An in vivo control map for the eukaryotic mRNA translation machinery

Rate control analysis defines the in vivo control map governing yeast protein synthesis and generates an extensively parameterized digital model of the translation pathway. Among other non-intuitive outcomes, translation demonstrates a high degree of functional modularity and comprises a non-stoichiometric combination of proteins manifesting functional convergence on a shared maximal translation rate. In exponentially growing cells, polypeptide elongation (eEF1A, eEF2, and eEF3) exerts the strongest control. The two other strong control points are recruitment of mRNA and tRNAi to the 40S ribosomal subunit (eIF4F and eIF2) and termination (eRF1; Dbp5). In contrast, factors that are found to promote mRNA scanning efficiency on a longer than-average 5′untranslated region (eIF1, eIF1A, Ded1, eIF2B, eIF3, and eIF5) exceed the levels required for maximal control. This is expected to allow the cell to minimize scanning transition times, particularly for longer 5′UTRs. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness. Remarkably, gene duplication is implicated in the fine control of cellular protein synthesis

Poisson-de Rham homology of hypertoric varieties and nilpotent cones

We prove a conjecture of Etingof and the second author for hypertoric varieties, that the Poisson-de Rham homology of a unimodular hypertoric cone is isomorphic to the de Rham cohomology of its hypertoric resolution. More generally, we prove that this conjecture holds for an arbitrary conical variety admitting a symplectic resolution if and only if it holds in degree zero for all normal slices to symplectic leaves. The Poisson-de Rham homology of a Poisson cone inherits a second grading. In the hypertoric case, we compute the resulting 2-variable Poisson-de Rham-Poincare polynomial, and prove that it is equal to a specialization of an enrichment of the Tutte polynomial of a matroid that was introduced by Denham. We also compute this polynomial for S3-varieties of type A in terms of Kostka polynomials, modulo a previous conjecture of the first author, and we give a conjectural answer for nilpotent cones in arbitrary type, which we prove in rank less than or equal to 2.Comment: 25 page

Geometric Satake, Springer correspondence, and small representations

For a simply-connected simple algebraic group $G$ over \C, we exhibit a subvariety of its affine Grassmannian that is closely related to the nilpotent cone of $G$, generalizing a well-known fact about $GL_n$. Using this variety, we construct a sheaf-theoretic functor that, when combined with the geometric Satake equivalence and the Springer correspondence, leads to a geometric explanation for a number of known facts (mostly due to Broer and Reeder) about small representations of the dual group.Comment: Version 2: minor revisions, 33 page

Cannabis treatment outcomes among legally coerced and non-coerced adults

<p>Abstract</p> <p>Background</p> <p>Treatment seeking for cannabis dependence in general, and particularly the number of criminal justice referrals to cannabis treatment, has increased over the past decade. This study aims to compare the characteristics, psychosocial functioning and treatment outcome of those legally coerced into cannabis treatment compared to those entering treatment without legal coercion.</p> <p>Methods</p> <p>This study is a retrospective audit of the administrative clinical records of 27,198 adults presenting to public Texas treatment programs with cannabis as their primary drug problem between 2000 and 2005.</p> <p>Results</p> <p>Of the 69% legally coerced into treatment, there was less psychological distress and greater likelihood of having completed treatment compared with non-coerced clients. Participants who were legally coerced into treatment were also more likely to have received less intensive forms of treatment and to have not used cannabis in the month prior to 90-day post-treatment follow-up.</p> <p>Conclusion</p> <p>More public health information is needed on cannabis dependence and increased availability of subsidised early and brief interventions in a variety of primary health care settings would reduce the late presentations of the more severely impaired voluntary clients. The limitations of this dataset are discussed.</p

