Publications by authors named "Ling Wu"

549 Publications

Calcium signaling in cancer progression and therapy.

FEBS J 2021 Jul 21. Epub 2021 Jul 21.

Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

The old Greek aphorism "Panta Rhei" ("everything flows") is true for all living things in general. As a dynamic process, calcium signaling plays fundamental roles in cellular activities under both normal and pathological conditions, with recent research uncovering its involvement in cell proliferation, migration, survival, gene expression and more. The major question we address here is how calcium signaling affects cancer progression and whether it could be targeted to combine with classic chemotherapeutics or emerging immunotherapies to improve their efficacy.
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http://dx.doi.org/10.1111/febs.16133DOI Listing
July 2021

An MRI Modality for Non-invasively Distinguishing Progression of Liver Fibrosis by Visualizing Hepatic Platelet-Derived Growth Factor Receptor-Beta Expression in Mice.

J Gastroenterol Hepatol 2021 Jul 19. Epub 2021 Jul 19.

Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.

Background And Aim: Activated hepatic stellate cells (HSCs) are the most critical cells responsible for liver fibrosis, and platelet-derived growth factor (PDGF) is the most prominent mitogen for HSCs in fibrogenesis. This study aimed to explore the potential of gadolinium (Gd)-labelled cyclic peptides (pPB) targeting PDGF receptor-β (PDGFR-β) as a magnetic resonance imaging (MRI) radiotracer to identify the progression of liver fibrosis by imaging hepatic PDGFR-β expression.

Methods: Mice treated with carbon tetrachloride (CCl ) were used to mimic hepatic fibrosis in vivo. The binding activity of FITC-labelled pPB to PDGFR-β was assessed in cultured human HSCs (HSC-LX2). MRI was performed to visualize hepatic PDGFR-β expression in mice with different degrees of liver fibrosis after Gd-labelled pPB was injected.

Results: Hepatic PDGFR-β expression level was correlated with the severity of liver fibrosis, and the majority of cells expressing PDGFR-β were found to be activated HSCs in fibrotic livers. Culture-activated human HSCs expressed abundant PDGFR-β, and FITC-labelled pPB could bind to these cells in a concentration- and time-dependent manner. With Gd-labelled pPB as a tracer, an MRI modality demonstrated that the relative hepatic T1-weighted MRI signal value progressively increased with the severity of hepatic fibrosis, and reduced with remission.

Conclusions: Hepatic PDGFR-β expression reflects the progression of hepatic fibrosis, and MRI using Gd-labelled pPB as a tracer exhibits potential for distinguishing liver fibrosis staging in mice.
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http://dx.doi.org/10.1111/jgh.15628DOI Listing
July 2021

Sensitive Detection of Single-Nucleotide Polymorphisms by Solid Nanopores Integrated With DNA Probed Nanoparticles.

Front Bioeng Biotechnol 2021 30;9:690747. Epub 2021 Jun 30.

College of Geography and Biological Information, Nanjing University of Posts and Telecommunications, Nanjing, China.

Single-nucleotide polymorphisms (SNPs) are the abundant forms of genetic variations, which are closely associated with serious genetic and inherited diseases, even cancers. Here, a novel SNP detection assay has been developed for single-nucleotide discrimination by nanopore sensing platform with DNA probed Au nanoparticles as transport carriers. The SNP of p53 gene mutation in gastric cancer has been successfully detected in the femtomolar concentration by nanopore sensing. The robust biosensing strategy offers a way for solid nanopore sensors integrated with varied nanoparticles to achieve single-nucleotide distinction with high sensitivity and spatial resolution, which promises tremendous potential applications of nanopore sensing for early diagnosis and disease prevention in the near future.
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http://dx.doi.org/10.3389/fbioe.2021.690747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279778PMC
June 2021

CTP regulates membrane-binding activity of the nucleoid occlusion protein Noc.

Mol Cell 2021 Jul 9. Epub 2021 Jul 9.

Department of Molecular Microbiology, John Innes Centre, Norwich, NR4 7UH, UK. Electronic address:

ATP- and GTP-dependent molecular switches are extensively used to control functions of proteins in a wide range of biological processes. However, CTP switches are rarely reported. Here, we report that a nucleoid occlusion protein Noc is a CTPase enzyme whose membrane-binding activity is directly regulated by a CTP switch. In Bacillus subtilis, Noc nucleates on 16 bp NBS sites before associating with neighboring non-specific DNA to form large membrane-associated nucleoprotein complexes to physically occlude assembly of the cell division machinery. By in vitro reconstitution, we show that (1) CTP is required for Noc to form the NBS-dependent nucleoprotein complex, and (2) CTP binding, but not hydrolysis, switches Noc to a membrane-active state. Overall, we suggest that CTP couples membrane-binding activity of Noc to nucleoprotein complex formation to ensure productive recruitment of DNA to the bacterial cell membrane for nucleoid occlusion activity.
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http://dx.doi.org/10.1016/j.molcel.2021.06.025DOI Listing
July 2021

Effects of exercise on markers of inflammation and indicators of nutrition in patients with chronic kidney disease: a systematic review and meta-analysis.

Int Urol Nephrol 2021 Jul 13. Epub 2021 Jul 13.

Department of Nephrology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.

Purpose: This meta-analysis aimed to reveal the effects of exercise training on markers of inflammation and indicators of nutrition in non-dialysis-dependent patients with chronic kidney disease (NDD-CKD).

Methods: We searched the MEDLINE, EMBASE, CENTRAL, Web of Science, CINAHL, CNKI, WANFANE, VIP, and CBM databases, from their inception up to October 2020 to identify randomized controlled trials that examined the effects of exercise training on inflammation and nutrition in NDD-CKD patients. A total of 16 trials, comprising 724 patients, were included in the analysis.

Results: The BMI (P = 0.005) and waist circumference (P = 0.004) decreased significantly after exercise training in NDD-CKD patients. Similarly, IL-6 (P = 0.03) decreased after exercise training in NDD-CKD patients. However, serum albumin level, body fat, CRP and hs-CRP were not different between patients who received exercise training and those who received usual care. Furthermore, BMI (P = 0.009), body weight (P = 0.009), and waist circumference (P = 0.010) were decreased in overweight patients (BMI ≧ 25 kg/m). Moreover, BMI (P = 0.003), body weight (P = 0.005), and waist circumference (P = 0.007) reduced when the length of intervention exceeded 48 weeks. Subgroup analyses revealed no significant alteration of serum albumin, body fat, CRP, or hs-CRP, when studies were divided based on BMI or intervention duration.

