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Between 10 and 20 million people worldwide are infected with the human T-cell lymphotropic virus type 1 (HTLV-1). Despite causing life-threatening pathologies there is no therapeutic regimen for this deltaretrovirus. Here, we screened a library of integrase strand transfer inhibitor (INSTI) candidates built around several chemical scaffolds to determine their effectiveness in limiting HTLV-1 infection. Naphthyridines with substituents in position 6 emerged as the most potent compounds against HTLV-1, with XZ450 having highest efficacy in vitro. Using single-particle cryo-electron microscopy we visualised XZ450 as well as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the active site of the deltaretroviral intasome. The structures reveal subtle differences in the coordination environment of the Mg2+ ion pair involved in the interaction with the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1 intasome and support their use for pre-exposure prophylaxis and possibly future treatment of HTLV-1 infection., Human T-cell lymphotropic virus type 1 (HTLV-1) is an oncogenic deltaretrovirus. Here the authors provide structural characterization of the binding mechanism of novel integrase strand transfer inhibitor (INSTI) candidates to limit HTLV-1 infection.

Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit reverse transcription and block the replication of HIV‐1. Currently, NNRTIs are usually used as part of a three‐drug combination given to patients as antiretroviral therapy. These combinations involve other classes of anti‐HIV‐1 drugs, commonly nucleoside reverse transcriptase inhibitors (NRTIs). However, attempts are being made to develop two‐drug maintenance therapies, some of which involve an NNRTI and an integrase strand transfer inhibitor. This has led to a renewed interest in developing novel NNRTIs, with a major emphasis on designing compounds that can effectively inhibit the known NNRTI‐resistant mutants. We have generated and tested novel rilpivirine (RPV) analogs. The new compounds were designed to exploit a small opening in the upper right periphery of the NNRTI‐binding pocket. The best of the new compounds, 12, was a more potent inhibitor of the NNRTI‐resistant mutants we tested than either doravirine or efavirenz but was inferior to RPV. We describe the limitations on the modifications that can be appended to the “upper right side” of the RPV core and the effects of substituting other cores for the central pyrimidine core of RPV and make suggestions about how this information can be used in NNRTI design., We developed rilpivirine (RPV) analogs that were designed to interact with a hydrophobic region in the non‐nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket of HIV‐1 reverse transcriptase near P225. The best of the new compounds, 12, was based on a previous lead 4. 12 potently inhibited WT HIV‐1 and several NNRTI‐resistant mutants in a single‐round replication assay but was not more effective against the mutants than rilpivirine (RPV). The data will help guide the design of novel NNRTIs.

Strengths and weaknesses of an HIV drug Retroviruses replicate by inserting a copy of their RNA, which has been reverse transcribed into DNA, into the host genome. This process involves the intasome, a nucleoprotein complex comprising copies of the viral integrase bound at the ends of the viral DNA. HIV integrase strand-transfer inhibitors (INSTIs) stop HIV from replicating by blocking the viral integrase and are widely used in HIV treatment. Cook et al. describe structures of second-generation inhibitors bound to the simian immunodeficiency virus (SIV) intasome and to an intasome with integrase mutations known to cause drug resistance. Passos et al. describe the structures of the HIV intasome bound to a second-generation inhibitor and to developmental compounds that are promising drug leads. These structures show how mutations can cause subtle changes in the active site that affect drug binding, show the basis for the higher activity of later-generation inhibitors, and may guide development of better drugs. Science , this issue p. 806 , p. 810

This study examines model-specific assumptions and projections of methane (CH4) emissions in deep mitigation scenarios generated by integrated assessment models (IAMs). For this, scenarios of nine models are compared in terms of sectoral and regional CH4emission reduction strategies, as well as resulting climate impacts. The models’ projected reduction potentials are compared to sector and technology-specific reduction potentials found in literature. Significant cost-effective and non-climate policy related reductions are projected in the reference case (10–36% compared to a “frozen emission factor” scenario in 2100). Still, compared to 2010, CH4emissions are expected to rise steadily by 9–72% (up to 412 to 654 Mt CH4/year). Ambitious CO2reduction measures could by themselves lead to a reduction of CH4emissions due to a reduction of fossil fuels (22–48% compared to the reference case in 2100). However, direct CH4mitigation is crucial and more effective in bringing down CH4(50–74% compared to the reference case). Given the limited reduction potential, agriculture CH4emissions are projected to constitute an increasingly larger share of total anthropogenic CH4emissions in mitigation scenarios. Enteric fermentation in ruminants is in that respect by far the largest mitigation bottleneck later in the century with a projected 40–78% of total remaining CH4emissions in 2100 in a strong (2 °C) climate policy case.

Integrase strand transfer inhibitors (INSTIs) block the integration step of the retroviral lifecycle and are first-line drugs used for the treatment of HIV-1/AIDS. INSTIs have a polycyclic core with heteroatom triads, chelate the metal ions at the active site, and have a halobenzyl group that interacts with viral DNA attached to the core by a flexible linker. The most broadly effective INSTIs inhibit both wild-type (WT) integrase (IN) and a variety of well-known mutants. However, because there are mutations that reduce the potency of all of the available INSTIs, new and better compounds are needed. Models based on recent structures of HIV-1 and red-capped mangabey SIV INs suggest modifications in the INSTI structures that could enhance interactions with the 3'-terminal adenosine of the viral DNA, which could improve performance against INSTI resistant mutants. We designed and tested a series of INSTIs having modifications to their naphthyridine scaffold. One of the new compounds retained good potency against an expanded panel of HIV-1 IN mutants that we tested. Our results suggest the possibility of designing inhibitors that combine the best features of the existing compounds, which could provide additional efficacy against known HIV-1 IN mutants.

Several studies have shown that the greenhouse gas reduction resulting from the current nationally determined contributions (NDCs) will not be enough to meet the overall targets of the Paris Climate Agreement. It has been suggested that more ambition mitigations of short-lived climate forcer (SLCF) emissions could potentially be a way to reduce the risk of overshooting the 1.5 or 2 °C target in a cost-effective way. In this study, we employ eight state-of-the-art integrated assessment models (IAMs) to examine the global temperature effects of ambitious reductions of methane, black and organic carbon, and hydrofluorocarbon emissions. The SLCFs measures considered are found to add significantly to the effect of the NDCs on short-term global mean temperature (GMT) (in the year 2040: − 0.03 to − 0.15 °C) and on reducing the short-term rate-of-change (by − 2 to 15%), but only a small effect on reducing the maximum temperature change before 2100. This, because later in the century under assumed ambitious climate policy, SLCF mitigation is maximized, either directly or indirectly due to changes in the energy system. All three SLCF groups can contribute to achieving GMT changes.

