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Groundwater is the world’s largest freshwater resource and is critically important for irrigation, and hence for global food security 1 – 3 . Already, unsustainable groundwater pumping exceeds recharge from precipitation and rivers 4 , leading to substantial drops in the levels of groundwater and losses of groundwater from its storage, especially in intensively irrigated regions 5 – 7 . When groundwater levels drop, discharges from groundwater to streams decline, reverse in direction or even stop completely, thereby decreasing streamflow, with potentially devastating effects on aquatic ecosystems. Here we link declines in the levels of groundwater that result from groundwater pumping to decreases in streamflow globally, and estimate where and when environmentally critical streamflows—which are required to maintain healthy ecosystems—will no longer be sustained. We estimate that, by 2050, environmental flow limits will be reached for approximately 42 to 79 per cent of the watersheds in which there is groundwater pumping worldwide, and that this will generally occur before substantial losses in groundwater storage are experienced. Only a small decline in groundwater level is needed to affect streamflow, making our estimates uncertain for streams near a transition to reversed groundwater discharge. However, for many areas, groundwater pumping rates are high and environmental flow limits are known to be severely exceeded. Compared to surface-water use, the effects of groundwater pumping are markedly delayed. Our results thus reveal the current and future environmental legacy of groundwater use. Estimates for when critical environmental streamflow limits will be reached—with potentially devastating economic and environmental effects—are obtained using a global model that links groundwater pumping with the groundwater flow to rivers.

Current global-scale models of water resources do not generally represent groundwater lateral flows and groundwater–surface water interactions. But, models that do represent groundwater in more detail are becoming available and this raises the question of how estimates of water flow, availability, and impacts might change compared to previous global estimates. In this study, we provide the first global quantification of cell-to-cell groundwater flow (GWF) using a high-resolution global-scale GWF model and compare estimated impacts of groundwater pumping using two model setups: (a) with and (b) without including cell-to-cell GWFs and realistic simulation of groundwater–surface water interactions at the global scale (simulated over 1960–2010). Results show that 40% of the land–surface cell-to-cell flows are a notable part of the cell’s water budget and that globally large differences in the impact of groundwater pumping are estimatd between the two runs. Globally, simulated groundwater discharge to rivers and streams increased by a factor of 1.2–2.2 when GWFs and interactions between groundwater and surface water were included. For eight heavily pumped aquifers, estimates of groundwater depletion decrease by a factor of 1.7–22. Furthermore, our results show that GWFs and interactions between groundwater and surface water contribute to the volume of groundwater that can be pumped without causing notable changes in storage. However, in approximately 40% of the world’s watersheds where groundwater is used, groundwater is being pumped notably at the expense of river flow, and in 15% of the area globally depletion is increased as a result of nearby groundwater pumping. Evaluation of the model results showed that when groundwater lateral flows and groundwater–-surface water interactions were taken into account, the indirect observations of groundwater depletion and groundwater discharge were mimicked much better than when these fluxes were not included. Based on these findings, we suggest that including GWFs in large-scale water resources assessments will benefit a realistic assessment of groundwater availability worldwide, the estimation of impacts associated with groundwater pumping, especially when one is interested in the feedback between groundwater use and groundwater and surface water availability, and the impacts of current and future groundwater uses on the hydrological system.

Precision-cut tissue slices (PCTS) are viable ex vivo explants of tissue with a reproducible, well defined thickness. They represent a mini-model of the organ under study and contain all cells of the tissue in their natural environment, leaving intercellular and cell-matrix interactions intact, and are therefore highly appropriate for studying multicellular processes. PCTS are mainly used to study the metabolism and toxicity of xenobiotics, but they are suitable for many other purposes. Here we describe the protocols to prepare and incubate rat and human liver and intestinal slices. Slices are prepared from fresh liver by making a cylindrical core using a drill with a hollow bit, from which slices are cut with a specially designed tissue slicer. Intestinal tissue is embedded in cylinders of agarose before slicing. Slices remain viable for 24 h (intestine) and up to 96 h (liver) when incubated in 6- or 12-well plates under 95% O 2 /5% CO 2 atmosphere.

