Development of an Oral Form of Azacytidine: 2′3′5′Triacetyl-5-Azacytidine

Myelodysplastic syndromes (MDSs) represent a group of incurable stem-cell malignancies which are predominantly treated by supportive care. Epigenetic silencing through promoter methylation of a number of genes is present in poor-risk subtypes of MDS and often predicts transformation to acute myelogenous leukemia (AML). Azacitidine and decitabine, two FDA-approved DNA methyltransferase (DNMT) inhibitors, are able to improve overall response although their oral bioavailability complicates their clinical use. This study evaluated 2′, 3′, 5′-triacetyl-5-azacitidine (TAC) as a potential prodrug for azacitidine. The prodrug demonstrated significant pharmacokinetic improvements in bioavailability, solubility, and stability over the parent compound. In vivo analyses indicated a lack of general toxicity coupled with significantly improved survival. Pharmacodynamic analyses confirmed its ability to suppress global methylation in vivo. These data indicate that esterified nucleoside derivatives may be effective prodrugs for azacitidine and encourages further investigation of TAC into its metabolism, activity, and possible clinical evaluation

Ubiquitin-conjugating Enzyme Cdc34 and Ubiquitin Ligase Skp1-Cullin-F-box Ligase (SCF) Interact through Multiple Conformations

In the ubiquitin-proteasome system, protein substrates are degraded via covalent modification by a polyubiquitin chain. The polyubiquitin chain must be assembled rapidly in cells, because a chain of at least four ubiquitins is required to signal for degradation, and chain-editing enzymes in the cell may cleave premature polyubiquitin chains before achieving this critical length. The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association. This rapid association has been attributed to electrostatic interactions between the acidic C-terminal tail of Cdc34 and a feature on SCF called the basic canyon. However, the structural aspects of the Cdc34-SCF interaction and how they permit rapid complex formation remain elusive. Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. We discuss how these results can explain the rapid association of Cdc34 and SCF

Retrievals of Cloud Droplet Size from the Research Scanning Polarimeter Data: Validation Using In Situ Measurements

We present comparisons of cloud droplet size distributions (DSDs) retrieved from the research scanning polarimeter (RSP) data with correlative in situ measurements made during the North Atlantic Aerosols and Marine Ecosystems Study (NAAMES). The airborne portion of this field experiment was based out of St. John's airport, Newfoundland, Canada with the focus of this paper being on the deployment in May - June 2016. RSP was onboard the NASA C-130 aircraft together with an array of in situ and other remote sensing instrumentation. The RSP is an along-track scanner measuring the polarized and total reflectance in 9 spectral channels. Its uniquely high angular resolution allows for characterization of liquid water droplet sizes using the rainbow structure observed in the polarized reflectance over the scattering angle range from 135 to 165.degrees The rainbow is dominated by single scattering of light by cloud droplets, so its structure is characteristic specifically of the droplet sizes at cloud top (within unit optical depth into the cloud, equivalent to approximately 50m). A parametric fitting algorithm applied to the polarized reflectance provides retrievals of the droplet effective radius and variance assuming a prescribed size distribution shape (gamma distribution). In addition to this, we use a non-parametric method, the Rainbow Fourier Transform (RFT), which allows us to retrieve the droplet size distribution itself. The latter is important in the case of clouds with complex microphysical structure, or multiple layers of cloud, which result in multi-modal DSDs. During NAAMES the aircraft performed a number of flight patterns specifically designed for comparisons between remote sensing retrievals and in situ measurements. These patterns consisted of two flight segments above the same straight ground track. One of these segments was flown above clouds allowing for remote sensing measurements, while the other was near the cloud top where cloud droplets were sampled. We compare the DSDs retrieved from the RSP data with in situ measurements made by the Cloud Droplet Probe (CDP). The comparisons generally show good agreement (better than 1 micron for effective radius and in most cases better than 0.02 for effective variance) with deviations explainable by the position of the aircraft within the cloud, or by the presence of additional cloud layers between the cloud being sampled by the in situ instrumentation and the altitude of the remote sensing segment. In the latter case, the multi-modal DSDs retrieved from the RSP data were consistent with the multi-layer cloud structures observed in the correlative High Spectral Resolution Lidar (HSRL) profiles. The results of these comparisons provide a rare validation of polarimetric droplet size retrieval techniques, demonstrating their accuracy and robustness and the potential of satellite data of this kind on a global scale

Seasonal updraft speeds change cloud droplet number concentrations in low-level clouds over the western North Atlantic