The currently recommended first-line therapy for HIV-1-infected patients is an integrase (IN) strand transfer inhibitor (INSTI), either dolutegravir (DTG) or bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by the INSTIs raltegravir (RAL) and elvitegravir (EVG). BIC has not been reported to select for resistance in treatment-naive patients, and DTG has selected for a small number of resistant viruses in treatment-naive patients. However, some patients who had viruses with substitutions selected by RAL and EVG responded poorly when switched to DTG-based therapies, and there are mutants that cause a considerable decrease in the potencies of DTG and BIC in in vitro assays. The new INSTI cabotegravir (CAB), which is in late-stage clinical trials, has been shown to select for novel resistant mutants in vitro. Thus, it is important to develop new and improved INSTIs that are effective against all the known resistant mutants. This led us to test our best inhibitors, in parallel with DTG, BIC, and CAB, in a single-round infection assay against a panel of the new CAB-resistant mutants. Of the INSTIs we tested, BIC and our compound 4d had the broadest efficacy. Both were superior to DTG, as evidenced by the data obtained with the IN mutant T66I/L74M/E138K/S147G/Q148R/S230N, which was selected by CAB using an EVG-resistant lab strain. These results support the preclinical development of compound 4d and provide information that can be used in the design of additional INSTIs that will be effective against a broad spectrum of resistant mutants.

The relatively short atmospheric lifetimes of methane (CH4) and black carbon (BC) have focused attention on the potential for reducing anthropogenic climate change by reducing Short-Lived Climate Forcer (SLCF) emissions. This paper examines radiative forcing and global mean temperature results from the Energy Modeling Forum (EMF)-30 multi-model suite of scenarios addressing CH4 and BC mitigation, the two major short-lived climate forcers. Central estimates of temperature reductions in 2040 from an idealized scenario focused on reductions in methane and black carbon emissions ranged from 0.18–0.26 °C across the nine participating models. Reductions in methane emissions drive 60% or more of these temperature reductions by 2040, although the methane impact also depends on auxiliary reductions that depend on the economic structure of the model. Climate model parameter uncertainty has a large impact on results, with SLCF reductions resulting in as much as 0.3–0.7 °C by 2040. We find that the substantial overlap between a SLCF-focused policy and a stringent and comprehensive climate policy that reduces greenhouse gas emissions means that additional SLCF emission reductions result in, at most, a small additional benefit of ~ 0.1 °C in the 2030–2040 time frame.

Background Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the FDA for the treatment of HIV-1 infections. INSTIs block the strand transfer reaction catalyzed by HIV-1 integrase (IN) and have been shown to potently inhibit infection by wild-type HIV-1. Of the three current FDA-approved INSTIs, Dolutegravir (DTG), has been the most effective, in part because treatment does not readily select for resistant mutants. However, recent studies showed that when INSTI-experienced patients are put on a DTG-salvage therapy, they have reduced response rates. Two new INSTIs, Cabotegravir (CAB) and Bictegravir (BIC), are currently in late-stage clinical trials. Results Both CAB and BIC had much broader antiviral profiles than RAL and EVG against the INSTI-resistant single, double, and triple HIV-1 mutants used in this study. BIC was more effective than DTG against several INSTI-resistant mutants. Overall, in terms of their ability to inhibit a broad range of INSTI-resistant IN mutants, BIC was superior to DTG, and DTG was superior to CAB. Modeling the binding of CAB, BIC, and DTG within the active site of IN suggested that the “left side” of the INSTI pharmacophore (the side away from the viral DNA) was important in determining the ability of the compound to inhibit the IN mutants we tested. Conclusions Of the two INSTIs in late stage clinical trials, BIC appears to be better able to inhibit the replication of a broad range of IN mutants. BIC retained potency against several of the INSTI-resistant mutants that caused a decrease in susceptibility to DTG. Electronic supplementary material The online version of this article (10.1186/s12977-018-0420-7) contains supplementary material, which is available to authorized users.

Emission inventory development for air pollutants, by compiling records from individual emission sources, takes many years and involves extensive multi-national effort. A complementary method to estimate air pollution emissions is in the use of satellite remote sensing. In this study, NO2 observations from the Ozone Monitoring Instrument are combined with re-analysis meteorology to estimate urban nitrogen oxide (NO X ) emissions for 80 global cities between 2005 and 2019. The global average downward trend in satellite-derived urban NOX emissions was 3.1%–4.0% yr−1 between 2009 and 2018 while inventories show a 0%–2.2% yr−1 drop over the same timeframe. This difference is primarily driven by discrepancies between satellite-derived urban NO X emissions and inventories in Africa, China, India, Latin America, and the Middle East. In North America, Europe, Korea, Japan, and Australasia, NOX emissions dropped similarly as reported in the inventories. In Europe, Korea, and Japan only, the temporal trends match the inventories well, but the satellite estimate is consistently larger over time. While many of the discrepancies between satellite-based and inventory emissions estimates represent real differences, some of the discrepancies might be related to the assumptions made to compare the satellite-based estimates with inventory estimates, such as the spatial disaggregation of emissions inventories. Our work identifies that the three largest uncertainties in the satellite estimate are the tropospheric column measurements, wind speed and direction, and spatial definition of each city.

Although well logs and core data show that there is significant oil content in Bakken shales, the oil transport behavior in these source rocks is still not well understood. This lack of understanding impedes the drilling and production operations in the shale members. A series of experiments were conducted to investigate the rock properties of the Bakken shales and how to extract oil from the shales using supercritical CO 2 . High-pressure mercury injection tests showed that pore throat radii are less than 10 nm for most pores in both the upper and lower Bakken samples. Such small pore sizes yield high capillary pressure in the rock and make fluid flow difficult. Total organic carbon content was measured using 180 shale samples, and kerogen was characterized by Rock-Eval pyrolysis, which indicated considerable organic carbon present (10–15 wt%) in the shales. However, oil and gas are difficult to mobilize from organic matter using conventional methods. A systematic experimental procedure was carried out to reveal the potential for extracting hydrocarbons from the shale samples using supercritical CO 2 under typical Bakken reservoir conditions (e.g., 34.5 MPa and 110 °C). Results showed that supercritical CO 2 enables extraction of a considerable portion (15–65%) of hydrocarbons from the Bakken shales within 24 h. Measurement of CO 2 adsorption isotherm showed that Bakken shale has a considerable capability to trap CO 2 (up to 17 mg/g) under a wide range of pressures. The experimental results suggest the possibility of using supercritical CO 2 injection to increase the ultimate oil recovery and store a considerable quantity of CO 2 in the Bakken Formation.

