Radio Spectra and NVSS Maps of Decametric Sources

We constructed radio spectra for ~1400 UTR-2 sources and find that 46% of them have concave curvature. Inspection of NVSS maps of 700 UTR sources suggests that half of all UTR sources are either blends of two or more sources or have an ultra-steep spectrum (USS). The fraction of compact USS sources in UTR may be near 10%. Using NVSS and the Digitized Sky Survey(s) we expect to double the UTR optical identification rate from currently ~19%.Comment: 2 pages, no figures; to appear in Proc. "Observational Cosmology with the New Radio Surveys", eds. M. Bremer, N. Jackson & I. Perez-Fournon, Kluwer Acad. Pres

AZI23'UTR Is a New SLC6A3 Downregulator Associated with an Epistatic Protection Against Substance Use Disorders

Regulated activity of SLC6A3, which encodes the human dopamine transporter (DAT), contributes to diseases such as substance abuse disorders (SUDs); however, the exact transcription mechanism remains poorly understood. Here, we used a common genetic variant of the gene, intron 1 DNP1B sequence, as bait to screen and clone a new transcriptional activity, AZI23'UTR, for SLC6A3. AZI23'UTR is a 3' untranslated region (3'UTR) of the human 5-Azacytidine Induced 2 gene (AZI2) but appeared to be transcribed independently of AZI2. Found to be present in both human cell nuclei and dopamine neurons, this RNA was shown to downregulate promoter activity through a variant-dependent mechanism in vitro. Both reduced RNA density ratio of AZI23'UTR/AZI2 and increased DAT mRNA levels were found in ethanol-naive alcohol-preferring rats. Secondary analysis of dbGaP GWAS datasets (Genome-Wide Association Studies based on the database of Genotypes and Phenotypes) revealed significant interactions between regions upstream of AZI23'UTR and SLC6A3 in SUDs. Jointly, our data suggest that AZI23'UTR confers variant-dependent transcriptional regulation of SLC6A3, a potential risk factor for SUDs

Hepatitis C virus 3'UTR regulates viral translation through direct interactions with the host translation machinery.

The 3' untranslated region (3'UTR) of hepatitis C virus (HCV) messenger RNA stimulates viral translation by an undetermined mechanism. We identified a high affinity interaction, conserved among different HCV genotypes, between the HCV 3'UTR and the host ribosome. The 3'UTR interacts with 40S ribosomal subunit proteins residing primarily in a localized region on the 40S solvent-accessible surface near the messenger RNA entry and exit sites. This region partially overlaps with the site where the HCV internal ribosome entry site was found to bind, with the internal ribosome entry site-40S subunit interaction being dominant. Despite its ability to bind to 40S subunits independently, the HCV 3'UTR only stimulates translation in cis, without affecting the first round translation rate. These observations support a model in which the HCV 3'UTR retains ribosome complexes during translation termination to facilitate efficient initiation of subsequent rounds of translation

Translation efficiency is a determinant of the magnitude of miRNA-mediated repression

Abstract MicroRNAs are well known regulators of mRNA stability and translation. However, the magnitude of both translational repression and mRNA decay induced by miRNA binding varies greatly between miRNA targets. This can be the result of cis and trans factors that affect miRNA binding or action. We set out to address this issue by studying how various mRNA characteristics affect miRNA-mediated repression. Using a dual luciferase reporter system, we systematically analyzed the ability of selected mRNA elements to modulate miRNA-mediated repression. We found that changing the 3′UTR of a miRNA-targeted reporter modulates translational repression by affecting the translation efficiency. This 3′UTR dependent modulation can be further altered by changing the codon-optimality or 5′UTR of the luciferase reporter. We observed maximal repression with intermediate codon optimality and weak repression with very high or low codon optimality. Analysis of ribosome profiling and RNA-seq data for endogenous miRNA targets revealed translation efficiency as a key determinant of the magnitude of miRNA-mediated translational repression. Messages with high translation efficiency were more robustly repressed. Together our results reveal modulation of miRNA-mediated repression by characteristics and features of the 5′UTR, CDS and 3′UTR

A conserved U-rich RNA region implicated in regulation of translation in Plasmodium female gametocytes.

Translational repression (TR) plays an important role in post-transcriptional regulation of gene expression and embryonic development in metazoans. TR also regulates the expression of a subset of the cytoplasmic mRNA population during development of fertilized female gametes of the unicellular malaria parasite, Plasmodium spp. which results in the formation of a polar and motile form, the ookinete. We report the conserved and sex-specific regulatory role of either the 3’- or 5’-UTR of a subset of translationally repressed mRNA species as shown by almost complete inhibition of expression of a GFP reporter protein in the female gametocyte. A U-rich, TR-associated element, identified previously in the 3’-UTR of TR-associated transcripts, played an essential role in mediating TR and a similar region could be found in the 5’-UTR shown in this study to be active in TR. The silencing effect of this 5’-UTR was shown to be independent of its position relative to its ORF, as transposition to a location 3’ of the ORF did not affect TR. These results demonstrate for the first time in a unicellular organism that the 5’ or the 3’-UTR of TR-associated transcripts play an important and conserved role in mediating TR in female gametocytes

MiR-103a-3p targets the 5\u27 UTR of GPRC5A in pancreatic cells.

