Publications by authors named "Tian Xia"

662 Publications

Comparative transcriptome provides insights into the selection adaptation between wild and farmed foxes.

Ecol Evol 2021 Oct 30;11(19):13475-13486. Epub 2021 Aug 30.

College of Life Science Qufu Normal University Qufu China.

The silver fox and blue fox are economically important fur species and were domesticated by humans from their wild counterparts, the arctic fox and red fox, respectively. Farmed foxes show obvious differences from their wild counterparts, including differences in physiology, body size, energy metabolism, and immunity. However, the molecular mechanisms underlying these differences are presently unclear. In this study, we built transcriptome libraries from multiple pooled tissues for each species of farmed fox, used RNA-seq to obtain a comprehensive dataset, and performed selection analysis and sequence-level analyses of orthologous genes to identify the genes that may be influenced by human domestication. More than 153.3, 248.0, 81.6, and 65.8 million clean reads were obtained and assembled into a total of 118,577, 401,520, 79,900, and 186,988 unigenes with an average length range from 521 to 667 bp for AF, BF, RF, and SF, respectively. Selective pressure analysis showed that 11 and 14 positively selected genes were identified, respectively, in the two groups (AF vs. BF and RF vs. SF). Several of these genes were associated with natural immunity ( and ), protein synthesis (, and ), and DNA damage repair (). Further functional enrichment analyses demonstrated that two positively selected genes ( and ) were involved in metabolic process (GO:0008152, -value = .032), representing a significant enrichment. Sequence analysis of 117 orthologous genes shared by the two groups showed that the , and genes might be affected by artificial selection in farmed foxes, with mutation sites located within sequences that are otherwise highly conserved across most mammals. Our results provide a valuable transcriptomic resource for future genetic studies and improvement in the assisted breeding of foxes and other farmed animals.
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http://dx.doi.org/10.1002/ece3.8071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495804PMC
October 2021

Constitutive signal bias mediated by the human GHRHR splice variant 1.

Proc Natl Acad Sci U S A 2021 Oct;118(40)

Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China;

Alternative splicing of G protein-coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone-releasing hormone receptor (GHRHR) is capable of transducing biased signal. Differing only at the receptor N terminus, GHRHR predominantly activates G while SV1 selectively couples to β-arrestins. Based on the cryogenic electron microscopy structures of SV1 in the state or GHRH-bound state in complex with the G protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, G versus β-arrestins. As suggested by mutagenesis and functional studies, it appears that GHRH-elicited signal bias toward β-arrestin recruitment is constitutively mediated by SV1. The level of SV1 expression in prostate cancer cells is also positively correlated with ERK1/2 phosphorylation but negatively correlated with cAMP response. Our findings imply that constitutive signal bias may be a mechanism that ensures cancer cell proliferation.
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http://dx.doi.org/10.1073/pnas.2106606118DOI Listing
October 2021

Metabolomic Characterization Reveals ILF2 and ILF3 Affected Metabolic Adaptions in Esophageal Squamous Cell Carcinoma.

Front Mol Biosci 2021 9;8:721990. Epub 2021 Sep 9.

Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China.

Esophageal cancer (EC) is a common malignant disease in eastern countries. However, a study of the metabolomic characteristics associated with other biological factors in esophageal squamous cell carcinoma (ESCC) is limited. Interleukin enhancer binding factor 2 (ILF2) and ILF3, double-stranded RNA-binding proteins, have been reported to contribute to the occurrence and development of various types of malignancy. Nevertheless, the underlying functions of ILF2 and ILF3 in ESCC metabolic reprogramming have never been reported. This study aimed to contribute to the metabolic characterization of ESCC and to investigate the metabolomic alterations associated with ILF2 and ILF3 in ESCC tissues. Here, we identified 112 differential metabolites, which were mainly enriched in phosphatidylcholine biosynthesis, fatty acid metabolism, and amino acid metabolism pathways, based on liquid chromatography-mass spectrometry and capillary electrophoresis-mass spectrometry approaches using ESCC tissues and paired para-cancer tissues from twenty-eight ESCC patients. In addition, and expression were significantly elevated in EC tissues compared to the histologically normal samples, and closely associated with PI3K/AKT and MAPK signaling pathways in ESCC. Moreover, in ESCC tissues with a high ILF2 expression, several short-chain acyl-carnitines (C3:0, C4:0, and C5:0) related to the BCAA metabolic pathway and long-chain acyl-carnitines (C14:0, C16:0, C16:0-OH, and C18:0) involved in the oxidation of fatty acids were obviously upregulated. Additionally, a series of intermediate metabolites involved in the glycolysis pathway, including G6P/F6P, F1,6BP, DHAP, G3P, and 2,3BPG, were remarkably downregulated in highly ILF3-expressed ESCC tissues compared with the corresponding para-cancer tissues. Overall, these findings may provide evidence for the roles of ILF2 and ILF3 during the process of ESCC metabolic alterations, and new insights into the development of early diagnosis and treatment for ESCC. Further investigation is needed to clarify the underlying mechanism of ILF2 and ILF3 on acyl-carnitines and the glycolysis pathway, respectively.
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http://dx.doi.org/10.3389/fmolb.2021.721990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459612PMC
September 2021

PRMT5 regulates cell pyroptosis by silencing CASP1 in multiple myeloma.

