Autocrine production of extracellular catalase prevents apoptosis of the human CEM T-cell line in serum-free medium.

CCRF-CEM is a human T-cell line originally isolated from a child with acute lymphoblastic leukemia. At cell densities > 2 x 10 cells per ml, CEM cells grow in serum-free medium, but at lower cell densities the cultures rapidly undergo apoptosis, or programmed cell death. The viability of lowdensity CEM cells could be preserved by supplementing the serum-free medium with "conditioned" medium from highdensity CEM cultures, but a variety of known growth factors and lymphokines were ineffective. Fractionation ofconditioned medium by sequential chromatography on DEAE-cellulose, propyl agarose, chromatofocusing, and hydrophobic-interaction HPLC resulted in the isolation of a 60-kDa protein capable of sustaining CEM growth in the absence ofserum. The active protein was identified as human catalase based on its amino acid sequence and composition and was subsequently shown to exhibit catalase activity and to be replaceable by human erythrocyte catalase or bovine liver catalase. Comparison of the level of intracellular catalase activity with the amount released into the culture medium demonstrated that the latter accounted for <3% of the total catalase activity present in the cell culture. These findings show that, despite its low amount, the catalase released by CEM cells, and perhaps by T cells in general, provides a critical rust Ilne of defense against hydrogen peroxide (11202) present in the extracellular milieu. Originally published Proceedings of the National Academy of Sciences, Vol. 90, No. 10, May 199

Scientific Visualization Using the Flow Analysis Software Toolkit (FAST)

Over the past few years the Flow Analysis Software Toolkit (FAST) has matured into a useful tool for visualizing and analyzing scientific data on high-performance graphics workstations. Originally designed for visualizing the results of fluid dynamics research, FAST has demonstrated its flexibility by being used in several other areas of scientific research. These research areas include earth and space sciences, acid rain and ozone modelling, and automotive design, just to name a few. This paper describes the current status of FAST, including the basic concepts, architecture, existing functionality and features, and some of the known applications for which FAST is being used. A few of the applications, by both NASA and non-NASA agencies, are outlined in more detail. Described in the Outlines are the goals of each visualization project, the techniques or 'tricks' used lo produce the desired results, and custom modifications to FAST, if any, done to further enhance the analysis. Some of the future directions for FAST are also described

The Origins of [CII] Emission in Local Star-forming Galaxies

The [CII] 158um fine-structure line is the brightest emission line observed in local star-forming galaxies. As a major coolant of the gas-phase interstellar medium, [CII] balances the heating, including that due to far-ultraviolet photons, which heat the gas via the photoelectric effect. However, the origin of [CII] emission remains unclear, because C+ can be found in multiple phases of the interstellar medium. Here we measure the fractions of [CII] emission originating in the ionized and neutral gas phases of a sample of nearby galaxies. We use the [NII] 205um fine-structure line to trace the ionized medium, thereby eliminating the strong density dependence that exists in the ratio of [CII]/[NII] 122um. Using the FIR [CII] and [NII] emission detected by the KINGFISH and Beyond the Peak Herschel programs, we show that 60-80% of [CII] emission originates from neutral gas. We find that the fraction of [CII] originating in the neutral medium has a weak dependence on dust temperature and the surface density of star formation, and a stronger dependence on the gas-phase metallicity. In metal-rich environments, the relatively cooler ionized gas makes substantially larger contributions to total [CII] emission than at low abundance, contrary to prior expectations. Approximate calibrations of this metallicity trend are provided.Comment: 8 pages, accepted for publication in Ap

Elucidating Drivers for Variations in the Explosive Human Immunodeficiency Virus Epidemic among People Who Inject Drugs in Pakistan