Conclusion: Overall, these findings suggest that exercise training may improve inflammation status in NDD-CKD patients, and enhance weight loss in obese adult CKD patients. Registration number: INPLASY2020100025.
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http://dx.doi.org/10.1007/s11255-021-02949-wDOI Listing
July 2021

Association between socioeconomic status and chronic obstructive pulmonary disease in Jiangsu province, China: a population-based study.

Chin Med J (Engl) 2021 Jun 22;134(13):1552-1560. Epub 2021 Jun 22.

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China.

Background: Chronic obstructive pulmonary disease (COPD) is a common public health problem worldwide. Recent studies have reported that socioeconomic status (SES) is related to the incidence of COPD. This study aimed to investigate the association between SES and COPD among adults in Jiangsu province, China, and to determine the possible direct and indirect effects of SES on the morbidity of COPD.

Methods: A cross-sectional study was conducted among adults aged 40 years and above between May and December of 2015 in Jiangsu province, China. Participants were selected using a multistage sampling approach. COPD, the outcome variable, was diagnosed by physicians based on spirometry, respiratory symptoms, and risk factors. Education, occupation, and monthly family average income (FAI) were used to separately indicate SES as the explanatory variable. Mixed-effects logistic regression models were introduced to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for examining the SES-COPD relationship. A pathway analysis was conducted to further explore the pulmonary function impairment of patients with different SES.

Results: The mean age of the 2421 participants was 56.63 ± 9.62 years. The prevalence of COPD was 11.8% (95% CI: 10.5%-13.1%) among the overall sample population. After adjustment for age, gender, residence, outdoor and indoor air pollution, body weight status, cigarette smoking, and potential study area-level clustering effects, educational attainment was negatively associated with COPD prevalence in men; white collars were at lower risk (OR: 0.60, 95% CI: 0.43-0.83) of experiencing COPD than blue collars; compared with those within the lower FAI subgroup, participants in the upper (OR: 0.68, 95% CI: 0.49-0.97) tertiles were less likely to experience COPD. Such negative associations between all these three SES indicators and COPD were significant among men only. Education, FAI, and occupation had direct or indirect effects on pulmonary function including post-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC), FEV1, FVC, and FEV1 percentage of predicted. Education, FAI, and occupation had indirect effects on pulmonary function indices of all participants mainly through smoking status, indoor air pollution, and outdoor air pollution. We also found that occupation could affect post-bronchodilator FEV1/FVC through body mass index.

Conclusions: Education, occupation, and FAI had an adverse relationship with COPD prevalence in Jiangsu province, China. SES has both direct and indirect associations with pulmonary function impairment. SES is of great significance for COPD morbidity. It is important that population-based COPD prevention strategies should be tailored for people with different SES.
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http://dx.doi.org/10.1097/CM9.0000000000001609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280072PMC
June 2021

Comparison of Transvaginal and Transumbilical Laparoscopic Single-Site Surgery for Ovarian Cysts.

JSLS 2021 Apr-Jun;25(2)

Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA.

Background: Minimally invasive surgery is currently a preferred treatment for symptomatic ovarian cyst(s), with single-site techniques, such as transumbilical laparoendoscopic single-site surgery (TU-LESS) and transvaginal laparoendoscopic single-site surgery (TV-LESS), gaining increasing popularity. Although both methods have delivered positive outcomes, there is currently limited literature directly comparing TU-LESS and TV-LESS.

Objectives: This study had two primary objectives: (1) to evaluate the safety and feasibility of TV-LESS and TU-LESS for the treatment of ovarian cysts and (2) to compare the surgical and postoperative outcomes of the two procedures.

Method: This was a prospective observational clinical analysis of 81 patients with a diagnosis of benign ovarian cyst with indication for TV-LESS or TU-LESS. Surgeries were performed at a tertiary hospital between February 1, 2018 and January 31, 2020. Patients were divided into TV-LESS (n = 40) and TU-LESS groups (n = 40), with one excluded due to severe pelvic adhesive disease. Demographics, operation outcomes, and follow-up details were compared.

Results: All 80 patients underwent uncomplicated procedures. The two groups were demographically matched (except age), with no difference in operation time, intra-operative blood loss, hemoglobin loss, and hospitalization costs (P > 0.05). However, TV-LESS patients had significantly faster time to ambulation (P < 0.001), faster time to return of bowel function (P < 0.001), less postoperative pain level (P < 0.001), and shorter length of hospital stay (P < 0.001). The cosmetic scores at 1, 4, and 24 weeks after surgery were also higher for the TV-LESS group.

Conclusion: Our preliminary experience suggested that TU-LESS and TV-LESS are both feasible and safe for ovarian cystectomy and salpingo-oophorectomy. However, TV-LESS may provide three main advantages including: (1) fewer postoperative complications (i.e. incisional hernia); (2) less postoperative pain; and (3) improved cosmetic satisfaction.
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http://dx.doi.org/10.4293/JSLS.2021.00019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249217PMC
July 2021

A pre-oxidation strategy to improve architecture stability and electrochemical performance of NaMnPOF particles-embedded carbon nanofibers.

J Colloid Interface Sci 2021 Jun 16;603:430-439. Epub 2021 Jun 16.

School of Iron and Steel, Soochow University, Suzhou 215000, China. Electronic address:

The rational design of an excellent architecture for active materials combined with carbon matrix is of particular importanceto obtain flexible electrode material with high electrochemical properties. Well-designed nanofibers possess unique 3D network structure, which can significantly improve the electron/ion transportation and supplies sufficient active sites for Li/Na insertion. Electrospinning-carbonization technology is a popular strategy to prepare nanofibers with active material embedded in carbon. It is found that the architecture of nanofibers tended to be wrecked and destroyed during the carbonization process without pre-oxidation treatment. In this study, we prepared NaMnPOF particles embedded in carbon nanofibers (NaMnPOF/C) using PVP as carbon source and investigated the strengthen mechanism of pre-oxidation on their architecture. The experiment and simulation results demonstrate that, without pre-oxidation, the main chain of PVP is severely ruptured during the carbonization procedure, consequently leads to fractured architecture of NaMnPOF/C nanofibers. In contrast, with pre-oxidation treatment, a long-chain and heat-resistance structured carbon matrix formed, and NaMnPOF/C nanofibers with stable architecture and improved electrochemical performance can be achieved. This study demonstrates a promising guide to construct carbon based nanofiber electrodes with stable architecture and high electrochemical performance.
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http://dx.doi.org/10.1016/j.jcis.2021.06.081DOI Listing
June 2021

Determination of Six Tetracyclines in Eggs and Chicken by Dispersive Liquid-Liquid Microextraction Combined with High-Performance Liquid Chromatography.

