Human populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE... Show moreHuman populations have been shaped by catastrophes that may have left long-lasting signatures in their genomes. One notable example is the second plague pandemic that entered Europe in ca. 1,347 CE and repeatedly returned for over 300 years, with typical village and town mortality estimated at 10%-40%.1 It is assumed that this high mortality affected the gene pools of these populations. First, local population crashes reduced genetic diversity. Second, a change in frequency is expected for sequence variants that may have affected survival or susceptibility to the etiologic agent (Yersinia pestis).2 Third, mass mortality might alter the local gene pools through its impact on subsequent migration patterns. We explored these factors using the Norwegian city of Trondheim as a model, by sequencing 54 genomes spanning three time periods: (1) prior to the plague striking Trondheim in 1,349 CE, (2) the 17th-19th century, and (3) the present. We find that the pandemic period shaped the gene pool by reducing long distance immigration, in particular from the British Isles, and inducing a bottleneck that reduced genetic diversity. Although we also observe an excess of large FST values at multiple loci in the genome, these are shaped by reference biases introduced by mapping our relatively low genome coverage degraded DNA to the reference genome. This implies that attempts to detect selection using ancient DNA (aDNA) datasets that vary by read length and depth of sequencing coverage may be particularly challenging until methods have been developed to account for the impact of differential reference bias on test statistics. Show less
Li, C.; Ma, J.; Groenewoud, A.; Ren, J.; Liu, S.; Snaar-Jagalska, B.E.; Dijke, P. ten 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
Li, R.; Napolitano, N.R.; Roy, N.; Tortora, C.; La Barbera, F.; Sonnenfeld, A.; ... ; Liu, S. 2022
Capillary zone electrophoresis-mass spectrometry (CE-MS) is a mature analytical tool for the efficient profiling of (highly) polar and ionizable compounds. However, the use of CE-MS in comparison... Show moreCapillary zone electrophoresis-mass spectrometry (CE-MS) is a mature analytical tool for the efficient profiling of (highly) polar and ionizable compounds. However, the use of CE-MS in comparison to other separation techniques remains underrepresented in metabolomics, as this analytical approach is still perceived as technically challenging and less reproducible, notably for migration time. The latter is key for a reliable comparison of metabolic profiles and for unknown biomarker identification that is complementary to high resolution MS/MS. In this work, we present the results of a Metabo-ring trial involving 16 CE-MS platforms among 13 different laboratories spanning two continents. The goal was to assess the reproducibility and identification capability of CE-MS by employing effective electrophoretic mobility (mu(eff)) as the key parameter in comparison to the relative migration time (RMT) approach. For this purpose, a representative cationic metabolite mixture in water, pretreated human plasma, and urine samples spiked with the same metabolite mixture were used and distributed for analysis by all laboratories. The mu(eff) was determined for all metabolites spiked into each sample. The background electrolyte (BGE) was prepared and employed by each participating lab following the same protocol. All other parameters (capillary, interface, injection volume, voltage ramp, temperature, capillary conditioning, and rinsing procedure, etc.) were left to the discretion of the contributing laboratories. The results revealed that the reproducibility of the mu(eff) for 20 out of the 21 model compounds was below 3.1% vs 10.9% for RMT, regardless of the huge heterogeneity in experimental conditions and platforms across the 13 laboratories. Overall, this Metabo-ring trial demonstrated that CE-MS is a viable and reproducible approach for metabolomics. Show less
Drouin, N.F.P.; Mever, M. van; Zhang, W.; Tobolkina, E.; Ferre, S.; Servais, A.C.; ... ; Ramautar, R. 2020
