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The spread of cancer from organ to organ (metastasis) is responsible for the vast majority of cancer deaths; however, most current anti-cancer drugs are designed to arrest or reverse tumor growth without directly addressing disease spread. It was recently discovered that tumor cell-secreted interleukin-6 (IL-6) and interleukin-8 (IL-8) synergize to enhance cancer metastasis in a cell-density dependent manner, and blockade of the IL-6 and IL-8 receptors (IL-6R and IL-8R) with a novel bispecific antibody, BS1, significantly reduced metastatic burden in multiple preclinical mouse models of cancer. Bispecific antibodies (BsAbs), which combine two different antigen-binding sites into one molecule, are a promising modality for drug development due to their enhanced avidity and dual targeting effects. However, while BsAbs have tremendous therapeutic potential, elucidating the mechanisms underlying their binding and inhibition will be critical for maximizing the efficacy of new BsAb treatments. Here, we describe a quantitative, computational model of the BS1 BsAb, exhibiting how modeling multivalent binding provides key insights into antibody affinity and avidity effects and can guide therapeutic design. We present detailed simulations of the monovalent and bivalent binding interactions between different antibody constructs and the IL-6 and IL-8 receptors to establish how antibody properties and system conditions impact the formation of binary (antibody-receptor) and ternary (receptor-antibody-receptor) complexes. Model results demonstrate how the balance of these complex types drives receptor inhibition, providing important and generalizable predictions for effective therapeutic design.

GS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under compassionate use to two Ebola patients, both of whom survived, and is currently in Phase 2 clinical development for treatment of Ebola virus disease. Here we report the antiviral activities of GS-5734 and the parent nucleoside analog across multiple virus families, providing evidence to support new indications for this compound against human viruses of significant public health concern.

LEDs offer a wide range of spectral output with high efficiencies. However, the efficiencies of solid-state LEDs with green and yellow wavelengths are rather low due to the lack of suitable direct bandgap materials. Here, we introduce and develop perylene-enhanced green LEDs that produce a higher wall-plug efficiency of 48% compared to 38% for a solid-state green LED. While the wall-plug efficiency of the perylene-enhanced red LED is still lower than that of a solid-state red LED, we demonstrate that remote phosphor colour converters are effective solutions for targeted spectral tuning across the visible spectrum for horticultural lighting. In this work, we retrofit existing white LEDs and augment photosynthesis via spectral output tuning to achieve a higher red-to-blue ratio. Our results show a significant improvement in plant growth by up to 39%, after a 4-month growth cycle. We observe no visible degradation of the colour converter even under continuous illumination with a current of 400 mA. This opens up new opportunities for using perylene-based colour converters for tuneable illumination with high brightness.

The growth in global methane (CH₄) concentration, which had been ongoing since the industrial revolution, stalled around the year 2000 before resuming globally in 2007. We evaluate the role of the hydroxyl radical (OH), the major CH₄ sink, in the recent CH₄ growth. We also examine the influence of systematic uncertainties in OH concentrations on CH₄ emissions inferred from atmospheric observations. We use observations of 1,1,1-trichloroethane (CH₃CCl₃), which is lost primarily through reaction with OH, to estimate OH levels as well as CH₃CCl₃ emissions, which have uncertainty that previously limited the accuracy of OH estimates. We find a 64–70% probability that a decline in OH has contributed to the post-2007 methane rise. Our median solution suggests that CH₄ emissions increased relatively steadily during the late 1990s and early 2000s, after which growth was more modest. This solution obviates the need for a sudden statistically significant change in total CH₄ emissions around the year 2007 to explain the atmospheric observations and can explain some of the decline in the atmospheric 13CH₄/12CH₄ ratio and the recent growth in C₂H₆. Our approach indicates that significant OH-related uncertainties in the CH₄ budget remain, and we find that it is not possible to implicate, with a high degree of confidence, rapid global CH₄ emissions changes as the primary driver of recent trends when our inferred OH trends and these uncertainties are considered.

The atmospheric concentration of trichlorofluoromethane (CFC-11) has been in decline since the production of ozone-depleting substances was phased out under the Montreal Protocol 1 , 2 . Since 2013, the concentration decline of CFC-11 slowed unexpectedly owing to increasing emissions, probably from unreported production, which, if sustained, would delay the recovery of the stratospheric ozone layer 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 – 12 . Here we report an accelerated decline in the global mean CFC-11 concentration during 2019 and 2020, derived from atmospheric concentration measurements at remote sites around the world. We find that global CFC-11 emissions decreased by 18 ± 6 gigagrams per year (26 ± 9 per cent; one standard deviation) from 2018 to 2019, to a 2019 value (52 ± 10 gigagrams per year) that is similar to the 2008−2012 mean. The decline in global emissions suggests a substantial decrease in unreported CFC-11 production. If the sharp decline in unexpected global emissions and unreported production is sustained, any associated future ozone depletion is likely to be limited, despite an increase in the CFC-11 bank (the amount of CFC-11 produced, but not yet emitted) by 90 to 725 gigagrams by the beginning of 2020. Atmospheric concentration measurements at remote sites around the world reveal an accelerated decline in the global mean CFC-11 concentration during 2018 and 2019, reversing recent trends and building confidence in the timely recovery of the stratospheric ozone layer.

