| 1. |
- Mahajan, Anubha, et al.
(author)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Journal article (peer-reviewed)abstract
- 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) 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.
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| 2. |
- Wang, Bochao, et al.
(author)
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The influence of particle chain-magnetic field spatial location, frequency, dynamic strain amplitude and the prestrain on the mechanical performance of anisotropic magneto-rheological elastomer
- 2021
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In: Polymer testing. - : Elsevier BV. - 0142-9418 .- 1873-2348. ; 104, s. 107411-
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Journal article (peer-reviewed)abstract
- Although there are literatures to characterize the properties of anisotropic magneto-rheological elastomer (MRE), more attention is paid when the particle chain is parallel to the applied magnetic field. However, in prospective of modeling and application design, mechanical characterization of anisotropic MRE under other particle chain-magnetic field spatial locations is needed. Herein, mechanical properties of anisotropic MRE with four kinds of particle chain-magnetic field spatial locations under varies frequencies, strain amplitudes and prestrains are tested. It shows that even the particle chain is perpendicular to the magnetic field, there exists an obvious MR effect. Besides the attraction of adjacent magnetized particles, the Maxwell stress tensor also contribute to the MR effect. Furthermore, an obvious strain amplitude dependent viscoelastic behavior is exhibited for anisotropic MRE. Moreover, the MR effect and the loss factor decrease as the increase of prestrain. The investigation contributes to the designing, modeling and applications of anisotropic MRE.
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| 3. |
- Li, Jingyi, et al.
(author)
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The crest phenotype in domestic chicken is caused by a 197 bp duplication in the intron of HOXC10
- 2021
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In: G3. - : Oxford University Press. - 2160-1836. ; 11:2
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Journal article (peer-reviewed)abstract
- The Crest mutation in chicken shows incomplete dominance and causes a spectacular phenotype in which the small feathers normally present on the head are replaced by much larger feathers normally present only in dorsal skin. Using whole-genome sequencing, we show that the crest phenotype is caused by a 197 bp duplication of an evolutionarily conserved sequence located in the intron of HOXC10 on chromosome 33. A diagnostic test showed that the duplication was present in all 54 crested chickens representing eight breeds and absent from all 433 non-crested chickens representing 214 populations. The mutation causes ectopic expression of at least five closely linked HOXC genes, including HOXC10, in cranial skin of crested chickens. The result is consistent with the interpretation that the crest feathers are caused by an altered body region identity. The upregulated HOXC gene expression is expanded to skull tissue of Polish chickens showing a large crest often associated with cerebral hernia, but not in Silkie chickens characterized by a small crest, both homozygous for the duplication. Thus, the 197 bp duplication is required for the development of a large crest and susceptibility to cerebral hernia because only crested chicken show this malformation. However, this mutation is not sufficient to cause herniation because this malformation is not present in breeds with a small crest, like Silkie chickens.
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| 4. |
- Li, Qishuang, et al.
(author)
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Identification of the cytochrome P450s responsible for the biosynthesis of two types of aporphine alkaloids and their de novo biosynthesis in yeast
- 2024
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In: Journal of Integrative Plant Biology. - 1672-9072 .- 1744-7909. ; 66:8, s. 1703-1717
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Journal article (peer-reviewed)abstract
- Aporphine alkaloids have diverse pharmacological activities; however, our understanding of their biosynthesis is relatively limited. Previous studies have classified aporphine alkaloids into two categories based on the configuration and number of substituents of the D-ring and have proposed preliminary biosynthetic pathways for each category. In this study, we identified two specific cytochrome P450 enzymes (CYP80G6 and CYP80Q5) with distinct activities toward (S)-configured and (R)-configured substrates from the herbaceous perennial vine Stephania tetrandra, shedding light on the biosynthetic mechanisms and stereochemical features of these two aporphine alkaloid categories. Additionally, we characterized two CYP719C enzymes (CYP719C3 and CYP719C4) that catalyzed the formation of the methylenedioxy bridge, an essential pharmacophoric group, on the A- and D-rings, respectively, of aporphine alkaloids. Leveraging the functional characterization of these crucial cytochrome P450 enzymes, we reconstructed the biosynthetic pathways for the two types of aporphine alkaloids in budding yeast (Saccharomyces cerevisiae) for the de novo production of compounds such as (R)-glaziovine, (S)-glaziovine, and magnoflorine. This study provides key insight into the biosynthesis of aporphine alkaloids and lays a foundation for producing these valuable compounds through synthetic biology.
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| 5. |
- Bi, Huijuan, et al.
(author)
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A frame-shift mutation in COMTD1 is associated with impaired pheomelanin pigmentation in chicken
- 2023
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In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 19:4
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Journal article (peer-reviewed)abstract
- The biochemical pathway regulating the synthesis of yellow/red pheomelanin is less well characterized than the synthesis of black/brown eumelanin. Inhibitor of gold (IG phenotype) is a plumage colour variant in chicken that provides an opportunity to further explore this pathway since the recessive allele (IG) at this locus is associated with a defect in the production of pheomelanin. IG/IG homozygotes display a marked dilution of red pheomelanin pigmentation, whilst black pigmentation (eumelanin) is only slightly affected. Here we show that a 2-base pair insertion (frame-shift mutation) in the 5th exon of the Catechol-O-methyltransferase containing domain 1 gene (COMTD1), expected to cause a complete or partial loss-of-function of the COMTD1 enzyme, shows complete concordance with the IG phenotype within and across breeds. We show that the COMTD1 protein is localized to mitochondria in pigment cells. Knockout of Comtd1 in a mouse melanocytic cell line results in a reduction in pheomelanin metabolites and significant alterations in metabolites of glutamate/glutathione, riboflavin, and the tricarboxylic acid cycle. Furthermore, COMTD1 overexpression enhanced cellular proliferation following chemical-induced transfection, a potential inducer of oxidative stress. These observations suggest that COMTD1 plays a protective role for melanocytes against oxidative stress and that this supports their ability to produce pheomelanin.
