The effect of the DLTIDDSYWYRI motif of the human laminin α2 chain on implant osseointegration

Considerable effort has been directed towards replacing lost teeth using tissue-engineering methods such as titanium implants. A number of studies have tried to modify bioinert titanium surfaces by coating them with functionally bioactive molecules for faster and stronger osseointegration than pure titanium surfaces. Recently, peptides have been recognized as valuable scientific tools in the field of tissue-engineering. The DLTIDDSYWYRI motif of the human laminin-2 α2 chain has been previously reported to promote the attachment of various cell types; however, the in vivo effects of the DLTIDDSYWYRI motif on new bone formation have not yet been studied. To examine whether a laminin-2-derived peptide can promote osseointegration by accelerating new bone formation in vivo, we applied titanium implants coated with the DLTIDDSYWYRI motif in a rabbit tibia model. The application of the DLTIDDSYWYRI motif-treated implant to tibia wounds enhanced collagen deposition and alkaline phosphatase expression. It significantly promoted implant osseointegration compared with treatment with scrambled peptide-treated implants by increasing the bone-to-implant contact ratio and bone area. These findings support the hypothesis that the DLTIDDSYWYRI motif acts as an effective osseointegration accelerator by enhancing new bone formation.Considerable effort has been directed towards replacing lost teeth using tissue-engineering methods such as titanium implants. A number of studies have tried to modify bioinert titanium surfaces by coating them with functionally bioactive molecules for faster and stronger osseointegration than pure titanium surfaces. Recently, peptides have been recognized as valuable scientific tools in the field of tissue-engineering. The DLTIDDSYWYRI motif of the human laminin-2 α2 chain has been previously reported to promote the attachment of various cell types; however, the in vivo effects of the DLTIDDSYWYRI motif on new bone formation have not yet been studied. To examine whether a laminin-2-derived peptide can promote osseointegration by accelerating new bone formation in vivo, we applied titanium implants coated with the DLTIDDSYWYRI motif in a rabbit tibia model. The application of the DLTIDDSYWYRI motif-treated implant to tibia wounds enhanced collagen deposition and alkaline phosphatase expression. It significantly promoted implant osseointegration compared with treatment with scrambled peptide-treated implants by increasing the bone-to-implant contact ratio and bone area. These findings support the hypothesis that the DLTIDDSYWYRI motif acts as an effective osseointegration accelerator by enhancing new bone formation.Tissue-engineeringThis work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by MEST (Grant No. 2011-0007662) and the Mid-career Researcher Program through NRF, funded by MEST (Grant No. 2010-0014662).OAIID:oai:osos.snu.ac.kr:snu2013-01/102/2008003883/1SEQ:1PERF_CD:SNU2013-01EVAL_ITEM_CD:102USER_ID:2008003883ADJUST_YN:NEMP_ID:A078517DEPT_CD:861CITE_RATE:7.404FILENAME:Biomaterials 201305 34(16) 4027-37.pdfDEPT_NM:치의학과EMAIL:[email protected]_YN:YCONFIRM:

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.Peer reviewedPublisher PD

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding Information: GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file : Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Learning Hierarchical Representations of Stories by UsingMulti-Layered Structures in Narrative Multimedia

Narrative works (e.g., novels and movies) consist of various utterances (e.g., scenes and episodes) with multi-layered structures. However, the existing studies aimed to embed only stories in a narrative work. By covering other granularity levels, we can easily compare narrative utterances that are coarser (e.g., movie series) or finer (e.g., scenes) than a narrative work. We apply the multi-layered structures on learning hierarchical representations of the narrative utterances. To represent coarser utterances, we consider adjacency and appearance of finer utterances in the coarser ones. For the movies, we suppose a four-layered structure (character roles 2 characters 2 scenes 2 movies) and propose three learning methods bridging the layers: Char2Vec, Scene2Vec, and Hierarchical Story2Vec. Char2Vec represents a character by using dynamic changes in the character's roles. To find the character roles, we use substructures of character networks (i.e., dynamic social networks of characters). A scene describes an event. Interactions between characters in the scene are designed to describe the event. Scene2Vec learns representations of a scene from interactions between characters in the scene. A story is a series of events. Meanings of the story are affected by order of the events as well as their content. Hierarchical Story2Vec uses sequential order of scenes to represent stories. The proposed model has been evaluated by estimating the similarity between narrative utterances in real movies.11Ysciescopu