MicroRNAs (miRNAs) are short noncoding RNAs that regulate the expression of their targets in a sequence-dependent manner. For protein-coding transcripts, miRNAs regulate expression levels through binding sites in either the 3\u27 untranslated region (3\u27 UTR) or the amino acid coding sequence (CDS) of the targeted messenger RNA (mRNA). Currently, for the 5\u27 untranslated region (5\u27 UTR) of mRNAs, very few naturally occurring examples exist whereby the targeting miRNA down-regulates the expression of the corresponding mRNA in a seed-dependent manner. Here we describe and characterize two miR-103a-3p target sites in the 5\u27 UTR of GPRC5A, a gene that acts as a tumor suppressor in some cancer contexts and as an ongocene in other cancer contexts. In particular, we show that the interaction of miR-103a-3p with each of these two 5\u27 UTR targets reduces the expression levels of both GPRC5A mRNA and GPRC5A protein in one normal epithelial and two pancreatic cancer cell lines. By ectopically expressing sponges that contain instances of the wild-type 5\u27 UTR targets we also show that we can reduce miR-103a-3p levels and increase GPRC5A mRNA and protein levels. These findings provide some first knowledge on the post-transcriptional regulation of this tumor suppressor/oncogene and present additional evidence for the participation of 5\u27 UTRs in miRNA driven post-transcriptional regulatory control

What's the Point of Reciprocal Trade Negotiations? Exports, Imports, and Gains from Trade

This paper explains why trade-policy makers may prefer reciprocal trade negotiations (RTN) to unilateral tariff reductions (UTR) for economic reasons. It answers puzzles like "Why WTO reciprocity?" and strengthens the unncecessarily weak case made for the WTO by those who downplay or dismiss benefits from foreign tariff reductions (FTR). RTN is superior to UTR because it provides economic benefits that UTR cannot -- namely, FTR benefits which are clearer than potentially important UTR benefits: Whereas each policy offers efficiency gains, any terms-of-trade effect of UTR generally detracts from these gains, while any terms-of-trade effect of FTR is typically beneficial (especially for a small price-taking country) with this benefit augmenting FTR's efficiency gains. Moreover, benefits from reductions in foreign barriers may come from several sources; they are not solely the result of terms-of-trade improvement -- or economies of scale (the two benefits already noted in the literature, though often dismissed). E.g. with foreign NTB elimination, possible home benefits are shown even with rising costs and terms-of-trade deterioration. RTN is also superior to UTR because, by eliminating protection in either NTB or tariff form, RTN provides an escape from not only a terms-of-trade prisoners' dilemma, but many other previously unrecognized prisoners' dilemmas, including one in international rent transfers, and several others with no economies-of-scale or terms-of-trade motivation. If reciprocity is an option, but only in a narrower CU or FTA form, such reciprocity may still be superior to UTR, or it may be inferior; theory cannot unambiguously rank these.

cis-acting sequences and trans-acting factors in the localization of mRNA for mitochondrial ribosomal proteins

mRNA localization is a conserved post-transcriptional process crucial for a variety of systems. Although several mechanisms have been identified, emerging evidence suggests that most transcripts reach the protein functional site by moving along cytoskeleton elements. We demonstrated previously that mRNA for mitochondrial ribosomal proteins are asymmetrically distributed in the cytoplasm, and that localization in the proximity of mitochondria is mediated by the 3′-UTR. Here we show by biochemical analysis that these mRNA transcripts are associated with the cytoskeleton through the microtubule network. Cytoskeleton association is functional for their intracellular localization near the mitochondrion, and the 3′-UTR is involved in this cytoskeleton-dependent localization. To identify the minimal elements required for localization, we generated DNA constructs containing, downstream from the GFP gene, deletion mutants of mitochondrial ribosomal protein S12 3′-UTR, and expressed them in HeLa cells. RT-PCR analysis showed that the localization signals responsible for mRNA localization are located in the first 154 nucleotides. RNA pulldown assays, mass spectrometry, and RNP immunoprecipitation assay experiments, demonstrated that mitochondrial ribosomal protein S12 3′-UTR interacts specifically with TRAP1 (tumor necrosis factor receptor-associated protein1), hnRNPM4 (heterogeneous nuclear ribonucleoprotein M4), Hsp70 and Hsp60 (heat shock proteins 70 and 60), and α-tubulin in vitro and in vivo

The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen

Increased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5'untranslated region (5'UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5'UTR, whereas, by contrast, the H-ferritin 5'UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5'UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5'UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1 μM IC(50)) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo