Antiviral Resistance and Correlates of Virologic Failure in the first Cohort of HIV-Infected Children Gaining Access to Structured Antiretroviral Therapy in Lima, Peru: A Cross-Sectional Analysis

Background: The impact of extended use of ART in developing countries has been enormous. A thorough understanding of all factors contributing to the success of antiretroviral therapy is required. The current study aims to investigate the value of cross-sectional drug resistance monitoring using DNA and RNA oligonucleotide ligation assays (OLA) in treatment cohorts in low-resource settings. The study was conducted in the first cohort of children gaining access to structured ART in Peru. Methods: Between 2002–5, 46 eligible children started the standard regimen of AZT, 3TC and NFV Patients had a median age of 5.6 years (range: 0.7-14y), a median viral load of 1.7·105 RNA/ml (range: 2.1·103 – 1.2·106), and a median CD4-count of 232 cells/μL (range: 1–1591). Of these, 20 patients were classified as CDC clinical category C and 31/46 as CDC immune category 3. At the time of cross-sectional analysis in 2005, adherence questionnaires were administered. DNA OLAs and RNA OLAs were performed from frozen PBMC and plasma, RNA genotyping from dried blood spots. Results: During the first year of ART, 44% of children experienced virologic failure, with an additional 9% failing by the end of the second year. Virologic failure was significantly associated with the number of resistance mutations detected by DNA-OLA (p < 0.001) during cross-sectional analysis, but also with low immunologic CDC-scores at baseline (p < 0.001). Children who had been exposed to unsupervised short-term antiretrovirals before starting structured ART showed significantly higher numbers of resistance mutations by DNA-OLA (p = 0.01). Detection of M184V (3TC resistance) by RNA-OLA and DNA-OLA demonstrated a sensitivity of 0.93 and 0.86 and specificity of 0.67 and 0.7, respectively, for the identification of virologic failure. The RT mutations N88D and L90M (NFV resistance) detected by DNA-OLA correlated with virologic failure, whereas mutations at RT position 215 (AZT resistance) were not associated with virologic failure. Conclusions: Advanced immunosuppression at baseline and previous exposures to unsupervised brief cycles of ART significantly impaired treatment outcomes at a time when structured ART was finally introduced in his cohort. Brief maternal exposures to with AZT +/− NVP for the prevention of mother-to-child transmission did not affect treatment outcomes in this group of children. DNA-OLA from frozen PBMC provided a highly specific tool to detect archived drug resistance. RNA consensus genotyping from dried blood spots and RNA-OLA fromplasma consistently detected drug resistance mutations, but merely in association with virologic failur

Gas phase formation of extremely oxidized pinene reaction products in chamber and ambient air

High molecular weight (300–650 Da) naturally charged negative ions have previously been observed at a boreal forest site in Hyytiälä, Finland. The long-term measurements conducted in this work showed that these ions are observed practically every night between spring and autumn in Hyytiälä. The ambient mass spectral patterns could be reproduced in striking detail during additional measurements of α-pinene (C&lt;sub&gt;10&lt;/sub&gt;H&lt;sub&gt;16&lt;/sub&gt;) oxidation at low-OH conditions in the Jülich Plant Atmosphere Chamber (JPAC). The ions were identified as clusters of the nitrate ion (NO&lt;sub&gt;3&lt;/sub&gt;&lt;sup&gt;&amp;minus;&lt;/sup&gt;) and α-pinene oxidation products reaching oxygen to carbon ratios of 0.7–1.3, while retaining most of the initial ten carbon atoms. Attributing the ions to clusters instead of single molecules was based on additional observations of the same extremely oxidized organics in clusters with HSO&lt;sub&gt;4&lt;/sub&gt;&lt;sup&gt;&amp;minus;&lt;/sup&gt; (Hyytiälä) and C&lt;sub&gt;3&lt;/sub&gt;F&lt;sub&gt;5&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;&lt;sup&gt;&amp;minus;&lt;/sup&gt; (JPAC). The most abundant products in the ion spectra were identified as C&lt;sub&gt;10&lt;/sub&gt;H&lt;sub&gt;14&lt;/sub&gt;O&lt;sub&gt;7&lt;/sub&gt;, C&lt;sub&gt;10&lt;/sub&gt;H&lt;sub&gt;14&lt;/sub&gt;O&lt;sub&gt;9&lt;/sub&gt;, C&lt;sub&gt;10&lt;/sub&gt;H&lt;sub&gt;16&lt;/sub&gt;O&lt;sub&gt;9&lt;/sub&gt;, and C&lt;sub&gt;10&lt;/sub&gt;H&lt;sub&gt;14&lt;/sub&gt;O&lt;sub&gt;11&lt;/sub&gt;. The mechanism responsible for forming these molecules is still not clear, but the initial reaction is most likely ozone attack at the double bond, as the ions are mainly observed under dark conditions. β-pinene also formed highly oxidized products under the same conditions, but less efficiently, and mainly C&lt;sub&gt;9&lt;/sub&gt; compounds which were not observed in Hyytiälä, where β-pinene on average is 4–5 times less abundant than α-pinene. Further, to explain the high O/C together with the relatively high H/C, we propose that geminal diols and/or hydroperoxide groups may be important. We estimate that the night-time concentration of the sum of the neutral extremely oxidized products is on the order of 0.1–1 ppt (~10&lt;sup&gt;6&lt;/sup&gt;–10&lt;sup&gt;7&lt;/sup&gt; molec cm&lt;sup&gt;−3&lt;/sup&gt;). This is in a similar range as the amount of gaseous H&lt;sub&gt;2&lt;/sub&gt;SO&lt;sub&gt;4&lt;/sub&gt; in Hyytiälä during day-time. As these highly oxidized organics are roughly 3 times heavier, likely with extremely low vapor pressures, their role in the initial steps of new aerosol particle formation and growth may be important and needs to be explored in more detail in the future

