Isospin Dynamics in Peripheral Heavy Ion Collisions at Fermi Energies

We present a detailed study of isospin dynamics in peripheral collisions at Fermi energies. We consider symmetric and mixed collisions of (124,112)Sn isotopes at 35 and 50 AMeV to study the isospin transport between the different reaction components (residues, gas and possibly intermediate mass fragments) and, in particular, the charge equilibration in the mixed system. We evaluate the effects of drift terms due to asymmetry and density gradients, which are directly related to the poorly known value and slope of the symmetry energy below saturation density. We verify the importance of an isoscalar momentum dependence of the mean field, which is found to influence the isospin transport since it changes the reaction times. We finally suggest two observables particularly sensitive to the isovector part of the nuclear equation-of-state: the correlation between isospin equilibration and kinetic energy loss for binary events, and the isospin content of the produced mid-rapidity fragments for neck fragmentation events.Comment: 34 pages, 15 figures, Nucl.Phys. A, in pres

Dynamics of mRNA and microRNA Expression in the Estrogen Response of Breast Cancer Cells

Cellular signaling leads to broad changes in gene expression that reprogram the cell and alter cell state. Signaling often begins with cellular receptors binding a ligand and initiating a transcriptional response. One example of this is the estrogen receptor, which binds the ligand estrogen and translocates to the nucleus where it binds to estrogen response elements and regulates the expression numerous target RNAs. The regulatory network of both messenger RNAs (mRNAs) and microRNAs (miRNAs) responding to estrogen stimulation is a complex, dynamic and multilayered program that is critical to the etiology of breast cancer. Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. Recent studies have demonstrated that in addition to its role in promoting proliferation, ERα also protects tumors against metastatic transformation. Current therapeutic strategies inhibit estrogen stimulated signaling and interfere with both beneficial and detrimental signaling pathways regulated by ERα. Additionally, ERα cyclically binds estrogen response elements and induces bursts of transcriptional activity. Together these observations suggest that ERα regulated genes and miRNAs may exhibit temporal variation in expression. Furthermore, it remains unclear if estrogen stimulated pathways exhibit the same temporal expression patterns, or if different pathways exhibit different temporal expression patterns. By combining both RNA-sequencing and small RNA-sequencing of cells responding to estrogen, we uncover the dynamics of both mRNA and miRNA expression in response to estrogen stimulation. Furthermore, we identify a regulatory circuit with potential therapeutic relevance to breast cancer that more specifically inhibits ERα-stimulated growth and survival pathways without interfering with its protective features. In response to estrogen stimulation, MCF7 cells (an estrogen receptor positive model cell line) exhibit induction of miR-503, and repression of the oncogene ZNF217. miR-503 inhibits proliferation in MCF7 cells, in part through its inhibition of the oncogene ZNF217 and the cell-cycle gene CCND1. While numerous regulatory interactions can be mined from this temporal profile of estrogen responsive mRNAs and miRNAs, the induction of the anti-proliferative microRNA, miR-503, both highlights the protective aspects of estrogen signaling and indicates that miR-503 holds promise as a therapeutic for breast cancer.Doctor of Philosoph

Effects of momentum-dependent symmetry potential on heavy-ion collisions induced by neutron-rich nuclei

Using an isospin- and momentum-dependent transport model we study effects of the momentum-dependent symmetry potential on heavy-ion collisions induced by neutron-rich nuclei. It is found that symmetry potentials with and without the momentum-dependence but corresponding to the same density-dependent symmetry energy $E_{sym}(\rho)$ lead to significantly different predictions on several $E_{sym}(\rho)$-sensitive experimental observables especially for energetic nucleons. The momentum- and density-dependence of the symmetry potential have to be determined simultaneously in order to extract the $E_{sym}(\rho)$ accurately. The isospin asymmetry of midrapidity nucleons at high transverse momenta is particularly sensitive to the momentum-dependence of the symmetry potential. It is thus very useful for investigating accurately the equation of state of dense neutron-rich matter.Comment: The version to appear in Nucl. Phys. A. A paragraph and a figure on neutron and proton effective masses in neutron-rich matter are adde