Cell Death Dis 2021 Sep 16;12(10):851. Epub 2021 Sep 16.

Department of Hematology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, People's Republic of China.

Protein arginine methyltransferase 5 (PRMT5), a histone methyltransferase responsible for the symmetric dimethylation of histone H4 on Arg 3 (H4R3me2s), is an enzyme that participates in tumor cell progression in a variety of hematological malignancies. However, the biological functions of PRMT5 in multiple myeloma (MM) and the underlying molecular mechanisms remain unclear. In this study, we conducted a bioinformatics analysis and found that PRMT5 expression was significantly upregulated in MM. In vitro and in vivo phenotypic experiments revealed that knockdown of PRMT5 expression enhanced cell pyroptosis in MM. Moreover, we found that CASP1 expression was negatively correlated with PRMT5 expression, and repressing PRMT5 expression rescued both the phenotype and expression markers (N-GSDMD, IL-1b, and IL-18). Inhibition of PRMT5 activity increased CASP1 expression and promoted MM cell pyroptosis. Finally, high expression of PRMT5 or low expression of CASP1 was correlated with poor overall survival in MM. Collectively, our results provide a mechanism by which PRMT5 regulates cell pyroptosis by silencing CASP1 in MM.
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http://dx.doi.org/10.1038/s41419-021-04125-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445991PMC
September 2021

Ddb1 Is Essential for the Expansion of CD4 Helper T Cells by Regulating Cell Cycle Progression and Cell Death.

Front Immunol 2021 30;12:722273. Epub 2021 Aug 30.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.

Follicular helper T (T) cells are specialized CD4 helper T cells that provide help to B cells in humoral immunity. However, the molecular mechanism underlying generation of T cells is incompletely understood. Here, we reported that Damage-specific DNA binding protein 1 (Ddb1) was required for expansion of CD4 helper T cells including T and Th1 cells, germinal center response, and antibody response to acute viral infection. deficiency in activated CD4 T cells resulted in cell cycle arrest at G2-M phase and increased cell death, due to accumulation of DNA damage and hyperactivation of ATM/ATR-Chk1 signaling. Moreover, mice with deletion of both and in activated CD4 T cells phenocopied -deficient mice, suggesting that E3 ligase-dependent function of Ddb1 was crucial for genome maintenance and helper T-cell generation. Therefore, our results indicate that Ddb1 is an essential positive regulator in the expansion of CD4 helper T cells.
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http://dx.doi.org/10.3389/fimmu.2021.722273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435776PMC
August 2021

Analysis of gut microbiota in three species belonging to different genera (, , and ) from the subfamily Caprinae in the absence of environmental variance.

Ecol Evol 2021 Sep 31;11(17):12129-12140. Epub 2021 Jul 31.

College of Life Science Qufu Normal University Qufu China.

This study aimed to identify the effects of host species on the gut microbial flora in three species (, , and ) from the subfamily Caprinae, by excluding the impact of environment factors. We investigated the differences in intestinal flora of three species belonging to Caprinae, which were raised in identical conditions. Fecal samples were collected from tahr, mouflon, and bharal, and the V3-V4 region of the 16S ribosomal RNA gene was analyzed by high-throughput sequencing. The analysis of 16S rRNA gene sequences reveals that fecal samples were mainly composed of four phyla: Firmicutes, Bacteroidetes, Spirochaetes, and Proteobacteria. The most abundant phyla included Firmicutes and Bacteroidetes accounting for >90% of the bacteria, and a higher Firmicutes/Bacteroidetes ratio was observed in tahrs. Moreover, significant differences existed at multiple levels of classifications in the relative abundance of intestinal flora, differing greatly between species. Phylogenetic analyses based on 16S rRNA gene indicated that mouflon is closely related to bharal, and it is inconsistent with previous reports in the species evolutionary relationships. In this study, we demonstrated that the gut microbiota in tahr had a stronger ability to absorb and store energy from the diet compared with mouflon and bharal, and the characteristics of host-microbiome interactions were not significant.
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http://dx.doi.org/10.1002/ece3.7976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427585PMC
September 2021

Effects of icariin on the fracture healing in young and old rats and its mechanism.

Pharm Biol 2021 Dec;59(1):1245-1255

Department of Orthopedics, Ruikang Hospital Affiliated with Guangxi University of Chinese Medicine, Nanning, China.

Context: Icariin has attracted increasing attention because of its wide variety of pharmacological effects.

Objective: This study investigates whether icariin could promote fracture healing in young and old rats and its mechanisms.

Materials And Methods: A Wistar rat model for the tibia fracture in relatively young and old rats, respectively, was established. The rats were divided into four groups: model group, L-icariin (50 mg/kg icariin), M-icariin (100 mg/kg icariin) and H-icariin (200 mg/kg icariin), and intragastric administration of icariin was performed for 10 days or 20 days. In addition, isolated and cultured rat bone mesenchymal stem cells (rBMSCs) from young and old rats were cultured with 5% and 20% of icariin-containing serum, respectively, then cell viability and alkaline phosphatase (ALP) activity were measured.

