ALBERT

Description: AMG 701 is a half-life extended BiTE® (bispecific T-cell engager) targeting the B cell maturation antigen (BCMA). Here, we confirmed AMG 701-mediated T cell-redirected lysis of MM cells, defined immunomodulatory effects of AMG 701, and investigated combination potential of AMG 701 with immunomodulatory drugs (IMiDs) in human MM. Firstly, AMG 701 induced specific and efficacious T cell-dependent cytotoxicity (TDCC) against all MM cell lines tested, regardless of sensitivity to current anti-MM agents and expression levels of BCMA. AMG 701-induced TDCC was minimally affected in the presence of myeloma-supporting cells and cytokines in the bone marrow (BM) microenvironment, including osteoclasts (OCs), BM stromal cells (BMSCs), and a proliferation-inducing ligand (100 ng/ml). Importantly, AMG 701 induced lysis of autologous patient cells from the relapse and refractory stage of MM (RRMM). AMG 701 rapidly upregulated cell surface expression of CD107a and the production of IFNγ and TNFα, more so in CD8 than CD4 T subsets. It stimulated the proliferation and activation of T cells, to a greater extent in CD8 vs CD4 T cells, leading to significantly increased ratios of CD8/CD4 T cells. Significantly, AMG 701 induced differentiation of naive T cells (CD4 and CD8) to T cells with memory phenotype. This includes central memory (CM), effector memory (EM) T cells, and stem cell like memory cells. Time-course immunophenotyping studies showed that AMG 701 transiently upregulated the expression of key immune checkpoint and costimulatory markers on both CD4 and CD8 T cells. The induced T cells purified from ex vivo co-cultures still effectively lysed MM cells with lower BCMA levels. This may suggest an increased T cell clonality. Furthermore, IMiDs (len or pom) enhanced AMG 701-mediated TDCC against MM cells at earlier time points, lower E/T ratios, lower concentrations, or in the presence of immunosuppressive OCs or BMSCs. The combination AMG 701 and IMiDs maximized MM cell lysis accompanied with a decreased EC50 value. Combined treatments induce a more pronounced immunomodulation than AMG 701 alone in the presence of OCs, as evidenced by higher percentage of CM+EM and CD8/CD4 ratio at d8. AMG 701 with IMiDs combination significantly enhance AMG 701-mediated autologous patient MM cell lysis in a synergistic manner (combination index 〈 1). In the human NCI-H929 xenograft model reconstituted with human T effector cells, AMG 701 effectively blocked tumor growth 5d after the first injection, regardless of doses (0.02-2 mg/kg). Tumors were completely eradicated following 3 separate injections in the host without weight loss. Next, sub-optimal doses and treatment schedules for AMG 701 and len were then used to investigate in vivo anti-MM effects by the combination vs monotherapy. Mice receiving MM cells were treated, from d15 until the end of the study, with len once daily, AMG 701 once weekly, or combination of AMG 701 and len. Two days after the first drug administration, all three treatments significantly inhibited MM tumor growth in mice (p

Description: The present study describes Rossby wave packet (RWP) properties in the upper troposphere and lower stratosphere (UTLS) with the use of Global Navigation Satellite System radio occultation (GNSS-RO) measurements. This global study covering both hemispheres' extratropics is the first to tackle medium- and synoptic-scale waves with GNSS-RO. We use 1 decade of GNSS-RO temperature and pressure data from the CHAMP, COSMIC, GRACE, Metop-A, Metop-B, SAC-C and TerraSAR-X missions, combining them into one gridded dataset for the years 2007–2016. Our approach to extract RWP anomalies and their envelope uses Fourier and Hilbert transforms over longitude without pre- or post-processing the data. Our study is purely based on observations, only using ERA-Interim winds to provide information about the background wind regimes. The RWP structures that we obtain in the UTLS agree well with theory and earlier studies, in terms of coherent phase or group propagation, zonal scale and distribution over latitudes. Furthermore, we show that RWP pressure anomalies maximize around the tropopause, while RWP temperature anomalies maximize right above the tropopause height with a contrasting minimum right below. RWP activity follows the zonal-mean tropopause during all seasons. RWP anomalies in the lower stratosphere are dynamically coupled to the upper troposphere. They are part of the same system with a quasi-barotropic structure across the UTLS. RWP activity often reaches up to 20 km height and occasionally higher, defying the Charney–Drazin criterion. We note enhanced amplitude and upward propagation of RWP activity during sudden stratospheric warmings. We provide observational support for improvements in RWP diagnostics and wave trend analysis in models and reanalyses. Wave quantities follow the tropopause, and diagnosing them on fixed pressure levels (which the tropopause does not follow) can lead to aliasing. Our novel approach analyzing GNSS-RO pressure anomalies provides wave signals with better continuity and coherence across the UTLS and the stratosphere, compared to temperature anomalies. Thus, RWP vertical propagation is much easier to analyze with pressure data.

Description: This study aims to quantify how much of the observed strength and variability in the zonal-mean extratropical tropopause inversion layer (TIL) comes from the modulation of the temperature field and its gradients around the tropopause by planetary- and synoptic-scale waves. By analyzing high-resolution observations, it also puts other TIL enhancing mechanisms into context.Using gridded Global Positioning System radio occultation (GPS-RO) temperature profiles from the COSMIC mission (2007–2013), we are able to extract the extratropical wave signal by a simplified wavenumber–frequency domain filtering method and quantify the resulting TIL enhancement. By subtracting the extratropical wave signal, we show how much of the TIL is associated with other processes, at mid- and high latitudes, for both hemispheres and all seasons.The transient and reversible modulation by planetary- and synoptic-scale waves is almost entirely responsible for the TIL in midlatitudes. This means that wave-mean flow interactions, inertia–gravity waves and the residual circulation are of minor importance for the strength and variability in the midlatitude TIL.At polar regions, the extratropical wave modulation is dominant for the TIL strength as well, but there is also a clear fingerprint from sudden stratospheric warmings (SSWs) and final warmings in both hemispheres. Therefore, polar vortex breakups are partially responsible for the observed polar TIL strength in winter (if SSWs occur) and spring. Also, part of the polar summer TIL strength cannot be explained by extratropical wave modulation.We suggest that our wave modulation mechanism integrates several TIL enhancing mechanisms proposed in previous literature while robustly disclosing the overall outcome of the different processes involved. By analyzing observations only, our study identifies which mechanisms dominate the extratropical TIL strength and their relative contribution. It remains to be determined, however, which roles the different planetary- and synoptic-scale wave types play within the total extratropical wave modulation of the TIL, as well as what causes the observed amplification of extratropical waves near the tropopause.

Description: The radiative effects induced by the zonally asymmetric part of the ozone field have been shown to significantly change the temperature of the NH winter polar cap, and correspondingly the strength of the polar vortex. In this paper, we aim to understand the physical processes behind these effects using the National Center for Atmospheric Research (NCAR)'s Whole Atmosphere Community Climate Model, run with 1960s ozone-depleting substances and greenhouse gases. We find a mid-winter polar vortex influence only when considering the quasi-biennial oscillation (QBO) phases separately, since ozone waves affect the vortex in an opposite manner. Specifically, the emergence of a midlatitude QBO signal is delayed by 1–2 months when radiative ozone-wave effects are removed. The influence of ozone waves on the winter polar vortex, via their modulation of shortwave heating, is not obvious, given that shortwave heating is largest during fall, when planetary stratospheric waves are weakest. Using a novel diagnostic of wave 1 temperature amplitude tendencies and a synoptic analysis of upward planetary wave pulses, we are able to show the chain of events that lead from a direct radiative effect on weak early fall upward-propagating planetary waves to a winter polar vortex modulation. We show that an important stage of this amplification is the modulation of individual wave life cycles, which accumulate during fall and early winter, before being amplified by wave–mean flow feedbacks. We find that the evolution of these early winter upward planetary wave pulses and their induced stratospheric zonal mean flow deceleration is qualitatively different between QBO phases, providing a new mechanistic view of the extratropical QBO signal. We further show how these differences result in opposite radiative ozone-wave effects between east and west QBOs.

