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

Longitudinal Water Permeability of Western Hemlock. I. Steady-State Permeability

Average initial permeability to water of sapwood was found to be 9.6 X 10-10 cm2, that of wetwood from heartwood was 6.64 X 10-10 cm2, and that of normal heartwood was 4.4 X 10-12 cm2. All the specimens were never-dried, approximately 0.95 cm in diameter and 2 cm long, and were embedded in a lucite tube using epoxy resin as binder.Using polyethylene glycol 1000 as an embedding agent, 23% of sapwood pits, 42% of pits in wetwood from heartwood, and 84% of pits in normal heartwood were found to be aspirated. Scanning electron microscopy revealed that the normal heartwood of freeze-dried heartwood was heavily incrusted, but that of wetwood was relatively free of incrustation. High water permeability of wet heartwood was attributed to a low level of pit aspiration and freedom from incrustation.Both sapwood and wetwood exhibited deterioration of permeability with time. In sapwood the cause was considered to be time-dependent pit aspiration because of hydrostatic pressure differentials during testing, but in wetwood the deterioration was attributed to extractives transported by water and deposited on pit membranes to form an impermeable coat of film.A further proposal is that formation of wet pockets during drying of western hemlock lumber is caused by formation of an impermeable zone from the incrustation of pits by extractives during the migration of water, which traps the moisture in lumber

Drying and Other Related Properties of Western Hemlock Sinker Heartwood

Sinker heartwood dries more slowly than normal heartwood of western hemlock. Extraction with ethanol or acetone and presteaming improved the rate of drying of sinker heart-wood. Electron microscopy was used to examine bordered pits in normal and sinker heartwood and extracted specimens of sinker heartwood. Parallel capacitance was lowest in sapwood, higher in normal heartwood, and highest in sinker heartwood. The range in capacitance was related to total extractive content at similar moisture contents

Identification of HIVEP2 as a dopaminergic transcription factor related to substance use disorders in rats and humans

Playing an important role in the etiology of substance use disorder (SUD), dopamine (DA) neurons are subject to various regulations but transcriptional regulations are largely understudied. For the first time, we report here that the Human Immunodeficiency Virus Type I Enhancer Binding Protein 2 (HIVEP2) is a dopaminergic transcriptional regulator. HIVEP2 is expressed in both the cytoplasm and nuclei of DA neurons. Therein, HIVEP2 can target the intronic sequence GTGGCTTTCT of SLC6A3 and thereby activate the gene. In naive rats from the bi-directional selectively bred substance-preferring P vs -nonpreferring NP rat model of substance abuse vulnerability, increased gene activity in males was associated with the vulnerability, whereas decreased gene activity in the females was associated with the same vulnerability. In clinical subjects, extensive and significant HIVEP2-SLC6A3 interactions were observed for SUD. Collectively, HIVEP2-mediated transcriptional mechanisms are implicated in dopaminergic pathophysiology of SUD

Rapid differentiation of sexual signals in invasive toads: call variation among populations

Advertisement calls tend to differ among populations, based on morphological and environmental factors, or simply geographic distance, in many taxa. Invasive cane toads (Rhinella marina) were introduced to Australia in 1935 and their distribution has expanded at increasing rates over time. Rapid evolution occurred in morphological and behavioural characters that accelerate dispersal, but the effects of rapid expansion on sexual signals have not been examined. We collected advertisement calls from four populations of different ages since invasion, and analysed the geographic differentiation of seven call parameters. Our comparisons indicate that the calls of R. marina differ among Australian populations. The signal variation was not simply clinal with respect to population age, climate, or morphological differentiation. We suggest that selection on signalling among populations has been idiosyncratic and may reflect local female preferences or adaptation to environmental factors that are not clinal such as energy availability

Foreground Predictions for the Cosmic Microwave Background Power Spectrum from Measurements of Faint Inverted Radio Sources at 5 GHz

