Publications by authors named "Shufeng Li"

201 Publications

Additive Effects of VDBP and 1,25(OH)2D3 on the Viability and Apoptosis of Rheumatoid Arthritis Synovial Fibroblasts.

Front Endocrinol (Lausanne) 2020 28;11:583229. Epub 2021 Jan 28.

Department of Orthopedic Surgery, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Aim: This study is to investigate the additive effect of Vitamin D-binding protein (VDBP) and 1,25(OH)2D3 on the viability and apoptosis of synovial cells from patients with rheumatoid arthritis (RA).

Methods: Synovial tissues and synovial fluid of patients with RA and osteoarthritis (OA) were collected. The expression of VDBP was analyzed with immunohistochemistry and ELISA. CCK-8 assay was applied to detect cell viability. Flow cytometry was used to analyze cell cycle and apoptosis.

Results: Immunohistochemical results showed that the expression of VDBP in the synovium of RA patients was significantly lower than that of OA (P<0.05). Similarly, ELISA results presented a lower expression of VDBP in the synovial fluid of RA patients. The results of CCK-8 assay showed that both 1,25(OH)2D3 and VDBP significantly inhibited the viability of rheumatoid arthritis synovial fibroblasts (RASF) (P<0.05). The treatment with 1,25(OH)2D3+VDBP led to more significantly inhibited viability of RASF, compared with 1,25(OH)2D3 alone (P<0.05). The results of flow cytometry showed that 1,25(OH)2D3 and VDBP both promoted the apoptosis of RASF (P<0.05) and 1,25(OH)2D3+VDBP led to a higher proportion of RASF apoptosis, compared with 1,25(OH)2D3 alone (P<0.05). However, 1,25(OH)2D3 and VDBP had no significant effect on the cell cycle of RASF. Additionally, 1,25(OH)2D3 promoted the expression of VDBP in RASF, but not concentration-dependently.

Conclusion: VDBP is reduced in the synovial tissue and synovial fluid of RA patients and can inhibit viability of RASF and promote the apoptosis of RASF. The 1,25(OH)2D3 can upregulate the expression of VDBP in RASF. Additionally, VDBP can enhance the effects of 1,25(OH)2D3 on viability and apoptosis of RASF.
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http://dx.doi.org/10.3389/fendo.2020.583229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876401PMC
January 2021

Association of Infertility and All-Cause Mortality: Analysis of US Claims Data.

Am J Obstet Gynecol 2021 Feb 9. Epub 2021 Feb 9.

Department of Urology, Stanford University Medical Center, Stanford, CA.

Background: The consequences of an infertility diagnosis extend beyond the pursuit of family building, as infertile women also face increased risks of severe maternal morbidity, cancer, and chronic disease.

Objective: To examine the association between female infertility and all-cause mortality.

Study Design: Retrospective analysis of 72,786 infertile women identified in the Optum Clinformatics Datamart from 2003-2019 by infertility diagnosis, testing and treatment codes compared with 3,845,790 non-infertile women seeking routine gynecologic care. Baseline comorbidities were assessed using the presence of ≥1 metabolic syndrome (MetS) diagnoses and the Charlson Comorbidity Index (CCI). The primary outcome of all-cause mortality was identified by linkage to Social Security Administration Death Master File outcomes and medical claims. The association of infertility with mortality was examined using Cox proportional hazard regression while adjusting for age, hypertension, hyperlipidemia, type II diabetes, year of evaluation, smoking, number of visits per year, nulliparity, obesity, region of country, and race.

Results: Among 16,473,458 person-years of follow up, 13,934 women died. Infertile women had a 32% higher relative risk of death from any cause (0.42% versus 0.35%, aHR 1.32, 95% CI 1.18-1.48) compared to non-infertile women. Mean follow up time per patient was 4.0±3.7 years versus 4.2±3.8 years for infertile and non-infertile women, respectively. When stratified by age < 35 or ≥35 years or baseline medical comorbidity, the association between infertility and mortality remained. Infertile women who delivered a child during the follow up period faced similar increased risk of mortality compared to the overall infertile group. Finally, receipt of fertility treatment was not associated with a higher risk of death compared to receiving an infertility diagnosis or testing alone.

Conclusions: While absolute risk of death was low in both groups, infertile women faced a higher relative risk of mortality compared to non-infertile women. The association remained across all age, race/ethnicity, morbidity, and delivery strata. Importantly, infertility treatment was not associated with an increased risk of death. These findings reinforce the disease burden associated with infertility and its potential for longer-term sequelae.
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http://dx.doi.org/10.1016/j.ajog.2021.02.010DOI Listing
February 2021

A novel intracellular nanobody against HPV16 E6 oncoprotein.

Clin Immunol 2021 Feb 4;225:108684. Epub 2021 Feb 4.

The Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University Medical School, 87 Dingjiaqiao Road, Nanjing 210009, China. Electronic address:

Cervical cancer occurs as a result of the persistent infection of high-risk human papillomavirus (HPV). HPV16 oncoproteins E6 and E7 exert different and concerted pro-tumor actions in cell transformation and malignance maintenance in various m echanisms. Nanobody expressed as "intracellular antibodies" (intrabodies) can target intracellular antigens to hamper their function efficaciously and specifically. In this work, phage-display approach was employed to select the high affinity HPV16 E6-specific nanobody, nanobody Nb9 against HPV16 E6 was selected. Nb9 has high affinity (Kaff =6.3 × 10 M) and can specifically bind endogenous HPV16 E6 protein in HPV16 positive CaSki and SiHa cells. In Nb9 overexpressed SiHa and CaSki cells, nucleus localization of HPV16 E6 was inhibited, p53 inactivation was prevented and increased apoptosis was observed. Moreover, tumor growth was inhibited in mouse xenograft model. Taken together, our results suggested that nanobody Nb9 could be a useful inhibitor for HPV16 E6 function and particularly appropriate for the treatment of HPV-associated disease.
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http://dx.doi.org/10.1016/j.clim.2021.108684DOI Listing
February 2021

Berberine improves dietary-induced cardiac remodeling by upregulating Kruppel-like factor 4-dependent mitochondrial function.

