Publications by authors named "Qiong Yang"

522 Publications

Molecular Identification of Leafmining Flies From Australia Including New Liriomyza Outbreaks.

J Econ Entomol 2021 Jul 19. Epub 2021 Jul 19.

Bio21 Institute, School of BioSciences, The University of Melbourne, Parkville, VIC, Australia.

Some leafmining fly species are pests of agricultural and ornamental plants but they also include many species with little economic importance. The taxonomy of leafmining flies is often challenging because of putative cryptic species. Following new outbreaks of Liriomyza (Diptera:Agromyzidae) in Australia, we here characterize 13 dipteran leafminer species collected from Australia based on cytochrome c oxidase subunit 1 (COI) DNA barcodes, and we compare these with overseas data. We confirm barcodes of nine species from the Agromyzidae (Liriomyza sativae, L. huidobrensis, L. trifolii, L. bryoniae, L. chinensis, L. brassicae, L. chenopodii, Phytomyza plantaginis and P. syngenesiae) and one species from the Drosophilidae (Scaptomyza flava); we describe new haplotypes for some of these species. Furthermore, we provide the first DNA barcodes for two species (Cerodontha milleri and Phytoliriomyza praecellens) from the Agromyzidae and one species (Scaptomyza australis) from the Drosophilidae. These findings provide a baseline for DNA-based identification of pest Liriomyza incursions spreading across the Australian east coast in relation to other species already present in Australia.
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http://dx.doi.org/10.1093/jee/toab143DOI Listing
July 2021

Stepwise Induction of Inner Ear Hair Cells From Mouse Embryonic Fibroblasts via Mesenchymal- to-Epithelial Transition and Formation of Otic Epithelial Cells.

Front Cell Dev Biol 2021 17;9:672406. Epub 2021 Jun 17.

State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Although embryonic stem cells or induced pluripotent stem cells are able to differentiate into inner ear hair cells (HCs), they have drawbacks limiting their clinical application, including a potential risk of tumourigenicity. Direct reprogramming of fibroblasts to inner ear HCs could offer an alternative solution to this problem. Here, we present a stepwise guidance protocol to induce mouse embryonic fibroblasts to differentiate into inner ear HC-like cells (HCLs) via mesenchymal-to-epithelial transition and then acquisition of otic sensory epithelial cell traits by overexpression of three key transcription factors. These induced HCLs express multiple HC-specific proteins, display protrusions reminiscent of ciliary bundle structures, respond to voltage stimulation, form functional mechanotransduction channels, and exhibit a transcriptional profile of HC signature. Together, our work provides a new method to produce functional HCLs , which may have important implications for studies of HC development, drug discovery, and cell replacement therapy for hearing loss.
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http://dx.doi.org/10.3389/fcell.2021.672406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248816PMC
June 2021

Pb Content, Risk Level and Primary-Source Apportionment in Wheat and Rice Grains in the Lihe River Watershed, Taihu Region, Eastern China.

Int J Environ Res Public Health 2021 06 9;18(12). Epub 2021 Jun 9.

Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou 510610, China.

This study detailed a complete research from Lead (Pb) content level to ecological and health risk to direct- and primary-sources apportionment arising from wheat and rice grains, in the Lihe River Watershed of the Taihu region, East China. Ecological and health risk assessment were based on the pollution index and US Environmental Protection Agency (EPA) health risk assessment model. A three-stage quantitative analysis program based on Pb isotope analysis to determine the relative contributions of primary sources involving (1) direct-source apportionment in grains with a two-end-member model, (2) apportionment of soil and dustfall sources using the IsoSource model, and (3) the integration of results of (1) and (2) was notedly first proposed. The results indicated that mean contents of Pb in wheat and rice grains were 0.54 and 0.45 mg/kg and both the bio-concentration factors (BCF) were <<1; the ecological risk pollution indices were 1.35 for wheat grains and 1.11 for rice grains; hazard quotient (HQ) values for adult and child indicating health risks through ingestion of grains were all <1; Coal-fired industrial sources account for up to 60% of Pb in the grains. This study provides insights into the management of grain Pb pollution and a new method for its source apportionment.
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http://dx.doi.org/10.3390/ijerph18126256DOI Listing
June 2021

HMGA1 promotes gastric cancer growth and metastasis by transactivating SUZ12 and CCDC43 expression.

Aging (Albany NY) 2021 06 24;13(12):16043-16061. Epub 2021 Jun 24.

Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

HMGA1 protein is an architectural transcription factor that has been implicated in the progression of multiple malignant tumors. However, the role of HMGA1 in the growth and metastasis of gastric cancer (GC) has not yet been elucidated. Here, we show that HMGA1 is overexpressed in GC cells and the high expression of HMGA1 was correlated with worse survival in GC patients using a bioinformatics assay. Functionally, HMGA1 affected the EdU incorporation, colony formation, migration and invasion of GC cells by exogenously increasing or decreasing the expression of HMGA1. Mechanistically, HMGA1 directly bound to the SUZ12 and CCDC43 promoter and transactivated its expression in GC cells. Inhibition of SUZ12 and CCDC43 attenuated the proliferation, migration and invasiveness of HMGA1-overexpressing GC cells . Moreover, both HMGA1 and SUZ12/CCDC43 were highly expressed in cancer cells but not in normal gastric tissues, and their expressions were positively correlated. Finally, a tail vein metastatic assay showed that HMGA1 promoted SUZ12/CCDC43-mediated GC cell metastasis . Our findings suggest that HMGA1 promotes GC growth and metastasis by transactivating SUZ12 and CCDC43 expression, highlighting HMGA1 as a potential prognostic biomarker in the treatment of GC.
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http://dx.doi.org/10.18632/aging.203130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266323PMC
June 2021

Fucoidan reduces lipid accumulation by promoting foam cell autophagy via TFEB.

