Metabolomics and bioanalysis of terpenoid derived secondary metabolites:Analysis of Cannabis sativa L. metabolite production and prenylases for cannabinoid production

Cannabinoid research has gained a renenewed interest by both the public and scientist. Focus is mainly directed to the medicinal activities, as reported for various cannabinoid structures. This thesis focusses on prenyl-derived secondary metabolites with main focus on cannabinoids. Firstly the production patterns and production location were investigated for standardiozed cultivated medicinal C.sativa variants. Metabolic profiling discriminated variants during the complete cultivation. Moreover, the densities and plant distribution of three classes of trichoma were reported and analyzed for their cannabinoid profile. Next an alternative enzyme for, the major cannabinoid precursor, cannabigerolic acid production was investigated. By providing a new hypothesis for the prenylation mechanism, evidence is provided for activity improvement on important substrates for cannabinoid production. Last the potential of X.dendrohous to produce terpene derived compounds after recombinant engineering was proven. The reported results linked production levels to enzyme levels and indicated the potential of this yeast to elevated production levels. Observation made within these thesis support further analytical research performed on cannabinoids. Furthermore it provides the basis for recombinant cannabinoid production by providing screening techniques for cannabinoid profiling and insights into the mechanism of cannabinoid precursor production

The Syntax and Pragmatics of Language Contact: a case study of Andean Spanish

In this paper, I report the results of tests that I designed to show how Andean Spanish(AS) word order is affected by language contact with Quechua. In AS the object appears in preverbal position more frequently than in Standard Spanish(SS). The main syntactic properties of focus-fronting in SS are weak-crossover and long-distance movement. I constructed tests to check for these syntactic properties and the pragmatics of focus in AS and Quechua. The results show that AS and SS are syntactically identical, but that there is pragmatic transfer from Quechua into AS. The study has implications for language contact and syntax

Pectins from various sources inhibit galectin-3-related cardiac fibrosis

Purpose of the study: A major challenge in cardiology remains in finding a therapy for cardiac fibrosis. Inhibition of galectin-3 with pectins attenuates fibrosis in animal models of heart failure. The purpose of this study is to identify pectins with the strongest galectin-3 inhibitory capacity. We evaluated the in vitro inhibitory capacity, identified potent pectins, and tested if this potency could be validated in a mouse model of myocardial fibrosis. Methods: Various pectin fractions were screened in vitro. Modified rhubarb pectin (EMRP) was identified as the most potent inhibitor of galectin-3 and compared to the well-known modified citrus pectin (MCP). Our findings were validated in a mouse model of myocardial fibrosis, which was induced by angiotensin II (Ang II) infusion. Results: Ang II infusion was associated with a 4–5-fold increase in fibrosis signal in the tissue of the left ventricle, compared to the control group (0•22±0•10 to 1•08±0•53%; P < 0•001). After treatment with rhubarb pectin, fibrosis was reduced by 57% vs. Ang II alone while this reduction was 30% with the well-known MCP (P = NS, P < 0•05). Treatment was associated with a reduced cardiac inflammatory response and preserved cardiac function. Conclusion: The galectin-3 inhibitor natural rhubarb pectin has a superior inhibitory capacity over established pectins, substantially attenuates cardiac fibrosis, and preserves cardiac function in vivo. Bioactive pectins are natural sources of galectin-3 inhibitors and may be helpful in the prevention of heart failure or other diseases characterized by fibrosis. Funding: Dr. Meijers is supported by the Mandema-Stipendium of the Junior Scientific Masterclass 2020-10, University Medical Center Groningen and by the Netherlands Heart Foundation (Dekkerbeurs 2021)Dr. de Boer is supported by the Netherlands Heart Foundation (CVON SHE-PREDICTS-HF, grant 2017-21; CVON RED-CVD, grant 2017-11; CVON PREDICT2, grant 2018-30; and CVON DOUBLE DOSE, grant 2020B005), by a grant from the leDucq Foundation (Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN), and by a grant from the European Research Council (ERC CoG 818715, SECRETE-HF)

The High-Risk Plaque Initiative: Primary Prevention of Atherothrombotic Events in the Asymptomatic Population

The High-Risk Plaque (HRP) Initiative is a research and development effort to advance the understanding, recognition, and management of asymptomatic individuals at risk for a near-term atherothrombotic event such as myocardial infarction or stroke. Clinical studies using the newest technologies have been initiated, including the BioImage Study in which novel approaches are tested in a typical health plan population. Asymptomatic at-risk individuals were enrolled, including a survey-only group (n = 865), a group undergoing traditional risk factor scoring (n = 718), and a group in which all were assessed for both risk factors and subclinical atherosclerosis (n = 6104). The latter two groups underwent baseline examination in a dedicated mobile facility equipped with advanced imaging tools suitable for noninvasive screening for subclinical atherosclerosis (coronary artery calcium by computed tomography [CT], carotid and aortic disease by ultrasound, and ankle-brachial index). Selected participants were offered advanced imaging (contrast-enhanced CT, magnetic resonance imaging, and positron emission tomography/CT). Plasma, PAXgene RNA, and DNA samples were obtained for biomarker discovery studies. All individuals will be followed until 600 major atherothrombotic events have occurred in those undergoing imaging

Controls on the spatio-temporal patterns of induced seismicity in Groningen constrained by physics-based modelling with Ensemble-Smoother data assimilation

The induced seismicity in the Groningen gas field, The Netherlands, presents contrasted spatio-temporal patterns between the central area and the south west area. Understanding the origin of this contrast requires a thorough assessment of two factors: (1) the stress development on the Groningen faults and (2) the frictional response of the faults to induced stresses. Both factors have large uncertainties that must be honoured and then reduced with the observational constraints. Ensembles of induced stress realizations are built by varying the Poisson's ratio in a poro-elastic model incorporating the 3-D complexities of the geometries of the Groningen gas reservoir and its faults, and the historical pore pressure distribution. The a priori uncertainties in the frictional response are mapped by varying the parameters of a seismicity model based on rate-and-state friction. The uncertainties of each component of this complex physics-based model are honoured through an efficient data assimilation algorithm. By assimilating the seismicity data with an Ensemble-Smoother, the prior uncertainties of each model parameter are effectively reduced, and the posterior seismicity rate predictions are consistent with the observations. Our integrated workflow allows us to disentangle the contributions of the main two factors controlling the induced seismicity at Groningen, induced stress development and fault frictional response. Posterior distributions of the model parameters of each modelling component are contrasted between the central and south west area at Groningen. We find that, even after honouring the spatial heterogeneity in stress development across the Groningen gas field, the spatial variability of the observed induced seismicity rate still requires spatial heterogeneity in the fault frictional response. This work is enabled by the unprecedented deployment of an Ensemble-Smoother combined with physics-based modelling over a complex case of reservoir induced seismicity