The reduced net carbon uptake over Northern Hemisphere land causes the close-to-normal CO2 growth rate in 2021 La Niña.

La Niña climate anomalies have historically been associated with substantial reductions in the atmospheric CO2 growth rate. However, the 2021 La Niña exhibited a unique near-neutral impact on the CO2 growth rate. In this study, we investigate the underlying mechanisms by using an ensemble of net CO2 fluxes constrained by CO2 observations from the Orbiting Carbon Observatory-2 in conjunction with estimates of gross primary production and fire carbon emissions. Our analysis reveals that the close-to-normal atmospheric CO2 growth rate in 2021 was the result of the compensation between increased net carbon uptake over the tropics and reduced net carbon uptake over the Northern Hemisphere mid-latitudes. Specifically, we identify that the extreme drought and warm anomalies in Europe and Asia reduced the net carbon uptake and offset 72% of the increased net carbon uptake over the tropics in 2021. This study contributes to our broader understanding of how regional processes can shape the trajectory of atmospheric CO2 concentration under climate change.

The worldwide COVID-19 lockdown impacts on global secondary inorganic aerosols and radiative budget.

Global lockdown measures to prevent the spread of the coronavirus disease 2019 (COVID-19) led to air pollutant emission reductions. While the COVID-19 lockdown impacts on both trace gas and total particulate pollutants have been widely investigated, secondary aerosol formation from trace gases remains unclear. To that end, we quantify the COVID-19 lockdown impacts on NOx and SO2 emissions and sulfate-nitrate-ammonium aerosols using multiconstituent satellite data assimilation and model simulations. We find that anthropogenic emissions over major polluted regions were reduced by 19 to 25% for NOx and 14 to 20% for SO2 during April 2020. These emission reductions led to 8 to 21% decreases in sulfate and nitrate aerosols over highly polluted areas, corresponding to >34% of the observed aerosol optical depth declines and a global aerosol radiative forcing of +0.14 watts per square meter relative to business-as-usual scenario. These results point to the critical importance of secondary aerosol pollutants in quantifying climate impacts of future mitigation measures.

Predictability of fossil fuel CO2 from air quality emissions.

Quantifying the coevolution of greenhouse gases and air quality pollutants can provide insight into underlying anthropogenic processes enabling predictions of their emission trajectories. Here, we classify the dynamics of historic emissions in terms of a modified Environmental Kuznets Curve (MEKC), which postulates the coevolution of fossil fuel CO2 (FFCO2) and NOx emissions as a function of macroeconomic development. The MEKC broadly captures the historic FFCO2-NOx dynamical regimes for countries including the US, China, and India as well as IPCC scenarios. Given these dynamics, we find the predictive skill of FFCO2 given NOx emissions constrained by satellite data is less than 2% error at one-year lags for many countries and less than 10% for 4-year lags. The proposed framework in conjunction with an increasing satellite constellation provides valuable guidance to near-term emission scenario development and evaluation at time-scales relevant to international assessments such as the Global Stocktake.

Attribution of Space-Time Variability in Global-Ocean Dissolved Inorganic Carbon.

The inventory and variability of oceanic dissolved inorganic carbon (DIC) is driven by the interplay of physical, chemical, and biological processes. Quantifying the spatiotemporal variability of these drivers is crucial for a mechanistic understanding of the ocean carbon sink and its future trajectory. Here, we use the Estimating the Circulation and Climate of the Ocean-Darwin ocean biogeochemistry state estimate to generate a global-ocean, data-constrained DIC budget and investigate how spatial and seasonal-to-interannual variability in three-dimensional circulation, air-sea CO2 flux, and biological processes have modulated the ocean sink for 1995-2018. Our results demonstrate substantial compensation between budget terms, resulting in distinct upper-ocean carbon regimes. For example, boundary current regions have strong contributions from vertical diffusion while equatorial regions exhibit compensation between upwelling and biological processes. When integrated across the full ocean depth, the 24-year DIC mass increase of 64 Pg C (2.7 Pg C year-1) primarily tracks the anthropogenic CO2 growth rate, with biological processes providing a small contribution of 2% (1.4 Pg C). In the upper 100 m, which stores roughly 13% (8.1 Pg C) of the global increase, we find that circulation provides the largest DIC gain (6.3 Pg C year-1) and biological processes are the largest loss (8.6 Pg C year-1). Interannual variability is dominated by vertical advection in equatorial regions, with the 1997-1998 El Niño-Southern Oscillation causing the largest year-to-year change in upper-ocean DIC (2.1 Pg C). Our results provide a novel, data-constrained framework for an improved mechanistic understanding of natural and anthropogenic perturbations to the ocean sink.