Description: Recent observational and modeling studies suggest that stratospheric ozone depletion not only influences the surface climate in the Southern Hemisphere (SH), but also impacts Northern Hemisphere (NH) spring, which implies a strong interaction between dynamics and chemistry. Here, we systematically analyze the importance of interactive chemistry with respect to the representation of stratosphere–troposphere coupling and in particular the effects on NH surface climate during the recent past. We use the interactive and specified chemistry version of NCAR's Whole Atmosphere Community Climate Model coupled to an ocean model to investigate differences in the mean state of the NH stratosphere as well as in stratospheric extreme events, namely sudden stratospheric warmings (SSWs), and their surface impacts. To be able to focus on differences that arise from two-way interactions between chemistry and dynamics in the model, the specified chemistry model version uses a time-evolving, model-consistent ozone field generated by the interactive chemistry model version. We also test the effects of zonally symmetric versus asymmetric prescribed ozone, evaluating the importance of ozone waves in the representation of stratospheric mean state and variability. The interactive chemistry simulation is characterized by a significantly stronger and colder polar night jet (PNJ) during spring when ozone depletion becomes important. We identify a negative feedback between lower stratospheric ozone and atmospheric dynamics during the breakdown of the stratospheric polar vortex in the NH, which contributes to the different characteristics of the PNJ between the simulations. Not only the mean state, but also stratospheric variability is better represented in the interactive chemistry simulation, which shows a more realistic distribution of SSWs as well as a more persistent surface impact afterwards compared with the simulation where the feedback between chemistry and dynamics is switched off. We hypothesize that this is also related to the feedback between ozone and dynamics via the intrusion of ozone-rich air into polar latitudes during SSWs. The results from the zonally asymmetric ozone simulation are closer to the interactive chemistry simulations, implying that under a model-consistent ozone forcing, a three-dimensional (3-D) representation of the prescribed ozone field is desirable. This suggests that a 3-D ozone forcing, as recommended for the upcoming CMIP6 simulations, has the potential to improve the representation of stratospheric dynamics and chemistry. Our findings underline the importance of the representation of interactive chemistry and its feedback on the stratospheric mean state and variability not only in the SH but also in the NH during the recent past.

Description: The impact of changes in incoming solar irradiance on stratospheric ozone abundances should be included in climate simulations to aid in capturing the atmospheric response to solar cycle variability. This study presents the first systematic comparison of the representation of the 11-year solar cycle ozone response (SOR) in chemistry–climate models (CCMs) and in pre-calculated ozone databases specified in climate models that do not include chemistry, with a special focus on comparing the recommended protocols for the Coupled Model Intercomparison Project Phase 5 and Phase 6 (CMIP5 and CMIP6). We analyse the SOR in eight CCMs from the Chemistry–Climate Model Initiative (CCMI-1) and compare these with results from three ozone databases for climate models: the Bodeker Scientific ozone database, the SPARC/Atmospheric Chemistry and Climate (AC&C) ozone database for CMIP5 and the SPARC/CCMI ozone database for CMIP6. The peak amplitude of the annual mean SOR in the tropical upper stratosphere (1–5 hPa) decreases by more than a factor of 2, from around 5 to 2 %, between the CMIP5 and CMIP6 ozone databases. This substantial decrease can be traced to the CMIP5 ozone database being constructed from a regression model fit to satellite and ozonesonde measurements, while the CMIP6 database is constructed from CCM simulations. The SOR in the CMIP6 ozone database therefore implicitly resembles the SOR in the CCMI-1 models. The structure in latitude of the SOR in the CMIP6 ozone database and CCMI-1 models is considerably smoother than in the CMIP5 database, which shows unrealistic sharp gradients in the SOR across the middle latitudes owing to the paucity of long-term ozone measurements in polar regions. The SORs in the CMIP6 ozone database and the CCMI-1 models show a seasonal dependence with enhanced meridional gradients at mid- to high latitudes in the winter hemisphere. The CMIP5 ozone database does not account for seasonal variations in the SOR, which is unrealistic. Sensitivity experiments with a global atmospheric model without chemistry (ECHAM6.3) are performed to assess the atmospheric impacts of changes in the representation of the SOR and solar spectral irradiance (SSI) forcing between CMIP5 and CMIP6. The larger amplitude of the SOR in the CMIP5 ozone database compared to CMIP6 causes a likely overestimation of the modelled tropical stratospheric temperature response between 11-year solar cycle minimum and maximum by up to 0.55 K, or around 80 % of the total amplitude. This effect is substantially larger than the change in temperature response due to differences in SSI forcing between CMIP5 and CMIP6. The results emphasize the importance of adequately representing the SOR in global models to capture the impact of the 11-year solar cycle on the atmosphere. Since a number of limitations in the representation of the SOR in the CMIP5 ozone database have been identified, we recommend that CMIP6 models without chemistry use the CMIP6 ozone database and the CMIP6 SSI dataset to better capture the climate impacts of solar variability. The SOR coefficients from the CMIP6 ozone database are published with this paper.