Biol Chem 2021 Jan 30. Epub 2021 Jan 30.

Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road,Harbin150001, Heilongjiang Province, China.

Multiple studies have showed that berberine protects against heart diseases, including obesityassociated cardiomyopathy. However, it is not fully disclosed the potential molecular mechanisms of berberine on controlling cardiac remodelling. Kruppel-like factor (KLF) 4, identified as a critical transcriptional factor, participates in multiple cardiac injuries. The present study was to explore whether KLF4 determined the cardioprotective benefits of berberine in dietary-induced obese mice. High fat diet-induced obese mice were treated with berberine with or without lentivirus encoding Klf4 siRNA, and cardiac parameters were analysed by multiple biological approaches. In dietary-induced obese mouse model, administration of berberine obviously increased cardiac level of KLF4, which closely correlated with improvement of cardiac functional parameters. Co-treatment of lentivirus encoding Klf4 siRNA abolished cardioprotective benefits of berberine, including induction of cardiac hypertrophy, fibrosis, functional disorders, inflammatory response and oxidative stress. Mechanistically, we found berberine improved cardiac mitochondrial biogenesis and activities, whereas silencing Klf4 decreased berberine-upregulated mitochondrial quality, ATP production and oxygen consumption. Our present study demonstrated that berberine protected against dietary-induced cardiac structural disorders and mitochondrial dysfunction dependent on cardiac KLF4 signaling. Cardiac KLF4 was one of potential therapeutic targets for obesityinduced cardiac injuries.
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http://dx.doi.org/10.1515/hsz-2020-0267DOI Listing
January 2021

Effects of physical exercise on macular vessel density and choroidal thickness in children.

Sci Rep 2021 Jan 21;11(1):2015. Epub 2021 Jan 21.

Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, 325027, Zhejiang, China.

We used swept-source (SS) optical coherence tomography (OCT) and OCT angiography (OCTA) to investigate the effects of moderate physical exercise on retinal and choroidal vessel densities (VDs) and thicknesses in children. One eye in each of 40 myopic children (mean age, 11.70 years) and 18 emmetropic children (mean age, 11.06 years) were included. SS-OCT 6 × 6-mm radial scans and SS-OCTA 3 × 3-mm images were centered on the macula. Heart rate (HR), systolic and diastolic blood pressure, and intraocular pressure (IOP) were recorded before and immediately after a 20-min stationary cycling exercise and after a 30-min rest. The subfoveal choroidal thickness (SFCT), choroidal thickness (CT), and VD at the superficial and deep retinal layers, choriocapillaris, and deeper choroidal vessels were determined. SFCT and CT were significantly lower at all locations immediately after exercise (p < 0.001) and did not fully recover after rest (p < 0.05). VD was lower in the deep retinal layer after exercise (p = 0.02) and higher in the superficial layer after rest (p = 0.03) in myopic eyes while it was higher in the superficial (p < 0.01) and deep layer (p < 0.01) after rest in emmetropic eyes. No significant exercise-related changes in the superficial retinal VD, choroidal VD, or IOP were observed. ΔCT% and ΔSFCT% were significantly correlated with increases in HR in myopic group (p = 0.04 and p = 0.03, respectively). Exercise increased retinal VD after rest in emmetropic eyes, and caused significant CT thinning that lasted for at least 30 min in both emmetropic and myopic eyes.
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http://dx.doi.org/10.1038/s41598-021-81770-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820247PMC
January 2021

Design and Application of Receptor-Targeted Fluorescent Probes Based on Small Molecular Fluorescent Dyes.

Bioconjug Chem 2021 Jan 7;32(1):4-24. Epub 2021 Jan 7.

Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.

In recent years, a variety of receptor-targeted fluorescent probes have been developed and widely used to realize the visualization of certain receptors, which facilitates the early diagnosis and treatment of diseases. In this Review, we focus on the recent achievements in design, chemical structure, imaging characterization, and potential applications of receptor-targeted fluorescent probes from the past 10 years. The development and application of receptor-targeted fluorescent probes will expand our knowledge of the distribution and function of disease-related receptors, shed light on the drug discovery for clinical diseases where receptors are implicated, and feed into the diagnosis and treatment of a plethora of diseases, including tumors.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00606DOI Listing
January 2021

Clinical characterization of novel HSPA9 splice variant in a Chinese woman.

Clin Genet 2021 Apr 5;99(4):609-610. Epub 2021 Jan 5.

Department of Hematology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.

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http://dx.doi.org/10.1111/cge.13910DOI Listing
April 2021

Recent achievements of bioluminescence imaging based on firefly luciferin-luciferase system.

Eur J Med Chem 2021 Feb 17;211:113111. Epub 2020 Dec 17.

Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China. Electronic address:

Bioluminescence imaging (BLI) is a newly developed noninvasive visual approach which facilitates the understanding of a plethora of biological processes in vitro and in vivo due to the high sensitivity, resolution and selectivity, low background signal, and the lack of external light excitation. BLI based on firefly luciferin-luciferase system has been widely used for the activity evaluation of tumor-specific enzymes, for the detection of diseases-related bioactive small molecules and metal ions, and for the diagnosis and therapy of diseases including the studies of drug transport, the research of immune response, and the evaluation of drug potency and tissue distribution. In this review, we highlight the recent achievements in luciferin derivatives with red-shifted emission spectra, mutant luciferase-luciferin pairs, and the diagnostic and therapeutic application of BLI based on firefly luciferin-luciferase system. The development and application of BLI will expand our knowledge of the occurrence and development of diseases and shed light on the diagnosis and treatment of various diseases.
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http://dx.doi.org/10.1016/j.ejmech.2020.113111DOI Listing
February 2021

Association between preconception paternal health and pregnancy loss in the USA: an analysis of US claims data.