Carbohydr Polym 2021 Sep 26;268:118247. Epub 2021 May 26.

Marine College, Shandong University, Weihai, Shandong, China. Electronic address:

Atherosclerotic cardiovascular disease became one of the major causes of morbidity and mortality worldwide. As a sulfated polysaccharide with anti-inflammatory and hypolipidemic activities, fucoidan can induce autophagy. We show here that fucoidan reduces lipid accumulation in foam cells, which is one of the causes of atherosclerosis. Further studies show that fucoidan promotes autophagy showed by the expression of p62/SQSTM1 and microtubule-associated protein light chain 3 (LC3) II, which can be blocked by autophagy inhibitors 3-MA and bafilomycin A1. In addition, the expression of transcription factor EB (TFEB), master regulator of autophagy and lysosome function, is upregulated after the treatment with fucoidan. Moreover, the knockout of TFEB with small interfering RNA suppressed the effect of fucoidan. Together, fucoidan reduces lipid accumulation in foam cells by enhancing autophagy through the upregulation of TFEB. In view of the role of foam cells in atherosclerosis, fucoidan can be valuable for the treatment of atherosclerosis.
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http://dx.doi.org/10.1016/j.carbpol.2021.118247DOI Listing
September 2021

Study on the file management method of data storage system for airborne radar.

R Soc Open Sci 2021 Jun 9;8(6):210221. Epub 2021 Jun 9.

School of Physics and Electronics, Hunan Normal University, Changsha 410081, People's Republic of China.

In order to solve the problem that the air-to-ground data transfer rate is much lower than the radar data rate, the onboard system is commonly used for storing the airborne radar data. However, there are two main problems in the data storage using the traditional file management method. The first is that the frequent data updating of the file allocation table (FAT) and the file directory table (FDT) cause a high frequency of address jumps among the discontinuous areas, which leads to a long response time. The second is that the updating frequencies of the FAT, the FDT and the data region are seriously inconsistent, which results in uneven wear of the three areas. To solve these two problems, a file management method, which optimizes the data writing in the three areas of the FAT, the FDT and the data region, is proposed in this study. An actual measurement is carried out on a data storage system of the airborne radar using the proposed file management method. The result shows that the proposed method significantly reduces the updating frequency of FAT and FDT, and achieves the wear levelling of file area and data region.
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http://dx.doi.org/10.1098/rsos.210221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187989PMC
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Predictive Value of Cerebrospinal Fluid Biomarkers for Tap Test Responsiveness in Patients With Suspected Idiopathic Normal Pressure Hydrocephalus.

Front Aging Neurosci 2021 20;13:665878. Epub 2021 May 20.

Department of Neurology, Aviation General Hospital, Beijing, China.

The value of cerebrospinal fluid (CSF) biomarkers for assessing idiopathic normal pressure hydrocephalus (iNPH) must be determined. This prospective study aimed to reveal the correlation between CSF biomarkers and clinical symptoms of iNPH and the predictive value of these biomarkers for tap test responsiveness. Thirty-nine patients with suspected iNPH were recruited, contributed qualified CSF, and underwent a tap test and unified pre- and post-test evaluations of the neurological function. The analysis of biomarkers from the patients' CSF showed decreased levels of tau and its phosphorylated form, especially in the tap test (+) group. The responsiveness of the tap test was also related to the number of combined symptoms ( < 0.01), and a correlation was found between the end pressure or pressure difference in CSF and tap test responsiveness ( < 0.05). The results of the binary logistic regression analysis showed that (tap test responsiveness) = 1/1 + e - (-5.505 + 55.314 * ratio of p/-tau - 1.586 * numbers of combined symptoms). The combined indicators (-5.505 + 0.553 * percentage of p/-tau - 1.586 * numbers of combined symptoms) resulted in the highest sensitivity and specificity of 94.12% and 72.73%, respectively. CSF biomarkers may be assessed to judge tap test responsiveness, which is beneficial for the feasibility of a clinical application.
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http://dx.doi.org/10.3389/fnagi.2021.665878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172576PMC
May 2021

Abnormal brain functional network dynamics in obsessive-compulsive disorder patients and their unaffected first-degree relatives.

Hum Brain Mapp 2021 Jun 5. Epub 2021 Jun 5.

Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, China; School of Psychology, Center for Studies of Psychological Application, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, China.

