SARS-CoV-2 was shown to infect and persist in the human brain cells up to 230 days, highlighting the need to treat the brain viral load. The CNS disposition of antiCOVID-19 drugs: Remdesivir,... Show moreSARS-CoV-2 was shown to infect and persist in the human brain cells up to 230 days, highlighting the need to treat the brain viral load. The CNS disposition of antiCOVID-19 drugs: Remdesivir, Molnupiravir, and Nirmatrelvir, remains, however, unexplored. Here, we assessed the human brain pharmacokinetic profile (PK) against the EC90 values of antiCOVID-19 drugs to predict drugs with favorable brain PK against the delta and omicron variants. We also evaluated the intracellular PK of GS443902 and EIDD2061, the active metabolites of Remdesivir and Molnupiravir. Towards this, we applied LeiCNS-PK3.0, the physiologically based pharmacokinetic framework with demonstrated adequate predictions of human CNS PK. Under the recommended dosing regimens, the predicted brain extracellular fluid PK of only Nirmatrelvir was above the variants' EC90. The intracellular levels of GS443902 and EIDD2061 were below the intracellular EC90. Summarizing, our model recommends Nirmatrelvir as the promising candidate for (pre)clinical studies investigating the CNS efficacy of antiCOVID-19 drugs. Show less
We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent)... Show moreWe assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations. Show less
Mroczkowski, T.; Donahue, M.; Marrewijk, J. van; Clarke, T.E.; Hoffer, A.; Intema, H.T.; ... ; Voit, M. 2022
The goal of personalized medicine is to develop a therapy using the right drug, at the right dose, at the right time, in the right patient. Developing a novel, effective strategy for... Show moreThe goal of personalized medicine is to develop a therapy using the right drug, at the right dose, at the right time, in the right patient. Developing a novel, effective strategy for diagnosing disease in individual patients can lead to a more effective personalized approach to disease management and prevention. Traditional Chinese medicine (TCM)-based concepts, including diagnostic concepts and herbal medicine intervention, can contribute extremely valuable information regarding personalized medicine. Measuring ultra-weak photon emission (UPE) is a non-invasive method for recording the physiological state in living organisms. Delayed luminescence (DL), which is the long-term emission of photons from various materials following excitation with light, has been proposed for use in studying Chinese medicinal herbs. The studies described in this thesis were performed to develop personalized approaches to health monitoring using UPE and DL methods in combination with TCM-based concepts. The results reported in this thesis indicate both UPE and DL have high potential for studying the concepts of medicine at the systems levels, and can be used to develop future research strategies guided by TCM‒based concepts. UPE and DL will likely provide valuable new insights into personalized medicine. Show less
He, M.; Wijk, E.P.A. van; Wietmarschen, H.A. van; Wang, M.; Sun, M.; Koval, V.V.; ... ; Greef, J. van der 2017
The increasing prevalence of rheumatoid arthritis has driven the development of new approaches and technologies for investigating the pathophysiology of this devastating, chronic disease. From the... Show moreThe increasing prevalence of rheumatoid arthritis has driven the development of new approaches and technologies for investigating the pathophysiology of this devastating, chronic disease. From the perspective of systems biology, combining comprehensive personal data such as metabolomics profiling with ultra-weak photon emission (UPE) data may provide key information regarding the complex pathophysiology underlying rheumatoid arthritis. In this article, we integrated UPE with metabolomics-based technologies in order to investigate collagen-induced arthritis, a mouse model of rheumatoid arthritis, at the systems level, and we investigated the biological underpinnings of the complex dataset. Using correlation networks, we found that elevated inflammatory and ROS-mediated plasma metabolites are strongly correlated with a systematic reduction in amine metabolites, which is linked to muscle wasting in rheumatoid arthritis. We also found that increased UPE intensity is strongly linked to metabolic processes (with correlation co-efficiency |r| value >0.7), which may be associated with lipid oxidation that related to inflammatory and/or ROS-mediated processes. Together, these results indicate that UPE is correlated with metabolomics and may serve as a valuable tool for diagnosing chronic disease by integrating inflammatory signals at the systems level. Our correlation network analysis provides important and valuable information regarding the disease process from a system-wide perspective. Show less
Sun, M.; Wijk, E.P.A. van; Koval, V.V.; Wijk, R. van; He, M.; Wang, M.; ... ; Greef, J. van der 2017
To present the possibilities pertaining to linking ultra-weak photon emission (UPE) with Chinese medicine-based diagnostics principles, we conducted a review of Chinese literature regarding UPE... Show moreTo present the possibilities pertaining to linking ultra-weak photon emission (UPE) with Chinese medicine-based diagnostics principles, we conducted a review of Chinese literature regarding UPE with respect to a systems view of diagnostics. Data were summarized from human clinical studies and animal models published from 1979 through 1998. The research fields can be categorized as follows: (1) human physiological states measured using UPE; (2) characteristics of human UPE in relation to various pathological states; and (3) the relationship between diagnosis (e.g., Chinese syndromes) and the dynamics of UPE in animal models. We conclude that UPE has clear potential in terms of understanding the systems view on health and disease as described using Chinese medicine-based diagnostics, particularly from a biochemistry-based regulatory perspective. Linking UPE with metabolomics can further bridge biochemistry-based Western diagnostics with the phenomenology-based Chinese diagnostics, thus opening new avenues for studying systems diagnostics in the early stage of disease, for prevention-based strategies, as well as for systems-based intervention in chronic disease. Show less
Sun, M.; Li, L; Wang, M.; Wijk, E.P.A. van; He, M.; Wijk, R. van; ... ; Wei, S. 2016
To improve the quality control of herbal drugs, there has been a major shift from evaluating individual chemicals to evaluating multiple-constituent chemicals, given the multi-pharmacology nature... Show moreTo improve the quality control of herbal drugs, there has been a major shift from evaluating individual chemicals to evaluating multiple-constituent chemicals, given the multi-pharmacology nature of herbal drugs. Therefore, rapid, systematic assays are needed in order to assess the quality of medicinal herbs using a comprehensive, integrated approach. Light-induced delayed luminescence (DL) is used to measure decaying long-term ultra-weak photon emissions following excitation with light. DL is considered to be a sensitive indicator for characterizing the properties of biological systems and herbal medicines with various therapeutic properties. The aim of this study was to examine the feasibility of using DL as a novel quality-assessment tool using rhubarb material as a model system, and to establish the correlation between DL parameters and the chemical constituents of rhubarb. Raw roots and rhizomes were collected from rhubarb (Rheum palmatum L.) at various elevations in western China. HPLC analysis was used to identify fourteen bioactive constituents. Five DL parameters were calculated from the DL decay curves of the rhubarb samples. Statistical tools, including principal component analysis, were used to classify the rhubarb samples using data obtained using two different assays. Finally, Spearman's correlation coefficient was calculated to quantify the correlation between the bioactive compounds and corresponding DL parameters. We found that both the chemical analysis and DL measurements reflect variations in the quality of rhubarb due to environment factor. The DL parameters were correlated significantly with the bioactive chemical constituents. Our results indicate that DL is a promising tool for evaluating multiple constituents and for assessing the therapeutic properties of herbal medicines. Thus, DL may be used as part of a comprehensive system for assessing the quality and/or therapeutic properties of herbal medicines. Show less