There is no age limit for methadone: a retrospective cohort study

BACKGROUND: Data from the US indicates that methadone-maintained populations are aging, with an increase of patients aged 50 or older. Data from European methadone populations is sparse. This retrospective cohort study sought to evaluate the age trends and related developments in the methadone population of Basel-City, Switzerland. METHODS: The study included methadone patients between April 1, 1995 and March 31, 2003. Anonymized data was taken from the methadone register of Basel-City. For analysis of age distributions, patient samples were split into four age categories from '20-29 years' to '50 years and over'. Cross-sectional comparisons were performed using patient samples of 1996 and 2003. RESULTS: Analysis showed a significant increase in older patients between 1996 and 2003 (p < 0.001). During that period, the percentage of patients aged 50 and over rose almost tenfold, while the proportion of patients aged under 30 dropped significantly from 52.8% to 12.3%. The average methadone dose (p < 0.001) and the 1-year retention rate (p < 0.001) also increased significantly. CONCLUSIONS: Findings point to clear trends in aging of methadone patients in Basel-City which are comparable, although less pronounced, to developments among US methadone populations. Many unanswered questions on medical, psychosocial and health economic consequences remain as the needs of older patients have not yet been evaluated extensively. However, older methadone patients, just as any other patients, should be accorded treatment appropriate to their medical condition and needs. Particular attention should be paid to adequate solutions for persons in need of care

Implementing a Definitive Notation for Interactive Graphics

This paper describes the application of a definitive (definition-based) programming paradigm to graphics software. The potential merits of using definitive principles for interactive graphics were considered from a theoretical perspective in [Be87]; this paper is complementary, in that it describes the insights gained through practical experience in implementing a prototype system. The main characteristics of the prototype implementation are illustrated by simple examples. Analysis of the abstract machine model underlying this implementation suggests a general purpose programming paradigm based on definitive principles that can be applied to more ambitious applications. Introduction This paper describes the application of a novel programming paradigm to graphics software. The programming paradigm - &quot;definitive programming&quot; - is based upon the use of definitions for interaction. The potential merits of using definitive principles for interactive graphics were considered from a the..

Business and IT Perspectives on AMORE: A Methodology using Object-Orientation in Re-engineering Enterprises.

This paper is both an outline and a critique of AMORE, A Methodology Based on Object-Orientation for Re-engineering Enterprises that is being developed at the University of Warwick under the auspices of EPSRC grant GR/M02675. The methodology involves two principal phases, which deal with re-engineering from business and software viewpoints respectively. AMORE proposes models and guidelines that are intended to achieve a closer integration between these two viewpoints than is possible with alternative approaches. To this end, it exploits business domain modelling that takes account of the business factors (such as goals, location and organisational structure) that influence the design of processes. The prospects for AMORE are reviewed first with reference to current thinking on BPR and software development for business information systems by IT specialists such as Jacobson and Warboys, and subsequently with reference to business applications of a new computer-based modelling paradigm that are being developed in parallel with AMORE by Beynon and Russ in the Department of Computer Science at the University of Warwick

Elevated Serum Gastrin Is Associated with Melanoma Progression: Putative Role in Increased Migration and Invasion of Melanoma Cells.

Micro-environmental factors, including stromal and immune cells, cytokines, and circulating hormones are well recognized to determine cancer progression. Melanoma cell growth was recently shown to be suppressed by cholecystokinin/gastrin (CCK) receptor antagonists, and our preliminary data suggested that melanoma patients with Helicobacter gastritis (which is associated with elevated serum gastrin) might have an increased risk of cancer progression. Therefore, in the present study, we examined how gastrin may act on melanoma cells. In 89 melanoma patients, we found a statistically significant association between circulating gastrin concentrations and melanoma thickness and metastasis, which are known risk factors of melanoma progression and prognosis. Immunocytochemistry using a validated antibody confirmed weak to moderate CCK2R expression in both primary malignant melanoma cells and the melanoma cell lines SK-MEL-2 and G361. Furthermore, among the 219 tumors in the Skin Cutaneous Melanoma TCGA Pan-Cancer dataset showing gastrin receptor (CCKBR) expression, significantly higher CCKBR mRNA levels were linked to stage III-IV than stage I-II melanomas. In both cell lines, gastrin increased intracellular calcium levels and stimulated cell migration and invasion through mechanisms inhibited by a CCK2 receptor antagonist. Proteomic studies identified increased MMP-2 and reduced TIMP-3 levels in response to gastrin that were likely to contribute to the increased migration of both cell lines. However, the effects of gastrin on tumor cell invasion were relatively weak in the presence of the extracellular matrix. Nevertheless, dermal fibroblasts/myofibroblasts, known also to express CCK2R, increased gastrin-induced cancer cell invasion. Our data suggest that in a subset of melanoma patients, an elevated serum gastrin concentration is a risk factor for melanoma tumor progression, and that gastrin may act on both melanoma and adjacent stromal cells through CCK2 receptors to promote mechanisms of tumor migration and invasion