We utilized dynamic functional network connectivity (dFNC) analysis to compare participants with obsessive-compulsive disorder (OCD) with their unaffected first-degree relative (UFDR) and healthy controls (HC). Resting state fMRI was performed on 46 OCD, 24 UFDR, and 49 HCs, along with clinical assessments. dFNC analyses revealed two distinct connectivity states: a less frequent, integrated state characterized by the predominance of between-network connections (State I), and a more frequent, segregated state with strong within-network connections (State II). OCD patients spent more time in State II and less time in State I than HC, as measured by fractional windows and mean dwell time. Time in each state for the UFDR were intermediate between OCD patients and HC. Within the OCD group, fractional windows of time spent in State I was positively correlated with OCD symptoms (as measured by the obsessive compulsive inventory-revised [OCI-R], r = .343, p<.05, FDR correction) and time in State II was negatively correlated with symptoms (r = -.343, p<.05, FDR correction). Within each state we also examined connectivity within and between established intrinsic connectivity networks, and found that UFDR were similar to the OCD group in State I, but more similar to the HC groups in State II. The similarities between OCD and UFDR groups in temporal properties and State I connectivity indicate that these features may reflect the endophenotype for OCD. These results indicate that the temporal dynamics of functional connectivity could be a useful biomarker to identify those at risk.
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http://dx.doi.org/10.1002/hbm.25555DOI Listing
June 2021

Real-Time Monitoring of APC /C-Mediated Substrate Degradation Using Xenopus laevis Egg Extracts.

Methods Mol Biol 2021 ;2329:29-38

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.

The anaphase promoting complex/cyclosome (APC/C), a large E3 ubiquitin ligase, is a key regulator of mitotic progression. Upon activation in mitosis, the APC/C targets its two essential substrates, securin and cyclin B, for proteasomal destruction. Cyclin B is the activator of cyclin-dependent kinase 1 (Cdk1), the major mitotic kinase, and both cyclin B and securin are safeguards of sister chromatid cohesion. Conversely, the degradation of securin and cyclin B promotes sister chromatid separation and mitotic exit. The negative feedback loop between Cdk1 and APC/C-Cdk1 activating the APC/C and the APC/C inactivating Cdk1-constitutes the core of the biochemical cell cycle oscillator.Since its discovery three decades ago, the mechanisms of APC /C regulation have been intensively studied, and several in vitro assays exist to measure the activity of the APC /C in different activation states. However, most of these assays require the purification of numerous recombinant enzymes involved in the ubiquitylation process (e.g., ubiquitin, the E1 and E2 ubiquitin ligases, and the APC /C) and/or the use of radioactive isotopes. In this chapter, we describe an easy-to-implement method to continuously measure APC /C activity in Xenopus laevis egg extracts using APC /C substrates fused to fluorescent proteins and a fluorescence plate reader. Because the egg extract provides all important enzymes and proteins for the reaction, this method can be used largely without the need for recombinant protein purification. It can also easily be adapted to test the activity of APC /C mutants or investigate other mechanisms of APC /C regulation.
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http://dx.doi.org/10.1007/978-1-0716-1538-6_3DOI Listing
January 2021

Deep Scoring Neural Network Replacing the Scoring Function Components to Improve the Performance of Structure-Based Molecular Docking.

ACS Chem Neurosci 2021 06 3;12(12):2133-2142. Epub 2021 Jun 3.

Institute of Modern Physics, Chinese Academy of Science, Lanzhou 730000, China.

Accurate prediction of protein-ligand interactions can greatly promote drug development. Recently, a number of deep-learning-based methods have been proposed to predict protein-ligand binding affinities. However, these methods independently extract the feature representations of proteins and ligands but ignore the relative spatial positions and interaction pairs between them. Here, we propose a virtual screening method based on deep learning, called Deep Scoring, which directly extracts the relative position information and atomic attribute information on proteins and ligands from the docking poses. Furthermore, we use two Resnets to extract the features of ligand atoms and protein residues, respectively, and generate an atom-residue interaction matrix to learn the underlying principles of the interactions between proteins and ligands. This is then followed by a dual attention network (DAN) to generate the attention for two related entities (i.e., proteins and ligands) and to weigh the contributions of each atom and residue to binding affinity prediction. As a result, Deep Scoring outperforms other structure-based deep learning methods in terms of screening performance (area under the receiver operating characteristic curve (AUC) of 0.901 for an unbiased DUD-E version), pose prediction (AUC of 0.935 for PDBbind test set), and generalization ability (AUC of 0.803 for the CHEMBL data set). Finally, Deep Scoring was used to select novel ERK2 inhibitor, and two compounds (D264-0698 and D483-1785) were obtained with potential inhibitory activity on ERK2 through the biological experiments.
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http://dx.doi.org/10.1021/acschemneuro.1c00110DOI Listing
June 2021

Expression Characteristics of microRNA in Pig Umbilical Venous Blood and Umbilical Arterial Blood.

Animals (Basel) 2021 May 27;11(6). Epub 2021 May 27.

College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China.

As the medium of material exchange between mother and fetus, umbilical cord blood is closely connected with fetal development. microRNA (miRNA) has a wide range of biological functions and has high flow characteristics. Small RNA sequencing of pig umbilical venous blood (UVB) and umbilical arterial blood (UAB) revealed that a total of 302 miRNAs were identified, and 106 and 22 miRNAs were specifically expressed in the UVB and UAB, respectively. Using the two methods of differential expression multiple and differential expression percentage, it is found that only 35% of the highly expressed miRNAs in the UVB by the two analysis modes overlap, but 56.25% of the enriched signal pathways are the same. Only 20% of the highly expressed miRNAs in the UAB overlap, but 62.07% of the signal pathways are the same. Further analysis revealed that miR-423 can be used as a characteristic miRNA of UVB and has the potential to treat muscle-related diseases. miR-122-5p can be used as a characteristic miRNA of UAB and may help to improve liver- and brain-related diseases. In summary, these results enrich understanding of miRNA in mother-fetal communication and provide a reference for the development and application of porcine cord blood products.
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http://dx.doi.org/10.3390/ani11061563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228062PMC
May 2021

Artificial intelligence for the detection of age-related macular degeneration in color fundus photographs: A systematic review and meta-analysis.