Hum Reprod 2021 Feb;36(3):785-793

Department of Urology, Stanford University School of Medicine, Stanford, CA 94305-5118, USA.

Study Question: Is preconception paternal health associated with pregnancy loss?

Summary Answer: Poor preconception paternal health is associated with a higher risk of pregnancy loss as confirmed in sensitivity analyses accounting for maternal age and health.

What Is Known Already: Preconception paternal health can negatively impact perinatal outcomes.

Study Design, Size, Duration: Retrospective cohort study of US insurance claims database from 2009 to 2016 covering 958 804 pregnancies.

Participants/materials, Setting, Methods: US insurance claims database including women, men and pregnancies within the USA between 2007 and 2016. Paternal preconception health status (e.g. metabolic syndrome diagnoses (MetS), Charlson comorbidity index (CCI) and individual chronic disease diagnoses) was examined in relation to pregnancy loss (e.g. ectopic pregnancy, miscarriage and stillbirth).

Main Results And The Role Of Chance: In all, 958 804 pregnancies were analyzed. The average paternal age was 35.3 years (SD 5.3) and maternal age was 33.1 years (SD 4.4). Twenty-two percent of all pregnancies ended in a loss. After adjusting for maternal factors, the risk of pregnancy loss increased with increasing paternal comorbidity. For example, compared to men with no components of MetS, the risk of pregnancy loss increased for men with one (relative risk (RR) 1.10, 95% CI 1.09-1.12), two (RR 1.15, 95% CI 1.13-1.17) or three or more (RR 1.19, 95% CI 1.14-1.24) components. Specifically, less healthy men had a higher risk of siring a pregnancy ending in spontaneous abortion, stillbirth and ectopic pregnancies. Similar patterns remained with other measures of paternal health (e.g. CCI, chronic diseases, etc.). When stratifying by maternal age as well as maternal health, a similar pattern of increasing pregnancy loss risk for men with 1, 2 or 3+ MetS was observed. A statistically significant but weak association between timing of pregnancy loss and paternal health was found.

Limitations, Reasons For Caution: Retrospective study design covering only employer insured individuals may limit generalizability.

Wider Implications Of The Findings: Optimization of a father's health may improve pregnancy outcomes.

Study Funding/competing Interests: National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085). M.L.E. is an advisor for Sandstone Diagnostics, Dadi, Hannah and Underdog. No other competing interests were declared.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa332DOI Listing
February 2021

CCNB1 Expedites the Progression of Cervical Squamous Cell Carcinoma via the Regulation by FOXM1.

Onco Targets Ther 2020 1;13:12383-12395. Epub 2020 Dec 1.

Department 1 of Gynecological Oncology, Jilin Cancer Hospital, Changchun 130012, Jilin, People's Republic of China.

Background: Cervical squamous cell carcinoma (CSCC) is responsible for 80-85% of cervical cancer. Cyclin B1 (CCNB1) represents a hub gene during the development of cervical cancer. However, the oncogenic role of CCNB1 in CSCC remains unclear. Our study aims to explore the mechanism underlying CCNB1 regulation on cell cycle progression in CSCC cells.

Methods: First, we analyzed differentially expressed genes from CSCC dataset GSE63678 and conducted gene function enrichment analysis. Subsequently, CCNB1 expression was knocked down in CSCC cell lines to assess cell proliferation, apoptosis, and cell cycle distribution. After the validation of the binding relationship between forkhead box protein M1 (FOXM1) and the promoter of CCNB1, the effect of FOXM1 on CCNB1 expression and on CSCC cell growth and apoptosis was verified. We further analyzed the histone ChIP-Seq data of CCNB1 in CSCC cells and measured the acetylation levels of the CCNB1 promoter histones.

Results: CCNB1 was overexpressed in CSCC tissues and cells, and CCNB1 silencing inhibited the growth of CSCC cells, and promoted cell cycle arrest and apoptosis. FOXM1 potentiated CCNB1 transcription by binding to its promoter and recruiting CBP/P300, a histone acetyltransferase. Further increasing FOXM1 expression or increasing P300 activity in CSCC cells with CCNB1 knockdown elevated CCNB1 expression and proliferation and cell cycle progression of CSCC cells. Knockdown of CCNB1 activated the p53 pathway in cells.

Conclusion: FOXM1 inhibited the activation of the p53 pathway by recruiting CBP/P300, which promoted the transcription of CCNB1, resulting in the growth and cell cycle progression of CSCC cells.
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http://dx.doi.org/10.2147/OTT.S279951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721124PMC
December 2020

Reproductive sequelae of parental severe illness before the pandemic: implications for the COVID-19 pandemic.

Fertil Steril 2020 12 23;114(6):1242-1249. Epub 2020 Sep 23.

Department of Urology, Stanford University School of Medicine, Stanford, California; Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California. Electronic address:

Objective: To investigate, with pre-COVID-19 data, whether parental exposure to severe systemic infections near the time of conception is associated with pregnancy outcomes.

Design: Retrospective cohort study.

Setting: Population-based study covering births within the United States from 2009 to 2016.

Participants: The IBM MarketScan Research database covers reimbursed health care claims data on inpatient and outpatient encounters that are privately insured through employment-sponsored health insurance. Our analytic sample included pregnancies to paired fathers and mothers.

Interventions(s): Parental preconception exposure (0-6 months before conception) to severe systemic infection (e.g., sepsis, hypotension, respiratory failure, critical care evaluation).

Main Outcome Measure(s): Preterm birth (i.e., live birth before 37 weeks) and pregnancy loss.

