Publications by authors named "ZhongHua Liu"

466 Publications

Comprehensive analyses of m6A regulators and interactive coding and non-coding RNAs across 32 cancer types.

Mol Cancer 2021 Apr 13;20(1):67. Epub 2021 Apr 13.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China.

N6-Methyladenosine (m6A) is an RNA modification that interacts with numerous coding and non-coding RNAs and plays important roles in the development of cancers. Nonetheless, the clinical impacts of m6A interactive genes on these cancers largely remain unclear since most studies focus only on a single cancer type. We comprehensively evaluated m6A modification patterns, including 23 m6A regulators and 83 interactive coding and non-coding RNAs among 9,804 pan-cancer samples. We used clustering analysis to identify m6A subtypes and constructed the m6A signature based on an unsupervised approach. We used the signatures to identify potential m6A modification targets across the genome. The prognostic value of one target was further validated in 3,444 samples from six external datasets. We developed three distinct m6A modification subtypes with different tumor microenvironment cell infiltration degrees: immunological, intermediate, and tumor proliferative. They were significantly associated with overall survival in 24 of 27 cancer types. Our constructed individual-level m6A signature was associated with survival, tumor mutation burden, and classical pathways. With the signature, we identified 114 novel genes as potential m6A targets. The gene shared most commonly between cancer types, BCL9L, is an oncogene and interacts with m6A patterns in the Wnt signaling pathway. In conclusion, m6A regulators and their interactive genes impact the outcome of various cancers. Evaluating the m6A subtype and the signature of individual tumors may inform the design of adjuvant treatments.
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http://dx.doi.org/10.1186/s12943-021-01362-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045265PMC
April 2021

An Omnibus Test for Detecting Multiple Phenotype Associations Based on GWAS Summary Level Data.

Front Genet 2021 17;12:644419. Epub 2021 Mar 17.

Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong, China.

Abundant Genome-wide association study (GWAS) findings have reflected the sharing of genetic variants among multiple phenotypes. Exploring the association between genetic variants and multiple traits can provide novel insights into the biological mechanism of complex human traits. In this article, we proposed to apply the generalized Berk-Jones (GBJ) test and the generalized higher criticism (GHC) test to identify the genetic variants that affect multiple traits based on GWAS summary statistics. To be more robust to different gene-multiple traits association patterns across the whole genome, we proposed an omnibus test (OMNI) by using the aggregated Cauchy association test. We conducted extensive simulation studies to investigate the type one error rates and compare the powers of the proposed tests (i.e., the GBJ, GHC and OMNI tests) and the existing tests (i.e., the minimum of the -values (MinP) and the cross-phenotype association test (CPASSOC) in a wide range of simulation settings. We found that all of these methods could control the type one error rates well and the proposed OMNI test has robust power. We applied those methods to the summary statistics dataset from Global Lipids Genetics Consortium and identified 19 new genetic variants that were missed by the original single trait association analysis.
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http://dx.doi.org/10.3389/fgene.2021.644419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009968PMC
March 2021

MRCIP: a robust Mendelian randomization method accounting for correlated and idiosyncratic pleiotropy.

Brief Bioinform 2021 Mar 11. Epub 2021 Mar 11.

Department of Statistics and Actuarial Science, The University of Hong Kong, Pokfulam Road, Hong Kong, China.

Mendelian randomization (MR) is a powerful instrumental variable (IV) method for estimating the causal effect of an exposure on an outcome of interest even in the presence of unmeasured confounding by using genetic variants as IVs. However, the correlated and idiosyncratic pleiotropy phenomena in the human genome will lead to biased estimation of causal effects if they are not properly accounted for. In this article, we develop a novel MR approach named MRCIP to account for correlated and idiosyncratic pleiotropy simultaneously. We first propose a random-effect model to explicitly model the correlated pleiotropy and then propose a novel weighting scheme to handle the presence of idiosyncratic pleiotropy. The model parameters are estimated by maximizing a weighted likelihood function with our proposed PRW-EM algorithm. Moreover, we can also estimate the degree of the correlated pleiotropy and perform a likelihood ratio test for its presence. Extensive simulation studies show that the proposed MRCIP has improved performance over competing methods. We also illustrate the usefulness of MRCIP on two real datasets. The R package for MRCIP is publicly available at https://github.com/siqixu/MRCIP.
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http://dx.doi.org/10.1093/bib/bbab019DOI Listing
March 2021

Accumulation and cross-linkage of β-1,3/1,6-glucan lead to loss of basal stipe cell wall extensibility in mushroom Coprinopsis cinerea.

Carbohydr Polym 2021 May 2;259:117743. Epub 2021 Feb 2.

Jiangsu Key Laboratory for Microbes and Microbial Functional Genomics, Jiangsu Engineering and Technology Research Center for Industrialization of Microbial Resources, College of Life Science, Nanjing Normal University, 1 Wenyuan Rd, Xianlin University Park, Nanjing 210046, PR China. Electronic address:

The mature basal stipe of mushroom Coprinopsis cinerea loses wall extensibility. We found that an endo-β-1,3-glucanase ENG from C. cinerea could restore mature basal stipe wall extensibility via pretreatment such that the ENG-pretreated basal stipe walls could be induced to extend by chitinase ChiIII. ENG pretreatment released glucose, laminaribiose, and 3-O-D-gentiobiose-D-glucose from the basal stipe walls, consistent with ENG-digested products of β-1,6-branched β-1,3-glucan. Different effects of endo-β-1,3-glucanase ENG and exo-β-1,3-glucanase EXG pretreatment on the structure, amount and ratio (β-1,3-glucoside bonds to β-1,6-glucoside bonds) of products from the basal stipe and the apical stipe cell walls, respectively, and on the cell wall extensibility and the cell wall ultra-architecture of the basal stipes were analyzed. All results demonstrate that the more accumulation and cross-linkage of β-1,6-branched β-1,3-glucan with wall maturation lead to loss of wall extensibility of the basal stipe regions compared to the apical stipe cell walls.
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http://dx.doi.org/10.1016/j.carbpol.2021.117743DOI Listing
May 2021

An Improved Genome-Wide Polygenic Score Model for Predicting the Risk of Type 2 Diabetes.

Front Genet 2021 11;12:632385. Epub 2021 Feb 11.

Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong, China.