Results: Icariin administration induced the expression of Runx2, Osterix, BMP-2, p-Smad5 and osteocalcin secretion (young rats: model: 2.50 ± 0.71; L-icariin: 10.10 ± 1.55; M-icariin: 24.95 ± 2.19; H-icariin: 36.80 ± 2.26; old rats: model: 1.55 ± 0.49; L-icariin:6.55 ± 0.50; M-icariin: 15.00 ± 0.85; H-icariin:20.50 ± 2.27) at the fracture site, and increased the levels of bone formation markers (OC, BAP, NTX-1 and CTX-1) in a dose-dependent manner. , icariin treatment promoted rBMSC viability, increased ALP activity and the expression of BMP-2/Smad5/Runx2 pathway proteins.

Discussion And Conclusions: Icariin may accelerate fracture healing by activating the BMP-2/Smad5/Runx2 pathway in relatively young and old rats. The research on the mechanism of icariin to promote fracture healing can provide a theoretical basis for the clinical application and promotion of icariin.
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http://dx.doi.org/10.1080/13880209.2021.1972121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439244PMC
December 2021

Microstructure and Mechanical Properties of Carbides Reinforced Nickel Matrix Alloy Prepared by Selective Laser Melting.

Materials (Basel) 2021 Aug 24;14(17). Epub 2021 Aug 24.

High-Temperature Materials Department, Central Iron & Steel Research Institute, Beijing 100081, China.

Selective laser melting was used to prepare the ceramic particles reinforced nickel alloy owing to its high designability, high working flexibility and high efficiency. In this paper, a carbides particles reinforced Haynes 230 alloy was prepared using SLM technology to further strengthen the alloy. Microstructures of the carbide particles reinforced Haynes 230 alloy were investigated using electron microscopy (SEM), electron probe microanalysis (EPMA) and transmission electron microscopy (TEM). Meanwhile, the tensile tests were carried out to determine the strengths of the composite. The results show that the microstructure of the composite consisted of uniformly distributed MC and MC type carbides and the strengths of the alloy were higher than the matrix alloy Haynes 230. The increased strengths of the carbide reinforced Haynes 230 alloy (room temperature yield strength 113 MPa increased, ~ 33.2%) can be attributed to the synergy strengthening including refined grain strengthening, Orowan strengthening and dislocation strengthening.
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http://dx.doi.org/10.3390/ma14174792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432457PMC
August 2021

Exosomal ERp44 derived from ER-stressed cells strengthens cisplatin resistance of nasopharyngeal carcinoma.

BMC Cancer 2021 Sep 8;21(1):1003. Epub 2021 Sep 8.

Department of Otorhinolaryngology Head and Neck surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.

Background: Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in head and neck. Platinum-based chemotherapy is an important treatment for NPC. However, the molecular mechanism of resistance to platinum drug remains unknown. Endoplasmic reticulum resident protein 44(ERp44), an unfolded protein response (UPR)-induced endoplasmic reticulum(ER) protein, is induced during ER stress. This research explored the mechanism of ERp44 in strengthening cisplatin resistance in NPC.

Methods: Western blot and immunohistochemistry were used to investigate the expression of ERp44 and Glucose-Regulated Protein 78(GRP78) in NPC. We took CCK8 to detect the role of ERp44 on cell chemosensitivity. Flow cytometric analysis and western blot were taken to analyze cell apoptosis. We performed differential centrifugation to isolate exosomes from serum or conditioned media of cells and analyzed the impact of exosomal ERp44 on cells cisplatin sensitivity. Finally, the results were confirmed in vivo.

Results: We found the increased expression of ERp44 and GRP78 in NPC and ERp44 was highly expressed in ER-stressed tissues. Cell proliferation was inhibited after cisplatin treatment when ERp44 was knocked down and ERp44 strengthened cisplatin resistance by influencing cell apoptosis and pyroptosis. Then we also collected exosomes and cell viability was increased after the addition of NPC-derived-exosomes with cisplatin treatment. More importantly, our results showed under ERS, NPC cells secreted exosomes containing ERp44 and could transfer them to adjacent cells to strengthen chemoresistance.

Conclusion: Our data suggested that exosomal ERp44 derived from ER-stressed NPC cells took an inevitable role in NPC chemoresistance and might act as a treatment target.
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http://dx.doi.org/10.1186/s12885-021-08712-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424889PMC
September 2021

A Novel Indomethacin-Tripeptide Hydrogel for Inhibiting Ocular Inflammation.

J Biomed Nanotechnol 2021 Jul;17(7):1417-1425

Institute of Biomedical Engineering, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China.