Variations in the coaching style used by supervisors and/or managers (n = 51) at a variety of businesses in mainland China were examined for their impact on a range of subordinates’ (n = 373) work outcomes. The data, collected in four waves over several months, showed as hypothesized that style variations reflected by guidance versus facilitation-based coaching had differential effects on subordinates’ adaptive performance (AP), task performance, and job-related feelings of anxiety. Guidance coaching, for example, was negatively related to AP, whereas facilitation was positively associated; this pattern was reversed for task performance. Also, as expected, AP partially mediated both the positive relationship between guidance coaching and task performance, as well as the negative association between facilitation and task performance. Finally, a post hoc study revealed that subordinates’ job-related anxiety partially mediated the negative relationship between guidance coaching and AP, as well as the positive association involving facilitation and AP.

Emissions of ozone-depleting substances, including trichlorofluoromethane (CFC-11), have decreased since the mid-1980s in response to the Montreal Protocol 1 , 2 . In recent years, an unexpected increase in CFC-11 emissions beginning in 2013 has been reported, with much of the global rise attributed to emissions from eastern China 3 , 4 . Here we use high-frequency atmospheric mole fraction observations from Gosan, South Korea and Hateruma, Japan, together with atmospheric chemical transport-model simulations, to investigate regional CFC-11 emissions from eastern China. We find that CFC-11 emissions returned to pre-2013 levels in 2019 (5.0 ± 1.0 gigagrams per year in 2019, compared to 7.2 ± 1.5 gigagrams per year for 2008–2012, ±1 standard deviation), decreasing by 10 ± 3 gigagrams per year since 2014–2017. Furthermore, we find that in this region, carbon tetrachloride (CCl 4 ) and dichlorodifluoromethane (CFC-12) emissions—potentially associated with CFC-11 production—were higher than expected after 2013 and then declined one to two years before the CFC-11 emissions reduction. This suggests that CFC-11 production occurred in eastern China after the mandated global phase-out, and that there was a subsequent decline in production during 2017–2018. We estimate that the amount of the CFC-11 bank (the amount of CFC-11 produced, but not yet emitted) in eastern China is up to 112 gigagrams larger in 2019 compared to pre-2013 levels, probably as a result of recent production. Nevertheless, it seems that any substantial delay in ozone-layer recovery has been avoided, perhaps owing to timely reporting 3 , 4 and subsequent action by industry and government in China 5 , 6 . Atmospheric data and chemical-transport modelling show that CFC-11 emissions from eastern China have again decreased, after increasing in 2013–2017, and a delay in ozone-layer recovery has probably been avoided.

We report a 40-year history of SF6 atmospheric mole fractions measured at the Advanced Global Atmospheric Gases Experiment (AGAGE) monitoring sites, combined with archived air samples, to determine emission estimates from 1978 to 2018. Previously we reported a global emission rate of 7.3±0.6 Gg yr−1 in 2008 and over the past decade emissions have continued to increase by about 24 % to 9.04±0.35 Gg yr−1 in 2018. We show that changing patterns in SF6 consumption from developed (Kyoto Protocol Annex-1) to developing countries (non-Annex-1) and the rapid global expansion of the electric power industry, mainly in Asia, have increased the demand for SF6-insulated switchgear, circuit breakers, and transformers. The large bank of SF6 sequestered in this electrical equipment provides a substantial source of emissions from maintenance, replacement, and continuous leakage. Other emissive sources of SF6 occur from the magnesium, aluminium, and electronics industries as well as more minor industrial applications. More recently, reported emissions, including those from electrical equipment and metal industries, primarily in the Annex-1 countries, have declined steadily through substitution of alternative blanketing gases and technological improvements in less emissive equipment and more efficient industrial practices. Nevertheless, there are still demands for SF6 in Annex-1 countries due to economic growth, as well as continuing emissions from older equipment and additional emissions from newly installed SF6-insulated electrical equipment, although at low emission rates. In addition, in the non-Annex-1 countries, SF6 emissions have increased due to an expansion in the growth of the electrical power, metal, and electronics industries to support their continuing development. There is an annual difference of 2.5–5 Gg yr−1 (1990–2018) between our modelled top-down emissions and the UNFCCC-reported bottom-up emissions (United Nations Framework Convention on Climate Change), which we attempt to reconcile through analysis of the potential contribution of emissions from the various industrial applications which use SF6. We also investigate regional emissions in East Asia (China, S. Korea) and western Europe and their respective contributions to the global atmospheric SF6 inventory. On an average annual basis, our estimated emissions from the whole of China are approximately 10 times greater than emissions from western Europe. In 2018, our modelled Chinese and western European emissions accounted for ∼36 % and 3.1 %, respectively, of our global SF6 emissions estimate.

Neutrophils are increasingly associated with tuberculosis (TB) disease. Neutrophil extracellular traps (NETs), which are released by neutrophils as a host antimicrobial defense mechanism, are also associated with tissue damage. However, a link between NET levels and TB disease has not been studied. Here we investigate plasma NETs levels in patients with active pulmonary tuberculosis using an ELISA assay that is suitable for high-throughput processing. We show that plasma NETs levels at baseline correlated with disease severity and decreased with antibiotic therapy. Our study demonstrates the biologic plausibility of measuring NETs in plasma samples from patients with TB.