In the area of the the Krško alluvial field, the Brežice hydroelectric power plant (BHPP), with its surface water reservoir, was completed in 2017. The new BHPP reservoir dam is located approximately ...7 km air distance downstream of the old Krško nuclear power plant (NEK) reservoir dam. The NEK dam was built in the 1970s. The primary purpose of the NEK reservoir is to provide fresh water for cooling the NEK nuclear reactor. To assess the impact of the newly built surface water reservoir on groundwater, we performed a series of data analyses prior to its construction. One part of the analysis relating to data from the monitoring facility of the NEK showed an interesting correspondence between the water level oscillation in the NEK reservoir and the groundwater oscillation in the nearby observation well. Based on measurements taken in 2000, we sought to estimate the clogging of the Sava riverbed sediments in the area of the old NEK surface water reservoir. To determine the permeability of the riverbed sediments, we applied geometry similar to that chosen by Hantush for his pumping test method. Using Fourier analysis, we determined the dominant frequencies from the hydrograph records of the NEK surface water reservoir and from the pressure probe in the nearby observation well. Based on the determination of the dominant frequency, we used the wave equation to compare the influence of different values of the hydraulic transmissivity of the clogged part of the NEK surface water reservoir on the transfer of its water oscillations to the groundwater in the observation well. For the hydraulic values of the non-clogged part of the aquifer (T, S), we assumed the values from the pumping experiments performed in the alluvial aquifer of Krško polje. We also assumed that the aquifer is homogeneous and isotropic, as Hantush had assumed in his method for the determination of semipervious river beds. The results obtained indicated the potential for estimation of the thickness of the clogging layer which, by analogy from applied geophysics, can be called the apparent thickness. This meant that the thickness could be determined on the basis of the default conceptual model rather than on real measurements. The presented method shows the potential for using the analysis of periodic oscillations in river reservoir level and nearby piezometers, as a method of monitoring riverbed clogging, in cases where periodical oscillations in reservoir level occur and observation wells are near enough to detect the oscillations.
Due to intrinsic characteristics of aquifers groundwater frequently passes between various types of aquifers without hindrance. The complex connection of underground water paths enables flow ...regardless of administrative boundaries. This can cause problems in water resources management. Numerical modelling is an important tool for the understanding, interpretation and management of aquifers. Useful and reliable methods of numerical modelling differ with regard to the type of aquifer, but their connections in a single hydrodynamic model are rare. The purpose of this study was to connect different models into an integrated system that enables determination of water travel time from the point of contamination to water sources. The worst-case scenario is considered. The system was applied in the Soča/Isonzo basin, a transboundary river in Slovenia and Italy, where there is a complex contact of karst and intergranular aquifers and surface flows over bedrock with low permeability. Time cell models were first elaborated separately for individual hydrogeological units. These were the result of numerical hydrological modelling (intergranular aquifer and surface flow) or complex GIS analysis taking into account the vulnerability map and tracer tests results (karst aquifer). The obtained cellular models present the basis of a contamination early-warning system, since it allows an estimation when contaminants can be expected to appear, and in which water sources. The system proves that the contaminants spread rapidly through karst aquifers and via surface flows, and more slowly through intergranular aquifers. For this reason, karst water sources are more at risk from one-off contamination incidents, while water sources in intergranular aquifers are more at risk in cases of long-term contamination. The system that has been developed is the basis for a single system of protection, action and quality monitoring in the areas of complex aquifer systems within or on the borders of administrative units.
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•An integrated system of hydrological and hydrogeological models has been created.•The system couples different porous media with complex water flow regimes.•The system is based on water travel time between surface and water source.•The study provides a scientific basis for an early-warning and monitoring system.•The system is applicable in transboundary water resources management.
The purpose of this article is to showcase opportunities for local communities to demonstrate self-sufficiency with respect to natural resources (gravel and sand) in the east of Slovenia. Limitations ...put in place for the exploitation of mineral resources by applicable regulations in the light of groundwater protection were analysed particularly in the context of mining undertaken in an area of shallow alluvium with a shallow groundwater table. It is essential that land disturbance (from mining activity) complies with the environmental limitations imposed by both EU and Slovenian law. The study highlights the factors directly indicating the inadequacy of the applicable regulations in Slovenia in relation to mining in areas of shallow groundwater; those limitations put in place the exploitation of mineral resources as unlawful works. This article outlines how such limitations negatively affect local communities’ self-sufficiency and the region with natural resources, specifically mineral resources. To this end, when selecting which alluvial plain to test, we focused on the area of the Drava and Ptuj Plain (Dravsko polje and Ptujsko polje) in Slovenia. The Drava River flows through the area in question across this alluvial plain. The artificially regulated power canal of the Zlatoličje hydroelectric power plant runs parallel to the river. Pursuant to environmental regulations, mineral resources can be exploited in these areas only up to two metres above the highest groundwater level. This criterion makes it almost impossible to pursue the additional exploitation of mineral resources in this area, as well as similar areas in the catchment area of the Danube River in Slovenia. We believe that in terms of the shared use of physical space it is necessary to change this limitation and link it directly to the percentage of exploited physical space and the application of relevant extraction technologies, which do not pollute groundwater either directly or indirectly. We also believe that the criterion put in place does not withstand expert judgment as the requirement for excavation to cease up to two metres above the highest groundwater level was not defined by means of the scientific method. The article analyses inconsistencies and puts forward measures for the ongoing eco-friendly and economically sustainable exploitation of mineral resources. As an alternative, we thus suggest implementing the EU Regulation via an act that would set out the necessary limitations, based on expert starting points arising from cartographic bases under consideration of the tetrahedral consensus-seeking methodology.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. ...Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase.