The global source–receptor relationships of sulfate concentrations, and direct and indirect radiative forcing (DRF and IRF) from 16 regions/sectors for years 2010–2014 are examined in this study through utilizing a sulfur source-tagging capability implemented in the Community Earth System Model (CESM) with winds nudged to reanalysis data. Sulfate concentrations are mostly contributed by local emissions in regions with high emissions, while over regions with relatively low SO2 emissions, the near-surface sulfate concentrations are primarily attributed to non-local sources from long-range transport. Regional source efficiencies of sulfate concentrations are higher over regions with dry atmospheric conditions and less export, suggesting that lifetime of aerosols, together with regional export, is important in determining regional air quality. The simulated global total sulfate DRF is −0.42 W m−2, with −0.31 W m−2 contributed by anthropogenic sulfate and −0.11 W m−2 contributed by natural sulfate, relative to a state with no sulfur emissions. In the Southern Hemisphere tropics, dimethyl sulfide (DMS) contributes 17–84 % to the total DRF. East Asia has the largest contribution of 20–30 % over the Northern Hemisphere mid- and high latitudes. A 20 % perturbation of sulfate and its precursor emissions gives a sulfate incremental IRF of −0.44 W m−2. DMS has the largest contribution, explaining −0.23 W m−2 of the global sulfate incremental IRF. Incremental IRF over regions in the Southern Hemisphere with low background aerosols is more sensitive to emission perturbation than that over the polluted Northern Hemisphere.

Here we quantify the regional co-benefits to future air quality on annual to daily mean timescales from implementing mitigation measures to stabilise future climate. Two consistent future emissions pathways are used within the composition-climate model HadGEM3-UKCA: one is a reference pathway of future economic growth and development (REF), whilst the Representative Concentration Pathway 4.5 (RCP4.5) assumes the same development pathway but stabilises anthropogenic radiative forcing at 4.5 W m−2 in 2100. Implementing greenhouse gas (GHG) mitigation measures in RCP4.5 reduces global mean air pollutant emissions by up to 30% in the 2050s, in addition to mitigating climate. Annual mean surface concentrations of ozone and PM2.5 decrease by 10%–20% from the combined reductions in emissions and climate change. The number of days exceeding the World Health Organization’s (WHO) daily mean air quality standards are reduced by up 47 days for ozone and 15 days for PM2.5 over different world regions. The air quality co-benefits from mitigation measures are mainly achieved from reductions in anthropogenic emissions, although benefits can be offset due to changes in climate. In terms of anthropogenic climate forcing, while the reduction in global mean effective radiative forcing (ERF) in 2050, relative to the 2000s, due to enacting carbon dioxide mitigation measures (−0.43 W m−2) is enhanced by decreases in tropospheric ozone (−0.26 W m−2) and methane (−0.2 W m−2), it is partially offset by a positive aerosol ERF from reductions in aerosols (+0.35 W m−2). This study demonstrates that policies to mitigate climate change have added co-benefits for global and regional air quality on annual to daily timescales. Furthermore, the effectiveness of the GHG policies in reducing anthropogenic climate forcing is enhanced in the near-term by reductions in ozone and methane despite the increased forcing due to reductions in aerosols.

Background Rilpivirine (RPV) is the latest non-nucleoside reverse transcriptase inhibitor (NNRTI) to be approved by Food and Drug Administration to combat HIV-1 infections. NNRTIs inhibit the chemical step in viral DNA synthesis by binding to an allosteric site located about 10 A from the polymerase active site of reverse transcriptase (RT). Although NNRTIs potently inhibit the replication of wild-type HIV-1, the binding site is not conserved, and mutations arise in the binding pocket. Doravirine (DOR) is a new NNRTI in phase III clinical trials. Methods Using a single round HIV-1 infection assay, we tested RPV and DOR against a broad panel of NNRTI-resistant mutants to determine their respective activities. We also used molecular modeling to determine if the susceptibility profile of each compound was related to how they bind RT. Results Several mutants displayed decreased susceptibility to DOR. However, with the exception of E138K, our data suggest that the mutations that reduce the potency of DOR and RPV are non-overlapping. Thus, these 2 NNRTIs have the potential to be used together in combination therapy. We also show that the location at which DOR and RPV bind with the NNRTI binding pocket of RT correlates with the differences in their respective susceptibility to the panel of NNRTI-resistance mutations. Conclusions This shows that (1) DOR is susceptible to a number of well-known NNRTI resistance mutations and (2) an understanding of the mutational susceptibilities and binding interactions of NNRTIs with RT could be used to develop pairs of compounds with non-overlapping mutational susceptibilities.

The Arctic temperature response to emissions of aerosols—specifically black carbon (BC), organic carbon (OC), and sulfate—depends on both the sector and the region where these emissions originate. Thus, the net Arctic temperature response to global aerosol emissions reductions will depend strongly on the blend of emissions sources being targeted. We use recently published equilibrium Arctic temperature response factors for BC, OC, and sulfate to estimate the range of present‐day and future Arctic temperature changes from seven different aerosol emissions scenarios. Globally, Arctic temperature changes calculated from all of these emissions scenarios indicate that present‐day emissions from the domestic and transportation sectors generate the majority of present‐day Arctic warming from BC. However, in all of these scenarios, this warming is more than offset by cooling resulting from SO2 emissions from the energy sector. Thus, long‐term climate mitigation strategies that are focused on reducing carbon dioxide (CO2) emissions from the energy sector could generate short‐term, aerosol‐induced Arctic warming. A properly phased approach that targets BC‐rich emissions from the transportation sector as well as the domestic sectors in key regions—while simultaneously working toward longer‐term goals of CO2 mitigation—could potentially avoid some amount of short‐term Arctic warming., Key Points Reductions in anthropogenic black carbon emissions alone could slow Arctic warming by mid‐centuryArctic cooling from reduced BC is more than offset by warming from reduced SO2 across all of the RCP mitigation scenariosDomestic and transport emissions from Asia hold the greatest potential for reducing Arctic warming from anthropogenic aerosols

HIV integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance. We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations. We found by analyzing crystal structures of inhibitors bound to the IN from the prototype foamy virus (PFV) that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3'-processing and the bound host DNA prior to strand transfer. Using this concept of "bi-substrate mimicry," we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA but also more completely fills the space they would normally occupy. Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs.

