Freshwater biodiversity has been threatened by eutrophication due to excessive nutrients in the environment. Releasing the freshwater species from such pressures requires efforts from industry and... Show moreFreshwater biodiversity has been threatened by eutrophication due to excessive nutrients in the environment. Releasing the freshwater species from such pressures requires efforts from industry and manufacturers to avoid emissions to vulnerable and high-risk regions. The first step is to know which nutrient influences where and the effects thereof on species loss. These impacts can be assessed by methods of life cycle impact assessment (LCIA). This thesis contributes to such knowledge by improving the LCIA method, for instance, by developing more regionalized and comprehensive indicators as well as adding the consideration of both phosphorus (P) and nitrogen (N) and which of these two nutrients is limiting. Show less
Inefficient global nutrient (i.e., phosphorus (P) and nitrogen (N)) management leads to an increase in nutrient delivery to freshwater and coastal ecosystems and induces eutrophication in these... Show moreInefficient global nutrient (i.e., phosphorus (P) and nitrogen (N)) management leads to an increase in nutrient delivery to freshwater and coastal ecosystems and induces eutrophication in these aquatic environments. This process threatens the various species inhabiting these ecosystems. In this study, we developed regionalized characterization factors (CFs) for freshwater eutrophication at 0.5 × 0.5-degree resolution, considering different fates for direct emissions to freshwater, diffuse emissions, and increased erosion due to agricultural land use. The CFs were provided for global and regional species loss of freshwater fish. CFs for global species loss were quantified by integrating global extinction probabilities. Results showed that the CFs for P and N impacts on freshwater fish are higher in densely populated regions that encompass either large lakes or the headwaters of large rivers. Focusing on nutrient-limited areas increases country-level CFs in 51.9 % of the countries for P and 49.5 % of the countries for N compared to not considering nutrient limitation. This study highlights the relevance of considering freshwater eutrophication impacts via both P and N emissions and identifying the limiting nutrient when performing life cycle impact assessments. Show less
Exposed to the natural light-dark cycle, living beings show robust 24 h rhythms in physiology and behavior. Interestingly, even in the absence of a light-dark cycle, for example in constant... Show moreExposed to the natural light-dark cycle, living beings show robust 24 h rhythms in physiology and behavior. Interestingly, even in the absence of a light-dark cycle, for example in constant conditions, such as under the constant darkness or the constant light, living beings maintain a robust rhythm of which the endogenous period (named free running period, FRP) is close to 24 h. The endogenous rhythms are regulated by a master clock located in the suprachiasmatic nucleus (SCN) of mammals, where the SCN neurons show heterogeneity in the sensitivity to the light. In this article, we examined how this heterogeneity influences the FRP under constant light. Using a Poincare model for the SCN network it is shown that the FRP increases with the increase of the degree of heterogeneity in the sensitivity of neuronal subpopulations to light. Moreover, the presence of a critical value where the periods of the subpopulation diverge, presents a mechanism dictating how some animals remain rhythmic under constant light conditions, while others lose their rhythms completely. Our findings help to understand how the neuronal heterogeneity to light sensitivity in the SCN influences the circadian behavior of the animal. (C) 2022 Elsevier B.V. All rights reserved. Show less
Papaver species P. setigerum, P. rhoeas, and P. somniferum accumulates different levels of morphine and noscapine. Here, the authors report the improved genome assembly of P. somniferum and de novo... Show morePapaver species P. setigerum, P. rhoeas, and P. somniferum accumulates different levels of morphine and noscapine. Here, the authors report the improved genome assembly of P. somniferum and de novo assembly of the other two species, and reveal the evolution of the benzylisoquinoline alkaloids biosynthetic pathway.For millions of years, plants evolve plenty of structurally diverse secondary metabolites (SM) to support their sessile lifestyles through continuous biochemical pathway innovation. While new genes commonly drive the evolution of plant SM pathway, how a full biosynthetic pathway evolves remains poorly understood. The evolution of pathway involves recruiting new genes along the reaction cascade forwardly, backwardly, or in a patchwork manner. With three chromosome-scale Papaver genome assemblies, we here reveal whole-genome duplications (WGDs) apparently accelerate chromosomal rearrangements with a nonrandom distribution towards SM optimization. A burst of structural variants involving fusions, translocations and duplications within 7.7 million years have assembled nine genes into the benzylisoquinoline alkaloids gene cluster, following a punctuated patchwork model. Biosynthetic gene copies and their total expression matter to morphinan production. Our results demonstrate how new genes have been recruited from a WGD-induced repertoire of unregulated enzymes with promiscuous reactivities to innovate efficient metabolic pathways with spatiotemporal constraint. Show less