J AOAC Int 2021 Jun 30. Epub 2021 Jun 30.

Sichuan University, West China School of Public Health and West China Fourth Hospital, Chengdu 610041, China.

Background: The wide livestock usage of tetracyclines may result in drug residues in foods. Therefore, it is necessary to develop reliable methods for the determination of tetracyclines in foods.

Objective: A dispersive liquid-liquid microextraction (DLLME) combined with high-performance liquid chromatography (HPLC) method was developed for the analysis of six tetracyclines in eggs and chicken.

Methods: After deproteinization, tetracyclines in acidic solutions were concentrated by vortex-assisted DLLME. Followed by the addition of NaCl (35% for eggs and 20% for chicken), a mixture of ionic liquid [Bmim]PF6 and ethyl acetate (300 μL-50 μL for eggs and 200 μL-60 μL for chicken) was used as the extractant. After centrifugation, the extract was collected for HPLC analysis.

Results: The developed method showed good linear relationship (10.0-500 μg/kg), low method detection limits (0.219-1.42 μg/kg) and quantification limits (0.731-4.72 μg/kg), satisfactory relative recoveries (87.1-104%) with intra-day and inter-day RSDs in the ranges of 0.853-8.62% and 1.65-11.8%, respectively. The established method was successfully applied for the determination of six tetracyclines in eggs and chicken of different parts. The contents of tetracyclines in all samples were lower than their maximum residue limits.

Conclusions: A DLLME-HPLC method has been developed for the analysis of six tetracyclines in animal derived foods using ionic liquid and ethyl acetate as the extractant.

Highlights: The developed method is simple, sensitive, cost-effective and has strong anti-interference ability. This method has been successfully applied to the analysis of six tetracyclines in eggs and chicken.
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http://dx.doi.org/10.1093/jaoacint/qsab082DOI Listing
June 2021

"Wow, woo, win": Healthcare students' and facilitators' experiences of interprofessional simulation in three-dimensional virtual world: A qualitative evaluation study.

Nurse Educ Today 2021 Jun 17;105:105018. Epub 2021 Jun 17.

Yong Loo Lin School Medicine, National University of Singapore, NUHS Tower Block, Level 11, 1E Kent Ridge Road, Singapore 119228, Singapore.

Background: In an age disrupted by COVID-19 pandemic, three-dimensional virtual world (3DVW) offers an opportunity for healthcare students from different higher education institutions to participate in interprofessional education. Despite its growing evidence, there is a need to unravel the complex learning process in order to ensure high quality of interprofessional education delivery.

Aim: This study aimed to explore the experiences of healthcare students and facilitators on the use of 3DVW for interprofessional team-based virtual simulation.

Methods: Interprofessional teams, each comprising six different healthcare students (Medicine, Nursing, Pharmacy, Physiotherapy, Occupational Therapy, and Medical Social Work) and two clinicians who acted as facilitators, logged into the 3DVW from their own remote locations to participate in team-based care delivery that included an interprofessional bedside round and a family conference. A qualitative descriptive study was conducted on a purposive sample of 30 healthcare students and 12 facilitators using focus group discussions and individual interviews.

Results: Four themes emerged from their experiences: the "wow experience", authentic experience on collaborative care, ease of learning, and preeminent role of the facilitator. The simulation provided the "wow" experiences through contextual, collaborative and experiential learning approaches. Despite technical challenges, the participants were wooed by the comforts of learning from home and the psychological safety in virtual environment. The facilitators played a critical role in optimizing learning engagement to win learners over.

Conclusion: Our study explicates how attention to the "wow, woo and win" trilateral factors can transform the interprofessional learning experiences offered by 3DVW simulation. Future developments in the use of this learning technology should include developing the clinicians' facilitation skills and the provision of technical support to make this 3DVW a success calls in winning students' learning engagement.
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http://dx.doi.org/10.1016/j.nedt.2021.105018DOI Listing
June 2021

Harnessing the power of antibodies to fight bone metastasis.

Sci Adv 2021 Jun 23;7(26). Epub 2021 Jun 23.

Department of Chemistry, Rice University, 6100 Main Street, Houston, TX 77005, USA.

Antibody-based therapies have proved to be of great value in cancer treatment. Despite the clinical success of these biopharmaceuticals, reaching targets in the bone microenvironment has proved to be difficult due to the relatively low vascularization of bone tissue and the presence of physical barriers. Here, we have used an innovative bone-targeting (BonTarg) technology to generate a first-in-class bone-targeting antibody. Our strategy involves the use of pClick antibody conjugation technology to chemically couple the bone-targeting moiety bisphosphonate to therapeutic antibodies. Bisphosphonate modification of these antibodies results in the delivery of higher conjugate concentrations to the bone metastatic niche, relative to other tissues. In xenograft mice models, this strategy provides enhanced inhibition of bone metastases and multiorgan secondary metastases that arise from bone lesions. Specific delivery of therapeutic antibodies to the bone, therefore, represents a promising strategy for the treatment of bone metastatic cancers and other bone diseases.
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http://dx.doi.org/10.1126/sciadv.abf2051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221630PMC
June 2021

LNG-IUS combined with progesterone ameliorates endometrial thickness and pregnancy outcomes of patients with early-stage endometrial cancer or atypical hyperplasia.

Am J Transl Res 2021 15;13(5):5412-5419. Epub 2021 May 15.

Department of Gynaecology, Huaian Maternal and Child Health Hospital Huaian 223001, Jiangsu Province, China.