Amazonian terrestrial water balance inferred from satellite-observed water vapor isotopes.

Atmospheric humidity and soil moisture in the Amazon forest are tightly coupled to the region's water balance, or the difference between two moisture fluxes, evapotranspiration minus precipitation (ET-P). However, large and poorly characterized uncertainties in both fluxes, and in their difference, make it challenging to evaluate spatiotemporal variations of water balance and its dependence on ET or P. Here, we show that satellite observations of the HDO/H2O ratio of water vapor are sensitive to spatiotemporal variations of ET-P over the Amazon. When calibrated by basin-scale and mass-balance estimates of ET-P derived from terrestrial water storage and river discharge measurements, the isotopic data demonstrate that rainfall controls wet Amazon water balance variability, but ET becomes important in regulating water balance and its variability in the dry Amazon. Changes in the drivers of ET, such as above ground biomass, could therefore have a larger impact on soil moisture and humidity in the dry (southern and eastern) Amazon relative to the wet Amazon.

Quantifying Northern High Latitude Gross Primary Productivity (GPP) Using Carbonyl Sulfide (OCS).

The northern high latitude (NHL, 40°N to 90°N) is where the second peak region of gross primary productivity (GPP) other than the tropics. The summer NHL GPP is about 80% of the tropical peak, but both regions are still highly uncertain (Norton et al. 2019, https://doi.org/10.5194/bg-16-3069-2019). Carbonyl sulfide (OCS) provides an important proxy for photosynthetic carbon uptake. Here we optimize the OCS plant uptake fluxes across the NHL by fitting atmospheric concentration simulation with the GEOS-CHEM global transport model to the aircraft profiles acquired over Alaska during NASA's Carbon in Arctic Reservoirs Vulnerability Experiment (2012-2015). We use the empirical biome-specific linear relationship between OCS plant uptake flux and GPP to derive the six plant uptake OCS fluxes from different GPP data. Such GPP-based fluxes are used to drive the concentration simulations. We evaluate the simulations against the independent observations at two ground sites of Alaska. The optimized OCS fluxes suggest the NHL plant uptake OCS flux of -247 Gg S year-1, about 25% stronger than the ensemble mean of the six GPP-based OCS fluxes. GPP-based OCS fluxes systematically underestimate the peak growing season across the NHL, while a subset of models predict early start of season in Alaska, consistent with previous studies of net ecosystem exchange. The OCS optimized GPP of 34 PgC yr-1 for NHL is also about 25% more than the ensembles mean from six GPP data. Further work is needed to fully understand the environmental and biotic drivers and quantify their rate of photosynthetic carbon uptake in Arctic ecosystems.

Societal shifts due to COVID-19 reveal large-scale complexities and feedbacks between atmospheric chemistry and climate change.

