Micro- and nanoplastics are emerging concerns due to their environmental ubiquity and currently largely unknown ecological impacts. Leveraging on a recently developed method using europium-doped... Show moreMicro- and nanoplastics are emerging concerns due to their environmental ubiquity and currently largely unknown ecological impacts. Leveraging on a recently developed method using europium-doped polystyrene particles (PS-Eu), our present work aimed to accurately trace the uptake and transport of micro- and nanoplastics in aquatic plants and shed insights into the potential of different aquatic plants for trapping and removal of plastics from water environment. Seedlings of Vallisneria denseserrulata Makino (submerged plant), Iris tectorum Maxim (emergent plant), and Eichhornia crassipes Solms (floating plant) were exposed to 100 nm and 2 μm PS-Eu in freshwater (5 μg/mL) or sediments (5 μg/g) for 8 weeks. Fluorescence imaging clearly evidenced that PS-Eu mainly accumulated in the intercellular space and were transported from roots to leaves via the apoplastic path and vascular bundle. Mass spectrum analysis demonstrated that up to 6250 μg/g nanoplastics were trapped in aquatic plants (mainly in roots) with a bioconcentration factor of 306.5, depending on exposure routes and plant species. Owing to their excellent capture capability and high tolerance to plastic exposures, floating plants like E. crassipes are promising for immobilizing and removing fine plastics from the water environment. Show less
Shrine, N.; Izquierdo, A.G.; Chen, J.; Packer, R.; Hall, R.J.; Guyatt, A.L.; ... ; Qatar Genome Program Res QGPR 2023
Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date,... Show moreLung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by & GE;2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.Multi-ancestry genome-wide association analyses and systematic variant-to-gene mapping strategies implicate new genes and pathways influencing lung function and chronic obstructive pulmonary disease risk. Show less
Background: The endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and... Show moreBackground: The endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and provides direction towards more effective and less toxic adjuvant treatment strategies for women with endometrial cancer. Primary objective(s): The RAINBO program of clinical trials will investigate four molecular class-directed adjuvant treatment strategies following surgical resection to either increase cure rates through the addition of novel targeted therapies or safely reduce toxicity and improve quality of life through treatment de-escalation. Study hypothesis: Molecular-directed adjuvant treatment strategies will improve clinical outcomes and reduce toxicity of unwarranted therapies in women with endometrial cancer. The overarching and translational research RAINBO program will advance knowledge of predictive and prognostic (bio)markers that will improve prognostication and treatment allocation. Trial design: The RAINBO program is a platform of four international clinical trials and an overarching research program. The randomized phase III p53abn-RED trial for women with invasive stage I-III p53abn endometrial cancer compares adjuvant chemoradiation followed by olaparib for 2 years with adjuvant chemoradiation alone. The randomized phase III MMRd-GREEN trial for women with stage II (with lymphovascular space invasion (LVSI)) or stage III mismatch repair-deficient (MMRd) endometrial cancer compares adjuvant radiotherapy with concurrent and adjuvant durvalumab for 1 year to radiotherapy alone. The randomized phase III NSMP-ORANGE trial is a treatment de-escalation trial for women with estrogen receptor positive stage II (with LVSI) or stage III no specific molecular profile (NSMP) endometrial cancer comparing radiotherapy followed by progestin for 2 years to adjuvant chemoradiation. The POLEmut-BLUE trial is a phase II trial in which the safety of de-escalation of adjuvant therapy is investigated for women with stage I-III POLEmut endometrial cancer: no adjuvant therapy for lower-risk disease and no adjuvant therapy or radiotherapy alone for higher-risk disease. The overarching RAINBO program will combine data and tumor material of all participants to perform translational research and evaluate molecular class-based adjuvant therapy in terms of efficacy, toxicity, quality of life, and cost-utility. Major inclusion/exclusion criteria: Inclusion criteria include a histologically confirmed diagnosis of endometrial cancer treated by hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel lymph node biopsy, with no macroscopic residual