Objective: To determine the positive effect of levonorgestrel-releasing intrauterine system (LNG-IUS) combined with progesterone on endometrial thickness and pregnancy outcomes of patients with atypical endometrial hyperplasia (AEH) or early-stage endometrial cancer (EEC).

Methods: Patients with AEH or EEC admitted to our hospital were enrolled, and assigned to a control group (con group) and a combination group (com group). Patients in the con group were treated with LNG-IUS, while those in the com group were treated with LNG-IUS combined with progesterone. After treatment, the two groups were compared in efficacy, menstrual blood volume (pictorial blood loss assessment chart (PBAC) score), and changes in endometrial thickness. In addition, the incidence of adverse drug reactions and pregnancy outcomes of the patients were analyzed.

Results: Before treatment, there was no significant difference in PBAC score and endometrial thickness between patients with AEH or EEC in the con group and those in the com group, but after 3 months and 6 months of treatment, the com group got a better PBAC score and better changes of endometrial thickness than the con group, and the incidence of adverse drug reactions in the com group was also significantly lower than that in the con group. In addition, the follow-up results of pregnancy outcomes of patients showed that the fertility rate and total effective rate of the com group were both significantly higher than those of the con group (both <0.05).

Conclusion: LNG-IUS combined with progesterone is more effective in treating patients with AEH or EEC. It can effectively improve the endometrial thickness of patients and fertility rate of those with fertility requirements after treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205653PMC
May 2021

Rational construction of Ni(OH) nanoparticles on covalent triazine-based framework for artificial CO reduction.

J Colloid Interface Sci 2021 May 25;602:23-31. Epub 2021 May 25.

State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, 2 Xue Yuan Road, New Campus, Minhou, Fujian 350108, PR China.

Artificial photoreduction of CO to chemical fuel is an intriguing and reliable strategy to tackle the issues of energy crisis and climate change simultaneously. In the present study, we rationally constructed a Ni(OH)-modified covalent triazine-based framework (CTF-1) composites to serve as cocatalyst ensemble for superior photoreduction of CO. In particular, the optimal Ni(OH)-CTF-1 composites (loading ratio at 0.5 wt%) exhibited superior photocatalytic activity, which surpassed the bare CTF-1 by 33 times when irradiated by visible light. The mechanism for the enhancement was systematically investigated based on various instrumental analyses. The origin of the superior activity was attributable to the enhanced CO capture, more robust visible-light response, and improved charge carrier separation/transfer. This study offers an innovative pathway for the fabrication of noble-metal-free cocatalysts on CTF semiconductors and deepens the understanding of photocatalytic CO reduction.
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http://dx.doi.org/10.1016/j.jcis.2021.05.131DOI Listing
May 2021

A 5-step systematic therapy (FSST) for treating plugged ducts and mastitis in breastfeeding women: a case control study.

Asian Nurs Res (Korean Soc Nurs Sci) 2021 May 25. Epub 2021 May 25.

Department of Breast Surgery, Guangzhou Women and Children's Medical Center, Guangzhou 510623, China. Electronic address:

Purpose: This study aimed to describe clinical response to 5-step systematic therapy (FSST) in the management of plugged ducts and mastitis. FSST was a comprehensive milk stasis dredging treatment, which contained five steps to make the milk out of the plugged duct.

Methods: This retrospective study included 922 breastfeeding women, 714 with plugged ducts and 208 with mastitis who received FSST from June to September 2017. The breast pain score, swelling degree and range of breast induration were recorded pre-FSST and post-FSST.

Results: After a single FSST, pain score and swelling degree were significantly improved (both, p <.001) in all cases. After FSST, the mean breast pain relief score was 1.69±.70, while the mean swelling fade-away degree was 1.61±.62. In subgroup analysis, pain score and swelling degree were significantly improved (both, p <.001) in the plugged ducts group and the mastitis group. The score of pain relief in the plugged ducts group was less than that in the mastitis group (1.63±.68 vs. 1.91±.70, t=5.30, p <.001), while improvement of swelling fade-away was greater in the plugged ducts group than the mastitis group (1.65±.64 vs. 1.48±.56, t=3.49, p =0.001). The composition ratio of changes in induration range between the two groups was statistically different (Pearsonχ=137.87, p <.001), of which more obvious improvement in the plugged ducts group than the mastitis group (χ=25.65, p <.001).

Conclusion: FSST can relieve pain, reduce breast swelling and range of induration, and for plugged ducts or mastitis varied degree differently.
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http://dx.doi.org/10.1016/j.anr.2021.04.001DOI Listing
May 2021

Novel biallelic mutations in MEI1: expanding the phenotypic spectrum to human embryonic arrest and recurrent implantation failure.

Hum Reprod 2021 Jul;36(8):2371-2381

Institute of Pediatrics, Children's Hospital of Fudan University and Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.

Study Question: Are any novel mutations and corresponding new phenotypes, other than recurrent hydatidiform moles, seen in patients with MEI1 mutations?

Summary Answer: We identified several novel mutations in MEI1 causing new phenotypes of early embryonic arrest and recurrent implantation failure.

What Is Known Already: It has been reported that biallelic mutations in MEI1, encoding meiotic double-stranded break formation protein 1, cause azoospermia in men and recurrent hydatidiform moles in women.

Study Design, Size, Duration: We first focused on a pedigree in which two sisters were diagnosed with recurrent hydatidiform moles in December 2018. After genetic analysis, two novel mutations in MEI1 were identified. We then expanded the mutational screening to patients with the phenotype of embryonic arrest, recurrent implantation failure, and recurrent pregnancy loss, and found another three novel MEI1 mutations in seven new patients from six families recruited from December 2018 to May 2020.

Participants/materials, Setting, Methods: Nine primary infertility patients were recruited from the reproduction centers in local hospitals. Genomic DNA from the affected individuals, their family members, and healthy controls was extracted from peripheral blood. The MEI1 mutations were screened using whole-exome sequencing and were confirmed by the Sanger sequencing. In silico analysis of mutations was performed with Sorting Intolerant From Tolerant (SIFT) and Protein Variation Effect Analyzer (PROVEAN). The influence of the MEI1 mutations was determined by western blotting and minigene analysis in vitro.