EClinicalMedicine 2021 May 8;35:100875. Epub 2021 May 8.

Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Medical Artificial Intelligence Research and Verification Key Laboratory of the Ministry of Industry and Information Technology, Beijing Tongren Hospital, Capital Medical University, 1 Dong Jiao Min Lane, Beijing 100730, China.

Background: Age-related macular degeneration (AMD) is one of the leading causes of vision loss in the elderly population. The application of artificial intelligence (AI) provides convenience for the diagnosis of AMD. This systematic review and meta-analysis aimed to quantify the performance of AI in detecting AMD in fundus photographs.

Methods: We searched PubMed, Embase, Web of Science and the Cochrane Library before December 31st, 2020 for studies reporting the application of AI in detecting AMD in color fundus photographs. Then, we pooled the data for analysis. PROSPERO registration number: CRD42020197532.

Findings: 19 studies were finally selected for systematic review and 13 of them were included in the quantitative synthesis. All studies adopted human graders as reference standard. The pooled area under the receiver operating characteristic curve (AUROC) was 0.983 (95% confidence interval (CI):0.979-0.987). The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were 0.88 (95% CI:0.88-0.88), 0.90 (95% CI:0.90-0.91), and 275.27 (95% CI:158.43-478.27), respectively. Threshold analysis was performed and a potential threshold effect was detected among the studies (Spearman correlation coefficient: -0.600,  = 0.030), which was the main cause for the heterogeneity. For studies applying convolutional neural networks in the Age-Related Eye Disease Study database, the pooled AUROC, sensitivity, specificity, and DOR were 0.983 (95% CI:0.978-0.988), 0.88 (95% CI:0.88-0.88), 0.91 (95% CI:0.91-0.91), and 273.14 (95% CI:130.79-570.43), respectively.

Interpretation: Our data indicated that AI was able to detect AMD in color fundus photographs. The application of AI-based automatic tools is beneficial for the diagnosis of AMD.

Funding: Capital Health Research and Development of Special (2020-1-2052).
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http://dx.doi.org/10.1016/j.eclinm.2021.100875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129891PMC
May 2021

Tetramethylpyrazine Alleviates Behavioral and Psychological Symptoms of Dementia Through Facilitating Hippocampal Synaptic Plasticity in Rats With Chronic Cerebral Hypoperfusion.

Front Neurosci 2021 6;15:646537. Epub 2021 May 6.

Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China.

Behavioral and psychological symptoms of dementia (BPSD) ubiquitously disturb all patients with dementia at some point in the disease course. Although a plethora of non-pharmacological and pharmacological methods targeting the relief BPSD have been developed, the therapeutic effect is still far from ideal. Here, a rat BPSD model combining the physiological changes with mental insults was successfully established. Meanwhile, our results indicated that TMP attenuated anxious behavior using an elevated plus maze (EPM) test, ameliorated recognitive ability and sociability through a novel object recognition test (NORT) and social interaction test (SIT), and improved learning and memory impairments a Barnes maze in rats with bilateral common carotid arteries occlusion (BCCAO) plus chronic restraint stress (CRS). Given that hippocampus chronic cerebral hypoperfusion (CCH) always causes damage to the hippocampus, and the majority of cognitive impairments, behaviors, and stress responses are associated with pathology in the hippocampus including anxiety and depression, we paid attention to investigate the role of the hippocampus in BPSD. Our results indicated that Tetramethylpyrazine (TMP) attenuated anxiety and ameliorated recognitive ability, sociability, learning, and memory impairments due to alleviating dendritic and spine deficits, and upregulating the expression of synapse-related proteins (including PSD95, SYN, GAP43, SYP) in the hippocampus. We also found that the underlying mechanism was that TMP could activate the TrkB/ERK/CREB signaling pathway to promote synaptic remodeling and . Mechanically, the present study enlarges the therapeutic scope of TMP in neurodegenerative disorders and provides basic knowledge and feasible candidates for treating BPSD, particularly for vascular dementia.
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http://dx.doi.org/10.3389/fnins.2021.646537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134703PMC
May 2021

Multiomic Profiling in Black and White Populations Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Adults.

Circ Genom Precis Med 2021 Jun 21;14(3):e003191. Epub 2021 May 21.

Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (D.H.K., U.A.T., D.N., M.D.B., X.S., M.J.K., D.S., M.H., J.M.R., Z.-Z.C., D.E.C., B.P., J.G.W., R.E.G.).

Background: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort.

Methods: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women).

Results: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; β=0.04; =2×10; hazard ratio, 1.48; =0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; β=0.05; =5×10). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; =0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups.

Conclusions: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine.
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http://dx.doi.org/10.1161/CIRCGEN.120.003191DOI Listing
June 2021

Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants.

Alzheimers Dement 2021 May 18. Epub 2021 May 18.

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.

Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures.

Methods: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk.

Results: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition.

Discussion: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.
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http://dx.doi.org/10.1002/alz.12333DOI Listing
May 2021

Caspase-11-Gasdermin D-Mediated Pyroptosis Is Involved in the Pathogenesis of Atherosclerosis.

Front Pharmacol 2021 26;12:657486. Epub 2021 Apr 26.

Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China.