In many regions globally, groundwater overuse exceeds natural replenishment, leading to immediate consequences such as reduced river flows and devastating impacts on freshwater ecosystems. In alluvial aquifers in particular, groundwater pumping contributes to river flow reduction in two significant ways: first, by intercepting water that would naturally discharge into the river, and second, by lowering groundwater levels below the riverbed, causing river water to infiltrate. Despite these critical interactions, large-scale water resources assessments often overlook the relationship between groundwater and surface water, hindering a comprehensive understanding of the consequences of groundwater pumping on both the groundwater and surface water systems. Our study, utilizing a coupled global-scale groundwater–surface water model, reveals that approximately 20% of globally pumped groundwater stems from diminished streamflow, while 16% results from reduced storage. Projections for the end of the century, accounting for climate change, suggest potential increases to 30% from reduced streamflow and a decrease to 12% from reduced storage. Notably, our results highlight that the impact on streamflow is more widespread and linked to smaller pumping rates, contrasting with impacts on storage associated with higher pumping rates. This study shows the crucial need to include groundwater–surface water interactions in large-scale water resources assessments, not only for accurate estimates of freshwater availability but also for a comprehensive understanding of the far-reaching impacts of groundwater overuse related to increasing water demands and climate change.

We present PCR-GLOBWB 2, a global hydrology and water resources model. Compared to previous versions of PCR-GLOBWB, this version fully integrates water use. Sector-specific water demand, groundwater and surface water withdrawal, water consumption, and return flows are dynamically calculated at every time step and interact directly with the simulated hydrology. PCR-GLOBWB 2 has been fully rewritten in Python and PCRaster Python and has a modular structure, allowing easier replacement, maintenance, and development of model components. PCR-GLOBWB 2 has been implemented at 5 arcmin resolution, but a version parameterized at 30 arcmin resolution is also available. Both versions are available as open-source codes on https://github.com/UU-Hydro/PCR-GLOBWB_model (Sutanudjaja et al., 2017a). PCR-GLOBWB 2 has its own routines for groundwater dynamics and surface water routing. These relatively simple routines can alternatively be replaced by dynamically coupling PCR-GLOBWB 2 to a global two-layer groundwater model and 1-D–2-D hydrodynamic models. Here, we describe the main components of the model, compare results of the 30 and 5 arcmin versions, and evaluate their model performance using Global Runoff Data Centre discharge data. Results show that model performance of the 5 arcmin version is notably better than that of the 30 arcmin version. Furthermore, we compare simulated time series of total water storage (TWS) of the 5 arcmin model with those observed with GRACE, showing similar negative trends in areas of prevalent groundwater depletion. Also, we find that simulated total water withdrawal matches reasonably well with reported water withdrawal from AQUASTAT, while water withdrawal by source and sector provide mixed results.

Water-table drawdown across peatlands increases carbon dioxide (CO2) and reduces methane (CH4) emissions. The net climatic effect remains unclear. Based on global observations from 130 sites, we found a positive (warming) net climate effect of water-table drawdown. Using a machine-learning-based upscaling approach, we predict that peatland water-table drawdown driven by climate drying and human activities will increase CO2 emissions by 1.13 (95% interval: 0.88–1.50) Gt yr−1 and reduce CH4 by 0.26 (0.14–0.52) GtCO2-eq yr−1, resulting in a net increase of greenhouse gas of 0.86 (0.36–1.36) GtCO2-eq yr−1 by the end of the twenty-first century under the RCP8.5 climate scenario. This drops to 0.73 (0.2–1.2) GtCO2-eq yr−1 under RCP2.6. Our results point to an urgent need to preserve pristine and rehabilitate drained peatlands to decelerate the positive feedback among water-table drawdown, increased greenhouse gas emissions and climate warming.The climate impact of water-table drawdown in peatlands is unclear as carbon dioxide emissions increase and methane emissions decrease due to drying. This study shows decreasing water-table depth results in net greenhouse gas emissions from global peatlands, despite reducing methane emissions.

A number of global hydrological models [GHMs) have been developed in recent decades in order to understand the impacts of climate variability and human activities on water resources availability. The spatial resolution of GHMs is mostly constrained at a 0.5° by 0.5° grid [∼50km by ∼50km at the equator). However, for many of the water‐related problems facing society, the current spatial scale of GHMs is insufficient to provide locally relevant information. Here using the PCR‐GLOBWB model we present for the first time an analysis of human and climate impacts on global water resources at a 0.1° by 0.1° grid [∼10km by ∼10km at the equator) in order to depict more precisely regional variability in water availability and use. Most of the model input data (topography, vegetation, soil properties, routing, human water use) have been parameterized at a 0.1° global grid and feature a distinctively higher resolution. Distinct from many other GHMs, PCR‐GLOBWB includes groundwater representation and simulates groundwater heads and lateral groundwater flows based on MODFLOW with existing geohydrological information. This study shows that global hydrological simulations at higher spatial resolutions are feasible for multi‐decadal to century periods. Key Points: A first high‐resolution simulation of global water resources and use Coupled surface water and groundwater simulation at 10 km by 10 km spatial resolution Global hydrological simulations at higher spatial resolutions are feasible for multidecadal periods