We present measurements of a population of matched radio sources at 1.4 and 5 GHz down to a flux limit of 1.5 mJy in 7 sq. degs. of the NOAO Deep Field South. We find a significant fraction of sources with inverted spectral indices that all have 1.4 GHz fluxes less than 10 mJy, and are therefore too faint to have been detected and included in previous radio source count models that are matched at multiple frequencies. Combined with the matched source population at 1.4 and 5 GHz in 1 sq. deg. in the ATESP survey, we update models for the 5 GHz differential number counts and distributions of spectral indices in 5 GHz flux bins that can be used to estimate the unresolved point source contribution to the cosmic microwave background temperature anisotropies. We find a shallower logarithmic slope in the 5 GHz differential counts than in previously published models for fluxes < 100 mJy as well as larger fractions of inverted spectral indices at these fluxes. Because the Planck flux limit for resolved sources is larger than 100 mJy in all channels, our modified number counts yield at most a 10% change in the predicted Poisson contribution to the Planck temperature power spectrum. For a flux cut of 5 mJy with the South Pole Telescope and a flux cut of 20 mJy with the Atacama Cosmology Telescope we predict a ~30% and ~10% increase, respectively, in the radio source Poisson power in the lowest frequency channels of each experiment relative to that predicted by previous models.Comment: 14 pages, 9 figures, includes ApJ proof correction

Matriptase regulates c-Met mediated proliferation and invasion in inflammatory breast cancer.

The poor prognosis for patients with inflammatory breast cancer (IBC) compared to patients with other types of breast cancers emphasizes the need to better understand the molecular underpinnings of this disease with the goal of developing effective targeted therapeutics. Dysregulation of matriptase expression, an epithelial-specific member of the type II transmembrane serine protease family, has been demonstrated in many different cancer types. To date, no studies have assessed the expression and potential pro-oncogenic role of matriptase in IBC. We examined the functional relationship between matriptase and the HGF/c-MET signaling pathway in the IBC cell lines SUM149 and SUM190, and in IBC patient samples. Matriptase and c-Met proteins are localized on the surface membrane of IBC cells and their expression is strongly correlated in infiltrating cancer cells and in the cancer cells of lymphatic emboli in patient samples. Abrogation of matriptase expression by silencing with RNAi or inhibition of matriptase proteolytic activity with a synthetic inhibitor impairs the conversion of inactive pro-HGF to active HGF and subsequent c-Met-mediated signaling, leading to efficient impairment of proliferation and invasion of IBC cells. These data show the potential of matriptase inhibitors as a novel targeted therapy for IBC, and lay the groundwork for the development and testing of such drugs

Macrophage Migration Inhibitory Factor Mediates Protease-Activated Receptor 4-Induced Bladder Pain Through Urothelial High Mobility Group Box 1

Macrophage migration inhibitory factor (MIF) mediates pain although the mechanisms are not well understood. Urothelial activation of protease activated receptor 4 (PAR4) results in urothelial MIF release, urothelial high mobility group box 1 (HMGB1) release and bladder pain in mice without bladder inflammation. All three effects are prevented by MIF inhibition while intravesical disulfide HMGB1 alone can induce bladder pain. This study utilizes genetic MIF deletion to determine whether MIF mediates PAR4-induced bladder pain and is upstream of HMGB1-induced bladder pain. Wild type (C57/BL6) and MIF knockout (KO) mice were treated with intravesical PAR4 activating peptide or disulfide HMGB1 and tested for abdominal mechanical hypersensitivity at baseline (before treatment) and 24 h after injection. Micturition parameters and bladder histology were examined after behavioral test. Real-time PCR and western blotting measured HMGB1 mRNA and protein levels in the bladders of naïve wild type and MIF KO mice, while immunofluorescence measured HMGB1 protein levels in the urothelium of both strains. Intravesical PAR4 activation resulted in abdominal mechanical hypersensitivity in wild-type mice but not MIF KO mice. Intravesical disulfide HMGB1 induced abdominal mechanical hypersensitivity in both strains. Neither treatment resulted in significant changes in micturition or bladder histology in either strain. HMGB1 mRNA and protein levels were higher in MIF KO mouse bladders and the urothelium of MIF KO bladder had greater immunostaining than the wild-type strain. MIF is a pivotal molecule mediating PAR4-induced bladder pain and regulating urothelial HMGB1 production and release to elicit bladder pain