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Implementing screening assays that identify functional and structural cardiotoxicity earlier in the drug development pipeline has the potential to improve safety and decrease the cost and time required to bring new drugs to market. In this study, a metabolic biomarker-based assay was developed that predicts the cardiotoxicity potential of a drug based on changes in the metabolism and viability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Assay development and testing was conducted in 2 phases: (1) biomarker identification and (2) targeted assay development. In the first phase, metabolomic data from hiPSC-CM spent media following exposure to 66 drugs were used to identify biomarkers that identified both functional and structural cardiotoxicants. Four metabolites that represent different metabolic pathways (arachidonic acid, lactic acid, 2′-deoxycytidine, and thymidine) were identified as indicators of cardiotoxicity. In phase 2, a targeted, exposure-based biomarker assay was developed that measured these metabolites and hiPSC-CM viability across an 8-point concentration curve. Metabolite-specific predictive thresholds for identifying the cardiotoxicity potential of a drug were established and optimized for balanced accuracy or sensitivity. When predictive thresholds were optimized for balanced accuracy, the assay predicted the cardiotoxicity potential of 81 drugs with 86% balanced accuracy, 83% sensitivity, and 90% specificity. Alternatively, optimizing the thresholds for sensitivity yields a balanced accuracy of 85%, 90% sensitivity, and 79% specificity. This new hiPSC-CM-based assay provides a paradigm that can identify structural and functional cardiotoxic drugs that could be used in conjunction with other endpoints to provide a more comprehensive evaluation of a drug’s cardiotoxicity potential.

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P

Ice core records of the major atmospheric greenhouse gases (CO2, CH4, N2O) and their isotopologues covering recent centuries provide evidence of biogeochemical variations during the Late Holocene and pre-industrial periods and over the transition to the industrial period. These records come from a number of ice core and firn air sites and have been measured in several laboratories around the world and show common features but also unresolved differences. Here we present revised records, including new measurements, performed at the CSIRO Ice Core Extraction LABoratory (ICELAB) on air samples from ice obtained at the high-accumulation site of Law Dome (East Antarctica). We are motivated by the increasing use of the records by the scientific community and by recent data-handling developments at CSIRO ICELAB. A number of cores and firn air samples have been collected at Law Dome to provide high-resolution records overlapping recent, direct atmospheric observations. The records have been updated through a dynamic link to the calibration scales used in the Global Atmospheric Sampling LABoratory (GASLAB) at CSIRO, which are periodically revised with information from the latest calibration experiments. The gas-age scales have been revised based on new ice-age scales and the information derived from a new version of the CSIRO firn diffusion model. Additionally, the records have been revised with new, rule-based selection criteria and updated corrections for biases associated with the extraction procedure and the effects of gravity and diffusion in the firn. All measurements carried out in ICELAB–GASLAB over the last 25 years are now managed through a database (the ICElab dataBASE or ICEBASE), which provides consistent data management, automatic corrections and selection of measurements, and a web-based user interface for data extraction. We present the new records, discuss their strengths and limitations, and summarise their main features. The records reveal changes in the carbon cycle and atmospheric chemistry over the last 2 millennia, including the major changes of the anthropogenic era and the smaller, mainly natural variations beforehand. They provide the historical data to calibrate and test the next inter-comparison of models used to predict future climate change (Coupled Model Inter-comparison Project – phase 6, CMIP6). The datasets described in this paper, including spline fits, are available at https://doi.org/10.25919/5bfe29ff807fb (Rubino et al., 2019).

To meet combustion quality requirements, Miscanthus is conventionally harvested in late winter/early spring after senescence due to a lowering of fuel nitrogen, chlorine and ash content. This can overcome combustion issues such as slagging, fouling and corrosion however there is a significant reduction in dry matter yields compared to early harvesting in the autumn. In this study, Miscanthus × giganteus harvested conventionally (after senescence) and early (green) have been pre-treated by hydrothermal carbonisation (HTC) at 200 °C and 250 °C. HTC at 200 °C improves the grindability of the biomass but results in limited energy densification. HTC at 250 °C results in increased energy densification producing a bio-coal with a HHV ranging from 27 to 28 MJ/kg for early and 25 to 26 MJ/kg for conventional harvesting; the Hardgrove Grindability Index (HGI) increases from 0 to 150. At higher HTC temperatures, the combustion profile of the bio-coal exhibits a ‘coal like’ single stage combustion profile. HTC results in a significant reduction in alkali metal content, increases safe combustion temperatures and reduces the theoretical propensity of the derived fuel to slag, foul and corrode. The results indicate that HTC can valorise both conventional and early harvested Miscanthus without producing any adverse effect on the yields and quality of the bio-coal. The challenges associated with early harvesting of Miscanthus appear to be largely overcome by HTC resulting in increased yields of up to 40% per hectare due to reduction in dry matter loss.