We examine past and future carbon emissions from global croplands, considering land-use change, changes in crop productivity, tillage practices, and residue removal. We find that emissions over the historical period are sensitive to the assumed productivity of arable land that is not planted in a given year and the assumed fraction of soil carbon that is released during land conversion. The role of this "other" arable land, both at present and over the historical period, is not well understood and should be examined further. The carbon balance of croplands over 21st century depends on changes in management practices, particularly the adoption of conservation tillage and the potential removal of residue for use as energy feedstocks. We find that croplands will not become large carbon sinks in the future, however, unless most crop residue is left on fields. Given the relatively low carbon "penalty" incurred by removal, residue use for energy feedstocks may be the preferred option.

Integrase strand transfer inhibitors (INSTIs) have emerged as clinically effective therapeutics that inhibit HIV-1 replication by blocking the strand transfer reaction catalyzed by HIV-1 integrase (IN). Of the three FDA-approved INSTIs, dolutegravir (DTG) is the least apt to select for resistance. However, recent salvage therapy regimens had low response rates with therapies that included DTG, suggesting that DTG resistance can be selected in patients. Using a single-round infection assay, we evaluated a collection of our best inhibitors and DTG against a broad panel of INSTI-resistant mutants. Two of the new compounds, 4c and 4d, had antiviral profiles against the mutants we tested superior to that of DTG. The susceptibility profiles of 4c and 4d suggest that the compounds are candidates for development as INSTIs. Modeling the binding of 4d to HIV-1 IN reinforced the significance of mimicking the DNA substrate in developing compounds that are broadly effective in their abilities to inhibit HIV-1 INs with mutations in the active site.

Integrase (IN) is an essential viral enzyme required for HIV-1 replication, which has been targeted by anti-AIDS therapeutics. Integrase strand transfer inhibitors (INSTIs) represent a new class of antiretroviral agents developed for the treatment of HIV-1 infections. Important structural features that are shared by many INSTIs include a coplanar arrangement of three heteroatoms that chelate two catalytic Mg(2+) ions in the IN active site and a linked halophenyl ring that binds in the hydrophobic pocket formed by the complex of IN with viral DNA. We recently reported bicyclic 6,7-dihydroxyoxoisoindolin-1-one-based IN inhibitors. In the current study, we modified these inhibitors in three ways. First, we increased the spacer length between the metal-chelating triad and the halophenyl group. Second, we replaced the indoline [5,6] bicycle with a fused dihydroxyisoquinolinones [6,6] ring system. Finally, we prepared bis-6,7-dihydroxyisoindolin-1-one-4-sulfonamides as dimeric HIV-1 IN inhibitors. These new analogues showed low micromolar inhibitory potency in in vitro HIV-1 integrase assays.

The ability to accurately quantify europium and terbium may be confounded by the presence of other lanthanides when using spectroscopic techniques such as optical emission spectroscopy, especially at microgram and sub microgram levels. Kinetic phosphorescence analysis (KPA) offers a method to avoid these interferences during measurement of trace levels. This study examined analysis parameters using KPA for europium and terbium by testing the effects of different acids, molarities, and the use of a complexing agent to determine the ideal conditions and limits of detection for each analyte in matrices containing various mixtures of lanthanides.

Carbonyl sulfide (COS) has recently emerged as an atmospheric tracer of gross primary production. All modeling studies of COS air-monitoring data rely on a climatological anthropogenic inventory that does not reflect present conditions or support interpretation of ice core and firn trends. Here we develop a global anthropogenic inventory for the years 1850 to 2013 based on new emission measurements and material-specific data. By applying methods from a recent regional inventory to global data, we find that the anthropogenic source is similar in magnitude to the plant sink, confounding carbon cycle applications. However, a material-specific approach results in a current anthropogenic source that is only one third of plant uptake and is concentrated in Asia, supporting carbon cycle applications of global air-monitoring data. Furthermore, changes in the anthropogenic source alone cannot explain the century-scale mixing ratio growth, which suggests that ice and firn data may provide the first global history of gross primary production.

Although most of the world's uranium exists as pitchblende or uraninite, this mineral can be weathered to a great variety of secondary uranium minerals, most containing the uranyl cation. Anthropogenic uranium compounds can also react in the environment, leading to spatial–chemical alterations that could be useful for nuclear forensics analyses. Soft X-ray absorption spectroscopy (XAS) has the advantages of being non-destructive, element-specific and sensitive to electronic and physical structure. The soft X-ray probe can also be focused to a spot size on the order of tens of nanometres, providing chemical information with high spatial resolution. However, before XAS can be applied at high spatial resolution, it is necessary to find spectroscopic signatures for a variety of uranium compounds in the soft X-ray spectral region. To that end, we collected the near edge X-ray absorption fine structure (NEXAFS) spectra of a variety of common uranyl-bearing minerals, including uranyl carbonates, oxyhydroxides, phosphates and silicates. We find that uranyl compounds can be distinguished by class (carbonate, oxyhydroxide, phosphate or silicate) based on their oxygen K-edge absorption spectra. This work establishes a database of reference spectra for future spatially resolved analyses. We proceed to show scanning X-ray transmission microscopy (STXM) data from a schoepite particle in the presence of an unknown contaminant. Bien que la plupart de l'uranium mondial soit contenu dans la pechblende ou l'uraninite, ces phases minerales peuvent etre alterees en une grande variete de mineraux uraniferes secondaires, la plupart contenant le cation uranyle. Les composes d'uranium anthropogeniques peuvent egalement reagir dans l'environnement, entrainant des alterations spatio-chimiques qui pourraient etre utiles pour les analyses dans le domaine de l'expertise scientifique nucleaire. La spectroscopie d'absorption des rayons X mous (XAS) presente l'avantage d'etre non destructive, specifique a l'element, et sensible a la structure physique et electronique. La sonde de rayons X mous peut egalement etre focalise pour atteindre une taille de spot de l'ordre de quelques dizaines de nanometres, fournissant ainsi des informations chimiques a haute resolution spatiale. Toutefois, avant que la XAS puisse etre appliquee a haute resolution spatiale, il est necessaire de trouver des signatures spectroscopiques pour une variete de composes d'uranium dans la region spectrale des rayons X mous. A cette fin, nous avons collecte les spectres de structure pres du front d'absorption des rayons X (NEXAFS) d'une variete de mineraux communs contenant des cations uranyles, y compris des carbonates d'uranyle, des oxyhydroxydes, des phosphates et des silicates. Nous montrons que les composes d'uranyle peuvent etre distingues par classe (carbonate, oxyhydroxyde, phosphate ou silicate) en fonction de leur spectre d'absorption des rayons X pres du seuil K de l'oxygene. Ce travail etablit une base de donnees de spectres de reference pour les futures analyses spatialement resolues. Nous presentons des donnees de microscopie a balayage par transmission des rayons X (STXM) d'une particule de schoepite en presence d'un contaminant inconnu.

Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described.

Introduction Epidemiological studies have demonstrated that the vaginal microbiota can significantly impact the risk of acquiring sexually transmitted infections. The human vagina often contains Lactobacillus spp., which produce lactic acid and create an acidic environment (pH 3.5–4) thought to reduce vaginal STIs. Unlike high d-lactate producers, Lactobacillus spp. that produce low amounts or no d-lactate, while achieving low pH do not reduce Chlamydia trachomatis infectivity. Further, exposure to culture supernatants from d-lactate producing Lactobacillus spp. reduces epithelial cell proliferation. We tested if low proliferation affects infection. Methods A 3D model of A2EN cervical epithelial cells was exposed to lactic acid (D, L or D/L) at concentrations that produce pH 7, 5.5 and 4 or to several Lactobacillus spp. conditioned media (LCM) and infected with C. trachomatis serovar L2. Lysates from these A2EN cells were used to infect HeLa cells, and IFUs counted to determine infectivity. 2D A2EN cells were exposed to lactic acid, proliferation chemical inhibitors or LCM followed by infection with C. trachomatis L2. Proliferation and infectivity were evaluated by microscopy. Results At pH 4, d-lactate and LCMs from high d-lactate producing vaginal Lactobacillus spp. afforded maximal protection compared to l-lactate. Interestingly, high infectivity was observed with HCl at pH 4, indicating that pH alone is not responsible for this protection. Exposure to d-lactate or LCMs reduced cell proliferation. Chemical cell proliferation inhibitors dramatically reduced C. trachomatis infectivity. Conclusion These results suggest a differential role for vaginal Lactobacillus spp. in protecting against C. trachomatis infections and potentially other STIs. This protection is driven by the production of d-lactate, which acts on epithelial cells by inhibiting cell proliferation, which appears to be required for infection.

The Aerosol Chemistry Model Intercomparison Project (AerChemMIP) is endorsed by the Coupled-Model Intercomparison Project 6 (CMIP6) and is designed to quantify the climate and air quality impacts of aerosols and chemically reactive gases. These are specifically near-term climate forcers (NTCFs: methane, tropospheric ozone and aerosols, and their precursors), nitrous oxide and ozone-depleting halocarbons. The aim of AerChemMIP is to answer four scientific questions. 1. How have anthropogenic emissions contributed to global radiative forcing and affected regional climate over the historical period? 2. How might future policies (on climate, air quality and land use) affect the abundances of NTCFs and their climate impacts? 3.How do uncertainties in historical NTCF emissions affect radiative forcing estimates? 4. How important are climate feedbacks to natural NTCF emissions, atmospheric composition, and radiative effects? These questions will be addressed through targeted simulations with CMIP6 climate models that include an interactive representation of tropospheric aerosols and atmospheric chemistry. These simulations build on the CMIP6 Diagnostic, Evaluation and Characterization of Klima (DECK) experiments, the CMIP6 historical simulations, and future projections performed elsewhere in CMIP6, allowing the contributions from aerosols and/or chemistry to be quantified. Specific diagnostics are requested as part of the CMIP6 data request to highlight the chemical composition of the atmosphere, to evaluate the performance of the models, and to understand differences in behaviour between them.

Emissions reductions focused on anthropogenic climate-forcing agents with relatively short atmospheric lifetimes, such as methane (CH 4 ) and black carbon, have been suggested as a strategy to reduce the rate of climate change over the next several decades. We find that reductions of methane and black carbon would likely have only a modest impact on near-term global climate warming. Even with maximally feasible reductions phased in from 2015 to 2035, global mean temperatures in 2050 would be reduced by 0.16 °C, with a range of 0.04–0.35 °C because of uncertainties in carbonaceous aerosol emissions and aerosol forcing per unit of emissions. The high end of this range is only possible if total historical aerosol forcing is relatively small. More realistic emission reductions would likely provide an even smaller climate benefit. We find that the climate benefit from reductions in short-lived forcing agents are smaller than previously estimated. These near-term climate benefits of targeted reductions in short-lived forcers are not substantially different in magnitude from the benefits from a comprehensive climate policy.

Retroviruses integrate into cellular DNA nonrandomly. Lentiviruses such as human immunodeficiency virus type 1 (HIV-1) favor the bodies of active genes and gene-enriched transcriptionally active regions of chromosomes. The interaction between lentiviral integrase and the cellular protein lens epithelium-derived growth factor (LEDGF)/p75 underlies the targeting of gene bodies, whereas recent research has highlighted roles for the HIV-1 capsid (CA) protein and cellular factors implicated in viral nuclear import, including transportin 3 (TNPO3) and nucleoporin 358 (NUP358), in the targeting of gene-dense regions of chromosomes. Here, we show that CA mutations, which include the substitution of Asp for Asn74 (N74D), significantly reduce the dependency of HIV-1 on LEDGF/p75 during infection and that this difference correlates with the efficiency of viral DNA integration. The distribution of integration sites mapped by Illumina sequencing confirms that the N74D mutation reduces integration into gene-rich regions of chromosomes and gene bodies and reveals previously unrecognized roles for NUP153 (another HIV-1 cofactor implicated in viral nuclear import) and LEDGF/p75 in the targeting of the viral preintegration complex to gene-dense regions of chromatin. A role for the CA protein in determining the dependency of HIV-1 on LEDGF/p75 during infection highlights a connection between the viral capsid and chromosomal DNA integration.