Main Results And The Role Of Chance: In this study, we identified five novel mutations in MEI1 in nine patients from seven independent families. Apart from recurrent hydatidiform moles, biallelic mutations in MEI1 were also associated with early embryonic arrest and recurrent implantation failure. In addition, we demonstrated that protein-truncating and missense mutations reduced the protein level of MEI1, while the splicing mutations caused abnormal alternative splicing of MEI1.

Limitations, Reasons For Caution: Owing to the lack of in vivo data from the oocytes of the patients, the exact molecular mechanism(s) involved in the phenotypes remains unknown and should be further investigated using knock-out or knock-in mice.

Wider Implications Of The Findings: Our results not only reveal the important role of MEI1 in human oocyte meiosis and early embryonic development, but also extend the phenotypic and mutational spectrum of MEI1 and provide new diagnostic markers for genetic counseling of clinical patients.

Study Funding/competing Interest(s): This work was supported by the National Key Research and Development Program of China (2018YFC1003800, 2017YFC1001500, and 2016YFC1000600), the National Natural Science Foundation of China (81725006, 81822019, 81771581, 81971450, and 81971382), the project supported by the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), the Project of the Shanghai Municipal Science and Technology Commission (19JC1411001), the Natural Science Foundation of Shanghai (19ZR1444500), the Shuguang Program of the Shanghai Education Development Foundation and the Shanghai Municipal Education Commission (18SG03), the Shanghai Health and Family Planning Commission Foundation (20154Y0162), the Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine, Ferring Pharmaceuticals and the Chinese Academy of Sciences (FIRMC200507) and the Chongqing Key Laboratory of Human Embryo Engineering (2020KFKT008). No competing interests are declared.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab118DOI Listing
July 2021

A Survey of Recent Patents in Engineering Technology for the Screening, Separation and Processing of Eggshell.

Front Bioeng Biotechnol 2021 4;9:677559. Epub 2021 May 4.

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.

The chicken egg is a well-known complete food of human daily consumption which serves as a cost-effective, high-quality nutrient resource. About 30% of table eggs are directed to breaker plants in developed countries, leading to the generation of substantial eggshell (ES) waste, which is increasingly explored for potential value-added applications. The number of patents describing ES-based applications has increased dramatically in recent years. This review provides insight into the most recent patents published between 2015 and 2020, with focus on different engineering technologies for the screening, separation, and processing of ES. Screening technologies include detection of ES surface spots and glossiness, ES cracks, and mechanical properties, along with identification of chicken breed and enumeration of surface bacterial count. Collection and separation technologies describe separation strategies of ES from egg white (EW), egg yolk (EY), liquid egg, eggshell membrane (ESM), hatchlings, and cooked egg. Separation of ES from liquid eggs utilizes gravity, rotational forces, or air pressure. Processing of ES involves washing and sterilization along with cutting, crushing, and pulverization technologies that enable the collection of ES suitable for value-added applications. In addition, ES carving (mechanical and laser) opens up the realm of artwork and decoration. Furthermore, intact ES can be utilized for food serving. The exponential increase in innovative screening, separation, collection, and processing technologies reflects industrial interest to upscale low-value ES waste material, and is a first crucial step in the emergence of advanced technologies that exploit the biomedical, chemical, engineering, and environmental applications for ES.
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http://dx.doi.org/10.3389/fbioe.2021.677559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130897PMC
May 2021

Network analysis reveals important genes in human placenta.

J Obstet Gynaecol Res 2021 May 18. Epub 2021 May 18.

Department of Gynaecology and Obstetrics, Fuzhou First Hospital Affiliated to Fujian Medical University, Fuzhou, China.

Aim: To determine which genes are important in placenta by network analysis.

Methods: Placenta expressing genes were screened from RNA-Seq data. Protein-protein interaction data were downloaded from STRING (v11.0) database. Google PageRank (PR) algorithm was used to identify important placental genes from protein interaction network. Six placental disease-related datasets were downloaded from NCBI GEO database, and the differential expression of the 99 genes was identified.

Results: We calculated PR for each placenta expressing gene and defined the top 99 genes with high PR as important genes. GAPDH has the highest PR. The 99 genes had different expression pattern in placental cell types. FN1 is up-regulated in 8 w EVT compared to 8 w CTB and 24 w EVT compared to 8 w EVT. HSPA4 is down-regulated in 8 w EVT compared to 8 w CTB and 24 w EVT compared to 8 w EVT. MIB2, TLR4, and UBB are consistently changed in preeclampsia (PE). UBB and ACTG1 were identified to be down-regulated in fetal growth restriction (FGR). SOD1 is down-regulated in preterm birth placenta.

Conclusion: Our findings confirmed that the importance of these genes in placenta-related diseases, and provide new candidates (MIB2, UBB, ACTG1, and SOD1) for placenta-related disease diagnosis and treatment.
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http://dx.doi.org/10.1111/jog.14820DOI Listing
May 2021

A novel bipartite antitermination system widespread in conjugative elements of Gram-positive bacteria.

Nucleic Acids Res 2021 06;49(10):5553-5567

Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), C. Nicolás Cabrera 1, Universidad Autónoma de Madrid, Canto Blanco, 28049 Madrid, Spain.

Transcriptional regulation allows adaptive and coordinated gene expression, and is essential for life. Processive antitermination systems alter the transcription elongation complex to allow the RNA polymerase to read through multiple terminators in an operon. Here, we describe the discovery of a novel bipartite antitermination system that is widespread among conjugative elements from Gram-positive bacteria, which we named conAn. This system is composed of a large RNA element that exerts antitermination, and a protein that functions as a processivity factor. Besides allowing coordinated expression of very long operons, we show that these systems allow differential expression of genes within an operon, and probably contribute to strict regulation of the conjugation genes by minimizing the effects of spurious transcription. Mechanistic features of the conAn system are likely to decisively influence its host range, with important implications for the spread of antibiotic resistance and virulence genes.
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http://dx.doi.org/10.1093/nar/gkab360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191782PMC
June 2021

Interaction between bovine serum albumin and chitooligosaccharides: I. Molecular mechanism.

Food Chem 2021 Oct 20;358:129853. Epub 2021 Apr 20.

