Mapping of domains on HIV envelope protein mediating association with calnexin and protein-disulfide isomerase.

The cell catalysts calnexin (CNX) and protein-disulfide isomerase (PDI) cooperate in establishing the disulfide bonding of the HIV envelope (Env) glycoprotein. Following HIV binding to lymphocytes, cell-surface PDI also reduces Env to induce the fusogenic conformation. We sought to define the contact points between Env and these catalysts to illustrate their potential as therapeutic targets. In lysates of Env-expressing cells, 15% of the gp160 precursor, but not gp120, coprecipitated with CNX, whereas only 0.25% of gp160 and gp120 coprecipitated with PDI. Under in vitro conditions, which mimic the Env/PDI interaction during virus/cell contact, PDI readily associated with Env. The domains of Env interacting in cellulo with CNX or in vitro with PDI were then determined using anti-Env antibodies whose binding site was occluded by CNX or PDI. Antibodies against domains V1/V2, C2, and the C terminus of V3 did not bind CNX-associated Env, whereas those against C1, V1/V2, and the CD4-binding domain did not react with PDI-associated Env. In addition, a mixture of the latter antibodies interfered with PDI-mediated Env reduction. Thus, Env interacts with intracellular CNX and extracellular PDI via discrete, largely nonoverlapping, regions. The sites of interaction explain the mode of action of compounds that target these two catalysts and may enable the design of further new competitive agents.

Spatial disaggregation and intensity correction of TRMM-based rainfall time series for hydrological applications in dryland catchments

A novel approach is presented for combining spatial and temporal detail from newly available TRMM-based data sets to derive hourly rainfall intensities at 1-km spatial resolution for hydrological modelling applications. Time series of rainfall intensities derived from 3-hourly 0.25° TRMM 3B42 data are merged with a 1-km gridded rainfall climatology based on TRMM 2B31 data to account for the sub-grid spatial distribution of rainfall intensities within coarse-scale 0.25° grid cells. The method is implemented for two dryland catchments in Tunisia and Senegal, and validated against gauge data. The outcomes of the validation show that the spatially disaggregated and intensity corrected TRMM time series more closely approximate ground-based measurements than non-corrected data. The method introduced here enables the generation of rainfall intensity time series with realistic temporal and spatial detail for dynamic modelling of runoff and infiltration processes that are especially important to water resource management in arid regions.

Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA)

As the mean age of the global population increases, breast cancer in older individuals will be increasingly encountered in clinical practice. Management decisions should not be based on age alone. Establishing recommendations for management of older individuals with breast cancer is challenging because of very limited level 1 evidence in this heterogeneous population. In 2007, the International Society of Geriatric Oncology (SIOG) created a task force to provide evidence-based recommendations for the management of breast cancer in elderly individuals. In 2010, a multidisciplinary SIOG and European Society of Breast Cancer Specialists (EUSOMA) task force gathered to expand and update the 2007 recommendations. The recommendations were expanded to include geriatric assessment, competing causes of mortality, ductal carcinoma in situ, drug safety and compliance, patient preferences, barriers to treatment, and male breast cancer. Recommendations were updated for screening, primary endocrine therapy, surgery, radiotherapy, neoadjuvant and adjuvant systemic therapy, and metastatic breast cancer.

The role of the international cocoa germplasm database and the international cocoa quarantine centre in information management and distribution of cocoa genetic resources

A range of physiological parameters (canopy light transmission, canopy shape, leaf size, flowering and flushing intensity) were measured from the International Clone Trial, typically over the course of two years. Data were collected from six locations, these being: Brazil, Ecuador, Trinidad, Venezuela, Côte d’Ivoire and Ghana. Canopy shape varied significantly between clones, although it showed little variation between locations. Genotypic variation in leaf size was differentially affected by the growth location; such differences appeared to underlie a genotype by environment interaction in relation to canopy light transmission. Flushing data were recorded at monthly intervals over the course of a year. Within each location, a significant interaction was observed between genotype and time of year, suggesting that some genotypes respond to a greater extent than others to environmental stimuli. A similar interaction was observed for flowering data, where significant correlations were found between flowering intensity and temperature in Brazil and flowering intensity and rainfall in Côte d’Ivoire. The results demonstrate the need for local evaluation of cocoa clones and also suggest that the management practices for particular planting material may need to be fine-tuned to the location in which they are cultivated.

