Publications by authors named "Chuan He"

754 Publications

Synthesis of Si-Stereogenic Silanols by Catalytic Asymmetric Hydrolytic Oxidation.

Angew Chem Int Ed Engl 2022 May 25. Epub 2022 May 25.

Southern University of Science and Technology, Chemistry, No 1088,xueyuan Rd., Xili, Nanshan District, 518055, Shenzhen, CHINA.

Despite a growing progress for the construction of chiral organosilicon compounds, the catalytic asymmetric synthesis of silicon-stereogenic silanols is less explored and remains a considerable challenge. Herein, we report the first enantioselective construction of silicon-stereogenic silanols via catalytic asymmetric hydrolytic oxidation of dihydrosilanes. This practical protocol features ambient reaction conditions, high atom economy, good functional-group compatibility, and cleaner manner with H2 as the only by-product, producing a wide range of valuable chiral silanols and bis-silanols in decent yields with excellent chemo- and stereoselectivity.
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http://dx.doi.org/10.1002/anie.202204912DOI Listing
May 2022

Development of Mild Chemical Catalysis Conditions for mA-to-mA Rearrangement on RNA.

ACS Chem Biol 2022 May 20. Epub 2022 May 20.

Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States.

The conversion of -methyladenosine (mA) to -methyladenosine (mA) on RNA is an important step for both allowing efficient reverse transcription read-though for sequencing analysis and mapping modifications in the transcriptome. Enzymatic transformation is often used, but the efficiency of the removal can depend on local sequence context. Chemical conversion through the application of the Dimroth rearrangement, in which mA rearranges into mA under heat and alkaline conditions, is an alternative, but the required alkaline conditions result in significant RNA degradation by hydrolysis of the phosphodiester backbone. Here, we report novel, mild pH conditions that catalyze mA-to-mA arrangement using 4-nitrothiophenol as a catalyst. We demonstrate the efficient rearrangement in mononucleosides, synthetic RNA oligonucleotides, and RNAs isolated from human cell lines, thereby validating a new approach for converting mA-to-mA in RNA samples for sequencing analyses.
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http://dx.doi.org/10.1021/acschembio.2c00178DOI Listing
May 2022

FTO mediates LINE1 mA demethylation and chromatin regulation in mESCs and mouse development.

Science 2022 May 5;376(6596):968-973. Epub 2022 May 5.

Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637, USA.

-methyladenosine (mA) is the most abundant internal modification on mammalian messenger RNA. It is installed by a writer complex and can be reversed by erasers such as the fat mass and obesity-associated protein FTO. Despite extensive research, the primary physiological substrates of FTO in mammalian tissues and development remain elusive. Here, we show that FTO mediates mA demethylation of long-interspersed element-1 (LINE1) RNA in mouse embryonic stem cells (mESCs), regulating LINE1 RNA abundance and the local chromatin state, which in turn modulates the transcription of LINE1-containing genes. FTO-mediated LINE1 RNA mA demethylation also plays regulatory roles in shaping chromatin state and gene expression during mouse oocyte and embryonic development. Our results suggest broad effects of LINE1 RNA mA demethylation by FTO in mammals.
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http://dx.doi.org/10.1126/science.abe9582DOI Listing
May 2022

Decoding pseudouridine: an emerging target for therapeutic development.

Trends Pharmacol Sci 2022 Jun 21;43(6):522-535. Epub 2022 Apr 21.

Division of Stem Cell Biology Research, Department of Stem Cell Biology and Regenerative Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Electronic address:

Pseudouridine (Ψ) is the most abundant post-transcriptional RNA modification and is widespread in multiple RNA species. Ψ impacts various aspects of RNA biology, conferring distinct structural and functional properties to the RNA molecules that it decorates. However, aberrant pseudouridylation contributes to a variety of human diseases, including cancer and genetic disorders. Dysregulation of the Ψ epitranscriptome can arise from mutations and abnormal expression of pseudouridylation machinery, impacting protein translation and other cellular processes. With advancing understanding of Ψ roles in health and disease, efforts are now invested in developing therapeutic and diagnostic approaches targeting Ψ. Emerging reports indicate that Ψ and its installation machinery could be potential pharmacological targets for therapeutic development and may serve as biomarkers for human diseases.
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http://dx.doi.org/10.1016/j.tips.2022.03.008DOI Listing
June 2022

PPARγ Gene Polymorphisms, Metabolic Disorders, and Coronary Artery Disease.

Front Cardiovasc Med 2022 23;9:808929. Epub 2022 Mar 23.

Department of Cardiology, Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu, China.

Being activated by endogenous and exogenous ligands, nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) enhances insulin sensitivity, promotes adipocyte differentiation, stimulates adipogenesis, and has the properties of anti-atherosclerosis, anti-inflammation, and anti-oxidation. The Human PPARγ gene () contains thousands of polymorphic loci, among them two polymorphisms (rs10865710 and rs7649970) in the promoter region and two polymorphisms (rs1801282 and rs3856806) in the exonic region were widely reported to be significantly associated with coronary artery disease (CAD). Mechanistically, polymorphisms lead to abnormal expression of gene and/or dysfunction of PPARγ protein, causing metabolic disorders such as hypercholesterolemia and hypertriglyceridemia, and thereby increasing susceptibility to CAD.
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http://dx.doi.org/10.3389/fcvm.2022.808929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8984027PMC
March 2022

The relationship between NTCP gene varieties and the progress of liver disease after HBV infection: an updated systematic review and meta-analysis.

Am J Med Sci 2022 Apr 6. Epub 2022 Apr 6.

Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Infection and Immunity Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, China. Electronic address:

Background: The aim of this study was to analyze the relationship between sodium taurocholate cotransporting polypeptide (NTCP) gene varieties and hepatitis B virus (HBV) infection and the progress of HBV-related liver disease.

Methods: PubMed, EMBASE, Web of Science and Cochrane library were used to search eligible studies. STATA software was performed to combine results. Pooled odds ratios (OR) was used to assess the potential genetic relationships.

Results: A total of 18 eligible case-control studies with 24960 cases and 28342 controls were included in this meta-analysis. The A allele of rs2296651 polymorphism was found to be significantly linked to a protection of HBV infection in the whole combined analysis (P = 0.000). Meanwhile, this allele was significantly associated with a decreased risk of hepatocellular carcinoma (HCC) (A vs. G: OR = 0.668, 95% CI: 0.571-0.782, P = 0.000), and was significantly associated with HBV nature clearance (A vs. G: OR = 0.744, 95% CI: 0.585-0.946, P = 0.016; AA+GA vs. GG: OR = 0.775, 95% CI: 0.613-0.980, P = 0.033; GA vs. GG: OR = 0.748, 95% CI: 0.588-0.952, P = 0.018). However, rs4646287 genetic varieties had no statistical differences in all models with HBV infection or HBV-related disease progress, liver cirrhosis, acute-on-chronic liver failure and HCC, as well as rs7154439, rs4646285, rs4646296.

Conclusions: Rs2296651 polymorphism (A allele) may protect HBV infection and the progress of HBV-related disease (HBV-related HCC). Future research about other single nucleotide polymorphisms (SNPs) (rs4646287, rs7154439, rs4646285, rs4646296) of NTCP may be needed to clarify the relationship of NTCP gene varieties with HBV infection and HBV-related disease.
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http://dx.doi.org/10.1016/j.amjms.2022.03.014DOI Listing
April 2022

A Study on Differences between Professional Endoscopists and Gastroenterologists in Endoscopic Detection and Standard Pathological Biopsy of Inflammatory Bowel Diseases.

Gastroenterol Res Pract 2022 26;2022:7333579. Epub 2022 Mar 26.

The First Hospital of Jilin University, Changchun, China.

Objective: To assess whether professional endoscopists need additional training on inflammatory bowel disease (IBD) diagnosis.

Methods: This retrospective study was conducted in patients with IBD, including Crohn's disease (CD) and ulcerative colitis (UC), which were diagnosed and treated for the first time in our hospital between January 2005 and December 2020. Doctors including gastroenterologists (group G) and professional endoscopists (group E) participated in the study. The data divided into CD or UC and group G or group E were compared.

Results: Patients with CD exhibited higher rates of terminal ileal lesions, reexamined colonoscopy within 6 months, and intestinal stenosis than patients with UC ( < 0.001). The positive endoscopic IBD diagnosis rate was significantly higher in group G than in group E (89.6% vs. 74.0%, < 0.001). In the subgroup analysis for patients with CD, the positive endoscopic IBD diagnosis rate was significantly higher for group G than for group E (81.5% vs. 41.8%, < 0.001). However, the two groups exhibited no significant difference in the subgroup analysis for patients with UC (94.1% vs. 86.5%, = 0.060). Group G exhibited a higher rate of terminal ileal intubation (83.1% vs. 65.3%, < 0.001) and standard pathological biopsy (72.7% vs. 26.0%, < 0.001) than Group E.

Conclusion: Professional endoscopists showed lower rates of terminal ileal intubation, positive endoscopic diagnosis, and standard pathological biopsy than gastroenterologists. Hence, additional training on IBD, particularly on CD, must be provided to professional endoscopists to increase their efficiency for terminal ileal intubation and positive endoscopic diagnosis and to enhance their awareness regarding standard biopsy.
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http://dx.doi.org/10.1155/2022/7333579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8976660PMC
March 2022

A longitudinal analysis of immune escapes from HLA-B*13-restricted T-cell responses at early stage of CRF01_AE subtype HIV-1 infection and implications for vaccine design.

BMC Immunol 2022 04 2;23(1):15. Epub 2022 Apr 2.

NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China.

Background: Identifying immunogens which can elicit effective T cell responses against human immunodeficiency virus type 1 (HIV-1) is important for developing a T-cell based vaccine. It has been reported that human leukocyte antigen (HLA)-B*13-restricted T-cell responses contributed to HIV control in subtype B' and C infected individuals. However, the kinetics of B*13-restricted T-cell responses, viral evolution within epitopes, and the impact on disease progression in CRF01_AE subtype HIV-1-infected men who have sex with men (MSM) are not known.

Results: Interferon-γ ELISPOT assays and deep sequencing of viral RNAs were done in 14 early HLA-B*13-positive CRF01_AE subtype HIV-1-infected MSM. We found that responses to RQEILDLWV (Nef, RV9), GQMREPRGSDI (Gag, GI11), GQDQWTYQI (Pol, GI9), and VQNAQGQMV (Gag, VV9) were dominant. A higher relative magnitude of Gag-specific T-cell responses, contributed to viral control, whereas Nef-specific T-cell responses were associated with rapid disease progression. GI11 (Gag) was conserved and strong GI11 (Gag)-specific T-cell responses showed cross-reactivity with a dominant variant, M228I, found in 3/12 patients; GI11 (Gag)-specific T-cell responses were positively associated with CD4 T-cell counts (R = 0.716, P = 0.046). Interestingly, the GI9 (Pol) epitope was also conserved, but GI9 (Pol)-specific T-cell responses did not influence disease progression (P > 0.05), while a D490G variant identified in one patient did not affect CD4 T-cell counts. All the other epitopes studied [VV9 (Gag), RQYDQILIEI (Pol, RI10), HQSLSPRTL (Gag, HL9), and RQANFLGRL (Gag RL9)] developed escape mutations within 1 year of infection, which may have contributed to overall disease progression. Intriguingly, we found early RV9 (Nef)-specific T-cell responses were associated with rapid disease progression, likely due to escape mutations.