BACKGROUND: Pakistan’s explosive human immunodeficiency virus (HIV) epidemic among people who inject drugs (PWID) varies widely across cities. We evaluated possible drivers for these variations. METHODS: Multivariable regression analyses were undertaken using data from 5 national surveys among PWID (n = 18 467; 2005–2017) to determine risk factors associated with variations in city-level HIV prevalence. A dynamic HIV model was used to estimate the population-attributable fraction (PAF; proportion of HIV infections prevented over 10 years when that risk factor is removed) of these risk factors to HIV transmission and impact on HIV incidence of reducing their prevalence. RESULTS: Regression analyses suggested that city-level HIV prevalence is strongly associated with the prevalence of using professional injectors at last injection, heroin use in last month, and injecting ≥4 times per day. Through calibrating a model to these associations, we estimate that the 10-year PAFs of using professional injectors, heroin use, and frequent injecting are 45.3% (95% uncertainty interval [UI], 4.3%–79.7%), 45.9% (95% UI, 8.1%–78.4%), and 22.2% (95% UI, 2.0%–58.4%), respectively. Reducing to lowest city-level prevalences of using professional injectors (2.8%; median 89.9% reduction), heroin use (0.9%; median 91.2% reduction), and frequent injecting (0.1%; median 91.8% reduction) in 2020 reduces overall HIV incidence by 52.7% (95% UI, 6.1%–82.0%), 53.0% (95% UI, 11.3%–80.2%), and 28.1% (95% UI, 2.7%–66.6%), respectively, over 10 years. CONCLUSIONS: Interventions should focus on these risk factors to control Pakistan’s explosive HIV epidemic among PWID, including a concomitant expansion of high-coverage needle/syringe provision, opioid substitution therapy, and antiretroviral therapy

Calibration and Characterization of the IceCube Photomultiplier Tube

Over 5,000 PMTs are being deployed at the South Pole to compose the IceCube neutrino observatory. Many are placed deep in the ice to detect Cherenkov light emitted by the products of high-energy neutrino interactions, and others are frozen into tanks on the surface to detect particles from atmospheric cosmic ray showers. IceCube is using the 10-inch diameter R7081-02 made by Hamamatsu Photonics. This paper describes the laboratory characterization and calibration of these PMTs before deployment. PMTs were illuminated with pulses ranging from single photons to saturation level. Parameterizations are given for the single photoelectron charge spectrum and the saturation behavior. Time resolution, late pulses and afterpulses are characterized. Because the PMTs are relatively large, the cathode sensitivity uniformity was measured. The absolute photon detection efficiency was calibrated using Rayleigh-scattered photons from a nitrogen laser. Measured characteristics are discussed in the context of their relevance to IceCube event reconstruction and simulation efforts.Comment: 40 pages, 12 figure

IceCube-Gen2: A Vision for the Future of Neutrino Astronomy in Antarctica

The recent observation by the IceCube neutrino observatory of an astrophysical flux of neutrinos represents the "first light" in the nascent field of neutrino astronomy. The observed diffuse neutrino flux seems to suggest a much larger level of hadronic activity in the non-thermal universe than previously thought and suggests a rich discovery potential for a larger neutrino observatory. This document presents a vision for an substantial expansion of the current IceCube detector, IceCube-Gen2, including the aim of instrumenting a $10\,\mathrm{km}^3$ volume of clear glacial ice at the South Pole to deliver substantial increases in the astrophysical neutrino sample for all flavors. A detector of this size would have a rich physics program with the goal to resolve the sources of these astrophysical neutrinos, discover GZK neutrinos, and be a leading observatory in future multi-messenger astronomy programs.Comment: 20 pages, 12 figures. Address correspondence to: E. Blaufuss, F. Halzen, C. Kopper (Changed to add one missing author, no other changes from initial version.

