Metal uptake and distribution in crops have been demonstrated to be highly variable and depending on the metal of interest and the crop type. However, no consensus is reached regarding the primary... Show moreMetal uptake and distribution in crops have been demonstrated to be highly variable and depending on the metal of interest and the crop type. However, no consensus is reached regarding the primary factor controlling metal uptake in crops. This study thus comparably investigated Hg, As, Zn, Pb, Cd and Cu uptake and distribution in three crops grown in a watershed near a copper mining field located in Yunnan, Southwestern China. The bioconcentration factor (BCF) and translocation factor (TF) were statistically compared for the same metal across different crops. Leafy crops had a stronger propensity to accumulate Hg, As and Zn than fruit crops. The ability of grain crops to accumulate Cd and Cu was much lower than leafy and fruit crops. The three crops all tended not to accumulate Pb in their edible tissues. The DTPA extracted metal concentrations were not statistically correlated with the metal concentrations in crop edible tissues. It is thus not practical to predict metal uptake of Hg, As, Pb and Zn through their available concentrations in soils. The contents of nitrogen and phosphorus, and competing metal ions present in paddy soil decreased the accumulation of Cu and Cd in rice grains. By means of hierarchical cluster analysis, the high accumulation of Zn in the edible tissues of fruit and grain crops was mainly due to dust inputs via phloem transport from leaves. This is why BCF(Zn) was the highest among the six metals for these two crops. For leafy crops, the accumulation of Hg, Cd and Zn in leaves was mainly through soil inputs by roots. Our findings serve as a scientific basis for the selection of crops in areas with high background of heavy metals. Show less
Zhang, J.; Dinther, M. van; Thorikay, M.; Gourabi, B.M.; Kruithof, B.P.T.; Dijke, P. ten 2023
Ubiquitin-specific protease (USP)19 is a deubiquitinating enzyme that regulates the stability and function of multiple proteins, thereby controlling various biological responses. The alternative... Show moreUbiquitin-specific protease (USP)19 is a deubiquitinating enzyme that regulates the stability and function of multiple proteins, thereby controlling various biological responses. The alternative splicing of USP19 results in the expression of two major encoded variants that are localized to the endoplasmic reticulum (ER) (USP19-ER) and cytoplasm (USP19-CY). The importance of alternative splicing for the function of USP19 remains unclear. Here, we demonstrated that USP19-CY promotes TGF-beta signaling by directly interacting with TGF-beta type I receptor (T beta RI) and protecting it from degradation at the plasma membrane. In contrast, USP19-ER binds to and sequesters T beta RI in the ER. By decreasing cell surface T beta RI levels, USP19-ER inhibits TGF-beta/SMAD signaling in a deubiquitination-independent manner. Moreover, USP19-ER inhibits TGF-beta-induced epithelial-mesenchymal transition (EMT), whereas USP19-CY enhances EMT, as well as the migration and extravasation of breast cancer cells. Furthermore, USP19-CY expression is correlated with poor prognosis and is higher in breast cancer tissues than in adjacent normal tissues. Notably, the splicing modulator herboxidiene inhibits USP19-CY, increases USP19-ER expression and suppresses breast cancer cell migration. Targeting USP19 splicing or its deubiquitinating activity may have potential therapeutic effects on breast cancer. Show less
Chlorpyrifos is a widely used organophosphorus insecticide because of its high efficiency and overall effectiveness, and it is commonly detected in aquatic ecosystems. However, at present, the... Show moreChlorpyrifos is a widely used organophosphorus insecticide because of its high efficiency and overall effectiveness, and it is commonly detected in aquatic ecosystems. However, at present, the impact of chlorpyrifos on the aquatic micro-ecological environment is still poorly understood. Here, we established aquatic microcosm systems treated with 0.2 and 2.0 µg/L chlorpyrifos, and employed omics biotechnology, including metagenomics and 16S rRNA gene sequencing, to investigate the effect of chlorpyrifos on the composition and functional potential of the aquatic and zebrafish intestinal microbiomes after 7 d and 14 d chlorpyrifos treatment. After 14 d chlorpyrifos treatment, the aquatic microbial community was adversely affected in terms of its composition, structure, and stability, while