The COVID-19 global pandemic and associated government lockdowns dramatically altered human activity, providing a window into how changes in individual behavior, enacted en masse, impact atmospheric composition. The resulting reductions in anthropogenic activity represent an unprecedented event that yields a glimpse into a future where emissions to the atmosphere are reduced. Furthermore, the abrupt reduction in emissions during the lockdown periods led to clearly observable changes in atmospheric composition, which provide direct insight into feedbacks between the Earth system and human activity. While air pollutants and greenhouse gases share many common anthropogenic sources, there is a sharp difference in the response of their atmospheric concentrations to COVID-19 emissions changes, due in large part to their different lifetimes. Here, we discuss several key takeaways from modeling and observational studies. First, despite dramatic declines in mobility and associated vehicular emissions, the atmospheric growth rates of greenhouse gases were not slowed, in part due to decreased ocean uptake of CO2 and a likely increase in CH4 lifetime from reduced NO x emissions. Second, the response of O3 to decreased NO x emissions showed significant spatial and temporal variability, due to differing chemical regimes around the world. Finally, the overall response of atmospheric composition to emissions changes is heavily modulated by factors including carbon-cycle feedbacks to CH4 and CO2, background pollutant levels, the timing and location of emissions changes, and climate feedbacks on air quality, such as wildfires and the ozone climate penalty.

Discovery of Pemigatinib: A Potent and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor.

Aberrant activation of FGFR has been linked to the pathogenesis of many tumor types. Selective inhibition of FGFR has emerged as a promising approach for cancer treatment. Herein, we describe the discovery of compound 38 (INCB054828, pemigatinib), a highly potent and selective inhibitor of FGFR1, FGFR2, and FGFR3 with excellent physiochemical properties and pharmacokinetic profiles. Pemigatinib has received accelerated approval from the U.S. Food and Drug Administration for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement. Additional clinical trials are ongoing to evaluate pemigatinib in patients with FGFR alterations.

Changes in global terrestrial live biomass over the 21st century.

Live woody vegetation is the largest reservoir of biomass carbon, with its restoration considered one of the most effective natural climate solutions. However, terrestrial carbon fluxes remain the largest uncertainty in the global carbon cycle. Here, we develop spatially explicit estimates of carbon stock changes of live woody biomass from 2000 to 2019 using measurements from ground, air, and space. We show that live biomass has removed 4.9 to 5.5 PgC year-1 from the atmosphere, offsetting 4.6 ± 0.1 PgC year-1 of gross emissions from disturbances and adding substantially (0.23 to 0.88 PgC year-1) to the global carbon stocks. Gross emissions and removals in the tropics were four times larger than temperate and boreal ecosystems combined. Although live biomass is responsible for more than 80% of gross terrestrial fluxes, soil, dead organic matter, and lateral transport may play important roles in terrestrial carbon sink.

Global tropospheric ozone responses to reduced NO x emissions linked to the COVID-19 worldwide lockdowns.

Efforts to stem the transmission of coronavirus disease 2019 (COVID-19) led to rapid, global ancillary reductions in air pollutant emissions. Here, we quantify the impact on tropospheric ozone using a multiconstituent chemical data assimilation system. Anthropogenic NO x emissions dropped by at least 15% globally and 18 to 25% regionally in April and May 2020, which decreased free tropospheric ozone by up to 5 parts per billion, consistent with independent satellite observations. The global total tropospheric ozone burden declined by 6TgO3 (∼2%) in May and June 2020, largely due to emission reductions in Asia and the Americas that were amplified by regionally high ozone production efficiencies (up to 4 TgO3/TgN). Our results show that COVID-19 mitigation left a global atmospheric imprint that altered atmospheric oxidative capacity and climate radiative forcing, providing a test of the efficacy of NO x emissions controls for co-benefiting air quality and climate.

Impacts of Degradation on Water, Energy, and Carbon Cycling of the Amazon Tropical Forests.

