Another "Loophole" in miRNA processing

In this issue of Molecular Cell, Suzuki et al. (2011) present the intriguing finding that an RNAse known to play an important role in immunity regulates miRNA processing in cancer and inflammation by cleaving the terminal loops of many miRNAs. © 2011 Elsevier Inc

RNA-Based Therapeutics: From Antisense Oligonucleotides to miRNAs.

The first therapeutic nucleic acid, a DNA oligonucleotide, was approved for clinical use in 1998. Twenty years later, in 2018, the first therapeutic RNA-based oligonucleotide was United States Food and Drug Administration (FDA) approved. This promises to be a rapidly expanding market, as many emerging biopharmaceutical companies are developing RNA interference (RNAi)-based, and RNA-based antisense oligonucleotide therapies. However, miRNA therapeutics are noticeably absent. miRNAs are regulatory RNAs that regulate gene expression. In disease states, the expression of many miRNAs is measurably altered. The potential of miRNAs as therapies and therapeutic targets has long been discussed and in the context of a wide variety of infections and diseases. Despite the great number of studies identifying miRNAs as potential therapeutic targets, only a handful of miRNA-targeting drugs (mimics or inhibitors) have entered clinical trials. In this review, we will discuss whether the investment in finding potential miRNA therapeutic targets has yielded feasible and practicable results, the benefits and obstacles of miRNAs as therapeutic targets, and the potential future of the field

Six Peaks Visible in the Redshift Distribution of 46,400 SDSS Quasars Agree with the Preferred Redshifts Predicted by the Decreasing Intrinsic Redshift Model

The redshift distribution of all 46,400 quasars in the Sloan Digital Sky Survey (SDSS) Quasar Catalog III, Third Data Release, is examined. Six Peaks that fall within the redshift window below z = 4, are visible. Their positions agree with the preferred redshift values predicted by the decreasing intrinsic redshift (DIR) model, even though this model was derived using completely independent evidence. A power spectrum analysis of the full dataset confirms the presence of a single, significant power peak at the expected redshift period. Power peaks with the predicted period are also obtained when the upper and lower halves of the redshift distribution are examined separately. The periodicity detected is in linear z, as opposed to log(1+z). Because the peaks in the SDSS quasar redshift distribution agree well with the preferred redshifts predicted by the intrinsic redshift relation, we conclude that this relation, and the peaks in the redshift distribution, likely both have the same origin, and this may be intrinsic redshifts, or a common selection effect. However, because of the way the intrinsic redshift relation was determined it seems unlikely that one selection effect could have been responsible for both.Comment: 12 pages, 12 figure, accepted for publication in the Astrophysical Journa

The loop structure and the RNA helicase p72/DDX17 influence the processing efficiency of the mice miR-132

miRNAs are small RNAs that are key regulators of gene expression in eukaryotic organisms. The processing of miRNAs is regulated by structural characteristics of the RNA and is also tightly controlled by auxiliary protein factors. Among them, RNA binding proteins play crucial roles to facilitate or inhibit miRNA maturation and can be controlled in a cell, tissue and species-specific manners or in response to environmental stimuli. In this study we dissect the molecular mechanism that promotes the overexpression of miR-132 in mice over its related, co-transcribed and co-regulated miRNA, miR-212. We have shown that the loop structure of miR-132 is a key determinant for its efficient processing in cells. We have also identified a range of RNA binding proteins that recognize the loop of miR-132 and influence both miR-132 and miR-212 processing. The DEAD box helicase p72/DDX17 was identified as a factor that facilitates the specific processing of miR-132

Author Correction: Triple SILAC identified progestin-independent and dependent PRA and PRB interacting partners in breast cancer

The original version of this Data Descriptor omitted the following author from the Author List: Sarah Bajan. This error has now been corrected in both the PDF and HTML versions of the Article

On the investigations of galaxy redshift periodicity

In this article we present a historical review of study of the redshift periodicity of galaxies, starting from the first works performed in the seventies of the twentieth century until the present day. We discuss the observational data and methods used, showing in which cases the discretization of redshifts was observed. We conclude that galaxy redshift periodisation is an effect which can really exist. We also discussed the redshift discretization in two different structures: the Local Group of galaxies and the Hercules Supercluster. Contrary to the previous studies we consider all galaxies which can be regarded as a structure member disregarding the accuracy of velocity measurements. We applied the power spectrum analysis using the Hann function for weighting, together with the jackknife error estimator. In both the structures we found weak effects of redshift periodisation.Comment: 10 pages, 4 figures, to be published in Part. and Nucl. Lett. 200

