During an airborne study in the Southeast United States, measured mixing ratios of biogenic hydrocarbons were systematically lower in air masses containing enhanced nitrogen oxides from power plants, ...which we attribute to increased concentrations of hydroxyl (OH) radicals within the power plant plumes. Plume transects at successively further downwind distances provide a decreasing gradient of nitrogen oxides (NOx) concentrations, which together with the implied loss rates of isoprene, constrains the OH dependence on NOx. We find that OH concentrations were highest at nitrogen dioxide concentrations near 1–2 ppbv and decreased at higher and at lower concentrations. These findings agree with the dependence of OH on NOx concentrations expected from known chemical reactions but are not consistent with some studies reporting direct OH measurements higher than expected in regions of the atmosphere with low NOx (NO < 0.08 and NO2 < 0.46 ppbv) and high biogenic hydrocarbon emissions.
Plain Language Summary
Hydroxyl radicals are the main chemical species that removes trace gases from the atmosphere. They determine the atmospheric lifetime of some greenhouse gases and chemicals involved with the destruction of the stratospheric ozone layer. Hydroxyl reactions also play an important role in air pollution chemistry. Measuring hydroxyl radicals is very challenging because of their high reactivity and low concentrations. Some recent measurements have shown unexpectedly high concentrations in relatively clean conditions. In this work, we indirectly estimated the dependence of hydroxyl radicals on the concentration of nitrogen oxides downwind from power plants in the Southeast United States. We observed that mixing ratios of isoprene, a reactive hydrocarbon released from deciduous trees to the atmosphere, were systematically lower in power plant plumes, caused by higher hydroxyl radical concentrations at the elevated nitrogen oxide concentrations. These findings can be explained by known chemical reactions but are not consistent with some studies that found unexpectedly high hydroxyl concentrations in relatively clean conditions.
Key Points
Isoprene was found to be reduced in power‐plant plumes in the Southeast United States because of enhanced removal by hydroxyl (OH) radicals
Observations at different downwind distances from two power plants allow the nitrogen‐oxide (NOx) dependence of OH to be constrained
The NOx dependence of OH is explained by known photochemistry, in contrast with some studies based on direct measurements of OH
An autochthonous model of pancreatic ductal adenocarcinoma (PDA) permitted the analysis of why immunotherapy is ineffective in this human disease. Despite finding that PDA-bearing mice had cancer ...cell-specific CD8 ⁺ T cells, the mice, like human patients with PDA, did not respond to two immunological checkpoint antagonists that promote the function of T cells: anti-cytotoxic T-lymphocyte-associated protein 4 (α-CTLA-4) and α-programmed cell death 1 ligand 1 (α-PD-L1). Immune control of PDA growth was achieved, however, by depleting carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). The depletion of the FAP ⁺ stromal cell also uncovered the antitumor effects of α-CTLA-4 and α-PD-L1, indicating that its immune suppressive activity accounts for the failure of these T-cell checkpoint antagonists. Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP ⁺ cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP ⁺ CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. The residual tumor was composed only of premalignant epithelial cells and inflammatory cells. Thus, a single protein, CXCL12, from a single stromal cell type, the FAP ⁺ CAF, may direct tumor immune evasion in a model of human PDA.
Anaphylaxis is a clinical emergency, and all healthcare professionals should be familiar with its recognition and acute and ongoing management. These guidelines have been prepared by the European ...Academy of Allergy and Clinical Immunology (EAACI) Taskforce on Anaphylaxis. They aim to provide evidence‐based recommendations for the recognition, risk factor assessment, and the management of patients who are at risk of, are experiencing, or have experienced anaphylaxis. While the primary audience is allergists, these guidelines are also relevant to all other healthcare professionals. The development of these guidelines has been underpinned by two systematic reviews of the literature, both on the epidemiology and on clinical management of anaphylaxis. Anaphylaxis is a potentially life‐threatening condition whose clinical diagnosis is based on recognition of a constellation of presenting features. First‐line treatment for anaphylaxis is intramuscular adrenaline. Useful second‐line interventions may include removing the trigger where possible, calling for help, correct positioning of the patient, high‐flow oxygen, intravenous fluids, inhaled short‐acting bronchodilators, and nebulized adrenaline. Discharge arrangements should involve an assessment of the risk of further reactions, a management plan with an anaphylaxis emergency action plan, and, where appropriate, prescribing an adrenaline auto‐injector. If an adrenaline auto‐injector is prescribed, education on when and how to use the device should be provided. Specialist follow‐up is essential to investigate possible triggers, to perform a comprehensive risk assessment, and to prevent future episodes by developing personalized risk reduction strategies including, where possible, commencing allergen immunotherapy. Training for the patient and all caregivers is essential. There are still many gaps in the evidence base for anaphylaxis.