Minority HIV-1 Drug Resistance Mutations Are Present in Antiretroviral Treatment–Naïve Populations and Associate with Reduced Treatment Efficacy

Using real-time PCR to detect HIV resistance mutations present at low levels, Jeffrey Johnson and colleagues investigate prevalence and clinical implications of minority transmitted mutations

Gardnerella subgroup dominant microbiomes are associated with divergent cervicovaginal immune responses in a longitudinal cohort of Kenyan women

Most cervicovaginal microbiome-immunology studies to date have relied on 16S rDNA microbial profiling which does not resolve the molecular subgroups of Gardnerella, believed to be central to the pathogenesis of bacterial vaginosis (BV) and subsequent risk of HIV acquisition. Here we used the cpn60 universal target which in addition to other microbial taxa, resolves four Gardnerella subgroups, for cervicovaginal microbial profiling in a longitudinal cohort of Kenyan women to examine associations with cellular and soluble markers of inflammation and HIV susceptibility. Participants (N = 41) were sampled, contributing 362 samples for microbiome analysis. All non-Lactobacillus dominant microbial communities were associated with high pro-inflammatory cytokine levels. Divergent associations were observed among different Gardnerella subgroup dominated communities with respect to the chemokine IP-10. Specifically, Gardnerella subgroup A dominant and polymicrobial communities were associated with reduced concentrations of IP-10 in adjusted linear mixed models (p&lt;0.0001), compared to microbial communities dominated by Lactobacillus (non-iners) species. However, these associations did not translate to significant differences in the proportion or absolute number of CCR5, HLA-DR and CD38 expressed on cervical CD4+ T- cells. These findings suggest that some associations between Gardnerella subgroup dominant microbiomes and mucosal immunity differ and are relevant for the study of BV-pathogenesis and understanding the mechanisms of BV-associated HIV risk

Phylogeographic Analysis of HIV-1 Subtype C Dissemination in Southern Brazil

The HIV-1 subtype C has spread efficiently in the southern states of Brazil (Rio Grande do Sul, Santa Catarina and Paraná). Phylogeographic studies indicate that the subtype C epidemic in southern Brazil was initiated by the introduction of a single founder virus population at some time point between 1960 and 1980, but little is known about the spatial dynamics of viral spread. A total of 135 Brazilian HIV-1 subtype C pol sequences collected from 1992 to 2009 at the three southern state capitals (Porto Alegre, Florianópolis and Curitiba) were analyzed. Maximum-likelihood and Bayesian methods were used to explore the degree of phylogenetic mixing of subtype C sequences from different cities and to reconstruct the geographical pattern of viral spread in this country region. Phylogeographic analyses supported the monophyletic origin of the HIV-1 subtype C clade circulating in southern Brazil and placed the root of that clade in Curitiba (Paraná state). This analysis further suggested that Florianópolis (Santa Catarina state) is an important staging post in the subtype C dissemination displaying high viral migration rates from and to the other cities, while viral flux between Curitiba and Porto Alegre (Rio Grande do Sul state) is very low. We found a positive correlation (r2 = 0.64) between routine travel and viral migration rates among localities. Despite the intense viral movement, phylogenetic intermixing of subtype C sequences from different Brazilian cities is lower than expected by chance. Notably, a high proportion (67%) of subtype C sequences from Porto Alegre branched within a single local monophyletic sub-cluster. These results suggest that the HIV-1 subtype C epidemic in southern Brazil has been shaped by both frequent viral migration among states and in situ dissemination of local clades

Drug Resistance Mutations for Surveillance of Transmitted HIV-1 Drug-Resistance: 2009 Update

Programs that monitor local, national, and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted drug resistance rates across geographic regions and times, the World Health Organization has recommended the adoption of a consensus genotypic definition of transmitted HIV-1 drug resistance. In January 2007, we outlined criteria for developing a list of mutations for drug-resistance surveillance and compiled a list of 80 RT and protease mutations meeting these criteria (surveillance drug resistance mutations; SDRMs). Since January 2007, several new drugs have been approved and several new drug-resistance mutations have been identified. In this paper, we follow the same procedures described previously to develop an updated list of SDRMs that are likely to be useful for ongoing and future studies of transmitted drug resistance. The updated SDRM list has 93 mutations including 34 NRTI-resistance mutations at 15 RT positions, 19 NNRTI-resistance mutations at 10 RT positions, and 40 PI-resistance mutations at 18 protease positions