disease after surgery and no distant metastases, and molecular classification according to the WHO 2020 algorithm. Primary endpoint(s): Recurrence-free survival at 3 years in the p53abn-RED, MMRd-GREEN, and NSMP-ORANGE trials and pelvic recurrence at 3 years in the POLEmut-BLUE trial. Sample size: The p53abn-RED trial will include 554 patients, the MMRd-GREEN trial 316, the NSMP-ORANGE trial 600, and the POLEmut-BLUE trial 145 (120 for lower-risk disease and approximately 25 for higher-risk disease). The overarching research program will pool the four sub-trials resulting in a total sample size of around 1600. Estimated dates for completing accrual and presenting results: The four clinical trials will have different completion dates; main results are expected from 2028. Show less
Lawrence, M.L.; Elhendawi, M.; Morlock, M.; Liu, W.; Liu, S.; Palakkan, A.; ... ; Davies, J.A. 2022
Advances in regenerative medicine have led to the construction of many types of organoids, which reproduce important aspects of endogenous organs but may be limited or disorganized in nature. While... Show moreAdvances in regenerative medicine have led to the construction of many types of organoids, which reproduce important aspects of endogenous organs but may be limited or disorganized in nature. While their usefulness for restoring function remains unclear, they have undoubted usefulness in research, diagnostics, and toxicology. In toxicology, there is an urgent need for better models for human kidneys. We used human iPS-cell (hiPSC)-derived renal organoids to identify HMOX1 as a useful marker of toxic stress via the oxidative stress pathway, and then constructed an HMOX1 reporter in hiPSCs. We used two forms of hiPSC-derived HMOX1-reporter renal organoids to probe their ability to detect nephrotoxicants in a panel of blind-coded compounds. Our results higI light the potential usefulness, and some limitations, of HMOX1-reporter renal organoids as screening tools. The results may guide development of similar stress-reporting organoid assays for other stem-cell-derived organs and tissues. Show less
Xiao, X.; Elsayed, S.S.M.A.; Wu, C.; Heul, H.U. van der; Metsä-Ketelä, M.; Du, C.; ... ; Wezel, G.P. van 2020
Angucyclines are a structurally diverse class of actinobacterial natural products defined by their varied polycyclic ring systems, which display a wide range of biological activities. We recently... Show moreAngucyclines are a structurally diverse class of actinobacterial natural products defined by their varied polycyclic ring systems, which display a wide range of biological activities. We recently discovered lugdunomycin (1), a highly rearranged polyketide antibiotic derived from the angucycline backbone thatis synthesized via several yet unexplained enzymatic reactions. Here, we show via in vivo, in vitro, and structural analysis that the promiscuous reductase LugOII catalyzes both a C6 and an unprecedented C1 ketoreduction. This then sets the stage for the subsequent C-ring cleavage that is key to the rearranged scaffolds of 1. The 1.1 Å structures of LugOII in complex with either ligand 8-O-Methylrabelomycin (4) or 8-O-Methyltetrangomycin (5) and of apoenzyme were resolved, which revealed a canonical Rossman fold and a remarkable conformational change during substrate capture and release. Mutational analysis uncovered key residues for substrate access, position, and catalysis as well as specific determinants that control its dual functionality. The insights obtained in this work hold promise for the discovery and engineering of other promiscuous reductases that may be harnessed for the generationof novel biocatalysts for chemoenzymatic applications. Show less
Xiao, X.; Elsayed, S.S.M.A.; Wu, C.; Heul, H.U. van der; Metsä-Ketelä, M.; Du, C.; ... ; Wezel, G.P. van 2020
Objective To assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1 alpha/beta dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand... Show moreObjective To assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1 alpha/beta dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA).Methods Patients with >= 1 erosive and >= 3 tender and/or swollen hand joints were randomised to placebo or lutikizumab 200 mg subcutaneously every 2 weeks for 24 weeks. The primary endpoint was change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints. Continuous endpoints were assessed using analysis of covariance models, with treatment and country as main factors and baseline measurements as covariates.Results Of 132 randomised subjects, 1 received no study drug and 110 completed the study (placebo, 61/67 (91%); lutikizumab, 49/64 (77%)). AUSCAN pain was not different