A master clock located in the suprachiasmatic nucleus (SCN) regulates the circadian rhythm of physiological and behavioral activities in mammals. The SCN has two main functions in the regulation:... Show moreA master clock located in the suprachiasmatic nucleus (SCN) regulates the circadian rhythm of physiological and behavioral activities in mammals. The SCN has two main functions in the regulation: an endogenous clock produces the endogenous rhythmic signal in body rhythms, and a calibrator synchronizes the body rhythms to the external light-dark cycle. These two functions have been determined to depend on either the dynamic behaviors of individual neurons or the whole SCN neuronal network. In this review, we first introduce possible network structures for the SCN, as revealed by time series analysis from real experimental data. It was found that the SCN network is heterogeneous and sparse, that is, the average shortest path length is very short, some nodes are hubs with large node degrees but most nodes have small node degrees, and the average node degree of the network is small. Secondly, the effects of the SCN network structure on the SCN function are reviewed based on mathematical models of the SCN network. It was found that robust rhythms with large amplitudes, a high synchronization between SCN neurons and a large entrainment ability exists mainly in small-world and scale-free type networks, but not other types. We conclude that the SCN most probably is an efficient small-world type or scale-free type network, which drives SCN function. Show less
Whiteway, M.R.; Biderman, D.; Friedman, Y.; Dipoppa, M.; Buchanan, E.K.; Wu, A.; ... ; Paninski, L. 2021
In this thesis an activity-based probe was discovered that could visualize the activity of PLAATs. With an optimized gel-based ABPP assay in hand, screening of a compound library led to the... Show moreIn this thesis an activity-based probe was discovered that could visualize the activity of PLAATs. With an optimized gel-based ABPP assay in hand, screening of a compound library led to the discovery of alpha-ketoamides as a hit for PLAAT3. Through extensive structural modifications of the hit, LEI110 was identified as the most potent inhibitor (Ki = 20nM) for PLAAT3. LEI110 reduced cellular arachidonic acid levels in PLAAT3 overexpressing U2OS cells and oleic acid-induced steatosis in human HepG2 cells. Gel-based ABPP and chemical proteomics showed that LEI110 is a selective pan-inhibitor of the Hrasls-family of thiol hydrolases (i.e. PLAAT2, PLAAT3 and PLAAT5). LEI110 could be an excellent starting point for the structure-based drug development of novel molecular therapies for obesity and/or common cold. In addition, a competitive, gel-based ABPP method for PLA2G4E using TAMRA-FP was successfully developed and applied to screen a focused library of lipase inhibitors. This resulted in the discovery of two clusters of inhibitors with different scaffolds. Optimization of the potency and selectivity of the inhibitors is required to the study of the biological role of PLA2G4E in an acute and dynamic setting with these novel tools. Together these novel chemical tools and methods will allow for a better understanding of the biosynthesis of the NAPEs and to study their biological role. Show less
The main clock in mammals, located in the suprachiasmatic nucleus (SCN) of hypothalamus, not only regulates the daily rhythms in physiological and behavioral activities, but also plays a key role... Show moreThe main clock in mammals, located in the suprachiasmatic nucleus (SCN) of hypothalamus, not only regulates the daily rhythms in physiological and behavioral activities, but also plays a key role as one of the control nodes in the brain regulating behavioral activity. As such, it induces scale-invariance in the temporal patterns of behavioral activity and of multi-unit neural activity of the SCN network. In particular, the scale-invariant patterns maintain across multiple time scales from 3 minutes to 10 hours, characterized by a scaling exponent around 1. Thus far, no study found the origin of the scale-invariance of the SCN network. Using the method of correlation-dependent balance estimation of diffusion entropy (cBEDE), we found that scale-invariance also exists in the individual neurons of the SCN, and the scale invariance properties are significantly increased when the neurons are coupled in a network of neurons. Improved scale invariance in the single neurons is, therefore, imposed by the emergent network properties of the SCN network. Our findings show that the scale-invariance of the SCN can already be found at the level of the individual neurons and that the application of a scale invariance measure, such as cBEDE, can help in determining the network status of the SCN. Show less