Conclusions: Our study strongly suggested the inclusion of GI11 (Gag) and exclusion of RV9 (Nef) for T-cell-based vaccine design for B*13-positive CRF01_AE subtype HIV-1-infected MSM and high-risk individuals.
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http://dx.doi.org/10.1186/s12865-022-00491-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8976269PMC
April 2022

USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy.

Nat Commun 2022 03 31;13(1):1700. Epub 2022 Mar 31.

Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.

Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15-25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8 T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy.
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http://dx.doi.org/10.1038/s41467-022-29401-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971425PMC
March 2022

Genome-wide Analysis Reflects Novel 5-Hydroxymethylcytosines Implicated in Diabetic Nephropathy and the Biomarker Potential.

Extracell Vesicles Circ Nucl Acids 2022 24;3(1):49-60. Epub 2022 Mar 24.

Department of Clinical Laboratory, Center for Gene Diagnosis & Program of Clinical Laboratory, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China.

Aim: Diabetic nephropathy (DN) has become the most common cause of end-stage renal disease (ESRD) in most countries. Elucidating novel epigenetic contributors to DN can not only enhance our understanding of this complex disorder, but also lay the foundation for developing more effective monitoring tools and preventive interventions in the future, thus contributing to our ultimate goal of improving patient care.

Methods: The 5hmC-Seal, a highly selective, chemical labeling technique, was used to profile genome-wide 5-hydroxymethylcytosines (5hmC), a stable cytosine modification type marking gene activation, in circulating cell-free DNA (cfDNA) samples from a cohort of patients recruited at Zhongnan Hospital, including T2D patients with nephropathy (DN, n = 12), T2D patients with non-DN vascular complications (non-DN, n = 29), and T2D patients without any complication (controls, n = 14). Differentially analysis was performed to find DN-associated 5hmC features, followed by the exploration of biomarker potential of 5hmC in cfDNA for DN using a machine learning approach.

Results: Genome-wide analyses of 5hmC in cfDNA detected 427 and 336 differential 5hmC modifications associated with DN, compared with non-DN individuals and controls, and suggested relevant pathways such as NOD-like receptor signaling pathway and tyrosine metabolism. Our exploration using a machine learning approach revealed an exploratory model comprised of ten 5hmC genes showing the possibility to distinguish DN from non-DN individuals or controls.

Conclusion: Genome-wide analysis suggests the possibility of exploiting novel 5hmC in patient-derived cfDNA as a non-invasive tool for monitoring DN in high risk T2D patients in the future.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8950161PMC
March 2022

mA RNA modifications are measured at single-base resolution across the mammalian transcriptome.

Nat Biotechnol 2022 Mar 14. Epub 2022 Mar 14.

Department of Chemistry, The University of Chicago, Chicago, IL, USA.

Functional studies of the RNA N-methyladenosine (mA) modification have been limited by an inability to map individual mA-modified sites in whole transcriptomes. To enable such studies, here, we introduce mA-selective allyl chemical labeling and sequencing (mA-SAC-seq), a method for quantitative, whole-transcriptome mapping of mA at single-nucleotide resolution. The method requires only ~30 ng of poly(A) or rRNA-depleted RNA. We mapped mA modification stoichiometries in RNA from cell lines and during in vitro monocytopoiesis from human hematopoietic stem and progenitor cells (HSPCs). We identified numerous cell-state-specific mA sites whose methylation status was highly dynamic during cell differentiation. We observed changes of mA stoichiometry as well as expression levels of transcripts encoding or regulated by key transcriptional factors (TFs) critical for HSPC differentiation. mA-SAC-seq is a quantitative method to dissect the dynamics and functional roles of mA sites in diverse biological processes using limited input RNA.
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http://dx.doi.org/10.1038/s41587-022-01243-zDOI Listing
March 2022

Enantioselective Intermolecular C-H Silylation of Heteroarenes for the Synthesis of Acyclic Si-Stereogenic Silanes.

Angew Chem Int Ed Engl 2022 May 16;61(21):e202117820. Epub 2022 Mar 16.

Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.

Intermolecular C-H silylation for the synthesis of acyclic silanes bearing a silicon-stereogenic center in one enantiomeric form remains unknown to date. Herein, we report the first enantioselective intermolecular C-H silylation of heteroarenes for the synthesis of acyclic silicon-stereogenic heteroarylsilanes. This process undergoes a rhodium-catalyzed direct intermolecular dehydrogenative Si-H/C-H cross-coupling, giving access to a variety of acyclic heteroarylated silicon-stereogenic monohydrosilanes, including bis-Si-stereogenic silanes, in decent yields with excellent chemo-, regio-, and stereo-control, which significantly enlarge the chemical space of the optically active silicon-stereogenic monohydrosilanes.
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http://dx.doi.org/10.1002/anie.202117820DOI Listing
May 2022

Cortical Inhibition State-Dependent iTBS Induced Neural Plasticity.

Front Neurosci 2022 17;16:788538. Epub 2022 Feb 17.

Department of Rehabilitation Medicine, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, China.

