julilili42/papers huggingface dataset:
Monitoring Mixture Effects of Neurotoxicants in Surface Water and Wastewater Treatment Plant Effluents with Neurite Outgrowth Inhibition in SH-SY5Y Cells
2022-08-17

Cell-based assays covering environmentally relevant modes of action are widely used for water quality monitoring. However, no high-throughput assays are available for testing developmental neurotoxicity of water samples. We implemented an assay that quantifies neurite outgrowth, which is one of the neurodevelopmental key events, and cell viability in human neuroblastoma SH-SY5Y cells using imaging techniques. We used this assay for testing of extracts of surface water collected in agricultural areas during rain events and effluents from wastewater treatment plants (WWTPs), where more than 200 chemicals had been quantified. Forty-one chemicals were tested individually that were suspected to contribute to the mixture effects among the detected chemicals in environmental samples. Sample sensitivity distributions indicated higher neurotoxicity for surface water samples than for effluents, and the endpoint of neurite outgrowth inhibition was six times more sensitive than cytotoxicity in the surface water samples and only three times more sensitive in the effluent samples. Eight environmental pollutants showed high specificity, and those ranged from pharmaceuticals (mebendazole and verapamil) to pesticides (methiocarb and clomazone), biocides (1,2-benzisothiazolin-3-one), and industrial chemicals (<i>N</i>-methyl-2-pyrrolidone, 7-diethylamino-4-methylcoumarin, and 2-(4-morpholinyl)benzothiazole). Although neurotoxic effects were newly detected for some of our test chemicals, less than 1% of the measured effects were explained by the detected and toxicologically characterized chemicals. The neurotoxicity assay was benchmarked against other bioassays: activations of the aryl hydrocarbon receptor and the peroxisome proliferator-activated receptor were similar in sensitivity, highly sensitive and did not differ much between the two water types, with surface water having slightly higher effects than the WWTP effluent. Oxidative stress response mirrored neurotoxicity quite well but was caused by different chemicals in the two water types. Overall, the new cell-based neurotoxicity assay is a valuable complement to the existing battery of effect-based monitoring tools.
The origin of chert in the Aurignacian of Vogelherd Cave investigated by infrared spectroscopy
2022-08-17

The analyses of raw material provenance offers the possibility of tracing short and long-distance raw material transport. So far, most studies of raw material of flint and chert in Europe have been based on macroscopic analyses. We apply infrared spectroscopy to Aurignacian assemblages from Vogelherd cave and to the Magdalenian site Randecker Maar in southwestern Germany. We compare raw material samples from three chert-bearing areas in Germany with archaeological samples from Vogelherd. Our results show that infrared spectroscopy can distinguish between different raw materials. Our archaeological samples from Vogelherd correspond to the sampled geological cherts in terms of their spectral signature. Our comparison of reference samples and archaeological samples highlights problems in commonly used macroscopic identifications of chert raw materials.
The evolution of strength, elasticity and rupture behaviour of birch tar made with ‘double‐pot’ techniques during tar cooking
2022-08-17

Abstract Birch tar was the first adhesive produced by humans. Its study has consequences for our understanding of human evolution and the development of specialised craftsmanship. One of the better‐documented birch tar making methods is the ‘double‐pot’ technique, where two containers are used, one containing bark, the other collecting the tar. Birch tar made with double‐pots has low viscosity and bad adhesive properties. To obtain a usable adhesive, it must be reduced in volume by cooking. We investigate the evolution of tar’s mechanical properties during cooking. We use lap‐shear tests to investigate strength, stiffness and failure behaviour. We found that tar must be cooked for 90 min to acquire adhesive properties. When cooked for longer, strength and stiffness increase over a 30 min lasting time span. Cooking for even longer, beyond this 30 min window, produced a substance that could no longer be used as an adhesive. The implications are that tar cooking requires a high level of skill because specific signs indicating the desired properties must be recognised during the process. Tar cooking constitutes a supplementary investment in time and resources and appears to be associated with a certain degree of risk.
Mechanism‐Based Design of the First GlnA4‐Specific Inhibitors
2022-08-17