Result(s): A total of 999,866 pregnancies were recorded with 214,057 pregnancy losses (21.4%) and 51,759 preterm births (5.2%). Mothers receiving intensive care in the preconception period had increased risk of pregnancy loss, as did fathers. Mothers with preconception sepsis had higher risk of preterm birth and pregnancy loss, and paternal sepsis exposure was associated with an increased risk of pregnancy loss. Similar results were noted for hypotension. In addition, a dose response was observed for both mothers and fathers between preconception time in intensive care and the risk of preterm birth and pregnancy loss.

Conclusion(s): In a pre-COVID-19 cohort, parental preconception severe systemic infection was associated with increased odds of preterm birth and pregnancy loss when conception was soon after the illness.
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http://dx.doi.org/10.1016/j.fertnstert.2020.09.153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510413PMC
December 2020

Rituximab Versus Mycophenolate in the Treatment of Recalcitrant Connective Tissue Disease-Associated Interstitial Lung Disease.

ACR Open Rheumatol 2021 Jan 4;3(1):3-7. Epub 2020 Dec 4.

Stanford University, Stanford, California, United States.

Objective: Interstitial lung disease (ILD) is a major cause of morbidity and mortality in connective tissue diseases (CTDs). We aimed to assess the effect of rituximab ± mycophenolate mofetil (MMF) compared with MMF on pulmonary function and prednisone dosage in patients with CTD-related ILD (CTD-ILD).

Methods: This retrospective study included 83 patients from Stanford and Centre Hospitalier de l'Universite de Montreal. Fifteen patients received rituximab ± MMF (rituximab group), and 68 patients received MMF only (control group).

Results: Median ILD duration at the start of treatment was longer in the rituximab group at 47 months (range: 4-170) versus 6.5 months (range: 0-164) in controls. Forced vital capacity (FVC) decreased by 3.0% (range: 11%-21%) after treatment in the rituximab group, whereas it increased by 2.0% (range: 14%-25%) in the control group (p = 0.025). Diffusing capacity of carbon monoxide (DLCO) decreased by 3.0% (range: 10%-12%) after treatment in the rituximab group, whereas it increased by 4.5% (range: 30%-36%) in the control group (p = 0.046). Mixed model analysis controlling for ILD duration, baseline DLCO, systemic sclerosis, pulmonary hypertension, and prednisone use showed no significant difference in FVC or DLCO between groups at 6 months or 1 year. The average daily prednisone dose score decreased after treatment in the rituximab group, whereas it remained unchanged in the control group (p = 0.017).

Conclusion: Rituximab ± MMF did not significantly change pulmonary function compared with MMF alone, but it did result in a relative decrease in average daily prednisone dose in a population with recalcitrant CTD-ILD.
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http://dx.doi.org/10.1002/acr2.11210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811692PMC
January 2021

Increased Mortality Among Men Diagnosed With Impaired Fertility: Analysis of US Claims Data.

Urology 2021 Jan 2;147:143-149. Epub 2020 Oct 2.

Department of Urology, Stanford University School of Medicine, Stanford, CA; Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA. Electronic address:

Objective: To determine whether male infertility or impaired spermatogenesis is associated with mortality.

Methods: The Optum de-identified Clinformatics Data Mart database was queried from 2003 to 2017. Infertile men were compared to subjects undergoing semen analysis (ie, infertility testing). Infertile men with oligozoospermia or azoospermia were included. Mortality was determined by data linkage to the Social Security Administration Death Master File. Results were adjusted for age, smoking, obesity, year of evaluation, and health care visits as well as for most prevalent comorbidities. We separately examined men with prevalent or incident cardiovascular disease and cancer diagnoses to determine associations with mortality.

Results: A total of 134,796 infertile men and 242,282 controls were followed for a mean of 3.6 and 3.1 years respectively. Overall, infertile men had a higher risk of death (Hazard Ratio [HR]= 1.42, 95% CI: 1.27-1.60) The diagnosis of azoospermia was associated with a significantly increased risk of death (HR= 2.01, 95% CI: 1.60-2.53) with a higher trend among men with oligospermia (HR: 1.17, 95% CI: 0.92-1.49) compared to controls. Subanalysis was done excluding prevalent cardiovascular and malignant disease (alone and combined) showing similar hazard ratios.

Conclusion: Male infertility is associated with a higher risk of mortality especially among azoospermic men. Prevalent disease (which is known to be higher among infertile men) did not explain the higher risk of death among infertile men. The implications for treatment and surveillance of infertile men require further study.
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http://dx.doi.org/10.1016/j.urology.2020.07.087DOI Listing
January 2021

Relationship between male age, semen parameters and assisted reproductive technology outcomes.

Andrology 2021 01 8;9(1):245-252. Epub 2020 Oct 8.

Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.

Background: Low semen quality often obligates the use of assisted reproductive technology; however, the association between semen quality and assisted reproductive technology outcomes is uncertain.

Objectives: To further assess the impact of semen quality on assisted reproductive technology outcomes.

Materials And Methods: A retrospective cohort study was carried out at a single academic reproductive medicine center (January 2012-December 2018). Patients undergoing at least one assisted reproductive technology cycle utilizing freshly ejaculated spermatozoa from the male partner were included. We assessed the association between semen quality (as stratified based on WHO 5th edition criteria), paternal age (< or ≥40), and reproductive/perinatal outcomes. To evaluate the differences in assisted reproductive technology outcomes by semen parameters and age, generalized estimating equations were applied for rates of fertilization, pregnancy, implantation, miscarriage, live birth, blast formation, gestational age, and normal embryo biopsy.