Pyroptosis is a form of cell death triggered by proinflammatory signals. Recent studies have reported that oxidized phospholipids function as caspase-11 agonists to induce noncanonical inflammasome activation in immune cells. As the levels of oxidized phospholipids derived from ox-LDL are largely elevated in atherosclerotic lesions, this study sought to determine whether oxidized lipids trigger pyroptosis and subsequent inflammation in the pathogenesis of atherosclerosis. In our current study, after integrating transcriptomic data available from the Gene Expression Omnibus with data from hyperlipidemic mice and ox-LDL-treated peritoneal macrophages, we discovered that caspase-4/11-gasdermin D-associated inflammatory signaling was significantly activated. Consistently, the mRNA expression of caspase-4 and gasdermin D was upregulated in peripheral blood mononuclear cells from patients with coronary heart disease. In particular, the expression of caspase-4 was closely associated with the severity of lesions in the coronary arteries. An study showed that caspase-11-gasdermin D activation occurred in response to a high-fat/high-cholesterol (HFHC) diet in ApoE mice, while caspase-11 deletion largely attenuated the volume and macrophage infiltration of atherosclerotic lesions. An mechanistic study showed that caspase-11-mediated inflammation occurred partly via gasdermin D-mediated pyroptosis in macrophages. Suppressing gasdermin D in HFHC-fed ApoE mice via delivery of an adeno-associated virus markedly decreased lesion volume and infiltrating macrophage numbers. Caspase-11-gasdermin D-mediated pyroptosis and the subsequent proinflammatory response in macrophages are involved in the pathogenesis of atherosclerosis. Therefore, targeting the caspase 11-gasdermin D may serve as an alternative strategy for the treatment of atherosclerosis.
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http://dx.doi.org/10.3389/fphar.2021.657486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109243PMC
April 2021

Allele-specific DNA methylation maps in monozygotic twins discordant for psychiatric disorders reveal that disease-associated switching at the EIPR1 regulatory loci modulates neural function.

Mol Psychiatry 2021 May 7. Epub 2021 May 7.

Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China.

The non-Mendelian features of phenotypic variations within monozygotic twins are likely complicated by environmental modifiers of genetic effects that have yet to be elucidated. Here, we performed methylome and genome analyses of blood DNA from psychiatric disorder-discordant monozygotic twins to study how allele-specific methylation (ASM) mediates phenotypic variations. We identified that thousands of genetic variants with ASM imbalances exhibit phenotypic variation-associated switching at regulatory loci. These ASMs have plausible causal associations with psychiatric disorders through effects on interactions between transcription factors, DNA methylations, and other epigenomic markers and then contribute to dysregulated gene expression, which eventually increases disease susceptibility. Moreover, we also experimentally validated the model that the rs4854158 alternative C allele at an ASM switching regulatory locus of EIPR1 encoding endosome-associated recycling protein-interacting protein 1, is associated with demethylation and higher RNA expression and shows lower TF binding affinities in unaffected controls. An epigenetic ASM switching induces C allele hypermethylation and then recruits repressive Polycomb repressive complex 2 (PRC2), reinforces trimethylation of lysine 27 on histone 3 and inhibits its transcriptional activity, thus leading to downregulation of EIPR1 in schizophrenia. Moreover, disruption of rs4854158 induces gain of EIPR1 function and promotes neural development and vesicle trafficking. Our study provides a powerful framework for identifying regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic variants in mediating psychiatric disorder susceptibility.
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http://dx.doi.org/10.1038/s41380-021-01126-wDOI Listing
May 2021

Physical Exercise is Associated with Glycemic Control among Women with Gestational Diabetes Mellitus: Findings from a Prospective Cohort in Shanghai, China.

Diabetes Metab Syndr Obes 2021 30;14:1949-1961. Epub 2021 Apr 30.

Clinical Research & Innovation Transformation Center, Shanghai Skin Diseases Hospital Affiliated to Tongji University, Shanghai, People's Republic of China.

Objective: Physical exercise during pregnancy is beneficial to women with gestational diabetes mellitus (GDM), but evidence on the association between physical exercise and glycemic control among women with GDM is limited in China. We conducted this study to understand the total exercise times, the percentage of abnormal plasma glucose (PG), and to explore if longer physical exercise is positively associated with a lower percentage of abnormal PG among GDM women.

Methods: During 2019 and 2020, we established a prospective cohort with 1,050 GDM women recruited. GDM was confirmed by a diagnostic 75g OGTT, and plasma glucose in over 10 hours overnight fasting and 2-hour after breakfast was implemented during a routine antenatal checkup. Information for demographic features and physical exercises among GDM women were collected by questionnaire interviews, and abnormal PG percentage was calculated as abnormal PG times divided by total PG test times.

Results: Among 1,050 GDM women, the percentage of exercise times <150 minutes/week, <30 minutes/day and <60 minutes/day was 17.33%, 26.57%, and 54.10%, respectively. The median percentage of abnormal PG was 40% (IQR=20-70%). GDM women with less exercise had a higher abnormal PG percentage (y=0.0049x-1.20x+88.96), ORs for women with exercise <150 minutes/week were 3.78 (95% CI=1.33-8.25), 6.97 (3.45-14.07), and 6.39 (3.61-11.33) compared with ≥ 150 minutes/week, and ORs for women with exercise <60 minutes/day were 4.62 (2.71-8.14), 3.58 (2.60-4.93), and 7.28 (4.31-12.30) compared with ≥60 minutes/day in groups divided by quartiles of P, P and P, respectively.