Polygenic risk score (PRS) has been shown to be predictive of disease risk such as type 2 diabetes (T2D). However, the existing studies on genetic prediction for T2D only had limited predictive power. To further improve the predictive capability of the PRS model in identifying individuals at high T2D risk, we proposed a new three-step filtering procedure, which aimed to include truly predictive single-nucleotide polymorphisms (SNPs) and avoid unpredictive ones into PRS model. First, we filtered SNPs according to the marginal association -values (≤ 5× 10) from large-scale genome-wide association studies. Second, we set linkage disequilibrium (LD) pruning thresholds () as 0.2, 0.4, 0.6, and 0.8. Third, we set -value thresholds as 5× 10, 5× 10, 5× 10, and 5× 10. Then, we constructed and tested multiple candidate PRS models obtained by the PRSice-2 software among 182,422 individuals in the UK Biobank (UKB) testing dataset. We validated the predictive capability of the optimal PRS model that was chosen from the testing process in identifying individuals at high T2D risk based on the UKB validation dataset ( = 274,029). The prediction accuracy of the PRS model evaluated by the adjusted area under the receiver operating characteristics curve (AUC) showed that our PRS model had good prediction performance [AUC = 0.795, 95% confidence interval (CI): (0.790, 0.800)]. Specifically, our PRS model identified 30, 12, and 7% of the population at greater than five-, six-, and seven-fold risk for T2D, respectively. After adjusting for sex, age, physical measurements, and clinical factors, the AUC increased to 0.901 [95% CI: (0.897, 0.904)]. Therefore, our PRS model could be useful for population-level preventive T2D screening.
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http://dx.doi.org/10.3389/fgene.2021.632385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905203PMC
February 2021

Achieving the Super Gas-Wetting Alteration by Functionalized Nano-Silica for Improving Fluid Flowing Capacity in Gas Condensate Reservoirs.

ACS Appl Mater Interfaces 2021 Mar 26;13(9):10996-11006. Epub 2021 Feb 26.

College of Petroleum Engineering, China University of Petroleum (East China), Qingdao 266580, China.

It is well-known that the production of gas-condensate reservoirs is significantly affected by the liquid condensation near the wellbore region. Gas-wetting alteration can be one of the most effective approaches to alleviate condensate accumulation and improve liquid distribution. However, gas well deliverability is still limited because the wettability of cores is altered only from liquid-wetting to intermediate gas-wetting by using traditional chemical stimulation. To solve this bottleneck problem, herein, we developed a fluorine-functionalized nanosilica to achieve super gas-wetting alteration, increasing the contact angles of water and n-hexadecane on the treated core surface from 23 and 0° to 157 and 145°, respectively. The surface free energy reduces rapidly from 67.97 to 0.23 mN/m. The super gas-wetting adsorption layer on the core surface formed by functionalized nanosilica not only increases the surface roughness but also reduces the surface free energy. The core flooding confirms that the required pressure for displacement is apparently reduced. Meanwhile, the core permeability can be dramatically restored after the super gas-wetting alteration. The microscopic visualization is employed to further understand the impact of fluorine-functionalized nanosilica on the fluid flow behavior and mechanism in porous media. The oil saturation in the micromodel decreases sharply from 48.75 to 7.84%, eliminating the "water locking effect" and "Jiamin effect", which indicates that the added functional nanosilica effectively improves fluid flow capacity and may contribute to production in the gas condensate reservoirs. In addition, this work reveals the fluid flow behavior and mechanism in the reservoir in detail, which will expand the better application of this material to many oilfields and other mining engineering systems.
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http://dx.doi.org/10.1021/acsami.0c22831DOI Listing
March 2021

The Role of -Catenin in Th1 Immune Response against Tuberculosis and Profiles of Expression in Patients with Pulmonary Tuberculosis.

J Immunol Res 2021 11;2021:6625855. Epub 2021 Feb 11.

Shanghai Clinical Research Center for Tuberculosis, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

-Catenin is a key molecule of canonical Wnt/-catenin pathway. Its roles and expression profiles in T cells of tuberculosis (TB) remain unclear. The aim of this study was to explore the role of -catenin in CD4 T cells and its expression characteristics in patients with pulmonary tuberculosis (PTB). In this study, CD4 T cell-specific -catenin conditional knockout mice (-CAT-cKO mice) were aerosol infected with () H37R with wild-type mice as controls. Four weeks after infection, the mRNA expression of IFN-, TNF-, and TCF-7 in the lungs of mice was measured. CD4, CD8, -catenin, IFN-, and TNF- in mononuclear cells from the lungs and spleens were measured by flow cytometry, and the pathological changes of lungs were also observed. Patients with PTB were enrolled, with blood samples collected and PBMCs isolated. The expressions of -catenin, IFN-, TNF-, and PD-1 in CD4 and CD8 T cells were measured by flow cytometry. Results showed a decreased frequency of and reduced IFN-/TNF- mRNA expression and secretion by CD4 T cells in the lungs of infected -CAT-cKO mice compared with infected wild-type controls, and only slightly more inflammatory changes were observed in the lungs. -catenin expressions in CD4 and CD8 T cells were significantly decreased in blood cells of patients with severe PTB compared with those in mild PTB. The stimulation of peripheral blood mononuclear cells (PBMCs) with lithium chloride (LiCl), a stimulant of -catenin, resulted in the increase in CD4 T cell frequency, as well as their secretion of IFN- and TNF-. -Catenin demonstrated a moderately positive correlation with PD-1 in CD4 T cells. -Catenin along with PD-1 and IFN- in CD4 T cells had a high correlation with those in CD8 T cells. In conclusion, -catenin may be involved in the regulation of Th1 response and CD4 T cell frequency in TB.
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http://dx.doi.org/10.1155/2021/6625855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892223PMC
February 2021

Thirty-six-month results of laparoscopic-based renal denervation plus unilateral laparoscopic adrenalectomy for the treatment of patients with resistant hypertension caused by unilateral aldosterone-producing adenoma.

J Clin Hypertens (Greenwich) 2021 Feb 16. Epub 2021 Feb 16.

Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China.

The aim of this study was to explore the long-term clinical results of Renal denervation (RDN) from the adventitia of the renal artery plus unilateral laparoscopic adrenalectomy to treat patients with resistant hypertension caused by unilateral aldosterone-producing adenoma (APA). Sixty patients with resistant hypertension caused by APA who were treated at Henan Provincial People's Hospital from December 2016 to March 2018 were selected and randomly assigned to undergo RDN from the adventitia of the renal artery plus adrenalectomy (RDN group, n = 30) or adrenalectomy alone (control group, n = 30). Office blood pressure (BP), antihypertensive medication usage and other laboratory characteristics were followed every 6 months through 36 months. Follow-up data were available at 36 months for 23 of 30 subjects in the RDN group and for 21 of 30 subjects who were in the control group. At 36 months postprocedure, the reduction in the RDN group was 42.2 ± 21.6 mmHg and that in the control group was 29.8 ± 13.5 mmHg (p = .029 between the groups). During the follow-up to 36 months postprocedure, no patients in either the RDN group or the control group died due to surgical complications, and the RDN group had no procedural complications, including renal artery dissection, perforation, and renal artery stenosis. There was no change in the mean eGFR of the two groups, and no serious adverse events were reported. In conclusion, RDN from the adventitia of the renal artery plus unilateral laparoscopic adrenalectomy resulted in sustained lowering of BP at 3 years in a selected population of subjects with resistant hypertension caused by unilateral APA without serious safety concerns.
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http://dx.doi.org/10.1111/jch.14223DOI Listing
February 2021

Pentacyclic triterpene compounds from loquat leaves reduce skin inflammation and epidermal hyperplasia in psoriasis via inhibiting the Th17 cells.