Results: A total of 2063 couples were identified who underwent 4517 assisted reproductive technology cycles. Average ages of the male and female partners were 39.8 and 37.7, respectively. Lower pregnancy rates were observed in cycles with lower sperm motility (ie <40%; 39.9% vs 44.1%) and total motile count (ie <9 million; 38.3% vs 43.5%). When examining only cycles utilizing Intracytoplasmic Sperm Injection, only a lower motility count was associated with a decline in pregnancy rate (39.1% vs 44.9%). No association was identified between semen quality and gestational age or birth weight. Paternal age was not associated with ART outcomes. However, among assisted reproductive technology cycles in women <40, aneuploidy rate was higher for older men (P < .001). In cycles with women >40, no association between aneuploidy and male age was identified.

Discussion: Sperm motility is associated with pregnancy rates, while other semen parameters are not. In cycles in women <40, paternal age is associated with embryo aneuploidy rate.

Conclusion: Paternal factors are associated with assisted reproductive technology outcomes, and future studies should explore mechanisms by which semen quality is associated with assisted reproductive technology outcomes.
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http://dx.doi.org/10.1111/andr.12908DOI Listing
January 2021

The Influence of Cochlear Implant-Based Electric Stimulation on the Electrophysiological Characteristics of Cultured Spiral Ganglion Neurons.

Neural Plast 2020 6;2020:3108490. Epub 2020 Sep 6.

ENT Institute and Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.

Background: Cochlear implant-based electrical stimulation may be an important reason to induce the residual hearing loss after cochlear implantation. In our previous study, we found that charge-balanced biphasic electrical stimulation inhibited the neurite growth of spiral ganglion neurons (SGNs) and decreased Schwann cell density in vitro. In this study, we want to know whether cochlear implant-based electrical stimulation can induce the change of electrical activity in cultured SGNs.

Methods: Spiral ganglion neuron electrical stimulation in vitro model is established using the devices delivering cochlear implant-based electrical stimulation. After 48 h treatment by 50 A or 100 A electrical stimulation, the action potential (AP) and voltage depended calcium current () of SGNs are recorded using whole-cell electrophysiological method.

Results: The results show that the of SGNs is decreased significantly in 50 A and 100 A electrical stimulation groups. The reversal potential of is nearly +80 mV in control SGN, but the reversal potential decreases to +50 mV in 50 A and 100 A electrical stimulation groups. Interestingly, the AP amplitude, the AP latency, and the AP duration of SGNs have no statistically significant differences in all three groups.

Conclusion: Our study suggests cochlear implant-based electrical stimulation only significantly inhibit the of cultured SGNs but has no effect on the firing of AP, and the relation of inhibition and SGN damage induced by electrical stimulation and its mechanism needs to be further studied.
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http://dx.doi.org/10.1155/2020/3108490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490630PMC
September 2020

Research progress of F labeled small molecule positron emission tomography (PET) imaging agents.

Eur J Med Chem 2020 Nov 25;205:112629. Epub 2020 Jul 25.

Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Co-innovation Center of Henan Province for New Drug R&D and Preclinical Safety, and School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China. Electronic address:

With the development of positron emission tomography (PET) technology, a variety of PET imaging agents labeled with radionuclide F have been developed and widely used in the diagnosis and treatment of various clinical diseases in recent years. For example, they have showed a great value of study in the field of tumor detection, tumor treatment and evaluation of tumor therapy in a non-invasive, qualitative and quantitative way. In this review, we highlight the recent development in chemical synthesis, structure and characterization, imaging characterization, and potential applications of these F labeled small molecule PET imaging agents for the past five years. The development and application of F labeled small molecules will expand our knowledge of the function and distribution of diseases-related molecular targets and shed light on the diagnosis and treatment of various diseases including tumors.
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http://dx.doi.org/10.1016/j.ejmech.2020.112629DOI Listing
November 2020

Sudden PSA rise to ≥20 ng/ml and prostate cancer diagnosis in the United States: A population-based study.

Prostate 2020 12 21;80(16):1438-1443. Epub 2020 Sep 21.

Department of Urology, Stanford University School of Medicine, Stanford, California, USA.

Purpose: While prostate-specific antigen (PSA) screening protocols vary, many clinicians have anecdotes of screened men with low PSA levels that rise significantly and are associated with high-risk prostate cancer (PC). We sought to better understand the frequency of high-risk cases that appear suddenly in a screened population.

Methods: We utilized data from a Commercial and Medicare advantage claims database to identify all US men ages 50 and above undergoing PSA screening who then had a sudden interval rise in PSA (e.g., PSA ≥ 20) and diagnosis of PC. We determined associations with age, race, screening intensity, and baseline PSA levels.

Results: In all, 526,120 men met entry criteria with an average age of 60.7 and follow-up of 5.6 years. As the baseline PSA increased, the rate of high-risk PC increased from 2/10,000 persons among men with the lowest baseline PSA (<1 ng/ml) to 14/10,000 person-years among men with a baseline PSA < 5 ng/ml. Moreover, as a man's age at baseline PSA increased, the rate of high-risk PC also increased. In contrast, the incidence of high-risk PC did not vary significantly by race/ethnicity. More screening PSAs and shorter intervals between PSA screenings were associated with a lower incidence of high-risk PC.

Conclusions: The incidence of high-risk PC in a screened population is low (<0.1%). Our findings suggest that systematic screening cannot eliminate all PC deaths and provide an estimate for the risk of the rapid development of high-risk cancers that is comparable to that observed in active surveillance populations.
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http://dx.doi.org/10.1002/pros.24075DOI Listing
December 2020

Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma.

Blood Adv 2020 09;4(18):4474-4482

Department of Dermatology.

The majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients. Cyclosporine or tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. Patients tolerated the transplant well, with 1- and 2-year nonrelapse mortality of 3% and 14%, respectively. The day +180 cumulative incidence of grade 2 to 4 acute GVHD was 16%, and the 2-year incidence of moderate/severe chronic GVHD was 32%. With a median posttransplant follow-up of 5.4 years, the 2-, 3-, and 5-year overall survival rates were 68%, 62%, and 56%. Using high-throughput sequencing of the T-cell receptor for minimal residual disease monitoring, we observed that 43% achieved molecular remission, which was associated with a lower incidence of disease progression or relapse (9% vs 87%; P = .02). Our study also showed that patients who were aged ≥65 years at the time of allotransplant had similar clinical outcomes compared with younger patients. Thus, we have developed an alternative and potentially curative nonmyeloablative allogeneic transplant regimen for patients with advanced stage MF/SS. This trial was registered at www.clinicaltrials.gov as #NCT00896493.
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http://dx.doi.org/10.1182/bloodadvances.2020001627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509879PMC
September 2020

Gastric antral vascular ectasia in systemic sclerosis: Association with anti-RNA polymerase III and negative anti-nuclear antibodies.

Semin Arthritis Rheum 2020 10 6;50(5):938-942. Epub 2020 Jul 6.

Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, USA; Department of Medicine, Division of Immunology and Rheumatology, Palo Alto Veterans Affairs Healthcare System, USA. Electronic address:

Objective: Gastric antral vascular ectasia (GAVE) is a vascular manifestation of systemic sclerosis (SSc) that can lead to iron deficiency anemia or acute gastrointestinal (GI) bleeding. We aimed to identify clinical features associated with GAVE.

Methods: We performed a cohort study of SSc patients who were seen at Stanford between 2004 and 2018 and had undergone esophagogastroduodenoscopy (EGD). We compared the clinical features of those with and without GAVE, and multivariable logistic regression was performed to identify clinical correlates with GAVE.

Results: A total of 225 patients with SSc who underwent EGD were included in this study and 19 (8.4%) had GAVE. Those with GAVE were more likely to have scleroderma renal crisis (SRC) (21% vs 3%; p < 0.01), positive anti-RNA polymerase III antibody (71% vs 19%; p < 0.01), nucleolar pattern of anti-nuclear antibody (ANA) (33% vs 11%; p=0.04), and negative ANA (<1:80 by immunofluorescence) (33% vs 11%; p=0.02). On multivariate analysis with multiple imputation, anti-RNA polymerase III positivity (OR 4.57; 95% CI (1.57 - 13.23), p < 0.01) and ANA negativity (OR 3.75; 95% CI (1.21 - 11.62), p=0.02) remained significantly associated with GAVE.

Conclusion: Positive anti-RNA polymerase III antibody and ANA negativity were significantly associated with GAVE. Further studies are necessary to determine whether patients with these autoantibody profiles should undergo screening endoscopies for GAVE.
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http://dx.doi.org/10.1016/j.semarthrit.2020.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584748PMC
October 2020

Calcinosis is associated with ischemic manifestations and increased disability in patients with systemic sclerosis.

Semin Arthritis Rheum 2020 10 17;50(5):891-896. Epub 2020 Jun 17.

Stanford University School of Medicine and Palo Alto VA Health Care System, Department of Immunology and Rheumatology and Dermatology (by courtesy), USA. Electronic address:

Objective: Calcinosis is a debilitating complication of systemic sclerosis (SSc) with no effective treatments. We sought to identify clinical correlations and to characterize complications and disability associated with calcinosis in a multi-center, international cohort of SSc patients.

Methods: We established a cohort of 568 consecutive SSc patients who fulfill 2013 revised ACR/EULAR criteria at 10 centers within North America, Australia, and Mexico. Calcinosis was defined as subcutaneous calcium deposition by imaging and/or physical examination, or a clear history of extruded calcium. All patients completed the Scleroderma Health Assessment Questionnaire Disability Index and Cochin Hand Functional Scale.

Results: 215 (38%) patients had calcinosis. In multivariable analysis, disease duration (OR=1.24, p = 0.029), digital ischemia (OR=1.8, p = 0.002) and Acro-osteolysis (OR=2.97, p = 0.008) were significantly associated with calcinosis. In the subset of patients with bone densitometry (n = 68), patients with calcinosis had significantly lower median T-scores than patients without (-2.2 vs. -1.7, p = 0.004). The most common location of calcinosis lesions was the hands (70%), particularly the thumbs (19%) with decreasing frequency moving to the fifth fingers (8%). The most common complications were tenderness (29% of patients) and spontaneous extrusion of calcinosis through the skin (20%), while infection was rare (2%). Disability and hand function were worse in patients with calcinosis, particularly if locations in addition to the fingers/thumbs were involved.

Conclusions: We confirmed a strong association between calcinosis and digital ischemia. Calcinosis in SSc patients most commonly affects the hands and is associated with a high burden of disability and hand dysfunction.
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http://dx.doi.org/10.1016/j.semarthrit.2020.06.007DOI Listing
October 2020

Fibronectin type III domain-containing 4 promotes the migration and differentiation of bovine skeletal muscle-derived satellite cells via focal adhesion kinase.

Cell Adh Migr 2020 12;14(1):153-164

Laboratory of Cellular and Developmental Biology, Life Science College, North-east Agricultural University , Harbin, China.

FNDC4 is an anti-inflammatory factor that alters the activation state of macrophages; it is used to treat colitis in mice. However, its role in muscle formation and mechanism of function remains unknown. We found that FNDC4 promotes the bovine MDSCs migration and differentiation. Furthermore, we reported that it interacts with integrin β1 (ITGβ1). FAK, mediated by ITGβ1, regulates cell migration. Our results found FNDC4 to influence the expression of p-FAK, p-paxillin, and vinculin. Then, overexpressed or added FNDC4 protein could not influence migration and differentiation any more when the activated form of FAK was reduced. Therefore, we concluded that FNDC4 promotes the differentiation and migration of bovine MDSCs via the FAK, mediated by the ITGβ1 receptor.
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http://dx.doi.org/10.1080/19336918.2020.1810508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513858PMC
December 2020

Correction to: Opposite Roles of NT-3 and BDNF in Synaptic Remodeling of the Inner Ear Induced by Electrical Stimulation.

