Prostate cancer: Re-focusing on androgen receptor signaling

Prostate cancer is the most common, non-dermatologic cancer in men. Since prostate cancer is highly associated with increased age, the incidence of this disease is expected to increase as the population ages. In its initial stages prostate cancer depends upon the actions of androgen, and androgen deprivation therapy induces tumor regression. Currently, androgen deprivation is achieved by either surgical or chemical androgen blockade. Unfortunately, nearly all prostate cancer patients develop tumors that grow despite androgen blockade and ultimately relapse. Many alterations in prostate cancer cells contribute to this state. Although chemotherapy induces short remissions in some patients, there are no curative therapies for metastatic disease. This review summarizes our current understanding in androgen signaling and the mechanisms that allow tumor cells to bypass androgen manipulation therapy. The identification of novel survival pathways and effector molecules that drive androgen independent growth is necessary to develop effective therapies for advanced prostate cancers.     

ProServer: a simple, extensible Perl DAS server

SUMMARY: The increasing size and complexity of biological databases has led to a growing trend to federate rather than duplicate them. In order to share data between federated databases, protocols for the exchange mechanism must be developed. One such data exchange protocol that is widely used is the Distributed Annotation System (DAS). For example, DAS has enabled small experimental groups to integrate their data into the Ensembl genome browser. We have developed ProServer, a simple, lightweight, Perl-based DAS server that does not depend on a separate HTTP server. The ProServer package is easily extensible, allowing data to be served from almost any underlying data model. Recent additions to the DAS protocol have enabled both structure and alignment (sequence and structural) data to be exchanged. ProServer allows both of these data types to be served. AVAILABILITY: ProServer can be downloaded from http://www.sanger.ac.uk/proserver/ or CPAN http://search.cpan.org/~rpettett/. Details on the system requirements and installation of ProServer can be found at http://www.sanger.ac.uk/proserver/.     

Predicting active site residue annotations in the Pfam database

Background

The recent increase in the use of high-throughput two-hybrid analysis has generated large quantities of data on protein interactions. Specifically, the availability of information about experimental protein-protein interactions and other protein features on the Internet enables human protein-protein interactions to be computationally predicted from co-evolution events (interolog). This study also considers other protein interaction features, including sub-cellular localization, tissue-specificity, the cell-cycle stage and domain-domain combination. Computational methods need to be developed to integrate these heterogeneous biological data to facilitate the maximum accuracy of the human protein interaction prediction.

Results

This study proposes a relative conservation score by finding maximal quasi-cliques in protein interaction networks, and considering other interaction features to formulate a scoring method. The scoring method can be adopted to discover which protein pairs are the most likely to interact among multiple protein pairs. The predicted human protein-protein interactions associated with confidence scores are derived from six eukaryotic organisms – rat, mouse, fly, worm, thale cress and baker's yeast.

Conclusion

Evaluation results of the proposed method using functional keyword and Gene Ontology (GO) annotations indicate that some confidence is justified in the accuracy of the predicted interactions. Comparisons among existing methods also reveal that the proposed method predicts human protein-protein interactions more accurately than other interolog-based methods.     

NEKTAR,SPICE and Vortonics: using federated grids for large scale scientific applications

In response to a joint call from US’s NSF and UK’s EPSRC for applications that aim to utilize the combined computational resources of the US and UK, three computational science groups from UCL, Tufts and Brown Universities teamed up with a middleware team from NIU/Argonne to meet the challenge. Although the groups had three distinct codes and aims, the projects had the underlying common feature that they were comprised of large-scale distributed applications which required high-end networking and advanced middleware in order to be effectively deployed. For example, cross-site runs were found to be a very effective strategy to overcome the limitations of a single resource. The seamless federation of a grid-of-grids remains difficult. Even if interoperability at the middleware and software stack levels were to exist, it would not guarantee that the federated grids can be utilized for large scale distributed applications. There are important additional requirements for example, compatible and consistent usage policy, automated advanced reservations and most important of all co-scheduling. This paper outlines the scientific motivation and describes why distributed resources are critical for all three projects. It documents the challenges encountered in using a grid-of-grids and some of the solutions devised in response.     