Mol Immunol 2021 04 2;132:30-40. Epub 2021 Feb 2.

Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China. Electronic address:

Psoriasis is a refractory inflammatory skin disease affecting 2 %-3 % of the world population, characterized by the infiltration and hyper-proliferation of inflammatory cells and aberrant differentiation of keratinocytes. Targeting the IL-23/ Th17 axis has been well recognized as a promising therapeutic strategy, as the IL-23/ Th17 signal plays a vital role in the pathology of psoriasis. Three pentacyclic triterpene compounds isolated from loquat leaves have been reported with significant inhibitory effects on RORγt transcription activity and Th17 cell differentiation, and excellent performance in preventing lupus nephritis pathogenesis. However, the potential effects of these pentacyclic triterpene compounds on psoriasis remain unknown. In this study, we demonstrated the potent therapeutic effects of these pentacyclic triterpene compounds on psoriasis. These three pentacyclic triterpene compounds significantly alleviated skin inflammation as well as aberrant keratinocyte proliferation in an imiquimod-induced mouse psoriasis model. These compounds also inhibited the infiltration of immune cells and the level of pro-inflammatory cytokine in the dermis, as well as the cells number and changed the cytokine profiling expression of Th17 cells. These compounds could reduce the amount of CD4 and CD8 T cells in local lymph node, but not in spleen, which is different from hydrocortisone, the positive control treatment. These results suggest better performance of these compounds than steroids on treating psoriasis with less side effects on the integrated immune system. In summary, our findings uncover the potent therapeutic effects of pentacyclic triterpene compounds on psoriasis, providing potential candidate compounds for drug development.
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http://dx.doi.org/10.1016/j.molimm.2021.01.019DOI Listing
April 2021

Paradoxical Association Between Intradialytic Blood Pressure Change and Long-Term Mortality with Different Levels of Interdialytic Weight Gain.

Int J Gen Med 2021 19;14:211-220. Epub 2021 Jan 19.

Division of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.

Background: A greater interdialytic weight gain (IDWG) implies a greater ultrafiltration rate, which might lead to hemodynamic instability and intradialytic blood pressure (BP) change in hemodialysis patients. However, current studies have not explicated the impact of IDWG on the association between intradialytic BP changes and prognosis, especially in patients without cardiac dysfunction and diabetes. In this study, we aimed to explore the relationship between absolute intradialytic BP changes and mortality with different IDWG levels.

Methods: A total of 204 hemodialysis patients (without cardiac dysfunction and diabetes) were included in this prospective observation study, with a mean follow-up of 55.32±20.99 months. Initially, we collected IDWG, IDWG% (percentages according to dry weight), and pre-/post-BPs of 36 consecutive dialysis sessions during three months enrollment. And the average value of them was defined as baseline value. Patients were divided into 3 cohorts according to IDWG% tertiles (<3.3%, 3.3%-4.6%, ≥4.6%). Comparisons between different tertiles were analyzed.

Results: Compared to the low IDWG% group (tertile 1, T1), patients of high IDWG% group (tertile 3, T3) were younger, had higher ultrafiltration rate, less residual kidney function, lower BMI and dry weight, longer dialysis vintage and higher N terminal pro B type natriuretic peptide levels (<0.05). Correlations were found between IDWG% and intradialytic BP changes. Kaplan-Meier analysis and multivariate Cox regression model adjusted for demographic data, dialysis information and predialysis BPs indicated that greater absolute intradialytic BP changes were associated with worse prognosis in T1 group (<0.05). While in T3 group, less absolute intradialytic BP changes were associated with higher mortality (<0.05).

Conclusion: There is a paradoxical association between absolute intradialytic BP changes and long-term mortality with different IDWG levels. Both BP stability and volume balance are crucial to patients' prognosis.
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http://dx.doi.org/10.2147/IJGM.S288038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829598PMC
January 2021

Association of Serum Mannose With Acute Respiratory Distress Syndrome Risk and Survival.

JAMA Netw Open 2021 01 4;4(1):e2034569. Epub 2021 Jan 4.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Importance: Acute respiratory distress syndrome (ARDS) confers high mortality risk among critically ill patients. Identification of biomarkers associated with ARDS risk may guide clinical diagnosis and prognosis.

Objective: To systematically evaluate the association of blood metabolites with ARDS risk and survival.

Design, Setting, And Participants: In this cohort study, data from the Molecular Epidemiology of ARDS (MEARDS) study, a prospective cohort of 403 patients with ARDS and 1227 non-ARDS controls, were analyzed. Patients were recruited in intensive care units (ICUs) at Massachusetts General Hospital and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts, from January 1, 1998, to December 31, 2014. Data analysis was performed from December 9, 2018, to January 4, 2019.

Main Outcomes And Measures: Participants were followed up daily for ARDS development defined by Berlin criteria, requiring fulfillment of chest radiograph and oxygenation criteria on the same calendar day during invasive ventilatory assistance. A 2-stage study design was used to explore novel metabolites associated with ARDS risk and survival.

Results: Of the 1630 participants from MEARDS who were admitted to the ICU , 403 (24.7%) were diagnosed with ARDS (mean [SD] age, 63.0 [17.0] years; 251 [62.3%] male) and 1227 (75.3%) were at-risk but did not have ARDS (mean [SD] age, 62.3 [16.9] years; 753 [61.4%] male). Mendelian randomization suggested that genetically regulated serum mannose was associated with ARDS risk (odds ratio [OR], 0.64; 95% CI, 0.53-0.78; P = 7.46 × 10-6) in the discovery stage. In the functional validation stage incorporating 83 participants with ARDS and matched at-risk participants in the control group from the ICU, the protective association of mannose with ARDS risk was validated (OR, 0.67; 95% CI, 0.46-0.97; P = .03). Furthermore, serum mannose was associated with 28-day (OR, 0.25; 95% CI, 0.11-0.56; P = 6.95 × 10-4) and 60-day (OR, 0.36; 95% CI, 0.19-0.71; P = 3.12 × 10-3) mortality and 28-day (hazard ratio, 0.49; 95% CI, 0.32-0.74; P = 6.41 × 10-4) and 60-day (hazard ratio, 0.55; 95% CI, 0.37-0.80; P = 2.11 × 10-3) survival.

