Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Usporedba foretičkih grinja na potkornjacima Ips typographus i Ips cembrae u središnjoj Hrvatskoj

In different locations of Croatia (Nova Gradiška, Koprivnica, Gospić and Jastrebarsko) adults and developmental stages of Ips cembrae, the large larch bark beetle, and Ips typographus, the European spruce bark beetle, were collected from Picea abies, Larix decidua und Pinus sylvestris together with substrate from their breeding galleries and examined for phoretic mites. Four different mite species were identified by collecting specimens directly from the beetles:Iponemus gaebleri (Tarsenomidae), Histiostoma piceae (Astigmata, Histiostomatoidea), Dendrolaelaps quadrisetus (Gamasina) and Urobovella sp. (Uropodidae). I. gaebleri was the most abundant mite on both beetle species.Three other mite species have been collected directly from bark beetle galleries.We also studied the attachment-areas of phoretic mites on their beetle carriers. I gaebleri and D. quadrisetus preferred the elytral declivity, while the phoretic deutonymphs of the Histiostomatidae commonly were found on the ventral side of the thorax.We discovered statistically significant differences concerning the total of attached mites and a clear preference of I. gaebleri for I. cembrae.Young callow adults of Ips cembrae, emerging from their maternal galleries carried significantly more phoretic mites than parental beetles, which were picked out of their breeding galleries.Females of an another species of genus Histiostoma were found in galleries of I. typographus. They all were largely covered by great numbers of two-chamber spores of a fungus belonging to the Ascomycota (Hypocreales).A dichotomous key to identify larvae and protonymphs of the Histiostomatidae is provided.Na nekoliko lokacija u Hrvatskoj (Nova Gradiška, Koprivnica, Gospić i Jastrebarsko) sa različitih vrsta drveća (Picea abies, Larix decidua i Pinus sylvestris) sakupljani su različiti stadiji ariševog potkornjaka, Ips cembrae i smrekinog pisara, Ips typographus te supstrat iz njihovih hodnika u svrhu sakupljana i identifikacije foretičkih grinja. Izravno sa tijela potkornjaka determinirano je 4 vrsta grinja: Iponemus gaebleri (Tarsenomidae), Histiostoma piceae (Astigmata, Histiostomatoidea), Dendrolaelaps quadrisetus (Gamasina) i Urobovella sp. (Uropodidae). Iponemus gaebleri bila je najčešća nađena vrsta kod obiju vrsta potkornjaka.Tri druge vtrste sakupljene su izravno iz hodničkih sustava. Istraživana su i mjesta spajanja foretičkih grinja s potkornjacima. Iponemus gaebleri i D. quadrisetus tako se najčešće nalaze na obronku zadka, dok se foretičke deutonimfe porodice Histiostomatidae obično nalaze na ventralnoj strani prsišta. Statističkom anlizom potvrđen je jasna preferencija I. gaebleri na I. cembrae. Mladi još nezreli kukci Ips cembrae, koji izlaze iz materinjih hodnika nose signifikantno više foretičkih grinja nego roditeljski. Ženke neidentifcirane vrste roda Histiostoma nađene su u hodnicima I. typographus. Grinje su uglavnom bile pokrivene s većim brojem neidentificiranim sporama gljiva iz skupine Ascomycota (Hypocreales).U radu se daje dihotomski ključ za identifikaciju larvi i protonimfi za porodicu Histiostomatidae

Transition Metal-Oxide Free Perovskite Solar Cells Enabled by a New Organic Charge Transport Layer

Various electron and hole transport layers have been used to develop high-efficiency perovskite solar cells. To achieve low-temperature solution processing of perovskite solar cells, organic n-type materials are employed to replace the metal oxide electron transport layer (ETL). Although PCBM (phenyl-C₆₁-butyric acid methyl ester) has been widely used for this application, its morphological instability in films (i.e., aggregation) is detrimental. Herein, we demonstrate the synthesis of a new fullerene derivative (isobenzofulvene–C₆₀–epoxide, IBF–Ep) that serves as an electron transporting material for methylammonium mixed lead halide-based perovskite (CH₃NH₃PbI_3–<i>x</i>Cl_<i>x</i>) solar cells, both in the normal and inverted device configurations. We demonstrate that IBF–Ep has superior morphological stability compared to the conventional acceptor, PCBM. IBF–Ep provides higher photovoltaic device performance as compared to PCBM (6.9% vs 2.5% in the normal and 9.0% vs 5.3% in the inverted device configuration). Moreover, IBF–Ep devices show superior tolerance to high humidity (90%) in air. By reaching power conversion efficiencies up to 9.0% for the inverted devices with IBF–Ep as the ETL, we demonstrate the potential of this new material as an alternative to metal oxides for perovskite solar cells processed in air

