Greenland Mass Trends From Airborne and Satellite Altimetry During 2011-2020.

We use satellite and airborne altimetry to estimate annual mass changes of the Greenland Ice Sheet. We estimate ice loss corresponding to a sea-level rise of 6.9 ± 0.4 mm from April 2011 to April 2020, with a highest annual ice loss rate of 1.4 mm/yr sea-level equivalent from April 2019 to April 2020. On a regional scale, our annual mass loss timeseries reveals 10-15 m/yr dynamic thickening at the terminus of Jakobshavn Isbræ from April 2016 to April 2018, followed by a return to dynamic thinning. We observe contrasting patterns of mass loss acceleration in different basins across the ice sheet and suggest that these spatiotemporal trends could be useful for calibrating and validating prognostic ice sheet models. In addition to resolving the spatial and temporal fingerprint of Greenland's recent ice loss, these mass loss grids are key for partitioning contemporary elastic vertical land motion from longer-term glacial isostatic adjustment (GIA) trends at GPS stations around the ice sheet. Our ice-loss product results in a significantly different GIA interpretation from a previous ice-loss product.

Accelerating Ice Loss From Peripheral Glaciers in North Greenland.

In recent decades, Greenland's peripheral glaciers have experienced large-scale mass loss, resulting in a substantial contribution to sea level rise. While their total area of Greenland ice cover is relatively small (4%), their mass loss is disproportionally large compared to the Greenland ice sheet. Satellite altimetry from Ice, Cloud, and land Elevation Satellite (ICESat) and ICESat-2 shows that mass loss from Greenland's peripheral glaciers increased from 27.2 ± 6.2 Gt/yr (February 2003-October 2009) to 42.3 ± 6.2 Gt/yr (October 2018-December 2021). These relatively small glaciers now constitute 11 ± 2% of Greenland's ice loss and contribute to global sea level rise. In the period October 2018-December 2021, mass loss increased by a factor of four for peripheral glaciers in North Greenland. While peripheral glacier mass loss is widespread, we also observe a complex regional pattern where increases in precipitation at high altitudes have partially counteracted increases in melt at low altitude.

Phosphate dysregulation via the XPR1-KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer.

Despite advances in precision medicine, the clinical prospects for patients with ovarian and uterine cancers have not substantially improved. Here, we analyzed genome-scale CRISPR-Cas9 loss-of-function screens across 851 human cancer cell lines and found that frequent overexpression of SLC34A2-encoding a phosphate importer-is correlated with sensitivity to loss of the phosphate exporter XPR1, both in vitro and in vivo. In patient-derived tumor samples, we observed frequent PAX8-dependent overexpression of SLC34A2, XPR1 copy number amplifications and XPR1 messenger RNA overexpression. Mechanistically, in SLC34A2-high cancer cell lines, genetic or pharmacologic inhibition of XPR1-dependent phosphate efflux leads to the toxic accumulation of intracellular phosphate. Finally, we show that XPR1 requires the novel partner protein KIDINS220 for proper cellular localization and activity, and that disruption of this protein complex results in acidic "vacuolar" structures preceding cell death. These data point to the XPR1-KIDINS220 complex and phosphate dysregulation as a therapeutic vulnerability in ovarian cancer.

High-Resolution Tritium Profile in an Ice Core from Camp Century, Greenland.

We measure 3H in an ice core from Camp Century. The temporal distribution of 3H concentration in the ice core corresponds generally well with the historical record of explosive yields of atmospheric nuclear weapons tests. Maximum 3H values observed in 1962-1963 are comparable to those in ice core or precipitation in many other locations in the Northern Hemisphere. There is no indication that significant 3H contamination was locally released into the air during the operation of the Camp Century reactor. It is, however, somewhat surprising that several prominent 3H peaks are still observed after 1980. We suggest that these are associated with airborne 3H releases from the civil nuclear industry. A wavelet analysis during 1970-2017 indicates the primary frequency of variability in the 3H record is annual 3H peaks. These annual peaks can be combined with the 3H spikes from global fallout of known nuclear weapons tests to benchmark and evaluate theoretical ice core dating scales back to the 1950s. A positive correlation is observed between annual 3H average concentration and variability of Arctic Oscillation (AO). This highlights the value of 3H as a potential tracer for air masses and airborne pollutants in the Arctic.

Cycling cancer persister cells arise from lineages with distinct programs.

Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure1, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment2. Although most cancer persisters remain arrested in the presence of the drug, a rare subset can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drugs. To study this rare, transiently resistant, proliferative persister population, we developed Watermelon, a high-complexity expressed barcode lentiviral library for simultaneous tracing of each cell's clonal origin and proliferative and transcriptional states. Here we show that cycling and non-cycling persisters arise from different cell lineages with distinct transcriptional and metabolic programs. Upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation are associated with persister proliferative capacity across multiple cancer types. Impeding oxidative stress or metabolic reprogramming alters the fraction of cycling persisters. In human tumours, programs associated with cycling persisters are induced in minimal residual disease in response to multiple targeted therapies. The Watermelon system enabled the identification of rare persister lineages that are preferentially poised to proliferate under drug pressure, thus exposing new vulnerabilities that can be targeted to delay or even prevent disease recurrence.

Vulnerability of the North Water ecosystem to climate change.

High Arctic ecosystems and Indigenous livelihoods are tightly linked and exposed to climate change, yet assessing their sensitivity requires a long-term perspective. Here, we assess the vulnerability of the North Water polynya, a unique seaice ecosystem that sustains the world's northernmost Inuit communities and several keystone Arctic species. We reconstruct mid-to-late Holocene changes in sea ice, marine primary production, and little auk colony dynamics through multi-proxy analysis of marine and lake sediment cores. Our results suggest a productive ecosystem by 4400-4200 cal yrs b2k coincident with the arrival of the first humans in Greenland. Climate forcing during the late Holocene, leading to periods of polynya instability and marine productivity decline, is strikingly coeval with the human abandonment of Greenland from c. 2200-1200 cal yrs b2k. Our long-term perspective highlights the future decline of the North Water ecosystem, due to climate warming and changing sea-ice conditions, as an important climate change risk.

A first constraint on basal melt-water production of the Greenland ice sheet.

The Greenland ice sheet has been one of the largest sources of sea-level rise since the early 2000s. However, basal melt has not been included explicitly in assessments of ice-sheet mass loss so far. Here, we present the first estimate of the total and regional basal melt produced by the ice sheet and the recent change in basal melt through time. We find that the ice sheet's present basal melt production is 21.4 +4.4/-4.0 Gt per year, and that melt generated by basal friction is responsible for about half of this volume. We estimate that basal melting has increased by 2.9 ± 5.2 Gt during the first decade of the 2000s. As the Arctic warms, we anticipate that basal melt will continue to increase due to faster ice flow and more surface melting thus compounding current mass loss trends, enhancing solid ice discharge, and modifying fjord circulation.

Cyclin-dependent Kinase 1 and Aurora Kinase choreograph mitotic storage and redistribution of a growth factor receptor.

Endosomal trafficking of receptors and associated proteins plays a critical role in signal processing. Until recently, it was thought that trafficking was shut down during cell division. Thus, remarkably, the regulation of trafficking during division remains poorly characterized. Here we delineate the role of mitotic kinases in receptor trafficking during asymmetric division. Targeted perturbations reveal that Cyclin-dependent Kinase 1 (CDK1) and Aurora Kinase promote storage of Fibroblast Growth Factor Receptors (FGFRs) by suppressing endosomal degradation and recycling pathways. As cells progress through metaphase, loss of CDK1 activity permits differential degradation and targeted recycling of stored receptors, leading to asymmetric induction. Mitotic receptor storage, as delineated in this study, may facilitate rapid reestablishment of signaling competence in nascent daughter cells. However, mutations that limit or enhance the release of stored signaling components could alter daughter cell fate or behavior thereby promoting oncogenesis.

Centennial response of Greenland's three largest outlet glaciers.

The Greenland Ice Sheet is the largest land ice contributor to sea level rise. This will continue in the future but at an uncertain rate and observational estimates are limited to the last few decades. Understanding the long-term glacier response to external forcing is key to improving projections. Here we use historical photographs to calculate ice loss from 1880-2012 for Jakobshavn, Helheim, and Kangerlussuaq glacier. We estimate ice loss corresponding to a sea level rise of 8.1 ± 1.1 millimetres from these three glaciers. Projections of mass loss for these glaciers, using the worst-case scenario, Representative Concentration Pathways 8.5, suggest a sea level contribution of 9.1-14.9 mm by 2100. RCP8.5 implies an additional global temperature increase of 3.7 °C by 2100, approximately four times larger than that which has taken place since 1880. We infer that projections forced by RCP8.5 underestimate glacier mass loss which could exceed this worst-case scenario.