Active co-delivery of tumor antigens (Ag) and alpha-galactosylceramide (alpha-GalCer), a potent agonist for invariant Natural Killer T (iNKT) cells, to cross-priming CD8 alpha(+) dendritic cells ... Show moreActive co-delivery of tumor antigens (Ag) and alpha-galactosylceramide (alpha-GalCer), a potent agonist for invariant Natural Killer T (iNKT) cells, to cross-priming CD8 alpha(+) dendritic cells (DCs) was previously shown to promote strong anti-tumor responses in mice. Here, we designed a nanoparticle-based vaccine able to target human CD141(+) (BDCA3(+)) DCs - the equivalent of murine CD8 alpha(+) DCs - and deliver both tumor Ag (Melan A) and alpha-GalCer. This nanovaccine was inoculated into humanized mice that mimic the human immune system (HIS) and possess functionaliNKT cells and CD8(+) T cells, called HIS-CD8/NKT mice. We found that multiple immunizations of HIS-CD8/NKT mice with the nanovaccine resulted in the activation and/or expansion of human CD141(+) DCs andiNKT cells and ultimately elicited a potent Melan-A-specific CD8(+) T cell response, as determined by tetramer staining and ELISpot assay. Single-cell proteomics further detailed the highly polyfunctional CD8(+) T cells induced by the nanovaccine and revealed their predictive potential for vaccine potency. This finding demonstrates for the first time the unique ability of humaniNKT cells to license cross-priming DCsin vivoand adds a new dimension to the current strategy of cancer vaccine development. Show less
Zhou, J.; Mock, E.D.; Al Ayed, K.; Di, X.; Kantae, V.; Burggraaff, L.; ... ; Stelt, M. van der 2020
The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines ... Show moreThe phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure–activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs. Show less
Zhou, J.; Mock, E.D.; Al, Ayed K.; Di, X.; Kantae, V.; Burggraaff, L.; ... ; Stelt, M. van der 2020
The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines ... Show moreThe phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified alpha-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure-activity relationships of the alpha-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs. Show less
In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear,... Show moreIn many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding. Show less
Angelantonio, E. di; Kaptoge, S.; Pennells, L.; Bacquer, D. de; Cooney, M.T.; Kavousi, M.; ... ; Kim 2019
Background To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk... Show moreBackground To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk models. Here, we report the derivation, validation, and illustration of the revised WHO cardiovascular disease risk prediction charts that have been adapted to the circumstances of 21 global regions.Methods In this model revision initiative, we derived 10-year risk prediction models for fatal and non-fatal cardiovascular disease (ie, myocardial infarction and stroke) using individual participant data from the Emerging Risk Factors Collaboration. Models included information on age, smoking status, systolic blood pressure, history of diabetes, and total cholesterol. For derivation, we included participants aged 40-80 years without a known baseline history of cardiovascular disease, who were followed up until the first myocardial infarction, fatal coronary heart disease, or stroke event. We recalibrated models using age-specific and sex-specific incidences and risk factor values available from 21 global regions. For external validation, we analysed individual participant data from studies distinct from those used in model derivation. We illustrated models by analysing data on a further 123 743 individuals from surveys in 79 countries collected with the WHO STEPwise Approach to Surveillance.Findings Our risk model derivation involved 376 177 individuals from 85 cohorts, and 19 333 incident cardiovascular events recorded during 10 years of follow-up. The derived risk prediction models discriminated well in external validation cohorts (19 cohorts, 1 096 061 individuals, 25 950 cardiovascular disease events), with Harrell's C indices ranging from 0.685 (95% CI 0 . 629-0 741) to 0.833 (0 . 783-0- 882). For a given risk factor profile, we found substantial variation across global regions in the estimated 10-year predicted risk. For example, estimated cardiovascular disease risk for a 60-year-old male smoker without diabetes and with systolic blood pressure of 140 mm Hg and total cholesterol of 5 mmol/L ranged from 11% in Andean Latin America to 30% in central Asia. When applied to data from 79 countries (mostly low-income and middle-income countries), the proportion of individuals aged 40-64 years estimated to be at greater than 20% risk ranged from less than 1% in Uganda to more than 16% in Egypt.Interpretation We have derived, calibrated, and validated new WHO risk prediction models to estimate cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd. Show less