To determine the impact of dynamic and aerosol processes on marine low clouds, we examine the seasonal impact of updraft speed w and cloud condensation nuclei concentration at 0.43% supersaturation (NCCN0:43%) on the cloud droplet number concentration (NC) of low-level clouds over the western North Atlantic Ocean. Aerosol and cloud properties were measured with instruments on board the NASA LaRC Falcon HU-25 during the ACTIVATE (Aerosol Cloud meTeorology Interactions oVer the western ATlantic Experiment) mission in summer (August) and winter (February–March) 2020. The data are grouped into different NCCN0:43% loadings, and the density functions of NC and w near the cloud bases are compared. For low updrafts (w <1.3ms1), NC in winter is mainly limited by the updraft speed and in summer additionally by aerosols. At larger updrafts (w >3ms1), NC is impacted by the aerosol population, while at clean marine conditions cloud nucleation is aerosol-limited, and for high NCCN0:43% it is influenced by aerosols and updraft. The aerosol size distribution in winter shows a bimodal distribution in clean marine environments, which transforms to a unimodal distribution in high NCCN0:43% due to chemical and physical aerosol processes, whereas unimodal distributions prevail in summer, with a significant difference in their aerosol concentration and composition. The increase of NCCN0:43% is accompanied with an increase of organic aerosol and sulfate compounds in both seasons. We demonstrate that NC can be explained by cloud condensation nuclei activation through upwards processed air masses with varying fractions of activated aerosols. The activation highly depends on w and thus supersaturation between the different seasons, while the aerosol size distribution additionally affects NC within a season. Our results quantify the seasonal influence of w and NCCN0:43% on NC and can be used to improve the representation of low marine clouds in models

Aerosol responses to precipitation along North American air trajectories arriving at Bermuda

North American pollution outflow is ubiquitous over the western North Atlantic Ocean, especially in winter, making this location a suitable natural laboratory for investigating the impact of precipitation on aerosol particles along air mass trajectories. These results highlight the sensitivity of remote marine boundary layer aerosol characteristics to precipitation along trajectories, especially when the air mass source is continental outflow from polluted regions like the US East Coast

Multi-campaign Ship and Aircraft Observations of Marine Cloud Condensation Nuclei and Droplet Concentrations

In-situ marine cloud droplet number concentrations (CDNCs), cloud condensation nuclei (CCN), and CCN proxies, based on particle sizes and optical properties, are accumulated from seven field campaigns: ACTIVATE; NAAMES; CAMP2EX; ORACLES; SOCRATES; MARCUS; and CAPRICORN2. Each campaign involves aircraft measurements, ship-based measurements, or both. Measurements collected over the North and Central Atlantic, Indo-Pacific, and Southern Oceans, represent a range of clean to polluted conditions in various climate regimes. With the extensive range of environmental conditions sampled, this data collection is ideal for testing satellite remote detection methods of CDNC and CCN in marine environments. Remote measurement methods are vital to expanding the available data in these difficult-to-reach regions of the Earth and improving our understanding of aerosol-cloud interactions. The data collection includes particle composition and continental tracers to identify potential contributing CCN sources. Several of these campaigns include High Spectral Resolution Lidar (HSRL) and polarimetric imaging measurements and retrievals that will be the basis for the next generation of space-based remote sensors and, thus, can be utilized as satellite surrogates

Overview and statistical analysis of boundary layer clouds and precipitation over the western North-Atlantic Ocean