Conclusion: This study indicated high physical exercise times and abnormal PG percentage among women with GDM in Shanghai, China. GDM women with more exercise times had a lower percentage of abnormal PG, especially when exercise times were ≥60 minutes/day, and supplementary treatments should be provided for women with over 70% abnormal plasma glucose.
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http://dx.doi.org/10.2147/DMSO.S308287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096418PMC
April 2021

Comparison of neonicotinoid residues in soils of different land use types.

Sci Total Environ 2021 Aug 27;782:146803. Epub 2021 Mar 27.

State Key Joint Laboratory for Environmental Simulation and Pollution Control, College of Environmental Sciences and Engineering, Peking University, Beijing 100871, China.

Neonicotinoid insecticides (NEOs) have attracted particular attention in recent years due to their wide occurrence and potential impacts on the ecosystem and human health. This study aimed to compare the composition and level of NEOs in soils of different land use types. Two rounds of sampling were performed in Tianjin, China, with 158 soil samples in fall and 61 soil samples in spring collected from five types of land, i.e., greenhouse, orchard, farm, park and residential area. The concentrations of eight NEOs, i.e., imidacloprid (IMI), acetamiprid (ACE), thiamethoxam (THX), clothianidin (CLO), thiacloprid (THA), dinotefuran (DIN), nitenpyram (NIT) and flonicamid (FLO), were analyzed in the soil samples using LC-MS/MS. Six NEOs were detected, with IMI, ACE and THX being the most frequently detected ones. Concentrations of NEOs (arithmetic means in fall and spring, respectively) in greenhouse were the highest (2.52×10 and 4.59×10 ng g), followed by in orchard (35.1 and 1.31×10 ng g), park (50.4 and 1.02×10 ng g), residential area (20.2 and 1.38×10 ng g) and farm (25.5 and 84.2 ng g). The contribution of individual NEO varied in soils of different land use types. Both IMI and THX were largely used in greenhouse, while IMI was the main NEO in the other four lands. The NEO levels in soils planted with different crops varied greatly. Extremely high levels of NEOs (>10 ng g) were observed in soils planted with watermelon, tomato and peach in greenhouse. The ubiquitous presence of NEOs in soils deserves more attention, particularly in greenhouse.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146803DOI Listing
August 2021

Transfer mechanism and bioaccumulation risk of potentially toxic elements in soil-rice systems comparing different soil parent materials.

Ecotoxicol Environ Saf 2021 Apr 10;216:112214. Epub 2021 Apr 10.

No. 4 Geology Team of Guangxi Zhuang Autonomic Region, Nanning 530031, PR China.

Although the accumulation of potentially toxic elements in soil and crops has attracted widespread attention, the characteristics of the transfer and accumulation of potentially toxic elements in soil-crop systems with different soil parent materials are still not clear. Soil and crop samples were collected from agricultural regions with different soil parent materials in Guangxi, China. This study analyzed the concentrations of Cd, Zn, and Fe in the roots, straws, and seeds of rice (Oryza sativa L.) and soils with Quaternary sediments and clastic rocks as the parent materials. The concentration of several potentially toxic elements in rice tissue from the two areas followed the order of C> C> C. The transport capability of Cd and Zn from roots to straws is higher than straws to seeds, and Fe showed a strong capability for transport from straws to seeds. In general, the transfer capacity of potentially toxic elements in the soil-rice system in the Quaternary sediments area was stronger than that in the soil-rice system in the clastic rocks area. Soil pH and minerals, which were represented by major elements, were the main factors affecting the transfer of metals from soil to seeds. This approach could help to evaluate the bioaccumulation risk of potentially toxic elements in crops in different areas quantitatively.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112214DOI Listing
April 2021

Multiomics integrative analysis identifies allele-specific blood biomarkers associated to Alzheimer's disease etiopathogenesis.

Aging (Albany NY) 2021 Apr 12;13(7):9277-9329. Epub 2021 Apr 12.

Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Alzheimer's disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analysed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by haplotype ( and ). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterised a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in and AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.
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http://dx.doi.org/10.18632/aging.202950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064208PMC
April 2021

Plug-in tubes allow tunable oil removal, droplet packing, and reaction incubation for time-controlled droplet-based assays.

Biomicrofluidics 2021 Mar 5;15(2):024108. Epub 2021 Apr 5.

Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.

Here, we report a unique microfluidic technique that utilizes a membrane filter and plug-in tubes to remove oil and pack water-in-oil droplets for controlled incubation of droplet-based assays. This technique could be modularly incorporated into most droplet-generation devices without a need to alter the original designs. Our results show that removing excess oil to form tightly packed droplets allows for extended and controllable incubation for droplets traveling in microchannels. The efficiency of this technique was evaluated and confirmed using a time-dependent enzyme assay with a fluorometric readout. The system is also readily generalizable to control inter-droplet distance, crucial for studying droplet communication and pattern formation.
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http://dx.doi.org/10.1063/5.0047924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024030PMC
March 2021

White Matter Alterations of the Goal-Directed System in Patients With Obsessive-Compulsive Disorder and Their Unaffected First-Degree Relatives.

Biol Psychiatry Cogn Neurosci Neuroimaging 2020 Dec 19. Epub 2020 Dec 19.