Amanita phalloides poisonings account for the majority of fatal mushroom poisonings. Recently, we identified hematotoxicity as a relevant aspect of Amanita poisonings. In this study, we investigated the effects of the main toxins of Amanita phalloides, α- and β-amanitin, on hematopoietic cell viability in vitro. Hematopoietic cell lines were exposed to α-amanitin or β-amanitin for up to 72 h with or without the pan-caspase inhibitor Z-VAD(OH)-FMK, antidotes N-acetylcysteine, silibinin, and benzylpenicillin, and organic anion-transporting polypeptide 1B3 (OATP1B3) inhibitors rifampicin and cyclosporin. Cell viability was established by trypan blue exclusion, annexin V staining, and a MTS assay. Caspase-3/7 activity was determined with Caspase-Glo assay, and cleaved caspase-3 was quantified by Western analysis. Cell number and colony-forming units were quantified after exposure to α-amanitin in primary CD34+ hematopoietic stem cells. In all cell lines, α-amanitin concentration-dependently decreased viability and mitochondrial activity. β-Amanitin was less toxic, but still significantly reduced viability. α-Amanitin increased caspase-3/7 activity by 2.8-fold and cleaved caspase-3 by 2.3-fold. Z-VAD(OH)-FMK significantly reduced α-amanitin-induced toxicity. In CD34+ stem cells, α-amanitin decreased the number of colonies and cells. The antidotes and OATP1B3 inhibitors did not reverse α-amanitin-induced toxicity. In conclusion, α-amanitin induces apoptosis in hematopoietic cells via a caspase-dependent mechanism.

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is considered as the master regulator of antioxidant and cytoprotective gene expressions. Moreover, it plays a pivotal role in cancer progression. Nrf2 mediates the adaptive response which contributes to the resistance to chemotherapeutic pro-oxidant drugs, such as cisplatin (CDDP), in various tumors, including bladder cancers. For this reason, Nrf2 could be a promising target to overcome chemoresistance. There are several known Nrf2 pharmacological inhibitors; however, most of them are not specific. The use of a specific small interfering RNA (siRNA) targeting the Nrf2 gene (siNrf2) loaded into nanovehicles is an attractive alternative, since it can increase specificity. This study aimed to evaluate the biological activity of siNrf2 loaded on guanidine-terminated carbosilane dendrimers (GCDs) in overcoming CDDP resistance in bladder cancer cells with a high level of Nrf2. Parameters such as viability, proliferation, apoptosis, migration, and oxidative stress level were taken into account. Results demonstrated that siNrf2-GCD treatment sensitized CDDP-resistant cells to CDDP treatment. Moreover, data obtained by treating the non-cancerous human kidney HK-2 cell line strongly suggest a good safety profile of the carbosilane dendrimers loaded with siNrf2. In conclusion, we suggest that siNrf2-GCD is a promising drug delivery system for gene therapy to be used in vivo; and it may represent an important tool in the therapy of CDDP-resistant cancer.

Irrigation expansion and subsequent deforestation substantially affect large basin variability. However, given the complex interactions between hydrological variables, a more comprehensive understanding of the hydrological impacts within the coexisting land use changes is needed. Here, we applied surface-groundwater-coupled simulations with historical river gauges and satellite observations to evaluate long-term and seasonal changes in Lancang-Mekong River Basin hydrology. Increasing irrigation elevated soil moisture but depleted groundwater storage. Conversely, deforestation reduced soil moisture, and increased lateral flow in areas with steep terrain compensated for groundwater depletion. Irrigation affected runoff by augmenting evapotranspiration and baseflow, which had opposite implications for runoff changes, causing a mixed spatial pattern of decreases and increases. Meanwhile, decreases in soil moisture due to deforestation offset increases in evapotranspiration due to irrigation, resulting in wider areas of runoff increases than decreases. These illustrate the distinct hydrological impacts of different land use changes and a pathway to complex system assessments. Impacts of irrigation and deforestation in the Lancang-Mekong River Basin are contrasting for soil moisture, groundwater, and other water variables causing complex runoff changes, according to analysis of modelling with river gauge and satellite data.