Multiplexed single-cell transcriptional response profiling to define cancer vulnerabilities and therapeutic mechanism of action.

Assays to study cancer cell responses to pharmacologic or genetic perturbations are typically restricted to using simple phenotypic readouts such as proliferation rate. Information-rich assays, such as gene-expression profiling, have generally not permitted efficient profiling of a given perturbation across multiple cellular contexts. Here, we develop MIX-Seq, a method for multiplexed transcriptional profiling of post-perturbation responses across a mixture of samples with single-cell resolution, using SNP-based computational demultiplexing of single-cell RNA-sequencing data. We show that MIX-Seq can be used to profile responses to chemical or genetic perturbations across pools of 100 or more cancer cell lines. We combine it with Cell Hashing to further multiplex additional experimental conditions, such as post-treatment time points or drug doses. Analyzing the high-content readout of scRNA-seq reveals both shared and context-specific transcriptional response components that can identify drug mechanism of action and enable prediction of long-term cell viability from short-term transcriptional responses to treatment.

Inferring Tunicate Relationships and the Evolution of the Tunicate Hox Cluster with the Genome of Corella inflata.

Tunicates, the closest living relatives of vertebrates, have served as a foundational model of early embryonic development for decades. Comparative studies of tunicate phylogeny and genome evolution provide a critical framework for analyzing chordate diversification and the emergence of vertebrates. Toward this goal, we sequenced the genome of Corella inflata (Ascidiacea, Phlebobranchia), so named for the capacity to brood self-fertilized embryos in a modified, "inflated" atrial chamber. Combining the new genome sequence for Co. inflata with publicly available tunicate data, we estimated a tunicate species phylogeny, reconstructed the ancestral Hox gene cluster at important nodes in the tunicate tree, and compared patterns of gene loss between Co. inflata and Ciona robusta, the prevailing tunicate model species. Our maximum-likelihood and Bayesian trees estimated from a concatenated 210-gene matrix were largely concordant and showed that Aplousobranchia was nested within a paraphyletic Phlebobranchia. We demonstrated that this relationship is not an artifact due to compositional heterogeneity, as had been suggested by previous studies. In addition, within Thaliacea, we recovered Doliolida as sister to the clade containing Salpida and Pyrosomatida. The Co. inflata genome provides increased resolution of the ancestral Hox clusters of key tunicate nodes, therefore expanding our understanding of the evolution of this cluster and its potential impact on tunicate morphological diversity. Our analyses of other gene families revealed that several cardiovascular associated genes (e.g., BMP10, SCL2A12, and PDE2a) absent from Ci. robusta, are present in Co. inflata. Taken together, our results help clarify tunicate relationships and the genomic content of key ancestral nodes within this phylogeny, providing critical insights into tunicate evolution.

Variable levels of drift in tunicate cardiopharyngeal gene regulatory elements.

BACKGROUND: Mutations in gene regulatory networks often lead to genetic divergence without impacting gene expression or developmental patterning. The rules governing this process of developmental systems drift, including the variable impact of selective constraints on different nodes in a gene regulatory network, remain poorly delineated. RESULTS: Here we examine developmental systems drift within the cardiopharyngeal gene regulatory networks of two tunicate species, Corella inflata and Ciona robusta. Cross-species analysis of regulatory elements suggests that trans-regulatory architecture is largely conserved between these highly divergent species. In contrast, cis-regulatory elements within this network exhibit distinct levels of conservation. In particular, while most of the regulatory elements we analyzed showed extensive rearrangements of functional binding sites, the enhancer for the cardiopharyngeal transcription factor FoxF is remarkably well-conserved. Even minor alterations in spacing between binding sites lead to loss of FoxF enhancer function, suggesting that bound trans-factors form position-dependent complexes. CONCLUSIONS: Our findings reveal heterogeneous levels of divergence across cardiopharyngeal cis-regulatory elements. These distinct levels of divergence presumably reflect constraints that are not clearly associated with gene function or position within the regulatory network. Thus, levels of cis-regulatory divergence or drift appear to be governed by distinct structural constraints that will be difficult to predict based on network architecture.

Holocene deceleration of the Greenland Ice Sheet.

Recent peripheral thinning of the Greenland Ice Sheet is partly offset by interior thickening and is overprinted on its poorly constrained Holocene evolution. On the basis of the ice sheet's radiostratigraphy, ice flow in its interior is slower now than the average speed over the past nine millennia. Generally higher Holocene accumulation rates relative to modern estimates can only partially explain this millennial-scale deceleration. The ice sheet's dynamic response to the decreasing proportion of softer ice from the last glacial period and the deglacial collapse of the ice bridge across Nares Strait also contributed to this pattern. Thus, recent interior thickening of the Greenland Ice Sheet is partly an ongoing dynamic response to the last deglaciation that is large enough to affect interpretation of its mass balance from altimetry.