Background Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiretroviral compounds that bind in an allosteric binding pocket in HIV-1 RT, located about 10 Å from the polymerase active site. Binding of an NNRTI causes structural changes that perturb the alignment of the primer terminus and polymerase active site, preventing viral DNA synthesis. Rilpivirine (RPV) is the most recent NNRTI approved by the FDA, but like all other HIV-1 drugs, suboptimal treatment can lead to the development of resistance. To generate better compounds that could be added to the current HIV-1 drug armamentarium, we have developed several RPV analogs to combat viral variants that are resistant to the available NNRTIs. Results Using a single-round infection assay, we identified several RPV analogs that potently inhibited a broad panel of NNRTI resistant mutants. Additionally, we determined that several resistant mutants selected by either RPV or Doravirine (DOR) caused only a small increase in susceptibility to the most promising RPV analogs. Conclusions The antiviral data suggested that there are RPV analogs that could be candidates for further development as NNRTIs, and one of the most promising compounds was modeled in the NNRTI binding pocket. This model can be used to explain why this compound is broadly effective against the panel of NNRTI resistance mutants. Electronic supplementary material The online version of this article (doi:10.1186/s12977-016-0244-2) contains supplementary material, which is available to authorized users.

On the basis of a series of lactam and phthalimide derivatives that inhibit HIV-1 integrase, we developed a new molecule, XZ-259, with biochemical and antiviral activities comparable to raltegravir. We determined the crystal structures of XZ-259 and four other derivatives in complex with the prototype foamy virus intasome. The compounds bind at the integrase-Mg(2+)-DNA interface of the integrase active site. In biochemical and antiviral assays, XZ-259 inhibits raltegravir-resistant HIV-1 integrases harboring the Y143R mutation. Molecular modeling is also presented suggesting that XZ-259 can bind in the HIV-1 intasome with its dimethyl sulfonamide group adopting two opposite orientations. Molecular dynamics analyses of the HIV-1 intasome highlight the importance of the viral DNA in drug potency.

The Global Warming Potential (GWP) index is currently used to create CO2-equivalent emission totals for multi-gas greenhouse targets. While many alternatives have been proposed, it is not possible to uniquely define a metric that captures the different impacts of emissions of substances with widely disparate atmospheric lifetimes, which leads to a wide range of possible index values. We examine the sensitivity of emissions and climate outcomes to the value of the index used to aggregate methane emissions using a technologically detailed integrated assessment model. The methane index is varied between 4 and 70, with a central value of 21, which is the 100-year GWP value currently used in policy contexts. We find that the sensitivity to index value is, at most, 10–18 % in terms of methane emissions but only 2–3 % in terms of the maximum total radiative forcing change, with larger regional emissions differences in some cases. The choice of index also affects estimates of the cost of meeting a given end of century forcing target, with total two-gas mitigation cost increasing by 7–9 % if the index is increased, and increasing in most scenarios from 4 to 23 % if the index is lowered, with a slight (1 %) decrease in total cost in one case. We find that much of the methane abatement occurs as the induced effect of CO2 abatement rather than explicit abatement, which is one reason why climate outcomes are relatively insensitive to the index value. We also find that the near-term climate benefit of increasing the methane index is small.

HIV-1 integrase (IN) is a validated therapeutic target for the treatment of AIDS. However, the emergence of resistance to raltegravir, the sole marketed FDA-approved IN inhibitor, emphasizes the need to develop second-generation inhibitors that retain efficacy against clinically relevant IN mutants. We report herein bicyclic hydroxy-1H-pyrrolopyridine-triones as a new family of HIV-1 integrase inhibitors that were efficiently prepared using a key 'Pummerer cyclization deprotonation cycloaddition' cascade of imidosulfoxides. In in vitro HIV-1 integrase assays, the analogs showed low micromolar inhibitory potencies with selectivity for strand transfer reactions as compared with 3'-processing inhibition. A representative inhibitor (5e) retained most of its inhibitory potency against the three major raltegravir-resistant IN mutant enzymes, G140S/Q148H, Y143R, and N155H. In antiviral assays employing viral vectors coding these IN mutants, compound 5e was approximately 200- and 20-fold less affected than raltegravir against the G140S/Q148H and Y143R mutations, respectively. Against the N155H mutation, 5e was approximately 10-fold less affected than raltegravir. Thus, our new compounds represent a novel structural class that may be further developed to overcome resistance to raltegravir, particularly in the case of the G140S/Q148H mutations.

Pollutant emissions such as aerosols and tropospheric ozone precursors substantially influence climate. While future century-scale scenarios for these emissions have become more realistic through the inclusion of emission controls, they still potentially lack consistency between surface pollutant concentrations and regional levels of affluence. We find that the default method of scenario construction, whereby emissions factors converge to similar values in different regions, does not yield pollution concentrations consistent with historical experience. We demonstrate a methodology combining use of an integrated assessment model and a three-dimensional atmospheric chemical transport model, whereby a reference scenario is constructed by requiring consistent surface pollutant concentrations as a function of regional income over the 21st century. By adjusting air pollutant emission control parameters, we improve consistency between projected PM2.5 and economic income among world regions through time; consistency for ozone is also improved but is more difficult to achieve because of the strong influence of upwind world regions. Reference case pollutant emissions described here were used to construct the RCP4.5 Representative Concentration Pathway climate policy scenario.

Raltegravir (RAL) and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) efficiently block viral replication in vitro and suppress viremia in patients. These small molecules bind to the IN active site, causing it to disengage from the deoxyadenosine at the 3′ end of viral DNA. The emergence of viral strains that are highly resistant to RAL underscores the pressing need to develop INSTIs with improved resistance profiles. Herein, we show that the candidate second-generation drug dolutegravir (DTG, S/GSK1349572) effectively inhibits a panel of HIV-1 IN variants resistant to first-generation INSTIs. To elucidate the structural basis for the increased potency of DTG against RAL-resistant INs, we determined crystal structures of wild-type and mutant prototype foamy virus intasomes bound to this compound. The overall IN binding mode of DTG is strikingly similar to that of the tricyclic hydroxypyrrole MK-2048. Both second-generation INSTIs occupy almost the same physical space within the IN active site and make contacts with the β4–α2 loop of the catalytic core domain. The extended linker region connecting the metal chelating core and the halobenzyl group of DTG allows it to enter farther into the pocket vacated by the displaced viral DNA base and to make more intimate contacts with viral DNA, compared with those made by RAL and other INSTIs. In addition, our structures suggest that DTG has the ability to subtly readjust its position and conformation in response to structural changes in the active sites of RAL-resistant INs.

