The research aims to explore the evolutionary adaptability of enzymes and the impact of temperature on protein evolution pathways, using M. tuberculosis β-lactamase BlaC as the object of study.... Show moreThe research aims to explore the evolutionary adaptability of enzymes and the impact of temperature on protein evolution pathways, using M. tuberculosis β-lactamase BlaC as the object of study. Enzymes inherently embody a delicate balance between activity and stability, and the acquisition of new enzymatic functions is often accompanied by trade-offs, such as decreased stability or reduction of the original activity. Probing evolutionary adaptability of BlaC with laboratory evolution in combination with structural characterization can provide information about the mechanisms of rapid adaptations observed for β-lactamases in the clinic. The role of temperature as a conventional selection pressure in such evolutionary adaptation is unclear. The cooperative nature of enzyme unfolding over a narrow temperature trajectory raises the question whether evolution at temperatures well below the melting point is influenced by temperature. The approach used in this work to answer these questions is by simulating evolution under different selection pressures and characterize the variant enzymes in terms of activity, structure, dynamics and melting temperature. The research makes clear how enzyme kinetics and dynamics vary with different selection pressures and maps the evolutionary path that enzymes may take. The underlying structural mechanisms are established to provide a rationale for the observed effects. Show less
Herein, we investigated to which extent metallic nanoparticles (MNPs) affect the trophic transfer of other coexisting MNPs from lettuce to terrestrial snails and the associated tissue-specific... Show moreHerein, we investigated to which extent metallic nanoparticles (MNPs) affect the trophic transfer of other coexisting MNPs from lettuce to terrestrial snails and the associated tissue-specific distribution using toxicokinetic (TK) modeling and single-particle inductively coupled plasma mass spectrometry. During a period of 22 days, snails were fed with lettuce leaves that were root exposed to AgNO3 (0.05 mg/L), AgNPs (0.75 mg/L), TiO2NPs (200 mg/L), and a mixture of AgNPs and TiO2NPs (equivalent doses as for single NPs). The uptake rate constants (ku) were 0.08 and 0.11 kg leaves/kg snail/d for Ag and 1.63 and 1.79 kg leaves/kg snail/d for Ti in snails fed with NPs single- and mixture-exposed lettuce, respectively. The elimination rate constants (ke) of Ag in snails exposed to single AgNPs and mixed AgNPs were comparable to the corresponding ku, while the ke for Ti were lower than the corresponding ku. As a result, single TiO2NP treatments as well as exposure to mixtures containing TiO2NPs induced significant biomagnification from lettuce to snails with kinetic trophic transfer factors (TTFk) of 7.99 and 6.46. The TTFk of Ag in the single AgNPs treatment (1.15 kg leaves/kg snail) was significantly greater than the TTFk in the mixture treatment (0.85 kg leaves/kg snail), while the fraction of Ag remaining in the body of snails after AgNPs exposure (36%) was lower than the Ag fraction remaining after mixture exposure (50%). These results indicated that the presence of TiO2NPs inhibited the trophic transfer of AgNPs from lettuce to snails but enhanced the retention of AgNPs in snails. Biomagnification of AgNPs from lettuce to snails was observed in an AgNPs single treatment using AgNPs number as the dose metric, which was reflected by the particle number-based TTFs of AgNPs in snails (1.67, i.e., higher than 1). The size distribution of AgNPs was shifted across the lettuce-snail food chain. By making use of particle-specific measurements and fitting TK processes, this research provides important implications for potential risks associated with the trophic transfer of MNP mixtures. Show less
Sun, J.; Chikunova, A.; Boyle, A.L.; Voskamp, P.; Timmer, M.; Ubbink, M. 2023
During infection, Salmonella hijacks essential host signaling pathways. These molecular manipulations disrupt cellular integrity and may induce oncogenic transformation. Systemic S. Typhi... Show moreDuring infection, Salmonella hijacks essential host signaling pathways. These molecular manipulations disrupt cellular integrity and may induce oncogenic transformation. Systemic S. Typhi infections are linked to gallbladder cancer, whereas severe non-typhoidal Salmonella (NTS) infections are associated with colon cancer (CC). These diagnosed infections, however, represent only a small fraction of all NTS infections as many infections are mild and go unnoticed. To assess the overall impact of NTS infections, we performed a retrospective serological study on NTS exposure in patients with CC. The magnitude of exposure to NTS, as measured by serum antibody titer, is significantly positively associated with CC. Repetitively infecting mice with low NTS exposure showed similar accelerated tumor growth to that observed after high NTS exposure. At the cellular level, NTS preferably infects (pre-)transformed cells, and each infection round exponentially increases the rate of transformed cells. Thus, repetitive exposure to NTS associates with CC risk and accelerates tumor growth. Show less