Capillary zone electrophoresis-mass spectrometry (CE-MS) is a mature analytical tool for the efficient profiling of (highly) polar and ionizable compounds. However, the use of CE-MS in comparison... Show moreCapillary zone electrophoresis-mass spectrometry (CE-MS) is a mature analytical tool for the efficient profiling of (highly) polar and ionizable compounds. However, the use of CE-MS in comparison to other separation techniques remains underrepresented in metabolomics, as this analytical approach is still perceived as technically challenging and less reproducible, notably for migration time. The latter is key for a reliable comparison of metabolic profiles and for unknown biomarker identification that is complementary to high resolution MS/MS. In this work, we present the results of a Metabo-ring trial involving 16 CE-MS platforms among 13 different laboratories spanning two continents. The goal was to assess the reproducibility and identification capability of CE-MS by employing effective electrophoretic mobility (mu(eff)) as the key parameter in comparison to the relative migration time (RMT) approach. For this purpose, a representative cationic metabolite mixture in water, pretreated human plasma, and urine samples spiked with the same metabolite mixture were used and distributed for analysis by all laboratories. The mu(eff) was determined for all metabolites spiked into each sample. The background electrolyte (BGE) was prepared and employed by each participating lab following the same protocol. All other parameters (capillary, interface, injection volume, voltage ramp, temperature, capillary conditioning, and rinsing procedure, etc.) were left to the discretion of the contributing laboratories. The results revealed that the reproducibility of the mu(eff) for 20 out of the 21 model compounds was below 3.1% vs 10.9% for RMT, regardless of the huge heterogeneity in experimental conditions and platforms across the 13 laboratories. Overall, this Metabo-ring trial demonstrated that CE-MS is a viable and reproducible approach for metabolomics. Show less
The Innovative Medicines Initiative Consortium RESOLUTE has started to develop tools and produce data sets to de-orphanize transporters in the solute carrier protein (SLC) superfamily, thereby... Show moreThe Innovative Medicines Initiative Consortium RESOLUTE has started to develop tools and produce data sets to de-orphanize transporters in the solute carrier protein (SLC) superfamily, thereby lowering the barrier for the scientific community to explore SLCs as an attractive drug target class Show less
In summary, this thesis focused on the understanding the underlying mechanisms driving TNBC metastatic progression. We established DUB activity profiling methods and identified UCHL1 as a candidate... Show moreIn summary, this thesis focused on the understanding the underlying mechanisms driving TNBC metastatic progression. We established DUB activity profiling methods and identified UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis. Importantly, we found UCHL1 activity inhibitor as a potential drug for TNBC therapy and developed UCHL1 activity-based probe. For vemurafenib-resistance melanoma, we provided insights that targeting TGFβ signaling may help to overcome drug resistant phenotype. Show less
Wang, N.; Huang, X.; Li, T.; Wang, M.; Yue, H.; Chen, C.; Liu, S. 2020
Therapies directed to specific molecular targets are still unmet for triple-negative breast cancer (TNBC) patients. Deubiquitinases (DUBs) are emerging drug targets. The identification of a highly... Show moreTherapies directed to specific molecular targets are still unmet for triple-negative breast cancer (TNBC) patients. Deubiquitinases (DUBs) are emerging drug targets. The identification of a highly active DUBs in TNBC may lead to novel therapies.\n biochemical methods. A specific inhibitor was synthesised and its biochemical and biological functions were assessed in a range of assays. Finally, we used patient sera samples to investigate clinical correlations.\nTwo DUB activity profiling approaches identified UCHL1 as being highly active in TNBC cell lines and aggressive tumors. Functionally, UCHL1 promoted metastasis in zebrafish and murine breast cancer xenograft models. Mechanistically, UCHL1 facilitates TGFβ signaling-induced metastasis by protecting TGFβ type I receptor and SMAD2 from ubiquitination. We found that these responses are potently suppressed by the specific UCHL1 inhibitor, 6RK73. Furthermore, UCHL1 levels were significantly increased in TNBC patient sera, and highly enriched in sera exosomes as well as TNBC cell conditioned media. UCHL1 enriched exosomes stimulated breast cancer migration and extravasation, suggesting that UCHL1 may act in a paracrine manner to promote tumor progression.\nOur DUB activity profiling identified UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis and may provide a potential target for TNBC treatment. Show less
