Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.

Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation. This suggests that competition between molecular chaperones and the LBD for the FQNLF motif regulates AR activation. We also show that, while the free NTD oligomerizes, binding to Hsp70 increases its solubility. Stabilizing the NTD-Hsp70 interaction with small molecules reduces AR aggregation and promotes its degradation in cellular and mouse models of the neuromuscular disorder spinal bulbar muscular atrophy. These results help resolve the mechanisms by which molecular chaperones regulate the balance between AR aggregation, activation and quality control

An insight into the sialome of Glossina morsitans morsitans

<p>Abstract</p> <p>Background</p> <p>Blood feeding evolved independently in worms, arthropods and mammals. Among the adaptations to this peculiar diet, these animals developed an armament of salivary molecules that disarm their host's anti-bleeding defenses (hemostasis), inflammatory and immune reactions. Recent sialotranscriptome analyses (from the Greek <it>sialo </it>= saliva) of blood feeding insects and ticks have revealed that the saliva contains hundreds of polypeptides, many unique to their genus or family. Adult tsetse flies feed exclusively on vertebrate blood and are important vectors of human and animal diseases. Thus far, only limited information exists regarding the Glossina sialome, or any other fly belonging to the Hippoboscidae.</p> <p>Results</p> <p>As part of the effort to sequence the genome of <it>Glossina morsitans morsitans</it>, several organ specific, high quality normalized cDNA libraries have been constructed, from which over 20,000 ESTs from an adult salivary gland library were sequenced. These ESTs have been assembled using previously described ESTs from the fat body and midgut libraries of the same fly, thus totaling 62,251 ESTs, which have been assembled into 16,743 clusters (8,506 of which had one or more EST from the salivary gland library). Coding sequences were obtained for 2,509 novel proteins, 1,792 of which had at least one EST expressed in the salivary glands. Despite library normalization, 59 transcripts were overrepresented in the salivary library indicating high levels of expression. This work presents a detailed analysis of the salivary protein families identified. Protein expression was confirmed by 2D gel electrophoresis, enzymatic digestion and mass spectrometry. Concurrently, an initial attempt to determine the immunogenic properties of selected salivary proteins was undertaken.</p> <p>Conclusions</p> <p>The sialome of <it>G. m. morsitans </it>contains over 250 proteins that are possibly associated with blood feeding. This set includes alleles of previously described gene products, reveals new evidence that several salivary proteins are multigenic and identifies at least seven new polypeptide families unique to <it>Glossina</it>. Most of these proteins have no known function and thus, provide a discovery platform for the identification of novel pharmacologically active compounds, innovative vector-based vaccine targets, and immunological markers of vector exposure.</p

Searching for network modules

When analyzing complex networks a key target is to uncover their modular structure, which means searching for a family of modules, namely node subsets spanning each a subnetwork more densely connected than the average. This work proposes a novel type of objective function for graph clustering, in the form of a multilinear polynomial whose coefficients are determined by network topology. It may be thought of as a potential function, to be maximized, taking its values on fuzzy clusterings or families of fuzzy subsets of nodes over which every node distributes a unit membership. When suitably parametrized, this potential is shown to attain its maximum when every node concentrates its all unit membership on some module. The output thus is a partition, while the original discrete optimization problem is turned into a continuous version allowing to conceive alternative search strategies. The instance of the problem being a pseudo-Boolean function assigning real-valued cluster scores to node subsets, modularity maximization is employed to exemplify a so-called quadratic form, in that the scores of singletons and pairs also fully determine the scores of larger clusters, while the resulting multilinear polynomial potential function has degree 2. After considering further quadratic instances, different from modularity and obtained by interpreting network topology in alternative manners, a greedy local-search strategy for the continuous framework is analytically compared with an existing greedy agglomerative procedure for the discrete case. Overlapping is finally discussed in terms of multiple runs, i.e. several local searches with different initializations.Comment: 10 page

Immuno-targeting the multifunctional CD38 using nanobody

published_or_final_versio

On the origin of the Boson peak in globular proteins

We study the Boson Peak phenomenology experimentally observed in globular proteins by means of elastic network models. These models are suitable for an analytic treatment in the framework of Euclidean Random Matrix theory, whose predictions can be numerically tested on real proteins structures. We find that the emergence of the Boson Peak is strictly related to an intrinsic mechanical instability of the protein, in close similarity to what is thought to happen in glasses. The biological implications of this conclusion are also discussed by focusing on a representative case study.Comment: Proceedings of the X International Workshop on Disordered Systems, Molveno (2006