Cell Mol Neurobiol 2020 Aug 25. Epub 2020 Aug 25.

ENT Institute and Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.

The original version of this article unfortunately contained an error in Figure 9.
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http://dx.doi.org/10.1007/s10571-020-00943-xDOI Listing
August 2020

Mechanical Integrity Degradation and Control of All-Solid-State Lithium Battery with Physical Aging Poly (Vinyl Alcohol)-Based Electrolyte.

Polymers (Basel) 2020 Aug 21;12(9). Epub 2020 Aug 21.

Shanghai Institute of Applied Mathematics and Mechanics, School of Mechanics and Engineering Science, Shanghai University, Shanghai 200072, China.

Ensuring the material durability of an electrolyte is a prerequisite for the long-term service of all-solid-state batteries (ASSBs). Herein, to investigate the mechanical integrity of a solid polymer electrolyte (SPE) in an ASSB upon electrochemical operation, we have implemented a sequence of quasi-static uniaxial tension and stress relaxation tests on a lithium perchlorate-doped poly (vinyl alcohol) electrolyte, and then discussed the viscoelastic behavior as well as the strength of SPE film during the physical aging process. On this basis, a continuum electrochemical-mechanical model is established to evaluate the stress evolution and mechanical detriment of aging electrolytes in an ASSB at a discharge state. It is found that the measured elastic modulus, yield stress, and characteristic relaxation time boost with the prolonged aging time. Meanwhile, the shape factor for the classical time-decay equation and the tensile rupture strength are independent of the aging history. Accordingly, the momentary relaxation modulus can be predicted in terms of the time-aging time superposition principle. Furthermore, the peak tensile stress in SPE film for the full discharged ASSB will significantly increase as the aging proceeds due to the stiffening of the electrolyte composite. It may result in the structure failure of the cell system. However, this negative effect can be suppressed by the suggested method, which is given by a 2D map under different lithiation rates and relative thicknesses of the electrolyte. These findings can advance the knowledge of SPE degradation and provide insights into reliable all-solid-state electrochemical device applications.
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http://dx.doi.org/10.3390/polym12091886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565167PMC
August 2020

Phenotypic heterogeneity of neurofibromatosis type 1 in a large international registry.

JCI Insight 2020 08 20;5(16). Epub 2020 Aug 20.

Department of Dermatology, Stanford University School of Medicine, Redwood City, California, USA.

Neurofibromatosis type 1 (NF1) is a rare genetic disorder, characterized by the development of benign and malignant nerve tumors. Although all individuals with NF1 harbor genetic alterations in the same gene, the clinical manifestations of NF1 are extremely heterogeneous even among individuals who carry identical genetic defects. In order to deepen the understanding of phenotypic manifestations in NF1, we comprehensively characterized the prevalence of 18 phenotypic traits in 2051 adults with NF1 from the Children's Tumor Foundation's NF1 registry. We further investigated the coassociation of traits and found positive correlations between spinal neurofibromas and pain, spinal neurofibromas and scoliosis, spinal neurofibromas and optic gliomas, and optic gliomas and sphenoid wing dysplasia. Furthermore, with increasing numbers of cutaneous neurofibromas, the odds ratio of malignant peripheral nerve sheath tumor increased. Phenotypic clustering revealed 6 phenotypic patient cluster subtypes: mild, freckling predominant, neurofibroma predominant, skeletal predominant, late-onset neural severe, and early-onset neural severe, highlighting potential phenotypic subtypes within NF1. Together, our results support potential shared molecular pathogenesis for certain clinical manifestations and illustrate the utility of disease registries for understanding rare diseases.
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http://dx.doi.org/10.1172/jci.insight.136262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455126PMC
August 2020

The association between cigarette smoking, cancer screening, and cancer stage: a prospective study of the women's health initiative observational cohort.

BMJ Open 2020 08 13;10(8):e037945. Epub 2020 Aug 13.

Department of Dermatology, Stanford University School of Medicine, Redwood City, California, USA

Objective: To assess the dose-dependent relationship between smoking history and cancer screening rates or staging of cancer diagnoses.

Design: Prospective, population-based cohort study.

Setting: Questionnaire responses from the Women's Health Initiative (WHI) Observational Study.

Participants: 89 058 postmenopausal women.

Outcome Measures: Logistic regression models were used to assess the odds of obtaining breast, cervical, and colorectal cancer screening as stratified by smoking status. The odds of late-stage cancer diagnoses among patients with adequate vs inadequate screening as stratified by smoking status were also calculated.

Results: Of the 89 058 women who participated, 52.8% were never smokers, 40.8% were former smokers, and 6.37% were current smokers. Over an average of 8.8 years of follow-up, current smokers had lower odds of obtaining breast (OR 0.55; 95% CI 0.51 to 0.59), cervical (OR 0.53; 95% CI 0.47 to 0.59), and colorectal cancer (OR 0.71; 95% CI 0.66 to 0.76) screening compared with never smokers. Former smokers were more likely than never smokers to receive regular screening services. Failure to adhere to screening guidelines resulted in diagnoses at higher cancer stages among current smokers for breast cancer (OR 2.78; 95% CI 1.64 to 4.70) and colorectal cancer (OR 2.26; 95% CI 1.01 to 5.05).

Conclusions: Active smoking is strongly associated with decreased use of cancer screening services and more advanced cancer stage at the time of diagnosis. Clinicians should emphasise the promotion of both smoking cessation and cancer screening for this high-risk group.
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http://dx.doi.org/10.1136/bmjopen-2020-037945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430331PMC
August 2020

The lncRNA ANRIL regulates endothelial dysfunction by targeting the let-7b/TGF-βR1 signalling pathway.

