Actions of Octocoral and Tobacco Cembranoids on Nicotinic Receptors

Nicotinic acetylcholine receptors (AChRs) are pentameric proteins that form agonist-gated cation channels through the plasma membrane. AChR agonists and antagonists are potential candidates for the treatment of neurodegenerative diseases. Cembranoids are naturally occurring diterpenoids that contain a 14-carbon ring. These diterpenoids interact with AChRs in complex ways: as irreversible inhibitors at the agonist sites, as noncompetitive inhibitors, or as positive modulators, but no cembranoid was ever shown to have agonistic activity on AChRs. The cembranoid eupalmerin acetate displays positive modulation of agonist-induced currents in the muscle-type AChR and in the related gamma-aminobutyric acid (GABA) type A receptor. Moreover, cembranoids display important biological effects, many of them mediated by nicotinic receptors. Cembranoids from tobacco are neuroprotective through a nicotinic anti-apoptotic mechanism preventing excitotoxic neuronal death which in part could result from anti-inflammatory properties of cembranoids. Moreover, tobacco cembranoids also have anti-inflammatory properties which could enhance their neuroprotective properties. Cembranoids from tobacco affect nicotine-related behavior: they increase the transient initial ataxia caused by first nicotine injection into naive rats and inhibit the expression of locomotor sensitization to repeated injections of nicotine. In addition, cembranoids are known to act as antitumor compounds. In conclusion, cembranoids provide a promising source of lead drugs for many clinical areas, including neuroprotection, smoking-cessation, and anti-cancer therapies

Design and development of a low-cost, electricity-generating cooking Score-Stove™

SCORE (www.score.uk.com) a US$4M, 5 year international collaboration research project aims to improve the life quality of the 1.5 billion people worldwide who cook on an open fire and do not have access to electricity. SCORE market evaluations1 indicate that at the upper-cost target of$120 with 20 Watts of electricity 60 million people would afford the stove. At the lower-cost target of $40 and 100 Watts it would be affordable to over 1 billion people. In November 2010, a wood burning Score-Stove™ prototype successfully developed 23 watts of electricity based on a planar Thermo-Acoustic Engine (TAE) [2],[3],[4],[5],[6] design, indicating that the new Score-Stove™ is now ready to be engaged with manufacturers to gear up for volume production, and therefore to meet the social and cooking requirements of the rural poor people. The development to a large-volume, easy to manufacture, low-cost TAE cooking stove using elements of the formal design methodologies of BS 7000 and TRIZ are discussed. By breaking down the system requirements into cost targets for each module, performing rig testing, and design refinements it is believed that the upper-cost target is achievable with the right level of investment

Thr 163 Phosphorylation Causes Mcl-1 Stabilization when Degradation is Independent of the Adjacent GSK3-Targeted Phosphodegron, Promoting Drug Resistance in Cancer

The antiapoptotic Bcl-2 family member Mcl-1 is a PEST protein (containing sequences enriched in proline, glutamic acid, serine, and threonine) and is subject to rapid degradation via multiple pathways. Impaired degradation leading to the maintenance of Mcl-1 expression is an important determinant of drug resistance in cancer. Phosphorylation at Thr 163 in the PEST region, stimulated by 12-O-tetradecanoylphorbol acetic acid (TPA)-induced activation of extracellular signal-regulated kinase (ERK), is associated with Mcl-1 stabilization in BL41-3 Burkitt lymphoma cells. This contrasts with the observation that Thr 163 phosphorylation in normal fibroblasts primes glycogen synthase kinase (GSK3)-induced phosphorylation at Ser 159, producing a phosphodegron that targets Mcl-1 for degradation. In the present follow-up studies in BL41-3 cells, Mcl-1 degradation was found to be independent of the GSK3-mediated pathway, providing a parallel to emerging findings showing that Mcl-1 degradation through this pathway is lost in many different types of cancer. Findings in Mcl-1-transfected CHO cells corroborated those in BL41-3 cells in that the GSK3-targeted phosphodegron did not play a major role in Mcl-1 degradation, and a phosphomimetic T163E mutation resulted in marked Mcl-1 stabilization. TPA-treated BL41-3 cells, in addition to exhibiting Thr 163 phosphorylation and Mcl-1 stabilization, exhibited an ∼10-fold increase in resistance to multiple chemotherapeutic agents, including Ara-C, etoposide, vinblastine, or cisplatin. In these cancer cells in which Mcl-1 degradation is not dependent on the GSK3/phosphodegron-targeted pathway, ERK activation and Thr 163 phosphorylation are associated with pronounced Mcl-1 stabilization and drug resistance – effects that can be suppressed by inhibition of ERK activation

POSTIRRADIATION EXAMINATION OF CENTRIFUGALLY BONDED EBR-11 DRIVER FUEL

BNW was requested by AEC/DRDT to assist ANL with the postirradiation examination of EBR-II driver fuel (U + 5Fs) pins that became shortened during irradiation. To date, three irradiated pins and one nonirradiated pin were examined