Nitrogen yield advantage from grass–legume mixtures is robust over a wide range of legume proportions and environmental conditions

Current challenges to global food security require sustainable intensification of agriculture through initiatives that include more efficient use of nitrogen (N), increased protein self‐sufficiency through homegrown crops, and reduced N losses to the environment. Such challenges were addressed in a continental‐scale field experiment conducted over 3 years, in which the amount of total nitrogen yield (N_tot) and the gain of N yield in mixtures as compared to grass monocultures (N_gainmix) was quantified from four‐species grass–legume stands with greatly varying legume proportions. Stands consisted of monocultures and mixtures of two N₂‐fixing legumes and two nonfixing grasses. The amount of N_tot of mixtures was significantly greater (P ≤ 0.05) than that of grass monocultures at the majority of evaluated sites in all 3 years. N_tot and thus N_gainmix increased with increasing legume proportion up to one‐third of legumes. With higher legume percentages, N_tot and N_gainmix did not continue to increase. Thus, across sites and years, mixtures with one‐third proportion of legumes attained ~95% of the maximum N_tot acquired by any stand and had 57% higher N_tot than grass monocultures. Realized legume proportion in stands and the relative N gain in mixture (N_gainmix/N_tot in mixture) were most severely impaired by minimum site temperature (R = 0.70, P = 0.003 for legume proportion; R = 0.64, P = 0.010 for N_gainmix/N_tot in mixture). Nevertheless, the relative N gain in mixture was not correlated to site productivity (P = 0.500), suggesting that, within climatic restrictions, balanced grass–legume mixtures can benefit from comparable relative gains in N yield across largely differing productivity levels. We conclude that the use of grass–legume mixtures can substantially contribute to resource‐efficient agricultural grassland systems over a wide range of productivity levels, implying important savings in N fertilizers and thus greenhouse gas emissions and a considerable potential for climate change mitigation.     

Discovery of a new class of glucosylceramide synthase inhibitors

A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo.     

Strategies for Neoglycan conjugation to human acid α-glucosidase

Engineering proteins for selective tissue targeting can improve therapeutic efficacy and reduce undesired side effects. The relatively high dose of recombinant human acid α-glucosidase (rhGAA) required for enzyme replacement therapy of Pompe disease may be attributed to less than optimal muscle uptake via the cation-independent mannose 6-phosphate receptor (CI-MPR). To improve muscle targeting, Zhu et al. (1) conjugated periodate oxidized rhGAA with bis mannose 6-phosphate bearing synthetic glycans and achieved 5-fold greater potency in a murine Pompe efficacy model. In the current study, we systematically evaluated multiple strategies for conjugation based on a structural homology model of GAA. Glycan derivatives containing succinimide, hydrazide, and aminooxy linkers targeting free cysteine, lysines, and N-linked glycosylation sites on rhGAA were prepared and evaluated in vitro and in vivo. A novel conjugation method using enzymatic oxidation was developed to eliminate side oxidation of methionine. Conjugates derived from periodate oxidized rhGAA still displayed the greatest potency in the murine Pompe model. The efficiency of conjugation and its effect on catalytic activity were consistent with predictions based on the structural model and supported its use in guiding selection of appropriate chemistries.     

Effect of personal response systems on student perception and academic performance in courses in a health sciences curriculum

To increase student engagement, active participation, and performance, personal response systems (clickers) were incorporated into six lecture-based sections of four required courses within the Health Sciences Department major curriculum: freshman-level Anatomy and Physiology I and II, junior-level Exercise Physiology, and senior-level Human Pathophysiology. Clickers were used to gather anonymous student responses to questions posed within the class period after individual thought and peer discussion. Students (n = 293, 88% of students completing the courses) completed a perceptual survey on clicker effectiveness inserted into the Student Assessment of Learning Gains online instrument. Across courses and years, students uniformly rated several dimensions of clicker use as providing good to great gain in engaging them in active learning, increasing participation and involvement during class, maintaining attention, applying material immediately, providing feedback concerning their understanding, and offering an anonymous format for participation. Within these four sections, quiz grades were compared between clicker and nonclicker years. Significant increases in pre- and posttest scores were seen in Exercise Physiology in clicker years and on some, but not all material, in Anatomy and Physiology I and II based on content quizzes. Human Pathophysiology results were unexpected, with higher quiz scores in the nonclicker year. The results support the hypothesis of increased engagement with clicker use. The hypothesis of increased student performance was not consistently supported. Increased performance was seen in Exercise Physiology. In Anatomy and Physiology I and II, performance improved on some content quizzes. In Human Pathophysiology, performance did not improve with clickers.