A highly efficient method for constructing indomethacin-peptide conjugates was developed using the natural amino acid tyrosine (Y) as the anchor for indomethacin (Idm). With pH = 6, Idm-YEE conjugate self-assembled in a low critical micelle concentration (CMC, 0.037 mg/mL) and formed a transparent hydrogel (0.4 wt%). The formed Idm-YEE hydrogel presented sustained drug release of indomethacin with a maximum of 40% during first 24 hours, which was superior to the reported Idm-containing supramolecular hydrogel systems. As kept at 4 °C, the Idm-YEE hydrogel showed good storage stability up to 30 days without obvious hydrolysis. As shown by MTT assay, the Idm-YEE hydrogel exhibited good cell compatibility against retinal pigment epithelial cells (ARPE-19) and Human corneal epithelial cells (HCEC). Ocular irritation test (i.e., clinical observations, fluorescein staining and H&E histological analysis) results showed good integrity of corneal architecture and no edema after Idm-YEE hydrogel treatment, which proved its good ocular biocompatibility. Besides, the LPS-stimulated levels of key inflammatory mediators, including NO, PGE₂ and IL-6, were greatly reduced by Idm-YEE hydrogel even in a low concentration (50 M) in Raw264.7 cells, which indicated its comparable anti-inflammatory activity to indomethacin. Furthermore, the therapeutic efficacy of Idm-YEE hydrogel was evaluated in endotoxin-induced uveitis (EIU) rabbit model. By treating with dm-YEE hydrogel, the rabbit eyes had significantly lowered inflammation and exudation in the anterior chamber. The results of histological analysis, clinical score, inflammatory cell counts, aqueous protein concentration and immunohistochemical staining also demonstrated its good therapeutic activity towards ocular inflammation. Therefore, with good ocular biocompatibility and comparable anti-inflammatory effect towards ocular inflammation, the novel indomethacin-tripeptide hydrogel (Idm-YEE) developed in this work provides a potential treatment for anterior uveitis.
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http://dx.doi.org/10.1166/jbn.2021.3118DOI Listing
July 2021

Single-cell transcriptional profiling reveals the heterogeneity in embryonal rhabdomyosarcoma.

Medicine (Baltimore) 2021 Aug;100(31):e26775

Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defect, Shanghai, China.

Abstract: Rhabdomyosarcoma is the most common soft tissue sarcoma in children, and embryonal rhabdomyosarcoma is the most typical type of rhabdomyosarcoma. The heterogeneity, etiology, and origin of embryonal rhabdomyosarcoma remain unknown.After obtaining the gene expression data of every cell in the tumor tissue by single-cell RNA sequencing, we used the Seurat package in R studio for quality control, analysis, and exploration of the data. All cells are divided into tumor cells and non-tumor cells, and we chose tumor cells by marker genes. Then, we repeated the process to cluster the tumor cells and divided the subgroups by their differentially expressed genes and gene ontology/Kyoto Encyclopedia of Genes and Genomes analysis. Additionally, Monocle 2 was used for pseudo-time analysis to obtain the evolution trajectory of cells in tumor tissues.Tumor cells were divided into 5 subgroups according to their functions, which were characterized by high proliferation, sensing and adaptation to oxygen availability, enhanced epigenetic modification, enhanced nucleoside phosphonic acid metabolism, and ossification. Evolution trajectory of cells in tumor tissues is obtained.We used pseudo-time analysis to distinguish between mesenchymal stem cells and fibroblasts, proved that embryonal rhabdomyosarcoma in the pelvic originated from skeletal muscle progenitor cells, showed the evolutionary trajectory of embryonal rhabdomyosarcoma, and improved the method of evaluating the degree of malignancy of embryonal rhabdomyosarcoma.
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http://dx.doi.org/10.1097/MD.0000000000026775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341243PMC
August 2021

Pyrimidine-Functionalized Covalent Organic Framework and its Cobalt Complex as an Efficient Electrocatalyst for Oxygen Evolution Reaction.

ChemSusChem 2021 Aug 10. Epub 2021 Aug 10.

State Key Laboratory of Marine Resource Utilization in South China Sea, Hainan Provincial Key Lab of Fine Chemistry, School of Chemical Engineering and Technology, Hainan University, Haikou, 570228, P. R. China.

A pyrimidine-modified covalent organic framework (COF-Pyr) was designed to be synthesized via the Povarov reaction. The nitrogen atom on the pyrimidine showed excellent coordination ability to metal ions. Their stable metal composite material ([email protected]) exhibited remarkable performance for electrocatalytic oxygen evolution reaction (OER) in 1.0 m KOH aqueous solution. The overpotential was 450 mV at 10 mA cm . The [email protected] with large specific surface area (392 m  g ) and regular crystal structure provided free passage for H O to move and make them fully contact with the uniformly dispersed cobalt ions on the surface. Thus, the turnover frequency of [email protected] was 0.1 s at the overpotential of 370 mV, which was higher than most reported OER catalysts. This work provided a new way to design and prepare nitrogen-containing heterocyclic functionalized COFs. They can be combined with metal ions to expand the application of COFs in the field of electrocatalysis.
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http://dx.doi.org/10.1002/cssc.202101434DOI Listing
August 2021

Nanocellulose Length Determines the Differential Cytotoxic Effects and Inflammatory Responses in Macrophages and Hepatocytes.

Small 2021 Sep 6;17(38):e2102545. Epub 2021 Aug 6.

Center of Environmental Implications of Nanotechnology (UC CEIN), California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA.