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| 6. |
- Deng, Bin, et al.
(author)
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Ketamine inhibits TNF-α-induced cecal damage by enhancing RIP1 ubiquitination to attenuate lethal SIRS
- 2022
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In: Cell death discovery. - : Springer Science and Business Media LLC. - 2058-7716. ; 8:1
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Journal article (peer-reviewed)abstract
- Systemic inflammatory response syndrome (SIRS) is a sepsis-associated inflammatory state and a self-defense mechanism against specific and nonspecific stimuli. Ketamine influences many key processes that are altered during sepsis. However, the underlying mechanisms remain incompletely understood. In this study, TNF-α-treated mice, as well as HT-29 and L929 cell models, were applied to characterize TNF-α-induced systemic and local cecal tissue inflammatory responses. Behavioral, biochemical, histological, and molecular biological approaches were applied to illustrate the related processes. Mice with TNF-α-induced SIRS showed systemic and local cecal tissue inflammatory responses, as indicated by increased levels of high mobility group box 1 protein (HMGB1), chemokines (C-X-C motif) ligand 10 (CXCL10), interleukin-6 (IL-6), and IL-10, as well as high mortality. Ketamine pretreatment alleviated death rates, symptoms, and the production of inflammatory cytokines induced by TNF-α in mice. Moreover, ketamine also protected the mice from TNF-α-induced cecal damage by suppressing the phosphorylation of receptor-interacting serine/threonine-protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). In addition, our results showed that ketamine efficiently inhibited TNF-α-induced necroptosis in HT-29 and L929 cells. Furthermore, we explored the mechanism using different L929 cell lines. The results displayed that ketamine inhibited TNF-α-induced necroptosis by enhancing RIP1 ubiquitination and reducing the RIP1-RIP3 and RIP3-MLKL interactions, as well as the formation of necrosomes. Thus, our study may provide a new theoretical and experimental basis for treating diseases characterized by SIRS-associated inflammatory factor storms. Moreover, our exploration may provide potential molecular mechanisms and targets for therapeutic intervention and clinical application of ketamine.
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| 7. |
- Dolinska, Monika, et al.
(author)
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Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option
- 2023
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
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Journal article (peer-reviewed)abstract
- Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
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| 8. |
- Dolinska, Monika, et al.
(author)
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Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option
- 2023
-
In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
-
Journal article (peer-reviewed)abstract
- Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long -term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
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| 9. |
- Du, Bisheng, et al.
(author)
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Customer's Channel Selection Behavior on Purchasing Standardized and Customized Products : Optimized Prices and Channel Performances
- 2022
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In: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 13
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Journal article (peer-reviewed)abstract
- Nowadays, the traditional production is unable to meet the new diverse needs of target customers. In the current customization era, more and more companies are required by customers to provide more desirable customized products. However, research on customization and standardization based on quantitative analysis has drawn little attention in the literature of dual channel supply chain. In this paper, we study the effect of adopting a dual channel supply chain on the performance of a two-level system (manufacturer-retailer) by using a novelty quantitative approach. We try to analyze the system to get optimal prices and maximize profits, where manufactures offer both standardized and customized products via their traditional and customized channels, respectively. We build a Stackelberg game mode to construct a centralized and a decentralized dual channel scenarios. Furthermore, we study the effects of the different channel structures on price, degree of customization, degree of standardization, and supply chain profitability. We also analyze the effects of both standardized and customized demand sensitivities on their prices and profits. Eventually, we introduce a cost-sharing coordinating contract to optimize the channel's performance. We find that the potential market demand for customization affects the price of customized products and the profits of customized channels. Compared with the decentralized dual channel case, the cost-sharing contract can achieve higher total channel profits. In the cost-coordination case, there is an optimal range for the proportion of standardized costs borne by manufacturers.
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| 10. |
- Fu, Keren, 1988, et al.
(author)
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Adaptive Multi-Level Region Merging for Salient Object Detection
- 2014
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In: British Machine Vision Conference (BMVC) 2014. ; , s. 11 -
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Conference paper (peer-reviewed)abstract
- Most existing salient object detection algorithms face the problem of either under or over-segmenting an image. More recent methods address the problem via multi-level segmentation. However, the number of segmentation levels is manually predetermined and only works well on specific class of images. In this paper, a new salient object detection scheme is presented based on adaptive multi-level region merging. A graph based merging scheme is developed to reassemble regions based on their shared contourstrength. This merging process is adaptive to complete contours of salient objects that can then be used for global perceptual analysis, e.g., foreground/ground separation. Such contour completion is enhanced by graph-based spectral decomposition. We show that even though simple region saliency measurements are adopted for each region, encouraging performance can be obtained after across-level integration. Experiments by comparing with 13 existing methods on three benchmark datasets including MSRA-1000, SOD and SED show the proposed method results in uniform object enhancement and achieves state-of-the-art performance.
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