Ancient Exaptation of a CORE-SINE Retroposon into a Highly Conserved Mammalian Neuronal Enhancer of the Proopiomelanocortin Gene

The proopiomelanocortin gene (POMC) is expressed in the pituitary gland and the ventral hypothalamus of all jawed vertebrates, producing several bioactive peptides that function as peripheral hormones or central neuropeptides, respectively. We have recently determined that mouse and human POMC expression in the hypothalamus is conferred by the action of two 5′ distal and unrelated enhancers, nPE1 and nPE2. To investigate the evolutionary origin of the neuronal enhancer nPE2, we searched available vertebrate genome databases and determined that nPE2 is a highly conserved element in placentals, marsupials, and monotremes, whereas it is absent in nonmammalian vertebrates. Following an in silico paleogenomic strategy based on genome-wide searches for paralog sequences, we discovered that opossum and wallaby nPE2 sequences are highly similar to members of the superfamily of CORE-short interspersed nucleotide element (SINE) retroposons, in particular to MAR1 retroposons that are widely present in marsupial genomes. Thus, the neuronal enhancer nPE2 originated from the exaptation of a CORE-SINE retroposon in the lineage leading to mammals and remained under purifying selection in all mammalian orders for the last 170 million years. Expression studies performed in transgenic mice showed that two nonadjacent nPE2 subregions are essential to drive reporter gene expression into POMC hypothalamic neurons, providing the first functional example of an exapted enhancer derived from an ancient CORE-SINE retroposon. In addition, we found that this CORE-SINE family of retroposons is likely to still be active in American and Australian marsupial genomes and that several highly conserved exonic, intronic and intergenic sequences in the human genome originated from the exaptation of CORE-SINE retroposons. Together, our results provide clear evidence of the functional novelties that transposed elements contributed to their host genomes throughout evolution

Cosmological Feedback from High-Redshift Dwarf Galaxies

We model how repeated supernova explosions in high-redshift dwarf starburst galaxies drive superbubbles and winds out of the galaxies. We compute the efficiencies of metal and mass ejection and energy transport from the galactic potentials, including the effect of cosmological infall of external gas. The starburst bubbles quickly blow out of small, high-redshift, galactic disks, but must compete with the ram pressure of the infalling gas to escape into intergalactic space. We show that the assumed efficiency of the star formation rate dominates the bubble evolution and the metal, mass, and energy feedback efficiencies. With star formation efficiency f*=0.01, the ram pressure of infall can confine the bubbles around high-redshift dwarf galaxies with circular velocities v_c>52 km/s. We can expect high metal and mass ejection efficiencies, and moderate energy transport efficiencies in halos with v_c~30-50 km/s and f*~0.01 as well as in halos with v_c~100 km/s and f*>>0.01. Such haloes collapse successively from 1-2 sigma peaks in LambdaCDM Gaussian density perturbations as time progresses. These dwarf galaxies can probably enrich low and high-density regions of intergalactic space with metals to 10^-3-10^-2 Zsun as they collapse at z~8 and z<5 respectively. They also may be able to provide adequate turbulent energy to prevent the collapse of other nearby halos, as well as to significantly broaden Lyman-alpha absorption lines to v_rms~20-40 km/s. We compute the timescales for the next starbursts if gas freely falls back after a starburst, and find that, for star formation efficiencies as low as f*<0.01, the next starburst should occur in less than half the Hubble time at the collapse redshift. This suggests that episodic star formation may be ubiquitous in dwarf galaxies.Comment: Accepted for ApJ v613, 60 pages, 15 figure

The essence of psychologic and pedagogical diagnostics

Уточняется понятие «психолого-педагогическая диагностика», рассматриваются функции, принципы, этапы психолого-педагогической диагностикиIn the article the idea of «psychologic and pedagogical diagnostics» is precised, also there are facilities, values, and phases of psychologic and pedagogical diagnostic

Herpes Simplex Virus Type-2 Cervicovaginal Shedding Among Women Living With HIV-1 and Receiving Antiretroviral Therapy in Burkina Faso: An 8-Year Longitudinal Study.