Affinity purification of 61- and 65-kDa rat brain corticotropin-releasing factor receptors and receptor-associated G proteins.

Corticotropin-releasing factor (CRF) has been shown to have a central role in physiological adaptation to stress. It is recognized for stimulating the release of adrenocorticotropin from the anterior pituitary gland, and has more recently been implicated as a regulator of autonomic and immunological responses to stress. Much confusion has surrounded the characterization of CRF receptors, with proteins of varying molecular weights having been identified but never purified and characterized. Recently, two CRF receptors have been cloned from brain and pituitary gland, but evidence from in-situ hybridization studies suggests that further CRF receptor types exist. We therefore developed two techniques which enable the isolation of CRF receptors from whole rat brain. The use of a solid-phase CRF analogue affinity column and elution using a competing ligand resulted in the purification of a single protein of 61 kDa. A second technique was devised which allowed the co-isolation of associated signalling proteins and the identification of CRF bound species following purification. CRF was covalently cross-linked to receptors and the complex purified using antibodies specific for the ligand. This enabled the purification of a CRF receptor of approximately 65 kDa and associated alpha and beta gamma G protein subunits. This study demonstrates the successful isolation of CRF receptors which are of different molecular weights to those previously observed from affinity cross-linking studies or predicted from cloned genes. In addition, we confirm the involvement of G proteins in CRF stimulated cell signalling by demonstrating their association with purified CRF receptor.

Conformation and self-association of peptide amphiphiles based on the KTTKS collagen sequence

Studying peptide amphiphiles (PAs), we investigate the influence of alkyl chain length on the aggregation behavior of the collagen-derived peptide KTTKS with applications ranging from antiwrinkle cosmetic creams to potential uses in regenerative medicine. We have studied synthetic peptides amphiphiles C14− KTTKS (myristoyl Lys-Thr-Thr-Lys-Ser) and C18−KTTKS(stearoyl-Lys-Thr Thr-Lys-Ser) to investigate in detail their physicochemical properties. It is presumed that the hydrophobic chain in these self-assembling peptide amphiphiles enhances peptide permeation across the skin compared to KTTKS alone. Subsequently Cn−KTTKS should act as a prodrug and release the peptide by enzymatic cleavage. Our results should be useful in the further development of molecules with collagen-stimulating activity.

The Prophetic Sound: a day and night of noise cabaret(symposium of talks and live performances)

'The Prophetic Sound: a day and night of noise cabaret' is the first event hosted by Agency of Noise. This all day event brought together artists and academics whose subject of focus is noise (in creative practice). Artists from across the UK were invited to consider a future post-digital era in which everything with a microchip has malfunctioned, as a thought exercise and starting point for response through sound. In response to Jacques Attali’s claim that music is prophecy, The Prophetic Sound asks us to consider if noise can communicate in an unbridled, unfiltered, way that is somehow not culturally coded -before it becomes sound that is recognised, refined, manipulated and exploited for musical or other cultured purpose. Featuring students from Reading, Brighton, LCC and Goldsmiths alongside more established artists and academics from across the UK, this event brings into focus locations where pattern, timbre, pitch, organisation and sequencing of sounds become distinguishable from noise and asks us to consider, through diversion within such locations, new origins for future communication systems. The Prophetic Sound included talks, films, presentations and performances from: Ryo Ikeshiro / Inigo Wilkins / Neal Spowage / Dane Sutherland / Poulomi Desai / Benedict Drew / AAS / Polly Fibre / Steven Dickie As part of The Prophetic Sound, POLLYFIBRE (Ellison, C.) performed LIVE RECORDING with Amplified Scissors. This industrial activity by POLLYFIBRE short-circuits the complicated chain that is music production. The distinctive roles of consumer, producer, composer, and performer collapse in a series of live ‘cuts’ where vinyl discs are produced with amplified scissors. Production happens through action and action becomes production. A limited edition of 9 flexi discs were produced and available for special collectors at the event.