<em>C. elegans</em> BLOC-1 Functions in Trafficking to Lysosome-Related Gut Granules

<div><p>The human disease Hermansky-Pudlak syndrome results from defective biogenesis of lysosome-related organelles (LROs) and can be caused by mutations in subunits of the BLOC-1 complex. Here we show that <em>C. elegans glo-2</em> and <em>snpn-1</em>, despite relatively low levels of amino acid identity, encode Pallidin and Snapin BLOC-1 subunit homologues, respectively. BLOC-1 subunit interactions involving Pallidin and Snapin were conserved for GLO-2 and SNPN-1. Mutations in <em>glo-2</em> and <em>snpn-1</em>,or RNAi targeting 5 other BLOC-1 subunit homologues in a genetic background sensitized for <em>glo-2</em> function, led to defects in the biogenesis of lysosome-related gut granules. These results indicate that the BLOC-1 complex is conserved in <em>C. elegans</em>. To address the function of <em>C. elegans</em> BLOC-1, we assessed the intracellular sorting of CDF-2::GFP, LMP-1, and PGP-2 to gut granules. We validated their utility by analyzing their mislocalization in intestinal cells lacking the function of AP-3, which participates in an evolutionarily conserved sorting pathway to LROs. BLOC-1(−) intestinal cells missorted gut granule cargo to the plasma membrane and conventional lysosomes and did not have obviously altered function or morphology of organelles composing the conventional lysosome protein sorting pathway. Double mutant analysis and comparison of AP-3(−) and BLOC-1(−) phenotypes revealed that BLOC-1 has some functions independent of the AP-3 adaptor complex in trafficking to gut granules. We discuss similarities and differences of BLOC-1 activity in the biogenesis of gut granules as compared to mammalian melanosomes, where BLOC-1 has been most extensively studied for its role in sorting to LROs. Our work opens up the opportunity to address the function of this poorly understood complex in cell and organismal physiology using the genetic approaches available in <em>C. elegans</em>.</p> </div

Gut granule formation in adults.

<p>In wild-type adults, autofluorescent gut granules accumulated markers of acidification (A–B), hydrophobicity (C–D), terminal endocytic compartments (E–F) and contained PGP-2::GFP (G–H). <i>glo-2(zu455)</i> adults had substantially reduced numbers of autofluorescent compartments (I). The majority of these organelles were stained with LysoTracker Red (I-J), Nile Red (K–L) and contained PGP-2::GFP (O–P). (M–N) In contrast, few of the autofluorescent compartments accumulated TRITC-Dextran and those that did localized the marker to a subdomain within the organelle. In all panels, white arrows identify autofluorescent compartments that contained the gut granule marker. The black arrows denote the location of the intestinal lumen.</p

Analyzing the identity of LMP-1::GFP compartments in <i>glo-2(</i>

<p>−<b><i>)</i></b><b> embryos.</b> The majority of LMP-1::GFP containing compartments (marked with white arrows in all panels) lacked RAB-5 and RAB-7 in wild type (A–F) and <i>glo-2(zu455)</i> (J–O), however a subset of LMP-1::GFP colocalized with RAB-7 (black arrows). In both wild type (G–I) and <i>glo-2(zu455</i>) (P-R), the lysosomal hydrolase F11E6.1::mCherry localized to LMP-1::GFP containing organelles. In all panels, black arrowheads flank the intestine of 1.5-fold stage embryos.</p

<i>C. elegans</i> BLOC-1 subunits.

<p>The gene name of each <i>C. elegans</i> BLOC-1 subunit and its human and <i>D. melanogaster</i> orthologues are listed. The amino acid identity of the <i>C. elegans</i> protein with each orthologue was derived from pairwise sequence alignments with the full length <i>C. elegans</i> protein.</p