National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Hubei International Scientific and Technological Cooperation Base of Food Hydrocolloids, Wuhan 430068, China; State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Sciences, Jinan, 250353, China. Electronic address:

The interaction between chitooligosaccharides (COS) and bovine serum albumin (BSA) is worthy of investigation, which provides support for improving the physical properties (gelling, foaming, and emulsifying) of food proteins via COS addition and in vivo research on COS bioactivity. Component analysis indicated that COS and COS were enriched in the COS-BSA precipitate. The fluorescence binding constant (1.73 × 10 M), ΔG of isothermal titration calorimetry (-6.7 kJ/mol), and the predicted ΔG of molecular docking (-10 to -5 kJ/mol) confirmed the weak interaction of COS-BSA. Quartz crystal microbalance dissipation and molecular docking indicated that electrostatic and hydrophobic interactions were the main stabilization forces. Molecular docking showed that the predicted ΔG of COS to BSA decreased with the increasing degree of polymerization. This work clarified the weak and selective interaction between COS and BSA via various methods, which is useful for the food application of COS.
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http://dx.doi.org/10.1016/j.foodchem.2021.129853DOI Listing
October 2021

Isolated heterotrophic nitrifying and aerobic denitrifying bacterium for treating actual refinery wastewater with low C/N ratio.

J Biosci Bioeng 2021 Jul 28;132(1):41-48. Epub 2021 Apr 28.

Hubei Province Key Laboratory of Coal Conversion and New Carbon Materials, School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, China.

Heterotrophic nitrifying and aerobic denitrifying bacteria that have been widely isolated from complicated activated sludge microflorae demonstrate dominant advantages in simultaneous removal of ammonium and nitrogen oxides under aerobic conditions. However, owing to the need of organic carbon to support bacterial growth, nitrogen removal of actual industrial wastewater with low carbon-to-nitrogen (C/N) ratio remains a challenge. Here, Pseudomonas mendocina Y7 was identified and presented to effectively remove nitrogen of actual refinery wastewater with low C/N ratio. The isolated bacterium showed high removal efficiency of NH-N, NO-N, and NO-N up to about 90% in single (100 mg/L) or mixed (200 mg/L) nitrogen source media at low C/N ratio of 6 when it was cultivated for 12 or 21 h. According to PCR amplification, the heterotrophic nitrification and aerobic denitrification capability of strain Y7 was attributed to the functional genes of amoA, hao, napA, and nirS. In activated sludge process for treating actual refinery wastewater with low C/N ratio, compared to abundant accumulation of NO-N and NO-N only using the activated sludge, strain Y7 significantly improved the removal efficiency of NH‒N and total nitrogen (with influent concentrations of about 40 and 55 mg/L) from about 47% and 22% to about 85% and 73%, respectively, without the accumulation of nitrogen oxides. Microbial community structure analysis revealed that strain Y7 could coexist well with other microorganisms in the activated sludge and maintain highly efficient and steady nitrogen removal in continuous treatment system. This discovery provides a promising treatment approach toward actual nitrogen-rich industrial wastewater.
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http://dx.doi.org/10.1016/j.jbiosc.2021.03.012DOI Listing
July 2021

Identification of Novel Mutations in : Expanding the Mutational Spectrum for Female Infertility.

Front Cell Dev Biol 2021 9;9:647130. Epub 2021 Apr 9.

Institute of Pediatrics, Children's Hospital of Fudan University and Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.

Oocyte maturation and fertilization are fundamental processes for successful human reproduction, and abnormalities in these processes will cause infertility. Recently, we identified biallelic mutations in that are responsible for human oocyte maturation arrest, fertilization failure, and early embryonic development arrest. In this study, we screened for further mutations in a new cohort of patients with abnormalities in oocyte maturation, fertilization, and early embryonic development. Through whole-exome sequencing, we identified the four novel mutations c.887G > A (p. Arg296Gln), c.964C > T (p.Arg322), c.1155G > C (p.Trp385Cys), and c.330 + 1G > A (p. Glu111Ilefs36) and one previously reported mutation c.965G > A (p.Arg322Gln) in in four infertile individuals from three independent families. The patients had different phenotypes of oocyte maturation arrest and fertilization failure resulting from the different mutations. This study confirms our previous research and expands the spectrum of known mutations in , providing new evidence supporting the function of in the genetic etiology of female infertility characterized by oocyte maturation arrest and fertilization failure.
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http://dx.doi.org/10.3389/fcell.2021.647130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063106PMC
April 2021

Three-Dimensional Dynamic Analysis of the Reproducibility of Verbal and Nonverbal Facial Expressions.

Cleft Palate Craniofac J 2021 Apr 22:10556656211001998. Epub 2021 Apr 22.

Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, People's Republic of China.

Objective: The aim of this study is to compare the short- and long-term reproducibility of verbal and nonverbal facial expressions of normal people using dynamic 3-dimensional (3-D) imaging.

Design: Prospective, cross-sectional, controlled study.

Setting: Peking University School and Hospital of Stomatology, Beijing, China.

Patients And Participants: Twenty-seven participants, 12 males and 15 females, were recruited for this study.

Methods: A 3-D dynamic system was applied to capture the process of 4 nonverbal facial expressions (smile lips closed, smile lips open, lip purse, cheek puff) and 2 verbal facial expressions (/i:/, /u:/) at an initial time point, 15 minutes later, and 1 week later. Key frames were selected from each expression recording sequence.

Main Outcome Measures: The root mean square (RMS) between each key frame and its corresponding frame at rest was calculated. ΔRMS reflected the difference of the same key frames between the different sessions of the same expression of the same participant. The reproducibility of different facial expressions at different time intervals were analyzed.

Results: There was no significant difference in verbal and nonverbal expression repeatability during a 15-minute interval, except for cheek puff motion. Following a 1-week interval, verbal expression repeatability was superior to that of nonverbal expressions ( < .01). Compared with nonverbal expressions, the repeatability of verbal expressions did not obviously decrease with the increase in recording interval.

Conclusions: Dynamic 3-D imaging is a useful technique for facial expression analysis. Verbal expressions showed greater reproducibility than nonverbal expressions.
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http://dx.doi.org/10.1177/10556656211001998DOI Listing
April 2021

Atomistic Insight into the Effects of Depositional Nanoparticle on Nanoscale Liquid Film Evaporation.

Langmuir 2021 May 21;37(17):5202-5212. Epub 2021 Apr 21.

Institute of Thermal Science and Technology, Shandong University, Jinan 250061, Shandong Province China.