The aim of this thesis was to develop a software pipeline for tissue analysis in IVOCT by systematically addressing different open questions for analysis. In Chapter 2, we report on a first attempt... Show moreThe aim of this thesis was to develop a software pipeline for tissue analysis in IVOCT by systematically addressing different open questions for analysis. In Chapter 2, we report on a first attempt to quantify the correlation between the position of the catheter with respect to the luminal wall and the image intensities. We implemented the Depth-Resolved (DR) model for IVOCT images in Chapter 3. In addition to the attenuation coefficient, we further extended the model to estimate a backscatter term, and proposed an algorithm to exclude the noisy region. For the first time, it was implemented in IVOCT images with fast and robust calculations. Results show that the IVOCT intensity, DR attenuation coefficient and backscatter term extracted with the reported implementation are complementary to each other in characterizing six tissue types. In Chapter 4, we applied an exact histogram specification technique to covert data generated using different vendors e.g. 8-bit Terumo data and 16-bit St. Jude data. For the application of the DR algorithm, the optical parameters were analyzed as features for the maturity of post-stenting neointima in Chapter 5. In Chapter 6, the three values were analyzed for the determination of thrombi types with high reproducibility. Show less
He, M.; Huang, X.; Liu, S.; Guo, C.; Xie, Y.; Meijer, A.H.; Wang, M. 2018
Ginseng Radix (Panax ginseng) is one of the most commonly used herbs worldwide for the treatment of inflammation-related diseases among others, supported by ancient historical records. Throughout... Show moreGinseng Radix (Panax ginseng) is one of the most commonly used herbs worldwide for the treatment of inflammation-related diseases among others, supported by ancient historical records. Throughout this long history, the large-scale cultivation of ginseng created an increasing demand for long-term storage of the harvested plant material, accelerating the development of post-harvesting procedures. Dried white ginseng and processed (steamed) red ginseng are the products of the two most common traditional post-harvest processes. Although there are a significant number of reports on practice-based therapeutic applications of ginseng, science-based evidence is needed to support these uses. Using a reverse pharmacology approach in conjunction with high-throughput techniques and animal models may offer clear, simple paths for the elucidation of the mechanisms of activity of herbal medicines. Moreover, it could provide a new and more efficient method for the discovery of potential drug candidates. From this perspective, the different chemical compositions of white ginseng and red ginseng could very likely result in different interactions with signaling pathways of diverse biological responses. This paper provides an overview of white ginseng and red ginseng, mainly focusing on their chemical profile and immunomodulation activities. Synergistic effects of ginseng herbal drugs with combinations of other traditional herbal drugs or with synthetic drugs were reviewed. The use of the zebrafish model for bioactivity testing greatly improves the prospects for future ginseng research. Show less
In this paper, we study the scheduling problem of the imprecise mixed-criticality model (IMC) under earliest deadline first with virtual deadline (EDF-VD) scheduling upon uniprocessor systems. Two... Show moreIn this paper, we study the scheduling problem of the imprecise mixed-criticality model (IMC) under earliest deadline first with virtual deadline (EDF-VD) scheduling upon uniprocessor systems. Two schedulability tests are presented. The first test is a concise utilization-based test which can be applied to the implicit deadline IMC task set. The suboptimality of the proposed utilization-based test is evaluated via a widely-used scheduling metric, speedup factors. The second test is a more effective test but with higher complexity which is based on the concept of demand bound function (DBF). The proposed DBF-based test is more generic and can apply to constrained deadline IMC task set. Moreover, in order to address the high time cost of the existing deadline tuning algorithm, we propose a novel algorithm which significantly improve the efficiency of the deadline tuning procedure. Experimental results show the effectiveness of our proposed schedulability tests, confirm the theoretical suboptimality results with respect to speedup factor, and demonstrate the efficiency of our proposed algorithm over the existing deadline tunning algorithm. In addition, issues related to the implementation of the IMC model under EDF-VD are discussed. Show less
Greenbaum, C.; Atkinson, M.; Baidal, D.; Battaglia, M.; Bingley, P.; Bosi, E.; ... ; Sh 2017