Mathematically gifted and talented learners: Theory and practice

This is an Author's Accepted Manuscript of an article published in International Journal of Mathematical Education in Science and Technology, 40(2), 213-228, 2009, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/00207390802566907.There is growing recognition of the special needs of mathematically gifted learners. This article reviews policy developments and current research and theory on giftedness in mathematics. It includes a discussion of the nature of mathematical ability as well as the factors that make up giftedness in mathematics. The article is set in the context of current developments in Mathematics Education and Gifted Education in the UK and their implications for Science and Technology. It argues that early identification and appropriate provision for younger mathematically promising pupils capitalizes on an intellectual resource which could provide future mathematicans as well as specialists in Science or Technology. Drawing on a Vygotskian framework, it is suggested that the mathematically gifted require appropriate cognitive challenges as well as attitudinally and motivationally enhancing experiences. In the second half of this article we report on an initiative in which we worked with teachers to identify mathematically gifted pupils and to provide effective enrichment support for them, in a number of London Local Authorities. A number of significant issues are raised relating to the identification of mathematical talent, enrichment provision for students and teachers’ professional development

A geometrical analysis of inclined and tilted spherical plough discs

An analysis is presented of the ef fect of disc geometry in relation to its areas of contact with soil at the working depth , treating the disc as a segment of a thin spherical shell . In addition , the ef fects of the disc angle of tilt , the disc angle of inclination to its direction of motion and the working depth are examined in detail . Shallow and deep disc concavities are considered . A presentation is made of formulae derived for disc critical angle and depth and for bearing and pressure areas of contact with the soil on vertical and horizontal planes . In addition , a study was made of the overlapping of soil working areas when adjacent discs are working in a gang arrangement . The ef fects of inside and outside sharpening of the circumferential edge of the disc are also examined . For the practical range of tilt angle (15 Њ to 25 Њ ) and disc angle (35 Њ to 55 Њ ) it is shown that the bearing area of the rear spherical area of discs is zero , so there is no soil contact with the rear surface of the disc . The vertical pressure area is only slightly af fected by tilt angle and there is little dif ference for the two disc concavities . Disc angle and working depth have significant ef fects on this area . The horizontal presssure area is not af fected by disc angle over its practical range . It has larger values for the 81 mm concavity than for the 51 mm concavity and is significantly influenced by tilt angle and working depth . Discs working in a gang , have overlapping of the areas of soil cut for disc angles and spacings (180 to 300 mm) adopted in practice . The area cut by an individual disc is not markedly af fected by disc angle . Inside and outside sharpening does not significantly af fect the overall findings concerning critical disc parameters . The flat bevelled surface formed by outside sharpening will generally be in contact with soil over the practical range of tilt and disc angles

Assessing the capacity of local ecosystems to meet industrial demand for ecosystem services

Despite the importance of ecosystems, engineering activities continue to ignore or greatly undervalue their role. Consequently, engineered systems often overshoot nature's capacity to support them, causing ecological degradation. Such systems tend to be inherently unsustainable, and they often fail to benefit from nature's ability to provide essential goods and services. This work explores the idea of including ecosystems in chemical processes, and assesses whether such a techno-ecological synergistic system can operate within ecological constraints. The demand for ecosystem services is quantified by emissions and resources used, while the supply is provided by ecosystems on the manufacturing site. Application to a biodiesel manufacturing site demonstrates that ecosystems can be economically and environmentally superior to conventional technologies for making progress toward zero emissions and net positive impact manufacturing. These results highlight the need for shifting the paradigm of engineering from that of dominating nature to embracing nature and respecting its limits

Improved outcome in children with advanced stage B-cell non-Hodgkin's lymphoma (B-NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol

From July 1990 to March 1996, 112 children with stage III or IV B-cell non-Hodgkin's lymphoma (B-NHL) with up to 70% FAB L3-type blasts (n= 42) in the bone marrow without central nervous system (CNS) disease were treated on the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol (identical to the French LMB 84). The median age was 8.3 years. There were 81 boys and 31 girls. According to the extent of the primary disease, patients were sub-staged into three groups: IIIA with unresectable abdominal tumour (n= 39); IIIB with abdominal multiorgan involvement (n= 57) and IIIX with extra-abdominal primary lymphoma often presenting as pleural effusion (n= 16). Univariate and multivariate analyses were carried out to evaluate the prognostic significance of lactate dehydrogenase (LDH) level at diagnosis, the sub-stage and the time to achieve complete remission (CR). With a median follow up of 48 months (range 12–92), the overall and event free survival (EFS) is 87% (95% confidence interval (CI) 79.2–92.1%) and 83.7% (95% CI 76.3–89.2%) respectively. Six patients (5.4%) never achieved CR, of whom one is alive following high-dose therapy. Eight patients (7.1%) relapsed after achieving CR, three are alive after second-line therapy. There were three early toxic deaths (2.7%), mainly from infection, and one late death from a second cancer. There was no significant difference in EFS according to LDH level at diagnosis, the sub-stage or the time to CR. This study confirms the overall good prognosis and low rate of toxic deaths in patients with advanced B-NHL treated with this intensive regimen. No significant difference in EFS according to the sub-stage, the time to achieve CR or LDH level at diagnosis making it difficult to identify a group that should not receive intensive therapy. © 2000 Cancer Research Campaig