Background: Intermittent theta burst stimulation (iTBS) is an effective stimulus for long-term potentiation (LTP)-like plasticity. However, iTBS-induced effects varied greatly between individuals. Ample evidence suggested that an initial decrease in local γ-aminobutyric acid (GABA) or enhancement in -methyl-D-aspartate (NMDA) facilitation neurotransmission is of vital importance for allowing LTP-like plasticity to occur. Therefore, we aimed to investigate whether the individual level of GABA or NMDA receptor-mediated activity before stimulation is correlated with the after-effect in cortical excitability induced by iTBS.

Methods: Fifteen healthy volunteers were recruited for the present study. We measured short-interval intracortical inhibitory (SICI), long-interval intracortical inhibitory (LICI), and intracortical facilitation (ICF), which index GABA receptor-, GABA receptor-, and glutamate receptor-mediated activity, respectively, in the cortex before conducting iTBS. After iTBS intervention, the changes of motor-evoked potential (MEP) amplitude were taken as a measure for cortical excitability in response to iTBS protocol.

Results: There was a significant negative correlation between the amount of SICI measured before iTBS and the after-effect of iTBS-induced LTP-like plasticity at the time points of 5, 10, and 15 min after inducing iTBS. A multiple linear regression model indicated that SICI was a good predictor of the after-effect in cortical excitability induced by iTBS at 5, 10, and 15 min following stimulation.

Conclusion: The present study found that GABA receptor-mediated activity measured before stimulation is negatively correlated with the after-effect of cortical excitability induced by iTBS. SICI, as the index of GABA receptor-mediated activity measured before stimulation, might be a good predictor of iTBS-induced LTP-like plasticity for a period lasting 15 min following stimulation.
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http://dx.doi.org/10.3389/fnins.2022.788538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891511PMC
February 2022

Brain-gut-microbiota axis in Parkinson's disease: A historical review and future perspective.

Brain Res Bull 2022 Jun 1;183:84-93. Epub 2022 Mar 1.

Department of Neurology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address:

Parkinson's disease (PD) is the second most common degenerative disease of the central nervous system (CNS) after Alzheimer's disease. In addition to the typical motor symptoms, the clinical manifestations of patients with PD include gastrointestinal symptoms, which even precede the motor symptoms. Recent research has found that the gut microbiota regulates the brain-gut axial interaction through immune, endocrine, and direct neural mechanisms, supporting the hypothesis that the pathological process of PD spreads from the gut to the brain. In this review article, we highlight the landmark findings in the field of PD, with particular attention to the brain-gut-microbiota axis. We summarize the changes and their clinical effects on the gut microbiota and metabolites observed in PD. The intestinal microbiota may contain appropriate targets for the prevention and treatment of PD. Clinical cohort studies suggest that certain intestinal microbes have protective or pathogenic effects on the progression of PD. A better understanding of the interaction between the gut-brain axis, the gut microbiota, and PD has the potential to lead to new diagnostic and therapeutic approaches. Animal experiments suggest that fecal microbiota transplantation (FMT) is helpful for treating PD, and FMT is expected to be an effective treatment for PD in the future.
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http://dx.doi.org/10.1016/j.brainresbull.2022.02.015DOI Listing
June 2022

Comparison of two cell-free therapeutics derived from adipose tissue: small extracellular vesicles versus conditioned medium.

Stem Cell Res Ther 2022 03 3;13(1):86. Epub 2022 Mar 3.

State Key Laboratory of Oral Disease and National Clinical Research Center for Oral Diseases and National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu, China.

Background: Cell-free therapy has been inspired as a promising approach to overcome the limitations of traditional stem cell therapy. However, the therapeutic effect between extracellular vesicles and conditioned medium with the same source had not been compared. Our previous studies have shown that both the conditioned medium of adipose tissue (adipose tissue extract, ATE) and its further purification product small extracellular vesicles (sEV-AT) contributed to adipose tissue regeneration. In this study, we aimed to compare the ATE and sEV-AT in composition, inductivity on cells and de novo adipose regenerative potential.

Methods: The characteristics of sEV-AT and ATE were compared through protein and particle yield, particle size distribution and composition. The inductivity of sEV-AT and ATE on cells were compared through co-culture of sEV-AT or ATE with ASC, HUVEC and RAW264.7 in vitro. The capacity of promoting de novo adipogenesis was compared by implanting the silicone tube containing sEV-AT or ATE subcutaneously in vivo.

Results: More particles and concentrated particle size distribution were detected in sEV-AT. In turn, more soluble factors and multiple peaks in particle size distribution were detected in ATE. In 1662 common proteins of sEV-AT and ATE, there were 984 (59.2%) proteins enriched twice more in sEV-AT than in ATE. With the prerequisite of equivalent protein concentration, sEV-AT outperformed ATE in promoting proliferation, migration and regeneration potential of cells those contributing adipose tissue regeneration in vitro. Furthermore, sEV-AT expedited the de novo adipose tissue regeneration and angiogenesis at the early stage than ATE in vivo, but sEV-AT and ATE group formed similar neoadipose tissue and new vessels at week 12.

Conclusions: Our results provided a direct comparison between EV and conditioned medium as cell-free therapeutic strategy. Both sEV and ATE had specific biological signature to facilitate tissue repair. Considering the convenience of extraction and acceptable effect, ATE represented a feasible product of cell-free therapy, providing another option for different situations in clinical application. Furthermore, the complex contents of both sEV-AT and ATE should be studied comprehensively to avoid possible negative effects and to ensure sufficient safety for clinical applications.
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http://dx.doi.org/10.1186/s13287-022-02757-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895642PMC
March 2022

Effects of posterior tibial slope on the mid-term results of medial unicompartmental knee arthroplasty.

Arthroplasty 2021 Apr 12;3(1):11. Epub 2021 Apr 12.

Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.