Abstract γ‐Glutamylamine synthetases are an important class of enzymes that play a key role in glutamate‐based metabolism. Methionine sulfoximine (MSO) is a well‐established inhibitor for the archetypal glutamine synthetase (GS) but inhibitors for most GS‐like enzymes are unknown. Assuming a conserved catalytic mechanism for GS and GS‐like enzymes, we explored if subtype‐selective inhibitors can be obtained by merging MSO with the cognate substrates of the respective GS‐like enzymes. Using GlnA4 Sc from Streptomyces coelicolor , an enzyme recently shown to produce γ‐glutamylethanolamine, we demonstrate that MSO can be reengineered in a straightforward fashion into potent and selective GlnA4 Sc inhibitors. Linkage chemistry as well as linker length between the MSO moiety and the terminal hydroxyl group derived from ethanolamine were in agreement with the postulated phosphorylated catalytic intermediate. The best GlnA4 inhibitor 7 b potently blocked S. coelicolor growth in the presence of ethanolamine as the sole nitrogen source. Our results provide the first GlnA4 Sc ‐specific inhibitors and suggest a general strategy to develop mechanism‐based inhibitors for GS‐like enzymes.
Acute effects of a motor coordination intervention on executive functions in kindergartners: a proof-of-concept randomized controlled trial
2022-08-17

Abstract Background Executive functions are pivotal for future academic and social functioning. Causal effects of physical activity on executive functions have been shown in adults. The primary objective of this study was to test the proof-of-concept (i.e., feasibility of implementation and acceptance) of a motor coordination intervention and a sedentary control condition in kindergartners and its preliminary effectiveness on subsequent executive function performance. Methods The study used a two-group post-test only design. All children aged between 4 and 7 years old were eligible. One hundred and three children (46% girls; age: M = 5.71 years, 95% CI = 5.50 to 5.92) recruited in a middle-sized town in Germany were randomly assigned to a 20-min motor coordination intervention ( n = 51) or a sedentary control condition ( n = 52), both of which were conducted in a one-on-one experimenter-child setting in the university or kindergarten. A second blinded-to-condition experimenter assessed the executive function outcomes directly following the conditions. Proof-of-concept criteria were the implementation of the intervention with a moderate-to-vigorous physical activity level assessed via heart rate sensors, and with motor coordination demands, analyzed via video recordings; children’s acceptance via self-reported enjoyment of the conditions; and the post-assessments of executive functions with a behavioral and computerized task. Results The motor coordination intervention and the control condition were feasible in a one-on-one setting with kindergartners. The intervention revealed heart rate increases and challenging motor coordination tasks. Children in both conditions indicated they enjoy them. Performance in the two executive function tasks did not differ between children in the motor coordination intervention and the control condition. Conclusions A one-on-one experimenter-child setting was feasible to deliver in kindergartners. Future intervention studies should consider pre-testing of executive functions and take into account children’s characteristics as potential moderators, such as motor coordination skills.
Expanding the calibration range of compound‐specific chlorine isotope analysis by the preparation of a 37 Cl‐enriched tetrachloroethylene
2022-08-17

Rationale The recent development of reliable GC/qMS methods for δ 37 Cl compound‐specific stable isotope analysis (CSIA) paves the way for dual carbon–chlorine isotope analysis of chlorinated ethenes and thus allows deeper insights into underlying transformation processes/mechanisms. A two‐point calibration is indispensable for the precise and correct conversion of raw data to the international δ 37 Cl SMOC scale. The currently available calibration standards for tetrachloroethylene (PCE) span only a very narrow range from −2.52‰ (EIL2) to +0.29‰ (EIL1), which is considerably smaller than observed δ 37 Cl isotope enrichment in (bio‐)transformation studies (up to 12‰). Methods We describe the preparation and evaluation of a new 37 Cl‐enriched PCE standard to avoid bias in δ 37 Cl CSIA arising from extrapolation beyond the calibration range. The preparation comprised: (i) partial PCE reduction by zero‐valent zinc in a system of PCE, ethanol (initial volume ratio 3/5) and trace amounts of water followed by (ii) liquid–liquid extraction and (iii) a subsequent fractional distillation to purify the 37 Cl‐enriched PCE. Results The obtained PCE (PCE enriched ) showed a purity of 98.8% (mole fraction) and a δ 37 Cl SMOC value of +10.8 ± 0.5‰. The evaluation of an experimental dataset with and without extrapolation showed no significant variation. Conclusions The new PCE standard (PCE enriched ) expands the calibration range to 13.3‰ (previously 2.8‰) and thus prevents potential bias introduced by extrapolation beyond the calibration range.
Definitional Reasoning in Proof-Theoretic Semantics and the Square of Opposition
2022-08-17