Experimental design for single-cell RNA sequencing

Single-cell RNA sequencing (scRNA-seq) has opened new avenues for the characterization of heterogeneity in a large variety of cellular systems. As this is a relatively new technique, the field is fast evolving. Here, we discuss general considerations in experimental design and the two most popular approaches, plate-based Smart-Seq2 and microdroplet-based scRNA-seq at the example of 10x Chromium. We discuss advantages and disadvantages of both methods and point out major factors to consider in designing successful experiments

Isospin Dynamics in Heavy Ion Collisions: EoS-sensitive Observables

Heavy Ion Collisions (HIC) represent a unique tool to probe the in-medium nuclear interaction in regions away from saturation and at high nucleon momenta. In this report we present a selection of reaction observables particularly sensitive to the isovector part of the interaction, i.e. to the symmetry term of the nuclear Equation of State (EoS) At low energies the behavior of the symmetry energy around saturation influences dissipation and fragment production mechanisms. Predictions are shown for deep-inelastic and fragmentation collisions induced by neutron rich projectiles. Differential flow measurements will also shed lights on the controversial neutron/proton effective mass splitting in asymmetric matter. The high density symmetry term can be derived from isospin effects on heavy ion reactions at relativistic energies (few AGeV range), that can even allow a ``direct'' study of the covariant structure of the isovector interaction in the hadron medium. Rather sensitive observables are proposed from collective flows and from pion/kaon production. The possibility of the transition to a mixed hadron-quark phase, at high baryon and isospin density, is finally suggested. Some signatures could come from an expected ``neutron trapping'' effect.Comment: 10 pages, 5 figures; espcrc1 style; IX Int.Conf. on Nucleus-Nucleus Collisions, Rio de Janeiro Aug.2006; to appear in Nucl.Phys.

An integrative transcriptomics approach identifies miR-503 as a candidate master regulator of the estrogen response in MCF-7 breast cancer cells

Estrogen receptor α (ERα) is an important biomarker of breast cancer severity and a common therapeutic target. In response to estrogen, ERα stimulates a dynamic transcriptional program including both coding and noncoding RNAs. We generate a fine-scale map of expression dynamics by performing a temporal profiling of both messenger RNAs (mRNAs) and microRNAs (miRNAs) in MCF-7 cells (an ER+ model cell line for breast cancer) in response to estrogen stimulation. We identified three primary expression trends—transient, induced, and repressed—that were each enriched for genes with distinct cellular functions. Integrative analysis of mRNA and miRNA temporal expression profiles identified miR-503 as the strongest candidate master regulator of the estrogen response, in part through suppression of ZNF217—an oncogene that is frequently amplified in cancer. We confirmed experimentally that miR-503 directly targets ZNF217 and that overexpression of miR-503 suppresses MCF-7 cell proliferation. Moreover, the levels of ZNF217 and miR-503 are associated with opposite outcomes in breast cancer patient cohorts, with high expression of ZNF217 associated with poor survival and high expression of miR-503 associated with improved survival. Overall, these data indicate that miR-503 acts as a potent estrogen-induced candidate tumor suppressor miRNA that opposes cellular proliferation and has promise as a novel therapeutic for breast cancer. More generally, our work provides a systems-level framework for identifying functional interactions that shape the temporal dynamics of gene expression

Thematic Review Series: Functional Regulation of Lipid Homeostasis by microRNA: Complexity of microRNA function and the role of isomiRs in lipid homeostasis

MicroRNAs (miRNAs) are key posttranscriptional regulators of biological pathways that govern lipid metabolic phenotypes. Recent advances in high-throughput small RNA sequencing technology have revealed the complex and dynamic repertoire of miRNAs. Specifically, it has been demonstrated that a single genomic locus can give rise to multiple, functionally distinct miRNA isoforms (isomiR). There are several mechanisms by which isomiRs can be generated, including processing heterogeneity and posttranscriptional modifications, such as RNA editing, exonuclease-mediated nucleotide trimming, and/or nontemplated nucleotide addition (NTA). NTAs are dominant at the 3′-end of a miRNA, are most commonly uridylation or adenlyation events, and are catalyzed by one or more of several nucleotidyl transferase enzymes. 3′ NTAs can affect miRNA stability and/or activity and are physiologically regulated, whereas modifications to the 5′-ends of miRNAs likely alter miRNA targeting activity. Recent evidence also suggests that the biogenesis of specific miRNAs, or small RNAs that act as miRNAs, can occur through unconventional mechanisms that circumvent key canonical miRNA processing steps. The unveiling of miRNA diversity has significantly added to our view of the complexity of miRNA function. In this review we present the current understanding of the biological relevance of isomiRs and their potential role in regulating lipid metabolism