Precision placement of fertiliser for optimising the early nutrition of vegetable crops: a review of the implications for the yield and quality of crops, and their nutrient use efficiency

The research outlined in this paper highlights the importance of the early nutrition of vegetable crops, and its long-term effects on their subsequent growth and development. Results are also presented to demonstrate how the nutrient supply during the establishment stages of young seedlings and transplants can be enhanced by targeting fertiliser to a zone close to their developing roots. Three different precision fertiliser placement techniques are compared for this purpose: starter, band or side-injected fertiliser. The use of each of these methods consistently produced the same (or greater) yields at lower application rates than those from conventional broadcast applications, increasing the apparent recovery of N, P and K, and the overall efficiency of nutrient use, while reducing the levels of residual nutrients in the soil. Starter fertilisers also advanced the maturity of some crops, and enhanced produce quality by increasing the proportions of the larger and/or more desirable marketable grades. The benefits of the different placement techniques are illustrated with selected examples from research at Warwick HRI using different vegetable crops, including lettuce, onion and carrot.

"Where am I?" Impact of display and content variables on spatial presence and comprehension in virtual environments

Forgetting immediate physical reality and having awareness of one�s location in the simulated world is critical to enjoyment and performance in virtual environments be it an interactive 3D game such as Quake or an online virtual 3d community space such as Second Life. Answer to the question "where am I?" at two levels, whether the locus is in the immediate real world as opposed to the virtual world and whether one is aware of the spatial co-ordinates of that locus, hold the key to any virtual 3D experience. While 3D environments, especially virtual environments and their impact on spatial comprehension has been studied in disciplines such as architecture, it is difficult to determine the relative contributions of specific attributes such as screen size or stereoscopy towards spatial comprehension since most of them treat the technology as monolith (box-centered). Using a variable-centered approach put forth by Nass and Mason (1990) which breaks down the technology into its component variables and their corresponding values as its theoretical basis, this paper looks at the contributions of five variables (Stereoscopy, screen size, field of view, level of realism and level of detail) common to most virtual environments on spatial comprehension and presence. The variable centered approach can be daunting as the increase in the number of variables can exponentially increase the number of conditions and resources required. We overcome this drawback posed by adoption of such a theoretical approach by the use of a fractional factorial design for the experiment. This study has completed the first wave of data collection and starting the next phase in January 2007 and expected to complete by February 2007. Theoretical and practical implications of the study are discussed.

A novel association of a polymorphism in the first intron of adiponectin gene with type 2 diabetes, obesity and hypoadiponectinemia in Asian Indians

Adiponectin is an adipose tissue specific protein that is decreased in subjects with obesity and type 2 diabetes. The objective of the present study was to examine whether variants in the regulatory regions of the adiponectin gene contribute to type 2 diabetes in Asian Indians. The study comprised of 2,000 normal glucose tolerant (NGT) and 2,000 type 2 diabetic, unrelated subjects randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Fasting serum adiponectin levels were measured by radioimmunoassay. We identified two proximal promoter SNPs (-11377C-->G and -11282T-->C), one intronic SNP (+10211T-->G) and one exonic SNP (+45T-->G) by SSCP and direct sequencing in a pilot study (n = 500). The +10211T-->G SNP alone was genotyped using PCR-RFLP in 4,000 study subjects. Logistic regression analysis revealed that subjects with TG genotype of +10211T-->G had significantly higher risk for diabetes compared to TT genotype [Odds ratio 1.28; 95% Confidence Interval (CI) 1.07-1.54; P = 0.008]. However, no association with diabetes was observed with GG genotype (P = 0.22). Stratification of the study subjects based on BMI showed that the odds ratio for obesity for the TG genotype was 1.53 (95%CI 1.3-1.8; P < 10(-7)) and that for GG genotype, 2.10 (95% CI 1.3-3.3; P = 0.002). Among NGT subjects, the mean serum adiponectin levels were significantly lower among the GG (P = 0.007) and TG (P = 0.001) genotypes compared to TT genotype. Among Asian Indians there is an association of +10211T-->G polymorphism in the first intron of the adiponectin gene with type 2 diabetes, obesity and hypoadiponectinemia.