A synthesis of the basal thermal state of the Greenland Ice Sheet.

The basal thermal state of an ice sheet (frozen or thawed) is an important control upon its evolution, dynamics and response to external forcings. However, this state can only be observed directly within sparse boreholes or inferred conclusively from the presence of subglacial lakes. Here we synthesize spatially extensive inferences of the basal thermal state of the Greenland Ice Sheet to better constrain this state. Existing inferences include outputs from the eight thermomechanical ice-flow models included in the SeaRISE effort. New remote-sensing inferences of the basal thermal state are derived from Holocene radiostratigraphy, modern surface velocity and MODIS imagery. Both thermomechanical modeling and remote inferences generally agree that the Northeast Greenland Ice Stream and large portions of the southwestern ice-drainage systems are thawed at the bed, whereas the bed beneath the central ice divides, particularly their west-facing slopes, is frozen. Elsewhere, there is poor agreement regarding the basal thermal state. Both models and remote inferences rarely represent the borehole-observed basal thermal state accurately near NorthGRIP and DYE-3. This synthesis identifies a large portion of the Greenland Ice Sheet (about one third by area) where additional observations would most improve knowledge of its overall basal thermal state.

Spatial and temporal distribution of mass loss from the Greenland Ice Sheet since AD 1900.

The response of the Greenland Ice Sheet (GIS) to changes in temperature during the twentieth century remains contentious, largely owing to difficulties in estimating the spatial and temporal distribution of ice mass changes before 1992, when Greenland-wide observations first became available. The only previous estimates of change during the twentieth century are based on empirical modelling and energy balance modelling. Consequently, no observation-based estimates of the contribution from the GIS to the global-mean sea level budget before 1990 are included in the Fifth Assessment Report of the Intergovernmental Panel on Climate Change. Here we calculate spatial ice mass loss around the entire GIS from 1900 to the present using aerial imagery from the 1980s. This allows accurate high-resolution mapping of geomorphic features related to the maximum extent of the GIS during the Little Ice Age at the end of the nineteenth century. We estimate the total ice mass loss and its spatial distribution for three periods: 1900-1983 (75.1 ± 29.4 gigatonnes per year), 1983-2003 (73.8 ± 40.5 gigatonnes per year), and 2003-2010 (186.4 ± 18.9 gigatonnes per year). Furthermore, using two surface mass balance models we partition the mass balance into a term for surface mass balance (that is, total precipitation minus total sublimation minus runoff) and a dynamic term. We find that many areas currently undergoing change are identical to those that experienced considerable thinning throughout the twentieth century. We also reveal that the surface mass balance term shows a considerable decrease since 2003, whereas the dynamic term is constant over the past 110 years. Overall, our observation-based findings show that during the twentieth century the GIS contributed at least 25.0 ± 9.4 millimetres of global-mean sea level rise. Our result will help to close the twentieth-century sea level budget, which remains crucial for evaluating the reliability of models used to predict global sea level rise.

Considering thermal-viscous collapse of the Greenland ice sheet.

We explore potential changes in Greenland ice sheet form and flow associated with increasing ice temperatures and relaxing effective ice viscosities. We define "thermal-viscous collapse" as a transition from the polythermal ice sheet temperature distribution characteristic of the Holocene to temperate ice at the pressure melting point and associated lower viscosities. The conceptual model of thermal-viscous collapse we present is dependent on: (1) sufficient energy available in future meltwater runoff, (2) routing of meltwater to the bed of the ice sheet interior, and (3) efficient energy transfer from meltwater to the ice. Although we do not attempt to constrain the probability of thermal-viscous collapse, it appears thermodynamically plausible to warm the deepest 15% of the ice sheet, where the majority of deformational shear occurs, to the pressure melting point within four centuries. First-order numerical modeling of an end-member scenario, in which prescribed ice temperatures are warmed at an imposed rate of 0.05 K/a, infers a decrease in ice sheet volume of 5 ± 2% within five centuries of initiating collapse. This is equivalent to a cumulative sea-level rise contribution of 33 ± 18 cm. The vast majority of the sea-level rise contribution associated with thermal-viscous collapse, however, would likely be realized over subsequent millennia.