Due to their fast evolution and large natural variability in macro- and microphysical properties, the accurate representation of boundary layer clouds in current climate models remains a challenge. One of the regions with large intermodel spread in the Coupled Model Intercomparison Project Phase 6 ensemble is the western North Atlantic Ocean. Here, statistically representative in situ measurements can help to develop and constrain the parameterization of clouds in global models. To this end, we performed comprehensive measurements of boundary layer clouds, aerosol, trace gases, and radiation in the western North Atlantic Ocean during the NASA Aerosol Cloud meTeorology Interactions oVer the western ATlantic Experiment (ACTIVATE) mission. In total, 174 research flights with 574 flight hours for cloud and precipitation measurements were performed with the HU-25 Falcon during three winter (February–March 2020, January–April 2021, and November 2021–March 2022) and three summer seasons (August–September 2020, May–June 2021, and May–June 2022). Here we present a statistical evaluation of 16 140 individual cloud events probed by the fast cloud droplet probe and the two-dimensional stereo cloud probe during 155 research flights in a representative and repetitive flight strategy allowing for robust statistical data analyses. We show that the vertical profiles of distributions of the liquid water content and the cloud droplet effective diameter (ED) increase with altitude in the marine boundary layer. Due to higher updraft speeds, higher cloud droplet number concentrations (Nliquid) were measured in winter compared to summer despite lower cloud condensation nucleus abundance. Flight cloud cover derived from statistical analysis of in situ data is reduced in summer and shows large variability. This seasonal contrast in cloud coverage is consistent with a dominance of a synoptic pattern in winter that favors conditions for the formation of stratiform clouds at the western edge of cyclones (post-cyclonic). In contrast, a dominant summer anticyclone is concomitant with the occurrence of shallow cumulus clouds and lower cloud coverage. The evaluation of boundary layer clouds and precipitation in the Nliquid ED phase space sheds light on liquid, mixed-phase, and ice cloud properties and helps to categorize the cloud data. Ice and liquid precipitation, often masked in cloud statistics by a high abundance of liquid clouds, is often observed throughout the cloud. The ACTIVATE in situ cloud measurements provide a wealth of cloud information useful for assessing airborne and satellite remote-sensing products, for global climate and weather model evaluations, and for dedicated process studies that address precipitation and aerosol–cloud interactions

Large-Eddy Simulations of Marine Boundary Layer Clouds Associated with Cold-Air Outbreaks during the ACTIVATE Campaign. Part II: Aerosol–Meteorology–Cloud Interaction

Aerosol effects on micro/macrophysical properties of marine stratocumulus clouds over the western North Atlantic Ocean (WNAO) are investigated using in situ measurements and large-eddy simulations (LES) for two cold-air outbreak (CAO) cases (28 February and 1 March 2020) during the Aerosol Cloud Meteorology Interactions over the Western Atlantic Experiment (ACTIVATE). The LES is able to reproduce the vertical profiles of liquid water content (LWC), effective radius reff and cloud droplet number concentration Nc from fast cloud droplet probe (FCDP) in situ measurements for both cases. Furthermore, we show that aerosols affect cloud properties (Nc, reff, and LWC) via the prescribed bulk hygroscopicity of aerosols (¯κ) and aerosol size distribution characteristics. Nc, reff, and liquid water path (LWP) are positively correlated to ¯κ and aerosol number concentration (Na) while cloud fractional cover (CFC) is insensitive to ¯κ and aerosol size distributions for the two cases. The realistic changes to aerosol size distribution (number concentration, width, and the geometrical diameter) with the same meteorology state allow us to investigate aerosol effects on cloud properties without meteorological feedback. We also use the LES results to evaluate cloud properties from two reanalysis products, ERA5 and MERRA-2. Compared to LES, the ERA5 is able to capture the time evolution of LWP and total cloud coverage within the study domain during both CAO cases while MERRA-2 underestimates them

Large-Eddy Simulations of Marine Boundary Layer Clouds Associated with Cold-Air Outbreaks during the ACTIVATE Campaign. Part I: Case Setup and Sensitivities to Large-Scale Forcings

ABSTRACT: Large-eddy simulation (LES) is able to capture key boundary layer (BL) turbulence and cloud processes. Yet, large-scale forcing and surface turbulent fluxes of sensible and latent heat are often poorly prescribed for LESs. We derive these quantities from measurements and reanalysis obtained for two cold-air outbreak (CAO) events during Phase I of the Aerosol Cloud Meteorology Interactions over the Western Atlantic Experiment (ACTIVATE) in February–March 2020. We study the two contrasting CAO cases by performing LES and test the sensitivity of BL structure and clouds to large-scale forcings and turbulent heat fluxes. Profiles of atmospheric state and large-scale divergence and surface turbulent heat fluxes obtained from ERA5 data agree reasonably well with those derived from ACTIVATE field measurements for both cases at the sampling time and location. Therefore, we adopt the time-evolving heat fluxes, wind, and advective tendencies profiles from ERA5 data to drive the LES. We find that large-scale thermodynamic advective tendencies and wind relaxations are important for the LES to capture the evolving observed BL meteorological states characterized by the hourly ERA5 data and validated by the observations. We show that the divergence (or vertical velocity) is important in regulating the BL growth driven by surface heat fluxes in LESs. The evolution of liquid water path is largely affected by the evolution of surface heat fluxes. The liquid water path simulated in LES agrees reasonably well with the ACTIVATE measurements. This study paves the path to investigate aerosol–cloud–meteorology interactions using LES informed and evaluated by ACTIVATE field measurements