Conclusions And Relevance: In this study, genetically regulated serum mannose appeared to be associated with ARDS risk and outcome, and increased serum mannose at admission was associated with reduced ARDS risk and better survival. These findings could inform prevention and clinical intervention in ARDS cases, which have increased with the expansion of the coronavirus disease 2019 pandemic.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.34569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841460PMC
January 2021

Engineering of highly potent and selective HNTX-III mutant against hNa1.7 sodium channel for treatment of pain.

J Biol Chem 2021 Jan 22:100326. Epub 2021 Jan 22.

The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410018, Hunan, China. Electronic address:

Human voltage-gated sodium channel (VGSC) Na1.7 (hNa1.7) is involved in the generation and conduction of neuropathic and nociceptive pain signals. Compelling genetic and preclinical studies have validated that hNa1.7 is a therapeutic target for the treatment of pain, however there is a dearth of currently available compounds capable of targeting hNav1.7 with high potency and specificity. Hainantoxin-III (HNTX-III) is a 33-residue polypeptide from the venom of the spider Ornithoctonus hainana. It is a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels. Here, we report the engineering of improved potency and Na selectivity of hNa1.7 inhibition peptides derived from the HNTX-III scaffold. Alanine scanning mutagenesis showed key residues for HNTX-III interacting with hNa1.7. Site-directed mutagenesis analysis indicated key residues on hNa1.7 interacting with HNTX-III. Molecular docking was conducted to clarify the binding interface between HNTX-III and Nav1.7 and guide the molecular engineering process. Ultimately, we obtained H4 [K0G1-P18K-A21L-V] based on molecular docking of HNTX-III and hNa1.7 with a 30-fold improved potency (IC 0.007 ± 0.001 μM) and > 1000-fold selectivity against Na1.4 and Na1.5. H4 also showed robust analgesia in the acute and chronic inflammatory pain model and neuropathic pain model. Thus, our results provide further insight into peptide toxins that may prove useful in guiding the development of inhibitors with improved potency and selectivity for Na subtypes with robust analgesia.
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http://dx.doi.org/10.1016/j.jbc.2021.100326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988488PMC
January 2021

Structural Characterization and Immunostimulatory Activity of Heteropolysaccharides from Fuzhuan Brick Tea.

J Agric Food Chem 2021 Feb 22;69(4):1368-1378. Epub 2021 Jan 22.

Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha, Hunan 410128, China.

Fuzhuan brick tea (FBT), one of the unique dark teas, has various health-promoting functions. In the present study, one polysaccharide fraction, namely FBTPS-2-1, was extracted and purified from FBT, and its structure and potential immunostimulatory activity were investigated. The results showed that FBTPS-2-1,one of typical heteropolysaccharides, was mainly composed of Gal, Ara, and Glc with little molar content of Man, Rha, GalA, and GlcA in molar ratio of 46.59:22.13:13.57:8.20:6.02:2.12:1.38 and molecular weight of 748 kDa. The backbone of FBTPS-2-1 contained →4)-β-d-Gal-(1→4)-β-d-Gal-(1→, →4)-β-d-Gal-(1→4)-α-d-Glc-(1→, →4)-α-d-Glc-(1→4)-α-d-Glc-(1→, →4)-α-d-Glc-(1→4)-β-d-Gal-(1→, →3)-β-d-Gal-(1→4)-β-d-Gal-(1→, →3,6)-β-d-Gal-(1→3)-β-d-Gal-(1→ and →3,6)-β-d-Gal-(1→3,6)-β-d-Gal-(1→. The linkages of branches in FBTPS-2-1 were mainly composed of α-l-Ara-(1→3,6)-β-d-Gal-(1→, →5)-α-l-Ara-(1→3,6)-β-d-Gal-(1→, →6)-β-d-Gal-(1→3,6)-β-d-Gal-(1→, α-l-Ara-(1→3,5)-α-l-Ara-(1→, →3,5)-α-l-Ara-(1→5)-α-l-Ara-(1→, α-d-Gal-(1→3,5)-α-l-Ara-(1→ and →5)-α-l-Ara-(1→6)-β-d-Gal-(1→. Furthermore, FBTPS-2-1 could increase the phagocytosis of macrophages and promote the secretion of NO and a variety of inflammatory cytokines, including TNF-α, IL-1β, and IL-6, indicating noticeable immune enhancement activity. Thus, FBTPS-2-1 could serve as a potentially functional food to improve human health by modulating the host immunoreaction.
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http://dx.doi.org/10.1021/acs.jafc.0c06913DOI Listing
February 2021

Pro-inflammatory cytokines as potential predictors for intradialytic hypotension.

Ren Fail 2021 Dec;43(1):198-205

Division of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, PR China.

Background: Intradialytic hypotension (IDH) is a common complication in maintaining hemodialysis (MHD) patients. Immune activation might be part of the mechanisms. However, the association between pro-inflammatory cytokines and blood pressure (BP) has not been deeply explored. So we aim to evaluate the potential role of pro-inflammatory cytokines in IDH.

Methods: MHD patients starting hemodialysis before January 2016 were enrolled in our retrospective study. Patients' characteristics, laboratory results, and intradialytic BP were collected. IDH was defined as nadir systolic BP ≤ 90 mmHg during hemodialysis. The definition of IDH group was that those who suffered from more than one hypotensive event during one month after the enrollment (10% of dialysis treatments). Spearman correlation analysis and logistic regression were employed to explore the relationship between pro-inflammatory cytokines and IDH.

Results: Among 390 patients, 72 were identified with IDH (18.5%). High levels of serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were observed in the IDH group ( < 0.001). Both TNF-α and IL-1β positively correlated with predialysis BP ( < 0.01). Receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic accuracy of serum IL-1β and TNF-α for IDH. The area under the curve of IL-1β was 0.772 (95% CI: 0.708-0.836,  < 0.01), and that of TNF-α was 0.701 (95% CI: 0.620-0.781,  < 0.01). After adjusting for patients' characteristics, biochemical parameters, comorbid conditions, predialysis BP, and medications, elevated TNF-α and IL-1β were still risk factors for IDH.

Conclusion: Pro-inflammatory cytokines (TNF-α and IL-1β) could be potential predictors for IDH.
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http://dx.doi.org/10.1080/0886022X.2021.1871921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833080PMC
December 2021

CD27 enhances the killing effect of CAR T cells targeting trophoblast cell surface antigen 2 in the treatment of solid tumors.

Cancer Immunol Immunother 2021 Jan 13. Epub 2021 Jan 13.

Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, N1311 Rm, No. 10 Bld, 74 Zhongshan 2nd Rd, Guangzhou, 510080, China.