Nanoscale liquid film evaporation plays an essential role in many engineering applications. This study carries out molecular dynamics simulations on the effects of the depositional nanoparticle's wettability and volume in base fluid on the evaporation process to understand how the depositional nanoparticle affects the evaporation heat transfer. Increasing the nanoparticle's wettability can enhance the evaporation heat transfer process, and the enhancement effect of the hydrophobic surface is more remarkable than that of the hydrophilic surface. This because the increasing wettability causes more significant solid-liquid interaction. However, the potential energy of argon atoms at the liquid-vapor interface is almost unaffected by wettability. Moreover, when the depositional nanoparticle locates below the free liquid film, increasing the nanoparticle volume has a better heat transfer performance. As the volume increases, the heat transfer through the nanoparticle becomes more obvious, which effectively enhances the heat transfer at the solid-liquid interface and the liquid-vapor interface. The latent heat of phase change at the liquid-vapor interface is almost unchanged so that the evaporation can be enhanced. This research provides an understanding of the effects of depositional nanoparticles on nanoscale evaporation, which can impact several engineering applications, including devices' cooling and fluid transport.
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http://dx.doi.org/10.1021/acs.langmuir.1c00149DOI Listing
May 2021

The bone microenvironment invigorates metastatic seeds for further dissemination.

Cell 2021 Apr 19;184(9):2471-2486.e20. Epub 2021 Apr 19.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.
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http://dx.doi.org/10.1016/j.cell.2021.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087656PMC
April 2021

The fate of flavonoids after oral administration: a comprehensive overview of its bioavailability.

Crit Rev Food Sci Nutr 2021 Apr 13:1-18. Epub 2021 Apr 13.

Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China.

Despite advancements in synthetic chemistry, nature remains the primary source of drug discovery, and this never-ending task of finding novel and active drug molecules will continue. Flavonoids have been shown to possess highly significant therapeutic activities such as anti-inflammatory, anti-oxidant, anti-viral, anti-diabetic, anti-cancer, anti-aging, neuroprotective, and cardioprotective, etc., However, it has been found that orally administered flavonoids have a critical absorption disorder and, therefore, have low bioavailability and show fluctuating pharmacokinetic and pharmacodynamic responses. A detailed investigation is required to assess and analyze the variation in the bioavailability of flavonoids due to interactions with the intestinal barrier. This review will emphasize on the bioavailability and the pharmacological applications of flavonoids, key factors affecting their bioavailability, and strategies for enhancing bioavailability, which may lead to deeper understanding of the extent of flavonoids as a treatment and/or prevention for different diseases in clinics.
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http://dx.doi.org/10.1080/10408398.2021.1898333DOI Listing
April 2021

Anti-GPR56 monoclonal antibody potentiates GPR56-mediated Src-Fak signaling to modulate cell adhesion.

J Biol Chem 2021 Jan-Jun;296:100261. Epub 2021 Jan 8.

The Brown Foundation Institute of Molecular Medicine and Center for Translational Cancer Research, University of Texas Health Science Center at Houston, Houston, Texas, USA. Electronic address:

GPR56 is a member of the adhesion G-protein-coupled receptor family shown to play important roles in cell adhesion, brain development, immune function, and tumorigenesis. GPR56 is highly upregulated in colorectal cancer and correlates with poor prognosis. Several studies have shown GPR56 couples to the Gα class of heterotrimeric G-proteins to promote RhoA activation. However, due to its structural complexity and lack of a high-affinity receptor-specific ligand, the complete GPR56 signaling mechanism remains largely unknown. To delineate the activation mechanism and intracellular signaling functions of GPR56, we generated a monoclonal antibody (mAb) that binds with high affinity and specificity to the extracellular domain (ECD). Using deletion mutants, we mapped the mAb binding site to the GAIN domain, which mediates membrane-proximal autoproteolytic cleavage of the ECD. We showed that GPR56 overexpression in 293T cells leads to increased phosphorylation of Src, Fak, and paxillin adhesion proteins and activation of the Gα-RhoA-mediated serum response factor (SRF) pathway. Treatment with the mAb potentiated Src-Fak phosphorylation, RhoA-SRF signaling, and cell adhesion. Consistently, GPR56 knockdown in colorectal cancer cells decreased Src-Fak pathway phosphorylation and cell adhesion. Interestingly, GPR56-mediated activation of Src-Fak phosphorylation occurred independent of RhoA, yet mAb-induced potentiation of RhoA-SRF signaling was Src-dependent. Furthermore, we show that the C-terminal portion of the Serine-Threonine-Proline-rich (STP) region, adjacent to the GAIN domain, was required for Src-Fak activation. However, autoproteolytic cleavage of the ECD was dispensable. These data support a new ECD-dependent mechanism by which GPR56 functions to regulate adhesion through activation of Src-Fak signaling.
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http://dx.doi.org/10.1016/j.jbc.2021.100261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948743PMC
January 2021

Multiple Layered Control of the Conjugation Process of the Plasmid pLS20.

Front Mol Biosci 2021 18;8:648468. Epub 2021 Mar 18.

Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom.

Bacterial conjugation is the main horizontal gene transfer route responsible for the spread of antibiotic resistance, virulence and toxin genes. During conjugation, DNA is transferred from a donor to a recipient cell via a sophisticated channel connecting the two cells. Conjugation not only affects many different aspects of the plasmid and the host, ranging from the properties of the membrane and the cell surface of the donor, to other developmental processes such as competence, it probably also poses a burden on the donor cell due to the expression of the large number of genes involved in the conjugation process. Therefore, expression of the conjugation genes must be strictly controlled. Over the past decade, the regulation of the conjugation genes present on the conjugative plasmid pLS20 has been studied using a variety of methods including genetic, biochemical, biophysical and structural approaches. This review focuses on the interplay between Rco, Rap and Phr*, the proteins that control the activity of the main conjugation promoter P located upstream of the conjugation operon. Proper expression of the conjugation genes requires the following two fundamental elements. First, conjugation is repressed by default and an intercellular quorum-signaling system is used to sense conditions favorable for conjugation. Second, different layers of regulation act together to repress the P promoter in a strict manner but allowing rapid activation. During conjugation, ssDNA is exported from the cell by a membrane-embedded DNA translocation machine. Another membrane-embedded DNA translocation machine imports ssDNA in competent cells. Evidences are reviewed indicating that conjugation and competence are probably mutually exclusive processes. Some of the questions that remain unanswered are discussed.
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http://dx.doi.org/10.3389/fmolb.2021.648468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014075PMC
March 2021

Structural characterization and pro-angiogenic property of a polysaccharide isolated from red seaweed Bangia fusco-purpurea.