Objective: To evaluate the effect of medial posterior tibial slope (PTS) on mid-term postoperative range of motion (ROM) and functional improvement of the knee after medial unicompartmental knee arthroplasty (UKA).

Methods: Medical records of 113 patients who had undergone 124 medial UKAs between April 2009 through April 2014 were reviewed retrospectively. The mean follow-up lasted 7.6 years (range, 6.2-11.2 years). Collected were demographic data, including gender, age, height, weight of the patients. Anteroposterior (AP) and lateral knee radiographs of the operated knees were available in all patients. The knee function was evaluated during office follow-up or hospital stay. Meanwhile, postoperative PTS, ROM, maximal knee flexion and Hospital for Special Surgery (HSS) knee score (pre-/postoperative) of the operated side were measured and assessed. According to the size of the PTS, patients were divided into 3 groups: group 1 (<4°), group 2 (4° ~ 7°) and group 3 (>7°). The association between PTS and the knee function was investigated.

Results: In our cohort, the average PTS was 2.7° ± 0.6° in group 1, 5.6° ± 0.9° in group 2 and 8.7° ± 1.2° in group 3. Pairwise comparisons showed significant differences among them (p < 0.01). The average maximal flexion range of postoperative knees in each group was 112.4° ± 5.6°, 116.4° ± 7.2°, and 117.5° ± 6.1°, respectively, with significant difference found between group 1 and group 2 (p < 0.05), and between group 1 and group 3 (p < 0.05). However, the gender, age, and body mass index (BMI) did not differ between three groups and there was no significant difference between groups in terms of pre-/postoperative HSS scores or postoperative knee ROM.

Conclusion: A mid-term follow-up showed that an appropriate PTS (4° ~ 7°) can help improve the postoperative flexion of knee. On the other hand, too small a PTS could lead to limited postoperative knee flexion. Therefore, the PTS less than 4° should be avoided during medial UKA.
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http://dx.doi.org/10.1186/s42836-021-00070-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8796409PMC
April 2021

Fabrication of highly sensitive and uniform Ag/PS/PDMS SERS substrate and its application fordetection.

Nanotechnology 2022 Mar 23;33(24). Epub 2022 Mar 23.

School of Science, Nantong University, Nantong, Jiangsu 226019, People's Republic of China.

In this study, we developed a flexible and transparent silver/polystyrene/polydimethylsiloxane (Ag/PS/PDMS) substrate with both high density of hot spots and satisfactory uniformity using a cost-effective approach. Via template-guided self-assembly, PS beads were arranged regularly in nanobowls of a square array on PDMS, whose surface structure was transferred from a commercial complementary metal oxide semiconductor chip. Roughness was introduced onto the PS bead surface by nitrogen plasma treatment, followed by sputtering of Ag which generated many hot spots. Differential roughness on the PS bead surface greatly influenced the morphology of the Ag/PS/PDMS substrate. A meat-ball like surface structure was formed with a plasma etching time of 5 min, whose growth mechanism was proposed based on the scanning electron microscope analysis. The high sensitivity and desirable uniformity of the meat-ball like Ag/PS/PDMS substrate were demonstrated by using crystal violet as a Raman reporter, exhibiting an enhancement factor of 2.7 × 10and a relative standard deviation of 5.04%. Thiram of a lower concentration than the maximum residue limit on the cucumber surface could easily be detectedby the proposed substrate, demonstrating its great potential forfood safety analysis.
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http://dx.doi.org/10.1088/1361-6528/ac59e9DOI Listing
March 2022

The chromatin organization of a chlorarachniophyte nucleomorph genome.

Genome Biol 2022 03 1;23(1):65. Epub 2022 Mar 1.

Department of Genetics, Stanford University, Stanford, CA, 94305, USA.

Background: Nucleomorphs are remnants of secondary endosymbiotic events between two eukaryote cells wherein the endosymbiont has retained its eukaryotic nucleus. Nucleomorphs have evolved at least twice independently, in chlorarachniophytes and cryptophytes, yet they have converged on a remarkably similar genomic architecture, characterized by the most extreme compression and miniaturization among all known eukaryotic genomes. Previous computational studies have suggested that nucleomorph chromatin likely exhibits a number of divergent features.

Results: In this work, we provide the first maps of open chromatin, active transcription, and three-dimensional organization for the nucleomorph genome of the chlorarachniophyte Bigelowiella natans. We find that the B. natans nucleomorph genome exists in a highly accessible state, akin to that of ribosomal DNA in some other eukaryotes, and that it is highly transcribed over its entire length, with few signs of polymerase pausing at transcription start sites (TSSs). At the same time, most nucleomorph TSSs show very strong nucleosome positioning. Chromosome conformation (Hi-C) maps reveal that nucleomorph chromosomes interact with one other at their telomeric regions and show the relative contact frequencies between the multiple genomic compartments of distinct origin that B. natans cells contain.

Conclusions: We provide the first study of a nucleomorph genome using modern functional genomic tools, and derive numerous novel insights into the physical and functional organization of these unique genomes.
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http://dx.doi.org/10.1186/s13059-022-02639-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887012PMC
March 2022

Utility of Perioperative Measurement of Cell-Free DNA and Circulating Tumor DNA in Informing the Prognosis of GI Cancers: A Systematic Review.

JCO Precis Oncol 2022 02;6:e2100337

Department of Surgery, University of Chicago, Chicago, IL.

Purpose: Current surveillance imaging and tumor markers lack sensitivity for the early detection of recurrence in GI cancers. This study critically evaluates the current literature on the role of sequential measurement of circulating tumor DNA (ctDNA) before and after curative resection in informing recurrence.