Selective logging, fragmentation, and understory fires directly degrade forest structure and composition. However, studies addressing the effects of forest degradation on carbon, water, and energy cycles are scarce. Here, we integrate field observations and high-resolution remote sensing from airborne lidar to provide realistic initial conditions to the Ecosystem Demography Model (ED-2.2) and investigate how disturbances from forest degradation affect gross primary production (GPP), evapotranspiration (ET), and sensible heat flux (H). We used forest structural information retrieved from airborne lidar samples (13,500 ha) and calibrated with 817 inventory plots (0.25 ha) across precipitation and degradation gradients in the eastern Amazon as initial conditions to ED-2.2 model. Our results show that the magnitude and seasonality of fluxes were modulated by changes in forest structure caused by degradation. During the dry season and under typical conditions, severely degraded forests (biomass loss ≥66%) experienced water stress with declines in ET (up to 34%) and GPP (up to 35%) and increases of H (up to 43%) and daily mean ground temperatures (up to 6.5°C) relative to intact forests. In contrast, the relative impact of forest degradation on energy, water, and carbon cycles markedly diminishes under extreme, multiyear droughts, as a consequence of severe stress experienced by intact forests. Our results highlight that the water and energy cycles in the Amazon are driven by not only climate and deforestation but also the past disturbance and changes of forest structure from degradation, suggesting a much broader influence of human land use activities on the tropical ecosystems.

Fire decline in dry tropical ecosystems enhances decadal land carbon sink.

The terrestrial carbon sink has significantly increased in the past decades, but the underlying mechanisms are still unclear. The current synthesis of process-based estimates of land and ocean sinks requires an additional sink of 0.6 PgC yr-1 in the last decade to explain the observed airborne fraction. A concurrent global fire decline was observed in association with tropical agriculture expansion and landscape fragmentation. Here we show that a decline of 0.2 ± 0.1 PgC yr-1 in fire emissions during 2008-2014 relative to 2001-2007 also induced an additional carbon sink enhancement of 0.4 ± 0.2 PgC yr-1 attributable to carbon cycle feedbacks, amounting to a combined sink increase comparable to the 0.6 PgC yr-1 budget imbalance. Our results suggest that the indirect effects of fire, in addition to the direct emissions, is an overlooked mechanism for explaining decadal-scale changes in the land carbon sink and highlight the importance of fire management in climate mitigation.

INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models.

Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to selected cancer patients, and proof-of-concept has been established in early clinical trials of FGFR inhibitors. Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials. INCB054828 pharmacokinetics and pharmacodynamics were investigated using cell lines and tumor models, and the antitumor effect of oral INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1, 2, or 3. Enzymatic assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2, and 3 by INCB054828 (half maximal inhibitory concentration [IC50] 0.4, 0.5, and 1.0 nM, respectively) with weaker activity against FGFR4 (IC50 30 nM). INCB054828 selectively inhibited growth of tumor cell lines with activation of FGFR signaling compared with cell lines lacking FGFR aberrations. The preclinical pharmacokinetic profile suggests target inhibition is achievable by INCB054828 in vivo with low oral doses. INCB054828 suppressed the growth of xenografted tumor models with FGFR1, 2, or 3 alterations as monotherapy, and the combination of INCB054828 with cisplatin provided significant benefit over either single agent, with an acceptable tolerability. The preclinical data presented for INCB054828, together with preliminary clinical observations, support continued investigation in patients with FGFR alterations, such as fusions and activating mutations.

Quantifying the Impact of Atmospheric Transport Uncertainty on CO2 Surface Flux Estimates.

We show that transport differences between two commonly used global chemical transport models, GEOS-Chem and TM5, lead to systematic space-time differences in modeled distributions of carbon dioxide and sulfur hexafluoride. The distribution of differences suggests inconsistencies between the transport simulated by the models, most likely due to the representation of vertical motion. We further demonstrate that these transport differences result in systematic differences in surface CO2 flux estimated by a collection of global atmospheric inverse models using TM5 and GEOS-Chem and constrained by in situ and satellite observations. While the impact on inferred surface fluxes is most easily illustrated in the magnitude of the seasonal cycle of surface CO2 exchange, it is the annual carbon budgets that are particularly relevant for carbon cycle science and policy. We show that inverse model flux estimates for large zonal bands can have systematic biases of up to 1.7 PgC/year due to large-scale transport uncertainty. These uncertainties will propagate directly into analysis of the annual meridional CO2 flux gradient between the tropics and northern midlatitudes, a key metric for understanding the location, and more importantly the processes, responsible for the annual global carbon sink. The research suggests that variability among transport models remains the largest source of uncertainty across global flux inversion systems and highlights the importance both of using model ensembles and of using independent constraints to evaluate simulated transport.