In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6.
A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients.
Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.).
Polyunsaturated fatty acids (PUFAs) are structural components of membrane phospholipids and precursors of oxygenated lipid mediators with diverse functions, including the control of cell growth, ...inflammation and tumourigenesis. However, the molecular pathways that control the availability of PUFAs for lipid mediator production are not well understood. Here, we investigated the crosstalk of three pathways in the provision of PUFAs for lipid mediator production: (i) secreted group X phospholipase A2 (GX sPLA2) and (ii) cytosolic group IVA PLA2 (cPLA2α), both mobilizing PUFAs from membrane phospholipids, and (iii) adipose triglyceride lipase (ATGL), which mediates the degradation of triacylglycerols (TAGs) stored in cytosolic lipid droplets (LDs).
We combined lipidomic and functional analyses in cancer cell line models to dissect the trafficking of PUFAs between membrane phospholipids and LDs and determine the role of these pathways in lipid mediator production, cancer cell proliferation and tumour growth in vivo.
We demonstrate that lipid mediator production strongly depends on TAG turnover. GX sPLA2 directs ω-3 and ω-6 PUFAs from membrane phospholipids into TAG stores, whereas ATGL is required for their entry into lipid mediator biosynthetic pathways. ATGL controls the release of PUFAs from LD stores and their conversion into cyclooxygenase- and lipoxygenase-derived lipid mediators under conditions of nutrient sufficiency and during serum starvation. In starving cells, ATGL also promotes the incorporation of LD-derived PUFAs into phospholipids, representing substrates for cPLA2α. Furthermore, we demonstrate that the built-up of TAG stores by acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is required for the production of mitogenic lipid signals that promote cancer cell proliferation and tumour growth.
This study shifts the paradigm of PLA2-driven lipid mediator signalling and identifies LDs as central lipid mediator production hubs. Targeting DGAT1-mediated LD biogenesis is a promising strategy to restrict lipid mediator production and tumour growth.
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•Phospholipase A2-induced lipid mediator production depends on lipid droplet turnover.•Group X sPLA2-released polyunsaturated fatty acids are incorporated into triglycerides.•Triglyceride lipolysis by ATGL drives lipid mediator production.•ATGL also delivers polyunsaturated fatty acids into phospholipids to be targeted by cPLA2α.•Inhibition of DGAT1 reduces cancer cell proliferation and tumour growth in vivo.
Cancer-associated, loss-of-function mutations in genes encoding subunits of the BRG1/BRM-associated factor (BAF) chromatin-remodeling complexes
often cause drastic chromatin accessibility changes, ...especially in important regulatory regions
. However, it remains unknown how these changes are established over time (for example, immediate consequences or long-term adaptations), and whether they are causative for intracomplex synthetic lethalities, abrogating the formation or activity of BAF complexes
. In the present study, we use the dTAG system to induce acute degradation of BAF subunits and show that chromatin alterations are established faster than the duration of one cell cycle. Using a pharmacological inhibitor and a chemical degrader of the BAF complex ATPase subunits
, we show that maintaining genome accessibility requires constant ATP-dependent remodeling. Completely abolishing BAF complex function by acute degradation of a synthetic lethal subunit in a paralog-deficient background results in an almost complete loss of chromatin accessibility at BAF-controlled sites, especially also at superenhancers, providing a mechanism for intracomplex synthetic lethalities.
Insects are a sustainable source of protein for human food and animal feed. We present a genome assembly, CRISPR gene editing, and life stage-specific transcriptomes for the yellow mealworm,
, one of ...the most intensively farmed insects worldwide.
Long and short reads and long-range data were obtained from a
male pupa. Sequencing transcripts from 12
life stages resulted in 279 million reads for gene prediction and genetic engineering. A unique plasmid delivery system containing guide RNAs targeting the eye color gene
flanking the muscle
gene promoter and EGFP marker was used in CRISPR/Cas9 transformation.
The assembly is approximately 53% of the genome size of 756.8 ± 9.6 Mb, measured using flow cytometry. Assembly was complicated by a satellitome of at least 11 highly conserved satDNAs occupying 28% of the genome. The injection of the plasmid into embryos resulted in knock-out of
and knock-in of EGFP.
The genome of
is longer than current assemblies (including ours) due to a substantial amount (26.5%) of only one highly abundant satellite DNA sequence. Genetic sequences and transformation tools for an insect important to the food and feed industries will promote the sustainable utilization of mealworms and other farmed insects.
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