Quality energy consumption data are important for many types of analysis, and global data sets estimate trends of county level energy consumption, derived from country reported data and regional reports. We present a novel basis for informing uncertainty in energy data by quantifying the changes in reported energy consumption as countries update their previously reported data. We use 17 editions of the British Petroleum World Energy Statistics (2001–2017) to evaluate how reported energy consumption is revised over time in aggregate coal, oil, and natural gas consumption data. We find that 70% of non-zero data points are adjusted by an average of 1.3% of a country's total fossil fuel use in the year after their first publication. Earlier data points are revised less often, but almost half of historical trends contain some revisions in later years. The size and rate of data revisions vary over countries and fuels: coal data points have larger, less frequent revisions while oil data points have smaller more frequent revisions, with natural gas in between. A k-means cluster analysis was performed to group together countries with similar revision patterns. These groups span income, economy classification, OECD membership, and regions. Standard country groupings, therefore, do not predict the extent to which a country's energy data has undergone revisions in the past.

The importance of sulfur dioxide emissions for climate change is now established, although substantial uncertainties remain. This paper presents projections for future sulfur dioxide emissions using the MiniCAM integrated assessment model. A new income-based parameterization for future sulfur dioxide emissions controls is developed based on purchasing power parity (PPP) income estimates and historical trends related to the implementation of sulfur emissions limitations. This parameterization is then used to produce sulfur dioxide emissions trajectories for the set of scenarios developed for the Special Report on Emission Scenarios (SRES). We use the SRES methodology to produce harmonized SRES scenarios using the latest version of the MiniCAM model. The implications, and requirements, for integrated assessment modeling of sulfur dioxide emissions are discussed. We find that sulfur emissions eventually decline over the next century under a wide set of assumptions. These emission reductions result from a combination of emission controls, the adoption of advanced electric technologies, and a shift away from the direct end use of coal with increasing income levels. Only under a scenario where incomes in developing regions increase slowly do global emission levels remain at close to present levels over the next century. Under a climate policy that limits emissions of carbon dioxide, sulfur dioxide emissions fall in a relatively narrow range. In most cases, the relative climatic effect of sulfur dioxide emissions decreases dramatically to a point where sulfur dioxide is only a minor component of climate forcing by the end of the century. Ecological effects of sulfur dioxide, however, could be significant in some developing regions for many decades to come.

Reactive gas emissions (CO, NOx, VOC) have indirect radiative forcing effects through their influences on tropospheric ozone and on the lifetimes of methane and hydrogenated halocarbons. These effects are quantified here for the full set of emissions scenarios developed in the Intergovernmental Panel on Climate Change Special Report on Emissions Scenarios. In most of these no-climate-policy scenarios, anthropogenic reactive gas emissions increase substantially over the twenty-first century. For the implied increases in tropospheric ozone, the maximum forcing exceed s1Wm 22 by 2100 (range 20.14 to 11.03 W m22). The changes are moderated somewhat through compensating influences from NO x versus CO and VOC. Reactive gas forcing influences through methane and halocarbons are much smaller; 2100 ranges are 20.20 to 10.23 W m22 for methane and 20.04 to 10.07 W m22 for the halocarbons. Future climate change might be reduced through policies limiting reactive gas emissions, but the potential for explicitly climate-motivated reductions depends critically on the extent of reductions that are likely to arise through air quality considerations and on the assumed baseline scenario.

There are currently three HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) approved by the FDA for the treatment of AIDS. However, the emergence of drug-resistant mutants emphasizes the need to develop additional agents that have improved efficacies against the existent resistant mutants. As reported herein, we modified our recently disclosed 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides IN inhibitors to develop compounds that have improved efficacies against recombinant IN in biochemical assays. These new compounds show single-digit nanomolar antiviral potencies against HIV vectors that carry wild-type (WT) IN in a single round replication assay and have improved potency against vectors harboring the major forms of drug resistant IN mutants. These compounds also have low toxicity for cultured cells, which in several cases, results in selectivity indices (CC50/EC50) of greater than 10000. The compounds have the potential, with additional structural modifications, to yield clinical agents that are effective against the known strains of resistant viruses.

International audience; Integrase (IN) inhibitors are the newest class of antiretroviral agents developed for the treatment of HIV-1 infections. Merck's Raltegravir (RAL) (October 2007) and Gilead's Elvitegravir (EVG) (August 2012), which act as IN strand transfer inhibitors (INSTIs), were the first anti-IN drugs to be approved by the FDA. However, the virus develops resistance to both RAL and EVG, and there is extensive cross-resistance to these two drugs. New "2nd-generation" INSTIs are needed that will have greater efficacy against RAL- and EVG-resistant strains of IN. The FDA has recently approved the first second generation INSTI, GSK's Dolutegravir (DTG) (August 2013). Our current article describes the design, synthesis, and evaluation of a series of 1,8-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides, 1,4-dihydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides, and 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides. This resulted in the identification of noncytotoxic inhibitors that exhibited single digit nanomolar EC50 values against HIV-1 vectors harboring wild-type IN in cell-based assays. Importantly, some of these new inhibitors retain greater antiviral efficacy compared to that of RAL when tested against a panel of IN mutants that included Y143R, N155H, G140S/Q148H, G118R, and E138K/Q148K.