Key Laboratory of Brain, Cognition and Education Sciences (South China Normal University), Ministry of Education, Beijing, China; School of Psychology, Center for Studies of Psychological Application, Guangzhou, China; Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, China. Electronic address:

Background: It has been postulated that the neurobiological mechanism responsible for the onset of symptoms of obsessive-compulsive disorder (OCD), especially compulsive behavior, is related to alterations of the goal-directed and habitual learning systems. However, little is known about whether changes in these learning systems co-occur with changes in the white matter structure of patients with OCD and their unaffected first-degree relatives (UFDRs).

Methods: Diffusion tensor imaging data were acquired from 32 patients with OCD (21 male), 32 UFDRs (16 male), and 32 healthy control subjects (16 male). White matter tracts in the goal-directed and habitual networks were reconstructed with seed-based probabilistic tractography. Partial least squares path modeling was used to measure the covariation between white matter connectivity, psychiatric symptoms, and cognitive flexibility.

Results: Patients with OCD showed reduced connectivity in the fiber tracts within the goal-directed but not within the habitual network compared with healthy control subjects. Using partial least squares path modeling, patients' symptoms were negatively associated with connectivity within the goal-directed but not within the habitual network. Cognitive flexibility was correlated negatively with caudate-dorsolateral prefrontal cortex tracts in patients with OCD. UFDRs also exhibited reduced white matter connectivity in the goal-directed network.

Conclusions: These findings suggest that the balance of learning systems in OCD may be disrupted, mainly impairing white matter in the goal-directed network. Alterations of the goal-directed network could explain overt symptoms and impaired cognitive flexibility in patients with OCD. Similar alterations in the goal-directed network are present in UFDRs. The impaired goal-directed system may be an endophenotype of OCD.
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http://dx.doi.org/10.1016/j.bpsc.2020.12.004DOI Listing
December 2020

Mutation analysis of the GLA gene in Chinese patients with intracerebral hemorrhage.

Neurobiol Aging 2021 Jun 2;102:220.e1-220.e4. Epub 2021 Feb 2.

Department of Neurology, Peking University Third Hospital, Beijing, China; Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Disorders, Beijing, China; Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing, China. Electronic address:

Fabry disease (FD) is an important underlying condition in young cryptogenic stroke patients and has also been implicated in cerebral small vessel disease. However, the contributions of causative GLA mutations in patients with intracerebral hemorrhage (ICH) remain unclear. In this study, GLA sequences were analyzed in a Chinese ICH cohort comprising 373 patients with computed tomography-confirmed ICH and 563 in-house controls and East Asians from public databases. Only one previously reported mutation, p. Ala15Val, responsible for Fabry disease was identified in a female patient with nonlobar ICH. Therefore, this definitive GLA mutation accounted for 0.27% (1/373) of Chinese patients with ICH. Another functional variant, rs2071225 (c.-10C>T), was present at minor allele frequency (MAF) of 9.1%, indicating no association with ICH, despite a trend of an association for male patients with lobar ICH. In conclusion, our results indicate that the GLA mutation is an uncommon genetic etiology of ICH in China.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.027DOI Listing
June 2021

A novel 7α-hydroxysteroid dehydrogenase: Magnesium ion significantly enhances its activity and thermostability.

Int J Biol Macromol 2021 Apr 13;177:111-118. Epub 2021 Feb 13.

Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China. Electronic address:

7α-Hydroxysteroid dehydrogenase (7α-HSDH) plays an important role in the efficient biotransformation of taurochenodeoxycholic acid (TCDCA) to tauroursodeoxycholic acid (TUDCA). In this paper, a novel NADP(H)-dependent 7α-HSDH (named J-1-1) was discovered, heterologously expressed in Escherichia coli and biochemically characterized. J-1-1 exhibited high enzymatic activities. The specific activities of J-1-1 toward TCDCA, glycochenodeoxycholic acid (GCDCA) and ethyl benzoylacetate (EBA) were 188.3 ± 0.2, 217.6 ± 0.4, and 20.0 ± 0.2 U·mg, respectively, in 50 mM Glycine-NaOH, pH 10.5. Simultaneously, J-1-1 showed high thermostability; 73% of its activity maintained after heat treatment at 40 °C for 100 h. Particularly noteworthy is that magnesium ion could stabilize the structure of J-1-1, resulting in the enhancement of its enzymatic activity and thermostability. The enzymatic activity of J-1-1 increased 40-fold in the presence of 50 mM Mg, and T increased by approximately 6 °C. Furthermore, after heat treatment at 40 °C for 20 min, the control group only retained 52% of the residual enzyme activity, while the residual enzyme activity of the experimental group was still 77% of the J-1-1 enzyme activity with Mg and without heat treatment. These properties of 7α-HSDH would be expected to contribute to more extensive applications in the biotransformation of related substrates.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.02.082DOI Listing
April 2021

Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk.

JCI Insight 2021 Mar 8;6(5). Epub 2021 Mar 8.

Cardiovascular Institute.