its diversity showed only a slight impact. Most functions, especially capacities for environmental information processing and metabolism, were destroyed by chlorpyrifos treatment for 14 d. We observed that chlorpyrifos increased the number of risky antibiotic resistance genes and aggravated the growth of human pathogens. Although no clear effects on the structure of the zebrafish intestinal microbial community were observed, chlorpyrifos treatment did alter the metabolic capacity of the zebrafish. Our study highlights the ecological risk of chlorpyrifos to the aquatic environment and provides a theoretical basis for the rational use of pesticides in agricultural production. Show less
Epithelial-mesenchymal transition (EMT) is pivotal in the initiation and development of cancer cell metastasis. We observed that the abundance of glycosphingolipids (GSLs), especially ganglioside... Show moreEpithelial-mesenchymal transition (EMT) is pivotal in the initiation and development of cancer cell metastasis. We observed that the abundance of glycosphingolipids (GSLs), especially ganglioside subtypes, decreased significantly during TGF-beta-induced EMT in NMuMG mouse mammary epithelial cells and A549 human lung adenocarcinoma cells. Transcriptional profiling showed that TGF-beta/SMAD response genes and EMT signatures were strongly enriched in NMuMG cells, along with depletion of UDP-glucose ceramide glucosyltransferase (UGCG), the enzyme that catalyzes the initial step in GSL biosynthesis. Consistent with this finding, genetic or pharmacological inhibition of UGCG promoted TGF-beta signaling and TGF-beta-induced EMT. UGCG inhibition promoted A549 cell migration, extravasation in the zebrafish xenograft model, and metastasis in mice. Mechanistically, GSLs inhibited TGF-beta signaling by promoting lipid raft localization of the TGF-beta type I receptor (T beta RI) and by increasing T beta RI ubiquitination and degradation. Importantly, we identified ST3GAL5-synthesized a-series gangliosides as the main GSL subtype involved in inhibition of TGF-beta signaling and TGF-beta-induced EMT in A549 cells. Notably, ST3GAL5 is weakly expressed in lung cancer tissues compared to adjacent nonmalignant tissues, and its expression correlates with good prognosis. Show less
In this study, generalized predictive models were developed to estimate KOA of four kinds of aromatic pollutants based on the calculated solvation free energy and taking the dimer effect into... Show moreIn this study, generalized predictive models were developed to estimate KOA of four kinds of aromatic pollutants based on the calculated solvation free energy and taking the dimer effect into account. Uncorrected log KOA values, which were directly estimated from the calculated solvation free energy of individual molecules, underestimated experimental values, and the deviation increased with increasing log KOA. Dimers were found to greatly affect the apparent KOA values of these aromatic pollutants, which were driven by π-π interactions. London dispersion and exchange-repulsion terms were identified to be dominant components of the underlying π-π interactions. It is interesting to find that the π-π interactions of polybrominated diphenyl ethers correlate with not only the molecular polarizability but also the size of opposing aromatic surfaces, which leads to a different trend of π-π interactions from other aromatic pollutants. A universal quantitative structure-activity relationship model was developed to estimate the proportion of dimers based on five molecular structural descriptors relevant to the π-π interactions. After calibration with the dimer effect, estimations of log KOA were consistent with experimental values. Therefore, the dimer effect should be taken into consideration when investigating the partition behavior of aromatic pollutants, and the solvation free energy model could be an alternative method for the prediction of KOA. Show less
Geyer, C.E.; Garber, J.E.; Gelber, R.D.; Yothers, G.; Taboada, M.; Ross, L.; ... ; OlympiA Clinical Trial Steering Committee and Investigators 2022
Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for... Show moreBackground: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Delta 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Delta 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Delta 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 35 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDES and DDFS with no new safety signals. Show less