Chimeric antigen receptor (CAR) T cell therapy, a type of adoptive cell therapy, has been successfully used when treating lymphoma malignancies, but not nearly as successful in treating solid tumors. Trophoblast cell surface antigen 2 (Trop2) is expressed in various solid tumors and plays a role in tumor growth, invasion, and metastasis. In this study, a CAR targeting Trop2 (T2-CAR) was developed with different co-stimulatory intercellular domains. T2-CAR T cells demonstrated a powerful killing ability in the presence of Trop2-positive cells following an in vitro assay. Moreover, T2-CAR T cells produced multiple effector cytokines under antigen stimulation. In tumor-bearing mouse models, the CD27-based T2-CAR T cells showed a higher antitumor activity. Additionally, more CD27-based T2-CAR T cells survived in tumor-bearing mice spleens as well as in the tumor tissue. CD27-based T2-CAR T cells were also found to upregulate IL-7Rα expression, while downregulating PD-1 expression. In conclusion, the CD27 intercellular domain can enhance the T2-CAR T cell killing effect via multiple mechanisms, thus indicating that a CD27-based T2-CAR T cell approach is suitable for clinical applications.
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http://dx.doi.org/10.1007/s00262-020-02838-8DOI Listing
January 2021

Discriminative Label Relaxed Regression with Adaptive Graph Learning.

Comput Intell Neurosci 2020 12;2020:8852137. Epub 2020 Dec 12.

College of Electronics and Information, Xi'an Polytechnic University, Xi'an, China.

The traditional label relaxation regression (LRR) algorithm directly fits the original data without considering the local structure information of the data. While the label relaxation regression algorithm of graph regularization takes into account the local geometric information, the performance of the algorithm depends largely on the construction of graph. However, the traditional graph structures have two defects. First of all, it is largely influenced by the parameter values. Second, it relies on the original data when constructing the weight matrix, which usually contains a lot of noise. This makes the constructed graph to be often not optimal, which affects the subsequent work. Therefore, a discriminative label relaxation regression algorithm based on adaptive graph (DLRR_AG) is proposed for feature extraction. DLRR_AG combines manifold learning with label relaxation regression by constructing adaptive weight graph, which can well overcome the problem of label overfitting. Based on a large number of experiments, it can be proved that the proposed method is effective and feasible.
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http://dx.doi.org/10.1155/2020/8852137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752280PMC
December 2020

Educational attainment protects against type 2 diabetes independently of cognitive performance: a Mendelian randomization study.

Acta Diabetol 2021 Jan 6. Epub 2021 Jan 6.

Department of Neurology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China.

Aims: Observational studies have reported a negative association between educational attainment and type 2 diabetes (T2D), but the causality remains largely unknown. The aim of this study is to investigate the potential causal effect of educational attainment on T2D and whether such an effect is independent of cognitive performance.

Methods: We conducted two-sample Mendelian randomization (MR) analysis using genetic variants strongly associated with educational attainment and cognitive performance to estimate the causal associations with T2D, among 61,714 T2D cases and 593,952 controls. We also performed multivariable MR to explore the independent effects of educational attainment and cognitive performance on T2D risk.

Results: In univariable MR, we found evidence that genetically predicted higher educational attainment [odds ratio (OR) 0.53 per 1-standard deviation (SD) increase; 95% confidence interval (CI) 0.47-0.60] and cognitive performance (OR 0.79 per 1-SD increase; 95%CI 0.69-0.91) were related to decreased risk of T2D. Our further multivariable MR results suggested that more years of education led to a reduced likelihood of T2D independently of cognitive performance (OR 0.52; 95%CI 0.42-0.64). However, the protective effect of cognitive performance on T2D was attenuated once educational attainment was controlled for (OR 1.08; 95%CI 0.88-1.32).

Conclusions: We provided evidence to suggest that educational attainment protects against T2D independently of cognitive performance, but does not support a negative causal association between cognitive performance and T2D independently of educational attainment. Education might represent a potential target for intervention to battle type 2 diabetes risk.
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http://dx.doi.org/10.1007/s00592-020-01647-wDOI Listing
January 2021

Intradialytic systolic blood pressure variation can predict long-term mortality in patients on maintenance hemodialysis.

Int Urol Nephrol 2021 Apr 2;53(4):785-795. Epub 2021 Jan 2.

Division of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.

Purpose: It is unclear which time-points of intradialytic blood pressure (BP) best predict prognosis. Thus, it is important to assess the association between different time-points of intradialytic BP and prognosis in clinical practice.

Methods: We recruited patients who underwent hemodialysis from January 2014 to June 2014. Data about dialysis were collected, including intradialytic BP. Cox regression analysis was performed to examine the association between different time-points of intradialytic BP and clinical events, with a follow-up through December 31, 2019. The primary endpoint was all-cause mortality.

Results: A total of 216 patients were recruited and 62 (30.7%) patients died (6.1 per 100-person year) during the follow-up. Intradialytic SBP varied greatly in fatalities. Univariate and multivariate Cox regression models indicated that the adjusted hazard ratio for death was 1.80 and 5.06 when intradialytic systolic blood pressure (SBP) variation was analyzed in increments of 20 mmHg. Furthermore, we divided intradialytic SBP variation into three categories: < 15 mmHg, 15 ~ 30 mmHg,  ≥ 30 mmHg. Kaplan-Meier analysis indicated that both all-cause mortality and cardiovascular mortality increased significantly for patients with intradialytic SBP variation over 30 mmHg (P = 0.006 and 0.021). Univariate and multivariate Cox regression models indicated that the adjusted hazard ratio for death was 3.78 and 12.62 as intradialytic SBP variation ≥ 30 mmHg vs. intradialytic SBP variation < 15 mmHg.

Conclusion: Intradialytic SBP variation, rather than BP of specific intradialytic time-points, has the potential to predict long-term mortality in hemodialysis patients. BP stability is crucial for patients' prognosis.
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http://dx.doi.org/10.1007/s11255-020-02701-wDOI Listing
April 2021

High ultrafiltration rate induced intradialytic hypotension is a predictor for cardiac remodeling: a 5-year cohort study.

Ren Fail 2021 Dec;43(1):40-48

Division of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, P. R. China.

Background: Intradialytic-hypotension (IDH) is a common complication of hemodialysis. High ultrafiltration rate (UFR) might lead to IDH. However, the relationships between UFR, IDH, and cardiac remodeling among hemodialysis patients in the long-term have not been deeply explored.

Methods: This retrospective cohort study collected clinical and echocardiographic data. Patients were enrolled from 1 January 2014 to 31 March 2014 and were followed-up for 5-year. Those who suffered from more than four hypotensive events during three months (10% of dialysis treatments) were defined as the IDH group. Subgroup analysis was done according to the UFR of 10 ml/h/kg. Associations between UFR, IDH, and alterations of cardiac structure/function were analyzed.