Within a framework of clausal definitions of atoms, four forms of judgement are distinguished: Direct and indirect assertion, and direct and indirect denial. Whereas direct assertion and direct denial are established by directly applying a definitional clause (“definitional closure”), indirect assertion and indirect denial result from showing that all possible premisses of the opposite judgement can be refuted (“definitional reflection”). The deductive relationships between these four forms of judgement correspond to those represented in the square of opposition, if direct assertion and direct denial are placed in the A and E corners, and indirect assertion and indirect denial in the I and O corners of the square.
Visual Alcohol Cue-Reactivity and Cognitive Control in Non-Dependent Heavy Alcohol Drinkers Assessed by Simultaneous fNIRS-EEG
2022-08-17

Impulsivity-related decreases in error monitoring during cue reactivity were mediated by alcohol consumption pattern. However, cognitive control was not affected by cue reactivity, suggesting more complex interactions than previously assumed.
Sustained deep-tissue voltage recording using a fast indicator evolved for two-photon microscopy
2022-08-18

Genetically encoded voltage indicators are emerging tools for monitoring voltage dynamics with cell-type specificity. However, current indicators enable a narrow range of applications due to poor performance under two-photon microscopy, a method of choice for deep-tissue recording. To improve indicators, we developed a multiparameter high-throughput platform to optimize voltage indicators for two-photon microscopy. Using this system, we identified JEDI-2P, an indicator that is faster, brighter, and more sensitive and photostable than its predecessors. We demonstrate that JEDI-2P can report light-evoked responses in axonal termini of Drosophila interneurons and the dendrites and somata of amacrine cells of isolated mouse retina. JEDI-2P can also optically record the voltage dynamics of individual cortical neurons in awake behaving mice for more than 30 min using both resonant-scanning and ULoVE random-access microscopy. Finally, ULoVE recording of JEDI-2P can robustly detect spikes at depths exceeding 400 μm and report voltage correlations in pairs of neurons.
Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers
2022-08-18

Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.
Harmicens, Novel Harmine and Ferrocene Hybrids: Design, Synthesis and Biological Activity
2022-08-18

Cancer and malaria are both global health threats. Due to the increase in the resistance to the known drugs, research on new active substances is a priority. Here, we present the design, synthesis, and evaluation of the biological activity of harmicens, hybrids composed of covalently bound harmine/β-carboline and ferrocene scaffolds. Structural diversity was achieved by varying the type and length of the linker between the β-carboline ring and ferrocene, as well as its position on the β-carboline ring. Triazole-type harmicens were prepared using Cu(I)-catalyzed azide-alkyne cycloaddition, while the synthesis of amide-type harmicens was carried out by applying a standard coupling reaction. The results of in vitro biological assays showed that the harmicens exerted moderate antiplasmodial activity against the erythrocytic stage of P. falciparum (IC50 in submicromolar and low micromolar range) and significant and selective antiproliferative activity against the MCF-7 and HCT116 cell lines (IC50 in the single-digit micromolar range, SI &gt; 5.9). Cell localization experiments showed different localizations of nonselective harmicene 36 and HCT116-selective compound 28, which clearly entered the nucleus. A cell cycle analysis revealed that selective harmicene 28 had already induced G1 cell cycle arrest after 24 h, followed by G2/M arrest with a concomitant drastic reduction in the percentage of cells in the S phase, whereas the effect of nonselective compound 36 on the cell cycle was much less pronounced, which agreed with their different localizations within the cell.
Physiologically Based Pharmacokinetic Modeling to Describe the CYP2D6 Activity Score-Dependent Metabolism of Paroxetine, Atomoxetine and Risperidone
2022-08-18

