MicroRNA history : discovery, recent applications and next frontiers

We thank the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for English language editing of the manuscript.Since 1993, when the first small non-coding RNA was identified, our knowledge about microRNAs has grown exponentially. In this review, we focus on the main progress in this field and discuss the most important findings under a historical perspective. In addition, we examine microRNAs as markers ofdisease diagnosis and prognosis, and as new therapeutic targets.M.I.A is supported by a PhD fellowship (SFRH/BD/47031/2008) from FCT (Fundação para a Ciência e Tecnologia) from Portugal. G.A.C. is supported as a Fellow at The University of Texas MD Anderson Research Trust, as a Fellow of The University of Texas System Regents Research Scholar, and by the CLL Global Research Foundation. Work in Dr. Calin’s laboratory was supported in part by NIH, by DoD, by 2009 Seena Magowitz – Pancreatic Cancer Action Network – AACR Pilot Grant and by the U.S./European Alliance for the Therapy of CLL

MicroRNAs and metastases--the neuroblastoma link

[Excerpt] MicroRNAs (miRNAs) are small noncoding RNAs of approximately 22 nucleotides in length that regulate gene expression post-transcriptionally. These small RNAs are fundamental regulators of several cellular processes, such as differentiation, development, apoptosis, proliferation, cell cycle regulation and metabolism, through the binding to 3' untranslated regions, coding sequence or 5' untranslated regions of target messenger RNAs (mRNAs), preventing their translation or causing their degradation.1 A modest change in only one miRNA will affect multiple mRNA targets; consequently, the deregulation of miRNAs has important consequences to the cellular homeostatic stability, and aberrant miRNAs expression patterns have been described in several types of cancer.2 Recently, miRNAs have been implicated in the metastatic process of several tumors such as human breast and colorectal cancers3 and, as reported this issue of Cancer Biology & Therapy by Guo et al. in neuroblastoma.4 These are extracranial solid tumors, arising from neural crest cells, that are most common in infants and children; metastasis, the main cause of death, is present at the time of diagnosis in approximately 60% of patients. (5) [...

Computational Techniques for Analysis of Genetic Network Dynamics

In this paper we propose modeling and analysis techniques for genetic networks that provide biologists with insight into the dynamics of such systems. Central to our modeling approach is the framework of hybrid systems and our analysis tools are derived from formal analysis of such systems. Given a set of states characterizing a property of biological interest P, we present the Multi-Affine Rectangular Partition (MARP) algorithm for the construction of a set of infeasible states I that will never reach P and the Rapidly Exploring Random Forest of Trees (RRFT) algorithm for the construction of a set of feasible states F that will reach P. These techniques are scalable to high dimensions and can incorporate uncertainty (partial knowledge of kinetic parameters and state uncertainty). We apply these methods to understand the genetic interactions involved in the phenomenon of luminescence production in the marine bacterium V. fischeri

Exact N=2 Supergravity Solutions With Polarized Branes

We construct several classes of exact supersymmetric supergravity solutions describing D4 branes polarized into NS5 branes and F-strings polarized into D2 branes. These setups belong to the same universality class as the perturbative solutions used by Polchinski and Strassler to describe the string dual of N=1* theories. The D4-NS5 setup can be interpreted as a string dual to a confining 4+1 dimensional theory with 8 supercharges, whose properties we discuss. By T-duality, our solutions give Type IIB supersymmetric backgrounds with polarized branes.Comment: 22 pages. v2 - references added, details clarifie

A novel gamma-N-methylaminobutyrate demethylating oxidase involved in catabolism of the tobacco alkaloid nicotine by Arthrobacter nicotinovorans pAO1