BACKGROUND: The impact of antiretroviral therapy (ART) on herpes simplex virus type-2 (HSV-2) replication is unclear. The aim of this study was to assess factors associated with cervicovaginal HSV-2 DNA shedding and genital ulcer disease (GUD) in a cohort of women living with human immunodeficiency virus type-1 (HIV-1) in Burkina Faso. METHODS: Participants were screened for cervicovaginal HSV-2 DNA, GUD, cervicovaginal and systemic HIV-1 RNA, and reproductive tract infections every 3-6 months over 8 years. Associations with HSV-2 shedding and quantity were examined using random-effects logistic and linear regression, respectively. RESULTS: Of the 236 women with data on HSV-2 shedding, 151 took ART during the study period. Cervicovaginal HSV-2 DNA was detected in 42% of women (99 of 236) in 8.2% of visits (151 of 1848). ART was associated with a reduction in the odds of HSV-2 shedding, which declined for each year of ART use (odds ratio [OR], 0.74; 95% confidence interval [CI], .59-.92). In the multivariable model, the impact of ART was primarily associated with suppression of systemic HIV-1 RNA (adjusted OR, 0.32; 95% CI, .15-.67). A reduction in the odds of GUD was also observed during ART, mainly in those with HIV-1 suppression (adjusted OR, 0.53; 95% CI, .25-1.11). CONCLUSIONS: ART is strongly associated with a decrease in cervicovaginal HSV-2 shedding, and the impact was sustained over several years

Low variability of single-molecule conductance assisted by bulky metal-molecule contacts

A detailed study of the trimethylsilylethynyl moiety, –C[triple bond]CSiMe3 (TMSE) , as an anchoring group in metalmoleculemetal junctions, using a combination of experiment and density functional theory is presented. It is shown that the TMSE anchoring group provides improved control over the molecule-substrate arrangement within metalmoleculemetal junctions, with the steric bulk of the methyl groups limiting the number of highly transmissive binding sites at the electrode surface, resulting in a single sharp peak in the conductance histograms recorded by both the in situ break junction and I(s) STM techniques. As a consequence of the low accessibility of the TMSE group to surface binding configurations of measurable conductance, only about 10% of gold break junction formation cycles result in the clear formation of molecular junctions in the experimental histograms. The DFT-computed transmission characteristics of junctions formed from the TMSE-contacted oligo(phenylene)ethynylene (OPE)-based molecules described here are dominated by tunneling effects through the highest-occupied molecular orbitals (HOMOs). This gives rise to similar conductance characteristics in these TMSE-contacted systems as found in low conductance-type junctions based on comparably structured OPE-derivatives with amine-contacts that also conduct through HOMO-based channels.R. R. F. thanks the Consejería de Educación del Principado de Asturias for a Severo Ochoa grant (BP11-069). V. M. G.-S. thanks the Spanish Ministerio de Economía y Competitividad for a Ramón y Cajal fellowship (RYC-2010-06053). R. R. F., J. F. and V. M. G.-S. wish to acknowledge financial support from the Spanish grant FIS2012-34858 and the Marie Curie Network MOLESCO. P. C. and S. M. are grateful for financial assistance from the Ministerio de Economía y Competitividad of Spain in the framework of the project CTQ2012-33198 as well as the award of the CTQ2013-50187-EXP grant. H. M. O., P. C., and S. M. thank the support from DGA and Fondos FEDER for funding through the Platon research group. H. M. O. is also grateful for financial assistance from the Secretaría Nacional de Educación Superior, Ciencia, Tecnología e Innovaciín from Ministerio de Educación (Ecuador). S. M. thanks the Ministerio de Educación from Spain for financial support through the framework of the Campus de Excelencia Internacional, CEI Iberus. S. J. H., R. J. N., P. J. L. and S. M.-G. thank the EPSRC for funding (EPSRC grants EP/K007785/1, EP/H035184/1, EP/K007548/1, EP/H005595/1). P. J. L. holds an Australian Research Council Future Fellowship (FT120100073) and gratefully acknowledges funding for this work from the ARC (DP140100855).Peer Reviewe

