A practical water–energy–climate solution for sustainable and resilient coastal cities: smart use of seawater in municipal services

Municipal services for buildings in developed (sub)tropical coastal cities contributed 18% of greenhouse gases (GHGs) in 2020. One mitigatory solution is the direct use of seawater for district cooling and toilet flushing, which has been applied in Hong Kong on various scales and achieved 30% water and energy savings. However, no systematic evaluation and strategy for this solution are available. Herein, we develop a high-resolution quantitative scheme to elaborate the co-benefits and optimal strategies for expanding this use of seawater. We find that in Hong Kong, Jeddah, and Miami, using local seawater at the city-scale would achieve life-cycle GHG mitigation (42%–56%), energy savings (45%–49%), and freshwater savings (11%–43%). High-resolution analysis reveals that population density and district marginal performance are essential to optimize the efficiency of seawater use. Our scheme confirms the utility of seawater for municipal services and is an effective tool for innovative municipal-service enhancement.

Hydroclimate change in the Garhwal Himalaya, India at 4200 yr BP coincident with the contraction of the Indus civilization

High-resolution analysis of a 3.80 m sediment core recovered from Deoria Tal, a mid-elevation lake located at 2393 m a.s.l. in the Garhwal Himalaya, documents long-term and abrupt hydroclimate fluctuations in northern India during the mid- to late Holocene. The sediment chronology, based on ten 14C dates, indicates the core spans 5200 years. Non-destructive, radiological imaging approaches (X-ray fluorescence (XRF), X-ray imaging, and CT scans) were used to assess the response of the lake system to changing hydroclimatic conditions. Variations in elemental concentrations and sediment density evidenced notable hydroclimate change episodes centered at 4850, 4200, and 3100 cal yr BP. Elevated detrital input, greater sediment density, decreased lake ventilation, and lower autochthonous productivity reflects lake deepening between 4350 and 4200 cal yr BP. An abrupt shift in elemental concentrations and sediment density indicated the onset of lake drawdown at 4200 cal yr BP and a negative hydroclimate anomaly between 4200 and 4050 cal yr BP. Lower detrital flux, decreased sediment density, increased oxygenation, and higher autochthonous productivity, reflects a reduction in lake volume between 3200 and 3100 cal yr BP. The potential link between abrupt climate change at 4200 cal yr BP and the contraction of the Indus civilization is explored.

Applications of Cryo-EM in small molecule and biologics drug design

Electron cryo-microscopy (cryo-EM) is a powerful technique for the structural characterization of biological macromolecules, enabling high-resolution analysis of targets once inaccessible to structural interrogation. In recent years, pharmaceutical companies have begun to utilize cryo-EM for structure-based drug design. Structural analysis of integral membrane proteins, which comprise a large proportion of druggable targets and pose particular challenges for X-ray crystallography, by cryo-EM has enabled insights into important drug target families such as G protein-coupled receptors (GPCRs), ion channels, and solute carrier (SLCs) proteins. Structural characterization of biologics, such as vaccines, viral vectors, and gene therapy agents, has also become significantly more tractable. As a result, cryo-EM has begun to make major impacts in bringing critical therapeutics to market. In this review, we discuss recent instructive examples of impacts from cryo-EM in therapeutics design, focusing largely on its implementation at Pfizer. We also discuss the opportunities afforded by emerging technological advances in cryo-EM, and the prospects for future development of the technique.

Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy

Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.