J Cell Physiol 2021 Mar 11;236(3):2058-2069. Epub 2020 Aug 11.

The Key Laboratory of Myocardial Ischaemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China.

The long noncoding RNA antisense noncoding RNA in the INK4 locus (ANRIL) plays a critical role in the development of atherosclerosis. However, the precise effect of ANRIL on endothelial dysfunction remains unclear. In this study, we investigated ANRIL expression in patients with coronary artery disease and elucidated the molecular mechanism underlying its effect. ANRIL expression was detected in the blood plasma of 111 patients. We analysed the correlation between ANRIL and endothelial dysfunction markers. We also examined the effect of ANRIL on the regulation of endothelial dysfunction. ANRIL levels were increased in patients with acute coronary syndrome. The expression of ANRIL is associated with the inflammatory cytokines monocyte chemoattractant protein-1 and interleukin-10, which are secreted in response to endothelial dysfunction. Knockdown of ANRIL significantly promoted cell proliferation and tubule formation and inhibited inflammatory activation and apoptosis of human umbilical vein endothelial cells (HUVEC). ANRIL-mediated inhibition of let-7b regulates HUVEC dysfunction by targeting the TGF-βR1/Smad signalling pathway. This study highlights a new therapeutic strategy for preventing endothelial dysfunction associated with cardiovascular disease.
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http://dx.doi.org/10.1002/jcp.29993DOI Listing
March 2021

SPARCL1 Influences Bovine Skeletal Muscle-Derived Satellite Cell Migration and Differentiation through an ITGB1-Mediated Signaling Pathway.

Animals (Basel) 2020 Aug 6;10(8). Epub 2020 Aug 6.

Laboratory of Cell and Developmental Biology, Northeast Agricultural University, Harbin 150030, China.

As an extracellular matrix protein, secreted protein acidic and rich in cysteine (SPARC)-like 1 (SPARCL1) is involved in various cell functions. It was previously implicated in bovine skeletal muscle-derived satellite cell (MDSC) differentiation; however, the underlying mechanism remains unknown. In this study, immunoprecipitation and mass spectrometry revealed that integrin β1 (ITGB1) combines with SPARCL1. Further, co-immunoprecipitation demonstrated that SPARCL1 interacts with ITGB1. Cell scratch assays explored the influence of SPARCL1 on MDSC migration through ITGB1. In addition, desmin staining for myotube fusion rate and MyoD protein expression results showed that SPARCL1 promotes MDSC early differentiation through ITGB1. Furthermore, Western blotting results demonstrated that SPARCL1 regulates the expression of p-FAK, p-paxillin, vinculin, Cdc42, and Arp2/3 through ITGB1. These findings indicate that SPARCL1 may influence bovine MDSC migration and differentiation through an ITGB1-mediated cell signaling pathway. Herein, we elucidated the mechanism through which SPARCL1 affects MDSC differentiation. Our results provide insight into the molecular mechanism of muscle development and may in the future facilitate skeletal muscle regeneration and treatment.
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http://dx.doi.org/10.3390/ani10081361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460340PMC
August 2020

Opposite Roles of NT-3 and BDNF in Synaptic Remodeling of the Inner Ear Induced by Electrical Stimulation.

Cell Mol Neurobiol 2020 Aug 8. Epub 2020 Aug 8.

ENT Institute and Department of Otolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.

With the development of neural prostheses, neural plasticity including synaptic remodeling under electrical stimulation is drawing more and more attention. Indeed, intracochlear electrical stimulation used to restore hearing in deaf can induce the loss of residual hearing and synapses of the inner hair cells (IHCs). However, the mechanism under this process is largely unknown. Considering that the guinea pig is always a suitable and convenient choice for the animal model of cochlea implant (CI), in the present study, normal-hearing guinea pigs were implanted with CIs. Four-hour electrical stimulation with the intensity of 6 dB above electrically evoked compound action potential (ECAP) threshold (which can decrease the quantity of IHC synapses and the excitability of the auditory nerve) resulted in the upregulation of Bdnf (p < 0.0001) and downregulation of Nt-3 (p < 0.05). Intracochlear perfusion of exogenous NT-3 or TrkC/Fc (which blocks NT-3) can, respectively, resist or aggravate the synaptic loss induced by electrical stimulation. In contrast, local delivery of exogenous BDNF or TrkB/Fc (which blocks BDNF) to the cochlea, respectively, exacerbated or protected against the synaptic loss caused by electrical stimulation. Notably, the synaptic changes were only observed in the basal and middle halves of the cochlea. All the findings above suggested that NT-3 and BDNF may play opposite roles in the remodeling of IHC synapses induced by intracochlear electrical stimulation, i.e. NT-3 and BDNF promoted the regeneration and degeneration of IHC synapses, respectively.
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http://dx.doi.org/10.1007/s10571-020-00935-xDOI Listing
August 2020

Generation of mWasabi fluorescent protein-binding nanobodies.

Anal Biochem 2020 11 31;608:113875. Epub 2020 Jul 31.

The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210046, PR China; Changzhou High-Tech Research Institute of Nanjing University and Jiangsu Target Pharma Laboratories,Inc., Changzhou, Jiangsu, 213164, PR China.

mWasabi is a bright monomeric green fluorescent protein. It can be used as a fusion tag to monitor various biological events, e.g. protein localization. Here we report the selection of camelid-derived single-domain antibody fragments (nanobodies) against mWasabi. In this work, phage-display approach was employed to select the high affinity mWasabi-specific Nb (nanobodies). These nanobodies were able to recognize mWasabi or in a fused fashion with PD1. The interesting binding characteristics of these two mWasabi-specific nanobodies could be valuable for design new tools for cellular tracing or targeting based on the mWasabi-fusing protein in many different biological research fields.
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http://dx.doi.org/10.1016/j.ab.2020.113875DOI Listing
November 2020