Results: Among 209 patients, 96 were identified with IDH (45.9%). The survival rate of IDH patients was lower than that of no-IDH patients (65.5% vs. 81.4%,  = .005). In IDH group, decreased ejection fraction (EF), larger left atrium diameter index (LADI), and left ventricular mass index (LVMI) ( < .05) were observed at the end of the follow-up. In multivariate logistic model, the interaction between UFR and IDH was notably associated with LVMI variation ( = 1.37). After adjusting covariates, UFR was still an independent risk factor of LVMI variation ( = 1.52) in IDH group. In subsequent analysis, we divided patients according to UFR 10 ml/h/kg. For IDH-prone patients, decreased EF, larger LADI, and LVMI ( < .05) were observed at the end of the study only in high-UFR group.

Conclusions: UFR and IDH have interactions on cardiac remodeling. High ultrafiltration rate induced IDH is a predictor for cardiac remodeling in long-term follow-up.
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http://dx.doi.org/10.1080/0886022X.2020.1853570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745843PMC
December 2021

Synergistic non-bonding interactions based on diketopyrrolo-pyrrole for elevated photoacoustic imaging-guided photothermal therapy.

Biomater Sci 2021 Feb;9(3):908-916

Laboratory for NanoMedical Photonics, School of Basic Medical Science, Henan University, Kaifeng 475004, China.

Conjugated polymers have excellent properties and can be used in photothermal therapy (PTT). Nevertheless, the concept to design and optimize the photothermal performance by cooperative non-bonding interactions is still in its infancy. Herein, a series of diketopyrrolopyrrole (DPP) derivatives containing chalcogen and fluorine atoms were synthesized to reveal how intra- and intermolecular interactions affect the therapeutic performance of cancer in vitro and in vivo. The synergistic π-π and FH interactions facilitate fluorine and selenium-substituted DPP-SeF to elevate their photothermal conversion efficiency up to 62% from 32% without fluorine and selenium-substituted DPP-SS, and the half-maximal inhibitory concentration drops to ∼8.36 μg mL-1 for DPP-SeF from 15.14 μg mL-1 for DPP-SS on A549 cells under 808 nm light irradiation. More interestingly, efficient tumor killing ability and magnificent biocompatibility on an animal model of A549 transplanted tumor reassert that DPP-SeF nanoagents have immense potential as photoacoustic/PTT agents. Thus, this work presents an efficient phototherapeutic agent, and meanwhile demonstrates the facile concept of accessing the synergistic effect of non-bonding interactions to promote antitumor efficiency by ingenious molecular engineering.
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http://dx.doi.org/10.1039/d0bm01569eDOI Listing
February 2021

Causal relationships between gut metabolites and Alzheimer's disease: a bidirectional Mendelian randomization study.

Neurobiol Aging 2021 Apr 12;100:119.e15-119.e18. Epub 2020 Nov 12.

Department of Epidemiology & Biostatistics, School of Public Health, Peking University, China; Department of Global Health, School of Public Health, Peking University, China; Key Laboratory of Molecular Cardiovascular Sciences (Peking University), Ministry of Education, China; Center for Intelligent Public Health, Institute for Artificial Intelligence, Peking University, China. Electronic address:

Observational studies have shown that gut microbiota-dependent metabolites are associated with the risk of Alzheimer's disease (AD). However, whether such association reflects a causality remains unclear. We conducted a bidirectional Mendelian randomization analysis to examine the causal relationships between gut microbiota-dependent metabolites trimethylamine N-oxide (TMAO) or its predecessors and AD. We observed that genetically predicted TMAO (odds ratio: 0.99, 95% confidence interval: 0.89 to 1.09 per 10 units, p = 0.775) or its predecessors including betaine (1.06, 1.00 to 1.12 per 10 units, p = 0.056), carnitine (1.05, 0.98 to 1.12 per 10 units, p = 0.178), and choline (1.01, 0.92 to 1.10 per 10 units, p = 0.905) were not associated with the risk of AD. Our Mendelian randomization estimates from AD to metabolites showed that genetically predicted higher risk of AD was also not causally associated with TMAO, betaine, carnitine, and choline levels. Our findings support that gut microbiota-dependent metabolites TMAO or its predecessors do not play causal roles in the development of AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.022DOI Listing
April 2021

Carboxymethyl chitosan based redox-responsive micelle for near-infrared fluorescence image-guided photo-chemotherapy of liver cancer.

Carbohydr Polym 2021 Feb 22;253:117284. Epub 2020 Oct 22.

Key Laboratory of Animal Cellular and Genetic Engineering of Heilongjiang Province, College of Life Science, Northeast Agricultural University, Harbin, Heilongjiang 150030, China; Food Science College, Northeast Agricultural University, Harbin, Heilongjiang 150030, China. Electronic address:

High-efficient vectors for the co-delivery of photosensitizers and chemotherapeutics were urgently needed for the combination therapy. In this work, a redox-responsive micelle (PCL-SS-CMC-GA) was prepared for the co-delivery of doxorubicin (DOX) and pheophorbide A (PHA). Poly-ε-caprolactone was linked to carboxymethyl chitosan through a disulfide bond, which was easily broken in the reductive solution to release the payloads. The charge conversion property and glycyrrhetinic acid (GA) targeting ligand of the micelles effectively extended the average residence time (up to 18 times) in circulation and improved their intracellular uptake by HepG2 cells. The micelles exhibited an enhanced tumor accumulation and near infrared (NIR) imaging performance. More interestingly, this nanoplatform could fully exert the synergistic effect of DOX and PHA to improve the inhibition efficiency (with an inhibitory rate of 80.5 %) in vivo. With impressive photo-chemo theranostic and NIR imaging capability, PCL-SS-CMC-GA@DOX/PHA showed great potential in image-guided treatment of liver cancer.
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http://dx.doi.org/10.1016/j.carbpol.2020.117284DOI Listing
February 2021

Terselenophene Regioisomer Conjugated Polymer Materials for High-Performance Cancer Phototheranostics.

ACS Appl Mater Interfaces 2020 Dec 1;12(50):55605-55613. Epub 2020 Dec 1.

Center of Super-Diamond and Advanced Films (COSDAF), Department of Chemistry, City University of Hong Kong, Hong Kong SAR 999077, P. R. China.