Destabilisation of Argonaute 2 generates a truncated protein: halfAgo2

The Argonaute 2 (Ago2) protein is an essential effector protein in miRNA-mediated mechanisms that regulate gene expression. Ago2 directly binds to the miRNA, forming the RISC. RISC function is critical to controlling key biological processes and when dysregulated can result in disease pathogenesis. Understanding Ago2 protein stability and turnover will further our understanding in how RISC function is regulated. In human cells, we discovered a previously unidentified ~55 kDa protein that is a truncated form of Ago2, that is formed from proteolytic cleavage of the full length Ago2 protein. Further experiments are needed to determine (i) the detailed mechanism that forms halfAgo2 (ii) the cellular or environmental triggers or stresses that initiate halfAgo2 production and (iii) if halfAgo2 has a potentially new role in gene regulation

Cell-penetrating peptides containing the progesterone receptor polyproline domain inhibits EGF signaling and cell proliferation in lung cancer cells.

Non-small cell lung cancer (NSCLC) accounts for the majority (80-85%) of all lung cancers. All current available treatments have limited efficacy. The epidermal growth factor receptor (EGFR) plays a critical role in the development and progression of NSCLC, with high EGFR expression associated with increased cell proliferation and poor prognosis. Thus, interfering with EGFR signaling has been shown to effectively reduce cell proliferation and help in the treatment of NSCLC. We previously demonstrated that the progesterone receptor (PR) contains a polyproline domain (PPD) that directly interacts with Src homology 3 (SH3) domain-containing molecules and expression of PR-PPD peptides inhibits NSCLC cell proliferation. In this study, we investigated whether the introduction of PR-PPD by cell-penetrating peptides (CPPs) could inhibit EGF-induced cell proliferation in NSCLC cells. PR-PPD was attached to a cancer-specific CPP, Buforin2 (BR2), to help deliver the PR-PPD into NSCLC cells. Interestingly, addition of BR2-2xPPD peptides containing two PR-PPD repeats was more effective in inhibiting NSCLC proliferation and significantly reduced EGF-induced phosphorylation of Erk1/2. BR2-2xPPD treatment induced cell cycle arrest by inhibiting the expression of cyclin D1 and CDK2 genes in EGFR-wild type A549 cells. Furthermore, the combination treatment of EGFR-tyrosine kinase inhibitors (TKIs), including Gefitinib or Erlotinib, with BR2-2xPPD peptides further suppressed the growth of NSCLC PC9 cells harboring EGFR mutations as compared to EGFR-TKIs treatment alone. Importantly, BR2-2xPPD peptides mediated growth inhibition in acquired Gefitinib- and Erlotinib- resistant lung adenocarcinoma cells. Our data suggests that PR-PPD is the minimal protein domain sufficient to inhibit NSCLC cell growth and has the potential to be developed as a novel NSCLC therapeutic agent

A cell cycle-coordinated Polymerase II transcription compartment encompasses gene expression before global genome activation

© 2019, The Author(s). Most metazoan embryos commence development with rapid, transcriptionally silent cell divisions, with genome activation delayed until the mid-blastula transition (MBT). However, a set of genes escapes global repression and gets activated before MBT. Here we describe the formation and the spatio-temporal dynamics of a pair of distinct transcription compartments, which encompasses the earliest gene expression in zebrafish. 4D imaging of pri-miR430 and zinc-finger-gene activities by a novel, native transcription imaging approach reveals transcriptional sharing of nuclear compartments, which are regulated by homologous chromosome organisation. These compartments carry the majority of nascent-RNAs and active Polymerase II, are chromatin-depleted and represent the main sites of detectable transcription before MBT. Transcription occurs during the S-phase of increasingly permissive cleavage cycles. It is proposed, that the transcription compartment is part of the regulatory architecture of embryonic nuclei and offers a transcriptionally competent environment to facilitate early escape from repression before global genome activation

A kinetic approach to eta' production from a CP-odd phase

The production of (eta,eta')- mesons during the decay of a CP-odd phase is studied within an evolution operator approach. We derive a quantum kinetic equation starting from the Witten-DiVecchia-Veneziano Lagrangian for pseudoscalar mesons containing a U_A(1) symmetry breaking term. The non-linear vacuum mean field for the flavour singlet pseudoscalar meson is treated as a classical, self-interacting background field with fluctuations assumed to be small. The numerical solution provides the time evolution of momentum distribution function of produced eta'- mesons after a quench at the deconfinement phase transition. We show that the time evolution of the momentum distribution of the produced mesons depend strongly on the shape of the effective potential at the end of the quench, exhibiting either parametric or tachyonic resonances. Quantum statistical effects are essential and lead to a pronounced Bose enhancement of the low momentum states.Comment: 10 pages, latex, epsfig, 6 figure