Nanocellulose including cellulose nanocrystal (CNC) and cellulose nanofiber (CNF) has attracted much attention due to its exceptional mechanical, chemical, and rheological properties. Although considered biocompatible, recent reports have demonstrated nanocellulose can be hazardous, including serving as drug carriers that accumulate in the liver. However, the nanocellulose effects on liver cells, including Kupffer cells (KCs) and hepatocytes are unclear. Here, the toxicity of nanocellulose with different lengths is compared, including the shorter CNCs (CNC-1, CNC-2, and CNC-3) and longer CNF (CNF-1 and CNF-2), to liver cells. While all CNCs triggered significant cytotoxicity in KCs and only CNC-2 induced toxicity to hepatocytes, CNFs failed to induce significant cytotoxicity due to their minimal cellular uptake. The phagocytosis of CNCs by KCs induced mitochondria ROS generation, caspase-3/7 activation, and apoptotic cell death as well as lysosomal damage, cathepsin B release, NLRP3 inflammasome and caspase-1 activation, and IL-1β production. The cellular uptake of CNC-2 by hepatocytes is through clathrin-mediated endocytosis, and it induced the caspase-3/7-mediated apoptosis. CNC-2 shows the highest levels of uptake and cytotoxicity among CNCs. These results demonstrate the length-dependent mechanisms of toxicity on liver cells in a cell type-dependent fashion, providing information to safely use nanocellulose for biomedical applications.
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http://dx.doi.org/10.1002/smll.202102545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460616PMC
September 2021

Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications.

Genet Med 2021 Aug 6. Epub 2021 Aug 6.

Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX, USA.

Purpose: Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted.

Methods: We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record.

Results: Notably, 32% of patients had a genetic finding with clinical management implications, even after excluding PGx results, including 9% who were molecularly diagnosed with a Mendelian condition. Among surveyed physicians, 84% reported medical management changes based on these results, including specialist referrals, cardiac tests, and medication changes. LPA polymorphisms and high polygenic risk of CAD were found in 20% and 9% of patients, respectively, leading to diet, lifestyle, and other changes. Warfarin and simvastatin pharmacogenetic variants were present in roughly half of the cohort.

Conclusion: Our results support the use of genetic information in routine cardiovascular health management and provide a roadmap for accompanying research.
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http://dx.doi.org/10.1038/s41436-021-01294-8DOI Listing
August 2021

Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2.

Proc Natl Acad Sci U S A 2021 Aug;118(32)

The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;

The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein-coupled receptor (GPCR) involved in the regulation of calcium transport, nociception mediation, and wound healing. Naturally occurring mutations in PTH2R were reported to cause hereditary diseases, including syndromic short stature. Here, we report the cryogenic electron microscopy structure of PTH2R bound to its endogenous ligand, tuberoinfundibular peptide (TIP39), and a heterotrimeric G protein at a global resolution of 2.8 Å. The structure reveals that TIP39 adopts a unique loop conformation at the N terminus and deeply inserts into the orthosteric ligand-binding pocket in the transmembrane domain. Molecular dynamics simulation and site-directed mutagenesis studies uncover the basis of ligand specificity relative to three PTH2R agonists, TIP39, PTH, and PTH-related peptide. We also compare the action of TIP39 with an antagonist lacking six residues from the peptide N terminus, TIP(7-39), which underscores the indispensable role of the N terminus of TIP39 in PTH2R activation. Additionally, we unveil that a disease-associated mutation G258D significantly diminished cAMP accumulation induced by TIP39. Together, these results not only provide structural insights into ligand specificity and receptor activation of class B1 GPCRs but also offer a foundation to systematically rationalize the available pharmacological data to develop therapies for various disorders associated with PTH2R.
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http://dx.doi.org/10.1073/pnas.2101279118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364112PMC
August 2021

Molecular mechanisms and therapeutic implications of dihydromyricetin in liver disease.

Biomed Pharmacother 2021 Oct 30;142:111927. Epub 2021 Jul 30.

The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, China; Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, China; Cancer Center, Zhejiang University, China. Electronic address:

Recent studies demonstrated that dihydromyricetin (DHM) has prominent therapeutic effects on liver injury and liver cancer. By summarizing the current preclinical in vitro and in vivo studies, the present review examines the preventive and therapeutic effects of DHM on liver disorders as well as its potential mechanisms. Briefly, in both chemical- and alcohol-induced liver injury models, DHM ameliorates hepatocyte necrosis and steatosis while promoting liver regeneration. In addition, DHM can alleviate nonalcoholic fatty liver disease (NAFLD) via regulating lipid/glucose metabolism, probably due to its anti-inflammatory or sirtuins-dependent mechanisms. Furthermore, DHM treatment inhibits cell proliferation, induces apoptosis and autophagy and regulates redox balance in liver cancer cells, thus exhibiting remarkable anti-cancer effects. The pharmacological mechanisms of DHM may be associated with its anti-inflammatory, anti-oxidative and apoptosis-regulatory benefits. With the accumulating interests in utilizing natural products to target common diseases, our work aims to improve the understanding of DHM acting as a novel drug candidate for liver diseases and to accelerate its translation from bench to bedside.
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http://dx.doi.org/10.1016/j.biopha.2021.111927DOI Listing
October 2021

Learning to synthesise the ageing brain without longitudinal data.

Med Image Anal 2021 10 18;73:102169. Epub 2021 Jul 18.

Institute for Digital Communications, School of Engineering, University of Edinburgh, West Mains Rd, Edinburgh EH9 3FB, UK; The Alan Turing Institute, London NW1 2DB, UK.