A Transgenic Marker for Newly Born Granule Cells in Dentate Gyrus

Neurogenesis in the dentate gyrus continues into adulthood, yet little is known about the function of newly born neurons or how they integrate into an existing network of mature neurons. We made transgenic mice that selectively and transiently express enhanced green fluorescent protein (EGFP) in newly born granule cells of the dentate gyrus under the transcriptional control of proopiomelanocortin (POMC) genomic sequences. Analysis of transgenic pedigrees with truncation or deletion mutations indicated that EGFP expression in the dentate gyrus required cryptic POMC promoter regions dispensable for arcuate hypothalamic or pituitary expression. Unlike arcuate neurons, dentate granule cells did not express the endogenous POMC gene. EGFP-positive neurons had immature properties, including short spineless dendrites and small action potentials. Colocalization with bromodeoxyuridine indicated that EGFP-labeled granule cells were 2 weeks postmitotic. EGFP-labeled cells expressed markers for immature granule cells but not the glial marker GFAP. The number of EGFP-labeled neurons declined with age and increased with exercise, paralleling neurogenesis. Our results indicate that POMC-EGFP marks immature granule cells and that adult-generated granule cells integrate quite slowly into the hippocampal circuitry

Towards molecular electronic devices based on 'all-carbon' wires

Nascent molecular electronic devices based on linear ‘all-carbon’ wires attached to gold electrodes through robust and reliable C–Au contacts are prepared via efficient in situ sequential cleavage of trimethylsilyl end groups from an oligoyne, Me3Si–(C[triple bond, length as m-dash]C)4–SiMe3 (1). In the first stage of the fabrication process, removal of one trimethylsilyl (TMS) group in the presence of a gold substrate, which ultimately serves as the bottom electrode, using a stoichiometric fluoride-driven process gives a highly-ordered monolayer, Au|C[triple bond, length as m-dash]CC[triple bond, length as m-dash]CC[triple bond, length as m-dash]CC[triple bond, length as m-dash]CSiMe3 (Au|C8SiMe3). In the second stage, treatment of Au|C8SiMe3 with excess fluoride results in removal of the remaining TMS protecting group to give a modified monolayer Au|C[triple bond, length as m-dash]CC[triple bond, length as m-dash]CC[triple bond, length as m-dash]CC[triple bond, length as m-dash]CH (Au|C8H). The reactive terminal C[triple bond, length as m-dash]C–H moiety in Au|C8H can be modified by ‘click’ reactions with (azidomethyl)ferrocene (N3CH2Fc) to introduce a redox probe, to give Au|C6C2N3HCH2Fc. Alternatively, incubation of the modified gold substrate supported monolayer Au|C8H in a solution of gold nanoparticles (GNPs), results in covalent attachment of GNPs on top of the film via a second alkynyl carbon–Au σ-bond, to give structures Au|C8|GNP in which the monolayer of linear, ‘all-carbon’ C8 chains is sandwiched between two macroscopic gold contacts. The covalent carbon–surface bond as well as the covalent attachment of the metal particles to the monolayer by cleavage of the alkyne C–H bond is confirmed by surface-enhanced Raman scattering (SERS). The integrity of the carbon chain in both Au|C6C2N3HCH2Fc systems and after formation of the gold top-contact electrode in Au|C8|GNP is demonstrated through electrochemical methods. The electrical properties of these nascent metal–monolayer–metal devices Au|C8|GNP featuring ‘all-carbon’ molecular wires were characterised by sigmoidal I–V curves, indicative of well-behaved junctions free of short circuits

Association between severe drought and HIV prevention and care behaviors in Lesotho: A population-based survey 2016–2017