The neuroendocrine tumours paraganglioma and pheochromocytoma (PPGLs) are commonly associated with succinate dehydrogenase (SDH) gene variants, but no human SDH-related PPGL-derived cell line has... Show moreThe neuroendocrine tumours paraganglioma and pheochromocytoma (PPGLs) are commonly associated with succinate dehydrogenase (SDH) gene variants, but no human SDH-related PPGL-derived cell line has been developed to date. The aim of this study was to systematically explore practical issues related to the classical 2D-culture of SDH-related human paragangliomas and pheochromocytomas, with the ultimate goal of identifying a viable tumour-derived cell line. PPGL tumour tissue/cells (chromaffin cells) were cultured in a variety of media formulations and supplements. Tumour explants and dissociated primary tumour cells were cultured and stained with a range of antibodies to identify markers suitable for use in human PPGL culture. We cultured 62 PPGLs, including tumours with confirmed SDHB, SDHC and SDHD variants, as well as several metastatic tumours. Testing a wide range of basic cell culture media and supplements, we noted a marked decline in chromaffin cell numbers over a 4-8 week period but the persistence of small numbers of synaptophysin/tyrosine hydroxylase-positive chromaffin cells for up to 99 weeks. In cell culture, immunohistochemical staining for chromogranin A and neuron-specific enolase was generally negative in chromaffin cells, while staining for synaptophysin and tyrosine hydroxylase was generally positive. GFAP showed the most consistent staining of type II sustentacular cells. Of the media tested, low serum or serum-free media best sustained relative chromaffin cell numbers, while lactate enhanced the survival of synaptophysin-positive cells. Synaptophysin-positive PPGL tumour cells persist in culture for long periods but show little evidence of proliferation. Synaptophysin was the most consistent cell marker for chromaffin cells and GFAP the best marker for sustentacular cells in human PPGL cultures. Show less
In the past decades, hundreds of antibiotics have been isolated from microbial metabolites or have been artificially synthesized for protecting humans, animals and crops from microbial infections.... Show moreIn the past decades, hundreds of antibiotics have been isolated from microbial metabolites or have been artificially synthesized for protecting humans, animals and crops from microbial infections. Their everlasting usage results in impacts on the microbial community composition and causes well-known collateral damage to the functioning of microbial communities. Nevertheless, the impact of different antibiotic properties on aquatic microbial communities have so far only poorly been disentangled. Here we characterized the environmental risk of 50 main kinds of antibiotics from 9 classes at a concentration of 10 μg/L for aquatic bacterial communities via metadata analysis combined with machine learning. Metadata analysis showed that the alpha diversity of the bacterial community increased only after treatment with aminoglycoside and β-lactam antibiotics, while its structure was changed by almost all tested antibiotics. The antibiotic treatment also disturbed the functions of the bacterial community, especially with regard to metabolic pathways, including amino acids, cofactors, vitamins, xenobiotics and carbohydrate metabolism. The critical characteristics (atom stereocenter count, number of hydrogen atoms in the antibiotic, and the adipose water coefficient) of antibiotics affecting the composition of the bacterial community in aquatic habitats were screened by machine learning. The key characteristics of antibiotics affecting the function bacterial communities were the number of hydrogen atoms, molecular weight and complexity. In summary, by developing machine learning models and by performing metadata analysis, this study provides the relationship between the properties of antibiotics and their adverse impacts on aquatic microbial communities from a macro perspective. The study also provides guidance for the rational design of antibiotics. Show less
