the three species with perennial ryegrass less favourable and hybrid ryegrass intermediate. Overall, despite the high yields and favourable nutritive value and ensilability traits recorded, the general differences between the three ryegrass species studied were in line with industry expectations. These findings justify assessing the nutritive value and ensilability of ryegrass species, in addition to yield, to allow farmers select species that match farming enterprise requirements.We acknowledge the Department of Agriculture, Food and the Marine for funding provided through the Research Stimulus Fund (07 526

Collaboration and complexity: an experiment on the effect of multi-actor coupled design

Design of complex systems requires collaborative teams to overcome limitations of individuals; however, teamwork contributes new sources of complexity related to information exchange among members. This paper formulates a human subjects experiment to quantify the relative contribution of technical and social sources of complexity to design effort using a surrogate task based on a parameter design problem. Ten groups of 3 subjects each perform 42 design tasks with variable problem size and coupling (technical complexity) and team size (social complexity) to measure completion time (design effort). Results of a two-level regression model replicate past work to show completion time grows geometrically with problem size for highly coupled tasks. New findings show the effect of team size is independent from problem size for both coupled and uncoupled tasks considered in this study. Collaboration contributes a large fraction of total effort, and it increases with team size: about 50–60 % of time and 70–80 % of cost for pairs and 60–80 % of time and 90 % of cost for triads. Conclusions identify a role for improved design methods and tools to anticipate and overcome the high cost of collaboration.American Society for Engineering Education. National Defense Science and Engineering Graduate Fellowshi

Strategic Engineering Gaming for Improved Design and Interoperation of Infrastructure Systems

Large physical networks of interrelated infrastructure components support modern societies as a collaborative system with significant technical and social complexity. Design and evolution of infrastructure systems seeks to reduce wasted resources and maximize lifecycle value. Interdependencies between constituent systems call for an integrative approach to improve interoperation but many existing techniques rely on centralized development and emphasize technical aspects of design. This paper presents a simulation gaming approach to collaborative infrastructure system design leveraging the technical strengths of simulation models and the social strengths of multi-player engagement in a game execution. In a strategic engineering game, models representing each constituent infrastructure system share a common graph-theoretic modeling framework and are integrated using the HLA-Evolved standard for interoperable federated simulations. A prototype game instantiation based on a space-based resource economy supporting future space exploration is discussed with the objective of identifying how factors of game play influence insights to collaborative system design. Future work seeks to develop, execute, and evaluate the prototype game to further research the use of simulation games in supporting collaborative system design

Double-stranded RNA elements associated with the MVX disease of Agaricus bisporus

Double-stranded RNA (dsRNA) has been isolated from Agaricus bisporus fruit bodies exhibiting a wide range of disease symptoms. The symptoms which occurred singularly or in combination included; bare cropping areas on commercial beds (primordia disruption), crop delay, premature veil opening, off- or brown-coloured mushrooms, sporophore malformations and loss of crop yield. All symptoms were associated with loss of yield and/or product quality. Collectively, these symptoms are described as mushroom virus X (MVX) disease. The dsRNA titre was much lower than that previously encountered with the La France viral disease of mushrooms and a modified cellulose CF11 protocol was used for their detection. A broad survey of cultivated mushrooms from the British industry identified dsRNA elements ranging between 640 bp and 20.2 kbp; the majority have not previously been described in A. bisporus. 26 dsRNA elements were identified with a maximum of 17, apparently non-encapsidated dsRNA elements, in any one sample. Three dsRNAs (16.2, 9.4 and 2.4 kbp) were routinely found in mushrooms asymptomatic for MVX. Previously, La France disease was effectively contained and controlled by minimising the on-farm production and spread of basidiospores. Our on-farm observations suggest that MVX could be spread by infected spores and/or mycelial fragments

Dopamine promotes instrumental motivation, but reduces reward-related vigour.

We can be motivated when reward depends on performance, or merely by the prospect of a guaranteed reward. Performance-dependent (contingent) reward is instrumental, relying on an internal action-outcome model, whereas motivation by guaranteed reward may minimise opportunity cost in reward-rich environments. Competing theories propose that each type of motivation should be dependent on dopaminergic activity. We contrasted these two types of motivation with a rewarded saccade task, in patients with Parkinson's disease (PD). When PD patients were ON dopamine, they had greater response vigour (peak saccadic velocity residuals) for contingent rewards, whereas when PD patients were OFF medication, they had greater vigour for guaranteed rewards. These results support the view that reward expectation and contingency drive distinct motivational processes, and can be dissociated by manipulating dopaminergic activity. We posit that dopamine promotes goal-directed motivation, but dampens reward-driven vigour, contradictory to the prediction that increased tonic dopamine amplifies reward expectation