Background A previous analysis of the impact of drought in Africa on HIV demonstrated an 11% greater prevalence in HIV-endemic rural areas attributable to local rainfall shocks. The Lesotho Population-Based HIV Impact Assessment (LePHIA) was conducted after the severe drought of 2014–2016, allowing for reevaluation of this relationship in a setting of expanded antiretroviral coverage. Methods and findings LePHIA selected a nationally representative sample between November 2016 and May 2017. All adults aged 15–59 years in randomly selected households were invited to complete an interview and HIV testing, with one woman per household eligible to answer questions on their experience of sexual violence. Deviations in rainfall for May 2014–June 2016 were estimated using precipitation data from Climate Hazards Group InfraRed Precipitation with Station Data (CHIRPS), with drought defined as <15% of the average rainfall from 1981 to 2016. The association between drought and risk behaviors as well as HIV-related outcomes was assessed using logistic regression, incorporating complex survey weights. Analyses were stratified by age, sex, and geography (urban versus rural). All of Lesotho suffered from reduced rainfall, with regions receiving 1%–36% of their historical rainfall. Of the 12,887 interviewed participants, 93.5% (12,052) lived in areas that experienced drought, with the majority in rural areas (7,281 versus 4,771 in urban areas). Of the 835 adults living in areas without drought, 520 were in rural areas and 315 in urban. Among females 15–19 years old, living in a rural drought area was associated with early sexual debut (odds ratio [OR] 3.11, 95% confidence interval [CI] 1.43–6.74, p = 0.004), and higher HIV prevalence (OR 2.77, 95% CI 1.19–6.47, p = 0.02). It was also associated with lower educational attainment in rural females ages 15–24 years (OR 0.44, 95% CI 0.25–0.78, p = 0.005). Multivariable analysis adjusting for household wealth and sexual behavior showed that experiencing drought increased the odds of HIV infection among females 15–24 years old (adjusted OR [aOR] 1.80, 95% CI 0.96–3.39, p = 0.07), although this was not statistically significant. Migration was associated with 2-fold higher odds of HIV infection in young people (aOR 2.06, 95% CI 1.25–3.40, p = 0.006). The study was limited by the extensiveness of the drought and the small number of participants in the comparison group. Conclusions Drought in Lesotho was associated with higher HIV prevalence in girls 15–19 years old in rural areas and with lower educational attainment and riskier sexual behavior in rural females 15–24 years old. Policy-makers may consider adopting potential mechanisms to mitigate the impact of income shock from natural disasters on populations vulnerable to HIV transmission

Impact of opioid substitution therapy on antiretroviral therapy outcomes:a systematic review and meta-analysis

BACKGROUND: Human immunodeficiency virus (HIV)-infected people who inject drugs (PWID) frequently encounter barriers accessing and remaining on antiretroviral therapy (ART). Some studies have suggested that opioid substitution therapy (OST) could facilitate PWID's engagement with HIV services. We conducted a systematic review and meta-analysis to evaluate the impact of concurrent OST use on ART-related outcomes among HIV-infected PWID. METHODS: We searched Medline, PsycInfo, Embase, Global Health, Cochrane, Web of Science, and Social Policy and Practice databases for studies between 1996 to November 2014 documenting the impact of OST, compared to no OST, on ART outcomes. Outcomes considered were coverage and recruitment onto ART, adherence, viral suppression, attrition from ART, and mortality. Meta-analyses were conducted using random-effects modeling, and heterogeneity assessed using Cochran Q test and I2 statistic. RESULTS: We identified 4685 articles, and 32 studies conducted in North America, Europe, Indonesia, and China were included. OST was associated with a 69% increase in recruitment onto ART (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.32-2.15), a 54% increase in ART coverage (odds ratio [OR], 1.54; 95% CI, 1.17-2.03), a 2-fold increase in adherence (OR, 2.14; 95% CI, 1.41-3.26), and a 23% decrease in the odds of attrition (OR, 0.77; 95% CI, .63-.95). OST was associated with a 45% increase in odds of viral suppression (OR, 1.45; 95% CI, 1.21-1.73), but there was limited evidence from 6 studies for OST decreasing mortality for PWID on ART (HR, 0.91; 95% CI, .65-1.25). CONCLUSIONS: These findings support the use of OST, and its integration with HIV services, to improve the HIV treatment and care continuum among HIV-infected PWID

Ubiquitylation of the ER-Shaping Protein Lunapark via the CRL3KLHL12 Ubiquitin Ligase Complex

Summary: Cullin-RING ligases (CRLs) control key cellular processes by promoting ubiquitylation of a multitude of soluble cytosolic and nuclear proteins. Subsets of CRL complexes are recruited and activated locally at cellular membranes; however, few CRL functions and substrates at these distinct cellular compartments are known. Here, we use a proteomic screen to identify proteins that are ubiquitylated at cellular membranes and found that Lunapark, an endoplasmic reticulum (ER)-shaping protein localized to ER three-way junctions, is ubiquitylated by the CRL3KLHL12 ubiquitin ligase. We demonstrate that Lunapark interacts with mechanistic target of rapamycin complex-1 (mTORC1), a central cellular regulator that coordinates growth and metabolism with environmental conditions. We show that mTORC1 binds Lunapark specifically at three-way junctions, and lysosomes, where mTORC1 is activated, make contact with three-way junctions where Lunapark resides. Inhibition of Lunapark ubiquitylation results in neurodevelopmental defects indicating that KLHL12-dependent ubiquitylation of Lunapark is required for normal growth and development