How will my face look when I get older? Or, for a more challenging question: How will my brain look when I get older? To answer this question one must devise (and learn from data) a multivariate auto-regressive function which given an image and a desired target age generates an output image. While collecting data for faces may be easier, collecting longitudinal brain data is not trivial. We propose a deep learning-based method that learns to simulate subject-specific brain ageing trajectories without relying on longitudinal data. Our method synthesises images conditioned on two factors: age (a continuous variable), and status of Alzheimer's Disease (AD, an ordinal variable). With an adversarial formulation we learn the joint distribution of brain appearance, age and AD status, and define reconstruction losses to address the challenging problem of preserving subject identity. We compare with several benchmarks using two widely used datasets. We evaluate the quality and realism of synthesised images using ground-truth longitudinal data and a pre-trained age predictor. We show that, despite the use of cross-sectional data, our model learns patterns of gray matter atrophy in the middle temporal gyrus in patients with AD. To demonstrate generalisation ability, we train on one dataset and evaluate predictions on the other. In conclusion, our model shows an ability to separate age, disease influence and anatomy using only 2D cross-sectional data that should be useful in large studies into neurodegenerative disease, that aim to combine several data sources. To facilitate such future studies by the community at large our code is made available at https://github.com/xiat0616/BrainAgeing.
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http://dx.doi.org/10.1016/j.media.2021.102169DOI Listing
October 2021

Performance Enhancement of Organic Solar Cells by Adding a Liquid Crystalline Molecule in Cathode and Anode Interlayers.

ACS Appl Mater Interfaces 2021 Aug 20;13(30):35639-35646. Epub 2021 Jul 20.

South China Academy of Advanced Optoelectronics, South China Normal University, Guangzhou 510006, China.

In this study, an effective and simple approach for optimizing the performance of both cathode and anode interlayers in OSCs is demonstrated using 4-heptyl-4'-cyanobiphenyl (7CB) to dope a classic cathode (ZnO and SnO) or an anode interlayer [poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)]. Because of the enhanced light absorption, improved physical contact between a photoactive layer and an interlayer, and increased carrier recombination, all of the devices based on a 7CB-doped interlayer show increased short-circuit current density (), fill factor (FF), and power conversion efficiency (PCE) compared to the corresponding undoped interlayer, regardless it is the anode interlayer or the cathode interlayer, which is a rare phenomenon in the interlayer modification field.
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http://dx.doi.org/10.1021/acsami.1c06329DOI Listing
August 2021

An Activatable Host-Guest Conjugate as a Nanocarrier for Effective Drug Release through Self-Inclusion.

ACS Appl Mater Interfaces 2021 Jul 19;13(29):33962-33968. Epub 2021 Jul 19.

Key Laboratory of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084, China.

There is a challenge in supramolecular chemotherapy for constructing a system equipped with both sufficient protection and high-efficiency release of drugs. To this end, a new strategy of an activatable host-guest conjugate with self-inclusion property is proposed. Based on the binding affinity gain of intramolecular host-guest self-inclusion, an activatable host-guest conjugate was designed, bearing cucurbit[7]uril as the host, an alkyl ammonium moiety as the guest, and the redox-responsive disulfide linkage. Oxaliplatin, a clinical antitumor drug, could be firmly encapsulated by the activatable host-guest conjugate to form the supramolecular drug with high stability. Moreover, oxaliplatin loaded in the activatable host-guest conjugate could be almost completely released by self-inclusion triggered by glutathione in a tumor microenvironment, thus exhibiting comparable antitumor bioactivity with naked oxaliplatin through in vitro cell experiments. It is highly anticipated that this line of research may open new horizons for programmable and on-demand supramolecular chemotherapy with high antitumor efficiency.
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http://dx.doi.org/10.1021/acsami.1c09823DOI Listing
July 2021

Association of HbA1c with all-cause mortality across varying degrees of glycemic variability in type 2 diabetes.

J Clin Endocrinol Metab 2021 Jul 19. Epub 2021 Jul 19.

Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital; Shanghai Clinical Center for Diabetes; Shanghai Key Clinical Center for Metabolic Disease; Shanghai Diabetes Institute; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China.

Context: The interaction of glycated hemoglobin A1c (HbA1c) and glycemic variability in relation to diabetes-related outcomes remains unknown.

Objective: To evaluate the relationship between HbA1c and all-cause mortality across varying degrees of glycemic variability in patients with type 2 diabetes.

Design, Setting, And Patients: This was a prospective study conducted in a single referral center. Data of 6090 hospitalized patients with type 2 diabetes was analyzed. Glucose coefficient of variation (CV) was obtained as the measure of glycemic variability by using continuous glucose monitoring (CGM) for 3 days. Cox proportional hazards regression models were used to estimate hazard ratios and 95% CIs for all-cause mortality.

Results: During a median follow-up of 6.8 years, 815 patients died. In patients with the lowest and middle tertiles of glucose CV, HbA1c ≥8.0% was associated with 136% (95%CI 1.46-3.81) and 92% (95%CI 1.22-3.03) higher risks of all-cause mortality as compared with HbA1c 6.0-6.9%, respectively, after adjusting for confounders. However, a null association of HbA1c with mortality was found in patients with the highest tertile of glucose CV.

Conclusions: HbA1c may not be a robust marker of all-cause mortality in patients with high degree of glycemic variability. New metrics of glycemic control may be needed in these individuals to achieve better diabetes management.
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http://dx.doi.org/10.1210/clinem/dgab532DOI Listing
July 2021

Neptune: an environment for the delivery of genomic medicine.