We present a new inventory of global sulfur dioxide emissions from anthropogenic activities for the years 1980–2000. Emissions were estimated in 11 world regions using country-level emissions inventories and regional fossil fuel sulfur content information. Estimated global emissions in 1990 are 72 TgS with an estimated uncertainty of ±8% due to random errors with additional systematic errors that suggest that true emissions may be higher than this central value. We estimate that 56% of 1990 world emissions are from coal, 24% from oil, 15% from industrial processes and 3% from biomass burning. When our results are compared with other studies, they are similar at the global-mean level, but show marked differences at the regional level. Globally, emissions have been roughly constant from 1980 to the present. However, a significant shift has occurred in the spatial distribution of emissions. While 60% of global emissions in 1980 were from around the North Atlantic basin, this region contributed less than 40% of the global total by 1995 and will contribute even less in the future. Currently, based on our estimates, the centrally planned Asia (CPA) region, dominated by China, is the largest contributor to global sulfur dioxide emissions. A gridded data set for 1990 emissions is also produced, including a consistent seasonal cycle and a stratification of emissions into low and elevated releases. Implications for climate modeling and detection studies are discussed.

Global-mean temperature and sea-level implications are calculated for four preliminary emissions scenarios presented elsewhere in this issue. Total anthropogenic temperature change in the year 2100 ranges from 1.3–4.0°C using the four scenarios for upper and lower bounds on emissions and high and low values for the climate sensitivity. The lower bound is higher than that given in the IPCC Second Assessment Report, due mainly to lower future sulfur dioxide emissions. These lower emissions also have the effect of reducing uncertainties associated with sulfate aerosol forcing. Significant future climate changes occur in all scenarios, indicating that adaptation policies need to be considered as an important component of climate-change policy.

Although the biochemistry of triglyceride synthesis has been studied for decades, an understanding of the molecular processes involved has been lacking. The recent cloning of a gene encoding acyl coenzyme A : diacylglycerol acyltransferase, an enzyme that catalyses the final step in triglyceride synthesis, has opened this area to molecular investigation and has begun to provide new insights into triglyceride metabolism.

The use of Global Warming Potentials (GWPs) to calculate ‘equivalent’ carbon dioxide emissions reductions in the climate change context is examined. We find that GWPs are accurate only for short time horizons. Over long time horizons their use implicitly leads to tradeoffs between near-term and long-term climate change. For one of the most policy-relevant cases, comparing reductions in methane and carbon dioxide, the long-term effect on climate of reducing methane emissions is relatively small, at variance with the common perception based on published GWP values.

The production of mutations in cellular oncogenes such as ras is involved in the development of many human cancers. These mutations result in the expression of mutant forms of the encoded p21 protein which can potentially serve as a biomarker for this carcinogenic process. Workers exposed to vinyl chloride (VC) who are at risk for the development of the sentinel neoplasm angiosarcoma of the liver (ASL) represent a model population for the study of such a mutant p21ras biomarker, since VC is known to cause a specific ras mutation in ASL. In order to determine the relationship between VC exposure and this biomarker, serum samples from a cohort of 225 French VC workers and 111 age-sex-race-smoking-drinking matched unexposed controls were examined for the presence of mutant p21ras by immunoblotting with a mouse monoclonal antibody specific for the mutant protein. Stratifying the exposed workers by degree of VC exposure in estimated ppm-years by quartiles yielded a statistically significant trend for increasing odds ratio for sero-positivity of the p21ras biomarker with increasing exposure. These results suggest that this serum biomarker is related to VC exposure and may be an early indicator of carcinogenic risk in exposed individuals.

At least four distinctive sterol functions have been defined in the yeast Saccharomyces cerevisiae. One of these functions, identified as sparking, has the lowest quantitative requirement for sterol, but has the greatest structural specificity. Based on studies utilizing a yeast strain auxotrophic for both heme and sterol biosynthesis, it had been reported that a delta 5-sterol was essential for the growth of the organism. We demonstrate here that heme, and not a heme precursor, can replace the delta 5-sparking sterol requirement of heme auxotrophic strains of yeast.

The evolution of global and regional anthropogenic SO2 emissions in the last decade has been estimated through a bottom-up calculation. After increasing until about 2006, we estimate a declining trend continuing until 2011. However, there is strong spatial variability, with North America and Europe continuing to reduce emissions, with an increasing role of Asia and international shipping. China remains a key contributor, but the introduction of stricter emission limits followed by an ambitious program of installing flue gas desulfurization on power plants resulted in a significant decline in emissions from the energy sector and stabilization of total Chinese SO2 emissions. Comparable mitigation strategies are not yet present in several other Asian countries and industrial sectors in general, while emissions from international shipping are expected to start declining soon following an international agreement to reduce the sulfur content of fuel oil. The estimated trends in global SO2 emissions are within the range of representative concentration pathway (RCP) projections and the uncertainty previously estimated for the year 2005.

Although an extensive body of scientific and patent literature exists describing the development of HIV-1 integrase (IN) inhibitors, Merck’s raltegravir and Gilead’s elvitegravir remain the only IN inhibitors FDA-approved for the treatment of AIDS. The emergence of raltegravir-resistant strains of HIV-1 containing mutated forms of IN underlies the need for continued efforts to enhance the efficacy of IN inhibitors against resistant mutants. We have previously described bicyclic 6,7-dihydroxyoxoisoindolin-1-ones that show good IN inhibitory potency. This report describes the effects of introducing substituents into the 4- and 5-positions of the parent 6,7-dihydroxyoxoisoindolin-1-one platform. We have developed several sulfonamide-containing analogs that enhance potency in cell-based HIV assays by more than two orders-of-magnitude and we describe several compounds that are more potent than raltegravir against the clinically relevant Y143R IN mutant.

Sulfur aerosols impact human health, ecosystems, agriculture, and global and regional climate. A new annual estimate of anthropogenic global and regional sulfur dioxide emissions has been constructed spanning the period 1850–2005 using a bottom-up mass balance method, calibrated to country-level inventory data. Global emissions peaked in the early 1970s and decreased until 2000, with an increase in recent years due to increased emissions in China, international shipping, and developing countries in general. An uncertainty analysis was conducted including both random and systemic uncertainties. The overall global uncertainty in sulfur dioxide emissions is relatively small, but regional uncertainties ranged up to 30%. The largest contributors to uncertainty at present are emissions from China and international shipping. Emissions were distributed on a 0.5° grid by sector for use in coordinated climate model experiments.

New tricyclic HIV-1 integrase (IN) inhibitors were prepared that combined structural features of bicyclic pyrimidinones with recently disclosed 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones. This combination resulted in the introduction of a nitrogen into the aryl ring and the addition of a fused third ring to our previously described inhibitors. The resulting analogues showed low micromolar inhibitory potency in in vitro HIV-1 integrase assays, with good selectivity for strand transfer relative to 3'-processing.