Current challenges and future directions in data assimilation and reanalysis

The first Joint WCRP1-WWRP2 Symposium on Data Assimilation and Reanalysis took place on13-17 September 2021, and it was organized in conjunction with the ECMWF Annual Seminaron observations. The last WCRP/WWRP-organized meetings were held separately for data assimilation and reanalysis in 2017 (Buizza et al. 2018; Cardinali et al. 2019). Since then, commonchallenges and new emerging topics have increased the need to bring these communities together toexchange new ideas and findings. Thus, a symposium involving the aforementioned communitieswas jointly organized by DWD3, HErZ4, WCRP, WWRP, and the ECMWF annual seminar. Majorgoals were to increase diversity, provide early career scientists with opportunities to present theirwork and extend their professional network, and bridge gaps between the various communities.The online format allowed more than 500 participants from over 50 countries to meet in avirtual setting, using the gathertown 5 platform as the central tool to access the meeting. A virtualconference center was created where people could freely move around and talk to other close-byparticipants. A lobby served as the main hub and it connected the poster halls and the conferencerooms for the oral presentations and the ECMWF seminar talks. The feedback from the participantswas overwhelmingly positive.Scientifically, the meeting offered opportunities to bring together the communities of Earth systemdata assimilation, reanalysis and observations to identify current challenges, seek opportunitiesfor collaboration, and strategic planning on more integrated systems for the longer term. Thecontributions totalled 140 oral and over 150 poster presentations covering a large variety oftopics with increased interest in Earth system approaches, machine learning and increased spatial resolutions. Key findings of the symposium and the ECMWF annual seminar are summarized insection 2. Section 3 highlights the common and emerging challenges of these communities.Fil: Valmassoi, Arianna. Hans-ertel-centre For Weather Research; Alemania. Institut Fur Geowissenschaften ; Universitaet Bonn;Fil: Keller, Jan D.. Deutscher Wetterdienst; AlemaniaFil: Kleist, Daryl T.. National Ocean And Atmospheric Administration; Estados UnidosFil: English, Stephen. European Center For Medium Range Weather Forecasting; Reino UnidoFil: Ahrens, Bodo. Goethe Universitat Frankfurt; AlemaniaFil: Ďurán, Ivan Bašták. Goethe Universitat Frankfurt; AlemaniaFil: Bauernschubert, Elisabeth. Deutscher Wetterdienst; AlemaniaFil: Bosilovich, Michael G.. National Aeronautics and Space Administration; Estados UnidosFil: Fujiwara, Masatomo. Hokkaido University; JapónFil: Hersbach, Hans. European Center For Medium Range Weather Forecasting; Reino UnidoFil: Lei, Lili. Nanjing University; ChinaFil: Löhnert, Ulrich. University Of Cologne; AlemaniaFil: Mamnun, Nabir. Helmholtz Centre for Environmental Research; AlemaniaFil: Martin, Cory R.. German Research Centre for Geosciences; AlemaniaFil: Moore, Andrew. California State University; Estados UnidosFil: Niermann, Deborah. Deutscher Wetterdienst; AlemaniaFil: Ruiz, Juan Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmósfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmósfera; ArgentinaFil: Scheck, Leonhard. Deutscher Wetterdienst; Alemani

Canine respiratory coronavirus employs caveolin-1-mediated pathway for internalization to HRT-18G cells

Canine respiratory coronavirus (CRCoV), identified in 2003, is a member of the Coronaviridae family. The virus is a betacoronavirus and a close relative of human coronavirus OC43 and bovine coronavirus. Here, we examined entry of CRCoV into human rectal tumor cells (HRT-18G cell line) by analyzing co-localization of single virus particles with cellular markers in the presence or absence of chemical inhibitors of pathways potentially involved in virus entry. We also targeted these pathways using siRNA. The results show that the virus hijacks caveolin-dependent endocytosis to enter cells via endocytic internalization

The IceCube Neutrino Observatory: Instrumentation and Online Systems

The IceCube Neutrino Observatory is a cubic-kilometer-scale high-energy neutrino detector built into the ice at the South Pole. Construction of IceCube, the largest neutrino detector built to date, was completed in 2011 and enabled the discovery of high-energy astrophysical neutrinos. We describe here the design, production, and calibration of the IceCube digital optical module (DOM), the cable systems, computing hardware, and our methodology for drilling and deployment. We also describe the online triggering and data filtering systems that select candidate neutrino and cosmic ray events for analysis. Due to a rigorous pre-deployment protocol, 98.4% of the DOMs in the deep ice are operating and collecting data. IceCube routinely achieves a detector uptime of 99% by emphasizing software stability and monitoring. Detector operations have been stable since construction was completed, and the detector is expected to operate at least until the end of the next decade.Comment: 83 pages, 50 figures; updated with minor changes from journal review and proofin

Prototype ATLAS IBL Modules using the FE-I4A Front-End Readout Chip

The ATLAS Collaboration will upgrade its semiconductor pixel tracking detector with a new Insertable B-layer (IBL) between the existing pixel detector and the vacuum pipe of the Large Hadron Collider. The extreme operating conditions at this location have necessitated the development of new radiation hard pixel sensor technologies and a new front-end readout chip, called the FE-I4. Planar pixel sensors and 3D pixel sensors have been investigated to equip this new pixel layer, and prototype modules using the FE-I4A have been fabricated and characterized using 120 GeV pions at the CERN SPS and 4 GeV positrons at DESY, before and after module irradiation. Beam test results are presented, including charge collection efficiency, tracking efficiency and charge sharing.Comment: 45 pages, 30 figures, submitted to JINS