Int J Biol Macromol 2021 Jun 24;181:705-717. Epub 2021 Mar 24.

College of Food and Biological Engineering, Jimei University, Xiamen, Fujian 361021, China; Fujian Provincial Key Laboratory of Food Microbiology and Enzyme Engineering, Xiamen, Fujian 361021, China; Key Laboratory of Systemic Utilization and In-depth Processing of Economic Seaweed, Xiamen Southern Ocean Research Center, Xiamen 361021, China; Research Center of Food Biotechnology of Xiamen City, Xiamen 361021, China. Electronic address:

In this study, we evaluated the structural characteristics and novel biological activity of polysaccharide purified from red seaweed Bangia fusco-purpurea (BFP). Methylation, GC/MS, and NMR analyses suggested that the proposal repeating structure of BFP was →3)-β-D-Galp-(1→, →3)-β-D-Galp6S-(1 → 4)-α-D-Galp-(1→, →4)-α-D-Galp-(1 → 4)-α-L-AnGalp-(1 → 3)-β-D-Galp-(1→, and →4)-α-D-Galp-(1 → at a molar ratio of 13: 1: 1: 1. Interestingly, BFP exhibited significant cell migration- and tube formation-promoting activities toward human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner via increasing the N-cadherin expression and decreasing the E-cadherin expression. Furthermore, ERK and p38 mitogen-activated protein kinase (MAPK) specific inhibitors exhibited potent inhibitory effects on BFP-induced cell migration but not JNK MAPK inhibitor, suggesting ERK and p38 MAPK signaling pathways were mainly involved in BFP-induced cell migration. Moreover, vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor significantly inhibited BFP-induced cell migration and tube formation in HUVECs, suggesting VEGF receptors of HUVECs were involved in the pro-angiogenesis activity of BFP. This is the first report that a sulfated polysaccharide possessing a pro-angiogenic effect was obtained from red seaweed. Our findings are expected to promote the practical use of red seaweed B. fusco-purpurea and its polysaccharide in the development of the in vitro and ex vivo vascular endothelial cell-based cell therapy products.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.03.123DOI Listing
June 2021

A Conserved Class II Type Thioester Domain-Containing Adhesin Is Required for Efficient Conjugation in Bacillus subtilis.

mBio 2021 03 16;12(2). Epub 2021 Mar 16.

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma, Madrid, Spain

Conjugation, the process by which a DNA element is transferred from a donor to a recipient cell, is the main horizontal gene transfer route responsible for the spread of antibiotic resistance and virulence genes. Contact between a donor and a recipient cell is a prerequisite for conjugation, because conjugative DNA is transferred into the recipient via a channel connecting the two cells. Conjugative elements encode proteins dedicated to facilitating the recognition and attachment to recipient cells, also known as mating pair formation. A subgroup of the conjugative elements is able to mediate efficient conjugation during planktonic growth, and mechanisms facilitating mating pair formation will be particularly important in these cases. Conjugative elements of Gram-negative bacteria encode conjugative pili, also known as sex pili, some of which are retractile. Far less is known about mechanisms that promote mating pair formation in Gram-positive bacteria. The conjugative plasmid pLS20 of the Gram-positive bacterium allows efficient conjugation in liquid medium. Here, we report the identification of an adhesin gene in the pLS20 conjugation operon. The N-terminal region of the adhesin contains a class II type thioester domain (TED) that is essential for efficient conjugation, particularly in liquid medium. We show that TED-containing adhesins are widely conserved in Gram-positive bacteria, including pathogens where they often play crucial roles in pathogenesis. Our study is the first to demonstrate the involvement of a class II type TED-containing adhesin in conjugation. Bacterial resistance to antibiotics has become a serious health care problem. The spread of antibiotic resistance genes between bacteria of the same or different species is often mediated by a process named conjugation, where a donor cell transfers DNA to a recipient cell through a connecting channel. The first step in conjugation is recognition and attachment of the donor to a recipient cell. Little is known about this first step, particularly in Gram-positive bacteria. Here, we show that the conjugative plasmid pLS20 of encodes an adhesin protein that is essential for effective conjugation. This adhesin protein has a structural organization similar to adhesins produced by other Gram-positive bacteria, including major pathogens, where the adhesins serve in attachment to host tissues during colonization and infection. Our findings may thus also open novel avenues to design drugs that inhibit the spread of antibiotic resistance by blocking the first recipient-attachment step in conjugation.
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http://dx.doi.org/10.1128/mBio.00104-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092201PMC
March 2021

Hepatic Gadd45β promotes hyperglycemia and glucose intolerance through DNA demethylation of PGC-1α.

J Exp Med 2021 May;218(5)

Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.

Although widely used for their potent anti-inflammatory and immunosuppressive properties, the prescription of glucocorticoid analogues (e.g., dexamethasone) has been associated with deleterious glucose metabolism, compromising their long-term therapeutic use. However, the molecular mechanism remains poorly understood. In the present study, through transcriptomic and epigenomic analysis of two mouse models, we identified a growth arrest and DNA damage-inducible β (Gadd45β)-dependent pathway that stimulates hepatic glucose production (HGP). Functional studies showed that overexpression of Gadd45β in vivo or in cultured hepatocytes activates gluconeogenesis and increases HGP. In contrast, liver-specific Gadd45β-knockout mice were resistant to high-fat diet- or steroid-induced hyperglycemia. Of pathophysiological significance, hepatic Gadd45β expression is up-regulated in several mouse models of obesity and diabetic patients. Mechanistically, Gadd45β promotes DNA demethylation of PGC-1α promoter in conjunction with TET1, thereby stimulating PGC-1α expression to promote gluconeogenesis and hyperglycemia. Collectively, these findings unveil an epigenomic signature involving Gadd45β/TET1/DNA demethylation in hepatic glucose metabolism, enabling the identification of pathogenic factors in diabetes.
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http://dx.doi.org/10.1084/jem.20201475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953268PMC
May 2021
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