Methods: A systematic search using a predefined, registered protocol was conducted for studies published between January 2010 and May 2020. Included studies described patients with GI cancers treated with curative-intent surgical resection and measurement of ctDNA both before and after surgery. Patients were divided into three groups on the basis of the presence or absence of ctDNA at these time points. The primary outcome was recurrence-free survival (RFS).

Results: The search yielded 3,873 articles; five met the inclusion criteria and collectively evaluated 57 patients. Pooled median RFS was 62 months (interquartile range 19 to not reached). Although median RFS was not reached in group 1 (- to -) or group 2 (+ to -), median RFS in group 3 (+ to +) was 15 months (interquartile range 9.6-60.4 months). Cox hazard ratio was 4.46 (95% CI, 1.17 to 16.99; = .028) between group 1 and group 2, and 10.47 (95% CI, 2.91 to 37.74; < .001) between group 2 and group 3.

Conclusion: Detectable ctDNA, either preoperatively or postoperatively, and its persistence after curative surgery are associated with a greater risk of recurrence and decreased RFS in GI cancers. Thus, perioperative measurement of ctDNA may be a useful postoperative risk stratification tool and guide additional therapies.
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http://dx.doi.org/10.1200/PO.21.00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8984241PMC
February 2022

VSNL1 Promotes Cell Proliferation, Migration, and Invasion in Colorectal Cancer by Binding with COL10A1.

Ann Clin Lab Sci 2022 Jan;52(1):60-72

Abdominal Surgery, Medical College of Nanchang University, Cancer Hospital of Jiangxi Province, Nanchang, Jiangxi, China

Objective: The study aimed to explore the role of VSNL1/COL10A1 axis in colorectal cancer.

Methods: The differential-expressed mRNA in colorectal cancer tissues and adjacent tissues were analyzed through GEO database and GEPIA database. The target genes of mRNA were predicted through the Starbase database, and the targeting relationship of mRNA was verified by co-IP assay. The expressions of VSNL1 and COL10A1 were detected by RT-PCR and immunohistochemistry. Cell viability and proliferation were detected by CCK8 assay and EdU assay, respectively. Cell migration and invasion were detected by transwell assay. The expression of related proteins was detected by western blot.

Results: VSNL1 was significantly overexpressed in colorectal cancer tissues compared with adjacent tissues. In addition, downregulation of VSNL1 could inhibit the proliferation, migration, and invasion of colorectal cancer cells. The co-IP experiment indicated that VSNL1 could bind with COL10A1. Further studies demonstrated that upregulation of COL10A1 could promote colorectal cells proliferation, migration, invasion, and reverse the effect of sh-VSNL1 on colorectal cancer cells.

Conclusion: VSNL1 could promote the proliferation, migration, and invasion of colorectal cancer by targeting COL10A1. VSNL1 might be a potential target for colorectal cancer treatment.
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January 2022

Vascular feature as a modulator of the aging brain.

Cereb Cortex 2022 Feb 17. Epub 2022 Feb 17.

The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, Center for Information in Medicine, School of Life Science and Technology, University of Electronic Science and Technology of China, No.4, Section 2, North Jianshe Road, Chengdu 610054, P. R. China.

The cerebral functional reorganization and declined cognitive function of aging might associate with altered vascular features. Here, we explored the altered cerebral hierarchical functional network of 2 conditions (task-free and naturalistic stimuli) in older adults and its relationship with vascular features (systemic microvascular and perfusion features, measured by magnetic resonance imaging) and behavior. Using cerebral gradient analysis, we found that compressive gradient of resting-state mainly located on the primary sensory-motor system and transmodal regions in aging, and further compress in these regions under the continuous naturalistic stimuli. Combining cerebral functional gradient, vascular features, and cognitive performance, the more compressive gradient in the resting-state, the worse vascular state, the lower cognitive function in older adults. Further modulation analysis demonstrated that both vascular features can regulate the relationship between gradient scores in the insula and behavior. Interestingly, systemic microvascular oxygenation also can modulate the relationship between cerebral gradient and cerebral perfusion. Furthermore, the less alteration of the compressive gradient with naturalistic stimuli came with lower cognitive function. Our findings demonstrated that the altered cerebral hierarchical functional structure in aging was linked with changed vascular features and behavior, offering a new framework for studying the physiological mechanism of functional connectivity in aging.
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http://dx.doi.org/10.1093/cercor/bhac039DOI Listing
February 2022

METTL16 exerts an mA-independent function to facilitate translation and tumorigenesis.

Nat Cell Biol 2022 02 10;24(2):205-216. Epub 2022 Feb 10.

City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.

METTL16 has recently been identified as an RNA methyltransferase responsible for the deposition of N-methyladenosine (mA) in a few transcripts. Whether METTL16 methylates a large set of transcripts, similar to METTL3 and METTL14, remains unclear. Here we show that METTL16 exerts both methyltransferase activity-dependent and -independent functions in gene regulation. In the cell nucleus, METTL16 functions as an mA writer to deposit mA into hundreds of its specific messenger RNA targets. In the cytosol, METTL16 promotes translation in an mA-independent manner. More specifically, METTL16 directly interacts with the eukaryotic initiation factors 3a and -b as well as ribosomal RNA through its Mtase domain, thereby facilitating the assembly of the translation-initiation complex and promoting the translation of over 4,000 mRNA transcripts. Moreover, we demonstrate that METTL16 is critical for the tumorigenesis of hepatocellular carcinoma. Collectively, our studies reveal previously unappreciated dual functions of METTL16 as an mA writer and a translation-initiation facilitator, which together contribute to its essential function in tumorigenesis.
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http://dx.doi.org/10.1038/s41556-021-00835-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9070413PMC
February 2022

Electrochemical α-thiolation and azidation of 1,3-dicarbonyls.