Recent advances in proteomic technologies have made high-throughput profiling of low-abundance proteins in large epidemiological cohorts increasingly feasible. We investigated whether aptamer-based proteomic profiling could identify biomarkers associated with future development of type 2 diabetes (T2DM) beyond known risk factors. We identified dozens of markers with highly significant associations with future T2DM across 2 large longitudinal cohorts (n = 2839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic, and clinical data from humans to nominate 1 specific candidate to test for potential causal relationships in model systems. Our studies identified functional effects of aminoacylase 1 (ACY1), a top protein association with future T2DM risk, on amino acid metabolism and insulin homeostasis in vitro and in vivo. Furthermore, a loss-of-function variant associated with circulating levels of the biomarker WAP, Kazal, immunoglobulin, Kunitz, and NTR domain-containing protein 2 (WFIKKN2) was, in turn, associated with fasting glucose, hemoglobin A1c, and HOMA-IR measurements in humans. In addition to identifying potentially novel disease markers and pathways in T2DM, we provide publicly available data to be leveraged for insights about gene function and disease pathogenesis in the context of human metabolism.
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http://dx.doi.org/10.1172/jci.insight.144392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021115PMC
March 2021

Decrease in leptin mediates rat bone metabolism impairments during high-fat diet-induced catch-up growth by modulating the OPG/RANKL balance.

3 Biotech 2021 Feb 30;11(2):103. Epub 2021 Jan 30.

Department of Clinical Laboratory, The Affiliated Hospital of Guilin Medical University, Guilin, People's Republic of China.

Due to catch-up growth (CUG), there are adverse effects on human health. However, there is little information about its influence on bone metabolism. This study aimed to investigate the effects of leptin on bone metabolism and formation during high-fat diet (HFD)-induced CUG. We randomly divided male Wistar rats (5 weeks old) into four groups: control (CTL), caloric restriction and normal chow (RN), caloric restriction (4 weeks), and HFD (RH), and RH + leptin antagonist (RH + LEPA). We monitored body weights, biochemical markers, and epididymal and perirenal fat in these rats. We then performed Hematoxylin and Eosin (H&E) staining to evaluate bone metabolism. We detected osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa b ligand (RANKL) by qRT-PCR and immunohistochemistry (IHC). We found that HFD increased the body weights in rats. In RN, RH, and RH + LEPA groups, major biochemical markers of bone metabolism in rat serum were significantly altered. We found that epididymal and perirenal fat tissues of RH and RH + LEPA groups were higher than those in the RN group. Severe bone formation impairment in the distal diaphysis and metaphysis of the left femora and lumbar vertebra was seen in the RH group compared to RN, which was even aggravated by a leptin antagonist. OPG in the left femora and lumbar vertebra was lower in RH than the RN group. The leptin antagonist decreased OPG during CUG in the RH group, whereas RANKL expression showed an opposite alteration. During HFD-induced CUG, bone formation was mediated by OPG and RANKL and was affected by the leptin content.
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http://dx.doi.org/10.1007/s13205-021-02658-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847480PMC
February 2021

TFF3 mediates the NF-κB/COX2 pathway to regulate PMN-MDSCs activation and protect against necrotizing enterocolitis.

Eur J Immunol 2021 May 23;51(5):1110-1125. Epub 2021 Feb 23.

Department of Clinical Laboratory, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, P. R. China.

Intestinal trefoil factor 3 (TFF3) plays an important role in repairing the intestinal mucosa. However, the detailed mechanism regarding immune regulation by TFF3 is not well defined. Here, we reported that treatment of mouse BM cells and human peripheral blood mononuclear cells from healthy volunteers with TFF3 activated polymorphnuclear myeloid-derived suppressor cells (PMN-MDSCs) in vitro. We also found that prostaglandin E2 is a major TFF3-mediated MDSC target, and that NF-κB/COX2 signaling was involved in this process. Moreover, TFF3 treatment or transfer of TFF3-derived PMN-MDSCs (TFF3-MDSCs) to experimental necrotizing enterocolitis (NEC) mice caused PMN-MDSC accumulation in the lamina propria (LP), which was associated with decreased intestinal inflammation, permeability, bacterial loading, and prolonged survival. Interestingly, no NEC severity remission was observed in Rag1 KO mice that were given TFF3-MDSCs, but coinjection with CD4 T cells significantly relieved NEC inflammation. Overall, TFF3 mediates the NF-κB/COX2 pathway to regulate PMN-MDSC activation and attenuates NEC in a T-cell-dependent manner, which suggests a novel mechanism in preventing NEC occurrence.
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http://dx.doi.org/10.1002/eji.202048768DOI Listing
May 2021

An evaluation of approaches for rare variant association analyses of binary traits in related samples.

Sci Rep 2021 Feb 4;11(1):3145. Epub 2021 Feb 4.

Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.

Recognizing that family data provide unique advantage of identifying rare risk variants in genetic association studies, many cohorts with related samples have gone through whole genome sequencing in large initiatives such as the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. Analyzing rare variants poses challenges for binary traits in that some genotype categories may have few or no observed events, causing bias and inflation in commonly used methods. Several methods have recently been proposed to better handle rare variants while accounting for family relationship, but their performances have not been thoroughly evaluated together. Here we compare several existing approaches including SAIGE but not limited to related samples using simulations based on the Framingham Heart Study samples and genotype data from Illumina HumanExome BeadChip where rare variants are the majority. We found that logistic regression with likelihood ratio test applied to related samples was the only approach that did not have inflated type I error rates in both single variant test (SVT) and gene-based tests, followed by Firth logistic regression that had inflation in its direction insensitive gene-based test at prevalence 0.01 only, applied to either related or unrelated samples, though theoretically logistic regression and Firth logistic regression do not account for relatedness in samples. SAIGE had inflation in SVT at prevalence 0.1 or lower and the inflation was eliminated with a minor allele count filter of 5. As for power, there was no approach that outperformed others consistently among all single variant tests and gene-based tests.
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http://dx.doi.org/10.1038/s41598-021-82547-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862354PMC
February 2021