Genet Med 2021 Oct 13;23(10):1838-1846. Epub 2021 Jul 13.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.

Purpose: Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process.

Methods: We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration.

Results: Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow.

Conclusion: Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .
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http://dx.doi.org/10.1038/s41436-021-01230-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487966PMC
October 2021

Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor.

Elife 2021 07 13;10. Epub 2021 Jul 13.

School of Pharmacy, Fudan University, Shanghai, China.

Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-EM structure of the human GIPR in complex with GIP and a G heterotrimer at a global resolution of 2.9 Å. GIP adopts a single straight helix with its N terminus dipped into the receptor transmembrane domain (TMD), while the C terminus is closely associated with the extracellular domain and extracellular loop 1. GIPR employs conserved residues in the lower half of the TMD pocket to recognize the common segments shared by GIP homologous peptides, while uses non-conserved residues in the upper half of the TMD pocket to interact with residues specific for GIP. These results provide a structural framework of hormone recognition and GIPR activation.
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http://dx.doi.org/10.7554/eLife.68719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298097PMC
July 2021

Identification and Characterization of Robust Hepatocellular Carcinoma Prognostic Subtypes Based on an Integrative Metabolite-Protein Interaction Network.

Adv Sci (Weinh) 2021 09 11;8(17):e2100311. Epub 2021 Jul 11.

CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.

Metabolite-protein interactions (MPIs) play key roles in cancer metabolism. However, our current knowledge about MPIs in cancers remains limited due to the complexity of cancer cells. Herein, the authors construct an integrative MPI network and propose a MPI network based hepatocellular carcinoma (HCC) subtyping and mechanism exploration workflow. Based on the expressions of hub proteins on the MPI network, two prognosis-distinctive HCC subtypes are identified. Meanwhile, multiple interdependent features of the poor prognostic subtype are observed, including hypoxia, DNA hypermethylation of metabolic pathways, fatty acid accumulation, immune pathway up-regulation, and exhausted T-cell infiltration. Notably, the immune pathway up-regulation is probably induced by accumulated unsaturated fatty acids which are predicted to interact with multiple immune regulators like SRC and TGFB1. Moreover, based on tumor microenvironment compositions, the poor prognostic subtype is further divided into two sub-populations showing remarkable differences in metabolism. The subtyping shows a strong consistency across multiple HCC cohorts including early-stage HCC. Overall, the authors redefine robust HCC prognosis subtypes and identify potential MPIs linking metabolism to immune regulations, thus promoting understanding and clinical applications about HCC metabolism heterogeneity.
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http://dx.doi.org/10.1002/advs.202100311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425875PMC
September 2021

Clinical efficacy and security of glycyrrhizic acid preparation in the treatment of anti-SARS-CoV-2 drug-induced liver injury: a protocol of systematic review and meta-analysis.

BMJ Open 2021 07 9;11(7):e051484. Epub 2021 Jul 9.

Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China

Introduction: COVID-19 is a highly infectious acute pneumonia. Glycyrrhizic acid preparation (GAP) has been found to have hepatoprotective and antiviral effects, but there is no supporting evidence on its efficacy and security for patients with COVID-19.

Methods And Analysis: The systematic review methods will be defined by Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This study will start on 1 July 2021 and end on 31 October 2021. A comprehensive electronic search will be conducted with the search of Web of Science, PubMed, Ovid web, China National Knowledge Infrastructure, Chinese Scientific and Journal Database, Wanfang Database and grey literature, and manual search will be conducted to search literature of randomised controlled trials, single-arm trials and retrospective studies about GAP in the treatment of anti-SARS-CoV-2 drug-induced liver injury from 1 December 2019 to 1 July 2021. There is no time limitations of publication and language will be restricted to Chinese and English. Retrieved studies will be independently screened by two researchers and relevant data will be extracted from studies. Interstudy heterogeneity will be assessed using the I statistic and explored through meta-regressions and subgroup analyses. Depending on data availability, we plan to conduct subgroup analyses by study population, geographical region and other selected clinical variables of interest. Quality assessment of the studies will be performed. Cochrane Handbook for Systematic Reviews of Interventions will be used to assess the risk of bias, and Grading of Recommendations Assessment, Development and Evaluation will be used to access the confidence in cumulative evidence.

Ethics And Dissemination: Ethical approval will not be required for no primary data of individual patients will be collected. The final report will be shared with the scientific community through publication in a peer-reviewed journal, as well as with key stakeholders, including patients, healthcare professionals and those working on COVID-19 research.

Prospero Registration Number: CRD42021234647.
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http://dx.doi.org/10.1136/bmjopen-2021-051484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275357PMC
July 2021

Microparticle sorting with a virtual optical chip.

Rev Sci Instrum 2021 May;92(5):053201

School of Physics and Electronics, Central South University, Changsha 410083, China.