Molecular isomerization is a fundamental issue in the development of functional materials, with a crucial impact on photophysical properties. However, up to now, their effect on photothermal conversion is rarely investigated. Here, two near-infrared (NIR)-absorbing regioisomer conjugated polymers integrated with /-terselenophenes are designed and synthesized as efficient photothermal agents to enhance cancer phototheranostics. It is demonstrated that enhanced quinoidal resonance of -terselenophenes allows the resulting -CP to possess more planar backbone to further increase the effective conjugation length and result in the strong absorption spectra at 808 nm. Characterization of photophysical properties has proved that the photothermal conversion efficiency of -CP nanoparticles is up to 61.4%, and they are 210% as strong as -CP nanoparticles (29.4%). Further and works demonstrate efficient photothermal therapeutic effects with the guidance of photoacoustic imaging. This work affords a new understanding of the molecular isomerization into the development of conjugated materials for high-performance cancer phototheranostics.
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http://dx.doi.org/10.1021/acsami.0c16064DOI Listing
December 2020

IRF-1 expressed in the inner cell mass of the porcine early blastocyst enhances the pluripotency of induced pluripotent stem cells.

Stem Cell Res Ther 2020 11 27;11(1):505. Epub 2020 Nov 27.

State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.

Background: Despite years of research, porcine-induced pluripotent stem cells (piPSCs) with germline chimeric capacity have not been established. Furthermore, the key transcription factors (TFs) defining the naïve state in piPSCs also remain elusive, even though TFs in the inner cell mass (ICM) are believed to be key molecular determinants of naïve pluripotency. In this study, interferon regulatory factor 1 (IRF-1) was screened to express higher in ICM than trophectoderm (TE). But the impact of IRF-1 on maintenance of pluripotency in piPSCs was not determined.

Methods: Transcriptome profiles of the early ICM were analyzed to determine highly interconnected TFs. Cells carrying these TFs' reporter were used to as donor cells for somatic cell nuclear transfer to detect expression patterns in blastocysts. Next, IRF1-Flag was overexpressed in DOX-hLIF-2i piPSCs and AP staining, qRT-PCR, and RNA-seq were conducted to examine the effect of IRF-1 on pluripotency. Then, the expression of IRF-1 in DOX-hLIF-2i piPSCs was labeled by GFP and qRT-PCR was conducted to determine the difference between GFP-positive and GFP-negative cells. Next, ChIP-Seq was conducted to identify genes target by IRF-1. Treatment with IL7 in wild-type piPSCs and STAT3 phosphorylation inhibitor in IRF-1 overexpressing piPSCs was conducted to confirm the roles of JAK-STAT3 signaling pathway in IRF-1's regulation of pluripotency. Moreover, during reprogramming, IRF-1 was overexpressed and knocked down to determine the change of reprogramming efficiency.

Results: IRF-1 was screened to be expressed higher in porcine ICM than TE of d6~7 SCNT blastocysts. First, overexpression of IRF-1 in the piPSCs was observed to promote the morphology, AP staining, and expression profiles of pluripotency genes as would be expected when cells approach the naïve state. Genes, KEGG pathways, and GO terms related to the process of differentiation were also downregulated. Next, in the wild-type piPSCs, high-level fluorescence activated by the IRF-1 promoter was associated with higher expression of naïve related genes in piPSCs. Analysis by ChIP-Seq indicated that genes related to the JAK-STAT pathway, and expression of IL7 and STAT3 were activated by IRF-1. The inhibitor of STAT3 phosphorylation was observed could revert the expression of primed genes in IRF-1 overexpressing cells, but the addition of IL7 in culture medium had no apparent change in the cell morphology, AP staining results, or expression of pluripotency related genes. In addition, knockdown of IRF-1 during reprogramming appeared to reduce reprogramming efficiency, whereas overexpression exerted the converse effect.

Conclusion: The IRF-1 expressed in the ICM of pigs' early blastocyst enhances the pluripotency of piPSCs, in part through promoting the JAK-STAT pathway.
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http://dx.doi.org/10.1186/s13287-020-01983-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694439PMC
November 2020

Modulation of gut homeostasis by exopolysaccharides from Aspergillus cristatus (MK346334), a strain of fungus isolated from Fuzhuan brick tea, contributes to immunomodulatory activity in cyclophosphamide-treated mice.

Food Funct 2020 Dec 25;11(12):10397-10412. Epub 2020 Nov 25.

College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China.

In this study, the crude exopolysaccharides (CEPSs) from fungus Aspergillus cristatus (MK346334, NCBI) isolated from Fuzhuan brick tea and its main purified fraction (EPSs-2) were investigated. Using the RAW264.7 cell model, EPSs-2 exhibited an excellent immunomodulatory effect in vitro. Then, the regulating effects of EPSs on immune function and gut microbiota were evaluated using a cyclophosphamide (Cy)-induced mice model. It was found that both CEPSs and EPSs-2 improved the body weight loss, immune organ indexes as well as the levels of TNF-α, IL-1β, IFN-γ and IgA, exhibiting potent immunoregulatory activity. Moreover, CEPSs and EPSs-2 not only attenuated the intestinal tissue damage, but also promoted the production of short-chain fatty acids and modulated the microbial composition by increasing the growth of Muribaculaceae, Prevotellaceae_UCG-001, Bacteroides, Parabacteroides and Tidjanibacter, while decreasing the relative abundances of Helicobacter, Bilophila, Mucispirillum, Lachnospiraceae, Ruminococcaceae and Clostridiales. These results indicated that the EPSs, especially EPSs-2, exhibited immunomodulatory activity associated with the modulation of gut microbiota to maintain gut homeostasis, which provided evidence for the development of novel potential prebiotics and immunomodulators.
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http://dx.doi.org/10.1039/d0fo02272aDOI Listing
December 2020

Dynamic changes in the metabolite profile and taste characteristics of Fu brick tea during the manufacturing process.

Food Chem 2021 May 7;344:128576. Epub 2020 Nov 7.

Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, PR China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, PR China; Collaborative Innovation Centre of Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan 410128, PR China. Electronic address:

Fu brick tea is a typical post-fermentation tea known for its special flavor and health benefits. Liquid chromatography-mass spectrometry, and sensory evaluation with multivariate analysis were used to characterize the dynamic changes in metabolite profile and taste characteristics. Seventy-one compounds were identified as critical metabolites, catechins, flavonoids, phenolic acids, terpenoids and others. During the manufacturing process, these compounds exhibited sharp fluctuations in content, the intensities of astringency, bitterness, and sourness of the tea materials reduced greatly, but the mellow intensity increased sharply. Several catechins and phenolic acids were positively related to the 'astringent', 'bitter', and 'sour' tastes attributes. The fungal genera, Aspergillus, Candida, unclassified_o_Hypocreales, unclassified_o_Saccharomycetales and Wallemia and the bacterial genus, Klebsiella, were identified as core functional microorganisms linked to the metabolic variations during the process. Overall, these findings provided a more comprehensive understanding of the formation of the sensory characteristics in Fu brick tea during the manufacturing process.
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http://dx.doi.org/10.1016/j.foodchem.2020.128576DOI Listing
May 2021

Causal Effects of Sleep Traits on Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study.