In support of descriptive studies; relevance to translational research

The contemporary scientific establishment equates hypothesis testing to good science. This stance bypasses the preliminary need to identify a worthwhile hypothesis through rigorous observation of natural processes. If alleviation of human suffering is claimed as the goal of a scientific undertaking, it would be unfair to test a hypothesis whose relevance to human disease has not been satisfactorily proven. Here, we argue that descriptive investigations based on direct human observation should be highly valued and regarded essential for the selection of worthwhile hypotheses while the pursuit of costly scientific investigations without such evidence is a desecration of the cause upon which biomedical research is grounded

Gene expression changes associated with Barrett's esophagus and Barrett's-associated adenocarcinoma cell lines after acid or bile salt exposure

<p>Abstract</p> <p>Background</p> <p>Esophageal reflux and Barrett's esophagus represent two major risk factors for the development of esophageal adenocarcinoma. Previous studies have shown that brief exposure of the Barrett's-associated adenocarcinoma cell line, SEG-1, or primary cultures of Barrett's esophageal tissues to acid or bile results in changes consistent with cell proliferation. In this study, we determined whether similar exposure to acid or bile salts results in gene expression changes that provide insights into malignant transformation.</p> <p>Methods</p> <p>Using previously published methods, Barrett's-associated esophageal adenocarcinoma cell lines and primary cultures of Barrett's esophageal tissue were exposed to short pulses of acid or bile salts followed by incubation in culture media at pH 7.4. A genome-wide assessment of gene expression was then determined for the samples using cDNA microarrays. Subsequent analysis evaluated for statistical differences in gene expression with and without treatment.</p> <p>Results</p> <p>The SEG-1 cell line showed changes in gene expression that was dependent on the length of exposure to pH 3.5. Further analysis using the Gene Ontology, however, showed that representation by genes associated with cell proliferation is not enhanced by acid exposure. The changes in gene expression also did not involve genes known to be differentially expressed in esophageal adenocarcinoma. Similar experiments using short-term primary cultures of Barrett's esophagus also did not result in detectable changes in gene expression with either acid or bile salt exposure.</p> <p>Conclusion</p> <p>Short-term exposure of esophageal adenocarcinoma SEG-1 cells or primary cultures of Barrett's esophagus does not result in gene expression changes that are consistent with enhanced cell proliferation. Thus other model systems are needed that may reflect the impact of acid and bile salt exposure on the esophagus <it>in vivo</it>.</p

A visual analytics framework for spatio-temporal analysis and modelling

To support analysis and modelling of large amounts of spatio-temporal data having the form of spatially referenced time series (TS) of numeric values, we combine interactive visual techniques with computational methods from machine learning and statistics. Clustering methods and interactive techniques are used to group TS by similarity. Statistical methods for TS modelling are then applied to representative TS derived from the groups of similar TS. The framework includes interactive visual interfaces to a library of modelling methods supporting the selection of a suitable method, adjustment of model parameters, and evaluation of the models obtained. The models can be externally stored, communicated, and used for prediction and in further computational analyses. From the visual analytics perspective, the framework suggests a way to externalize spatio-temporal patterns emerging in the mind of the analyst as a result of interactive visual analysis: the patterns are represented in the form of computer-processable and reusable models. From the statistical analysis perspective, the framework demonstrates how TS analysis and modelling can be supported by interactive visual interfaces, particularly, in a case of numerous TS that are hard to analyse individually. From the application perspective, the framework suggests a way to analyse large numbers of spatial TS with the use of well-established statistical methods for TS analysis

On the cosmic evolution of the scaling relations between black holes and their host galaxies: Broad Line AGN in the zCOSMOS survey

(Abriged) We report on the measurement of the rest frame K-band luminosity and total stellar mass of the hosts of 89 broad line Active Galactic Nuclei detected in the zCOSMOS survey in the redshift range 1<z<2.2. The unprecedented multiwavelength coverage of the survey field allows us to disentangle the emission of the host galaxy from that of the nuclear black hole in their Spectral Energy Distributions. We derive an estimate of black hole masses through the analysis of the broad Mg II emission lines observed in the medium-resolution spectra taken with VIMOS/VLT as part of the zCOSMOS project. We found that, as compared to the local value, the average black hole to host galaxy mass ratio appears to evolve positively with redshift, with a best fit evolution of the form (1+z)^{0.68 \pm0.12 +0.6 -0.3}, where the large asymmetric systematic errors stem from the uncertainties in the choice of IMF, in the calibration of the virial relation used to estimate BH masses and in the mean QSO SED adopted. A thorough analysis of observational biases induced by intrinsic scatter in the scaling relations reinforces the conclusion that an evolution of the MBH-M* relation must ensue for actively growing black holes at early times: either its overall normalization, or its intrinsic scatter (or both) appear to increase with redshift. This can be interpreted as signature of either a more rapid growth of supermassive black holes at high redshift, a change of structural properties of AGN hosts at earlier times, or a significant mismatch between the typical growth times of nuclear black holes and host galaxies.Comment: 47 pages, 8 figures. Accepted for publication in Ap