Absence of Association of Metabolic Syndrome with PPARGC1A, PPARG and UCP1 Gene Polymorphisms in Asian Indians

The objective of this study was to evaluate the association of PPARG coactivator1 alpha (PPARGC1A), peroxisome proliferator activated receptor gamma (PPARG), and uncoupling protein1 (UCP1) gene polymorphisms with the metabolic syndrome (MS) in an Asian Indian population. Nine common polymorphisms were genotyped via polymerase chain reaction restriction fragment length polymorphism and direct sequencing in 950 normal glucose-tolerant subjects and 550 type 2 diabetic subjects, chosen randomly from the Chennai Urban Rural Epidemiological Study, an ongoing population based study in Southern India. Among the 9 polymorphisms examined, only the Thr394Thr variant of the PPARGC1A gene was significantly associated with diabetes and obesity. The genotype frequency of GA of Thr394Thr variant was 16% (138/887) in the nonMS group and 22% (136/613) in the MS group, and this genotype frequency was significantly higher with MS both in males (p = 0.01) and females (p = 0.05), compared to the without-MS group. Logistic regression analysis revealed that the odds ratio for MS for the susceptible genotype GA of Thr394Thr was 1.411 [95% CI: 1.03-1.84, p = 0.012]. In the multiple logistic regression analysis, however, there was no association of this polymorphism as an independent factor with MS. Hence, the study shows that the polymorphisms in the PPARGC1A, PPARG and UCP1 genes are not associated with MS in Asian Indians.

Game-theoretic aspects of international mergers: Theory and case studies

This paper studies the exclusion of potential competition as a motivating factor for international mergers. We propose a simple game-theoretic framework in order to discuss the conditions under which mergers that prevent reciprocal domestic competition will occur. Our analysis highlights the shortcomings of antitrust policies based on pre-merger/post-merger concentration comparisons. A review of several recent European cases suggests that actual merger policy often fails to consider potential competition.

Association between Mediterranean and Nordic diet scores and changes in weight and waist circumference: influence of FTO and TCF7L2 loci

BACKGROUND: Several studies have shown that adherence to the Mediterranean Diet measured by using the Mediterranean diet score (MDS) is associated with lower obesity risk. The newly proposed Nordic Diet could hold similar beneficial effects. Because of the increasing focus on the interaction between diet and genetic predisposition to adiposity, studies should consider both diet and genetics. OBJECTIVE: We investigated whether FTO rs9939609 and TCF7L2 rs7903146 modified the association between the MDS and Nordic diet score (NDS) and changes in weight (Δweight), waist circumference (ΔWC), and waist circumference adjusted for body mass index (BMI) (ΔWCBMI). DESIGN: We conducted a case-cohort study with a median follow-up of 6.8 y that included 11,048 participants from 5 European countries; 5552 of these subjects were cases defined as individuals with the greatest degree of unexplained weight gain during follow-up. A randomly selected subcohort included 6548 participants, including 5496 noncases. Cases and noncases were compared in analyses by using logistic regression. Continuous traits (ie, Δweight, ΔWC, and ΔWCBMI) were analyzed by using linear regression models in the random subcohort. Interactions were tested by including interaction terms in models. RESULTS: A higher MDS was significantly inversely associated with case status (OR: 0.98; 95% CI: 0.96, 1.00), ΔWC (β = -0.010 cm/y; 95% CI: -0.020, -0.001 cm/y), and ΔWCBMI (β = -0.008; 95% CI:-0.015, -0.001) per 1-point increment but not Δweight (P = 0.53). The NDS was not significantly associated with any outcome. There was a borderline significant interaction between the MDS and TCF7L2 rs7903146 on weight gain (P = 0.05), which suggested a beneficial effect of the MDS only in subjects who carried 1 or 2 risk alleles. FTO did not modify observed associations. CONCLUSIONS: A high MDS is associated with a lower ΔWC and ΔWCBMI, regardless of FTO and TCF7L2 risk alleles. For Δweight, findings were less clear, but the effect may depend on the TCF7L2 rs7903146 variant. The NDS was not associated with anthropometric changes during follow-up.