EPCO-11. SINGLE-NUCLEI TRANSCRIPTOMICS RELATES GLIOBLASTOMA INFILTRATION TO DISTINCT GLIAL PROGENITOR STATES

Our understanding of glioblastoma (GBM) intratumoral heterogeneity, particularly in the context of neurodevelopment, has thus far been primarily focused on the more surgically accessible tumor core niche. In contrast, the biology of GBM cells at the infiltrative edge, which evade surgical resection and drive tumor recurrence, remains poorly characterized. To this end, we microdissected and performed single-nuclei RNA sequencing (snRNA-seq) on approximately 62,000 nuclei taken from the tumor core and from the infiltrative edge of six GBM tumors with diverse genomic drivers, including IDH1, EGFR, PDGFRA, FGFR3, and NF1. Unbiased clustering reveals distinct neoplastic and non-neoplastic populations, further distinguished using copy number variation analysis. After projecting previously defined signatures taken from snRNA-seq analysis of human adult neocortex/subventricular zone and prenatal germinal matrix, we find that approximately 90% of tumor cells recapitulate a neurodevelopment-like molecular phenotype, reprising gene expression signatures of prenatal astrocytes and of a distinct glial intermediate progenitor cell population (g-IPC) that precedes both astrocyte and oligodendrocyte lineage differentiation. Examining the infiltrative edge of samples with the most confident microdissection (n=4), we see that while distinct populations of tumor cells in this niche express proneural and classical signatures, these cells are overall enriched for a g-IPC-like phenotype, relative to the tumor core, irrespective of the tumors’ genomic alterations. A subset of cells at the infiltrative edge, in particular, recapitulates the signature of an uncommitted g-IPC subtype, expressing both astroglial and oligodendroglial markers. Trajectory analyses also reveal distinct branches of core and edge tumor cells, which are predominantly astrocyte- and g-IPC-like, respectively. Differential gene expression analysis of GBM cells at the infiltrative edge vs. tumor core reveals a migration signature, dominated by EGFR, ERBB4, PCDH9, and PCDH15. Ultimately, this high resolution analysis of heterogeneity at the infiltrative edge allows us to uncover potentially targetable drivers of invasion in GBM.

High Resolution Analysis of Proteome Dynamics during Bacillus subtilis Sporulation

Bacillus subtilis vegetative cells switch to sporulation upon nutrient limitation. To investigate the proteome dynamics during sporulation, high-resolution time-lapse proteomics was performed in a cell population that was induced to sporulate synchronously. Here, we are the first to comprehensively investigate the changeover of sporulation regulatory proteins, coat proteins, and other proteins involved in sporulation and spore biogenesis. Protein co-expression analysis revealed four co-expressed modules (termed blue, brown, green, and yellow). Modules brown and green are upregulated during sporulation and contain proteins associated with sporulation. Module blue is negatively correlated with modules brown and green, containing ribosomal and metabolic proteins. Finally, module yellow shows co-expression with the three other modules. Notably, several proteins not belonging to any of the known transcription regulons were identified as co-expressed with modules brown and green, and might also play roles during sporulation. Finally, levels of some coat proteins, for example morphogenetic coat proteins, decreased late in sporulation.

Assessing the Impact of the Assimilation of SWOT Observations in a Global High-Resolution Analysis and Forecasting System – Part 2: Results

A first attempt was made to quantify the impact of the assimilation of Surface Water Ocean Topography (SWOT) swath altimeter data in a global 1/12° high resolution analysis and forecasting system through a series of Observing System Simulation Experiments (OSSEs). The OSSE framework (Nature Run and Free Run) and data assimilation scheme have been described in detail in a companion article (Benkiran et al., 2021). The impact of assimilating data from SWOT and three nadir altimeters was quantified by estimating analysis and forecast error variances for sea surface height (SSH), temperature, salinity, zonal, and meridional velocities. Wave-number spectra and coherence analyses of SSH errors were also computed. SWOT data will significantly improve the quality of ocean analyses and forecasts. Adding SWOT observations to those of three nadir altimeters globally reduces the variance of SSH and surface velocities in analyses and forecasts by about 30 and 20%, respectively. Improvements are greater in high-latitude regions where space/time coverage of SWOT is much denser. The combination of SWOT data with data from three nadir altimeters provides a better resolution of wavelengths between 50 and 200 km with a more than 40% improvement outside tropical regions with respect to data from three nadir altimeters alone. The study has also highlighted that the impact of using SWOT data is likely to be very different depending on geographical areas. Constraining smaller spatial scales (wavelengths below 100 km) remains challenging as they are also associated with small time scales. Although this is only a first step, the study has demonstrated that SWOT data could be readily assimilated in a global high-resolution analysis and forecasting system with a positive impact at all latitudes and outstanding performances.

Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM

Engineered ectodomain trimer immunogens based on BG505 envelope glycoprotein are widely utilized as components of HIV vaccine development platforms. In this study, we used rhesus macaques to evaluate the immunogenicity of several stabilized BG505 SOSIP constructs both as free trimers and presented on a nanoparticle. We applied a cryoEM-based method for high-resolution mapping of polyclonal antibody responses elicited in immunized animals (cryoEMPEM). Mutational analysis coupled with neutralization assays were used to probe the neutralization potential at each epitope. We demonstrate that cryoEMPEM data can be used for rapid, high-resolution analysis of polyclonal antibody responses without the need for monoclonal antibody isolation. This approach allowed to resolve structurally distinct classes of antibodies that bind overlapping sites. In addition to comprehensive mapping of commonly targeted neutralizing and non-neutralizing epitopes in BG505 SOSIP immunogens, our analysis revealed that epitopes comprising engineered stabilizing mutations and of partially occupied glycosylation sites can be immunogenic.