Lin28A and Lin28B Inhibit let-7 MicroRNA Biogenesis by Distinct Mechanisms

SummaryLin28A and Lin28B selectively block the expression of let-7 microRNAs and function as oncogenes in a variety of human cancers. Lin28A recruits a TUTase (Zcchc11/TUT4) to let-7 precursors to block processing by Dicer in the cell cytoplasm. Here we find that unlike Lin28A, Lin28B represses let-7 processing through a Zcchc11-independent mechanism. Lin28B functions in the nucleus by sequestering primary let-7 transcripts and inhibiting their processing by the Microprocessor. The inhibitory effects of Zcchc11 depletion on the tumorigenic capacity and metastatic potential of human cancer cells and xenografts are restricted to Lin28A-expressing tumors. Furthermore, the majority of human colon and breast tumors analyzed exclusively express either Lin28A or Lin28B. Lin28A is expressed in HER2-overexpressing breast tumors, whereas Lin28B expression characterizes triple-negative breast tumors. Overall our results illuminate the distinct mechanisms by which Lin28A and Lin28B function and have implications for the development of new strategies for cancer therapy

Quark-Gluon String Model Description of Baryon Production in K^{\pm}N Interactions

The process of baryon production in K p collisions at high energies is considered in the framework of the Quark-Gluon String Model. The contribution of the string-junction mechanism to the strange baryon production is analysed. The results of numerical calculations are in reasonable agreement with the data on inclusive spectra of p, Lambda, bar{Lambda}, and on the bar{Lambda}/Lambda asymmetry. The predictions for Xi and Omega baryons are presented.Comment: 19 pages, 7 figure

Interactions of Heavy Hadrons using Regge Phenomenology and the Quark Gluon String Model

The search for stable heavy exotic hadrons is a promising way to observe new physics processes at collider experiments. The discovery potential for such particles can be enhanced or suppressed by their interactions with detector material. This paper describes a model for the interactions in matter of stable hadrons containing an exotic quark of charges $\pm {1/3}e$ or $\pm {2/3}e$ using Regge phenomenology and the Quark Gluon String Model. The influence of such interactions on searches at the LHC is also discussed

Feynman scaling violation on baryon spectra in pp collisions at LHC and cosmic ray energies

A significant asymmetry in baryon/antibaryon yields in the central region of high energy collisions is observed when the initial state has non-zero baryon charge. This asymmetry is connected with the possibility of baryon charge diffusion in rapidity space. Such a diffusion should decrease the baryon charge in the fragmentation region and translate into the corresponding decrease of the multiplicity of leading baryons. As a result, a new mechanism for Feynman scaling violation in the fragmentation region is obtained. Another numerically more significant reason for the Feynman scaling violation comes from the fact that the average number of cutted Pomerons increases with initial energy. We present the quantitative predictions of the Quark-Gluon String Model (QGSM) for the Feynman scaling violation at LHC energies and at even higher energies that can be important for cosmic ray physics.Comment: 21 pages, 11 figures, and 1 table. arXiv admin note: substantial text overlap with arXiv:1107.1615, arXiv:1007.320

Asymmetries between the production of D+ and D- mesons from 500 GeV/c pi- nucleon interactions as a function of xF and pt**2

We present asymmetries between the production of D+ and D- mesons in Fermilab experiment E791 as a function of xF and pt**2. The data used here consist of 74,000 fully-reconstructed charmed mesons produced by a 500 GeV/c pi- beam on C and Pt foils. The measurements are compared to results of models which predict differences between the production of heavy-quark mesons that have a light quark in common with the beam (leading particles) and those that do not (non-leading particles). While the default models do not agree with our data, we can reach agreement with one of them, PYTHIA, by making a limited number of changes to parameters used

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

DAZL Relieves miRNA-Mediated Repression of Germline mRNAs by Controlling Poly(A) Tail Length in Zebrafish

BACKGROUND:During zebrafish embryogenesis, microRNA (miRNA) miR-430 contributes to restrict Nanos1 and TDRD7 to primordial germ cells (PGCs) by inducing mRNA deadenylation, mRNA degradation, and translational repression of nanos1 and tdrd7 mRNAs in somatic cells. The nanos1 and tdrd7 3'UTRs include cis-acting elements that allow activity in PGCs even in the presence of miRNA-mediated repression. METHODOLOGY/PRINCIPAL FINDINGS:Using a GFP reporter mRNA that was fused with tdrd7 3'UTR, we show that a germline-specific RNA-binding protein DAZ-like (DAZL) can relieve the miR-430-mediated repression of tdrd7 mRNA by inducing poly(A) tail elongation (polyadenylation) in zebrafish. We also show that DAZL enhances protein synthesis via the 3'UTR of dazl mRNA, another germline mRNA targeted by miR-430. CONCLUSIONS/SIGNIFICANCE:Our present study indicated that DAZL acts as an "anti-miRNA factor" during vertebrate germ cell development. Our data also suggested that miRNA-mediated regulation can be modulated on specific target mRNAs through the poly(A) tail control

Charmed particle production in hadron-hadron collision

In the framework of Quark--Gluon--String Model developed recently in ITEP we calculate spectra of charmed particles $D$, $D_s$, $\Lambda_c$, $\Xi_c$, $\Omega_c$ in hadron--hadron collisions taking into account the decays of $S$--wave resonances like $D^*$, $D^*_s$, $\Sigma_c$, $\Sigma^*_c$, $\Xi^*_c$, $\Xi'_c$, and $\Omega^*_c$. We describe the bulk of the existing data on $D$, $D^*$, and $\Lambda_c$ production in $\pi p$ and $pp$ collisions and predict the yield of charmed particles in $\Sigma^-p$ and $\Xi^-p$ reactions at hyperon beam energies of $340\;GeV/c$ and $600\;GeV/c$. Because of significant production of baryon resonances our predictions for unfavored fragmentation differ from predictions of other models which do not take resonance production into account.Comment: Latex,19 pages, 12figs. can be received by reques

TGF-ß induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression.

Abstract TGF-ß/Activin induces epithelial-to-mesenchymal transition (EMT) and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-ß transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-ß also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-ß-mediated response indicating that these miRNAs are important TGF-ß effectors. We integrated AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell-cell junctions’ pathways. Together, we uncover that TGF-ß induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b, play opposing roles in controlling PDAC tumourigenesis