Description: It is well established that variable wintertime planetary wave forcing in the stratosphere controls the variability of Arctic stratospheric ozone through changes in the strength of the polar vortex and the residual circulation. While previous studies focused on the variations in upward wave flux entering the lower stratosphere, here the impact of downward planetary wave reflection on ozone is investigated for the first time. Utilizing the MERRA2 reanalysis and a fully coupled chemistry–climate simulation with the Community Earth System Model (CESM1(WACCM)) of the National Center for Atmospheric Research (NCAR), we find two downward wave reflection effects on ozone: (1) the direct effect in which the residual circulation is weakened during winter, reducing the typical increase of ozone due to upward planetary wave events and (2) the indirect effect in which the modification of polar temperature during winter affects the amount of ozone destruction in spring. Winter seasons dominated by downward wave reflection events (i.e., reflective winters) are characterized by lower Arctic ozone concentration, while seasons dominated by increased upward wave events (i.e., absorptive winters) are characterized by relatively higher ozone concentration. This behavior is consistent with the cumulative effects of downward and upward planetary wave events on polar stratospheric ozone via the residual circulation and the polar temperature in winter. The results establish a new perspective on dynamical processes controlling stratospheric ozone variability in the Arctic by highlighting the key role of wave reflection.

Description: This paper describes the recommended solar forcing dataset for CMIP6 and highlights changes with respect to CMIP5. The solar forcing is provided for radiative properties, namely total solar irradiance (TSI), solar spectral irradiance (SSI), and the F10.7 index as well as particle forcing, including geomagnetic indices Ap and Kp, and ionization rates to account for effects of solar protons, electrons, and galactic cosmic rays. This is the first time that a recommendation for solar-driven particle forcing has been provided for a CMIP exercise. The solar forcing datasets are provided at daily and monthly resolution separately for the CMIP6 preindustrial control, historical (1850–2014), and future (2015–2300) simulations. For the preindustrial control simulation, both constant and time-varying solar forcing components are provided, with the latter including variability on 11-year and shorter timescales but no long-term changes. For the future, we provide a realistic scenario of what solar behavior could be, as well as an additional extreme Maunder-minimum-like sensitivity scenario. This paper describes the forcing datasets and also provides detailed recommendations as to their implementation in current climate models.For the historical simulations, the TSI and SSI time series are defined as the average of two solar irradiance models that are adapted to CMIP6 needs: an empirical one (NRLTSI2–NRLSSI2) and a semi-empirical one (SATIRE). A new and lower TSI value is recommended: the contemporary solar-cycle average is now 1361.0 W m−2. The slight negative trend in TSI over the three most recent solar cycles in the CMIP6 dataset leads to only a small global radiative forcing of −0.04 W m−2. In the 200–400 nm wavelength range, which is important for ozone photochemistry, the CMIP6 solar forcing dataset shows a larger solar-cycle variability contribution to TSI than in CMIP5 (50 % compared to 35 %).We compare the climatic effects of the CMIP6 solar forcing dataset to its CMIP5 predecessor by using time-slice experiments of two chemistry–climate models and a reference radiative transfer model. The differences in the long-term mean SSI in the CMIP6 dataset, compared to CMIP5, impact on climatological stratospheric conditions (lower shortwave heating rates of −0.35 K day−1 at the stratopause), cooler stratospheric temperatures (−1.5 K in the upper stratosphere), lower ozone abundances in the lower stratosphere (−3 %), and higher ozone abundances (+1.5 % in the upper stratosphere and lower mesosphere). Between the maximum and minimum phases of the 11-year solar cycle, there is an increase in shortwave heating rates (+0.2 K day−1 at the stratopause), temperatures ( ∼  1 K at the stratopause), and ozone (+2.5 % in the upper stratosphere) in the tropical upper stratosphere using the CMIP6 forcing dataset. This solar-cycle response is slightly larger, but not statistically significantly different from that for the CMIP5 forcing dataset.CMIP6 models with a well-resolved shortwave radiation scheme are encouraged to prescribe SSI changes and include solar-induced stratospheric ozone variations, in order to better represent solar climate variability compared to models that only prescribe TSI and/or exclude the solar-ozone response. We show that monthly-mean solar-induced ozone variations are implicitly included in the SPARC/CCMI CMIP6 Ozone Database for historical simulations, which is derived from transient chemistry–climate model simulations and has been developed for climate models that do not calculate ozone interactively. CMIP6 models without chemistry that perform a preindustrial control simulation with time-varying solar forcing will need to use a modified version of the SPARC/CCMI Ozone Database that includes solar variability. CMIP6 models with interactive chemistry are also encouraged to use the particle forcing datasets, which will allow the potential long-term effects of particles to be addressed for the first time. The consideration of particle forcing has been shown to significantly improve the representation of reactive nitrogen and ozone variability in the polar middle atmosphere, eventually resulting in further improvements in the representation of solar climate variability in global models.