Effects of Epacadostat on Brain Extracellular Fluid Concentrations of Serotonin-an Intracerebral Microdialysis Study in Sprague-Dawley Rats.

Epacadostat (EPAC) is an indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor that has been examined in multiple clinical trials. The substrate for IDO1 is tryptophan and there is a theoretical concern that inhibition of IDO1 may increase the concentrations of tryptophan and subsequently serotonin, potentially leading to serotonin syndrome (SS). The objective of this study was to evaluate the effect of EPAC, either alone or with linezolid, a monoamine oxidase inhibitor (MAOI), on brain extracellular fluid (ECF) concentrations of serotonin in rats, using microdialysis. While fluoxetine, a selective serotonin reuptake inhibitor, increased the serotonin ECF concentration by 2-fold, the combination of fluoxetine with linezolid (a positive control used in the study) resulted in a 9-fold increase. Neither EPAC monotherapy nor combination with linezolid had any effect on serotonin concentration. In addition, EPAC was shown to have poor penetration across the rat blood-brain barrier. Across multiple phase I/II clinical studies with EPAC, four SS-like episodes were observed out of 2490 subjects, but none of the incidences were confirmed as a true case of SS. These data suggest that EPAC is unlikely to cause SS following either monotherapy or in combination with MAOIs. Thus, the exclusion of MAOI from clinical studies with EPAC has been lifted.

Response to Comment on "Contrasting carbon cycle responses of the tropical continents to the 2015-2016 El Niño".

Chevallier showed a column CO2 ([Formula: see text]) anomaly of ±0.5 parts per million forced by a uniform net biosphere exchange (NBE) anomaly of 2.5 gigatonnes of carbon over the tropical continents within a year, so he claimed that the inferred NBE uncertainties should be larger than presented in Liu et al We show that a much concentrated NBE anomaly led to much larger [Formula: see text] perturbations.

Preclinical characterization of INCB053914, a novel pan-PIM kinase inhibitor, alone and in combination with anticancer agents, in models of hematologic malignancies.

The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine protein kinases are overexpressed in many hematologic and solid tumor malignancies and play central roles in intracellular signaling networks important in tumorigenesis, including the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. The three PIM kinase isozymes (PIM1, PIM2, and PIM3) share similar downstream substrates with other key oncogenic kinases and have differing but mutually compensatory functions across tumors. This supports the therapeutic potential of pan-PIM kinase inhibitors, especially in combination with other anticancer agents chosen based on their role in overlapping signaling networks. Reported here is a preclinical characterization of INCB053914, a novel, potent, and selective adenosine triphosphate-competitive pan-PIM kinase inhibitor. In vitro, INCB053914 inhibited proliferation and the phosphorylation of downstream substrates in cell lines from multiple hematologic malignancies. Effects were confirmed in primary bone marrow blasts from patients with acute myeloid leukemia treated ex vivo and in blood samples from patients receiving INCB053914 in an ongoing phase 1 dose-escalation study. In vivo, single-agent INCB053914 inhibited Bcl-2-associated death promoter protein phosphorylation and dose-dependently inhibited tumor growth in acute myeloid leukemia and multiple myeloma xenografts. Additive or synergistic inhibition of tumor growth was observed when INCB053914 was combined with selective PI3Kδ inhibition, selective JAK1 or JAK1/2 inhibition, or cytarabine. Based on these data, pan-PIM kinase inhibitors, including INCB053914, may have therapeutic utility in hematologic malignancies when combined with other inhibitors of oncogenic kinases or standard chemotherapeutics.

Leveraging benefit design for better diabetes self-management and A1C control.