Chem Commun (Camb) 2022 Feb 22;58(16):2758-2761. Epub 2022 Feb 22.

Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.

A highly efficient electrochemical α-thiolation and azidation of 1,3-dicarbonyl compounds is developed. This electrochemical process is conducted under mild conditions without the use of a chemical oxidant, and exhibits a wide scope with good functional group tolerance. The applicability of this methodology was successfully demonstrated by modifying an anti-inflammatory drug on a gram scale.
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http://dx.doi.org/10.1039/d1cc06891aDOI Listing
February 2022

Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis.

Nat Cancer 2021 09 16;2(9):932-949. Epub 2021 Aug 16.

Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA.

Pseudouridine is the most frequent epitranscriptomic modification. However, its cellular functions remain largely unknown. Here, we show that pseudouridine synthase 7 (PUS7) is highly expressed in glioblastoma versus normal brain tissues, and high PUS7 expression levels are associated with worse survival in patients with glioblastoma. PUS7 expression and catalytic activity are required for glioblastoma stem cell (GSC) tumorigenesis. Mechanistically, we identify PUS7 targets in GSCs through small RNA pseudouridine sequencing and show that pseudouridylation of PUS7-regulated transfer RNA is critical for codon-specific translational control of key regulators of GSCs. Moreover, we identify chemical inhibitors for PUS7 and show that these compounds prevent PUS7-mediated pseudouridine modification, suppress tumorigenesis and extend the life span of tumor-bearing mice. Overall, we identify an epitranscriptomic regulatory mechanism in glioblastoma and provide preclinical evidence of a potential therapeutic strategy for glioblastoma.
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http://dx.doi.org/10.1038/s43018-021-00238-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809511PMC
September 2021

Crocetin alleviates the caerulein-induced apoptosis and inflammation in AR42J cells by activating SIRT1 via NF-κB.

Authors:
Lin Zhu Chuan He

J Nat Med 2022 Mar 30;76(2):410-418. Epub 2022 Jan 30.

Hematology Department, West China Hospital of Sichuan University, No. 37 Huangmenhou Street, Chengdu, 610041, Sichuan, China.

The anti-inflammatory and anti-apoptotic properties of crocetin have been widely demonstrated in numerous diseases. However, the exact role and mechanism of crocetin in acute pancreatitis have not been elucidated. Thus, this paper aims at exploring whether crocetin could be used to alleviate acute pancreatitis and further demonstrating the underlying mechanisms. Cell viability of caerulein-induced pancreatic exocrine cell line AR42J treated with crocetin was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT). Apoptosis and inflammation of these treated cells were detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), western blot and enzyme linked immunosorbent assay (ELISA). The expression of sirtuin-1 (SIRT1) was quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. After knockdown of SIRT1, cell viability, apoptosis and inflammation were measured again by corresponding kits. Finally, the NF-κB nuclear translocation and proteins in the NF-κB signaling were examined. Crocetin remarkably suppressed the apoptosis and inflammation of caerulein-induced AR42J cells. The decreased expression of SIRT1 was increased in caerulein-induced AR42J cells after exposure to crocetin. After knockdown of SIRT1, the alleviative effects of crocetin were found to be canceled in these cells. Furthermore, SIRT1 knockdown promoted the NF-κB signal transduction. On the whole, we presented the first evidence for the importance of SIRT1-NF-κB axis in acute pancreatitis and proposed that crocetin alleviates the caerulein-induced apoptosis and inflammation in AR42J cells by activating SIRT1 via NF-κB.
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http://dx.doi.org/10.1007/s11418-021-01597-9DOI Listing
March 2022

5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Early Warning Biomarkers for COVID-19 Progression and Myocardial Injury.

Front Cell Dev Biol 2021 6;9:781267. Epub 2022 Jan 6.

Department of Pharmacy and Department of Intensive Care Unit, Peking University Third Hospital, Beijing, China.

The symptoms of coronavirus disease 2019 (COVID-19) range from moderate to critical conditions, leading to death in some patients, and the early warning indicators of the COVID-19 progression and the occurrence of its serious complications such as myocardial injury are limited. We carried out a multi-center, prospective cohort study in three hospitals in Wuhan. Genome-wide 5-hydroxymethylcytosine (5hmC) profiles in plasma cell-free DNA (cfDNA) was used to identify risk factors for COVID-19 pneumonia and develop a machine learning model using samples from 53 healthy volunteers, 66 patients with moderate COVID-19, 99 patients with severe COVID-19, and 38 patients with critical COVID-19. Our warning model demonstrated that an area under the curve (AUC) for 5hmC warning moderate patients developed into severe status was 0.81 (95% CI 0.77-0.85) and for severe patients developed into critical status was 0.92 (95% CI 0.89-0.96). We further built a warning model on patients with and without myocardial injury with the AUC of 0.89 (95% CI 0.84-0.95). This is the first study showing the utility of 5hmC as an accurate early warning marker for disease progression and myocardial injury in patients with COVID-19. Our results show that phosphodiesterase 4D and ten-eleven translocation 2 may be important markers in the progression of COVID-19 disease.
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http://dx.doi.org/10.3389/fcell.2021.781267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8770986PMC
January 2022

ACS Chemical Biology─2022 Editorial Statement.

Authors:
Chuan He

ACS Chem Biol 2022 01;17(1)

Department of Chemistry, Department of Biochemistry and Molecular Biology and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, United States.