among subjects treated with lutikizumab versus placebo at week 16 (least squares mean difference, 1.5 (95% CI -1.9 to 5.0)). Other clinical and imaging endpoints were not different between lutikizumab and placebo. Lutikizumab significantly decreased serum high-sensitivity C reactive protein levels, IL-1 alpha and IL-1 beta levels, and blood neutrophils. Lutikizumab pharmacokinetics were consistent with phase I studies and not affected by antidrug antibodies. Injection site reactions and neutropaenia were more common in the lutikizumab group; discontinuations because of adverse events occurred more frequently with lutikizumab (4/64) versus placebo (1/67).Conclusion Despite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA compared with placebo. Show less
The hominin record from southern Asia for the early Late Pleistocene epoch is scarce. Well-dated and well-preserved fossils older than ∼45,000 years that can be unequivocally attributed to Homo... Show moreThe hominin record from southern Asia for the early Late Pleistocene epoch is scarce. Well-dated and well-preserved fossils older than ∼45,000 years that can be unequivocally attributed to Homo sapiens are lacking. Here we present evidence from the newly excavated Fuyan Cave in Daoxian (southern China). This site has provided 47 human teeth dated to more than 80,000 years old, and with an inferred maximum age of 120,000 years. The morphological and metric assessment of this sample supports its unequivocal assignment to H. sapiens. The Daoxian sample is more derived than any other anatomically modern humans, resembling middle-to-late Late Pleistocene specimens and even contemporary humans. Our study shows that fully modern morphologies were present in southern China 30,000-70,000 years earlier than in the Levant and Europe. Our data fill a chronological and geographical gap that is relevant for understanding when H. sapiens first appeared in southern Asia. The Daoxian teeth also support the hypothesis that during the same period, southern China was inhabited by more derived populations than central and northern China. This evidence is important for the study of dispersal routes of modern humans. Finally, our results are relevant to exploring the reasons for the relatively late entry of H. sapiens into Europe. Some studies have investigated how the competition with H. sapiens may have caused Neanderthals' extinction (see ref. 8 and references therein). Notably, although fully modern humans were already present in southern China at least as early as ∼80,000 years ago, there is no evidence that they entered Europe before ∼45,000 years ago. This could indicate that H. neanderthalensis was indeed an additional ecological barrier for modern humans, who could only enter Europe when the demise of Neanderthals had already started. Show less
Medema, M.H.; Kottmann, R.; Yilmaz, P.; Cummings, M.; Biggins, J.B.; Blin, K.; ... ; Zhang, C. 2015
The majority of the work presented in this thesis involves the design and synthesis of paramagnetic NMR probes, including lanthanoids caged probes and spin labels. An overview of the development of... Show moreThe majority of the work presented in this thesis involves the design and synthesis of paramagnetic NMR probes, including lanthanoids caged probes and spin labels. An overview of the development of different types of lanthanoids caged probes is given. Among all of the reported lanthanoid probes, the caged lanthanoid NMR probe version 5 (CLaNP-5) shows the largest paramagnetic effects due to the fact that it is tagged to proteins via two-point attachment and its free complex presents a single conformation. Although CLaNP-5 is successfully applied to study proteins and protein complexes, the net charge of Ln CLaNP-5 complex and the weak disulfide linker are the drawbacks. A new paramagnetic probe, CLaNP-7, was synthesized, for which the net charge of lanthanoids complexes was reduced to +1 by introducing p-nitrophenol. The __-tensor of CLaNP-7 is pH-dependent when a histidine residue is located close to the attachment site. It is proposed that the pH dependence is due to the fact that the histidine forms a hydrogen bond with a water that acts as the ninth ligand of the lanthanoid. In order to enhance the stability of the tag linkers, two approaches, thioether and bioorthogonal reactions, were investigated. The results showed that a new thio-reactive CLaNP-9 was successfully attached to protein and the reaction product was stable in the reductive conditions. Moreover, inhibitor-based paramagnetic probes were also synthesized and the co-crystal structures of protein with inhibitor-based probes were also presented. Show less