OBJECTIVES: To evaluate the relationship between cost sharing for blood glucose testing strips and glycemic control rates. STUDY DESIGN: A retrospective observational study using medical and pharmacy claims data integrated with laboratory glycated hemoglobin (A1C) values for patients using insulin and testing strips. A new user study design was utilized to identify individuals from 14 commercial US health plans who filled testing strips with assumed intention to monitor blood glucose. METHODS: Patients were divided into low (<20% of annual testing strip cost; n = 3575) and high (≥20%; n = 3580) cost-sharing categories. We compared the likelihood of patients in low and high cost-sharing categories achieving glycemic control (A1C <8.0%) through modified Poisson regression models. RESULTS: Patients with low cost sharing for testing strips had higher rates of control than those with high cost sharing (58.1% vs 50.3%; P <.001). Low cost sharing was associated with greater probability of glycemic control (adjusted risk ratio [aRR], 1.14; 95% CI, 1.09-1.20; P <.0001). Glycemic control was more likely for patients in areas with median household income greater than $60,000 versus less than $40,000 (aRR, 1.16; 95% CI, 1.07-1.25; P <.01) and greater than $80,000 versus less than $40,000 (aRR, 1.18; 95% CI, 1.06-1.32; P <.01). CONCLUSIONS: We found a statistically significant correlation between cost sharing for testing strips and better A1C control for patients using insulin medication. Lower cost sharing for testing strips can remove a barrier to diabetes self-management and may lead to improved glycemic control at the population level. Future efforts should study the potential benefits of reducing diabetic complications and associated cost savings.

INCB040093 Is a Novel PI3Kδ Inhibitor for the Treatment of B Cell Lymphoid Malignancies.

Phosphatidylinositol 3-kinase delta (PI3Kδ) is a critical signaling molecule in B cells and is considered a target for development of therapies against various B cell malignancies. INCB040093 is a novel PI3Kδ small-molecule inhibitor and has demonstrated promising efficacy in patients with Hodgkin's lymphoma in clinical studies. In this study, we disclose the chemical structure and the preclinical activity of the compound. In biochemical assays, INCB040093 potently inhibits the PI3Kδ kinase, with 74- to >900-fold selectivity against other PI3K family members. In vitro and ex vivo studies using primary B cells, cell lines from B cell malignancies, and human whole blood show that INCB040093 inhibits PI3Kδ-mediated functions, including cell signaling and proliferation. INCB040093 has no significant effect on the growth of nonlymphoid cell lines and was less potent in assays that measure human T and natural killer cell proliferation and neutrophil and monocyte functions, suggesting that the impact of INCB040093 on the human immune system will likely be restricted to B cells. INCB040093 inhibits the production of macrophage-inflammatory protein-1ß (MIP-1beta) and tumor necrosis factor-ß (TNF-beta) from a B cell line, suggesting a potential effect on the tumor microenvironment. In vivo, INCB040093 demonstrates single-agent activity in inhibiting tumor growth and potentiates the antitumor growth effect of the clinically relevant chemotherapeutic agent, bendamustine, in the Pfeiffer cell xenograft model of non-Hodgkin's lymphoma. INCB040093 has a favorable exposure profile in rats and an acceptable safety margin in rats and dogs. Taken together, data presented in this report support the potential utility of orally administered INCB040093 in the treatment of B cell malignancies.

Contrasting carbon cycle responses of the tropical continents to the 2015-2016 El Niño.

The 2015-2016 El Niño led to historically high temperatures and low precipitation over the tropics, while the growth rate of atmospheric carbon dioxide (CO2) was the largest on record. Here we quantify the response of tropical net biosphere exchange, gross primary production, biomass burning, and respiration to these climate anomalies by assimilating column CO2, solar-induced chlorophyll fluorescence, and carbon monoxide observations from multiple satellites. Relative to the 2011 La Niña, the pantropical biosphere released 2.5 ± 0.34 gigatons more carbon into the atmosphere in 2015, consisting of approximately even contributions from three tropical continents but dominated by diverse carbon exchange processes. The heterogeneity of the carbon-exchange processes indicated here challenges previous studies that suggested that a single dominant process determines carbon cycle interannual variability.