Background: Heart development relies on tight spatiotemporal control of cardiac gene expression. Genes involved in this intricate process have been identified using animals and pluripotent stem... Show moreBackground: Heart development relies on tight spatiotemporal control of cardiac gene expression. Genes involved in this intricate process have been identified using animals and pluripotent stem cell-based models of cardio(myo)genesis. Recently, the repertoire of cardiomyocyte differentiation models has been expanded with iAM-1, a monoclonal line of conditionally immortalized neonatal rat atrial myocytes (NRAMs), which allows toggling between proliferative and differentiated (ie, excitable and contractile) phenotypes in a synchronized and homogenous manner. Methods: In this study, the unique properties of conditionally immortalized NRAMs (iAMs) were exploited to identify and characterize (lowly expressed) genes with an as-of-yet uncharacterized role in cardiomyocyte differentiation. Results: Transcriptome analysis of iAM-1 cells at different stages during one cycle of differentiation and subsequent dedifferentiation identified approximate to 13 000 transcripts, of which the dynamic changes in expression upon cardiomyogenic differentiation mostly opposed those during dedifferentiation. Among the genes whose expression increased during differentiation and decreased during dedifferentiation were many with known (lineage-specific) functions in cardiac muscle formation. Filtering for cardiac-enriched low-abundance transcripts, identified multiple genes with an uncharacterized role during cardio(myo)genesis including Sbk2 (SH3 domain binding kinase family member 2). Sbk2 encodes an evolutionarily conserved putative serine/threonine protein kinase, whose expression is strongly up- and downregulated during iAM-1 cell differentiation and dedifferentiation, respectively. In neonatal and adult rats, the protein is muscle-specific, highly atrium-enriched, and localized around the A-band of cardiac sarcomeres. Knockdown of Sbk2 expression caused loss of sarcomeric organization in NRAMs, iAMs and their human counterparts, consistent with a decrease in sarcomeric gene expression as evinced by transcriptome and proteome analyses. Interestingly, co-immunoprecipitation using Sbk2 as bait identified possible interaction partners with diverse cellular functions (translation, intracellular trafficking, cytoskeletal organization, chromatin modification, sarcomere formation). Conclusions: iAM-1 cells are a relevant and suitable model to identify (lowly expressed) genes with a hitherto unidentified role in cardiomyocyte differentiation as exemplified by Sbk2: a regulator of atrial sarcomerogenesis. Show less
Ponzio, R.; Yusuf, N.; Larik, J.E.; Arjomand, B.; Siddiqui, M.; Zhang, J.; Durch, W. 2022
Fears of rising conflict, new COVID-19 variants, irreversible climate change, and eroding collaboration in the global economy threaten to undermine the 2030 Agenda for Sustainable Development and... Show moreFears of rising conflict, new COVID-19 variants, irreversible climate change, and eroding collaboration in the global economy threaten to undermine the 2030 Agenda for Sustainable Development and other efforts to advance human progress. Yet, a once-in-a-generation opportunity to review and dramatically improve global tools for managing such enormous challenges, a Summit of the Future, is under serious consideration for September 2023 by the United Nations’ 193 Member States. Informed by research and policy dialogues—initially undertaken for the Albright-Gambari Commission and its follow-through, and most recently to help flesh out key proposals in the Secretary-General’s seminal report, Our Common Agenda—this report’s twenty main recommendations are intended to encourage more ambitious, forward-looking thinking and deliberation on global governance renewal and innovation in the run-up to next year’s Summit. Show less
Het onderzoek beschreven in dit proefschrift is gericht op de identificatie en karakterisering van regulatoren en/of effectoren van TGF-β-signalering en TGF-β-geïnduceerde EMT in pancreas-, long-... Show moreHet onderzoek beschreven in dit proefschrift is gericht op de identificatie en karakterisering van regulatoren en/of effectoren van TGF-β-signalering en TGF-β-geïnduceerde EMT in pancreas-, long- en borstkankertypes. Deze nieuw geïdentificeerde componenten en mechanismen kunnen worden onderzocht voor de ontwikkeling van geneesmiddelen voor kankertherapie. Show less