Nat Sci Sleep 2020 21;12:783-790. Epub 2020 Oct 21.

Department of Neurology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang, People's Republic of China.

Background: Unfavorable sleep habits have been linked with ischemic stroke in observational studies, but the causality remains unclear. The aim of this study is to investigate the potential causal role of three sleep traits, including sleep duration, insomnia, and chronotype, in ischemic stroke and its subtypes.

Methods: We conducted two-sample Mendelian randomization (MR) analysis using single nucleotide polymorphisms associated with sleep duration, insomnia, and chronotype as instruments to estimate causal associations with ischemic stroke and its subtypes, among 34,217 ischemic stroke cases and 406,111 controls from the MEGASTROKE consortium. Inverse-variance weighted method was used as the main analyses. Alternative MR methods and sensitivity analyses were further performed.

Results: We found suggestive evidence that per doubling of genetic liability for short sleep duration (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.01-1.58) and frequent insomnia symptoms (OR, 1.19; 95% CI, 1.00-1.41) were associated with a modest increase in risk of large artery stroke (LAS) but not with small vessel stroke, cardioembolic stroke, or any ischemic stroke. The association of frequent insomnia symptoms with LAS was stronger after the exclusion of the outlier (OR, 1.25; 95% CI, 1.04-1.50). No significant association was observed for chronotype with any ischemic stroke subtype. Results were overall robust to sensitivity analyses, and there was little evidence of horizontal pleiotropy.

Conclusion: We provided suggestive evidence for a potential causal role of short sleep duration and insomnia symptoms in LAS. Future researches are required to investigate whether improved sleep habits could help to mitigate LAS risk.
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http://dx.doi.org/10.2147/NSS.S265946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585859PMC
October 2020

Molecular diversification of antimicrobial peptides from the wolf spider Lycosa sinensis venom based on peptidomic, transcriptomic, and bioinformatic analyses.

Acta Biochim Biophys Sin (Shanghai) 2020 Dec;52(11):1274-1280

The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, Hunan Normal University, Changsha 410081, China.

The venom of Lycosoidea spiders is a complex multicomponent mixture of neurotoxic peptides (main components) and antimicrobial peptides (AMPs) as minor components. In this study, we described the high-throughput identification and analysis of AMPs from Lycosa sinensis venom (named LS-AMPs) using a combination strategy that includes the following three different analysis approaches: (i) peptidomic analysis, namely reversed-phase high-performance liquid chromatography (RP-HPLC) separation plus top-down sequencing by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MS); (ii) transcriptomic analysis, namely cDNA library construction plus DNA sequencing; (iii) bioinformatic analysis, namely analysis and prediction for molecular characters of LS-AMPs by the online biology databases. In total, 52 sequences of AMPs were identified from L. sinensis venom, and all AMPs can be categorized into eight different families according to phylogenetic analysis and sequence identity. This is the largest number of AMPs identified from a spider species so far. In the present study, we demonstrated molecular characteristics, such as complex precursor, N- and/or C-terminally truncated analogs, and C-terminal amidation of LS-AMPs from L. sinensis venom. This is a preliminary investigation on the molecular diversification of venom-derived AMPs from the wolf spider species (family Lycosidae), and a detailed investigation on the functional diversity of LS-AMPs will be preformed in the future.
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http://dx.doi.org/10.1093/abbs/gmaa107DOI Listing
December 2020

Rapid diagnosis of Ralstonia solanacearum infection sweet potato in China by loop-mediated isothermal amplification.

Arch Microbiol 2021 Mar 14;203(2):777-785. Epub 2020 Oct 14.

Institute of Crop Sciences, Fujian Academy of Agricultural Sciences, Fuzhou, 350013, Fujian, China.

Bacterial wilt of sweet potato is caused by Ralstonia solanacearum, which is distributed in southern China and causes significant economic losses each year. The pathogen is soil- and rhizome-borne, and thus its rapid detection may prevent the occurrence and spread of the disease. R. solanacearum has been listed as a quarantine disease in China. With the advent of molecular biology, many novel tools have been explored for the rapid identification of plant pathogens. In this study, a strain-specific detection method was developed for this specific pathogen that infects sweet potato using loop-mediated isothermal amplification (LAMP). A set of new LAMP-specific primers was designed from the orf428 gene, which can specifically detect the R. solanacearum bacterium that infect sweet potato. The LAMP reaction consisted of 8.0 mmol·LMg, 1.4 mmol·L dNTPs, and 0.32U μL Bst 2.0 DNA polymerase and was performed at 65 °C for 1 h. The amplification products were detected by visualizing a mixture of color changes using SYBR Green I dye and assessing ladder-like bands by electrophoresis. Our method has specificity, i.e., it only detected R. solanacearum in sweet potato, and it has high sensitivity, with a detection limit of 100 fg·μL genomic DNA and 10 CFU·mL of bacterial fluid. In addition, R. solanacearum could be directly detected in infected sweet potato tissues without the need for DNA extraction. The LAMP method established in this study is a highly specific, sensitive, and rapid tool for the detection of bacterial wilt in sweet potato caused by R. solanacearum.
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http://dx.doi.org/10.1007/s00203-020-02059-8DOI Listing
March 2021

Chitosan based pH-responsive polymeric prodrug vector for enhanced tumor targeted co-delivery of doxorubicin and siRNA.

Carbohydr Polym 2020 Dec 29;250:116781. Epub 2020 Jul 29.

Key Laboratory of Animal Cellular and Genetic Engineering of Heilongjiang Province, College of Life Science, Northeast Agricultural University, Harbin, Heilongjiang, 150030, China; Food Science College, Northeast Agricultural University, Harbin, Heilongjiang, 150030, China. Electronic address:

The co-delivery of chemotherapeutic drugs and siRNA has gained increasing attentions owing to the enhanced antitumor efficacy over single administration. In this work, a chitosan-based pH-responsive prodrug vector was developed for the co-delivery of doxorubicin (DOX) and Bcl-2 siRNA. The accumulation of fabricated nanoparticles in hepatoma cells was enhanced by glycyrrhetinic acid receptor-mediated endocytosis. The cumulative release amount of the encapsulated DOX and siRNA reached 90.2 % and 81.3 % in 10 h, respectively. More strikingly, this nanoplatform can efficiently integrate gene- and chemo-therapies with a dramatically enhanced tumor inhibitory rate (88.0 %) in vivo. This co-delivery system may provide the latest strategy to meet the needs of combination therapies for tumors, offering safe and efficient improvements to the synergistic antitumor efficacy of gene-chemotherapies.
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http://dx.doi.org/10.1016/j.carbpol.2020.116781DOI Listing
December 2020