Nicotine catabolism, linked in Arthrobacter nicotinovorans to the presence of the megaplasmid pAO1, leads to the formation of gamma-N-methylaminobutyrate from the pyrrolidine ring of the alkaloid. Until now the metabolic fate of gamma-N-methylaminobutyrate has been unknown. pAO1 carries a cluster of ORFs with similarity to sarcosine and dimethylglycine dehydrogenases and oxidases, to the bifunctional enzyme methylenetetrahydrofolate dehydrogenase/cyclohydrolase and to formyltetrahydrofolate deformylase. We cloned and expressed the gene carrying the sarcosine dehydrogenase-like ORF and showed, by enzyme activity, spectrophotometric methods and identification of the reaction product as gamma-aminobutyrate, that the predicted 89 395 Da flavoprotein is a demethylating gamma-N-methylaminobutyrate oxidase. Site-directed mutagenesis identified His67 as the site of covalent attachment of FAD and confirmed Trp66 as essential for FAD binding, for enzyme activity and for the spectral properties of the wild-type enzyme. A K-m of 140 mum and a k(cat) of 800 s(-1) was determined when gamma-N-methylaminobutyrate was used as the substrate. Sarcosine was also turned over by the enzyme, but at a rate 200-fold slower than gamma-N-methylaminobutyrate. This novel enzyme activity revealed that the first step in channelling the gamma-N-methylaminobutyrate generated from nicotine into the cell metabolism proceeds by its oxidative demethylation

Lagrangian Variational Framework for Boundary Value Problems

A boundary value problem is commonly associated with constraints imposed on a system at its boundary. We advance here an alternative point of view treating the system as interacting "boundary" and "interior" subsystems. This view is implemented through a Lagrangian framework that allows to account for (i) a variety of forces including dissipative acting at the boundary; (ii) a multitude of features of interactions between the boundary and the interior fields when the boundary fields may differ from the boundary limit of the interior fields; (iii) detailed pictures of the energy distribution and its flow; (iv) linear and nonlinear effects. We provide a number of elucidating examples of the structured boundary and its interactions with the system interior. We also show that the proposed approach covers the well known boundary value problems.Comment: 41 pages, 3 figure

Holomorphic matrix models

This is a study of holomorphic matrix models, the matrix models which underlie the conjecture of Dijkgraaf and Vafa. I first give a systematic description of the holomorphic one-matrix model. After discussing its convergence sectors, I show that certain puzzles related to its perturbative expansion admit a simple resolution in the holomorphic set-up. Constructing a `complex' microcanonical ensemble, I check that the basic requirements of the conjecture (in particular, the special geometry relations involving chemical potentials) hold in the absence of the hermicity constraint. I also show that planar solutions of the holomorphic model probe the entire moduli space of the associated algebraic curve. Finally, I give a brief discussion of holomorphic $ADE$ models, focusing on the example of the $A_2$ quiver, for which I extract explicitly the relevant Riemann surface. In this case, use of the holomorphic model is crucial, since the Hermitian approach and its attending regularization would lead to a singular algebraic curve, thus contradicting the requirements of the conjecture. In particular, I show how an appropriate regularization of the holomorphic $A_2$ model produces the desired smooth Riemann surface in the limit when the regulator is removed, and that this limit can be described as a statistical ensemble of `reduced' holomorphic models.Comment: 45 pages, reference adde

MYC-microRNA-9-metastasis connection in breast cancer

[Excerpt] Metastasis accounts for more than 90% of cancer patients’ mortality. The metastatic process involves multiple steps [1]. Initially, cancer cells from the primary tumor invade adjacent stroma. To acquire this capacity, cells undergo a process called epithelial-mesenchymal transition (EMT), in which cells in re-sponse to signals from the surrounding stroma, undergo a switch between cell phenotypes and acquire mesenchymal properties and show reduced intercel-lular adhesion, allowing cells to be-come motile. Then cells enter systemic circulation, either through the blood or lymph, and finally extravasate into the parenchyma of distant tissues, where they form micrometastasis and prolifer-ate to form secondary tumors [2]. [...

Single event effects in static and dynamic registers in a 0.25−μ−m0.25-\mu-m CMOS technology

We have studied single event effects in static and dynamic registers designed in a quarter micron CMOS process. In our design, we systematically used guardrings and enclosed (edgeless) transistor geometry to improve the total dose tolerance. This design technique improved both the SEL and SEU sensitivity of the circuits. Using SPICE simulations, the measured smooth transition of the cross-section curve between LET threshold and saturation has been traced to the presence of four different upset modes, each corresponding to a different critical charge and sensitive area. A new architecture to protect the content of storage cells has been developed, and a threshold LET around 89 MeV cm/sup 2/ mg/sup -1/ has been measured for this cell at a power supply voltage of 2 V