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http://dx.doi.org/10.1021/acschembio.1c00994DOI Listing
January 2022

Natural History of Spinal Cord Cavernous Malformations: A Multicenter Cohort Study.

Neurosurgery 2022 04;90(4):390-398

Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute, Beijing, China.

Background: The natural history of spinal cord cavernous malformations (SCCMs) remains relatively unclear.

Objective: To investigate the natural history for hemorrhagic risks and neurological outcomes, as well as relevant predicting factors, of SCCMs.

Methods: All patients between 2002 and 2019 with diagnosis of SCCMs were identified retrospectively. An observational study of patients with conservative management was performed to reveal the natural history of SCCMs.

Results: We identified 305 patients in the full cohort, including 126 patients who were conservatively treated for at least 6 months (median observational period, 24.0 months). Forty-five hemorrhage events occurred during 527 person-years of follow-up, yielding an annual hemorrhage rate of 8.5% per person-year. The 1-, 2-, and 5-year cumulative risks of hemorrhage were 13.9%, 26.1%, and 35.1%, respectively. Prior hemorrhage (hazard ratio [HR] = 12.948, P = .012) and pediatric patients (HR = 2.841, P = .031) were independent predictors of hemorrhage in the long-term follow-up. Familial form (adjusted odds ratio [OR] = 30.695, P = .010) and subsequent hemorrhage events (adjusted OR = 16.333, P = .000) were independent risk factors for worsening of neurological function, and baseline neurological status (adjusted OR = 78.984, P = .000) and presence of subsequent hemorrhage (adjusted OR = 9.611, P = .001) were significantly associated with neurological outcomes.

Conclusion: The natural history of SCCMs varies. Baseline characteristics, such as pediatric patients, familial form, and baseline neurological status, as well as prior and subsequent hemorrhagic events, significantly affect the natural history of the SCCMs, which prompts a differentiated treatment strategy.
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http://dx.doi.org/10.1227/NEU.0000000000001842DOI Listing
April 2022

The METTL5-TRMT112 N-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation.

J Biol Chem 2022 03 14;298(3):101590. Epub 2022 Jan 14.

Department of Chemistry, University of Chicago, Chicago, Illinois, USA; Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA. Electronic address:

Ribosomal RNAs (rRNAs) have long been known to carry chemical modifications, including 2'O-methylation, pseudouridylation, N-methyladenosine (mA), and Ndimethyladenosine. While the functions of many of these modifications are unclear, some are highly conserved and occur in regions of the ribosome critical for mRNA decoding. Both 28S rRNA and 18S rRNA carry single mA sites, and while the methyltransferase ZCCHC4 has been identified as the enzyme responsible for the 28S rRNA mA modification, the methyltransferase responsible for the 18S rRNA mA modification has remained unclear. Here, we show that the METTL5-TRMT112 methyltransferase complex installs the mA modification at position 1832 of human 18S rRNA. Our work supports findings that TRMT112 is required for METTL5 stability and reveals that human METTL5 mutations associated with microcephaly and intellectual disability disrupt this interaction. We show that loss of METTL5 in human cancer cell lines and in mice regulates gene expression at the translational level; additionally, Mettl5 knockout mice display reduced body size and evidence of metabolic defects. While recent work has focused heavily on mA modifications in mRNA and their roles in mRNA processing and translation, we demonstrate here that deorphanizing putative methyltransferase enzymes can reveal previously unappreciated regulatory roles for mA in noncoding RNAs.
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http://dx.doi.org/10.1016/j.jbc.2022.101590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8857481PMC
March 2022

Intestinal Microbiota and Host Cooperate for Adaptation as a Hologenome.

mSystems 2022 Feb 11;7(1):e0126121. Epub 2022 Jan 11.

Department of Animal Science, School of Agriculture and Biology, Shanghai Jiao Tong Universitygrid.16821.3c, Shanghai, People's Republic of China.

Multiomic analyses reported here involved two lines of chickens, from a common founder population, that had undergone long-term selection for high (HWS) or low (LWS) 56-day body weight. In these lines that differ by around 15-fold in body weight, we observed different compositions of intestinal microbiota in the holobionts and variation in DNA methylation, mRNA expression, and microRNA profiles in the ceca. Insulin-like growth factor 2 mRNA-binding protein 1 () was the most upregulated gene in HWS ceca with its expression likely affected by the upregulation of expression of gga-miR-2128 and a methylated region near its transcription start site (388 bp). Correlation analysis showed that expression was associated with an abundance of microbes, such as and These findings suggest that was regulated in the hologenome in adapting to long-term artificial selection for body weight. Our study provides evidence that adaptation of the holobiont can occur in the microbiome as well as in the epigenetic profile of the host. The hologenome concept has broadened our perspectives for studying host-microbe coevolution. The multiomic analyses reported here involved two lines of chickens, from a common founder population, that had undergone long-term selection for high (HWS) or low (LWS) 56-day body weight. In these lines that differ by around 15-fold in body weight, we observed different compositions of intestinal microbiota in the holobionts, and variation in DNA methylation, mRNA expression, and microRNA profiles in ceca. The insulin-like growth factor 2 mRNA-binding protein 1 () was the most upregulated gene in HWS ceca with its expression likely affected by a methylated region near its transcription start site and the upregulation of expression of gga-miR-2128. Correlation analysis also showed that expression was associated with the abundance of microbes, such as Lactobacillus and . These findings suggest that was regulated in the hologenome in response to long-term artificial selection for body weight. Our study shows that the holobiont may adapt in both the microbiome and the host's epigenetic profile.
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http://dx.doi.org/10.1128/msystems.01261-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751389PMC
February 2022
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