We proposed an automatic sorting method based on a virtual optical chip, which was formed by a complex-amplitude beam shaping system. The automatic sorting of different micro-particles was realized by the optical forces of the intensity and phase gradients of the reconstructed optical beam. The method was verified with theoretical analysis and experimental results. Compared with the traditional optical sorting methods, the proposed one does not need high-precision mechanical and/or microfluidic devices. The optical chip is flexible in structure and efficient in optical sorting and can be used in the fields of medical detection and material sensing.
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http://dx.doi.org/10.1063/5.0047316DOI Listing
May 2021

lncRNA MALAT1 regulated ATAD2 to facilitate retinoblastoma progression via miR-655-3p.

Open Med (Wars) 2021 24;16(1):931-943. Epub 2021 Jun 24.

Department of Ophthalmology, Weihai Central Hospital, No. 3, Mishandongluxi, Wendeng District, Weihai, 264400, Shandong, China.

Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was reported as an oncogene in many tumors including retinoblastoma (RB). This research mainly focused on the functions and mechanism of MALAT1 in RB. MALAT1 was upregulated in RB tissues and cells, and it served as a competing endogenous RNA (ceRNA) and inhibited miRNA-655-3p (miR-655-3p) expression, which eventually regulated the expression of miR-655-3p downstream target ATPase Family AAA Domain Containing 2 (ATAD2). The level of ATAD2 significantly increased, while that of miR-655-3p remarkably decreased in RB tissues and cells. MALAT1 depletion inhibited cell proliferation, metastasis, and epithelial-mesenchymal transition (EMT), but promoted apoptosis and blocked xenograft tumor growth . MALAT1 exerted its oncogenic functions in RB by regulating miR-655-3p/ATAD2 axis.
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http://dx.doi.org/10.1515/med-2021-0290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231467PMC
June 2021

Genomic evidence of adaptive evolution in the reptilian SOCS gene family.

PeerJ 2021 24;9:e11677. Epub 2021 Jun 24.

College of Life Science, Qufu Normal University, Qufu, Shandong, China.

The suppressor of the cytokine signaling (SOCS) family of proteins play an essential role in inhibiting cytokine receptor signaling by regulating immune signal pathways. Although SOCS gene functions have been examined extensively, no comprehensive study has been performed on this gene family's molecular evolution in reptiles. In this study, we identified eight canonical SOCS genes using recently-published reptilian genomes. We used phylogenetic analysis to determine that the SOCS genes had highly conserved evolutionary dynamics that we classified into two types. We identified positive selection signals in whole reptile lineages and selection signals in the crocodilian lineage. Selective pressure analyses using the branch model and Z-test revealed that these genes were under different negative selection pressures compared to reptile lineages. We also concluded that the nature of selection pressure varies across different reptile lineages on , and the crocodilian lineage has experienced rapid evolution. Our results may provide a theoretical foundation for further analyses of reptilian SOCS genes' functional and molecular mechanisms, as well as their roles in reptile growth and development.
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http://dx.doi.org/10.7717/peerj.11677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236234PMC
June 2021

Effect of Heat Treatment on Microstructure and Mechanical Properties of a Selective Laser Melting Processed Ni-Based Superalloy GTD222.

Materials (Basel) 2021 Jun 30;14(13). Epub 2021 Jun 30.

High-Temperature Materials Department, Central Iron & Steel Research Institute, Beijing 100081, China.

Additive manufacturing (AM) of nickel-based superalloys is of high interest for application in complex hot end parts. However, it has been widely suggested that the microstructure-properties of the additive manufacturing processed superalloys are not yet fully clear. In this study, the GTD222, an important superalloy for high-temperature hot-end part, were prepared using selective laser melting and then subjected to heat treatment. The microstructure evolution of the GTD222 was investigated and the mechanical properties of heat treated GTD222 were tested. The results have shown that the grain size of the heat treated GTD222 was close to its as-built counterparts. Meanwhile, a large amount of γ' and nano-scaled carbides were precipitated in the heat treated GTD222. The microstructure characteristics implied that the higher strength of the heat treated GTD222 can be attributed to the γ' and nano-scaled carbides. This study provides essential microstructure and mechanical properties information for optimizing the heat treatment process of the AM processed GTD222.
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http://dx.doi.org/10.3390/ma14133668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269798PMC
June 2021

Pulmonary arterial hypertension and flavonoids: A role in treatment.

Chin J Physiol 2021 May-Jun;64(3):115-124

Department of Pharmacology, College of Pharmacy; Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education; Ningxia Characteristic Traditional Chinese Medicine Modernization Engineering Technology Research Center, Ningxia Medical University, Yinchuan, China.

Pulmonary arterial hypertension (PAH) is a high mortality progressive pulmonary vascular disease that can lead to right heart failure. The use of clinical drugs for the treatment of PAH is limited to a great extent because of its single target and high price. Flavonoids are widely distributed in nature, and have been found in fruits, vegetables, and traditional Chinese medicine. They have diverse biological activities and various pharmacological effects such as antitumor, antioxidation, and anti-inflammatory. This review summarizes the progress in pharmacodynamics and mechanism of flavonoids in the treatment of PAH in recent years, in order to provide some theoretical references for relevant researchers.
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http://dx.doi.org/10.4103/cjp.cjp_25_21DOI Listing
June 2021

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.

Nat Commun 2021 06 18;12(1):3763. Epub 2021 Jun 18.

School of Pharmacy, Fudan University, Shanghai, China.

The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.
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http://dx.doi.org/10.1038/s41467-021-24058-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213797PMC
June 2021
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