AimsSoil biotic communities can strongly impact plant performance. So far, most studies on plant-soil-interactions have estimated the effect of the soil microbial community on plant mass after a... Show moreAimsSoil biotic communities can strongly impact plant performance. So far, most studies on plant-soil-interactions have estimated the effect of the soil microbial community on plant mass after a fixed duration of plant growth. However, these interactions may change over time and several studies have argued that plant-soil interactions are more important for young seedlings than for older plants. In this paper we ask the question: how long-lasting the effect of the soil microbial community on plant growth is. This is important as the growth rate of a plant is not only determined by the growing conditions but also by the size of the plant itself. Therefore, plant with a reduced growth rate early in life, due to negative effects of the soil microbial community, may increase less in biomass for a much longer period even though the relative growth rates do not differ any longer.MethodsWe examined the plant growth rates at three stages: early growth (0-21 days), mid growth (22 to 42 days) and late growth (43 to 63 days). We performed two growth experiments with Jacobaea vulgaris lasting 49 and 63 days. Plants were grown in sterilized soil or in sterilized soil inoculated with natural dune soil. In a third experiment, we examined the effect of the timing of soil inoculation prior to planting on the (relative-) growth rate of J. vulgaris plants with four different timing treatments.Important findingsIn all experiments, differences in biomass of plants grown in sterilized soil and inoculated soil (live soil) increased throughout the experiment. Interestingly, linear regression models with ln transformed dry weight against time for younger plants and for older plants in sterilized soil and live soil, respectively, showed that the relative growth rate of plants in the sterilized soil was only significantly higher than that of plants in the live soil in the first two to three weeks. After that period there was no longer a negative effect of the live soil on the relative growth rate of plants. In the third experiment, plant biomass decreased with increasing time between inoculation and planting. Overall, our results show that plants of J. vulgaris grew less well in live soil than in sterilized soil. The negative effects of soil inoculation on plant mass appeared to extend over the whole growth period but arise from the negative effects on relative growth rates that occurred in the first weeks after planting when plants have only less than 5% of the mass they obtained after 42 days. Our study highlights the importance of examining relative growth rates rather than final biomass to estimate the effects of soil microbial communities on plants. Show less
Zhang, J.; Zhang, Z.J.; Holst, S.; Bloechl, C.; Madunic, K.; Wuhrer, M.; ... ; Zhang, T. 2022
Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and high mortality. Transforming growth factor-beta (TGF-beta) plays a key role in PDAC tumor progression, which is often... Show morePancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and high mortality. Transforming growth factor-beta (TGF-beta) plays a key role in PDAC tumor progression, which is often associated with aberrant glycosylation. However, how PDAC cells respond to TGF-beta and the role of glycosylation therein is not well known. Here, we investigated the TGF-beta-mediated response and glycosylation changes in the PaTu-8955S (PaTu-S) cell line deficient in SMA-related and MAD-related protein 4 (SMAD4), a signal transducer of the TGF-beta signaling. PaTu-S cells responded to TGF-beta by upregulating SMAD2 phosphorylation and target gene expression. We found that TGF-beta induced expression of the mesenchymal marker N-cadherin but did not significantly affect epithelial marker E-cadherin expression. We also examined differences in N-glycans, O-glycans, and glycosphingolipid-linked glycans in PaTu-S cells upon TGF-beta stimulation. TGF-beta treatment primarily induced N-glycome aberrations involving elevated levels of branching, core fucosylation, and sialylation in PaTu-S cells, in agreement with TGF-beta-induced changes in the expression of glycosylation-associated genes. In addition, we observed differences in O glycosylation and glycosphingolipid glycosylation profiles after TGF-beta treatment, including lower levels of sialylated Tn antigen and neoexpression of globosides. Furthermore, the expression of transcription factor sex-determining region Y-related high-mobility group box 4 was upregulated upon TGF-beta stimulation, and its depletion blocked TGF-beta-induced N-glycomic changes. Thus, TGF-beta-induced N-glycosylation changes can occur in a sex-determining region Y-related high-mobility group box 4-dependent and SMAD4-independent manner in the pancreatic PaTu-S cancer cell line. Our results open up avenues to study the relevance of glycosylation in TGF-beta signaling in SMAD4-inactivated PDAC. Show less
Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models... Show moreEmerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals. Show less
