DC-ATLAS: a systems biology resource to dissect receptor specific signal transduction in dendritic cells

BACKGROUND: The advent of Systems Biology has been accompanied by the blooming of pathway databases. Currently pathways are defined generically with respect to the organ or cell type where a reaction takes place. The cell type specificity of the reactions is the foundation of immunological research, and capturing this specificity is of paramount importance when using pathway-based analyses to decipher complex immunological datasets. Here, we present DC-ATLAS, a novel and versatile resource for the interpretation of high-throughput data generated perturbing the signaling network of dendritic cells (DCs). RESULTS: Pathways are annotated using a novel data model, the Biological Connection Markup Language (BCML), a SBGN-compliant data format developed to store the large amount of information collected. The application of DC-ATLAS to pathway-based analysis of the transcriptional program of DCs stimulated with agonists of the toll-like receptor family allows an integrated description of the flow of information from the cellular sensors to the functional outcome, capturing the temporal series of activation events by grouping sets of reactions that occur at different time points in well-defined functional modules. CONCLUSIONS: The initiative significantly improves our understanding of DC biology and regulatory networks. Developing a systems biology approach for immune system holds the promise of translating knowledge on the immune system into more successful immunotherapy strategies

Azobenzene as a Photoregulator Covalently Attached to RNA: A Quantum Mechanics/Molecular Mechanics-Surface Hopping Dynamics Study

The photoregulation of nucleic acids by azobenzene photoswitches has recently attracted considerable interest in the context of emerging biotechnological applications. To understand the mechanism of photoinduced isomerisation and conformational control in these complex biological environments, we employ a Quantum Mechanics/Molecular Mechanics (QM/MM) approach in conjunction with nonadiabatic Surface Hopping (SH) dynamics. Two representative RNA-azobenzene complexes are investigated, both of which contain the azobenzene chromophore covalently attached to an RNA double strand via a beta-deoxyribose linker. Due to the pronounced constraints of the local RNA environment, it is found that trans-to-cis isomerization is slowed down to a time scale of ~15 picoseconds, in contrast to 500 femtoseconds in vacuo, with a quantum yield reduced by a factor of two. By contrast, cis-to-trans isomerization remains in a sub-picosecond regime. A volume-conserving isomerization mechanism is found, similarly to the pedal-like mechanism previously identified for azobenzene in solution phase. Strikingly, the chiral RNA environment induces opposite right-handed and left-handed helicities of the ground-state cis-azobenzene chromophore in the two RNA-azobenzene complexes, along with an almost completely chirality conserving photochemical pathway for these helical enantiomers

Proceedings of the discoveries on post-transcriptional Bcl-2 deregulation in human leukemias/lymphomas: DOI: 10.14800/rd.694

The Bcl-2 (B-cell lymphoma 2) antiapoptotic gene has been discovered since over-expressed in B-cell leukemias/lymphomas carrying the 14;18 chromosomal translocation [t(14;18)], which places the Bcl-2 gene next to the immunoglobulin heavy chain (IgH) locus. In this condition, the Bcl-2 moiety of the Bcl-2/IgH fusion gene is over-transcribed in virtue of the four enhancers located in 3’ of the IgH moiety leading to excessive amounts of the Bcl-2 protein, which confers a survival advantage associated with neoplastic transformation. Nevertheless, in most malignancies, comprising chronic lymphocytic leukemias, breast, prostate, colorectal and lung cancer, the over-expression of Bcl-2 does not imply chromosomal rearrangements, suggesting it could be caused by alterations at post-transcriptional level. We first disclosed the existence of a Bcl-2 post-transcriptional control, which is based on interplay among an Adenine and uracil-Rich cis-acting Element (ARE) located in the 3’UTR of Bcl-2 mRNA and several trans-acting ARE-Binding Proteins (AUBPs), and demonstrated its deregulation in human leukemias/lymphomas. In particular, we have identified some Bcl-2 AUBPs - such as AUF-1, TINO/hMex-3D, the Bcl-2 protein itself and ?-Crystallin - and described their qualitative or quantitative alterations in cancer cells. Moreover, in the attempt to correct Bcl-2 deregulation in the human diseases characterized by defects or excesses of apoptosis, we have modulated exogenously Bcl-2 expression by means of different antisense strategies. In this research highlight, we briefly report our proceedings, in which a long non coding Bcl-2/IgH antisense RNA (Bcl-2/IgH AS) we discovered in a serendipitous manner has played a key role

Azobenzene as a Photoregulator Covalently Attached to RNA: A Quantum Mechanics/Molecular Mechanics-Surface Hopping Dynamics Study

The photoregulation of nucleic acids by azobenzene photoswitches has recently attracted considerable interest in the context of emerging biotechnological applications. To understand the mechanism of photoinduced isomerisation and conformational control in these complex biological environments, we employ a Quantum Mechanics/Molecular Mechanics (QM/MM) approach in conjunction with nonadiabatic Surface Hopping (SH) dynamics. Two representative RNA-azobenzene complexes are investigated, both of which contain the azobenzene chromophore covalently attached to an RNA double strand via a beta-deoxyribose linker. Due to the pronounced constraints of the local RNA environment, it is found that trans-to-cis isomerization is slowed down to a time scale of ~15 picoseconds, in contrast to 500 femtoseconds in vacuo, with a quantum yield reduced by a factor of two. By contrast, cis-to-trans isomerization remains in a sub-picosecond regime. A volume-conserving isomerization mechanism is found, similarly to the pedal-like mechanism previously identified for azobenzene in solution phase. Strikingly, the chiral RNA environment induces opposite right-handed and left-handed helicities of the ground-state cis-azobenzene chromophore in the two RNA-azobenzene complexes, along with an almost completely chirality conserving photochemical pathway for these helical enantiomers