Essential Function of Dicer in Resolving DNA Damage in the Rapidly Dividing Cells of the Developing and Malignant Cerebellum

Maintenance of genomic integrity is critical during neurodevelopment, particularly in rapidly dividing cerebellar granule neuronal precursors that experience constitutive replication-associated DNA damage. As Dicer was recently recognized to have an unexpected function in the DNA damage response, we examined whether Dicer was important for preserving genomic integrity in the developing brain. We report that deletion of Dicer in the developing mouse cerebellum resulted in the accumulation of DNA damage leading to cerebellar progenitor degeneration, which was rescued with p53 deficiency; deletion of DGCR8 also resulted in similar DNA damage and cerebellar degeneration. Dicer deficiency also resulted in DNA damage and death in other rapidly dividing cells including embryonic stem cells and the malignant cerebellar progenitors in a mouse model of medulloblastoma. Together, these results identify an essential function of Dicer in resolving the spontaneous DNA damage that occurs during the rapid proliferation of developmental progenitors and malignant cells

The Liquid-Gas Phase Transitions in a Multicomponent Nuclear System with Coulomb and Surface Effects

The liquid-gas phase transition is studied in a multi-component nuclear system using a local Skyrme interaction with Coulomb and surface effects. Some features are qualitatively the same as the results of Muller and Serot which uses relativistic mean field without Coulomb and surface effects. Surface tension brings the coexistance binodal surface to lower pressure. The Coulomb interaction makes the binodal surface smaller and cause another pair of binodal points at low pressure and large proton fraction with less protons in liquid phase and more protons in gas phase.Comment: 20 pages including 7 postscript figure

Pseudogenes transcribed in breast invasive carcinoma show subtype-specific expression and ceRNA potential

BackgroundRecent studies have shown that some pseudogenes are transcribed and contribute to cancer when dysregulated. In particular, pseudogene transcripts can function as competing endogenous RNAs (ceRNAs). The high similarity of gene and pseudogene nucleotide sequence has hindered experimental investigation of these mechanisms using RNA-seq. Furthermore, previous studies of pseudogenes in breast cancer have not integrated miRNA expression data in order to perform large-scale analysis of ceRNA potential. Thus, knowledge of both pseudogene ceRNA function and the role of pseudogene expression in cancer are restricted to isolated examples.ResultsTo investigate whether transcribed pseudogenes play a pervasive regulatory role in cancer, we developed a novel bioinformatic method for measuring pseudogene transcription from RNA-seq data. We applied this method to 819 breast cancer samples from The Cancer Genome Atlas (TCGA) project. We then clustered the samples using pseudogene expression levels and integrated sample-paired pseudogene, gene and miRNA expression data with miRNA target prediction to determine whether more pseudogenes have ceRNA potential than expected by chance.ConclusionsOur analysis identifies with high confidence a set of 440 pseudogenes that are transcribed in breast cancer tissue. Of this set, 309 pseudogenes exhibit significant differential expression among breast cancer subtypes. Hierarchical clustering using only pseudogene expression levels accurately separates tumor samples from normal samples and discriminates the Basal subtype from the Luminal and Her2 subtypes. Correlation analysis shows more positively correlated pseudogene-parent gene pairs and negatively correlated pseudogene-miRNA pairs than expected by chance. Furthermore, 177 transcribed pseudogenes possess binding sites for co-expressed miRNAs that are also predicted to target their parent genes. Taken together, these results increase the catalog of putative pseudogene ceRNAs and suggest that pseudogene transcription in breast cancer may play a larger role than previously appreciated.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1227-8) contains supplementary material, which is available to authorized users