Ever since the seven so-called earliest Chinese Christian manuscripts were removed from Dunhuang Cave 17 in 1900 and published by the first generation of scholars, they were quickly recognized... Show moreEver since the seven so-called earliest Chinese Christian manuscripts were removed from Dunhuang Cave 17 in 1900 and published by the first generation of scholars, they were quickly recognized as sources used by the Tang church, an offshoot of the Church of the East that entered China in 635 and allegedly disappeared after 845. This empirical, technical and philological work, however, finds: The putative earliest manuscripts made in the 640s, The Messiah Sutra and On One God, might be the latest sources that were created between 800-1010s. The only two dated sources, Kojima Manuscripts A and B, are modern forgeries. Only two manuscripts, Mysterious Bliss Sutra and Sutra of Origins of Daqin Jingjiao, are actual Tang documents that may be made between 745 and 787. Manuscript P.3847 is the work of post-Tang Christians. All the findings, as a whole, give us food for thought, encouraging us to rethink the traditional historiography of Christianity in China before 1200. It compels us to draw a picture of a local Dunhuang Christian community. It also prompts us to alter our current thinking about the institution known as the Tang church. Moreover, it challenges the present consensus that Christianity was extinguished after 845. Show less
O'Donnell, M.; Nelson, L.D.; Ackermann, E.; Aczel, B.; Akhtar, A.; Aldrovandi, S.; ... ; Zrubka, M. 2018
Dijksterhuis and van Knippenberg (1998) reported that participants primed with a category associated with intelligence (“professor”) subsequently performed 13% better on a trivia test than... Show moreDijksterhuis and van Knippenberg (1998) reported that participants primed with a category associated with intelligence (“professor”) subsequently performed 13% better on a trivia test than participants primed with a category associated with a lack of intelligence (“soccer hooligans”). In two unpublished replications of this study designed to verify the appropriate testing procedures, Dijksterhuis, van Knippenberg, and Holland observed a smaller difference between conditions (2%–3%) as well as a gender difference: Men showed the effect (9.3% and 7.6%), but women did not (0.3% and −0.3%). The procedure used in those replications served as the basis for this multilab Registered Replication Report. A total of 40 laboratories collected data for this project, and 23 of these laboratories met all inclusion criteria. Here we report the meta-analytic results for those 23 direct replications (total N = 4,493), which tested whether performance on a 30-item general-knowledge trivia task differed between these two priming conditions (results of supplementary analyses of the data from all 40 labs, N = 6,454, are also reported). We observed no overall difference in trivia performance between participants primed with the “professor” category and those primed with the “hooligan” category (0.14%) and no moderation by gender. Show less
Worldwide, cervix carcinoma is among the most dangerous cancer types, and novel therapies are under development. Cancer treatments are often hampered because of lack of specificity. The chicken... Show moreWorldwide, cervix carcinoma is among the most dangerous cancer types, and novel therapies are under development. Cancer treatments are often hampered because of lack of specificity. The chicken anemia virus-derived apoptin induces apoptosis selectively in tumor cells and leaves normal cells unharmed. Here, we have carried out in-vitro and in-vivo studies on the cytotoxic effect of apoptin in a cervix carcinoma model. Apoptin was fused to the protein transduction domain 4 (PTD4), enabling delivery of the fusion protein across cellular membranes. PTD4-apoptin protein is located in the nuclei of human cervical carcinoma HeLa cells and in the cytoplasm of normal cells L02. By MTT and flow cytometry analysis, we have proven that PTD4-apoptin protein induced apoptosis in the cervical carcinoma cells. PTD4-apoptin enhanced the level of active executioner caspase-3. Neither caspase-3 activation nor apoptin-induced accumulation of the mitochondrial outer-membrane protein Mfn-2 was affected by ectopic Bcl-2 expression. In contrast, apoptin-mediated AKT activation was inhibited by Bcl-2. In vivo, cervix carcinoma xenografts were treated for 7 days with PTD4-apoptin protein. The PTD4-apoptin treatment induced a decrease in the cervix carcinoma, whereas the PTD4-GFP protein-treated controls expanded significantly. TUNEL analysis showed that PTD4-apoptin protein induced apoptosis in cervix carcinoma cells, in contrast to the control PTD-GFP-treated ones. Our results indicate that apoptin is a potential anticancer agent for treating cervix carcinoma. Show less
The central theme of this dissertation is the investigation of the images of China in Europe in the seventeenth century through the works of China made by Johan Nieuhof on the visit of the first... Show moreThe central theme of this dissertation is the investigation of the images of China in Europe in the seventeenth century through the works of China made by Johan Nieuhof on the visit of the first Dutch embassy to China in 1655__57, and of the reproductions made on the basis of his sketches. Involving mainly the drawings in the Paris manuscript, the engravings in the first Dutch edition in 1665, and later works of chinoiserie inspired by the engravings, my analysis concentrates on the issues including what kinds of images of China were represented by Nieuhof, and how to interpret the __na het leven__ claim of the drawings and the engravings in the context of Dutch pictorial conventions of the seventeenth century. The main contribution of this dissertation is to shed light on the studies of images of China presented to European audiences, the illustrations of Dutch travelogue and the __na het leven__ images made by Dutch artists in the seventeenth century. Meanwhile, the study of the __na het leven__ quality of the drawings and illustrations reveals a more complicated relationship between Nieuhof__s images of China and chinoiserie. Show less