The cytochrome P450 2D6 (CYP2D6) genotype is the single most important determinant of CYP2D6 activity as well as interindividual and interpopulation variability in CYP2D6 activity. Here, the CYP2D6 activity score provides an established tool to categorize the large number of CYP2D6 alleles by activity and facilitates the process of genotype-to-phenotype translation. Compared to the broad traditional phenotype categories, the CYP2D6 activity score additionally serves as a superior scale of CYP2D6 activity due to its finer graduation. Physiologically based pharmacokinetic (PBPK) models have been successfully used to describe and predict the activity score-dependent metabolism of CYP2D6 substrates. This study aimed to describe CYP2D6 drug–gene interactions (DGIs) of important CYP2D6 substrates paroxetine, atomoxetine and risperidone by developing a substrate-independent approach to model their activity score-dependent metabolism. The models were developed in PK-Sim®, using a total of 57 plasma concentration–time profiles, and showed good performance, especially in DGI scenarios where 10/12, 5/5 and 7/7 of DGI AUClast ratios and 9/12, 5/5 and 7/7 of DGI Cmax ratios were within the prediction success limits. Finally, the models were used to predict their compound’s exposure for different CYP2D6 activity scores during steady state. Here, predicted DGI AUCss ratios were 3.4, 13.6 and 2.0 (poor metabolizers; activity score = 0) and 0.2, 0.5 and 0.95 (ultrarapid metabolizers; activity score = 3) for paroxetine, atomoxetine and risperidone active moiety (risperidone + 9-hydroxyrisperidone), respectively.
Legume NCRs and nodule-specific defensins of actinorhizal plants—Do they share a common origin?
2022-08-18

The actinorhizal plant Datisca glomerata (Datiscaceae, Cucurbitales) establishes a root nodule symbiosis with actinobacteria from the earliest branching symbiotic Frankia clade. A subfamily of a gene family encoding nodule-specific defensin-like cysteine-rich peptides is highly expressed in D . glomerata nodules. Phylogenetic analysis of the defensin domain showed that these defensin-like peptides share a common evolutionary origin with nodule-specific defensins from actinorhizal Fagales and with nodule-specific cysteine-rich peptides (NCRs) from legumes. In this study, the family member with the highest expression levels, DgDef1 , was characterized. Promoter- GUS studies on transgenic hairy roots showed expression in the early stage of differentiation of infected cells, and transient expression in the nodule apex. DgDef1 contains an N-terminal signal peptide and a C-terminal acidic domain which are likely involved in subcellular targeting and do not affect peptide activity. In vitro studies with E . coli and Sinorhizobium meliloti 1021 showed that the defensin domain of DgDef1 has a cytotoxic effect, leading to membrane disruption with 50% lethality for S . meliloti 1021 at 20.8 μM. Analysis of the S . meliloti 1021 transcriptome showed that, at sublethal concentrations, DgDef1 induced the expression of terminal quinol oxidases, which are associated with the oxidative stress response and are also expressed during symbiosis. Overall, the changes induced by DgDef1 are reminiscent of those of some legume NCRs, suggesting that nodule-specific defensin-like peptides were part of the original root nodule toolkit and were subsequently lost in most symbiotic legumes, while being maintained in the actinorhizal lineages.
Incorporation of Ambient Water-H into the C-Bonded H Pool of Bacteria during Substrate-Specific Metabolism
2022-08-18