Measurements of hydroxyl (OH) and hydroperoxy (HO2*) radical concentrations were made at the Pasadena ground site during the CalNex‐LA 2010 campaign using the laser‐induced fluorescence‐fluorescence ...assay by gas expansion technique. The measured concentrations of OH and HO2* exhibited a distinct weekend effect, with higher radical concentrations observed on the weekends corresponding to lower levels of nitrogen oxides (NOx). The radical measurements were compared to results from a zero‐dimensional model using the Regional Atmospheric Chemical Mechanism‐2 constrained by NOx and other measured trace gases. The chemical model overpredicted measured OH concentrations during the weekends by a factor of approximately 1.4 ± 0.3 (1σ), but the agreement was better during the weekdays (ratio of 1.0 ± 0.2). Model predicted HO2* concentrations underpredicted by a factor of 1.3 ± 0.2 on the weekends, while measured weekday concentrations were underpredicted by a factor of 3.0 ± 0.5. However, increasing the modeled OH reactivity to match the measured total OH reactivity improved the overall agreement for both OH and HO2* on all days. A radical budget analysis suggests that photolysis of carbonyls and formaldehyde together accounted for approximately 40% of radical initiation with photolysis of nitrous acid accounting for 30% at the measurement height and ozone photolysis contributing less than 20%. An analysis of the ozone production sensitivity reveals that during the week, ozone production was limited by volatile organic compounds throughout the day during the campaign but NOx limited during the afternoon on the weekends.
Key Points
Measurements of OH and HO2 during CalNex‐LA displayed a weekend effect
Modeled OH and HO2 agreed with measurements after accounting for missing OH reactivity
Ozone production was VOC limited on the weekdays but NOx limited on the weekends
Leadership research, traditionally focused on the behavior of an appointed/elected leader, is rapidly shifting towards a distributed, group process form of leadership known as “shared leadership”. ...Since empirical research supporting this approach is limited, we extend prior work exploring antecedents and outcomes of shared leadership and develop a framework examining its role as a mediator between task and team characteristics (internal team environment, task cohesion and task ambiguity) and task and team-level consequences (task satisfaction, team satisfaction and team performance). Analyzing experimental data through a mixed-methods approach (quantitative via regression-based analysis and qualitative using thematic analysis for unstructured data in NVivo 10), our results indicate that, in the context of a creative task, internal team environment and task cohesion predict shared leadership, which, in turn, determines task satisfaction. We discuss implications of these findings and future paths for exploring shared leadership antecedents and outcomes.
Emissions of volatile organic compounds (VOCs) associated with oil and natural gas production in the Uintah Basin, Utah were measured at a ground site in Horse Pool and from a NOAA mobile laboratory ...with PTR-MS instruments. The VOC compositions in the vicinity of individual gas and oil wells and other point sources such as evaporation ponds, compressor stations and injection wells are compared to the measurements at Horse Pool. High mixing ratios of aromatics, alkanes, cycloalkanes and methanol were observed for extended periods of time and for short-term spikes caused by local point sources. The mixing ratios during the time the mobile laboratory spent on the well pads were averaged. High mixing ratios were found close to all point sources, but gas well pads with collection and dehydration on the well pad were clearly associated with higher mixing ratios than other wells. The comparison of the VOC composition of the emissions from the oil and natural gas well pads showed that gas well pads without dehydration on the well pad compared well with the majority of the data at Horse Pool, and that oil well pads compared well with the rest of the ground site data. Oil well pads on average emit heavier compounds than gas well pads. The mobile laboratory measurements confirm the results from an emissions inventory: the main VOC source categories from individual point sources are dehydrators, oil and condensate tank flashing and pneumatic devices and pumps. Raw natural gas is emitted from the pneumatic devices and pumps and heavier VOC mixes from the tank flashings.
Molecular self-assembly of peptides into ordered nanotubes is highly important for various technological applications. Very short peptide building blocks, as short as dipeptides, can form assemblies ...with unique mechanical, optical, piezoelectric, and semiconductive properties. Yet, the control over nanotube length in solution has remained challenging, due to the inherent sequential self-assembly mechanism. Here, in line with polymer chemistry paradigms, we applied a supramolecular polymer coassembly methodology to modulate peptide nanotube elongation. Utilizing this approach, we achieved a narrow, controllable nanotube length distribution by adjusting the molecular ratio of the diphenylalanine assembly unit and its end-capped analogue. Kinetic analysis suggested a slower coassembly organization process as compared to the self-assembly dynamics of each of the building blocks separately. This is consistent with a hierarchal arrangement of the peptide moieties within the coassemblies. Mass spectrometry analysis demonstrated the bimolecular composition of the coassembled nanostructures. Moreover, the peptide nanotubes’ length distribution, as determined by electron microscopy, was shown to fit a fragmentation kinetics model. Our results reveal a simple and efficient mechanism for the control of nanotube sizes through the coassembly of peptide entities at various ratios, allowing for the desired end-product formation. This dynamic size control offers tools for molecular engineering at the nanoscale exploiting the advantages of molecular coassembly.
Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. ...Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting.
IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0–1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1–21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1–21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (<18 months vs ≥18 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279.
Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7·3 months (IQR 3·7–13·6). Median overall survival was 8·87 months (95% CI 7·00–10·61) with atezolizumab plus cobimetinib, 7·10 months (6·05–10·05) with atezolizumab, and 8·51 months (6·41–10·71) with regorafenib; the hazard ratio was 1·00 (95% CI 0·73–1·38; p=0·99) for the combination versus regorafenib and 1·19 (0·83–1·71; p=0·34) for atezolizumab versus regorafenib. Grade 3–4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3–4 adverse events in the combination group were diarrhoea (20 11% of 179), anaemia (ten 6%), increased blood creatine phosphokinase (12 7%), and fatigue (eight 4%). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis) and one in the regorafenib group (intestinal perforation).
IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer.
F Hoffmann-La Roche Ltd/Genentech Inc.
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