Is groundwater abundant in Antarctica and does it modulate ice flow? Answering this question matters because ice streams flow by gliding over a wet substrate of till. Water fed to icestream beds thus influences ice-sheet dynamics and, potentially, sea-level rise. It is recognized that both till and the sedimentary basins from which it originates are porous and could host a reservoir of mobile groundwater that interacts with the subglacial interfacial system. According to recent numerical modelling, up to half of all water available for basal lubrication, and time lags between hydrological forcing and ice-sheet response as long as millennia, may have been overlooked in models of ice flow. Here, we review evidence in support of Antarctic groundwater and propose how it can be measured to ascertain the extent to which it modulates ice flow. We present new seismoelectric soundings of subglacial till, and magnetotelluric and transient electromagnetic forward models of subglacial groundwater reservoirs. We demonstrate that multifaceted and integrated geophysical datasets can detect, delineate and quantify the groundwater contents of subglacial sedimentary basins and, potentially, monitor groundwater exchange rates between subglacial till layers. The paper thus describes a new area of glaciological investigation and how it should progress in future.

Constraining how much and how fast the West Antarctic Ice Sheet (WAIS) will change in the coming decades has recently been identified as the highest priority in Antarctic research (National Academies, 2015). Here we review recent research on WAIS and outline further scientific objectives for the area now identified as the most likely to undergo near-term significant change: Thwaites Glacier and the adjacent Amundsen Sea. Multiple lines of evidence point to an ongoing rapid loss of ice in this region in response to changing atmospheric and oceanic conditions. Models of the ice sheet's dynamic behavior indicate a potential for greatly accelerated ice loss as ocean-driven melting at the Thwaites Glacier grounding zone and nearby areas leads to thinning, faster flow, and retreat. A complete retreat of the Thwaites Glacier basin would raise global sea level by more than three meters by entraining ice from adjacent catchments. This scenario could occur over the next few centuries, and faster ice loss could occur through processes omitted from most ice flow models such as hydrofracture and ice cliff failure, which have been observed in recent rapid ice retreats elsewhere. Increased basal melt at the grounding zone and increased potential for hydrofracture due to enhanced surface melt could initiate a more rapid collapse of Thwaites Glacier within the next few decades.

Although 90% of Antarctica's discharge occurs via its fast-flowing ice streams, our ability to project future ice-sheet response has been limited by poor observational constraints on the ice-bed conditions used in numerical models to determine basal slip. We have helped address this observational deficit by acquiring and analysing a series of seismic reflection profiles to determine basal conditions beneath the main trunk and tributaries of Pine Island Glacier (PIG), West Antarctica. Seismic profiles indicate large-scale sedimentary deposits. Combined with seismic reflection images, measured acoustic impedance values indicate relatively uniform bed conditions directly beneath the main trunk and tributaries, comprising a widespread reworked sediment layer with a dilated sediment lid of minimum thickness 1.5 ± 0.4 m. Beneath a slow-moving inter-tributary region, a discrete low-porosity sediment layer of 7 ± 3 m thickness is imaged. Despite considerable basal topography, seismic observations indicate that a till layer at the ice base is ubiquitous beneath PIG, which requires a highly mobile sediment body to maintain an abundant supply. These results are compatible with existing ice-sheet models used to invert for basal shear stress: existing basal conditions upstream will not inhibit further rapid retreat of PIG if the high-friction region currently restraining flow, directly upstream of the grounding line, is breached. However, small changes in the pressure regime at the bed, as a result of stress reorganisation following retreat, may result in a less-readily deformable bed and conditions which are less likely to maintain high ice-flow rates.