The stable isotope ratios of C-bonded H (δ2Hn values) can be used to locate soil samples for forensic purposes because of their close correlation with the δ2H values of precipitation. Post-sampling bacterial activity might change the δ2Hn values via glycolysis. We tested to which degree C-bonded H is replaced by H from ambient water under favorable and unfavorable growing conditions. We provided two heterotrophic bacteria (Bacillus atrophaeus, Escherichia coli) with glucose (favorable) or lysine (unfavorable) under aerobic conditions. We assessed the H incorporation from ambient water via 2H labeling. We found that the H incorporation into bacterial biomass in the glucose treatment was 79 ± 5.9% (B. atrophaeus) and 43 ± 3.0% (E. coli), likely as a consequence of glycolysis and conservation of the δ2H value in the anabolic mode of the tricarboxylic acid (TCA) cycle. Differences between species were possibly related with different compositions of metabolite mixtures. The bacteria did hardly grow with lysine while respiration continued, and we found no H incorporation because the catabolic mode of the TCA cycle, which was active when the bacteria grew on lysine, is associated with CO2 release and a complete cleavage of former C–2H bonds. Our results support the glycolysis pathway as a mechanism underlying the incorporation of ambient-water H into the C-bonded H pool of bacteria. Stressful conditions forcing bacteria into a catabolism-dominated metabolism disable the incorporation of ambient-water H, and δ2Hn values can be applied to identify the origin of soil samples in forensics.
Dataset related to publication: Discovery of Human Constitutive androstane receptor (CAR) agonists with imidazo[1,2-a]pyridine structure
2022-08-18

MD simulation data related to the publication Ivana Mejdrová et al.:Discovery of Human Constitutive androstane receptor (CAR) agonists with imidazo[1,2-a]pyridine structure Individual .zip files contain raw-desmond trajectories (trj. zip files) individual raw-data.zip files corresponde to the trajectory analysis. 5us_XVP_619 corresponding name in the manuscript is ; 5us_XVP_37 5us_XVP_676 corresponding name in the manuscript is ; 5us_XVP_39 5us_XVP_693 corresponding name in the manuscript is ; 5us_XVP_40 5us_XVP_763 corresponding name in the manuscript is ; 5us_XVP_48 5us_XVP_CIT corresponding name in the manuscript is ; 5us_XVP_CITCO
Aurignacian dynamics in Southeastern Europe based on spatial analysis, sediment geochemistry, raw materials, lithic analysis, and use-wear from Românești-Dumbrăvița
2022-08-19

Abstract The Aurignacian is one of the first cultural-technological traditions commonly associated with the expansion of Homo sapiens in Europe. Early Homo sapiens demographics across the continent are therefore typically inferred using the distribution of Aurignacian assemblages. Western Romania has been used as a tie-point to connect the well-researched lithic assemblages from the eastern Mediterranean and Western Europe through its early Homo sapiens fossils. However, Romania’s archeological record remains underexplored thereby hindering our ability to directly connect better understood regions through time and space. Here we report on excavations from the open-air Middle/Upper Paleolithic site of Româneș﻿ti- Dumbrăvița I in southwestern Romania. Three stratified Paleolithic assemblages were extensively excavated within a 1-m-thick eolian-deposited sequence. Spatial, geochemical, raw material, techno-typological, and use-wear analysis of the site reveal patterns of artifact configuration, resource exploitation, fire history, knapping objectives, and functionality. Taken together, Românești- Dumbrăvița I is the first well-contextualized archeological site in close spatiotemporal proximity to many early, well-preserved human fossils and in East-Central Europe.
Discovery of Ircinianin Lactones B and C—Two New Cyclic Sesterterpenes from the Marine Sponge Ircinia wistarii
2022-08-19

Two new ircinianin-type sesterterpenoids, ircinianin lactone B and ircinianin lactone C (7 and 8), together with five known entities from the ircinianin compound family (1, 3–6) were isolated from the marine sponge Ircinia wistarii. Ircinianin lactones B and C (7 and 8) represent new ircinianin terpenoids with a modified oxidation pattern. Despite their labile nature, the structures could be established using a combination of spectroscopic data, including HRESIMS and 1D/2D NMR techniques, as well as computational chemistry and quantum-mechanical calculations. In a broad screening approach for biological activity, the class-defining compound ircinianin (1) showed moderate antiprotozoal activity against Plasmodium falciparum (IC50 25.4 μM) and Leishmania donovani (IC50 16.6 μM).